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Principles of drug therapy

Therapeutic management
Clinical monographs of commonly used medicines
Complementary medicines monographs
Counselling guides for common ailments

An invaluable pharmacy practice


resource. Whether youre dispensing,
counselling, providing advice to
consumers, carrying out medicines
reviews or studying pharmacy, APF22
has information to make it easier for
you. Reap the benefits of having APF22
as a constant companion and support
in your everyday pharmacy practice.

Policies and professional practice

Optimise health outcomes for your


patients. A handy source of information
to help you identify drug-related issues,
make clinical decisions and advise on
appropriate drug therapy. From weight
management to wound care, children to
older people, APF22 has it covered.

Australian
Pharmaceutical
Formulary
and Handbook
The Everyday Guide to
Pharmacy Practice

Compounding and dispensing


Principles of drug therapy
Therapeutic management
Clinical monographs of commonly used medicines
Complementary medicines monographs
Counselling guides for common ailments
Provision of Pharmacist Only medicines
Policies and professional practice

PSA2683

apf22

Counselling information at your fingertips.


A convenient source of practical
information to assist pharmacists when
counselling consumers on the safe and
effective use of their medicines and to
provide pharmacy students with a sound
knowledge base of counselling essentials.

Australian Pharmaceutical Formulary and Handbook

Provision of Pharmacist Only medicines

Health information and resources

22

apf22

Compounding and dispensing

Health information and resources

The Everyday Guide to


Pharmacy Practice

APF22

Australian
Pharmaceutical
Formulary
and Handbook

Compounding and dispensing


Principles of drug therapy
Therapeutic management
Clinical monographs of commonly used medicines
Complementary medicines monographs
Counselling guides for common ailments
Provision of Pharmacist Only medicines
Policies and professional practice
Health information and resources

Pharmaceutical Society of Australia, 2012


The material in this handbook has been provided by the Pharmaceutical Society of Australia, the Commonwealth and third
parties. Copyright in material provided by the Commonwealth or third parties belong to them. PSA owns the copyright in the
handbook as a whole and all material in the handbook that has been developed by PSA. In relation to PSA owned material, no
part may be reproduced by any process except in accordance with the provisions of the Copyright Act 1968 (Cth), or the written
permission of PSA. Requests and inquiries regarding permission to use PSA material should be addressed to: The Pharmaceutical
Society of Australia, PO Box 42, Deakin West ACT 2600. Where you would like to use material that has been provided by the
Commonwealth or third parties, contact them directly.
First published in 1902
Nineteenth edition, 2004
Twentieth edition, 2006. Reprinted 2007
Twenty-first edition, 2009
Twenty-second edition, 2012
Publisher: The Pharmaceutical Society of Australia, ACT
Project Managers: Lyn Todd, Caroline Khalil
Design and Typesetting: Publications Unit, Pharmaceutical Society of Australia, ACT
Copy Editors: Chris Pirie, Comprehensive Editorial Services, Biotext Pty Ltd, ACT
Printed by: GEON Print & Communication Solutions
JN: 2683
National Library of Australia Cataloguing-in-Publication data
Title: Australian Pharmaceutical Formulary and Handbook
Edition: Twenty-two
Chair, Editorial Board: Sansom, Lloyd
Date of Publication: January 2012
Publisher: Pharmaceutical Society of Australia
ISBN: 978-0-646-57019-8
ISSN: 1446-2710
Recommended citation:
Sansom LN, ed. Australian pharmaceutical formulary and handbook. 22nd edn. Canberra: Pharmaceutical Society of Australia, 2012.

Disclaimer
The Pharmaceutical Society of Australia has prepared this handbook to assist pharmacists to comply with Australian
pharmaceutical conditions and standards. PSA makes this handbook available on the understanding that users exercise their
own skill and care with respect to its use, and understand that this handbook is subject to revision and regular updates.
This handbook is no substitute for professional knowledge and judgment, and use of the information contained in this
handbook is strictly at the users own risk. While every care has been taken to ensure that the information contained
in this handbook accords with the accepted Australian Standards and/or clinical practice at the time of production,
no representation or warranty (express or implied) is made as to the currency, completeness, accuracy, reliability and
suitability of the information contained in this handbook, having regard to constant changes in information resulting
from continuing research and clinical experience, reasonable differences in opinions among authorities, unique aspects of
individual situations and the possibility of human error in preparing such an extensive text. It is the responsibility of the user
to conduct their own investigations to ensure that the information provided is accurate, complete and relevant for their
purpose. This may include consulting and comparing information from other sources such as the manufacturers Product
Information approved by the Commonwealth Government of Australia.
PSA does not specifically endorse products, suppliers, manufacturers or services cited in this handbook.
Any person or organisation proposing to use this handbook in a country other than Australia should check local conditions
and standards to determine whether the information contained in this handbook complies with local conditions, standards,
and the manufacturers product information.
PSA and all other contributors expressly disclaim liability to any person whatsoever in respect of anything done by any such
person in reliance, whether in whole or in part, on this handbook including for, but not limited to:




II

use of this handbook for a purpose for which it was not intended;
any errors or omissions in this handbook;
any inaccuracy in the information or data on which this handbook is based or which is contained in this handbook;
any interpretations or opinions stated in, or which may be inferred from, this handbook; or
any non-compliance with conditions and standards in any country.

Contents
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

VI

Section A: Compounding and dispensing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1


Dispensing practice. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Counselling and cautionary advisory labels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Extemporaneous dispensing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
General formulary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Childrens formulary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Modification of oral formulations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Cold chain management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Appendix A1: Emulsifiers and stabilisers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Appendix A2: Units of concentration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Appendix A3: Isosmotic and isotonic solutions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Appendix A4: Buffer solutions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Appendix A5: pKa Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Appendix A6: Latin abbreviations used in prescription writing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Appendix A7: Medical abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Section B: Principles of drug therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Pharmacokinetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Therapeutic drug monitoring. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Drug interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Medicines in older people. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
Dose calculations for children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Dosing in renal impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Medicines in breast milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
Individualised medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Section C: Therapeutic management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
HIV and antiretroviral therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
Insulin preparations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
Medicines review. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
Medicine-induced discolouration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Medicines and urinary incontinence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
Missed doses of oral contraceptives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
Normal physiological values. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Opioid conversion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
Opioid-induced constipation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
Opioid substitution therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Palliative care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
Weight management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
Wound management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

III

Section D: Clinical monographs of commonly used medicines

. . . . . . . . . . . . . . . . . . . . . . .

239

Clinical monographs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240


Section E: Complementary medicines monographs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Complementary medicines monographs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
Section F: Counselling guides for common ailments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
Using the counselling guides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
Constipation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
Cough . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
Diarrhoea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
Gastroenteritis in children. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
Gastro-oesophageal reflux disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
Hay fever. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517
Headache and migraine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521
Head lice. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526
Mouth ulcers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
Nappy rash. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
Smoking cessation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
Tinea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542
Vaginal thrush. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
Section G: Provision of Pharmacist Only medicines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551
Chloramphenicol as a Pharmacist Only medicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552
Codeine as a Pharmacist Only medicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555
Levonorgestrel as a Pharmacist Only medicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559
Fluconazole as a Pharmacist Only medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563
Orlistat as a Pharmacist Only medicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
Proton pump inhibitors as Pharmacist Only medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
Prochlorperazine as a Pharmacist Only medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
Short acting beta-agonists as Pharmacist Only medicines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
Section H: Policies and professional practice. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581
Policies in practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582
Code of ethics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
The National Medicines Policy and regulation of therapeutic goods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585
Guidelines for drug donations to developing countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589
Section I: Health information and resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
Drugs in sport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594
Evidence-based medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
Exclusion periods for infectious conditions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
Food additives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
Information from the internet. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
Medical and surgical emergencies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624
Poisoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630
Travel medicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
IV

Preface
It is with great pleasure
that I bring to you the 22nd
edition of the Australian
Pharmaceutical Formulary
and Handbook (APF)
apublication now in its
108th year.
Since it was first published in
1902, the APF has changed
considerably. It started life as
a small formulary and was considered the pharmacists
essential reference of extemporaneous dispensing. Today,
it covers multiple aspects of pharmacy practice and
has developed into a comprehensive clinical handbook
which is an invaluable clinical and practice resource for
pharmacists and pharmacy students, both in Australia
and overseas.
The continual development of the APF has been in
response to the constantly changing and expanding role
of the pharmacist. It has kept pace with the growing
needs of pharmacists as they fulfil their professional
obligations in an ever-changing practice environment.
Tenets of current pharmacy practice include counselling,
evidence-based medicine, and encouraging and
helping consumers to actively participate in their own
healthcare. The APF22 provides practical, current and
evidence-based information to assist pharmacists in
upholding these professional principles. It can be used
to quickly find information and guidance on many areas
of pharmacy theory and practice, including identifying
drug-related issues; making clinical judgements;
counselling consumers on the safe and effective use of
their medicines; and preparing extemporaneous products
or modified oral formulations.

The content of the APF22 has been rigorously developed


and reviewed by a range of experts, with industry
stakeholders also consulted. The various sections
have been re-organised to make this edition easier to
navigate, and the fresh new style enhances readability.
This 22nd edition of the APF introduces a number of
new sections, including Dispensing practice, HIV and
antiretroviral therapy, and Palliative care. Other additions
include a section on opioid conversion explaining the
principles of converting from one opioid analgesic
to another, and a section titled Dose calculations for
children. The recently published Code of Ethics for
Pharmacists has also been included.
In keeping with the APFs intent as the everyday guide
to pharmacy practice, this edition provides valuable
information for all pharmacists, whether working in the
community, hospital or academic setting, and pharmacy
students. Readers are advised to refer regularly to the
APF website (www.psa.org.au/apf) for updates and
general information. The 22nd edition of the APF
supersedes and replaces all previous editions.
Finally, I commend the Pharmaceutical Society of
Australia and its staff for producing another quality
edition of the APF.

Emeritus Professor Lloyd Sansom

AO, PhC, BSc, PhD, Hon

DHlth (Ncle), Hon DSc (Qld), DUniv (Grif), FPS

Chair, APF22 Editorial Board

Acknowledgements
The Pharmaceutical Society of Australia gratefully
acknowledges the significant effort of all those who
have contributed to the development and production of
this edition, particularly its staff and the Editorial Board.
In addition, the efforts of contributors to past editions of
the APF are acknowledged.
Contributions to this edition have been made by:

Emeritus Professor Lloyd Sansom (Chair),


AO, PhC, BSc, PhD, Hon DHlth (Ncle), Hon DSc (Qld), DUniv (Grif), FPS

Ms Marlene Cutajar

BPharm

Associate Professor Jeffery Hughes

BPharm, GradDipPharm,

MPharm, PhD, MPS, MSHP, AACPA

Mr Grant Martin

Mr Chris Flood B.Pharm


Pharmacy Guild of Australia

Mr Grant Martin BPharm, MPS


Australian Association of Consultant Pharmacy
Dr Brett MacFarlane BPharm (Hons), PhD, FACP
The Australian College of Pharmacy

MAppSci, AACPA, FPS

Ms Michelle Lynch

PSA would like to acknowledge the guidance and feedback


recieved from the following:

Mr Paul Gysslink BPharm, BEcon, DipEd, MPS


The Association of Professional Engineers,
Scientists & Managers, Australia

Editorial Board

Mr David Cosh

Contributors and Reviewers

Ms Meredith Page BPharm (Hons), MPharm, MSHP


NPS - Better choices, Better health
Ms Mary Emanuel BPharm, MPS
Australian Self-Medication Industry

BPharm, MPS

BPharm, MPS

Professor Ross McKinnon

BPharm, BSc (Hons), PhD

Professor Andrew McLachlan

BPharm (Hons), PhD, FPS, FACP,

PSA would like to acknowledge the following authors


andreviewers.

MCPA, MSHP

Mr Adam Phillips

BSc, BPharm (Hons), AACPA, MPS, MSHP

Associate Professor Louis Roller

BPharm, BSc, MSc, PhD,

DipEd, FPS

Ms Carolyn Allen

BPharm, AACPA, MPS

Dr Katrina Allen

FRACGP, FAChSHM

Dr. Chris Angley

MBBS, FACEM

Ms Claire Antrobus

Working Group of the Editorial Board

BPharm, BSc, MPS

Associate Professor Parisa Aslani

BPharm (Hons), MSc, PhD,

Grad Cert Ed Stud (Higher Ed), MPS, MRPharmS

Counselling and Cautionary Advisory Labels


for Medicines
Mr John Barratt

BPharm, BAppSc (Comp Stud), GradDipCPP

Mr Peter Bayly

PhC, AUA, FPS

Mr David Cosh

MAppSci, FPS, AACPA

Mr Vaughn Eaton
Mr Grant Martin

AO, PhC, BSc, PhD, Hon

DHlth (Ncle), Hon DSc (Qld), DUniv (Grif), FPS

Ms Kirsty Scarborough

Mr Jason Bratuskins

BPharm, MPS

MAppSci, FPS, AACPA


BPharm (Hons), AACPA, MPS

Professor Trisha Dunning


Mr Vaughn Eaton

BPharm, GradDipClinPharm

Emeritus Professor Lloyd Sansom

BPharm (Hons)

Ms Sarah Curulli

BPharm, MClinPharm, FSHP, AACPA

BPharm (Hons), GradDipClinPharm

AM, RN, MEd, PhD

BPharm, MClinPharm, FSHP, AACPA

Associate Professor Lynne Emmerton BPharm (Hons), PhD MPS


Ms Marnie Firipis

BPharm, GradDipEnt&Inn, CertHealthEcon, MPS

Ms Meredith Freeman
Miss Emma French
Ms Jennifer Giam

VI

BPharm (Hons), PhD, MPS, AACPA

Mr Wayne Boundey

Mr David Cosh

BPharm, MPS

Ms Olimpia Nigro

Dr Luke Bereznicki

BPharm, FSHP, MPS

BPharm

BPharm (Hons), MPS

Ms Lynn Greig

DipPharm, AACPA, MPS

Mr Neil Hotham

BPharm

Associate Professor Jeffery Hughes

BPharm, GradDipPharm,

MPharm, PhD, MPS, MSHP, AACPA

Mr Francis Ip

BPharm (Hons), BComm, MPH

Ms Phoebe King

BPharm, MPS

Mr Stefan Kowalski

BPharm, MAppSc, CGP

Ms Judith Kristensen

BPharm, MPS

Associate Professor Karin Leder


Ms Julie Lord

BPharm, MSHP

Ms Jill Malek

BPharm, MPS

Professor Ross McKinnon

MBBS, FRACP, PhD, MPH

BPharm, BSc (Hons), PhD

Professor Andrew McLachlan

BPharm (Hons), PhD, FPS, FACP,

MCPA, MSHP

Dr Geraldine Moses

BPharm, DClinPharm, FPS, FACP, MSHP,

AACPA, MRPharmS

Associate Professor Mark Naunton

BPharm (Hons), PhD,

MPS, AACPA

Mr Irvine Newton

OAM, BPharm, FACP, FPS

Professor Gregory Peterson

BPharm (Hons), PhD, MBA, FSHP,

FACP, AACPA, MPS

Mr Adam Phillips
Dr Lisa Pont

BSc, BPharm (Hons), AACPA, MPS, MSHP

BSc, BPharm, PhD (Groningen, NL)

Ms Debbie Rigby

BPharm, GradDipClinPharm, AdvDipNutrPharm,

CGP, AACPA, FASCP, FPS, FACP

Emeritus Professor Lloyd Sansom

AO, PhC, BSc, PhD,

HonDHlth (Ncle), Hon DSc (Qld), DUniv (Grif), FPS

Ms Hayley Smilie

BPharm, MPS

Dr Kay Sorimachi

BPharm, MPharm, PhD, MPS

Mr Andrew Stafford

BPharm (Hons), MPS, AACPA

Associate Professor Geoff Sussman

OAM, JP, PhC (Vic), FPS,

FAWMA, FACP, FAIPM

Mr Angus Thompson

MSc, BPharm (Hons), GradDip, MRPharmS

Miss Madeline Thompson


Ms Lyn Todd

BPharm, MPH, MPS

BPharm, MPS

Ms Penelope Tuffin
Mr Justin Turner
Dr Michael Ward

BPharm, AACPA
BPharm (Hons), PhD

Ms Kylie Woolcock
Ms Carol Wylie

BPharm, PGDip Pharm, AACPA

BPharm, GradCertHealthEcon, MPS

BPharm, Post Grad Dip Hosp Clin Pharmacy

VII

VIII

Section A
Compounding and
dispensing
This section covers the key aspects of dispensing and compounding. It includes information on the dispensing process,
the appropriate use of cautionary advisory labels, compounding methods, the application of relevant professional
practice standards, the basics of drug delivery and absorption, and principles of risk management. It aims to help
pharmacists prepare and dispense safe and effective products, meet their professional obligations and achieve a
consistently high standard of professional practice. It is also a useful resource for pharmacists preparing and supplying
extemporaneous products or modified oral formulations, and for pharmacy students learning the art of compounding
and the principles of dispensing.

Dispensing practice. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Counselling and cautionary


advisory labels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Extemporaneous dispensing . . . . . . . . . . . . . . . . . . . . .

32

General formulary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38

Applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Creams. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ear drops. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Elixirs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Emulsifying waxes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Eye drops. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Eye lotions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Gels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Inhalations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Insufflations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Irrigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Linctuses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Liniments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Lotions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Mixtures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Mucilages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nasal instillations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38
38
39
43
45
45
45
47
47
48
48
48
49
49
50
51
52
53

Ointments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Paints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pastes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Powders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Shampoos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Solutions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Spirits. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Suppositories. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Syrups. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Waters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54
56
57
58
58
59
60
60
60
61

Childrens formulary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62

Modification of oral formulations. . . . . . . . . . . . . . . .

68

Cold chain management . . . . . . . . . . . . . . . . . . . . . . . . .

77

Emulsifiers and stabilisers. . . . . . . . . . . . . . . . . . . . . . . .

79

Units of concentration. . . . . . . . . . . . . . . . . . . . . . . . . . . .

81

Isosmotic and isotonic solutions . . . . . . . . . . . . . . . . .

83

Buffer solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

86

pKa values. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

88

Latin abbreviations used in


prescription writing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

92

Medical abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . .

94

Dispensing practice

Compounding and dispensing

Dispensing is a fundamental component of pharmacy


practice. In addition to the labelling and supply of a
product according to legal and regulatory requirements,
it involves the interpretation and evaluation of the
prescription, selection or preparation of a pharmaceutical
product, and the provision of information to ensure
safe and effective use of the product.1 Pharmacists must
dispense accurately, reflect the prescribers intentions and
be consistent with the needs and safety of the consumer.2
The Professional Practice Standards2 relate to the
systems and procedures that will enable pharmacists
to undertake consistently high-quality dispensing.
The National Competency Standards Framework for
Pharmacists in Australia3 contains a description of
the skills, attitudes, values and beliefs necessary for
pharmacists to review and supply prescribed medicines
effectively. The Guidelines for dispensing of medicines4
by the Pharmacy Board of Australia outlines matters of
professional practice, and professional conduct.
Following is a brief overview of the principles of
dispensing; readers are advised to refer to the relevant
standards and guidelines for detailed guidance on
meeting their professional obligations.

The review and supply of


prescribed medicines
Good dispensing practice calls for a systematic approach,
consideration of risk management throughout the entire
process, and clear documentation.

Assess the prescription


The prescription is assessed to ensure that the details
are accurate and complete and clearly communicate
the prescribers intentions. This minimises the risk of a
dispensing error resulting from misinterpretation of the
prescribers instructions. It also ensures that pharmacists
fulfil their legal obligations by assessing the validity and
authenticity of the prescription before dispensing and
contacting the prescriber if there is any doubt about his
or her intentions.3,4

Consider the appropriateness


of therapy
Gather relevant information
Information is systematically collected, accurately
recorded and assessed to enable informed decision
making about the supply of medicines. Relevant
consumer details (e.g. pre-existing medical conditions,
allergies and age) and a medication history can reveal
2

potential medication-related concerns. Such information


also helps pharmacists determine what the consumers
needs and expectations are.2,3,5
Where appropriate, brand substitution should also be
discussed. Clarify the consumers knowledge, preferences
and previous use of alternative brands in order to
identify any real or potential medicine-related concerns
resulting from misunderstanding or confusion about the
changing of brands.
All information is treated as confidential and should
be obtained only with the consumers consent, after
explaining why the information is needed and how it will
be used.

Review prescribed medicines


At each dispensing the prescription is reviewed in terms
of the medicines safety, suitability, dosage regimen and
any dosage changes, as well as potential interactions,
contraindications, precautions and lack of concordance
with the prescribed course (suspected over- or
underutilisation). This process of reviewing a persons
prescription in the context of their complete therapeutic
regimen supports the quality use of medicines.2
Professional judgment and pharmacotherapeutic
knowledge are used to evaluate the suitability and safety
of the prescribed medicine.3
Particular attention is given to medicines with a narrow
therapeutic index in view of the potentially serious
consequences associated with this group of medicines
if dosing errors occur.6 For further information about
monitoring medicines with a narrow therapeutic index,
see Therapeutic drug monitoring, in SectionB.

Promote optimal medicines use


In some situations it might be necessary to contact
the prescriber to discuss aspects of the consumers
prescription or therapeutic regimen. This interaction
(such as discussing the need for an HMR) provides an
opportunity for the pharmacist to be involved in clinical
decision making and facilitates collaboration between
primary health care professionals in order to optimise
health outcomes for the consumer. The prescriber should
be contacted in the following circumstances:

if there is concern about the suitability of the


medicine for the consumer

if there is concern about the potential for


drug misadventure

if there is doubt about the legality or validity of


the prescription; or

if there is any uncertainty about the


prescribers intentions.3,4

Section A | Dispensing practice

The matter causing concern should be clearly


communicated, along with supportive evidence of
the clinical relevance or potential for adverse patient
outcomes relating to the specific issue.
Documenting the results of the discussion with the
prescriber and making a notation on the prescription
provides a record of proof and evidence to support
any clinical decisions. If the prescriber is unavailable
or is unwilling to accept the pharmacists advice, the
pharmacist must make a professional judgment as to
what action is required to satisfy their duty of care to the
consumer. Where possible, the pharmacist should obtain
the consumers consent before contacting the prescriber
and inform them of the result of the consultation.

assembling the dispensed products with their labels


and paperwork, including repeat authorisations,
receipts and written information for checking.25

Pharmaceutical Defence Limited (PDL) has produced a


Guide to Good Dispensing chart outlining the correct
procedures of the dispensing process.

Risk management
In the interests of consumer safety, all reasonable steps
should be taken to minimise the risk of dispensing
errors.5 A number of risk management techniques
can be used:

limiting distractions during the dispensing process


ensuring that prescriptions are legible
and unambiguous

using barcode scanners to verify selected


prescription medicines

Systematic procedure

taking care when dispensing look-alike and


soundalike medicines

organising and de-cluttering the dispensary


workflow area

thoroughly checking all prescriptions

ensuring that pharmacists workloads are reasonable


and manageable

The following steps are central to the dispensing and


labelling process:

always providing comprehensive patient


counselling.811

accurately recording patient and prescription details


on the pharmacy computer

selecting the medicine to be dispensed

A final verification process is a check of each dispensed


medicine for accuracy before the medicine is supplied to
the consumer. It involves:

checking the expiry date and placing labels so that


any of the manufacturers statements that may be
important to the patient, including the expiry date,
storage conditions and where possible, the name
and strength of the drug are visible

A logical, systematic dispensing procedure that includes


sequential checks for accuracy will minimise the chance
of dispensing errors. The aim is to ensure that the correct
medicine is supplied to the intended consumer and
minimise the potential for harm and distress resulting
from an error.

taking account of factors likely to compromise the


medicines efficacy, stability and safety if repackaging
it out of its original container

using labels that provide clear dosing instructions


and text that is legible and unambiguous

affixing cautionary and advisory labels (CALs) in


accordance with legal requirements and professional
conventions

for extemporaneously prepared products, meeting


the relevant professional practice standards and
considering the use of such products only if no
suitable proprietary preparation is available.
For further information see Extemporaneous
dispensing, page 32

completing prescription records and associated


documentation for dispensed medicines, including
controlled substances, in accordance with all
statutory and professional requirements7

checking each dispensed prescription against the


doctors original prescription

verifying the consumers name and address,


prescribed medicine, dosage, strength, directions
for use, quantity and number of repeats, and the
prescribers name and qualification

seeking confirmation of the consumers identity to


ensure that the correct medicine is handed to the
correct consumer.2,4,5

Compounding and dispensing

The process of dispensing


and labelling

If a dispensing error does occur, pharmacists should


promptly assess the overall risk to the consumer and act
to redress or minimise the impact of the error, and reduce
the risk of recurrence. Pharmaceutical Defence Limited
(PDL) has a documented procedure that can be followed
in the event of becoming aware of a dispensing error.12

Counselling
Counselling is essential to the dispensing process, and
pharmacists need to communicate effectively when
providing verbal and written information. Consumers
should receive adequate dosing instructions and
understand how to use, store and dispose of dispensed
medicines correctly and safely. Good counselling promotes
3

Section A | Dispensing practice

the quality use of medicines by providing to consumers


sufficient information to allow an understanding of their
medicines and the intended therapeutic effect and to
minimise the risk of adverse effects.

Compounding and dispensing

Counselling should be offered to the consumer at


every dispensing, although consumers reserve the right
not to be counselled. Medicines that are new for the
consumer or have not recently been dispensed should
be clearly identified and counselling offered. Among
the counselling points that can be discussed are the
following25:

Comprehensive records of dispensing errors, near


misses, complaints and other incidents associated
with risk should be integral to the pharmacys quality
improvement process. These records form part of the
procedure for the provision of pharmacy services such
as dispensing practice, and should be stored carefully
because of the potential for litigation at a later time.

References

what the medicine is used for

how and when to take the medicine

how long to continue taking the medicine

what steps to take if a dose is missed

2. Pharmaceutical Society of Australia. Standard 4. Dispensing.


Professional practice standards. Version 4. Canberra: PSA, 2010.

how to recognise adverse effects and what to do


if they occur

3. Pharmaceutical Society of Australia. Domain 4. Review and supply


prescribed medicines. National Competency Standards Framework
for Pharmacists in Australia. Canberra: PSA, 2010.

how to store the medicine appropriately

any lifestyle advice

4. Pharmacy Board of Australia. Guidelines for dispensing of


medicines. Melbourne: PBA, 2010.

any potential interactions with other medicines


or foods.13

Consumers should be given the opportunity to ask for


clarification of any information, and the pharmacist
should re-confirm any points of particular importance.
Counselling is a two-way process: it involves the giving
and receiving of information on the part of both the
consumer and the pharmacist.
Offering counselling when dispensing repeat
prescriptions enables the pharmacist to provide
additional information if necessary, determine whether
a consumer is experiencing adverse effects or has other
concerns about their medicine, and assess whether
medication adherence is a concern and whether
continuation of therapy is appropriate.2,3
Consumer medicine information (CMI) leaflets should
be provided on initiation of any prescription medicine
and offered at each subsequent dispensing according
to established guidelines.14 Discussing the contents
of a leaflet in the context of the individuals medical
history and circumstances minimises confusion or alarm.
Written information is intended to supplement verbal
counselling.
Consumers should be encouraged to report any
perceived adverse effect or concern with their medicine
to their pharmacist or doctor, who can then take action
if necessary. This advice is particularly important when
initiating a new therapy, and when medicines are new to
the market.

Quality improvement

1. Weidenmayer K, Summers RS, Mackie CA et al. Developing


pharmacy practice: a focus on patient care. Rotterdam: World Health
Organization & International Pharmaceutical Federation, 2006.

5. Pharmaceutical Society of Australia. Dispensing practice guidelines.


Canberra: PSA, 1997.
6. Pharmaceutical Defence Limited. Warnings: narrow therapeutic
index drugs. At: www.pdl.org.au/publications/warnings/narindex.
7. Victorian Department of Health. Interstate prescriptions for
Schedule 8 poisons in Victoria. Melbourne: Department of Health,
September 2010.
8. Nair RP, Kappil D, Woods TM. Ten strategies for minimizing
dispensing errors. Pharmacy Times; January 2010.
At: www.pharmacytimes.com/issue/pharmacy/2010/January2010/
P2PDispensingErrors-0110.
9. Woger M. Dispensing errors and solutions. Guild Insurance NZ;
Feb 2009.
10. Pharmaceutical Defence Limited. Warnings: reduce the risk
of dispensing errors. 2010. At: www.pdl.org.au/publications/
warnings/diserror.
11. Pharmaceutical Defence Limited. Matters of interest: similar names
or commonly confused medication names. 2008. At: www.pdl.org.
au/publications/similar_drug_names.
12. Pharmaceutical Defence Limited. Procedure to follow in case of
a dispensing error. April 2010. At: www.pdl.org.au/publications/
dispensing_error_procedure.
13. Azzopardi LM. Lecture notes in pharmacy practice. London:
Pharmaceutical Press, 2010.
14. Pharmaceutical Society of Australia. Guidelines: consumer medicine
information and the pharmacist. Canberra: PSA, January 2007.

Counselling and cautionary advisory labels


Counselling
Consumer counselling is an integral component of
pharmacy practice. It is a process of communication
that enables the pharmacist to establish the needs of
the consumer and provide them with the necessary
information to use their medicines safely and effectively.
Standard 3 of the Professional Practice Standards1
outlines how pharmacists can ensure that they deliver
quality counselling services.

It is the pharmacists responsibility to ensure that


consumers receive the necessary verbal and written
information. Verbal counselling should be reinforced
with written instructions, including appropriate labelling
of medicines, and consumer medicine information
leaflets (CMIs) and other suitable materials should be
provided. CMIs can be used to complement verbal
counselling; when they are offered to consumers,
their content and relevance to the medicine supplied
should be explained to the consumer. Refer to
Consumer medicine information and the pharmacist
at www.psa.org.au/supporting-practice/guidelines.
Counselling for repeat prescriptions is also important:
it enables the pharmacist to determine, by appropriate
questioning and information exchange, whether a
patient is experiencing adverse effects or has other
concerns relating to their medicine.

These CALs have been approved by the APF Editorial


Board and, while there may be other appropriate
supplementary labels in use, they are not approved by
the Editorial Board. The design and specifications of
the CALs are based on advice and information from
Vision Australia.2 Their colours, levels of contrast, type
sizes, typefaces, type styles and spacing are designed
to optimise the legibility of the CALs, particularly
for consumers with vision impairment. A full set of
specifications suitable for printing companies can be
obtained by contacting the PSA directly on 0262834777.
Pharmacists should note that changes to CALs from the
previous edition are marked using
. These changes
might represent a therapeutic protocol change or a
clarification recommended by the CAL Working Group
of the APF Editorial Board to assist consumers.
To avoid confusion, superseded versions of CALs
should not be used.

Medicines requiring labels


TableA.1 lists medicines for which CALs are required.
Medicines are considered for inclusion in the list by the
CAL Working Group of the APF Editorial Board if they
meet at least three of the following criteria:

The medicine is in clinical use in Australia.

The medicine has been registered in Australia since


the previous edition of the APF.

The medicine is taken orally or routinely selfadministered by injectionexcluding those


administered within a healthcare facility.

The medicine is considered by the CAL Working


Group to warrant additional information to satisfy
quality use of medicines principles.

Cautionary advisory labels


Cautionary advisory labels (CALs)either as an Ancillary
label or as Additional instructionsprovide written
instructions for using medicines safely and storing them
correctly. These labels are affixed to the primary medicine
container, thereby acting as a continual reminder to
consumers. CALs are intended to be used to support
verbal counselling on medicine-related issues. They
are a convenient and effective way for pharmacists to
reinforce communication with consumers about the safe
and effective use of their medicines.
Examples of each CAL are included in this section to
assist with identification of the correct label to be used.

Compounding and dispensing

Pharmacists must offer counselling to consumers at


every opportunity, including each time a medicine or
therapeutic device is required or supplied. Appropriate
counselling promotes the quality use of medicines by
ensuring that consumers have sufficient knowledge
and understanding of their medicines to achieve the
intended therapeutic effect and to minimise the risk of
adverse effects.

The examples indicate what types of medicines the label


should be used on, why its use is recommended, and
how it is to be applied in pharmacy practice.

Medicines that are not currently registered in Australia


but are likely to be available in the near future are
also included.
For combination products, pharmacists should refer to all
of the individual medicines in TableA.1, page 16.

Correct use of labels


The appropriate and necessary CALs for each medicine
have been determined by considering:

evidence from the published literature, including


the approved product information and consumer
medicine information
5

Section A | Counselling and cautionary advisory labels

the risk of the particular adverse outcome

current clinical best practice

statutory requirements included in AppendixK of the


Standard for the Uniform Scheduling of Medicines
and Poisons (SUSMP).3

It might also be appropriate for pharmacists to add


the designated label(s) to non-prescription products
if such information is not provided on the immediate
container, package label, or product information leaflet
in the package.
The prescriber can recommend that a CAL not be used,
but in this circumstance the prescription should specify
the exact requirements regarding patient counselling.
Pharmacists should be aware that specific state and
territory legislation regarding labelling of medicines
may have requirements in addition to what is specified
in this section.

Ancillary labels
Ancillary labels are to be attached to the immediate
container of the dispensed medicine, whenever possible.
They fall into two categories:

those that warn against undesirable effects,


including interactions with other medicines or foods

those that are designed to optimise efficacy in the


use of the medicine.

Refer to AppendixK of the SUSMP3 for a list of


medicines legally required to be labelled with a sedation
warning using either label1 or label1a.
Consider providing the PSA Pharmacy Self Care Fact Card
Medicines and driving.

Label 1a

Label 1a

1a

Compounding and dispensing

Pharmacists are advised to use their knowledge and


professional discretion in deciding whether to omit
one or more ancillary labels for a specific consumer or
circumstance, apart from medicines for which legislation
requires that certain labels be used. AppendixK of the
SUSMPa includes a list of drugs that must to be labelled
with a specifically worded sedation warning, as used in
label1 and label1a.

greater than expected. If alcohol is contraindicated


(due to the risk of significant CNS depression or other
hazardous effects when taken with these medicines),
label2 should also be used. Hazardous effects such as
sleep driving (driving while asleep, with associated
amnesia) have been reported for a number of hypnotics,
including zolpidem. The risk is increased when the
medicine is combined with alcohol or other CNS
depressants.

If the medicine is intended for use as an aid to sleep


and is to be taken as a single bedtime or nightly dose,
label1a replaces label1. The effects of these medicines
might still be present the following day.
Counselling might be necessary to establish whether
sleep induction is a primary or secondary effect. Alcohol
may be absolutely contraindicated if there is a risk of
significant CNS depression or other hazardous effects
when it is taken with these medicines.
Refer to AppendixK of the SUSMP3 for a list of
medicines legally required to be labelled with a sedation
warning using either label1 or label1a.

Label 2

Label 1

This medicine may cause


drowsiness and may increase
the effects of alcohol.
Ifaffected, do not drive a motor
vehicle or operate machinery.

Label1 is used for medicines whose primary or


secondary effect is sedation. These medicines can impair
psychomotor function and the ability to drive a car or
carry out other tasks requiring alertness. Alcohol may
cause additive central nervous system (CNS) depressant
effects when taken in combination with these medicines,
and a patient's usual response to alcohol might be

Do not take alcohol

Label 1

This preparation is to aid sleep.


Drowsiness may continue the
following day. If affected, do not
drive or operate machinery.
Avoid alcohol.

while being treated with


this medicine.

Label2 is used for medicines that have been reported


to interfere with the metabolism of alcohol, yielding
adverse effects (e.g. a disulfiram-like reaction), or where
the consumption of alcohol may be contraindicated.
For example, female patients taking acitretin should
not consume alcohol during, and for 2months after
stopping, therapy. Alcohol may increase the formation of
etretinate, a metabolite with a much longer half-life than
acitretin, prolonging the period after therapy when there
is a risk of teratogenicity if the woman conceives.

a. The Australian Pharmaceutical Formulary and Handbook does not include those drugs listed in AppendixK that are no longer available in
Australia or are administered only by a health professional.

Section A | Counselling and cautionary advisory labels

Label 3a

Label3a is used for medicines administered four times


a day and where ingestion with food can cause a
significant reduction in bioavailability. For medicines
administered less than four times a day, label3b or
additional instruction C (see Additional instructions,
page 11) should be used in place of this label.
Pharmacists should exercise professional judgment
and consider practical issues such as adherence when
providing advice on correct dose administration.
Pharmacists may recommend actual times of dosing that
are compatible with the patients lifestyle, ensuring that at
least half an hour has elapsed before ingestion of food.

3b

Take on an empty stomach


at least half an hour before
food or two hours after food.

Label 4

Do not take dairy products, antacids,


iron or calcium supplements within two
hours of each dose of this medicine.

Label4 is used for tetracyclines, oral bisphosphonates,


fluoroquinolone antibiotics and other medicines
that can bind with metallic ions to form poorly
soluble compounds (chelates), which are less readily
absorbed by the gastrointestinal tract, resulting in
reduced bioavailability and potentially decreased
therapeutic effectiveness.
The reference to dairy products is to be deleted for
certain medicines (e.g. minocycline, doxycycline)
whose absorption is not significantly affected by
coadministration with dairy products.

Label5 is used for medicines that are responsible for a


number of medicines interactions, potentially leading to
therapeutic failure or adverse effects. The mechanism
of these interactions is commonly via enzyme inhibition
or induction that alters the metabolic clearance of the
affected medicines. Label5 is also used for medicines
with narrow therapeutic indices, such that the severity
of an interaction with another medicine is likely to cause
a clinically significant outcome (see Drug interactions,
SectionB).
This label is intended to alert consumers that, while they
are taking this medicine, they are advised to consult their
doctor or pharmacist before using any other medicines,
including over-the-counter or herbal products. When
dispensing a medicine that requires label 5, pharmacists
should assess the consumers medication regimen to
determine whether there are any potential interactions
that are contraindicated or require close monitoring.
Pharmacists should also reinforce to consumers,
through verbal counselling, that the prescribed medicine
should not be taken with some other medicines unless
otherwise advised.
Certain complementary medicines also have the
potential to interact with other medicines, and patients
must be warned of this when taking these products
(see Complementary medicines, SectionE). These
interactions could be pharmacodynamic in nature or
caused by alterations in the absorption or clearance of
the medicine.
Pharmacists are advised to consult, Drug interactions,
SectionB; a medicines information reference; or the
approved product information for more details.

Label 6

The label is also used for medicines, such as


ketoconazole, whose dissolution is adversely affected
by antacids due to increased gastric pH.

Ask your doctor or pharmacist


before using any other medicine
including over-the-counter
medicines or health products.

Compounding and dispensing

Label 3b

3a

Take on an empty stomach


at least half an hour before
meals and at bedtime.

Label 5

RefRigeRate

Do not freeze

Certain medicinal products must be stored at


temperatures between 2C and 8C to minimise
decomposition. The lower shelves of a household
refrigerator (but not the shelves of the refrigerator door)
are generally suitable for short-term storage of medicines
that require refrigeration.
For insulins, the vial or cartridge currently being used by
the patient does not need to be refrigerated and may
be kept at room temperature (below 25C) for up to
4weeks.
See also Label7b.

Section A | Counselling and cautionary advisory labels

Label 7a

Label 9

7a

Discard contents after

or

The abrupt cessation of prolonged therapy with


certain medicines has the potentialto cause serious
consequences. Examples of medicines that should be
gradually ceased are:

Label 7b
Discard

Compounding and dispensing

7b

Date opened

days after opening.

Some products have a limited shelf life due to chemical


instability or the possibility of microbial contamination.
The expiry date of a product is influenced by the stability
and rate of decomposition of the active ingredient,
and the preservatives contained in the formulation.
Pharmacists should refer to the approved product
information for information on the shelf life of the
product once it has been dispensed or opened.
The shelf life of eye preparations is generally 28days
after opening, unless otherwise specified.

Do noT sTop TAking This


meDicine AbrupTly unless
otherwise advised by your doctor.

benzodiazepinesabrupt cessation may produce


withdrawal symptoms including anxiety, insomnia,
irritability, nightmares, sweating, hallucinations,
hypertension and tachycardia

long-term oral corticosteroidsadrenal suppression


may occur with long-term use; sudden cessation
may precipitate acute adrenal insufficiency

beta-blockersabrupt withdrawal may worsen


angina, or precipitate rebound hypertension,
myocardial infarction or ventricular arrhythmias

anticonvulsant therapysudden withdrawal may


lead to increased frequency and severity of seizures

antiplatelet medicinessudden discontinuation,


particularly in high-risk individuals (i.e. those with
dual antiplatelet therapy), may cause an increased
risk of myocardial infarction, or death due to a
rebound increase in platelet aggregation.

Insulin vials or cartridges currently being used by the


consumer can be kept at room temperature (below
25C) for up to 28days.

For expiry dates of individual extemporaneous products,


see Extemporaneous dispensing on page32.

Label 8

Avoid excessive skin exposure


to sunlight and sunlamps while
being treated with this medicine.

Some cytotoxic medicines and immunosuppressive


agents increase the incidence of some skin cancers.
Patients prescribed these medicines should therefore
avoid excessive sunlight or sunlamp exposure, and wear
protective clothing, hats and sunscreen.

Pharmacists should use their professional judgment and


consider whether the use of this label clearly conflicts
with the prescribers directions (e.g. prednisolone
25mg, once daily for 4days).

Label 10a
10a

Certain medicines can induce a phototoxic or


photoallergic reaction when patients are exposed
to sunlight or sunlamps. Individuals receiving these
medicines should be encouraged to minimise their
exposure to direct sunlight or sunlamps, and to use
30+ sunscreen agents and/or protective clothing.

The risk of these effects occurring and the severity of


symptoms will depend on the duration and dose of
therapy, and the rate of dose reduction.

Do not take more than one aspirin


tablet or capsule each day while
being treated with this medicine.

Label10a should be used when any medicine to treat


diabetes is dispensed, including insulin. High doses of
aspirin can stimulate insulin secretion, increasing the risk
of hypoglycaemia when taken with antidiabetic agents.
Doses used for antiplatelet effect (less than 300mg/day)
are unlikely to have this effect.
This label may also be used when non-steroidal
antiinflammatories (NSAIDs) are taken concurrently
with aspirin. The combined use of NSAIDs (including
selective COX-2 inhibitors) and aspirin increases the risk
of gastrointestinal adverse effects, including bleeding.
In some people, the benefit of reduced cardiovascular
risk from low-dose aspirin may be considered to

Section A | Counselling and cautionary advisory labels

outweigh this risk. High doses of aspirin (i.e. analgesic/


antiinflammatory doses) with NSAIDs should be avoided.

Label 10b
10b

Do not take aspiRin

while being treated with this medicine


unless advised by your doctor.

12

Label10a is also used when certain antiplatelet


medicines (e.g. clopidogrel, cilostazol, prasugrel) are
dispensed. These medicines may be co-prescribed with
low-dose aspirin. Because aspirin products are available
over the counter, patients should be warned against
self-administering additional doses of aspirin (i.e. higher
analgesic/anti-inflammatory doses) due to a further
increase in the risk of bleeding if aspirin is taken with
antiplatelet therapies.

Label 12
This medicine may affect mental
alertness and/or coordination.
if affected, do not drive a
motor vehicle or operate machinery.

Label12 is used for medicines with the potential to


cause CNS disturbances (e.g. dizziness, light-headedness,
fatigue) and impair psychomotor performance. These
symptoms frequently disappear with continued therapy,
however, certain individuals (e.g. the elderly) may be
more susceptible to these effects. Because impaired
motor coordination is associated with risks to safety, this
label should be used for such medicines.
In certain cases, label12 is appropriate only on initiation
of therapy or when the dose is increased.

Label 13

11

Do not take potassiUM

while being treated with this medicine


unless advised by your doctor.

Label11 is to be used for potassium-sparing medicines


(e.g. spironolactone, elprenolone), ACE inhibitors,
angiotensin II receptor antagonists and aliskiren.
Cases of serious hyperkalaemia have been reported
when these agents are used in combination with
potassium supplements. If such a combination has been
intentionally prescribed, regular monitoring of serum
potassium and renal function is recommended.
Pharmacists should be aware that some glucosamine
potassium chloride complex products contain sufficient
potassium to raise serum potassium levels, increasing
the risk of hyperkalaemia, especially in high-risk groups.
(For further information, refer to Glucosamine in the
Complementary Medicine monographs, Section E.)

Do not remove from


original packaging until
dose required.

In general, medicines should not be removed from


their original packaging until a dose is required. Many
medicines are supplied in child-resistant containers or
blister packaging. To minimise the risk of accidental
poisoning and/or loss of therapeutic efficacy, consumers
should be discouraged from transferring these medicines
to other containers. Some medicines (e.g. tricyclic
antidepressants, iron salts) can cause significant toxicity
if inadvertently ingested by children.

Compounding and dispensing

Label 11

13

Label10b should be used when oral anticoagulants


(e.g. warfarin, rivaroxaban, dabigatran) are dispensed.
Antiplatelet drugs, including aspirin at any dose,
interfere with platelet aggregation and are not
recommended for patients receiving oral anticoagulants
unless intentionally prescribed.

The stability and shelf life of products have been


determined using the container/packaging approved
for marketing. Some products use specially designed
packaging to maximise their stability (e.g. amoxycillin
with clavulanic acid, aspirin, sodium valproate),
and removal from the original packaging can
accelerate deterioration of the product and reduce
therapeutic efficacy.
The suitability of a preparation for inclusion in a
dose-administration aid depends on the formulation
(e.g. effervescent or orally disintegrating tablets or
wafers), and the susceptibility of the product to the
effects of moisture and prolonged exposure to light.
Pharmacists should consider available stability data
from the approved product information. The medicine
should be removed from the original packing as close to
the administration time as possible, and generally only
if stability data are available to confirm that removal
from the original packaging will not adversely affect
the products stability. For further information, refer to
the Professional Practice Standards1Standard7: Dose
administration aids service.

Section A | Counselling and cautionary advisory labels

Label 14

Label 17
Label17 has been replaced by label5.

14

Rinse MoUth

Label 15a
This medicine replaces
15a

Do not use both.

Label 15

Label 15b
Active
ingredient:
This medicine
replaces:

DO
NOT
USE
BOTH

Labels15a or 15b will be used when one brand of a


medicine is replaced by another. They should also be
used when one medicine in a particular therapeutic class
is replaced by another medicine in the same class, and
it is not intended that the patient take both products.
Ensuring that patients can name the active ingredient
will help reduce the chance of inadvertent double dosing
due to brand substitution.

Label 16
16

This medicine may cause dizziness


especially when you stand up quickly.
Ask your doctor or
pharmacist for advice.

Label16 is to be used for medicines that are likely


to cause orthostatic hypotension. Older patients are
particularly susceptible to a drop in blood pressure on
standing, with an associated risk of falls and fractures.
Pharmacists should provide adequate verbal and written
counselling, including advice on rising slowly from a
sitting or lying position.
Consider providing the PSA Pharmacy Self Care Fact Card
Preventing falls.

Label 19a
contains pArAceTAmol.
consult your doctor or pharmacist before
taking other paracetamol products.

Label19a is necessary for all products containing


paracetamol. Paracetamol is the most widely used
over-the-counter analgesic, and concurrent use of
multiple products whose labelling does not always
clearly indicate its presence may result in inadvertent
overdose. Consumers might fail to adhere to dosage
recommendations because they are unaware of the
paracetamol content of each product.

Label 19b
19b

Brand substitution between original brand products


and the numerous generic brands of the same medicine
can potentially cause confusion for patients. It is
recommended that, in chronic therapy, brand consistency
is maintained where appropriate. If a generic substitution
occurs, the patient should be verbally counselled
regarding the substitution.

Avoid eating grapefruit or drinking


grapefruit juice while being
treated with this medicine.

Certain constituents of grapefruit have been shown to


cause alterations in drug bioavailability by selectively
inhibiting CYP3A4 isoenzymes in the small intestine,
which metabolise drugs within the intestinal wall. This
can increase the bioavailability of some medicines and
the risk of adverse events. The effect of grapefruit is
unpredictable and is likely to vary greatly between
patients. Since no recommendation can be made on the
quantity that may be safely consumed, people should
be advised to avoid ingestion of grapefruit in any form
while undergoing treatment with these medicines. Refer
to Drug interactions, SectionB for further information.

19a

Compounding and dispensing

or

18

Inhaled steroids increase the risk of oral fungal


infections. Rinsing the mouth after use reduces the
incidence of this problem. Patients should be advised to
spit out the water after rinsing.

10

Label 18

with water after each use.

consult your doctor or pharmacist


before taking other medicines for
pain or inflammation.

Label19b is used for oral and rectal formulations


containing non-steroidal anti-inflammatories (NSAIDs).
Use of multiple systemic NSAIDs is associated with an
increased risk of gastrointestinal bleeding, renal failure
and adverse cardiovascular effects. Consumers might
inadvertently self-administer multiple NSAIDs (e.g.
combining prescription and over-the-counter NSAID
products, or multiple NSAIDs prescribed for different
indications).

Section A | Counselling and cautionary advisory labels

Label 20
20

Take once weekly on the


same day.

Some bisphosphonates and antimalarials are also


administered once a week.

Label 21
21

special handling and


disposal required
ask your pharmacist.

Label21 is also used for transdermal patches (e.g.


buprenorphine, fentanyl, nicotine, nitrate and hormone
replacement) that could contain residual amounts of
active ingredient after normal therapeutic use and may
be potentially harmful to others if not disposed of safely
after removal. Upon removal, the used patch should be
folded over on itself, with the adhesive side inwards, and
then replaced in the original packaging. Consumers are
encouraged to return any unwanted, ceased or expired
medicines to the pharmacy for safe disposal.

22

use only with approved


or recommended device.

B
TaKe wITh oR sooN
aFTeR FooD

Add the words Take with or soon after food. For


some medicines, gastrointestinal adverse effects can
be reduced by administration with food. For some oral
hypoglycaemic agents, it is important that the drug
is co-administered with food to minimise the risk of
hypoglycaemic episodes. The extent of absorption of
ketoconazole is increased when administered with food
because of a reduced stomach-emptying rate and greater
dissolution in the acidic environment of the stomach.
The absorption of griseofulvin is increased when
administered with food because of greater dissolution
caused by the stimulated flow of bile.

Label 22

swallow whole
Do not crush or chew

Add the words Swallow whole for preparations


such as enteric-coated and modified-release products
whose release characteristics depend on the product
being swallowed whole, or where breaking or crushing
products may cause an excessive dose to be released,
with the possibility of toxicity. Some tablets can be
broken into dosage sections, but the portions should not
be chewed or crushed. Some capsules may be opened,
but the pellets they contain may need to be swallowed
whole (see Modification of oral formulations,
page68).

Label21 is used for medicines with the potential to


cause harm to individuals from exposure to the agent.
These products should be swallowed whole where
possible, and should not be removed from their original
packaging for transfer into a dose-administration
aid. Label21 is to be used for all cytotoxic agents.
Pharmacists can also refer to the Society of Hospital
Pharmacists of Australia Standards of practice for
the safe handling of cytotoxic drugs in pharmacy
departments.

Compounding and dispensing

The pharmacist should encourage patients to take the


medicine consistently, on the same day each week.

Additional instructions provide information about the


appropriate use and storage of the medicine. They are
either attached to the primary medicine container or
incorporated into the text of the main dispensing label.
Pharmacists can use their professional judgment in
deciding where to place the instructions.

For some inflammatory conditions (e.g. rheumatoid


arthritis and psoriasis), anti-inflammatory/
immunosuppressive agents (e.g. methotrexate) are used
in low-dose, once-a-week regimens. Serious adverse
outcomes (including death) have occurred following
inadvertent excessive dosing. Pharmacists must confirm
that the dose is appropriate and emphasise the
importance of once-a-week dosing.

Additional instructions

TaKe aT leasT halF aN


houR beFoRe FooD

Add the words Take at least half an hour before food.

Label22 is to be used for packages of capsules that


contain powder intended for inhalation, rather than oral
administration (e.g. tiotropium capsules). Instances of
these being swallowed have occurred.

11

Section A | Counselling and cautionary advisory labels

Add the words Until all used or Until all taken.


Completion of a recommended course of therapy
with antibiotics or antibacterial agents can reduce the
incidence of relapse and minimise the emergence of
resistant strains. This additional instruction may not be
appropriate with paediatric dosage forms where the
total number of doses in the preparation is greater than
needed to define an adequate course of therapy. For
example, antibiotics are commonly given as a five to
seven day course only. Patients should be advised that
this instruction does not override the need to consult the
prescriber if adverse effects occur.

Add the words Certain foods should be avoided. This


additional instruction is for use with the non-selective
monoamine oxidase inhibitors (e.g. phenelzine) and
should be accompanied by appropriate counselling and
the provision of the monoamine oxidase inhibitors advice
card (see page15).

E
J

shaKe well
beFoRe eaCh use

Add the words Shake well before each use.

Add the words For external use only.

TaKe ImmeDIaTely
beFoRe FooD

Add the words Continue for 14days after symptoms


cease. This instruction is to be used for topical
antifungal preparations. It cannot be inferred from the
disappearance of symptoms that the causal organism of
a dermal fungal infection has been eradicated.

Compounding and dispensing

CoNTINue FoR 14 Days


aFTeR sympToms Cease

CeRTaIN FooDs
shoulD be avoIDeD

Add the words Take immediately before food.

FoR eXTeRNal use oNly

CauTIoN
NoT To be TaKeN

Add the words Caution. Not to be taken.

TaKe IN The moRNINg


drink plenty of water

Add the words Take in the morning. Drink plenty of


water. For example, cyclophosphamide can cause severe
cystitis. Ample fluid intake and frequent voiding may
reduce the incidence of this adverse effect. This can be
achieved by administration of the drug in the morning
and advising the patient to drink plenty of water during
the day.

Do NoT swallow

Add the words Do not swallow.

CoNTaINs peaNuT oIl

sToRe FRozeN

Add the words store frozen.

12

Due to a risk of serious hypersensitivity reactions in


individuals with an allergy to peanuts, add the words
Contains peanut oil to products containing, or with the
risk of contamination with, peanut (or arachis) oil.

Section A | Counselling and cautionary advisory labels

Instructions for administration


of different dosage forms

Figure A.2 Administering eye ointment

Eye drops

Wash hands thoroughly.

Sit or lie down.

Shake suspensions (cloudy liquids) gently before use.

Tilt head back and look upwards.

Gently pull down the lower eyelid to form a pouch.

Hold the bottle dropper near the lid, but do not let
the tip of the bottle touch the eyes or skin.

Put one drop into the pouch.

Ear drops

Apply gentle pressure with a finger against the


inner corner of the eye (over the tear duct) for
a few minutes. This increases the effectiveness
of the medicine by reducing the amount that is
drained from the eye.

The external ear canal should be clean and dry, with


no trace of soap remains.

Sit or lie down with the affected ear facing upwards.

The bottle can be held in the hands for several


minutes to reduce the viscosity of the liquid.

Blot excess solution around the eye with a tissue.

If putting more than one drop in the eye (of the


same or different preparations), separate each drop
by several minutes. This will prevent drops being
washed out of the eye and might increase the
amount of active ingredient that is absorbed.

Put drop directly into the ear canal (if there is


minimal swelling) and allow it to remain in position
for several minutes.

If there is swelling that narrows the ear canal, a


gauze wick saturated with drops can be inserted into
the ear canal. The wick should be replaced every
24hours.

Figure A.1 Administering eye drops

Compounding and dispensing

Try not to blink, but close the eyes gently and do


not rub them.

Figure A.3 Administering eardrops

Eye ointments

Wash hands thoroughly.

Sit or lie down.

Gently pull down the lower eyelid to form a pouch.

Squeeze a small amount of the ointment (about


1cm length) along the pouch, but do not let the tip
of the tube touch the eyes or skin.

Nasal drops

Clear the nose by gently blowing.

Lie down with the head lower than the shoulders.

Insert the appropriate number of drops.

Remain in the same position for several minutes to


allow drops to penetrate.

Blink several times to spread the ointment.

If drops are being used at a similar time of day,


use the ointment last.

The dropper should be used by one person only and


should be rinsed after each use.

Do not use drops more often than directed.


13

Section A | Counselling and cautionary advisory labels

Nasal sprays

Clear the nose by gently blowing.

Shake the bottle before use and follow the


manufacturer's advice about priming if needed.

Put the nozzle just inside the nose, aiming towards


the outside wall.

Block the other nostril and, while sniffing gently,


squirt once or twice (in two different directions
along the outside wall).

Avoid sniffing too hard or the contents are likely to


go straight down the throat.

Repeat for the other nostril.

Figure A.4 Administering nasal sprays

Insert enema tip gently into the rectum as far as


is comfortable.

The tip or nozzle can be lubricated with petroleum


jelly or other non-medicated ointment or cream to
ease insertion.

Squeeze the syringe gently, allowing the solution


to flow into the rectum slowly, until all the
liquid is expelled.

The liquid should be retained until lower abdominal


cramping is experienced (generally 510minutes).

Further information
Pray WS. Nonprescription product therapeutics. 2nd edn. Maryland:
Lippincott Williams & Wilkins; 2006.
Berardi RR, Ferreri SP, Hume AL et al. Handbook of nonprescription
drugs. 16th edn. Washington: American Pharmacists Association; 2009.

Compounding and dispensing

Respiratory Expert Group. Therapeutic guidelines: respiratory. Version4.


Melbourne: Therapeutic Guidelines Limited, 2009.

References
1. Pharmaceutical Society of Australia. Professional practice standards,
version 4. Canberra: PSA, 2010. At: www.psa.org.au/supportingpractice/professional-practice-standards.
2. Pharmaceutical Society of Australia. CALs in practice. Australian
Pharmacist. 2010; 29(3):2023.
3. Standard for the Uniform Scheduling of Medicines and Poisons No.
1 (SUSMP 1). Poisons Standard 2010. At: www.comlaw.gov.au/
Details/F2010L02386.

Suppositories

Wash hands.

Remove the suppository from its wrapping.

Lie on one side with the knees pulled up towards


the chest.

Gently push the suppository (narrow end first) in as


far as possible.

Lower the legs, roll over onto the stomach and


remain still for a few minutes.

Resist the urge to expel the suppository.

Lie still and press the buttocks together to allow the


suppository to dissolve in the rectum.

Wash hands.

Enemas
Enemas are liquid rectal preparations that are
administered using an enema syringe, in a similar way
to suppositories.
14

Section A | Counselling and cautionary advisory labels

Counselling advice for monoamine oxidase inhibitors


Figure A.5 The monoamine oxidase inhibitors advice card
PATIENT
MEDICINES
Unless otherwise advised, the following foods and medicines should be avoided while taking this medication and for
at least 2 weeks after ceasing therapy:

FOODS
The medicine that has been prescribed for you reacts with tyramine, which is found in a variety of foods, some of
which you will need to avoid. It is important to eat food that is as FRESH as possible. DO NOT use leftover foods.
This rule applies particularly to protein foods, such as meat, fish, game and offal (liver, heart, brains, sweetbreads,
tripe, kidneys). Avoid any food that has caused you unpleasant reactions in the past.

Matured cheeses
Beers and chianti
Yeast extract products (Marmite, Bovril, Vegemite, Promite, Bonox, vitamin products)
Salted or pickled herrings
Fermented or aged foods (such as some game, salami, dried sausage, pt)

These foods may be consumed in amounts not greater than listed

Compounding and dispensing

Avoid at all times

Bananas (not overripe)2 medium per day


Avocado1 medium per day
Wines (other than chianti)1 glass per day
Spirits1 measure per day

MEDICINES
Consult your pharmacist or doctor before using any other medicine, including complementary medicines.
If you are to receive an anaesthetic for surgical or other purposes, advise the doctor or dentist that you are taking
this medicine.

Avoid using
Nasal drops or sprays containing ephedrine, phenylephrine.
Cough mixtures or cold or hay fever preparations containing ephedrine, pseudoephedrine, phenylephrine or
dextromethorphan.

15

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels

Compounding and dispensing

Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Medicine

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Abacavir

12

Abatacept

Abiraterone

3b, 5

Acamprosate

2, A, B

Acarbose

10a, B

Acetazolamide

10a, B

Aciclovir

D (oral)

Acitretin

2 (women), 5, 8, B

Adalimumab

Adefovir

Agomelatine

5, 12

Alendronate

4, 20 (certain dosage forms), A, C

Aliskiren

11, 12, 16

Allopurinol

12, B

Alprazolam

1, 9

Alprostadil

6 (reconstituted)

Amantadine

9, 12, 16, B

Amiloride

11, 12, 16

Aminoglutethimide

1, 16

Aminophylline

5, B

Amiodarone

5, 8, 18

Amisulpride

oral solution: 1, 7b, 12, 16


other dosage forms: 1, 12, 16

Amitriptyline

1, 9, 13, 16

Amlodipine

9, 12

Amoxycillin

suspension: 6, 7a, D
other dosage forms: D

Amoxycillin with clavulanic acid

suspension: 6, 7a, D, F
tablets: 13, D, F

Amphotericin B

Anagrelide

1, 16

Anakinra

Anastrozole

12

Apixaban

10b

Aprepitant

Aripiprazole

1, 16

Artemether with lumefantrine

12, A, B

Asenapine

1, 13, 16

Aspirin

9, 13, 19b (high doses), A*, B

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

16

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)


Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Medicine

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Atazanavir

5, B

Atenolol

9, 12

Atomoxetine

5, 12, A

Atorvastatin

18

Atovaquone

B, D

Auranofin

Azathioprine

8, 21, A*, B

Azithromycin

suspension: 7a, D
other dosage forms: D

Baclofen

1, 9, B

Balsalazide

A, B

Beclomethasone

14 (oral inhalation)

Benzhexol

1, 9 (long-term regular therapy)

Benztropine

1, 9 (long-term regular therapy)

Betahistine

1, 16

Bethanechol

3a or C

Bicalutamide

16, B

Bifonazole

Bimatoprost

7b

Biperiden

1, 9 (long-term regular therapy)

Bisoprolol

9, 12, A

Boceprevir

5, 6, 12, B

Bosentan

1, 5, 16

Brinzolamide

7b

Bromazepam

1, 3b, 9

Bromocriptine

5, 12, 16, B

Brompheniramine

1, 13

Budesonide

oral capsules: 9, 18, A, F


oral inhalation/nebules: 14

Bumetanide

16

Buprenorphine

sublingual tablets/sublingual film: 1, 13


patches: 1, 21

Buprenorphine with naloxone

1, 13

Bupropion

5, 12, 16, A

Buspirone

1, 18

Busulfan

21, A

Butoconazole

Cabergoline

12, 16, B

Calcipotriol

Compounding and dispensing

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

17

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)

Compounding and dispensing

Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Medicine

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Calcitriol

Calcium folinate

3b

Candesartan

11, 12, 16

Capecitabine

12, 21, B

Captopril

dose less than 50 mg: 3b, 11, 12, 16


suspension: 7a, 11, 12, 16
other dosage forms in dose >50 mg: 11, 12, 16

Carbamazepine

5, 9, 12, 13, 18, A*, B

Carvedilol

9, 12, 13, 16

Cefaclor

tablets: A*, B, D
oral suspension: 6, 7a, D

Cefuroxime

B, D

Celecoxib

10a, 12, 19b

Cephalexin

suspension: 6, 7a, D
other dosage forms: D

Certolizumab

Cetirizine

Chloral hydrate

1a, 2, 12

Chlorambucil

6, 12, 21

Chloramphenicol

7b (eye preparations)

Chloroquine

13, B

Chlorpheniramine

Chlorpromazine

1, 8, 9 (long-term regular therapy), 16

Chlorthalidone

16, B

Cholecalciferol

Ciclesonide

14

Cilostazol

3b, 10a, 12

Cimetidine

Cinacalcet

5, B

Ciprofloxacin (oral)

3b, 4, 8, 12, D

Citalopram

5, 9, 12

Clarithromycin

suspension: 5, 7b, D
other dosage forms: 5, D

Clindamycin

D (oral)

Clobazam

1, 9

Clodronate

3b (1 hour before or 2 hours after), 4, A

Clofazimine

8, 12, B

Clomiphene

12

Clomipramine

1, 9, 13, 16

Clonazepam

1, 9

!
!
!

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

18

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)


Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Medicine

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Clonidine

1, 9, 16

Clopidogrel

9, 10a

Clopidogrel with aspirin

9, 10b

Clotrimazole

E (dermal)

Clozapine

1, 9, 12, 13, 16

Codeine

1 (greater than 20 mg dose)

Colchicine

5, 18

Cortisone

9, B

Cromoglycate

22 (capsules for inhalation)

Cyclophosphamide

8, 13, 21, G

Cyclosporin

oral solution: 5, 7a, 8, 18


other dosage forms: 5, 8, 18

Cyproheptadine

1, 13

Cyproterone

12, B

Dabigatran

7b (30 days), 10b, 13, A

Dacarbazine

8, 21

Danazol

5, 8

Dantrolene

1, 8

Dapsone

Darbepoetin

Darunavir

Dasatinib

4 (antacids), 5, 12, 18, A

Deferasirox

3b, 13

Deferiprone

5, 13, B

Delavirdine

Demeclocycline

3b, 4, 8, D

Denosumab

Desmopressin

5, 13

Desvenlafaxine

9, 12, A

Dexamethasone

oral: 9 (except short courses), B


other dosage forms: 9 (except short courses)

Dexchlorpheniramine

Dextropropoxyphene

Diazepam

1 or 1a, 9

Diazoxide

16

Diclofenac

10a, 12, 19b, A*, B

Dicloxacillin

3a, D

Didanosine

3b, 12, A*

Compounding and dispensing

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

19

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)

Compounding and dispensing

Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Medicine

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Digoxin

Dihydrocodeine

Dihydroergotamine

5, 18

Diltiazem

5, 9, 12, A*

Dimenhydrinate

Diphenhydramine

Diphenoxylate

1, 13

Dipyridamole

10a, 16, A*

Dipyridamole with aspirin

10b, 16, A, B

Disopyramide

Disulfiram

2, 5

Domperidone

Donepezil

12, 16

Dornase alfa

Dothiepin

1, 9, 13, 16

Doxepin

1, 9, 13, 16

Doxycycline

4 (delete dairy products), 8, B, D

Doxylamine

Dronedarone

5, 18, B

Droperidol

Duloxetine

5, 9, 12, A

Dutasteride

13, 21, A

Dutasteride with tamsulosin

12, 13, 16, 21, A, B

Efavirenz

3b, 5, 12

Eformoterol

22 (capsules for inhalation)

Eletriptan

12, 13, A

Eltrombopag

Emtricitabine

12

Enalapril

11, 12, 16

Enfuvirtide

12

Entacapone

4 (delete milk, antacids, calcium), 5, 9, 12, 16

Entecavir

3b, 12

Eplerenone

11, 12, 18

Epoetin

Eprosartan

11, 12, 16

Erlotinib

3b, 5

Erythromycin

5, A, C, D

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

20

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)


Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Medicine

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Erythromycin ethyl succinate

suspension: 5, 6, 7a, D
other dosage forms: 5, D

Escitalopram

5, 9, 12

Esomeprazole

A*

Etanercept

Ethacrynic acid

16, B

Ethosuximide

1, 9

Etidronate

4, A, C (2 hours)

Etoposide

18, 21, C

Etoricoxib

10a, 12, 19b

Etravirine

5, B

Everolimus

5, 8, 18, A*

Exemestane

Exenatide

6, 7b, 10a

Famciclovir

Felodipine

9, 12, 18, A

Fenofibrate

8, A

Fentanyl

patch and lozenge: 1, 21


other dosage forms: 1

Ferrous fumarate

13, B*

Ferrous sulfate

4 (delete dairy products), 13, A*, C

Finasteride

13, 21

Fingolimod

12, 13

Flecainide

9, 12, 13

Flucloxacillin

oral suspension: 3a or 3b, 6, 7a, D


solid oral dosage forms: 3a or 3b, D

Fluconazole

5, D

Fludarabine

12, A*

Fludrocortisone

6, 9, B

Flunitrazepam

1 or 1a, 9

Fluorouracil

8, 21

Fluoxetine

5, 9, 12

Flupenthixol

1, 16

Fluphenazine

1, 8, 16

Flutamide

Fluticasone

14 (oral inhalation)

Fluvoxamine

5, 9, 12, A*

Fosamprenavir

3a (suspension), 5

Compounding and dispensing

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

21

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)

Compounding and dispensing

Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Medicine

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Fosinopril

11, 12, 16

Frusemide

oral solution: 6, 7b, 16


other dosage forms: 16

Gabapentin

1, 9, 12

Galantamine

5, 12, A*, B

Gatifloxacin

4 (delete dairy products, calcium), 12, D

Gefitinib

5, 12

Gemfibrozil

3b

Glatiramer

Glibenclamide

10a, B

Gliclazide

10a, A*, B

Glimepiride

10a, F (or add with a meal)

Glipizide

10a, B

Glyceryl trinitrate

sublingual tablets: 7b, 13, 16


patches: 13, 16, 21
other dosage forms: 16

Golimumab

Granisetron

12

Griseofulvin

2, 8, 12, B, D

Haloperidol

1, 16

Hydralazine

12, 16

Hydrochlorothiazide

16

Hydrocortisone

oral dosage forms: 9, B

Hydromorphone

1, A*

Hydroxychloroquine

8 (delete skin), 13, B

Hydroxyurea

21, B

Hyoscine

12

Hyoscyamine

12

Ibandronate

4, A*, C

Ibuprofen

10a, 12, 19b, B

Icatibant

12

Idarubicin

21, A*, B

Iloprost

12, 22

Imatinib

Imipramine

1, 9, 13, 16

Imiquimod

8, K

Indacaterol

22

Indapamide

16, A*

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

22

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)


Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Indinavir

3b, 5, 12, 18

Indomethacin

10a, 12, 19b, A*, B

Infliximab

Insulins

6 (except vial or cartridge in use), 7b, 10a

Interferon alpha

6, 12

Irbesartan

11, 12, 16

Isoniazid

3b

Isosorbide dinitrate

16

Isosorbide mononitrate

16, A*

Isotretinoin

8, B, D

Itraconazole

4 (delete iron and calcium), 5, B, D

Itraconazole solution

5, C (one hour), D

Ivabradine

5, 13, 18, B

Ketoconazole

dermal: E
oral dosage forms: 4 (delete iron and calcium), 5, B, D

Ketoprofen

10a, 12, 19b, A*, B

Ketorolac

10a, 12, 19b, A*, B

Labetalol

9, 12, 16

Lacosamide

9, 12

Lamivudine

12

Lamotrigine

1, 9

Lansoprazole

A*

Lanreotide

Lanthanum

5, B

Lapatinib

3b, 5, 12, 18

Latanoprost

7b

Leflunomide

Lenalidomide

12, A

Lercanidipine

9, 12, 18, C

Letrozole

12

Levamisole

2, 12

Levetiracetam

1, 9

Levocabastine

Levodopa with decarboxylase inhibitor

4 (delete dairy and calcium), 9, 16, A*

Linagliptin

10a

Linezolid

5, D, I

Liraglutide

6, 7b

Lisinopril

11, 12, 16

Compounding and dispensing

Medicine

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

23

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)

Compounding and dispensing

Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Medicine

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Lithium carbonate

5, 13, A*, B

Lomustine

2, 3b, 21

Lopinavir with ritonavir

solution: 5, 6, B
tablets: 5, A, B

Lorazepam

1 or 1a, 9

Losartan

11, 12, 16

Maraviroc

5, 12

Medroxyprogesterone

12

Mefenamic acid

10a, 12, 19b, B

Mefloquine

12

Megestrol

12

Melatonin

Meloxicam

10a, 12, 19b, A*, B

Melphalan

3b, 6, 21

Memantine

12

Mepyramine

1, 13

Mercaptopurine

3b, 8, 21

Mesalazine

oral dosage forms: 3b*, 13, A*

Metformin

10a, A*, B

Methadone

Methotrexate

8, 10a, 20, 21

Methoxsalen

Methyldopa

12, 16

Methylnaltrexone

16

Methylphenidate

12, 13, A*

Methysergide

5, 12, B

Metoclopramide

12

Metoprolol

9, 12, A*

Metronidazole

suspension: 2, 5, C, D
tablets: 2, 5, B, D

Mianserin

1, 9, 13, 16

Miconazole

oral dosage forms: D


dermal: E

Midazolam

1 or 1a

Minocycline

4 (delete dairy products), 8, 12, B, D

Minoxidil

16 (oral)

Mirtazapine

orally distintegrating tablets: 1, 9, 13, A*


tablets: 1, 9, A*

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

24

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)


Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Ancillary label (number) and/or


additional instruction (letter)

Misoprostol

Moclobemide

9, 12, B

Modafinil

12

Morphine

1, A*

Moxifloxacin

4 (delete dairy products and calcium), 12, D

Moxonidine

1, 9, 12, 16

Mycophenolate/mycophenolic acid

8, 9, A

Naltrexone

12

Naproxen

10a, 12, 19b, A*, B

Naratriptan

12

Nebivolol

9, 12

Nevirapine

Nicorandil

9, 12,13

Nicotine

21 (patch)

Nicotinic acid

Nifedipine

9, 12, 13, 18, A*

Nilotinib

4, 5, 18, A

Nilutamide

2, 12

Nitrazepam

1 or 1a, 9

Nitrofurantoin

12, B, D

Norfloxacin

3b, 4, 8, 12, D

Nortriptyline

1, 9, 13, 16

Nystatin

oral dosage forms: B*, D


dermal: E

Octreotide

Olanzapine

oral wafers: 1, 8, 13, 16


other dosage forms: 1, 8, 16

Olmesartan

11, 12, 16

Olsalazine

A*, B

Omeprazole

13, A*

Opium

Orlistat

Orphenadrine

1, 13

Oseltamivir

A*, D

Oxazepam

1 or 1a, 9

Oxcarbazepine

5, 9, 12, 13

Oxpentifylline

A, B

Oxprenolol

9, 12, A

Change from
previous edition

Compounding and dispensing

Medicine

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

25

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)

Compounding and dispensing

Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Medicine

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Oxybutynin

12

Oxycodone

1, A*

Paliperidone

1, 16, A

Pancreatic extract BP

A, B

Pancrelipase

A, B

Pantoprazole

A*

Paracetamol (and products containing paracetamol)

13, 19a, A*

Paricalcitol

5, 12

Paroxetine

5, 9, 12, B

Pazopanib

3b, 5, 18, A

Penicillamine

3a, 4

Peppermint oil

oral capsule: 3b, A

Pergolide

9, 12, 16, B

Perhexiline

5, 12

Pericyazine

1, 9 (long-term regular therapy), 16

Perindopril

11, 12, 16

Pethidine

Phenelzine

1, 5, 6, 13, 16, I

Phenindione

10b

Pheniramine

1, 13

Phenobarbitone

1, 5, 9

Phenoxybenzamine

12, 16

Phenoxymethylpenicillin

3a or 3b, D

Phentermine

12, A

Phenytoin

5, 9, 12, 13

Pholcodine

Pimozide

1, 16

Pindolol

9, 12

Pioglitazone

10a

Piperazine oestrone sulfate

12, 16

Piroxicam

10a, 12, 19b, B

Pizotifen

Posaconazole

5, 12, B, J

Potassium chloride

A*, B

Pramipexole

1, 9, 12, 16, A*

Prasugrel

9, 10a

Praziquantel

12, B

Prazosin

12, 16

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

26

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)


Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Medicine

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Prednisolone

9 (oral, except short courses), B. (Some oral products


may require 6.)

Prednisone

9 (oral, except short courses), B

Pregabalin

1, 9, 12

Primaquine

Primidone

1, 5, 9

Probenecid

10a, B

Procarbazine

2, 5, 21, I

Prochlorperazine

1, 16

Proguanil

4 (delete milk, iron and calcium), B

Promethazine

Propantheline

9, 12

Propranolol

9, 12

Prucalopride

12

Pyridostigmine

A*

Quetiapine

1, 9, 12, 16

Quinapril

11, 12, 16

Quinine

13, A*

Rabeprazole

Raltegravir

12

Ramipril

11, 12, 16

Rasagiline

Reboxetine

9, 12, 16

Repaglinide

10a

Rifabutin

5, D

Rifampicin

3b, 5, D

Rilpivirine

12, B

Riluzole

12

Risedronate

4, 20*, A, C*

Risperidone

orally disintegrating tablets: 1, 13, 16


other dosage forms: 1, 16

Ritonavir

solution: 5, B
tablets: 5, A, B
capsules: 5, 6, B

!
!
!

Rivaroxaban

10b

Rivastigmine

12, B

Rizatriptan

12, 13

Ropinirole

12

Rosiglitazone

10a

Rotigotine

1, 6, 9, 12, 16, 21

Compounding and dispensing

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

27

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)

Compounding and dispensing

Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Medicine

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Roxithromycin

3b, D

Salbutamol

capsules and nebules: 22


foil wrapping: 7b

Salcatonin

Saquinavir

5, B

Saxagliptin

10a

Selegiline

5, 12, B

Sertindole

5, 12, 16, 18

Sertraline

5, 9, 12

Sevelamer

13, A, B

Sildenafil

5, 16

Simvastatin

18

Sirolimus

solution: 5, 6, 7b, 8, 18
other dosage forms: 5, 8, 18

Sitagliptin

10a

Sodium acid phosphate

13 (effervescent tablets)

Sodium fusidate

3b, A*, D

Solifenacin

12, A

Somatropin

6*, 7b

Sorafenib

3b, 5

Sotalol

4 (delete antacids and iron), 9, 12, C (12 hours)

Spironolactone

11, 12, 16, B

Stavudine

12

Strontium ranelate

Sucralfate

3b, 5

Sulfadoxine with pyrimethamine

8, B

Sulfasalazine

A*, B

Sulindac

10a, 12, 19b, B

Sulthiame

Sumatriptan

12

Sunitinib

5, 12

Tacrolimus

3b, 5, 8, 12, 13, 18

Tadalafil

5, 16

Tafluprost

7b (multi-dose container)

Tamoxifen

12

Tamsulosin

12, 16, A

Tapentadol

1, 5, 16

Telaprevir

5, 12, B

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

28

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)


Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Medicine

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Telbivudine

12

Telmisartan

11, 12, 16

Temazepam

1 or 1a, 9

Temozolomide

21, C (1 hour)

Tenofovir

12, B

Terazosin

12, 16

Terbinafine

Teriparatide

6, 7b

Tetrabenazine

Thalidomide

1, 16

Theophylline

5, A*, B

Thioguanine

8, 21

Thioridazine

1, 8, 9 (long-term regular therapy), 16

Thyroxine

3b, 4, 6

Tiagabine

1, 9, B

Tiaprofenic acid

10a, 12, 19b, B

Ticagrelor

10a

Ticlopidine

10a, A, B

Tiludronate

4, A, C (2 hours)

Tinidazole

2, B, D

Tiotropium

22 (capsules for inhalation)

Tipranavir

Tolterodine

12, 16

Topiramate

1, 9, 12, A*

Topotecan

6, 21, A

Tramadol

1, 5, A*

Trandolapril

11, 12, 16

Tretinoin

8, B (oral)

Triamterene

11, B

Triazolam

1 or 1a, 9, 18

Trifluoperazine

1, 8, 9 (long-term regular therapy), 16

Trimeprazine

1, 7b, 13

Trimethoprim

Trimethoprim sulfamethoxazole

8, B, D

Trimipramine

1, 9, 13, 16

Triprolidine

1, 13

Tropisetron

12, C (1 hour)

Ustekinumab

Compounding and dispensing

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

29

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)

Compounding and dispensing

Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Medicine

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Valaciclovir

Valganciclovir

12, 13, 21, A, B

Valproate

9, 10a, 12, 13, A*, B

Valsartan

11, 12, 16

Vancomycin

Vardenafil

5, 16

Varenicline

12, 13, A, B

Venlafaxine

5, 9, 12, A, B

Verapamil

5, 9, 12, 13, 18, A*, B*

Vigabatrin

9, 12

Vildagliptin

10a

Voriconazole

5, 8, 12, C, D

Vorinostat

5, A, B

Warfarin

5, 10b

Zafirlukast

3b

Zalcitabine

12

Zanamivir

Zidovudine

12

Zinc sulfate

Ziprasidone hydrochloride

1, 12, 16, B

Zolmitriptan

12

Zolpidem

1a, 2, A*

Zonisamide

1, 5, 9

Zopiclone

1a, 2

Zuclopenthixol

1, 8, 13, 16

Groups of compounds
Angiotensin converting enzyme inhibitors

11, 12, 16

Angiotensin II receptor antagonists

11, 12, 16

Antibiotics

Anticoagulants

10b

Anticonvulsants

Antidepressantstricyclic and tetracyclic

1, 9, 13, 16

Antidepressantsselective serotonin reuptake inhibitors

5, 9, 12

Antifungals (oral and vaginal)

Antifungals (topical)

Antihistamines (except desloratadine, fexofenadine


and loratadine)

Beta-blockers

9, 12

Benzodiazepines

1 or 1a, 9

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.
! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

30

Section A | Counselling and cautionary advisory labels

Table A.1 Medicines requiring cautionary advisory labels (continued)


Pharmacists are expected to meet legislative labelling requirements and exercise professional judgment when deciding whether to omit one or
more cautionary advisory labels for a particular patient. The labels are a tool for pharmacists to use as an aid to counselling. They are intended to
reinforce, rather than replace, verbal counselling.

Ancillary label (number) and/or


additional instruction (letter)

Change from
previous edition

Calcium channel blockers

12

Corticosteroids (oral)

9 (except short courses), B

Cytotoxics

8, 21

Diuretics

16

Eye preparations (28 days unless otherwise specified or


authorised)

7b

Hypnotics

1a

Hypoglycaemic agents

10a, B

Immunosuppressants

Insulins

6 (except vial or cartridge in use), 7b, 10a

Medicines packed in child-resistant or strip packaging

13

Monoamine oxidase inhibitors, non-selective

1, 13, 16, I

Nitrates

16

Non-steroidal anti-inflammatory agents

10a, 12, 19b, B

Nucleoside reverse transcriptase inhibitors

12

Phenothiazines (as antipsychotics)

1, 8, 9 (long-term regular therapy), 16

Protease inhibitors

Quinolone antibacterials (except topical)

3b, 4, 8, 12, D

Tetracyclines

4, 8, D

Vaccines

Most appropriate during initial treatment or when dosage is increased.


* Some products have specific indications or specialised formulations or coatings that give rise to instructions different from those applicable generally to
the conventional dose form. In cases of doubt concerning specific products with specialised formulations or coatings, reference should be made to the
recommendations contained in the manufacturers information.

Compounding and dispensing

Medicine

! Updated recommendations for cautionary advisory labels since the previous edition of this table, for drugs newly approved for marketing in Australia, or as a
result of updated clinical review of product information.
Antacids will decrease the absorption of many medicines. Unless specifically indicated to the contrary, the administration of antacids should be separated by a
period of about 2hours from other orally administered medicines, whenever possible. Similar separation of the dosing of cholestyramine, colestipol, lanthanum
and sevelamer from other medicines is also recommended.

Further information
Pharmaceutical Society of Australia. Consumer medicine information
and the pharmacist. Canberra: PSA; January 2007. Available to PSA
members at www.psa.org.au.

31

Extemporaneous dispensing

Compounding and dispensing

Preparation and provision of a pharmaceutical product to


a consumer constitute a professional service not limited
to the accurate and safe blending of raw ingredients.
Also involved is consideration of clinical information in
order to make professional judgments associated with
the quality use of medicines.1 Pharmacists must ensure
that extemporaneously prepared preparations supplied
to consumers are safe, efficacious, and of consistently
reproducible quality.2
The National Competency Standards Framework for
Pharmacists in Australia1 describes the skills pharmacists
need in order to prepare extemporaneous preparations.
The Professional Practice Standards2 relate to the systems
and procedures that will enable pharmacists to provide
prepared products of consistently high quality.
The following provides a brief overview of the principles
of extemporaneous product preparation; readers
are advised to refer to the relevant standards and
guidelines for more detailed guidance on meeting their
professional obligations.

Product considerations

Professional obligations
Pharmacists must prepare and dispense compounded
products in such a manner as to ensure their quality,
safety and efficacy. Standard 10 Compounding, of the
Professional Practice Standards2 provides guidance on
how pharmacists can meet their professional obligations
by ensuring that an extemporaneous product is of
suitable quality. Personnel must be suitably trained, and
all equipment, premises and raw materials must be of an
acceptable standard for compounding purposes.

Product need
Legislative obligations
Extemporaneous dispensing, or compounding, means
the preparation and supply of a single unit of issue
of a therapeutic product intended for immediate use
by a specific person in response to an identified need.
In Australia, therapeutic goods must be entered on
the Australian Register of Therapeutic Goods (ARTG)
and, unless exempt, must be manufactured in premises
licensed by the Therapeutic Goods Administration
(TGA). An extemporaneous preparation prepared in
a community pharmacy for an individual consumer is
exempt from registration with the TGA, so the premises
do not need to be accredited under the Code of Good
Manufacturing Practice (GMP). The product must
nevertheless be prepared according to the accepted
professional standards.
Complex compounding means the preparation and
supply of a single unit of issue of a therapeutic product
that is intended for immediate use by a specific patient
and that requires or involves special competencies,
equipment, processes or facilities. Examples are sterile
preparations and preparations containing ingredients
that pose an occupational health and safety hazard
(such as cytotoxics or hormones), micro-dose singleunit
dosage forms, and sustained-release or other
modifiedrelease preparations.

32

Extemporaneous (batch) manufacturing is the creation


of a batch of multiple units of product. Pharmacists
who engage in extemporaneous manufacturing, in
anticipation that there will be individual consumers with
a need for a product or intending to store preparations
for supply over a extended period of time, have in
addition to meeting the accepted pharmacy professional
standards, an obligation to comply with the Code of
Good Manufacturing Practice for medicinal products3
(GMP), and ensure that preparations are labelled
according to the requirements of Therapeutic Goods
Order No. 69.4

A prescriber can request extemporaneous preparations


for any of the following reasons:5,6

a liquid formulation is needed because a patient


is unable to swallow solid dose forms or there are
other patient-specific requirements;

a registered product has been discontinued or is


unavailable; or

a product must be freshly made.

A documented, systematic procedure should be used to


identify and take account of individual factors such as
the patients age, their existing medical conditions, their
current medications, and the safety and efficacy of all
the active ingredients and excipients in the formula.

Formulation considerations
When receiving a request for an extemporaneous
product, pharmacists must use their professional
judgment to assess the potential risksto staff and the
consumerassociated with preparing and dispensing an
extemporaneous product.
This handbook includes formulae for some
preparations that are available commercially,
predominantly for teaching purposes.

Section A | Extemporaneous dispensing

Among the factors that should be considered are the


suitability and sensitivity of the equipment used in
compounding and the level of training and experience of
the staff preparing the product. The dosage form chosen
can present an additional risk because of the complexity
of the formulation, instability or the need for sterile
preparation, and the ingredients can be highly potent or
hazardous, requiring protective apparel and containment
systems for pharmacy personnel.

Figure A.6 Risk assessment process for


the preparation of extemporaneous
preparations1,7
Is a suitable commercial product available?

Is there a suitable therapeutic alternative?

Is it possible to use an existing pharmacopoeial


formula?

An additional risk assessment is required if the use


of a non-pharmacopoeial formula is necessary. This
can include:
a literature searchjournals, books,
and so on
availability of stability data
liasion with the prescriber.

Reformulation of commercial products


Occasionally it might be necessary to prepare liquid
oral preparations by reformulating commercially
available injections, tablets or capsules. Modification

When dispersing tablets in water and taking an aliquot


of the dispersion, it is important to consider the solubility
of the medication and whether the dispersion forms
a suspension that allows for an accurate dose to be
measured. Pharmacists are advised to contact a hospital
pharmacy department for advice and/or to liaise with
the prescriber in relation to formula modification where
necessary. See also Modification of oral formulations,
page 68.
Unless otherwise stated, sustained-release
and enteric-coated products should not be
reformulated.
When using tablets or capsules, the highest strength
available should be used wherever possible to minimise
the amount of excipients. Product information and
consumer medicine information leaflets can be used to
check suitability for reformulation before preparation:
some products can contain excipients that render
the product unsuitable for use in the preparation of
liquid formulations.

Compounding and dispensing

Pharmacists should also consider whether there is a listed


or registered commercial product that can be efficaciously
and safely used for the intended purpose in place of
an extemporaneously prepared product. Generally, it
is appropriate to prepare an extemporaneous product
only if the pharmacist has established that there are no
commercially available formulations or suitable therapeutic
alternatives. It is then necessary to determine whether
a current pharmacopoeial formula exists and whether
the required excipients are available. It is the role of the
pharmacist to search the literature for evidencebased
formulae and liaise with the prescriber should a current
pharmacopoeial formula not be available. Figure A.6
shows the risk assessment to be carried out when
responding to a request to prepare an extemporaneous
preparation.

of commercially available products for extemporaneous


preparation should be done with caution since some
therapeutically inactive excipients and fillers, and
alteration of release characteristics (e.g. crushing
extended-release formulations) might affect
bioavailability and stability.8

Tablets used for reformulation should be finely crushed


and the powder triturated with a small amount of
the vehicle before making to volume. These types of
preparations are likely to contain undissolved active
ingredients, and suspending agents might be needed.
For more information about liquid medications, see
Modification of oral formulations, page 68, or a
paediatric pharmacopoeia.

Facilities and equipment


Pharmacists should not compound preparations if
they do not have suitable facilities or equipment.
Some compounding techniquese.g. aseptic transfer,
sterilisation and handling of cytotoxic agentscall for
specialised equipment and facilities and should be used
only at properly designed and equipped premises by
trained and experienced personnel. Equipment used
for preparation of sterile products and equipment used
for preparation of cytotoxic products should be stored
separately and designated exclusively for that use.
To minimise the risk of contamination, all compounding
should take place in a designated area away from routine
dispensing activities and high-traffic areas. All working
surfaces should be in good condition, hygienic and
covered with impervious washable materials. They should
be thoroughly cleaned before and after compounding.
The temperature of compounding and storage facilities
should be monitored and recorded to ensure that
33

Compounding and dispensing

Section A | Extemporaneous dispensing

storage conditions are suitable. A powder containment


system is needed to protect personnel if hazardous
materials such as hormones are compounded.

the US Pharmacopoeia, the National Formulary,


and the International Pharmacopoeiaor other
relevant standards.

Environmental conditionssuch as the temperature


of compounding areas, refrigerators and freezers
should be monitored and documented. Records of
the maintenance and calibration of equipment should
also be kept. To ensure the safety of staff and the
environment, there should be a documented procedure
for disposal of expired compounds and materials.

The designation BP refers to the current edition of the


British Pharmacopoeia. Water used in the preparation of
non-sterile extemporaneous products should be Purified
Water BP that has been freshly boiled and cooled or
Water for Irrigation BP. Water used in the preparation
of sterile extemporaneous products should be Water for
InjectionsBP.

All equipment should be used exclusively for


compounding and must be protected from potential
damage and contamination during storage. Equipment
must be thoroughly cleaned after and immediately
before each use. Balances and measures should be
regularly checked and calibrated at specified intervals.
The sensitivity of balances must be appropriate for the
quantities being weighed.

Microwave ovens

Preparation of some extemporaneous products calls for


specialised training and skills and a considered approach
to safety.

A pharmacist should carry out all compounding


or directly supervise trained staff involved in
compounding activities.

Precautions should be taken to minimise the risk


of contamination of products and personnel. Staff
should wear protective clothing (e.g. a laboratory
coat, disposable gloves and a hair cover) during any
compounding procedures. Additional precautions
(e.g. eye protection, a respirator mask and powdercontainment systems) might be warranted when
handling potent substances such as hormones.
Baseline and periodic pathology monitoring might
be needed if ingredients present a risk of toxicity.

Eating and drinking are not permitted in preparation


areas, and hands should be thoroughly washed and
dried before any compounding activity.

The preparation of sterile products entails additional


requirements, such as specific training and skills
maintenance in sterile techniques, the use of
non-shedding apparel, hair and shoe covers, sterile
gloves, scrubbing of hands, and removal of jewellery
and make-up.

Microwave ovens should be used with extreme caution


in the preparation of compounded products. Microwave
radiation has the potential to affect drug stability by
causing the formation of free radicals and areas of high
heat (hot spots) because of uneven radiation fields.9

Product preparation
Quality of raw materials
It is preferable to use pure chemical ingredients from
a TGA-licensed supplier in extemporaneously prepared
products. If the ingredients are not available from a
TGA-licensed supplier or in a registered product and
must be procured elsewhere, it is the pharmacists
responsibility to ensure that the material is appropriate
for its intended use and meets pharmacopoeial or other
quality standards.
A certificate of analysis (C of A) is a statement from a
supplier of raw materials listing the results of a range
of analytical tests to show the identity and purity of
the substance. Pharmacists use the results to assess the
suitability of a material for use in compounded products.
Wherever possible, pharmacists should obtain ingredients
from reputable suppliers who can provide a certificate of
analysis. Materials must be stored under recommended
conditions and be labelled with a validated expiry date
and batch number.
All excipients and ingredients used by pharmacists in
the preparation of compounded products must be
of the highest pharmaceutical grade, be suitable for
use in humans, and comply with the requirements
of pharmacopoeial standardse.g. the British
Pharmacopoeia, the European Pharmacopoeia,

34

Workplace safety

Material safety data sheets


A material safety data sheet (MSDS) is a document
containing important information about the safe
handling and storage requirements for a hazardous
chemical and is available from the supplier of the
compounding ingredients.
Employers and business owners must meet occupational
health and safety requirements with respect to MSDSs
and the labelling of hazardous chemicals in the
workplace10:

Obtain an MSDS for a hazardous substance from


the supplier.

Keep a register containing a list of all hazardous


substances used at the workplace and put a copy of
MSDSs obtained in the register.

Section A | Extemporaneous dispensing

Take reasonable steps to ensure that the MSDS is


not changed by anyone other than the manufacturer
or importer.

In order to avoid confusion, microgram or microg


should be used instead of the abbreviated form.

Keep the MSDS close to where the substance is


being used.

Storage and expiry dates

Ensure that a label is fixed to a hazardous


substance container.

Ensure that warnings are given about enclosed


systems containing hazardous substances.

Contact the relevant state or territory government


workplace health and safety organisation for
further information.

Packaging

The containers used for extemporaneous preparations


should be such as to maintain the quality and stability of
the product. Use secure packaging such as child-resistant
closures where appropriate. See Therapeutic Goods
Order No. 80, Child-resistant packaging requirements
for medicines11, if applicable.

Labelling
Extemporaneously prepared preparations should be
labelled in accordance with the relevant state or territory
legislation. The label should also include the approved
pharmacopoeial or Australian Pharmaceutical Formulary
name, the name and amount or concentration of any
added preservatives, the amount or concentration of all
active ingredients (especially if a formulation other than
a pharmacopeial or APF formulation is used), the expiry
date, directions for use, and required ancillary labels and
storage details.
Particular care should be taken when labelling and
packaging high-risk sterile cytotoxic products to ensure
that the route of administration is clearly stated.

Units of measure
For liquid preparations, the metric dose, in millilitres,
should also be shown on the preparations label. It is
important to unambiguously note the strength of the
product (i.e. mg per mL or mg per 5 mL): confusion
can arise with preparations that are available in
multiple strengths, especially if the instructions are
x mL per dose.
Weights should be shown in multiples or fractions of a
gram, milligram or microgram. Fluid measures should
be shown in multiples or fractions of a millilitre. The
following abbreviations can be used:

ggram

mgmilligram

mLmillilitre.

Store below 18C (Deep freeze).

Store below 5C (Freeze).

Store at 28C (Refrigerate. Do not freeze).

Store below 8C (Refrigerate).

Store below 25C.

Store below 30C.

The shelf life of a product is dependent on the


conditions of storage. Stability and efficacy can be
compromised if the product is kept for any prolonged
period outside the labelled temperature range, when
the expiry date marked on it has been passed, or if it
is repackaged.
Preparations that must be stored below 18C, below
5C, below 8C or below 25C should be kept
below the prescribed temperature at all times. Storage
below 5C will generally be attainable in the freezer
compartment of a domestic refrigerator; storage below
8C will generally be attainable in the main storage
compartment of a domestic refrigerator; storage below
25C will be attainable by standard air conditioning in
places where the ambient temperature exceeds 25C.
Preparations that must be stored below 25C or below
30C should be kept below the nominated temperature
for at least 95% of the time and should never be stored
at a temperature exceeding 40C.

Compounding and dispensing

Containers

The following standard storage instructions have been


adopted in Australia for labelling of therapeutic goods:

Unless otherwise specified, an expiry date of 28 days


or less should be assigned to the product. Assigning
an expiry date longer than 28 days should be based
on reliable literature. Since extemporaneous products
are intended for immediate use, an expiry date of
no more than six months should be assigned for
nonsterile preparations.12 When a product must be
freshly prepared, it should be issued within 24 hours of
preparation. When a product must have been prepared
recently before use, this suggests that deterioration is
likely if the product is stored for longer than four weeks;
it is therefore desirable for the product to be issued
within seven days of preparation.

Counselling
Pharmacists need to provide to the consumer instructions
on the correct use of the compounded product,
including specific storage requirements, correct handling
and the expiry date. A written consumer medicines
information leaflet will not usually be available for
35

Section A | Extemporaneous dispensing

extemporaneous preparations. It is crucial that the


consumer receives all the information necessary to
enable them to use the product safely and effectively
and that pharmacists verify that the consumer has
understood the instructions. The consumer should
receive instructions on how to use a correctly calibrated
medicinal measure or syringe: use of domestic spoons
should be discouraged.

Complaints and recalls


Errors, defects and complaints in relation to
extemporaneous preparations should be documented
and investigated, and steps should be taken to remedy
the problems. A recall procedure should be documented
in the event that a dispensed preparation must be
recovered.

Further information

Quality assurance

Compounding and dispensing

Documentation
The pharmacist is responsible for the quality of an
extemporaneously prepared preparation. Before
dispensing, it is necessary to verify that the preparation
has been prepared according to the documented
procedures and meets the required specifications.
There should be a systematic approach to quality
improvement in extemporaneous dispensing activities.
Instituting product testing as a quality control measure
should be based on an assessment of risk. Reviews of
processes and procedures should be conducted at regular
intervals in order to identify areas for improvement, and
the action taken as a result should be documented.

Extemporaneous dispensing form


A record must be kept of all extemporaneous
dispensing. Clear and comprehensive documentation
of compounding activity is a quality assurance
requirement. It reduces the risk of error and ensures that
the compounding process is systematic and produces
products of consistently high quality. This record should
be kept for two years from the date of dispensing of the
preparation or according to state or territory legislative
requirements. FigureA.7 shows an example of an
extemporaneous dispensing form.
The pharmacopoeial name (if applicable), the formula
and its source, the manufacturers of the ingredients, and
the batch numbers and expiry dates should be recorded
on an extemporaneous dispensing form. Any notes
about stability, methodology, calculations and references
should also be recorded on the form, to ensure that the
product and its ingredients are fully traceable and to
facilitate preparation of an identical product should that
be necessary in the future.
The form should also record the names of any supervised
staff and be signed and dated by the supervising or
compounding pharmacist. A duplicate label should
be attached to the form. For preparations prepared
frequently, a master extemporaneous dispensing form
should be kept and working copies can be made
from that.13

36

PharmInfoTech. Background to extemporaneous preparation of oral


liquids. At: www.pharminfotech.co.nz/manual/Formulation/oral.htm.

References
1. Pharmaceutical Society of Australia. Domain 5. Prepare
pharmaceutical products. National Competency Standards
Framework for Pharmacists in Australia. Canberra: PSA, 2010.
2. Pharmaceutical Society of Australia. Standard 10. Compounding
(also known as extemporaneous dispensing). Professional Practice
Standards. Version 4. Canberra: PSA, 2010.
3. Therapeutic Goods Administration. Code of Good Manufacturing
Practice for Medicinal Products. At: www.tga.gov.au/industry/
manuf-medicines-cgmp.htm.
4. Therapeutic Goods Administration. Therapeutic Goods Order No.
69: general requirements for labels for medicines.
At: www.comlaw.gov.au/Details/F2009C00264.
5. Buurma H, de Smet P, van den Hoff O et al. Frequency, nature
and determinants of pharmacy compounded medicines in Dutch
community pharmacies. Pharmacy World & Science. 2003;
25:2807.
6. British Pharmacopoeia Commission. British Pharmacopeia 2007,
vol. IV. Supplementary chapter V Unlicensed medicines. London:
HMSO, 2007.
7. Glass B, Haywood A. Historical extemporaneous formulae: what
are the risks? Australian Pharmacist. July 2011; 5534.
8. Marriott J, Wilson K, Langley C et al. Pharmaceutical compounding
and dispensing. London: The Pharmaceutical Press, 2006.
9. Lund W. The Pharmaceutical Codex. 12th edn. London: The
Pharmaceutical Press, 1994.
10. Workplace Health and Safety Queensland. Material safety data
sheets. 2011. At: www.deir.qld.gov.au/workplace/subjects/
hazardousmaterials/definition/msds/index.htm.
11. Therapeutic Goods Administration. Guidance on Therapeutic
Goods Order No.80: child-resistant packaging requirements. 2008.
At: www.tga.gov.au/pdf/legislation-tgo-80-guide.pdf.
12. United States Pharmacopeia. Pharmaceutical compounding
Nonsterile preparations. <USP795>. US Pharmacopeia 29. 2011.
At: www.pharmacopeia.cn/v29240/usp29nf24s0_c795.html.
13. Pharmaceutical Inspection Convention. Pharmaceutical Inspection
Co-operation SchemePIC/S guide to good practices for
preparation of medicinal products in healthcare establishments.
2008. At: www.picscheme.org/publication.php?id=8.

Section A | Extemporaneous dispensing

Figure A.7 Extemporaneous dispensing form: an example


Pharmacy name
Patients name
Patients contact details
Prescriber name
Prescriber contact details
Prescription

Date of preparation
Product prepared by
Working formula
Ingredient

Manufacturer

Batch number

Expiry date

Measured quantity

Measured by

Checked by

Compounding and dispensing

Formula source (if applicable)

Methods and notes

Container description and size

Additional labels

Attach copy of label used on product


Expiry date
Product released by
(name and signature)

37

General formulary
Applications

Capsules

Applications can be solutions, suspensions or emulsions.


They have similar physicochemical properties to
lotions but have traditionally been used to administer
antiparasitic medicines. Applications are intended for
application to the skin, without friction, and without
dressing or covering material.1,2
Label. These preparations should be labelled FOR
EXTERNAL USE ONLY (label K) and SHAKE WELL BEFORE
EACH USE (labelJ), if applicable.3

Compounding and dispensing

Container. Dispense in amber, fluted poison bottles;


consider using a child-resistant closure.
Storage. Store below 25C unless otherwise specified.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

benzyl benzoate application


Applic. Benzyl. Benz.; benzyl benzoate lotion
benzyl benzoate ..................................................... 25 g
emulsifying wax*.......................................................2 g
purified water, freshly boiled and cooled......... to 100 mL
* See p 45 for formula of emulsifying wax.

Strength. Contains 25% of benzyl benzoate in a


suitable oil-in-water emulsified base (limits 22.5 to
27.5% w/v of benzyl benzoate, C14H12O2).
Method. Melt the emulsifying wax, then add the benzyl
benzoate and mix. Add this mixture to 70mL of purified
water previously heated to about 70C. Stir until cold
and adjust to 100mL with purified water.
Use. Treatment of scabies.
Dose. After a bath, apply with a brush to the whole
of the body except the face and head; leave on for
24hours without bathing; application should be
repeated in 510days.
Label. This preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ).

Capsules are solid dosage forms that consist of individual


doses of powders enclosed in hard or soft shells, or
capsules, usually composed of gelatin. They are generally
intended for oral administration, to be swallowed
whole with water, with the powder being released in
the stomach. Some capsules may be opened and the
contents inside crushed, however, this might affect
the release and absorption characteristics of the active
ingredient.14
Capsules have the advantages that they are easy to
swallow, contain an accurate dose of medicine and are
able to mask unpleasant-tasting medicines. Capsules
of medication are generally available commercially.
However, occasionally a small quantity of medicine may
be required that is not available in this form.
The capacity of each capsule depends on the actual
powder density of the fill ingredients.1,2 Hard, empty
gelatin capsules are available in the sizes (codes)4 listed
in TableA.2, which also shows the approximate capsule
capacity (mg) based on size and powder density.
Method. An appropriate capsule size should be
selected that holds the quantity of powder needed for
an individual dose (see TableA.2). The quantity of bulk
powder required to fill the prescription should then be
calculated; for most prescriptions, an excess quantity
of bulk powder should be prepared (i.e. sufficient to
fill one or two additional capsules). This will ensure
that there is sufficient powder to fill the last capsule
and cover any loss of powder in the filling process.
The ingredients for inclusion in the capsule should
be carefully blended, using a mortar and pestle, to
produce a fine and uniform powder. Potent medicines,
particularly if prescribed in small doses, may be mixed
with an inert diluent or filler (e.g. lactose, starch) before
filling into capsules. To fill capsules individually, the
correct amount of prepared powder may be weighed
and transferred carefully into the capsule. Alternatively,

Table A.2 Capsule filling weights (mg) based on capsule size and density of filling powder4
Capsule size

38

Volume (mL)

Capsule filling weight (mg)


Powder density
0.4g/mL

Powder density
0.6g/mL

Powder density
0.8g/mL

Powder density
1.0g/mL

Powder density
1.2g/mL

No. 3 (smallest)

0.30

120

180

240

300

360

No. 2

0.37

148

222

296

370

444

No. 1

0.50

200

300

400

500

600

No. 0

0.68

272

408

544

680

816

No. 00 (largest)

0.95

380

570

760

950

1140

Section A | General formulary

the process of punching may be used, in which the


final powder is spread (using a spatula) in a layer about
5mm thick, and the body of the empty capsule is
punched into the powder until it is filled. The weight
should be continually checked on a tared balance until
correct. A number of manual capsulefilling machines
are also available, which require careful determination
of the capsule formula.14
Container. Dispense in well-sealed containers; consider
the use of child-resistant closures.
Storage. Store below 25C unless otherwise specified.

boric acid vaginal capsule


boric acid........................................................... 600 mg
Method. As for preparation of capsules
(describedabove), using No.0 or No.00 capsules.

Dose. One capsule, inserted into the vagina, once daily


for 1014days.5
Label. These capsules are intended for intravaginal
administration and should be labelled CAUTION: NOT TO
BE TAKEN (labelL).

Creams
Creams are viscous semi-solid preparations, usually
emulsions, that are intended for application to
the skin. They may be water miscible (oil-in-water
emulsions)described in this formulary as aqueous
creamsor oil miscible (water-in-oil emulsions)
described as oily creams. Creams are used to apply active
ingredients to the skin, for protective, therapeutic or
prophylactic purposes, where a highly occlusive effect
is not necessary.1,4
Preservative. When chlorocresol is used as the
preservative, it should be dissolved using warm water in
a closed container.
Label. If the product is for topical use, the preparation
should be labelled FOR EXTERNAL USE ONLY (labelK).
If the product is for nasal, otic, vaginal or rectal use, the
preparation should be labelled CAUTION: NOT TO BE
TAKEN (labelL). The label should include the name and
percentage of any preservative agent used.
Container. Dispense in well-sealed containers that
prevent evaporation. Collapsible tubes of metal or
suitable plastics should be used whenever possible.
Storage. Store below 25C unless otherwise specified.

Oily creams
Oily creams are protective and emollient in nature.
Oily cream, cold cream and oily glycerol cream are
bases of this type. Such bases are not suitable for the

Aqueous creams
Aqueous creams can effectively deliver medicaments to
body surfaces. These creams may become concentrated
through loss of water, so caution must be exercised in
relation to the strengths of caustic medicines used with
them. Aqueous creams are water miscible and readily
removed by washing.
Aqueous creams may be used for water-soluble
antiseptics (e.g. chlorhexidine), water-soluble local
anaesthetics and most other dermatological agents.
The water present in aqueous creams may reduce the
stability of many active ingredients and encourage the
growth of microorganisms unless suitable preservatives
are included. The preservatives specified in aqueous
creams may be replaced by suitable alternative
antimicrobial preservative agents, provided that the
name and concentration of the alternative agent used
are stated on the label.
Care must be taken to avoid contamination during
preparation of aqueous creams. The apparatus used
and the final containers should be thoroughly cleansed,
rinsed in freshly boiled and cooled water, and dried.
Purified water used in the preparation of creams should
be freshly boiled and cooled before use.

Compounding and dispensing

Use. Treatment of vaginal candidiasis caused by Candida


glabrata and other non-albicans species.5

presentation of water-soluble antiseptics. They may be


used for local protectives (e.g. calamine, zinc oxide) and
for the application of some oil-soluble medicaments
(e.g. camphor, menthol, methyl salicylate).

Aqueous creams may be further classified according to the


chemical type of the emulgent (emulsifying agent) used.

Anionic creams
Anionic creams contain emulgents that yield large
anions and therefore are potentially incompatible with
cationic drugs. An ion pair is likely to form between
the anionic emulgent and the cationic drug, and this
may reduce either the efficacy of the emulgent or the
activity of the drug (see Emulsifiers and stabilisers,
page79). Aqueous cream is a cream of this type.

Cationic creams
Cationic creams contain emulgents that yield large
cations and therefore are potentially incompatible with
anionic drugs. An ion pair is likely to form between the
cationic emulgent and the anionic drug, and this may
reduce either the efficacy of the emulgent or the activity
of the drug (see Emulsifiers and stabilisers, page 79).
Cetrimide cream aqueous is a cream of this type.

Non-ionic creams
Non-ionic creams contain emulgents that yield virtually
no ions. The emulgents are often polyoxyethylene esters
or ethers. These creams are usually compatible with
both anionic and cationic drugs. Cetomacrogol cream
aqueous is a cream of this type.
39

Section A | General formulary

Note. This cream has a pH of approximately 6. If kept in


aluminium tubes, the inside surfaces should be coated.3

aluminium acetate cream oily


Burows cream
aluminium acetate solution*................................... 5 mL
zinc oxide................................................................ 20 g
wool fat ................................................................. 25 g
arachis oil............................................................. 25 mL
purified water, freshly boiled and cooled............... 27 mL
The above quantities make100 g of cream.
Method. Melt the wool fat with the arachis oil with
the aid of gentle heat. Triturate the zinc oxide with
this mixture until smooth, and allow to cool. Mix the
aluminium acetate solution and the purified water, and
incorporate into the oil phase.

Compounding and dispensing

g
g
g
g
g
g

* See p 45 for formula of cetomacrogol emulsifying wax.

Strength. Contains 4% of calamine and 3% of zinc


oxide in a suitable oil-in-water emulsified base (limits 4.3
to 5.3% w/w of zinc, Zn).

Use. Mild antipruritic in subacute dermatitis.


Label. This preparation should be labelled CONTAINS
PEANUT OIL (labelN).

aqueous cream
simple cream; Hydrous emulsifying ointment; Ung.
Emulsif. Aquos. (UEA)
emulsifying ointment*............................................. 30 g
glycerol.................................................................. 5 mL
phenoxyethanol ........................................................1 g
purified water, freshly boiled and cooled............to 100 g
* See p 54 for formula of emulsifying ointment.

Method. Melt the cetomacrogol emulsifying wax in the


arachis oil at 70C. Add the chlorocresol to a warmed
200mL container, then add 55mL of just-boiled purified
water (>80C), close the container and shake to
dissolve. Mix the two phases and stir until a semi-solid
cream forms. Adjust to 93g with purified water and
mix thoroughly. Triturate the calamine and zinc oxide
with a small portion of the cream, then incorporate in
the remainder.
Use. Antipruritic.
Label. This preparation should be labelled CONTAINS
PEANUT OIL (labelN).

When this product is ordered with cationic drugs (see


Emulsifiers and stabilisers, page 79), it should
be replaced by cetomacrogol cream or aqueous
cetrimide cream.

calamine cream oily

Method. Melt the emulsifying ointment and mix with


5mL of glycerol and 60mL of purified water heated to
approximately 70C. Stir until a semi-solid cream forms,
then add the phenoxyethanol and adjust to 100 g with
the purified water. Mix thoroughly.
Use. Anionic base, emollient. May be a useful vehicle for
incorporating drugs such as sulfur, salicylic acid, phenol
and coal tar.

calamine ................................................................ 32 g
oleic acid............................................................. 0.5 mL
phenoxyethanol ..................................................... 1 mL
arachis oil ......................................................... 21.5 mL
wool fat............................................................... 17.5 g
calcium hydroxide solution* .............................. 29.5 mL
* See p 59 for formula of calcium hydroxide solution.

These quantities make 100g of cream.


Strength. Contains 32% of calamine (limits 16.5 to
20.1% w/w, calculated as zinc, Zn).

buffered cream aqueous


g
g
g
g
g

* See p 54 for formula of emulsifying ointment.

Method. Add the solids to a warmed 200 mL container,


then add 65 mL of just-boiled purified water (>80C),
close the container and shake to dissolve. Mix with the
melted emulsifying ointment and stir until a semi-solid
cream forms. Adjust to 100g with purified water and
mix thoroughly.
40

calamine cream aqueous


calamine...................................................................4
zinc oxide..................................................................3
cetomacrogol emulsifying wax*.................................6
arachis oil ............................................................... 30
chlorocresol ........................................................... 0.1
purified water, freshly boiled and cooled ...........to 100

* See p59 for formula of aluminium acetate solution.

sodium phosphate.................................................. 2.5


citric acid monohydrate ......................................... 0.5
chlorocresol ........................................................... 0.1
emulsifying ointment*............................................. 30
purified water, freshly boiled and cooled ...........to 100

Use. Anionic base, emollient. May be a useful vehicle for


incorporating drugs such as sulfur, salicylic acid, phenol
and coal tar.

Method. Melt the wool fat in the arachis oil and


the oleic acid. Add the phenoxyethanol. Triturate the
calamine with this mixture in a mortar until smooth and
incorporate the calcium hydroxide solution.
Use. Protective, antipruritic.
Label. This preparation should be labelled CONTAINS
PEANUT OIL (labelN).

Section A | General formulary

cetomacrogol cream aqueous


non-ionic cream; sorbolene cream
cetomacrogol emulsifying wax*............................... 15 g
liquid paraffin.......................................................... 10 g
white soft paraffin................................................... 10 g
chlorocresol ........................................................... 0.1 g
propylene glycol .................................................... 5 mL
purified water, freshly boiled and cooled ...........to 100g
* See p 45 for formula of cetomacrogol emulsifying wax.

Use. Non-ionic base, emollient. This non-ionic cream


base may be used for incorporating cationic, non-ionic
and anionic substances.

Method. Melt the cetomacrogol emulsifying wax


(seeCetomacrogol cream aqueous) in the liquid
paraffin and mix with 50mL of purified water heated to
approximately 70C. Stir until a semi-solid cream forms.
Mix the chlorhexidine gluconate solution BP with the
remaining 10mL of purified water and stir through the
cream in three separate 5mL portions. Adjust to 100g
if necessary.
Note. Protect from light.
Use. Antiseptic preparation for furunculosis or folliculitis.
Container. Dispense in an amber plastic or glass
container.

coal tar and zinc cream oily


coal tar.....................................................................1 g
castor oil...................................................................1 g
zinc cream oily*....................................................... 98 g
* See p 43 for formula of zinc cream oily.

cetrimide cream aqueous


Crem. Cetrimid. Aquos.
cetrimide ............................................................... 0.5 g
chlorocresol ........................................................... 0.1 g
cetostearyl alcohol.................................................. 7.5 g
liquid paraffin.......................................................... 50 g
purified water, freshly boiled and cooled ...........to 100g
Strength. Contains 0.5% of cetrimide (limits 0.44 to
0.53% w/w of cetrimide, C17H38BrN).

Strength. Contains about 31% of zinc oxide (limits 29.2


to 33.6% w/w of zinc oxide, ZnO).
Method. Triturate the coal tar with the castor oil and
mix with the zinc cream.
Note. May stain skin, hair and clothing.
Use. Antipruritic, protective.
Label. This preparation should be labelled CONTAINS
PEANUT OIL (labelN).

Method. Melt the cetostearyl alcohol in the liquid


paraffin at 60C. Add the cetrimide and the chlorocresol
to a warmed 200mL container, then add approximately
40mL of just-boiled purified water (>80C), close the
container and shake to dissolve. Mix the two phases and
stir until a semi-solid cream forms, then adjust to 100g
with purified water and mix thoroughly.

white beeswax........................................................ 17 g
liquid paraffin.......................................................... 45 g
borax........................................................................1 g
purified water, freshly boiled and cooled............... 37 mL

Use. Cationic base, emollient, antiseptic. This cream


base may be used for incorporating cationic substances
such as chlorhexidine, aminacrine, acriflavine and
ichthammol.

Method. Melt the white beeswax in the liquid paraffin.


Warm the purified water to about 70C and use it
to dissolve the borax. Mix the two phases and stir
until cool.

chlorhexidine cream aqueous


chlorhexidine gluconate solution BP*...................... 5 mL
cetomacrogol emulsifying wax#................................ 25 g
liquid paraffin.......................................................... 10 g
purified water, freshly boiled and cooled ...........to 100 g

Compounding and dispensing

Method. Melt the cetomacrogol emulsifying wax in


the paraffins at about 70C. Add the chlorocresol to a
warmed 200mL container, then add 60mL of just-boiled
purified water (>80C), close the container and shake
to dissolve. Immediately add the propylene glycol to the
aqueous phase, then mix both phases and stir until a
semi-solid cream forms. Adjust to 100g with purified
water and mix thoroughly.

Strength. Contains 1% of chlorhexidine gluconate


(limits 0.9 to 1.1% w/w of chlorhexidine gluconate,
C22H30Cl2N10.2C6H12O7).

cold cream
Ceratum Hydrosum; Crem. Refrig. Oleos.; Ung. Refrig.

Note. The proportions of white beeswax and liquid


paraffin may be varied to suit the prevailing temperature.
Use. Water-repellent cream.

* Chlorhexidine gluconate solution BP is an aqueous solution


containing 19 to 21% w/v of chlorhexidine gluconate.
# See p 45 for formula of cetomacrogol emulsifying wax.

41

Compounding and dispensing

Section A | General formulary

dimethicone cream aqueous

ichthammol and zinc cream oily

silicone cream

oily ichthammol cream

dimethicone 350 .................................................... 10 g


liquid paraffin.......................................................... 40 g
cetostearyl alcohol.....................................................5 g
cetrimide ............................................................... 0.5 g
chlorocresol............................................................ 0.1 g
purified water, freshly boiled and cooled ...........to 100g

ichthammol...............................................................5 g
wool fat.................................................................. 15 g
zinc cream oily* ...................................................... 80 g

Method. Melt the cetostearyl alcohol in the dimethicone


350 and liquid paraffin. Add the cetrimide and
chlorocresol to a warmed 200mL container, then add
approximately 40mL of just-boiled purified water
(>80C), close the container and shake to dissolve. Mix
the two phases and stir until a semi-solid cream forms,
then adjust to 100g with warm purified water and mix
thoroughly. Stir until cool.

Method. Triturate the wool fat (may need to be melted


with the aid of gentle heat) with the zinc cream oily until
smooth. Incorporate the ichthammol.

Use. Water-repellent cream.

glycerol cream aqueous


Crem. Glycer. Aquos.
glycerol .................................................................. 15 g
cetomacrogol emulsifying wax*............................... 15 g
liquid paraffin ......................................................... 10 g
white soft paraffin .................................................. 10 g
chlorocresol ........................................................... 0.1 g
purified water, freshly boiled and cooled............to 100g
* See p 45 for formula of cetomacrogol emulsifying wax.

Method. Melt the cetomacrogol emulsifying wax


and white soft paraffin in the liquid paraffin. Add the
chlorocresol to a warmed 200mL container, then add
approximately 45mL of just-boiled purified water
(>80C), close the container and shake to dissolve. Add
the glycerol to the aqueous phase, then mix both phases,
and stir until a semi-solid cream forms. Adjust to 100g
with purified water and mix thoroughly.
Use. Emollient.

* See p 43 for formula of zinc cream oily.

Strength. Contains 25.6% of zinc oxide (limits 23.1 to


29.1% w/w of zinc oxide, ZnO).

Note. If required, this preparation may be diluted


with zinc cream oily to give lower concentrations of
ichthammol.
Use. Traditional application for inflammatory and
eczematous disorders.
Label. This preparation should be labelled CONTAINS
PEANUT OIL (labelN).

methyl salicylate compound cream


Crem. Meth. Sal. Co.
methyl salicylate................................................... 25 mL
eucalyptus oil ...................................................... 10 mL
menthol ...................................................................4 g
cetomacrogol emulsifying wax*............................... 20 g
purified water, freshly boiled and cooled............to 100g
* See p 45 for formula of cetomacrogol emulsifying wax.

Method. Melt the cetomacrogol emulsifying wax to


about 60C. Dissolve the menthol in the eucalyptus
oil and add, together with the methyl salicylate, to the
melted wax. Warm 38mL of purified water and add to
the mixture while stirring. Adjust to 100g with purified
water and continue to stir until cool.
Note. The product will thicken over time, although
thickening can be accelerated by cooling to 28C.
Use. Topical analgesic, rubefacient.

glycerol cream oily


Crem. Glycer. Oleos.; oily glycerin cream
glycerol................................................................... 20 g
calcium hydroxide solution*.................................. 32 mL
arachis oil................................................................ 22 g
wool fat.................................................................. 26 g
* See p59 for formula of calcium hydroxide solution.

Method. Melt the wool fat in the arachis oil. Triturate


this mixture with small portions of the calcium hydroxide
solution. Add the glycerol (also in small portions) and
mix.
Use. Traditional emollient.
Label. This preparation should be labelled CONTAINS
PEANUT OIL (labelN).

42

oily cream
hydrous ointment; wool alcohols cream
wool alcohols ointment*.......................................... 50 g
phenoxyethanol.........................................................1 g
dried magnesium sulfate ........................................ 0.5 g
purified water, freshly boiled and cooled............to 100g
* See p 55 for formula of wool alcohols ointment.

Method. Melt the wool alcohols ointment at a


temperature below 65C. Warm 45 mL of purified water
to about the same temperature and use it to dissolve
the magnesium sulfate and phenoxyethanol. Mix the
two phases and adjust to 100g with purified water.
Stir until cool.

Section A | General formulary

Note. The phenoxyethanol may be replaced by benzyl


alcohol or a suitable concentration of another effective
preservative, provided that the patient has not developed
a sensitivity to the alternative preservative. If, on
storage, some aqueous liquid separates, it is readily
reincorporated by stirring.3
Use. Dermatological oily base.

propylene glycol cream

zinc cream oily


zinc cream; Crem. Zinc. Oleos.
zinc oxide................................................................ 32 g
oleic acid............................................................. 0.5 mL
arachis oil.......................................................... 21.5 mL
wool fat............................................................... 17.5 g
calcium hydroxide solution*............................... 30.5 mL
* See p 59 for formula of calcium hydroxide solution.

The above quantities make 100g of cream.


propylene glycol ..................................................... 15
cetomacrogol emulsifying wax* .............................. 15
white soft paraffin................................................... 10
liquid paraffin.......................................................... 10
chlorocresol ........................................................... 0.1
purified water, freshly boiled and cooled ...........to 100

g
g
g
g
g
g

* See p 45 for formula of cetomacrogol emulsifying wax.

Method. Melt the wool fat in the arachis oil and the
oleic acid with the aid of gentle heat. Triturate the zinc
oxide with the mixture until smooth. Allow to cool
slowly. Incorporate the calcium hydroxide solution in
several portions. Best prepared in a mortar using the
method of doubling.
Use. Protective, sunscreen agent.
Label. This preparation should be labelled CONTAINS
PEANUT OIL (labelN).

Ear drops

Use. Emollient.

salicylic acid and sulfur cream


aqueous
Crem. Acid. Salicyl. et Sulfur.
salicylic acid .............................................................2 g
sulfur .......................................................................2 g
aqueous cream*...................................................... 96 g
* See p 40 for formula of aqueous cream.

Strength. Contains 2% of salicylic acid (limits 1.8 to


2.2% w/w of salicylic acid, C7H6O3) and 2% of sulfur
(limits 1.8 to 2.2% w/w of sulfur, S).
Method. Triturate the salicylic acid and sulfur along with
a small amount of aqueous cream to make a smooth
paste. Gradually incorporate the remaining aqueous
cream to make 100g.

Ear drops are solutions, suspensions or emulsions of


active ingredients in water, glycerol, propylene glycol,
diluted ethanol or another suitable vehicle. They are
intended for instillation into the ear canal. A preservative
may be required if the ear drops are packaged in a
multidose container, and it may be appropriate to filter
the ear drops if particulate matter is present.13

Compounding and dispensing

Method. Melt the cetomacrogol emulsifying wax in


the paraffins at about 70C. Add the chlorocresol to
a warmed 200mL container, then add approximately
45mL of just-boiled purified water (>80C), close the
container and shake to dissolve. Immediately add the
propylene glycol to the aqueous phase, then mix both
phases and stir until a semi-solid cream forms. Adjust to
100g with purified water and stir until cool.

Strength. Contains 32% of zinc oxide (limits 30 to 34%


w/w of zinc oxide, ZnO).

Ear drops intended for application to the injured ear,


particularly if the eardrum is perforated or before
surgery, should be sterile, free from preservatives and
supplied in single-use containers.1 Propylene glycol
should be avoided if the eardrum is perforated because
ototoxicity has been reported.6 For further instructions
on correct administration of ear drops, see Instructions
for administration of different dosage forms in
Counselling and cautionary advisory labels, page 5.

Note. Avoid contact with metals. May stain skin, hair


and clothing. Must not be applied to inflamed or broken
skin; contact with eyes and mucous membranes must be
avoided.7

Label. These preparations should be labelled CAUTION:


NOT TO BE TAKEN (labelL) and SHAKE WELL BEFORE
EACH USE (labelJ), if applicable. The name and
concentration of any preservative agent added should
also be shown.

Use. Treatment of seborrhoeic dermatitis of the scalp


and mild acne.

Container. Dispense in bottles with a dropper, or in


suitable plastic containers.
Storage. Store below 25C unless otherwise specified.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

43

Section A | General formulary

acetic acid ear drops

hydrogen peroxide ear drops

acetic acid (33% w/w)............................................ 3 mL


purified water, freshly boiled and cooled ........ to 100 mL

hydrogen peroxide solution (6% w/v).................... 25 mL


purified water, freshly boiled and cooled......... to 100 mL

Strength. Contains about 1% of acetic acid (limits 0.91


to 1.12% w/v of acetic acid, C2H4O2).

Strength. Contains about 1.5% of hydrogen peroxide


(limits 1.12 to 1.83% w/v of hydrogen peroxide, H2O2),
which corresponds to about five times its volume of
available oxygen.

Use. Treatment of otitis externa.

aluminium acetate ear drops

Compounding and dispensing

Aurist. Alumin. Acet.


aluminium acetate solution................................... 60 mL
purified water, freshly boiled and cooled......... to 100 mL

Use. Removal of ear wax.2,7

Strength. Contains about 8% of aluminium acetate


(limits 0.9 to 1.2% w/v of aluminium, Al).

Storage. If the preparation does not contain a stabiliser,


it should be stored below 15C.

Note. The aluminium acetate ear drops of the British


pharmacopoeia consist of undiluted aluminium acetate
solution.
Use. Treatment of otitis externa.

chlorhexidine ear drops

Container. Dispense in an amber plastic or glass container.

salicylic acid ear drops


Aurist. Acid. Salicyl.
salicylic acid..............................................................2 g
ethanol (90% v/v)................................................. 50 mL
purified water, freshly boiled and cooled......... to 100 mL

chlorhexidine acetate............................................ 0.05 g


purified water, freshly boiled and cooled......... to 100 mL

Strength. Contains 2% of salicylic acid (limits 1.8 to


2.2% w/v of salicylic acid, C7H6O3).

Strength. Contains 0.05% w/v (1 in 2,000) of


chlorhexidine acetate.

Method. Dissolve the salicylic acid in ethanol and adjust


to 100mL with purified water.

Note. These ear drops must not be used if the eardrum


is perforated. Aqueous solutions of chlorhexidine
salts may be susceptible to contamination with
microorganisms. To reduce this risk, a sterilised
preparation should be used or, where necessary,
solutions should be freshly prepared using appropriate
measures to prevent contamination during storage and
dilution. Protect from light.7

Use. Treatment of otitis externa.7

Use. Treatment of otitis externa.


Container. Dispense in an amber plastic or glass container.

hydrocortisone ear drops


hydrocortisone....................................................... 0.5 g
glycerol.......................................................... to 100 mL
Strength. Contains 0.5% of hydrocortisone (limits 0.45
to 0.55% w/v of hydrocortisone, C21H30O5).
Method. Add the hydrocortisone to the warmed glycerol
and stir to dissolve.
Note. Protect from light.

44

Note. These ear drops should be freshly prepared. Avoid


contact with metals and oxidising or reducing agents.
Protect from light.

sodium bicarbonate ear drops


Aurist. Sod. Bicarb.
sodium bicarbonate...................................................5 g
glycerol................................................................ 30 mL
purified water, freshly boiled and cooled......... to 100 mL
Strength. Contains 5% of sodium bicarbonate (limits
4.7 to 5.3% of sodium bicarbonate, NaHCO3).
Method. Dissolve the sodium bicarbonate in 60mL of
purified water without the aid of heat. Add the glycerol
and adjust to 100mL with purified water.
Note. These ear drops should be recently prepared.
Use. Removal of ear wax.7

spirit ear drops


Aurist. Spirit.

Use. Anti-inflammatory and emollient.

ethanol (90% v/v)................................................. 50 mL


purified water, freshly boiled and cooled......... to 100 mL

Container. Dispense in an amber plastic or glass container.

Use. Drying agent.

Section A | General formulary

Elixirs

Eye drops

Elixirs are clear, aromatic liquid preparations that


are a convenient means of administering potent or
potentially nauseating medicaments in a palatable form
in smalldose volumes. The solvent frequently contains
a high proportion of ethanol and/or syrup, but other
solvents such as glycerol are sometimes used.
Container. Dispense in well-sealed containers.
Storage. Store below 25C unless otherwise specified.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

Emulsifying waxes

Container. Store in well-sealed containers.


Storage. Store below 25C unless otherwise specified.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

cetomacrogol emulsifying wax


non-ionic emulsifying wax
cetostearyl alcohol .................................................. 80 g
cetomacrogol 1,000................................................ 20 g
The above quantities make 100g of wax.
Method. Melt the cetostearyl alcohol and cetomacrogol
1,000 together and stir until cold.
Use. Non-ionic emulsifying wax.

emulsifying wax
anionic emulsifying wax
cetostearyl alcohol .................................................. 90 g
sodium lauryl sulfate................................................ 10 g
purified water, freshly boiled and cooled ................ 4 mL
The above quantities make 100g of wax.
Method. Melt the cetostearyl alcohol and heat to about
95C. Add the sodium lauryl sulfate and mix. Add the
purified water, heat to 115C and maintain at this
temperature, stirring vigorously, until frothing ceases and
the product is translucent. Cool quickly.
Use. Anionic emulsifying wax.

Standard 11: Compounding sterile preparations of the


Professional Practice Standards provides guidance on
how pharmacists can meet their professional obligations
when preparing sterile products. For further instructions
on correct administration of eye drops, see Instructions
for administration of different dosage forms in
Counselling and cautionary advisory labels, page 5.
Vehicle. For aqueous solutions, Water for Injections
BP should be used. Eye drops should be prepared in a
vehicle that is bactericidal and fungicidal. The eye drops
described in this handbook should have all particulate
matter removed by filtration through a membrane filter.
Wherever possible, the eye drops have been formulated
to be approximately isotonic with lachrymal secretion
(equivalent to 0.9% w/v sodium chloride), using
sodium chloride or another suitable adjusting substance
(seeIsosmotic and isotonic solutions, page83).
Buffered vehicles for eye drops may be required;
suitable formulae are set out in Buffersolutions,
page86. It should be recognised that such vehicles
may reduce the time and temperature stability of certain
medicaments; modified methods of preparation and
sterilisation may be required. Should a thickened vehicle
be required, 0.3% w/v of hypromellose 4,500 may
be added.

Compounding and dispensing

Emulsifying waxes are the main emulsifiers used in


external products. They are usually further categorised as
anionic, cationic and non-ionic emulsifying waxes. Each
usually consists of two ingredients: cetostearyl alcohol
and a surface active agent (surfactant).1,2

Eye drops are aqueous or oily solutions or suspensions of


active ingredients that are intended for instillation into
the eye. They must be sterile and should be prepared
in facilities that meet Australian standards for the
preparation of sterile products.

Strength. The strengths of eye drops in this handbook


are those commonly used in ophthalmic practice. If a
variation in the proportion of active ingredient is desired,
the prescriber should state the required strength, and
any required adjustment to the vehicle will be made by
the pharmacist.
Preservative. Following repeated application of eye
drops at short intervals or over a long period, the user
might develop a sensitivity to certain preservatives
included in the formulation. Should this occur, a different
preservative may be substituted, having due regard
tocompatibility.
Sterilisation. The procedure recommended for
sterilisation is stated in each formula. The methods
stated, such as sterilise by heating in an autoclave
or sterilise by filtration, are those specified in the
BritishPharmacopoeia.3
Note. The benzalkonium chloride solution used in
some of the eye drops described in this handbook is
a British Pharmacopoeia formula containing 50% of
benzalkonium chloride.

45

Section A | General formulary

Compounding and dispensing

Label. These preparations should be labelled CAUTION:


NOT TO BE TAKEN (labelL). The label on the container
must bear the name and the strength of the preservative
used and the date of preparation.
Container. Dispense in sterilised containers capable of
being closed so as to exclude microorganisms. Dropper
bottles are suitable, but the user must be cautioned
about avoiding contamination during use. Containers
made of materials other than glass, and the rubber teats
used on droppers, should be impregnated with any
bactericide or preservative included in the eye drops.
Containers made of materials other than glass may be
permeable to oxygen and unsuitable for formulations
that undergo oxidation; they may also release unwanted
substances (e.g. plasticisers). The volume of solution
dispensed in each container should be limited, to
discourage prolonged storage. For drops containing
antibiotics, cocaine or corticosteroids, the volume should
generally be limited to 5mL.
Storage. Store below 25C unless otherwise specified.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

adrenaline eye drops strong


adrenaline.................................................................1 g
boric acid............................................................... 0.5 g
sodium metabisulfite.............................................. 0.1 g
disodium edetate.................................................... 0.1 g
benzalkonium chloride solution BP..................... 0.02 mL
water for injections BP ................................... to 100 mL
Strength. Contains 1% of adrenaline (limits 0.9 to 1.1%
w/v of adrenaline, C9H13NO3).
Sterilisation. Sterilise by filtration.
Note. If vasoconstrictor adrenaline eye drops are
required, zinc and adrenaline eye drops may be suitable.
These eye drops should be recently prepared. Protect
from light.
Use. Treatment of open-angle glaucoma.

homatropine and cocaine eye drops


Gutt. Homatrop. et Cocain.
homatropine hydrobromide .......................................2 g
cocaine hydrochloride................................................2 g
boric acid............................................................... 0.5 g
chlorhexidine acetate............................................ 0.01 g
water for injections BP ................................... to 100 mL
Strength. Contains 2% of homatropine hydrobromide
(limits 1.8 to 2.2% w/v) and 2% of cocaine hydrochloride
(limits 1.9 to 2.1% w/v of cocaine hydrochloride).
Sterilisation. Sterilise by heating in an autoclave.
Note. These eye drops should not be prescribed or
dispensed in volumes exceeding 5mL. Protect from light.
Use. Pupillary dilation and local anaesthetic.
Container. Dispense in an amber plastic or glass container.

physostigmine eye drops


Gutt. Physostig.; eserine eye drops
physostigmine sulfate............................................. 0.5 g
sodium metabisulfite.............................................. 0.1 g
sodium chloride...................................................... 0.8 g
benzalkonium chloride solution BP..................... 0.02 mL
disodium edetate.................................................. 0.05 g
water for injections BP ................................... to 100 mL
Strength. Contains 0.5% of physostigmine sulfate
[limits 0.45 to 0.55% w/v of physostigmine sulfate,
(C15H21N3O2)2.H2SO4].
Sterilisation. Sterilise by filtration.
Note. Individuals prescribed physostigmine eye drops
should be advised not to use the eye drops if they are
more than slightly discoloured.7 Protect from light.
Use. Treatment of glaucoma.
Container. Dispense in an airtight, amber plastic or
glass container.

zinc and adrenaline eye drops


BZA eye drops

Container. Dispense in an amber plastic or glass container.

cocaine eye drops strong


cocaine hydrochloride................................................5 g
chlorhexidine acetate............................................ 0.01 g
water for injections BP ................................... to 100 mL
Strength. Contains 5% of cocaine hydrochloride (limits
4.75 to 5.25% w/v of cocaine hydrochloride, C17H21NO4.
HCl).

Strength. Contains 0.25% of zinc sulfate (limits 0.22 to


0.28% w/v of zinc sulfate, ZnSO4.7H2O).

Sterilisation. Sterilise by heating in an autoclave.

Sterilisation. Sterilise by heating in an autoclave.

Note. Cocaine eye drops should not be prescribed or


dispensed in volumes exceeding 5mL. Protect from light.

Note. Adrenaline solution BP contains 0.1% w/v


adrenaline as adrenaline acid tartrate. Protect from light.

Use. Local anaesthetic.2


Container. Dispense in an amber plastic or glass container.
46

zinc sulfate .......................................................... 0.25 g


adrenaline solution BP.......................................... 10 mL
boric acid............................................................... 1.5 g
sodium metabisulfite............................................ 0.05 g
chlorbutol.............................................................. 0.5 g
glycerol.................................................................. 1 mL
water for injections BP ................................... to 100 mL

Use. Astringent.
Container. Dispense in an amber plastic or glass container.

Section A | General formulary

Eye lotions
Eye lotions are sterile aqueous solutions that are used
in large volume to rinse or bathe the eye to remove
foreign materials and relieve irritation. They are intended
for single use only. Preservatives may be added only if
prescribed. Eye lotions must be sterile and should be
prepared in facilities that meet Australian standards for
the preparation of sterile products.
Sterilisation. The procedure recommended for
sterilisation is stated in each formula. The methods
stated, such as sterilise by heating in an autoclave or
sterilise by filtration, are those specified in the British
Pharmacopoeia.3

Container. Dispense in fluted bottles so that the


preparation is easily distinguishable from preparations
intended for internal use. Eye lotions intended for first
aid should be in bottles with an outlet that permits the
lotion to be poured straight out of the container into
the eye. Plastic squeeze bottles with a nozzle stopper
permitting air entry and with the outlet covered by a
removable cap are suitable.
Storage. Store below 25C unless otherwise specified.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

disodium edetate eye lotion

Gels are transparent or translucent semi-solid


preparations that are used for applying active ingredients
to the skin and mucous membranes. They generally
consist of a liquid phase suspended within a threedimensional polymer matrix. The active ingredients can
either be dissolved in the liquid phase or suspended in
the matrix. Gels tend to be smooth and elegant, and
produce a cooling effect from the evaporation of water
from the skin; they may also dry out to form a residual
film on the skin. They have the advantage over aqueous
solutions of maintaining contact with the skin and
mucous membranes for longer periods.13
The consistency of gels varies considerably, depending
on the type and concentration of the gelling agent used.
Common gelling agents used to produce aqueous gels
include tragacanth, alginates, methylcellulose, carbomer
and polyvinyl alcohol (see Mucilages p.52).
Methylcellulose provides a more durable adhesive film
than other gelling agents. These gels are compatible
with anionic and most cationic substances.
Sterilisation. Gels may be sterilised by autoclaving.
Containers. Dispense in well-sealed containers that
prevent evaporation.
Storage. Store below 25C unless otherwise specified.
Expiry. The expiry date is 28days from the date
of preparation unless otherwise specified. Gels
containing tragacanth are particularly prone to bacterial
contamination and should be discarded 28days after
manufacture unless a shorter period is indicated.

chlorhexidine gel

Sterilisation. Sterilise by heating in an autoclave.

chlorhexidine gluconate solution BP*................... 2.5 mL


tragacanth............................................................. 2.5 g
glycerol................................................................ 25 mL
purified water, freshly boiled and cooled............to 100 g

Use. For removing calcium deposits in the cornea.

* Chlorhexidine gluconate solution BP is an aqueous solution


containing 19 to 21% w/v of chlorhexidine gluconate.

disodium edetate ................................................... 0.4 g


water for injections BP.................................... to 100 mL

sodium bicarbonate eye lotion


Collyr. Sod. Bicarb.; alkaline eye lotion
sodium bicarbonate ............................................... 3.5 g
water for injections BP.................................... to 100 mL
Sterilisation. Place the solution in the final container
and pass carbon dioxide through it for at least 1minute.
Seal the container so that it is gas-tight and sterilise
by heating in an autoclave. The container must not
be opened until at least 2hours after the solution has
cooled to room temperature.
Use. To be applied undiluted for removing mucus from
the eye.

Compounding and dispensing

Label. These preparations should be labelled CAUTION:


NOT TO BE TAKEN (labelL) and should state the date of
preparation. In addition, directions should be given that
any portion of the solution not used after the seal is first
broken should be discardedfor example, CONTAINS
NO PRESERVATIVE. USE ONCE AND DISCARD ANY
RESIDUE.

Gels

Strength. Contains 0.5% of chlorhexidine gluconate


(limits 0.42 to 0.58% w/w of chlorhexidine gluconate,
C22H30Cl2N10.2C6H12O7).
Method. Mix the tragacanth with the glycerol and add
most of the purified water. Heat to boiling, cool, then
add the chlorhexidine gluconate solution. Adjust to
100g with purified water and mix thoroughly.
Use. Antiseptic lubricant.
Container. Dispense in an amber plastic or glass
container. If the gel is to be applied to broken skin or
used for surgical procedures, it should be produced as a
sterile product in single-use units.

47

Section A | General formulary

glyco-gelatin gel

menthol and pine inhalation

glyco-gelatin base

compound menthol inhalation

gelatin.................................................................... 25 g
glycerol (by weight) ................................................ 40 g
purified water, freshly boiled and cooled ................. 80 g

menthol ...................................................................1 g
pumilio pine oil* ................................................ 2.5 mL
ethanol (90% v/v) ............................................ to 50 mL

The above quantities make 100g of gel.

* Melaleuca alternifolia oil (tea-tree oil) may be substituted.

Method. Soak the gelatin for about 10minutes in 80g


of purified water in a tared dish to soften. Add the
glycerol and heat in a water bath, stirring occasionally,
until the gelatin has dissolved. Continue heating until
the product weighs 100g without adding further water.
When used as a pessary base, heat at 100C for 1hour
before incorporating the active ingredient.

Compounding and dispensing

Note. This product should not be confused with glycerol


suppositories, in which glycerol is the active ingredient.
Use. As a suppository or pessary base for the
incorporation of other drugs.

Inhalations
Inhalations are liquid preparations containing volatile
substances that, on vaporisation, are intended to be
brought into contact with the respiratory tract. They are
usually added to hot (but not boiling) water, or placed
on a pad, and the vapour inhaled. Generally used as
nasal decongestants.
Method. The following inhalations should be prepared
without the aid of heat.
Labelling. This preparation should be labelled CAUTION:
NOT TO BE TAKEN (labelL).
Container. Dispense in amber, fluted bottles; consider
using a child-resistant closure.
Storage. Store below 25C unless otherwise specified.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

Insufflations
Insufflations are powders, prepared with a small particle
size, that are intended for introduction into the ear,
nose, throat, body cavities or wounds. A device is
commonly used to administer these products; however,
the use of insufflations is limited because of the difficulty
in obtaining a uniform dose. Specialised devices (e.g.
Turbuhaler) are now often used to deliver standard doses
of finely micronised particles, ensuring uniform dose
delivery and greater stability.4
Container. Dispense in well-sealed containers.
Storage. Store below 25C unless otherwise specified.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

iodine insufflation
iodine ................................................................... 0.8 g
potassium iodide ................................................... 0.4 g
anaesthetic ether ................................................. 10 mL
lactose, in fine powder ........................................ 98.8 g
Method. Dissolve the iodine and potassium iodide in the
anaesthetic ether in a glass mortar. Add the lactose and
mix quickly. Allow ether to evaporate. Protect from heat,
or the iodine will volatilise.
Note. The preparation may be introduced into the ear
via a tube (e.g. a straw).
Caution. Ether is extremely flammable.
Use. Antiseptic.

benzoin and menthol inhalation


menthol ...................................................................1 g
compound benzoin tincture*............................ to 50 mL
* Compound benzoin tincture is also known as Friars balsam.3

Method. Dissolve the menthol in a small volume of


compound benzoin tincture. Adjust to 50mL with
compound benzoin tincture and mix thoroughly.

menthol inhalation
menthol ...................................................................1 g
ethanol (90% v/v) ............................................ to 50 mL

48

Irrigations
Irrigations are sterile aqueous solutions that are used in
large volume for irrigation of body surfaces and wounds
for example, during surgical procedures. They are intended
for one use only.4 Irrigations must be sterile and should be
prepared in facilities that meet Australian standards for the
preparation of sterile products. The following preparations
are intended for use as bladder irrigations.
Sterilisation. The procedure recommended for
sterilisation is stated in each formula. The methods
stated, such as sterilise by heating in an autoclave
or sterilise by filtration, are those specified in the British
Pharmacopoeia.3

Section A | General formulary

Label. These preparations should be labelled CAUTION:


NOT TO BE TAKEN (labelL) and should state the date of
preparation. In addition, directions should be given that
any portion of the solution not used after the seal is first
broken should be discardedfor example, CONTAINS NO
PRESERVATIVE. USE ONCE AND DISCARD ANY RESIDUE.
Container. Dispense in well-sealed containers; a seal
should be used.
Storage. Store below 25C unless otherwise specified.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

acetic acid irrigation


acetic acid (33% w/w)............................................ 6 mL
water for injections BP ................................... to 100 mL

Expiry. The expiry date is 28days from the date of


preparation unless otherwise specified.

codeine linctus
Linct. Codein
codeine phosphate ............................................ 500 mg
purified water...................................................... 10 mL
glycerol................................................................ 20 mL
methyl hydroxybenzoate solution............................ 1 mL
syrup*............................................................ to 100 mL
* If commercially available syrup containing a hydroxybenzoate is used,
the amount of methyl hydroxybenzoate added should be adjusted.

Strength. Contains 0.5% of codeine phosphate (limits


0.45 to 0.55% w/v of codeine phosphate, C18H21NO3.
H3PO4.H2O).
Note. Protect from light.

Method. Sterilise by heating in an autoclave.3

Use. Antitussive.

Use. Antibacterial.

Adult dose. 5mL (=25mg) to be taken three or four


times a day, when required.7

chlorhexidine irrigation
chlorhexidine gluconate solution BP*................... 0.1 mL
water for injections BP.................................... to 100 mL
* Chlorhexidine gluconate solution BP is an aqueous solution
containing 19 to 21% w/v of chlorhexidine gluconate.

Strength. Contains 0.02% w/v (1 in 5,000) of


chlorhexidine gluconate, C22H30Cl2N10.2C6H12O7.
Method. Sterilise by heating in an autoclave.3
Note. Protect from light.3
Use. Antibacterial.
Container. Dispense in an amber plastic or glass container.

sodium citrate irrigation


sodium citrate...........................................................4 g
water for injections BP ................................... to 100 mL
Strength. Contains 4% of sodium citrate (limits 3.7 to
4.3% w/v of sodium citrate, C6H5Na3O7.2H2O).

Label. This preparation should be labelled THIS MEDICINE


MAY CAUSE DROWSINESS AND MAY INCREASE THE
EFFECTS OF ALCOHOL. IF AFFECTED, DO NOT DRIVE A
MOTOR VEHICLE OR OPERATE MACHINERY (label1).
Container. Dispense in an amber plastic or glass container.

Compounding and dispensing

Strength. Contains about 2% w/v of acetic acid (limits


1.88 to 2.15% w/v of acetic acid, C2H4O2).

Storage. Store below 25C unless otherwise specified.

simple linctus
citric acid monohydrate.......................................... 2.5 g
concentrated anise water ....................................... 1 mL
methyl hydroxybenzoate solution............................ 1 mL
syrup*............................................................ to 100 mL
* If commercially available syrup containing a hydroxybenzoate is used,
the amount of methyl hydroxybenzoate added should be adjusted.

Use. Linctus base and mild antitussive.8


Dose. 5mL to be taken three or four times a day, when
required.8

Liniments

Method. Sterilise by heating in an autoclave.


Use. Alkalinising irrigation.

Linctuses
Linctuses are viscous liquid preparations of active
ingredients that are intended for oral administration
in doses of small volume. They are designed to be
swallowed slowly without the addition of water, usually
for the relief of cough, and have demulcent, expectorant
or sedative properties.
Container. Dispense in well-sealed containers.

Liniments are alcoholic, oil or soap-based solutions or


emulsions containing active ingredients that are intended
for application to the skin with friction. They may
contain substances possessing analgesic, rubefacient,
soothing or stimulating properties. They should be
applied only to intact skin.1,3,4
Label. These preparations should be labelled FOR
EXTERNAL USE ONLY (labelK).
Container. Dispense in amber, fluted poison bottles;
consider using a child-resistant closure.
Storage. Store below 25C unless otherwise specified.

49

Section A | General formulary

Expiry. The expiry date is 28days from the date of


preparation unless otherwise specified.

aluminium acetate lotion aqueous


Burows lotion

methyl salicylate liniment


Lin. Methyl. Salicyl.
methyl salicylate................................................... 25 mL
arachis oil ...................................................... to 100 mL
Strength. Contains 25% of methyl salicylate (limits 23.0
to 26.5% v/v of methyl salicylate, C8H8O3).
Method. Prepare by dissolution into final calibrated
bottle; avoid contact with water.
Use. Counter-irritant, analgesic.

Compounding and dispensing

Label. This preparation should be labelled CONTAINS


PEANUT OIL (labelN).

methyl salicylate compound


liniment
Lin. Methyl. Salicyl. Co.
menthol....................................................................4 g
eucalyptus oil....................................................... 10 mL
methyl salicylate................................................... 25 mL
arachis oil ...................................................... to 100 mL
Strength. Contains 25% of methyl salicylate (limits 23.0
to 26.5% v/v of methyl salicylate, C8H8O3).
Method. Prepare by dissolution into final calibrated
bottle; avoid contact with water. If crushing menthol
crystals, use a glass mortar.
Use. Counter-irritant, analgesic.
Label. This preparation should be labelled CONTAINS
PEANUT OIL (labelN).

Lotions
Lotions are liquid or semi-liquid preparations containing
active ingredients that are intended for application to
the skin without friction. They may contain aqueous,
ethanolic or emulsified vehicles possessing antiseptic,
analgesic, soothing or protective properties. Lotions
tend to produce a cooling effect from the evaporation
of water from the skin; they may also dry out to form a
residual film on the skin. They should be applied only to
intact skin.1,3,4
Label. These preparations should be labelled FOR
EXTERNAL USE ONLY (labelK) and SHAKE WELL BEFORE
EACH USE (labelJ), if applicable.
Container. Dispense in amber, fluted poison bottles;
consider using a child-resistant closure.
Storage. Store below 25C unless otherwise specified.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

50

aluminium acetate solution*................................... 5 mL


purified water, freshly boiled and cooled ........ to 100 mL
* See p 59 for formula of aluminium acetate solution.

Strength. Contains 0.7% of aluminium acetate (limits


0.07 to 0.1% w/v of aluminium acetate, calculated as
aluminium, Al).
Note. The lotion should be freshly prepared and used
within 7days, taking care to limit the possibility of
microbial contamination.
When aluminium acetate lotion is prescribed, aqueous
aluminium acetate lotion should be dispensed.
Use. Wet dressings in acute weeping dermatoses.

calamine lotion
Lot. Calam.
calamine................................................................. 15 g
zinc oxide .................................................................5 g
bentonite, sterilised...................................................3 g
sodium citrate........................................................ 0.5 g
liquefied phenol.................................................. 0.5 mL
glycerol.................................................................. 5 mL
purified water, freshly boiled and cooled......... to 100 mL
Method. Sterilise the bentonite by heating at not less
than 160C for at least 2hours. Dissolve the sodium
citrate in about 70mL of purified water. Triturate the
zinc oxide with the glycerol, then add the calamine,
bentonite and sodium citrate solution. Triturate until
smooth, then add the liquefied phenol, adjust to 100mL
with purified water, and mix. Usually prepared in a
mortar using the method of doubling.
Caution. Liquefied phenol is very caustic.
Use. Soothing and protective agent, antipruritic.4

calamine lotion oily


Lot. Calam. Oleos.
calamine ..................................................................5 g
wool fat ...................................................................1 g
arachis oil............................................................. 50 mL
oleic acid............................................................. 0.5 mL
calcium hydroxide solution* ........................... to 100 mL
* See p 59 for formula of calcium hydroxide solution.

Strength. Contains 5% of calamine (limits 2.52 to


3.35% w/w, calculated as zinc, Zn).
Method. Melt the wool fat, arachis oil and oleic acid
together, then triturate the calamine with this liquid.
Incorporate 47mL of calcium hydroxide solution into the
oil phase. Usually prepared in a mortar using the method
of doubling.
Use. Antipruritic.
Label. This preparation should be labelled CONTAINS
PEANUT OIL (labelN).

Section A | General formulary

cetomacrogol lotion
cleansing lotion
cetomacrogol emulsifying wax*.................................3 g
liquid paraffin ...................................................... 10 mL
glycerol ............................................................... 10 mL
chlorhexidine gluconate solution BP#.................... 0.1 mL
purified water, freshly boiled and cooled......... to 100 mL
* See p 45 for formula of cetomacrogol emulsifying wax.
# Chlorhexidine gluconate solution BP is an aqueous solution
containing 19 to 21% w/v of chlorhexidine gluconate.

Use. Cleansing lotion.

formaldehyde lotion

Mixtures are liquid preparations containing active


ingredients that are dissolved or suspended in
an essentially aqueous vehicle intended for oral
administration.
Mixtures can also be prepared by modifying an oral
dose form intended for adult use into a suitable form.
Alsorefer to Childrens Formulary, page 62.
Mixtures are not formulated to keep for long periods.
In some cases, it is essential that the mixture be
freshlyprepared.13
The particles of active ingredients should be small,
uniformly sized and evenly distributed within the
suspension to facilitate accurate and reproducible
dosing. Insoluble and indiffusible substances may need
to be suspended by using various colloidal substances
of high viscosity so that, when the mixture is shaken,
the insoluble materials remain in suspension long
enough for a dose to be measured.13
Usual proportions of suspending agents are:

formalin lotion

compound tragacanth powder2 to 3%

formaldehyde solution BP*..................................... 3 mL


purified water, freshly boiled and cooled......... to 100 mL

tragacanth mucilage10 to 20%

acacia mucilage25 to 50%

methylcellulose mucilage50%

carboxymethylcellulose mucilage20 to 40%

sodium alginate0.5 to 2%.

* Formaldehyde solution BP contains 34.5 to 38%w/w of


formaldehyde, with methanol as a stabiliser.3

Strength. Contains 1% of formaldehyde (limits 0.95 to


1.25% w/v of formaldehyde, CH2O).
Note. This lotion should be freshly prepared.
Caution. Handle formaldehyde with careuse
appropriate precautions.
Use. Treatment of plantar warts, especially in patients
with associated hyperhidrosis. Sensitisation may occur
with use.

salicylic acid and coal tar lotion


salicylic acid .............................................................2 g
coal tar solution..................................................... 5 mL
castor oil................................................................ 1 mL
spike lavender oil ................................................ 0.1 mL
ethanol (90% v/v) .......................................... to 100 mL
Method. Dissolution.
Note. Must not be applied to inflamed or broken skin;
contact with eyes and mucous membranes must be
avoided.7
Use. Treatment of psoriasis of the scalp.

Compounding and dispensing

Method. Melt the cetomacrogol emulsifying wax


(seeCetomacrogol cream aqueous, p. 41) in the
liquid paraffin and mix with 50mL of purified water
heated to approximately 70C. Stir until a semi-solid
cream forms. Mix the chlorhexidine gluconate solution
with the glycerol and 25mL of purified water, then
incorporate this in portions into the cream. Adjust to
100mL and mix.

Mixtures

Label. If the active ingredients are suspended in the


mixture, the preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ) to ensure even distribution of
the contents before the dose is given.
Container. Dispense in well-sealed containers.
Storage. Store below 25C unless otherwise specified.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

ferrous sulfate mixture


ferrous sulfate...........................................................3 g
ascorbic acid ..................................................... 100 mg
orange syrup.......................................................... 5 mL
benzoic acid solution ............................................. 2 mL
purified water, freshly boiled and cooled......... to 100 mL
Strength. Contains 3% of ferrous sulfate (limits 2.7 to
3.3% w/v of ferrous sulfate, FeSO4.7H2O).
Method. Dissolve the ferrous sulfate in 50mL of purified
water. Add the ascorbic acid, orange syrup and benzoic
acid solution, and mix until dissolved. Adjust to 100mL
with purified water and mix thoroughly.
Note. Should be recently prepared. Protect from light.
Use. Iron replacement therapy.

51

Section A | General formulary

Dose. 10mL (dose equals 300mg of ferrous sulfate)


well diluted with water. May be taken up to three times
daily via a straw to reduce staining of the teeth.9
Container. Dispense in an amber plastic or glass container.

gentian alkaline mixture


Mist. Gent. Alk.
concentrated compound gentian infusion.............. 10 mL
sodium bicarbonate...................................................5 g
compound hydroxybenzoate solution...................... 1 mL
purified water, freshly boiled and cooled......... to 100 mL
Strength. Contains 5% of sodium bicarbonate (limits
4.7 to 5.3% w/v of sodium bicarbonate, NaHCO3).

senega and ammonia mixture


Mist. Seneg. et Ammon.
ammonium bicarbonate ......................................... 2.5 g
compound camphor spirit .................................... 10 mL
liquorice liquid extract ........................................... 5 mL
concentrated senega infusion................................. 5 mL
compound hydroxybenzoate solution ..................... 1 mL
purified water, freshly boiled and cooled......... to 100 mL
Use. Expectorant, decongestant.9
Adult dose. 1020mL up to four times daily.9

sodium citrate mixture


Mist. Sod. Cit.

Note. Should be recently prepared.

Compounding and dispensing

Use. Treatment of loss of appetite.9,10


Adult dose. 10mL three times daily in water before
meals.9,10

potassium citrate mixture


Mist. Pot. Cit.
potassium citrate..................................................... 20 g
citric acid monohydrate.............................................4 g
lemon syrup......................................................... 10 mL
methyl hydroxybenzoate solution............................ 1 mL
purified water, freshly boiled and cooled......... to 100 mL
Strength. Contains 20% of potassium citrate (limits
18.5 to 21.5% w/v of potassium citrate, C6H5K3O7.H2O).
Note. Each 10mL contains 2g of potassium citrate and
approximately 19mmol of potassium.9
Use. Urinary alkaliniser.9
Adult dose. 1020mL well diluted with water up to
three times daily.9

potassium citrate and sodium


bicarbonate mixture
potassium citrate..................................................... 10 g
sodium bicarbonate................................................ 7.5 g
orange syrup........................................................ 10 mL
methyl hydroxybenzoate solution............................ 1 mL
purified water, freshly boiled and cooled......... to 100 mL
Strength. Contains 10% of potassium citrate (limits 9.2
to 10.8% w/v of potassium citrate, C6H5K3O7.H2O).
Note. Each 10mL contains approximately 9mmol of
both potassium and sodium.
Use. Urinary alkaliniser.10
Adult dose. 1020mL well diluted with water up to
three times daily.9

52

sodium citrate......................................................... 20 g
citric acid monohydrate.............................................4 g
lemon syrup......................................................... 10 mL
methyl hydroxybenzoate solution............................ 1 mL
purified water, freshly boiled and cooled......... to 100 mL
Strength. Contains 20% of sodium citrate (limits 18.5
to 21.5% w/v of sodium citrate, C6H5Na3O7.2H2O).
Use. Urinary alkaliniser.9,10
Dose. 1020mL well diluted with water up to three
times daily.9

Mucilages
Mucilages are thick, viscous aqueous solutions that are
most commonly produced by dispersing a gum in water.
They may be used for suspending insoluble substances
in mixtures. Mucilages are prone to decomposition,
and show significant reduction in viscosity on storage;
they should not be made in quantities greater than the
formula requires.2,4
Container. Dispense in a well-sealed, wide-mouthed
container.
Storage. Store at 28C unless otherwise specified, to
prevent decomposition.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

carboxymethylcellulose mucilage
carboxymethylcellulose sodium............................... 1.5 g
ethanol (90% v/v)................................................... 5 mL
compound hydroxybenzoate solution ..................... 1 mL
purified water, freshly boiled and cooled......... to 100 mL
Method. Mix the carboxymethylcellulose sodium with the
ethanol in a dry calibrated bottle. As quickly as possible,
add most of the purified water and shake vigorously. Add
the compound hydroxybenzoate solution, shake, then
adjust to 100mL with purified water.

Section A | General formulary

Note. Carboxymethylcellulose is commonly found


as the sodium salt, carmellose sodium. It is used at
concentrations ranging from 0.25 to 1% in suspension,
and is most viscous within the pH range 410.1,11
Use. Anionic mucilage.1

methylcellulose mucilage
Mucil. Methylcellulos.
methylcellulose (4001,500 cps) ................................2 g
compound hydroxybenzoate solution ..................... 1 mL
purified water, freshly boiled and cooled ........ to 100 mL
Method. Add the methylcellulose to 20mL of purified
water previously heated to about 95C. When the
powder is moistened, chill quickly. Add the compound
hydroxybenzoate solution and adjust to 100mL with
cold purified water. Mix thoroughly.

tragacanth mucilage
tragacanth, finely powdered ................................ 1.25 g
ethanol (90% v/v)................................................... 2 mL
benzoic acid solution.............................................. 2 mL
compound hydroxybenzoate solution ..................... 1 mL
purified water, freshly boiled and cooled ........ to 100 mL
Method. Mix the tragacanth with the ethanol in a dry
calibrated bottle. As quickly as possible, add most of the
purified water and shake vigorously. Add the benzoic acid
solution and the compound hydroxybenzoate solution,
shake, then adjust to 100mL with purified water.
Note. There is often confusion between tragacanth
powder and tragacanth powder compound. The latter is
not appropriate for this formula.

Nasal instillations
Nasal instillations are liquid preparations (solutions,
emulsions or suspensions) of active ingredients that are
intended for instillation into the nasal passages. They
are administered into the nostrils as drops or sprays,
and may be designed to cause local or systemic effects.
Viscosity, tonicity and pH of nasal instillations should
approximate those of nasal secretions, to avoid adversely
affecting ciliary action.14
Oily solutions should not be used; the oil retards the
ciliary action of the nasal mucosa, and drops of oil may
enter the trachea and cause aspiration pneumonitis.1

Container. Dispense in bottles with a dropper or in


suitable plastic containers. Nasal sprays should be
dispensed in containers that allow the delivery of a
reproducible dose of the preparation in a fine spray.
Storage. Store below 25C unless otherwise specified.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

ephedrine instillation
ephedrine nasal drops; ephedrine nasal spray
ephedrine hydrochloride............................................1 g
chlorbutol ............................................................. 0.5 g
sodium chloride ..................................................... 0.5 g
propylene glycol..................................................... 5 mL
purified water, freshly boiled and cooled......... to 100 mL
Strength. Contains 1% of ephedrine hydrochloride
(limits 0.9 to 1.1% w/v of ephedrine hydrochloride,
C10H15NO.HCl).
Note. If 0.5% of ephedrine is prescribed, the amount of
sodium chloride does not need adjustment. Continual
use may lead to rebound congestion. Protect from light.
Use. Decongestant.7
Container. Dispense in an amber plastic or glass container.

Compounding and dispensing

Note. The viscosity of methylcellulose solutions depends


on the grade of methylcellulose used. Various grades
are available, with the apparent viscosity of a 2% w/w
solution at 20C indicated by an appended number.
Large amounts of electrolytes can cause precipitation of
methylcellulose, leading to instability.1,11

Label. These preparations should be labelled CAUTION:


NOT TO BE TAKEN (labelL) and SHAKE WELL BEFORE
EACH USE (labelJ), if applicable.

phenylephrine instillation
phenylephrine nasal drops; phenylephrine nasal spray
phenylephrine hydrochloride ................................ 0.25 g
sodium metabisulfite ............................................. 0.1 g
sodium chloride ..................................................... 0.6 g
chlorbutol ............................................................. 0.5 g
propylene glycol..................................................... 5 mL
purified water, freshly boiled and cooled......... to 100 mL
Note. Continued use can lead to rebound congestion.
Protect from light.
Use. Decongestant.7
Container. Dispense in a small, well-filled, airtight,
amber plastic or glass container.

alkaline nasal douche


powder for saline instillation
sodium bicarbonate................................................. 50 g
sodium chloride....................................................... 50 g
The above quantities make 100g of douche.
Use. Nasal douche.
Dose. Dissolve 2g in 100mL of warm water for use as a
nasal douche.

53

Section A | General formulary

Ointments
Ointments are semi-solid preparations, usually solutions
or dispersions, of active ingredients in a suitable nonaqueous base that are intended for application to the
skin or certain mucous membranes. They have emollient
and protective properties.13
Label. These preparations should be labelled FOR
EXTERNAL USE ONLY (labelK). If the product is for nasal
or otic use, the preparation should be labelled CAUTION:
NOT TO BE TAKEN (labelL).

Compounding and dispensing

Container. Dispense in well-sealed containers.


Collapsible tubes of metal or suitable plastics should be
used whenever possible.

than 1% may be applied for very short exposure periods


of 2030minutes, before being removed from the skin.
This ointment stains skin, fair hair and clothing. Contact
with the eyes must be avoided.
Use. Treatment of psoriasis.3
Container. Dispense in an amber plastic or glass
container, since the product darkens on exposure to light.

dithranol and salicylic acid ointment


dithranol, in fine powder........................................ 0.1
salicylic acid........................................................... 0.5
liquid paraffin.......................................................... 20
emulsifying ointment*.......................................... 79.4
* See below for formula of emulsifying ointment.

Storage. Store below 25C unless otherwise specified.

The above quantities make 100g of ointment.

Expiry. The expiry date is 28days from the date of


preparation unless otherwise specified.

Method. Triturate the dithranol and the salicylic acid


separately with small amounts of liquid paraffin, mix
together, and gradually incorporate the emulsifying
ointment using the method of doubling. Avoid the use
of metal spatulas.

benzoic acid ointment compound


Ung. Acid Benz. Co.; Whitfields ointment
benzoic acid, in fine powder......................................6 g
salicylic acid, in fine powder ......................................3 g
emulsifying ointment*............................................. 91 g
* See p 54 for formula of emulsifying ointment.

The above quantities make 100g of ointment.


Strength. Contains 6% of benzoic acid (limits 5.7 to
6.3% w/w of benzoic acid, C7H6O2) and 3% of salicylic
acid (limits 2.7 to 3.3% w/w of salicylic acid, C7H6O3).
Method. Triturate the benzoic acid and the salicylic
acid with a small amount of emulsifying ointment until
smooth. Gradually incorporate the remainder of the
emulsifying ointment using the method of doubling.
Note. Must not be applied to inflamed or broken skin;
contact with eyes and mucous membranes must be
avoided.7
Use. Treatment of chronic dry-scaling tinea.
Dose. Apply to affected areas up to three times a day.9
Label. This preparation should be labelled CONTINUE
FOR 14 DAYS AFTER SYMPTOMS CEASE (labelE).

Note. The concentration of dithranol may be cautiously


increased to a maximum of 0.5%. Concentrations higher
than 1% may be applied for very short exposure periods
of 2030minutes, before being removed from the skin.
This ointment is intended for application to the scalp
and is readily removed with warm water. The ointment
stains skin, fair hair and clothing. Must not be applied to
inflamed or broken skin; contact with eyes and mucous
membranes must be avoided.7
Use. Treatment of psoriasis.
Container. Dispense in an amber plastic or glass
container, since the product darkens on exposure to light.

emulsifying ointment
emulsifying wax*..................................................... 30 g
white soft paraffin................................................... 50 g
liquid paraffin.......................................................... 20 g
* See p 45 for formula of emulsifying wax.

The above quantities make 100g of ointment.


Method. Melt together and stir until cool.

dithranol ointment

Note. This formula complies with the requirements of


the British Pharmacopoeia.3

dithranol in fine powder......................................... 0.1 g


white soft paraffin ............................................... 99.9 g

Use. Anionic base; capable of absorbing considerable


amounts of water or aqueous fluids.

The above quantities make 100g of ointment.


Method. Triturate the dithranol with a small amount
of the paraffin until smooth. Gradually incorporate the
remainder of the white soft paraffin using the method of
doubling. Avoid the use of metal spatulas.3
Note. The concentration of dithranol may be cautiously
increased to a maximum of 1%. Concentrations greater

54

g
g
g
g

Section A | General formulary

lignocaine and adrenaline ointment

salicylic acid and coal tar ointment

lignocaine hydrochloride ...........................................1 g


purified water, freshly boiled and cooled................. 4 mL
adrenaline solution BP*........................................ 10 mL
wool fat.................................................................. 15 g
liquid paraffin.......................................................... 20 g
white soft paraffin................................................... 50 g

salicylic acid..............................................................3 g
coal tar solution .................................................... 6 mL
white soft paraffin................................................... 50 g
emulsifying ointment*............................................. 41 g

* Adrenaline solution BP contains 0.1% w/v adrenaline as adrenaline


acid tartrate.3

The above quantities make 100g of ointment.


Strength. Contains 1% of lignocaine hydrochloride
(limits 0.9 to 1.1% w/w lignocaine hydrochloride,
C14H22N2O.HCl.H2O).

Note. Protect from light.


Use. Topical anaesthetic.
Container. Dispense in an amber plastic or glass container.

macrogol ointment
polyethylene glycol ointment
macrogol 4000 ....................................................... 35 g
macrogol 400 ......................................................... 65 g
Method. Melt the macrogols together at 60C and cool
to room temperature.
Note. The proportion of the macrogols may be varied
to change the consistency to suit the prevailing
temperature.
Use. An unreactive, non-greasy water-miscible ointment
base that does not ionise in the presence of water and is
therefore compatible with both anionic and cationic drugs.

salicylic acid ointment


salicylic acid..............................................................2 g
wool alcohols ointment*.......................................... 98 g
* See p 55 for formula of wool alcohols ointment.

Strength. Contains 2% of salicylic acid (limits 1.9 to


2.1% w/w of salicylic acid, C7H6O3).
Method. Triturate the salicylic acid with a small amount
of the wool alcohols ointment until smooth. Gradually
incorporate the remainder of the base using the method
of doubling.
Note. Must not be applied to inflamed or broken skin;
contact with eyes and mucous membranes must be
avoided.7

The above quantities make 100g of ointment.


Method. Melt the white soft paraffin and emulsifying
ointment and stir until cold. Triturate the salicylic acid
and coal tar solution with a small amount of the base
until smooth. Gradually incorporate the remainder of the
base using the method of doubling.
Note. Must not be applied to inflamed or broken skin;
contact with eyes and mucous membranes must be
avoided.7
Use. Treatment of psoriasis.

simple ointment white


wool fat....................................................................5
hard paraffin ............................................................5
cetostearyl alcohol.....................................................5
white soft paraffin................................................... 85

g
g
g
g

Method. Melt together (may be warmed if necessary),


and stir until cold.
Note. When simple ointment is used in a white
ointment, it should be prepared with white soft paraffin;
when used in a coloured ointment, it may be prepared
with yellow soft paraffin. This formula complies with the
requirements of the British Pharmacopoeia.3

Compounding and dispensing

Method. Melt the wool fat and soft paraffin in


the liquid paraffin using gentle heat. Stir until just
solidified. Dissolve the lignocaine hydrochloride in the
purified water and mix with the adrenaline solution.
Incorporate the aqueous solution in the oil phase and
mix thoroughly.

* See p 54 for formula of emulsifying ointment.

Use. Greasy base.

wool alcohols ointment


wool alcohols ...........................................................6
hard paraffin .......................................................... 17
white soft paraffin or yellow soft paraffin................. 17
liquid paraffin.......................................................... 60

g
g
g
g

Method. Melt together at a temperature not exceeding


65C and stir until cold.
Note. In preparing wool alcohols ointment, the
proportions of hard paraffin, soft paraffin and liquid
paraffin may be varied to produce wool alcohols
ointment with suitable properties. When wool alcohols
ointment is used in a white ointment, it should be
prepared with white soft paraffin; when used in a
coloured ointment, it may be prepared with yellow soft
paraffin.3
Use. Greasy base capable of absorbing considerable
amounts of water or aqueous fluids.

Use. Keratolytic.9
Dose. Apply to affected areas up to three times a day.9
55

Section A | General formulary

be advised to keep bottles tightly closed to minimise


evaporation of the contents.

zinc and castor oil ointment


zinc oxide .............................................................. 7.5
castor oil................................................................. 50
cetostearyl alcohol.....................................................2
white beeswax........................................................ 10
arachis oil ............................................................ 30.5

g
g
g
g
g

The above quantities make 100g of ointment.

Method. Triturate the zinc oxide with a small amount


of the castor oil until smooth. Add the mixture to the
remainder of the ingredients, which have previously been
melted together, and stir until cold.

Compounding and dispensing

Expiry. The expiry date is 28days from the date of


preparation unless otherwise specified.

cetrimide and chlorhexidine paint


cetrimide................................................................ 0.5 g
chlorhexidine gluconate solution BP* .................. 2.5 mL
ethanol (90% v/v) ................................................ 75 mL
purified water, freshly boiled and cooled......... to 100 mL

Use. Protective, emollient.


Label. This preparation should be labelled CONTAINS
PEANUT OIL (labelN).

* Chlorhexidine gluconate solution BP is an aqueous solution


containing 19 to 21% w/v of chlorhexidine gluconate.

zinc and coal tar ointment


Ung. Zinc et Pic.
g
g
g
g

Strength. Contains 20% of zinc oxide (limits 18.5 to


21.0% w/w of zinc oxide, ZnO).

Method. Dissolve the cetrimide in the ethanol. Add the


chlorhexidine gluconate solution and adjust to 100mL
with purified water.
Note. Protect from light.
Use. Antibacterial skin cleanser.
Container. Dispense in an amber plastic or glass container.

coal tar paint

Method. Mix the coal tar with the castor oil. Triturate
the zinc oxide and a small amount of the paraffin.
Mix the two together and gradually incorporate the
remainder of the base.

coal tar................................................................... 10 g
acetone.......................................................... to 100 mL

Use. Antipruritic, protective.

Method. Dissolve and filter if necessary.

zinc oxide ointment


zinc ointment
zinc oxide................................................................ 15 g
simple ointment white*........................................... 85 g
* See p 55 for formula of simple ointment white.

Strength. Contains 15% of zinc oxide (limits 14 to 16%


w/w of zinc oxide, ZnO).
Method. Triturate the zinc oxide with a small amount
of the simple ointment white until smooth. Gradually
incorporate the remainder of the base.
Use. Protective, sunscreen agent.

Paints
Paints are liquid preparations, solutions or dispersions
of active ingredients that are intended for application in
limited amounts to the skin or mucous surfaces. Since
paints often contain volatile solvents, patients should

56

Container. Dispense in amber, fluted, airtight bottles;


consider using a child-resistant closure.
Storage. Store below 25C unless otherwise specified.

Strength. Contains 7.5% of zinc oxide (limits 7.0 to


8.0% w/w of zinc oxide, ZnO).

zinc oxide................................................................ 20
coal tar.....................................................................5
castor oil ..................................................................3
white soft paraffin .................................................. 72

Label. These preparations should be labelled FOR


EXTERNAL USE ONLY (labelK) if they are to be applied to
skin, or CAUTION: NOT TO BE TAKEN (labelL) if they are
to be applied to mucous membranes.

Caution. This preparation is flammable; keep it away


from naked flame.
Use. For thick, scaling plaques of psoriasis or chronic
dermatitis.

formaldehyde and salicylic


acid paint
formaldehyde solution BP*................................... 10 mL
salicylic acid ........................................................... 10 g
acetone................................................................ 40 mL
ethanol (90% v/v) .......................................... to 100 mL
* Formaldehyde solution BP contains 34.5 to 38.0%w/w of
formaldehyde with methyl alcohol as a stabiliser.

Method. Dissolve the salicylic acid in 40mL of ethanol,


add formaldehyde solution and acetone, and adjust to
100mL with ethanol.
Note. Must not be applied to inflamed or broken skin;
contact with eyes and mucous membranes must be
avoided.7
Use. Treatment of warts.

Section A | General formulary

lactic acid and salicylic acid paint


lactic acid............................................................. 20 mL
salicylic acid ........................................................... 20 g
flexible collodion............................................ to 100 mL
Note. This paint should not be applied to the face. Must
not be applied to inflamed or broken skin; contact with
eyes and mucous membranes must be avoided.7
Use. Treatment of warts.

salicylic acid paint


salicylic acid collodion; corn paint
salicylic acid ........................................................... 10 g
flexible collodion............................................ to 100 mL

Note. Must not be applied to inflamed or broken skin;


contact with eyes and mucous membranes must be
avoided.7
Use. Treatment of warts.

cocaine hydrochloride.............................................. 10
adrenaline acid tartrate......................................... 0.18
chlorbutol ................................................................1
liquid paraffin.......................................................... 45
white soft paraffin................................................... 44

g
g
g
g
g

The above quantities make 100g of paste.


Method. Melt the white soft paraffin in the liquid
paraffin and dissolve the chlorbutol in this base. Triturate
the adrenaline acid tartrate and cocaine hydrochloride
with the base until smooth.
Note. Protect from light.
Use. Nasal anaesthetic.
Container. Dispense in an amber plastic or glass container.

cocaine and adrenaline paste25%


cocaine hydrochloride.............................................. 25
adrenaline acid tartrate ........................................ 0.18
chlorbutol.................................................................1
liquid paraffin.......................................................... 45
white soft paraffin................................................... 29

g
g
g
g
g

The above quantities make 100g of paste.

Pastes
Pastes are semi-solid preparations with protective
properties that may also be used for delivery of active
ingredients intended for application to the skin or certain
mucous membranes. They consist of finely powdered
active ingredients combined with white soft paraffin
or liquid paraffin, or with a non-greasy base consisting
of glycerol, mucilages, soaps, emulsifying waxes and
ointments. Pastes often contain a large proportion of
powdered ingredients, making them stiff and difficult to
spread, which results in localised delivery of the active
ingredients.13
Label. These preparations should be labelled FOR
EXTERNAL USE ONLY (labelK) if they are to be applied to
skin, or CAUTION: NOT TO BE TAKEN (labelL) if they are
to be applied to mucous membranes.
Container. Dispense in well-sealed containers.
Storage. Store below 25C unless otherwise specified.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

coal tar and zinc paste


coal tar paste
coal tar ....................................................................1 g
castor oil...................................................................1 g
compound zinc paste............................................... 98 g
Method. Triturate the coal tar with the castor oil, and
mix with the compound zinc paste.
Use. Treatment of psoriasis.7

Method. Melt the white soft paraffin in the liquid


paraffin and dissolve the chlorbutol in this base. Triturate
the adrenaline acid tartrate and cocaine hydrochloride
with the base until smooth.

Compounding and dispensing

Strength. Contains 10% of salicylic acid (limits 9 to


11% w/w of salicylic acid, C7H6O3).

cocaine and adrenaline paste10%

Use. Nasal anaesthetic.


Container. Dispense in an amber plastic or glass container.

dithranol paste
dithranol and zinc paste
dithranol................................................................ 0.1 g
zinc and salicylic acid paste* ................................ 99.9 g
* See p 58 for formula of zinc and salicylic acid paste.

The above quantities make 100g of paste.


Method. Triturate the dithranol with a small amount
of the paste until the consistency is smooth and even.
Gradually incorporate the remainder of the zinc and
salicylic acid paste using the method of doubling.
Note. Avoid the use of metal spatulas. The
concentration of dithranol may be cautiously increased
to a maximum of 2%. The paste can be removed from
the skin using liquid paraffin.
This paste stains skin, fair hair and clothing. Must not
be applied to inflamed or broken skin; contact with eyes
and mucous membranes must be avoided.7
Use. Treatment of psoriasis.
Container. Store and supply in an opaque container,
since the preparation discolours on exposure to light.
Expiry. The expiry date is 6months from the date of
preparation unless otherwise specified.
57

Section A | General formulary

trichloracetic acid paste


Uptons paste
trichloracetic acid ................................................... 10 g
salicylic acid............................................................ 60 g
glycerol*................................................................. 20 g
* Or sufficient quantity to make a stiff paste.

The above quantities make approximately 100g of paste.


Method. Triturate the trichloroacetic acid and salicylic
acid with about half the glycerol until smooth. Gradually
incorporate the remainder of the glycerol, or sufficient
quantity to make a stiff paste.
Note. Must not be applied to inflamed or broken
skin; contact with eyes and mucous membranes must
be avoided.7

Compounding and dispensing

Use. Caustic.

zinc paste
zinc paste compound
zinc oxide ............................................................... 25 g
starch...................................................................... 25 g
white soft paraffin................................................... 50 g
Strength. Contains 25% of zinc oxide (limits 23.5 to
26.5% w/w of zinc oxide, ZnO).
Method. Triturate the zinc oxide with the starch and add
to the melted white soft paraffin. Stir until cool.
Use. Protective.

zinc and salicylic acid paste


Lassars paste
salicylic acid..............................................................2 g
liquid paraffin............................................................2 g
zinc paste* ............................................................. 96 g
* See p 58 for formula of zinc paste.

The above quantities make approximately 100g of paste.


Strength. Contains 2% of salicylic acid (limits 1.9 to
2.1% w/w of salicylic acid, C7H6O3) and 24% of zinc
oxide (limits 22.5 to 25.5% w/w of zinc oxide, ZnO).
Method. Triturate the salicylic acid with liquid paraffin
until smooth, and gradually incorporate the zinc paste.
Note. Must not be applied to inflamed or broken skin;
contact with eyes and mucous membranes must be
avoided.7
Use. Protective, mild astringent.

Powders
Powders are usually mixtures of two or more
powdered active ingredients that are intended for
oral administration. The active ingredients are usually
non-potent, and accurate measurement of the dose
by the patient is not critical. However, if potent active
ingredients are prescribed undiluted, they should be
supplied, suitably wrapped, as single doses.
Container. If any of the constituents are deliquescent
or volatile, the powder should be stored and supplied in
airtight containers. When supplied as single doses, the
powder should be double-wrapped, the inner wrapper
being waxed paper.
Some powders are used as pharmaceutical adjuncts.

tragacanth powder compound


tragacanth, finely powdered ................................... 15
acacia, finely powdered........................................... 20
starch, finely powdered ........................................... 20
sucrose, finely powdered......................................... 45

g
g
g
g

Use. As a suspending agent for preparations intended


for internal use at concentrations of 23%.

Shampoos
Shampoos are usually liquid preparations that are
intended for application to the scalp and subsequent
washing away with water. They may be emulsions,
suspensions or solutions and normally contain surfaceactive agents. When rubbed into the scalp, they usually
form a foam consistency.
Label. These preparations should be labelled FOR
EXTERNAL USE ONLY (labelK).
Container. Dispense in well-sealed bottles; consider
using a child-resistant closure.
Storage. Store below 25C unless otherwise specified.

cetrimide shampoo
cetrimide ................................................................ 40 g
ethanol (90% v/v)................................................. 30 mL
purified water, freshly boiled and cooled............... 30 mL
Method. Dissolve the cetrimide in the ethanol and
slowly add the purified water. Avoid vigorous shaking
during preparation.
Use. Treatment of seborrhoea. Dilute 1 part in 20 parts
of water before use.
Label. This preparation should be labelled KEEP OUT OF
REACH OF CHILDREN: EXTREMELY TOXIC TO CHILDREN.

58

Section A | General formulary

compound hydroxybenzoate
solution

Solutions
Solutions are homogenous mixtures of one or more
solutes dissolved in a solvent.

aluminium acetate solution

methyl hydroxybenzoate............................................8 g
propyl hydroxybenzoate.............................................2 g
propylene glycol............................................. to 100 mL
Use. Preservative (when diluted 1 in 100).

Burows solution
aluminium sulfate................................................. 22.5 g
calcium carbonate................................................... 10 g
tartaric acid ........................................................... 4.5 g
acetic acid (33% w/w).......................................... 25 mL
purified water, freshly boiled and cooled............... 75 mL
Strength. Contains about 13% of aluminium acetate
(limits 1.7 to 1.9% w/v of aluminium, Al).

Use. Astringent, antiseptic.


Storage. Store below 25C in well-filled containers.

Lugols solution
iodine.......................................................................5 g
potassium iodide..................................................... 10 g
purified water, freshly boiled and cooled ........ to 100 mL
Strength. Contains 5% iodine (limits 4.75 to
5.25% w/v) and 10% potassium iodide (limits 9.5 to
10.5% w/v of potassium iodide, KI).
Method. Dissolve the iodine and potassium iodide in
10mL of water and adjust to volume.
Use. Pre-operative treatment of thyrotoxicosis.
Dose. 0.10.3mL three times daily for 7days
immediately before surgery.12 Take well diluted with
water, milk or juice.

benzoic acid solution

methyl hydroxybenzoate solution

benzoic acid..............................................................5 g
propylene glycol................................................... 75 mL
purified water, freshly boiled and cooled......... to 100 mL

methyl hydroxybenzoate............................................5 g
propylene glycol............................................. to 100 mL

Use. A convenient source of benzoic acid for use as a


preservative (when diluted 1 in 50 or 1 in 100).

Compounding and dispensing

Method. Dissolve the aluminium sulfate in 60mL of


the purified water. Add the acetic acid, then the calcium
carbonate mixed with the remainder of the purified
water. Allow to stand for not less than 24hours in a cool
place, stirring occasionally. Filter. Add the tartaric acid to
the filtered solution and mix.

iodine solution aqueous

Use. Preservative (when diluted 1 in 50 or 1 in 100).

soap solution alcoholic


spirit shampoo

calcium hydroxide solution


lime water
calcium hydroxide......................................................1 g
purified water, freshly boiled and cooled......... to 100 mL
Method. Shake together until a saturated solution has
been achieved, and allow to stand. Decant the clear
supernatant solution as required.
Use. Used to form calcium soaps of fatty acids in waterin-oil emulsions.

coal tar solution


Liq. Picis. Carb.
coal tar................................................................... 20 g
polysorbate 80..........................................................5 g
ethanol (90% v/v) .......................................... to 100 mL
Method. Macerate the coal tar and the polysorbate 80
with 80mL of ethanol for 7days in a closed vessel, with
occasional agitation. Filter, then pass sufficient ethanol
through the filter to produce 100mL.

soft soap................................................................. 50 g
ethanol (90% v/v) .......................................... to 100 mL
Note. Ingredients such as thymol 0.5% or coal tar
solution 5% may be added to this shampoo.

tolu solution
tolu balsam...............................................................5 g
ethanol (90% v/v) ................................................ 30 mL
sucrose .................................................................. 50 g
purified water, freshly boiled and cooled......... to 100 mL
Method. Dissolve the tolu balsam in 20mL of ethanol.
Add 10g of sterilised purified talc and 35mL of water
heated to 70C. Shake vigorously, allow to stand for
24hours, and filter. Dissolve the sucrose in the filtrate,
add the remainder of the ethanol and adjust to volume
with purified water.

59

Section A | General formulary

Spirits
Spirits are solutions of one or more often volatile
ingredients dissolved in ethanol. When they are added
to aqueous vehicles, some salts may precipitate out
of solution. There may also be precipitation of the
ingredients dissolved in the spirit itself.1
Container. Store in well-sealed containers of
glass or other suitable materials; consider using a
child-resistant closure.

Hydrocortisone acetate..............................................1.5
Metronidazole ..........................................................1.7
Morphine hydrochloride or sulfate ............................1.6
Paracetamol .............................................................1.5
Phenobarbitone ........................................................1.1
Theophylline .............................................................1.5
Label. Containers should be labelled CAUTION: NOT TO
BE TAKEN (labelL).
Container. Keep in well-sealed containers.
Storage. Store at 28C unless otherwise specified.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

Compounding and dispensing

camphor spirit compound


camphor ............................................................... 0.3 g
benzoic acid........................................................... 0.5 g
anise oil ............................................................. 0.3 mL
ethanol (60% v/v) .......................................... to 100 mL

lemon spirit
terpeneless lemon oil ........................................... 10 mL
ethanol (96% v/v)........................................... to 100 mL

Syrups are aqueous solutions with high concentrations


of sucrose or other sugars that are used as sweetened,
flavoured vehicles.
Container. Store in well-sealed containers.
Expiry. The expiry date is 28days from the date of
preparation unless otherwise specified.

aromatic syrup

Suppositories

Syr. Aromat.

Suppositories are solid-dose forms shaped for rectal


administration and usually containing medicaments
that are intended for local or systemic delivery. They
are usually made with a suitable fatty base, provided
that the melting point of the suppositories is not higher
than 37C. If a water-miscible base is required, a
glycogelatin or macrogol base may be used. An example
of a macrogol base is 20% w/w macrogol 400 with 80%
macrogol 4,000.

orange tincture....................................................... 5 mL
lemon spirit ........................................................ 0.5 mL
syrup APF....................................................... to 100 mL

Moulds with a capacity equivalent to 13g of fatty base


are used unless otherwise specified.

Strength. Contains 0.5% of codeine phosphate


(limits 0.45 to 0.55% w/v of codeine phosphate,
C18H21NO3H3PO4.H2O). Codeine syrup contains 5mg of
codeine phosphate in each 1mL.

When an amount as a dose (as distinct from a


percentage) of medicament is prescribed, an allowance
must be made for the volume occupied by the
medicament in each suppository. To facilitate this
procedure, displacement values (densities of medicament
relative to fatty bases) are listed here. These values
are guidelines only; displacement values will vary with
powder density. A displacement value of 1 is generally
used for liquids. If a medicament has a displacement
value of 2, then 2g occupies the same volume as,
and therefore displace, 1g of fatty base, 1.2g of
glycogelatin base or 1.2g of macrogol base.

Medicament displacement value


Aminophylline...........................................................1.3
Aspirin .....................................................................1.3
Cinchocaine hydrochloride.........................................1.3
Hydrocortisone .........................................................1.5

60

Syrups

codeine syrup
codeine phosphate ............................................ 500 mg
purified water, freshly boiled and cooled.............. 1.5 mL
syrup APF....................................................... to 100 mL

Method. Dissolve the codeine phosphate in the purified


water, add sufficient syrup to produce the required
volume, and mix.
Use. Antitussive.
Dose. Adults: 36mL (1530mg) three or four
times daily.12
Label. Containers should be labelled with THIS
MEDICINE MAY CAUSE DROWSINESS AND MAY
INCREASE THE EFFECTS OF ALCOHOL. IF AFFECTED,
DO NOT DRIVE A MOTOR VEHICLE OR OPERATE
MACHINERY (label1).

Section A | General formulary

lemon syrup
lemon spirit ........................................................ 0.5 mL
citric acid monohydrate.......................................... 2.5 g
syrup APF ...................................................... to 100 mL

References
1. Lund W, ed. The pharmaceutical codex: principles and practice of
pharmaceutics. 12th edn. London: Pharmaceutical Press; 1994.
2. Marriott JF, Wilson KA, Langley CA, et al. Pharmaceutical
compounding and dispensing. London: Pharmaceutical Press; 2006.
3. British Pharmacopoeia Commission. British pharmacopoeia 2008.
London: Pharmaceutical Press; 2007.

lemon syrup neutral

4. Gennaro A, ed. Remington: the science and practice of pharmacy.


20th edn. Philadelphia: Lippincott Williams & Wilkins; 2000.

lemon spirit ........................................................ 0.5 mL


syrup APF....................................................... to 100 mL

5. Dermatology Expert Group. Therapeutic guidelines: dermatology.


Version 3. Melbourne: Therapeutic Guidelines Ltd; 2009.

orange syrup
orange tincture....................................................... 6 mL
syrup APF ...................................................... to 100 mL

6. Vernon J, Brummett R, Walsh T. The ototoxic potential of


propylene glycol in guinea pigs. Archives of Otolaryngology. 1978;
104(12):7269.
7. Sweetman S, ed. Martindale: the complete drug reference. London:
The Pharmaceutical Press; 2009.
8. Ashley C, Currie A, eds. The renal drug handbook. 3rd edn.
Oxford: Radcliffe Publishing; 2009.
9. Product Information. eMIMs. St Leonards: CMPMedica Australia Pty
Ltd; 2011.

sucrose ............................................................... 66.7 g


purified water, freshly boiled and cooled............to 100 g
Method. Heat together until dissolved and adjust to 100g.

tolu syrup
tolu solution ........................................................ 10 mL
syrup APF ...................................................... to 100 mL

10. British Medical Association, Royal Pharmaceutical Society of Great


Britain. British national formulary (BNF). 61st edn. London: BMJ
Group and RPS Publishing; 2011.
11. Woods DJ, ed. Formulation in pharmacy practice. 2nd edn.
Dunedin: PharmInfoTech Ltd; 2001. At: www.pharminfotech.co.nz.
12. Rossi S, ed. Australian medicines handbook. Adelaide: Australian
Medicines Handbook Pty Ltd; 2011.

Compounding and dispensing

syrup APF

Waters
Aromatic waters are solutions of volatile oils or other
aromatic or volatile substances.3
Aromatic waters may be prepared by diluting the
concentrated water with 39 times its volume of freshly
boiled and cooled purified water.
Label. These preparations should be labelled PROTECT
FROM LIGHT.
Container. Store in well-sealed containers.

anise water concentrated


anise oil ................................................................ 2 mL
ethanol (90% v/v)................................................. 70 mL
purified water, freshly boiled and cooled......... to 100 mL
Method. Dissolve the anise oil in the ethanol. Add
sufficient purified water, in successive small portions, to
produce the required volume, shaking vigorously after
each addition. Add 5g of sterilised, purified talc. Shake
occasionally over a few hours, and filter.3

61

Childrens formulary
This section contains some formulae that can be used
for children or adults who have difficulty swallowing
oral solid-dose forms such as capsules and tablets.
Additional formulae of liquids are also contained in the
Generalformulary.

Compounding and dispensing

It is important to refer to Extemporaneousdispensing,


page 32, for the overriding principles of extemporaneous
preparations, including use of appropriate containers,
storage and expiry. The formulae included in this section
have been designed for preparations prepared for individual
dispensing, and have an expiry date in accordance with the
guide in Extemporaneous dispensing: 28days after the
date of preparation unless otherwise specified.
A range of published stability data exist for various
formulae and settings, and a range of formulae,
methodology and stability for individual formulations
might be identified in various reference sources.13

acetazolamide suspension CF
25 mg/mL
acetazolamide tablets 250 mg*...................................10
methylcellulose mucilage 2% APF#........................ 25 mL
compound hydroxybenzoate solution APF#.............. 1 mL
water#........................................................... to 100 mL
citric acid#.............. qs if necessary to provide pH 4.05.0
* Pure acetazolamide is available from wholesalers of
compounding ingredients.
# Approximately 100mL of a 1:1 mixture of commercial Vehicle
for Oral Suspension USP-NF and Vehicle for Oral Solution USP-NF
may be substituted for the methylcellulose mucilage, compound
hydroxybenzoate solution and vehicle. This mixture has a pH of
45, and citric acid will not need to be added.

Strength. Contains 25mg/mL of acetazolamide base.

Modifying proprietary
formulations
If a licensed proprietary product is unable to meet the
individual needs of a specific patient (e.g. use in feeding
tubes or paediatrics), an extemporaneously prepared
oral liquid may be necessary. Although it is generally
preferable to use the pure drug as the source of active
ingredient, an adult solid-dose form can be altered by
crushing or dispersing tablets.1 However, tablets and
capsules used as the source of active ingredient in a
mixture also contain inactive excipients and fillers that
may affect bioavailability and stability of mixtures. Where
possible, it is preferable to obtain the pure drug.
Refer to Modification of oral formulations, page 68,
for further information on preparing oral liquids from
tablets or powdered drug, including palatability, taste
and texture of the final product; dose uniformity if
tablets are split or crushed; stability issues; and choice of
a suitable formulation.
Before reformulating proprietary formulations that are
not included in this section, pharmacists are advised to
seek guidance on formulation, stability and other risk
management issues from sources such as those listed
under Further information, page 67.

Commercial vehicles
Vehicles that facilitate extemporaneous dispensing of liquid
formulations are available commercially. Forexample,
in Australia, Vehicle for Oral Suspension USP-NF and
Vehicle for Oral Solution USP-NF are manufactured by the
Professional Compounding Chemists of Australia (PCCA)
and Paddock Laboratories (Ora-Plus and Ora-Sweet).
62

# indicates that in the specific formulary, a 1:1 mixture of Vehicle


for Oral Suspension USP-NF and Vehicle for Oral Solution USP-NF
may be substituted for the identified ingredients.

Method. Crush the tablets to a smooth paste with


10mL of the mucilage in a mortar. Gradually add the
remaining ingredients. Transfer to a measuring flask,
rinsing the mortar well with vehicle, and make up to
final volume. Test the pH and add citric acid if necessary.
Note. The optimal pH for stability of this mixture
is pH 45. Injectable products should not be used
for preparation.
Label. This preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ) to ensure even distribution
of the contents before each dose is given, and
REFRIGERATE. DO NOT FREEZE (label6).
Container. Use an amber glass bottle to protect
from light.
Storage. Refrigerate. Protect from light.
Expiry. The expiry date is 28days from the date
of preparation.4

Section A | Children's formulary

amlodipine suspension CF1 mg/mL


amlodipine tablets 5 mg*...........................................20
methylcellulose mucilage 2% APF#........................ 25 mL
purified water, freshly boiled and cooled#.............. 25 mL
compound hydroxybenzoate solution APF#.............. 1 mL
syrup#............................................................ to 100 mL
* Pure amlodipine is available from wholesalers of compounding
ingredients.
# Approximately 100mL of a 1:1 mixture of commercial Vehicle for
Oral Suspension USP-NF and Vehicle for Oral Solution USP-NF may
be substituted for the methylcellulose mucilage, water, compound
hydroxybenzoate solution APF and vehicle.

Strength. Contains 1mg/mL of amlodipine base.


Method. Crush tablets to a smooth paste with 10mL of
the mucilage in a mortar. Gradually add the remaining
ingredients. Transfer to a measuring flask, rinsing the
mortar well with vehicle, and make up to final volume.

Container. Use an amber glass bottle to protect


from light.
Expiry. The expiry date is 28 days from the date
of preparation.5

baclofen suspension CF5 mg/mL


baclofen tablets 20 mg*.............................................15
gycerol#............................................................... 12 mL
syrup#.................................................................... 6 mL
methylcellulose mucilage 2% APF#........................ 15 mL
compound hydroxybenzoate solution APF#........... 0.6 mL
water#.............................................................. to 60 mL
citric acid#.............. qs if necessary to provide pH 4.05.0
* Pure baclofen is available from wholesalers of compounding
ingredients.
# Approximately 60mL of a 1:1 mixture of commercial Vehicle for
Oral Suspension USP-NF and Vehicle for Oral Solution USP-NF may
be substituted for the glycerol, syrup, methylcellulose mucilage,
compound hydroxybenzoate solution and vehicle. This mixture will
not require the addition of citric acid.

Method. Crush the tablets to a smooth paste with


10mL of the mucilage in a mortar. Gradually add the
remaining ingredients. Transfer to a measuring flask,
rinsing the mortar well with vehicle, and make up to
final volume. Test the pH and add citric acid if necessary
(up to 50100mg of citric acid may be required).
Label. This preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ) to ensure even distribution
of the contents before each dose is given, and
REFRIGERATE. DO NOT FREEZE (label6).
Container. Use an amber glass bottle to protect
from light.
Storage. Refrigerate.
Expiry. The expiry date is 28days from the date of
preparation.6

dexamethasone* ............................................... 100 mg


ethanol (90% v/v)................................................. 15 mL
glycerol................................................................ 40 mL
compound hydroxybenzoate solution APF................ 2 mL
methylcellulose mucilage APF.......................... to 100 mL
* Dexamethasone tablets may be used.

Method. If using tablets, grind them to a fine powder


in a porcelain mortar. Wet the powder with the ethanol,
and add the glycerol and compound hydroxybenzoate
solution. Add the methylcellulose mucilage to make up
to final volume.
Label. This preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ), and REFRIGERATE. DO NOT
FREEZE (label6).
Container. Use an amber glass bottle to protect
from light.
Storage. Store at 28C.
Expiry. The expiry date is 28days from the date
of preparation.7

domperidone suspension CF
1 mg/mL
Domperidone tablets 10 mg*......................................10
glycerol#............................................................... 20 mL
methylcellulose mucilage 2% APF#........................ 25 mL
compound hydroxybenzoate solution APF#.............. 1 mL
water#............................................................ to 100 mL
citric acid#.............. qs if necessary to provide pH 4.24.5

Compounding and dispensing

Label. This preparation should be labelled SHAKE WELL


BEFORE EACH USE (labelJ) to ensure even distribution of
the contents before each dose is given.

dexamethasone suspension CF
1 mg/mL

* Pure domperidone is available from wholesalers of compounding


ingredients.
# Approximately 100mL of a 1:1 mixture of commercial Vehicle
for Oral Suspension USP-NF and Vehicle for Oral Solution USP-NF
may be substituted for the glycerol, methylcellulose mucilage,
compound hydroxybenzoate solution and vehicle. This mixture will
not require the addition of citric acid.

Method. Crush the tablets to a smooth paste with


10mL of the mucilage in a mortar. Gradually add the
remaining ingredients. Transfer to a measuring flask,
rinsing the mortar well with vehicle, and make up to
final volume. Test the pH and add citric acid if necessary
(up to 50100mg of citric acid may be required).
Label. This preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ) to ensure even distribution
of the contents before each dose is given, and
REFRIGERATE. DO NOT FREEZE (label6).
Container. Use an amber glass bottle to protect
from light.
Storage. Refrigerate.
Expiry. The expiry date is 28days from the date
of preparation.8

63

Section A | Children's formulary

folic acid solution CF1 mg/mL


folic acid* ......................................................... 100 mg
sodium hydroxide solution (1 molar)...... qs to provide pH 8
compound hydroxybenzoate solution APF................ 1 mL
purified water, freshly boiled and cooled......... to 100 mL
* Folic acid tablets or injection may be used.
Sodium hydroxide solution (1 molar) is 4g of sodium hydroxide
dissolved in 100mL of purified water.

Compounding and dispensing

Method. If using tablets, grind them to a fine powder in


a porcelain mortar. Add the compound hydroxybenzoate
solution and triturate with 25mL of the purified water.
Add 70mL of the purified water and adjust the pH to 8
using the sodium hydroxide solution. Make up to volume
with purified water.

indomethacin suspension CF
2 mg/mL
indomethacin capsules 25 mg*.....................................4
ethanol (95% v/v)................................................. 10 mL
compound hydroxybenzoate solution APF............. 0.5 mL
syrup................................................................ to 50 mL
* Indomethacin is practically insoluble in water and sparingly
soluble in alcohol. Indomethacin is available from wholesalers of
compounding ingredients. This suspension will be prone to caking
and difficulties with resuspension of insoluble material if capsules
are used, and pure indomethacin may be preferred.10

Method. Empty the contents of the capsules into a


mortar with the ethanol and triturate to a smooth paste.
Add the compound hydroxybenzoate solution and transfer
to a measuring flask using syrup. Make up to volume.

Label. This preparation should be labelled SHAKE WELL


BEFORE EACH USE (labelJ) if folic acid tablets are used,
because tablet excipients will not necessarily all dissolve;
and REFRIGERATE. DO NOT FREEZE (label6).

Label. This preparation should be labelled SHAKE WELL


BEFORE EACH USE (labelJ) to ensure even distribution of
the contents before each dose is given.

Container. Use an amber glass bottle to protect


from light.

Storage. Store below 25C.

Storage. Store at 28C. Protect from light.


Expiry. The expiry date is 28days from the date
of preparation.

gabapentin mixture CF40 mg/mL


gabapentin tablets 800 mg*.........................................5
methylcellulose mucilage 2% APF#........................ 25 mL
purified water, freshly boiled and cooled#.............. 25 mL
compound hydroxybenzoate solution APF#.............. 1 mL
syrup#........................................................... to 100 mL
* Pure gabapentin is available from wholesalers of compounding
ingredients.
# Approximately 100mL of a 1:1 mixture of commercial Vehicle
for Oral Suspension USP-NF and Vehicle for Oral Solution USP-NF
may be substituted for the methylcellulose mucilage, compound
hydroxybenzoate solution and vehicle.
The quantity of syrup in the non-commercial vehicle may be
replaced with glycerol, if required.

Method. Crush the tablets to a smooth paste with


10 mL of the mucilage in a mortar. Gradually add the
remaining ingredients. Transfer to a measuring flask,
rinsing the mortar well with vehicle, and make up to
final volume.
Label. This preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ) to ensure even distribution of
the contents before each dose is given.
Container. Use an amber glass bottle to protect
from light.
Storage. Store below 25C.
Expiry. The expiry date is 28days from the date
of preparation.9

Container. Use an amber glass bottle to protect from light.


Expiry. The expiry date is 28days from the date
of preparation.

nitrofurantoin suspension CF
10 mg/mL
nitrofurantoin tablets 50 mg*.....................................20
Vehicle for Oral Suspension USP-NF....................... 50 mL
Vehicle for Oral Solution USP-NF........................... 50 mL
* Pure nitrofurantoin is available from wholesalers of compounding
ingredients.

Method. Mix the Vehicle for Oral Suspension USP-NF


and Vehicle for Oral Solution USP-NF to form vehicle.
Crush the tablets to a smooth paste with 10mL of
vehicle in a mortar. Gradually add the remaining vehicle.
Transfer to a measuring flask, rinsing the mortar well
with vehicle, and make up to final volume.
Label. This preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ) to ensure even distribution of
the contents before each dose is given.
Container. Use an amber glass bottle to protect
from light.
Storage. Store below 25C.
Expiry. The expiry date is 28days from the date
of preparation.11

omeprazole dispersion CF2 mg/mL


omeprazole*...................................................... 200 mg
sodium bicarbonate...................................................8 g
compound hydroxybenzoate solution APF................ 1 mL
purified water, freshly boiled and cooled......... to 100 mL
* Omeprazole 20 mg capsules may be used.

64

Section A | Children's formulary

Method. Dissolve the sodium bicarbonate in the purified


water. Empty the capsule contents into a container, add
the sodium bicarbonate solution and shake vigorously
until a white dispersion forms. The pellets may take
many hours to fully disperse.
Note.

Container. Use an amber glass bottle to protect


from light.2
Storage. Store at 28C.
Label. This preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ), and REFRIGERATE. DO NOT
FREEZE (label6).
Expiry. The expiry date is 28days from the date
of preparation.

potassium citrate .................................................... 20 g


citric acid monohydrate ............................................4 g
lemon syrup ........................................................ 20 mL
methylhydroxybenzoate solution APF* .................... 1 mL
purified water, freshly boiled and cooled ........ to 100 mL
* Compound hydroxybenzoate APF solution can be substituted for
methylhydroxybenzoate solution APF.

Strength. Contains 20% of potassium citrate (limits


18.5 to 21.5% w/v of potassium citrate, C6H5K3O7.H2O).
Dose. Dose to be tailored to electrolyte requirements.
Give diluted with water.
Container. Use an amber glass bottle to protect
from light.
Storage. Store below 25C.
Expiry. The expiry date is 28days from the date
of preparation.

propranolol mixture CF5 mg/mL


propranolol hydrochloride*................................. 500 mg
citric acid monohydrate.............................................1 g
sodium benzoate................................................ 100 mg
syrup.................................................................... 40 mL
purified water, freshly boiled and cooled......... to 100 mL
* Propranolol hydrochloride tablets may be used.

pantoprazole dispersion CF
2 mg/mL
pantoprazole*.................................................... 200 mg
sodium bicarbonate................................................ 8.4 g
compound hydroxybenzoate solution APF................ 1 mL
purified water, freshly boiled and cooled......... to 100 mL
* Use pantoprazole tablets.

Method. Dissolve the sodium bicarbonate in the purified


water. Crush the pantoprazole tablets in a mortar
and triturate with the sodium bicarbonate solution,
transferring to the final container. Shake vigorously for
10minutes to obtain a uniform dispersion.
Note.

See note under Omeprazole dispersion (above) for


electrolyte monitoring.
The bioavailability of this product is approximately
75% that of the intact tablets.

Label. This preparation should be labelled SHAKE WELL


BEFORE EACH USE (labelJ), and REFRIGERATE. DO NOT
FREEZE (label6).
Container. Use an amber glass bottle to protect
from light.
Storage. Store at 28C. Protect from light.
Expiry. The expiry date is 28days from the date
of preparation.

Compounding and dispensing

The sodium bicarbonate load can cause problems,


especially in those with renal impairment and the
very young. Check electrolyte and acidbase status
of infants below 6months of age and anyone with
renal impairment.
The bioavailability of this product is approximately
50% that of the capsules.
As an alternative, omeprazole tablets may be
dispersed in water, orange juice or yoghurt and
given orally within 30minutes. The resulting pellets
must not be chewed or crushed. If pellets are
crushed, omeprazole degrades rapidly12 if the pH is
less than 7.8.

potassium citrate mixture CF


200 mg/mL

Method. If using tablets, grind them to a fine powder in


a porcelain mortar with the other solid ingredients, and
add syrup to form a smooth paste. Slowly add portions
of water to make up to volume.
Note. Do not use brands of propranolol tablets
containing calcium carbonate as an excipient.
Label. This preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ) if propranolol tablets are
used, because tablet excipients will not necessarily all
dissolve; and REFRIGERATE. DO NOT FREEZE (label6).
Container. Use an amber glass bottle to protect
from light.2
Storage. Store at 28C. Protect from light.
Expiry. The expiry date is 28days from the date
of preparation.

sildenafil suspension CF2 mg/mL


sildenafil 100 mg*........................................................1
methylcellulose 2% mucilage#............................... 25 mL
purified water#..................................................... 25 mL
compound hydroxybenzoate solution APF#.............. 1 mL
syrup APF#.................................................... .to 100 mL
* Sildenafil tablets may be used.
# Approximately 100mL of a 1:1 mixture of commercial Vehicle
for Oral Suspension USP-NF and Vehicle for Oral Solution USP-NF
may be substituted for the methylcellulose mucilage, compound
hydroxybenzoate solution, water and vehicle.

65

Section A | Children's formulary

Method. Mix the sildenafil to a smooth paste with


10mL of vehicle in a mortar. Gradually add the
remaining ingredients. Transfer to a measuring flask,
rinsing the mortar well with vehicle, and make up to
final volume.
Label. This preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ) to ensure even distribution of
the contents before each dose is given.
Container. Use an amber glass bottle to protect
from light.
Storage. Store below 25C.
Expiry. The expiry date is 28days from the date
of preparation.

Compounding and dispensing

sodium citrate mixture CF


200 mg/mL
sodium citrate......................................................... 20 g
citric acid monohydrate ............................................4 g
lemon syrup......................................................... 20 mL
methylhydroxybenzoate solution APF* .................... 1 mL
purified water, freshly boiled and cooled......... to 100 mL
* Compound hydroxybenzoate solution APF may be substituted for
methylhydroxybenzoate solution APF.

Strength. Contains 20% of sodium citrate (limits 18.5


to 21.5% w/v of sodium citrate, C6H5Na3O7.2H2O).
Dose. Dose to be tailored to electrolyte requirements.
Give diluted with water.
Storage. Store below 25C.
Expiry. The expiry date is 28days from the date
of preparation.

spironolactone mixture CF
1 mg/mL
spironolactone* ................................................. 100 mg
carboxymethylcellulose mucilage APF.................... 20 mL
syrup.................................................................... 40 mL
purified water, freshly boiled and cooled......... to 100 mL
* Spironolactone tablets may be used.

Method. Crush the tablets or powder in a mortar, and


add syrup to form an even paste. Slowly add portions of
water to make up to volume.
Label. This preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ) to ensure even distribution
of the contents before each dose is given, and
REFRIGERATE. DO NOT FREEZE (label6).

66

sotalol mixture CF5 mg/mL


sotalol hydrochloride tablets 80 mg*.............................5
methylcellulose mucilage 2% APF#........................ 30 mL
compound hydroxybenzoate solution APF#.............. 1 mL
syrup#................................................................. 25 mL
water#.............................................................. to 80 mL
citric acid#.............. qs if necessary to provide pH 4.05.0
* Pure sotalol is available from wholesalers of compounding
ingredients.
# A 1:1 mixture of commercial Vehicle for Oral Suspension USP-NF
and Vehicle for Oral Solution USP-NF may be substituted for the
methylcellulose mucilage, compound hydroxybenzoate solution,
syrup (or glycerol, if used) and water. This mixture will not require
the addition of citric acid.
The 25mL of syrup in the non-commercial vehicle may be replaced
with glycerol, if required.

Method. Crush the tablets to a smooth paste with


the syrup in a mortar. Gradually add the remaining
ingredients. Transfer to a measuring flask, rinsing the
mortar well with vehicle, and make up to final volume.
Test the pH and add citric acid if necessary.
Note. Sotalol hydrochloride is soluble in water, but
tablet excipients may be insoluble.
Label. This preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ) to ensure even distribution of
the contents before each dose is given.
Container. Use an amber glass bottle to protect
from light.
Storage. Store below 25C.
Expiry. The expiry date is 28days from the date
of preparation.13

sulfasalazine suspension CF
100 mg/mL
sulfasalazine tablets 500 mg*.....................................20
Vehicle for Oral Suspension USP-NF....................... 50 mL
Vehicle for Oral Solution USP-NF........................... 50 mL
* Pure sulfasalazine is available from wholesalers of compounding
ingredients.

Method. Mix the Vehicle for Oral Suspension USP-NF


and Vehicle for Oral Solution USP-NF to form vehicle.
Crush the tablets to a smooth paste with 10mL of
vehicle in a mortar. Gradually add the remaining vehicle.
Transfer to a measuring flask, rinsing the mortar well
with vehicle, and make up to final volume.
Label. This preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ) to ensure even distribution of
the contents before each dose is given.

Container. Use an amber glass bottle to protect


from light.

Container. Use an amber glass bottle to protect


from light.

Storage. Store at 28C. Protect from light.

Storage. Store below 25C.

Expiry. The expiry date is 28 days from the date


of preparation.

Expiry. The expiry date is 28days from the date


of preparation.14

Section A | Children's formulary

trimethoprim mixture CF
10 mg/mL
trimethoprim*...........................................................1 g
methylcellulose mucilage 2% APF......................... 25 mL
purified water, freshly boiled and cooled............... 25 mL
compound hydroxybenzoate solution APF................ 1 mL
syrup.............................................................. to 100 mL

11. Ensom M, Decarie D. Stability of nitrofurantoin in


extemporaneously compounded suspensions. Canadian Journal of
Hospital Pharmacy. 2006; 59:2933.
12. Trissel L. Trissels stability of compounded formulations. 4th edn.
Washington, DC: American Pharmacists Association; 2009.
13. Nahata M, Morosco R. Stability of sotalol in two liquid formulations
at two temperatures. Annals of Pharmacotherapy. 2003;
37(4):5069.
14. Lingertat-Walsh K, Walker SE, Law S, et al. Stability of sulfasalazine
oral suspension. Canadian Journal of Hospital Pharmacy. 2006;
59:194200.

*Trimethoprim tablets may be used.

Method. Crush the tablets or powder in a mortar, and


add syrup to form an even paste. Make up to volume.
Label. This preparation should be labelled SHAKE WELL
BEFORE EACH USE (labelJ), and REFRIGERATE. DO NOT
FREEZE (label6).
Container. Use an amber plastic container.2
Storage. Store at 28C. Protect from light.

Further information
Database of oral liquid formulations. New Zealand: PharmInfoTech;
2011. At: www.pharminfotech.co.nz/manual/Formulation/mixtures/
index.htm.
Jackson M, Lowey A. Handbook of extemporaneous preparation: a
guide to pharmaceutical compounding. London: Pharmaceutical Press;
2010.
British Pharmacopoeia Commission. British pharmacopoeia 2008.
London: Pharmaceutical Press; 2008.
USP pharmacists pharmacopeia 20082009. 2nd edn. Maryland: The
United States Pharmacopeial Convention Inc; 2008.

Compounding and dispensing

Expiry. The expiry date is 28days from the date


of preparation.

References
1. Marriott J, Wilson K, Langley C, et al. Pharmaceutical compounding
and dispensing. London: Pharmaceutical Press; 2006.
2. Woods DJ. Extemporaneous formulations of oral liquidsa guide.
At: www.pharminfotech.co.nz/manual/Formulation/extemprep.pdf.
3. Jackson M, Lowey A. Handbook of extemporaneous preparation:
a guide to pharmaceutical compounding. London: Pharmaceutical
Press; 2010.
4. Allen LV Jr, Erickson MA. Stability of acetazolamide, allopurinol,
azathioprine, clonazepam, and flucytosine in extemporaneously
compounded oral liquids. American Journal of Health-System
Pharmacy. 1996; 53(16):19449.
5. Nahata MC, Morosco RS, Hipple TF. Stability of amlodipine besylate
in two liquid dosage forms. Journal of American Pharmacists
Association. 1999; 39(3):3757.
6. Johnson C, Hart S. Stability of an extemporaneously compounded
baclofen oral liquid. American Journal of Health-System Pharmacy.
1993; 50(11):23535.
7. Accordino A, Chambers R, Thompson B. A short term stability
study of an oral solution of dexamethasone. Australian Journal of
Hospital Pharmacy. 1994; 24:31216.
8. Ensom MHH, Decarie D, Hamilton DP. Stability of domperidone in
extemporaneously compounded suspensions. Journal of Informed
Pharmacotherapy. 2002; 8:1004.
9. Nahata MC. Development of two stable oral suspensions for
gabapentin. Pediatric Neurology. 1999; 20(3):1957.
10. Stewart PJ, Doherty PG, Bostock JM, et al. The stability
of extemporaneously prepared paediatric formulations of
indomethacin. Australian Journal of Hospital Pharmacy. 1985;
15:5560.

67

Modification of oral formulations

Compounding and dispensing

Many people, especially among paediatric and geriatric


populations, have difficulty swallowing oral soliddose forms such as capsules and tablets. In some
instances, it may be necessary to alter solid-dose forms
(e.g.bycrushing tablets or opening capsules) to facilitate
oral administration in individuals with swallowing
difficulties, or to allow administration via an alternative
route (e.g.enteral feeding tube) in individuals who are
unable to take medicines orally.
Pharmacists are often asked to provide advice to
healthcare workers, non-medical carers or the public
on whether a solid-dose oral formulation is suitable
for alteration and, if so, the appropriate methods to
alter and administer the product. In these situations,
pharmacists will need to consider the potential risks
associated with altering a preparation, including
reduced medicine efficacy, increased toxicity, instability,
unacceptable taste or texture, and occupational health
and safety hazards.1,2
Pharmacists need to consider the legal and professional
implications of advising on the practice of altering a
medicines formulation. This includes potential liability
should an adverse clinical outcome occur, given
that once a commercial product has been altered
(e.g.crushed) it is no longer being used in accordance
with the manufacturers product licence.3,4
Pharmacists are advised to use their professional
judgment when providing advice on the medication
management of patients with swallowing difficulties.
The decision to alter solid oral medicines for ease of
administration should be carefully considered and made
on an individual basis. It is important that pharmacists
clearly document the reason for altering the medicine.

Risk assessment

aspiration and oesophageal irritation; and lead to


malnutrition from poor oral intake.4,5
Referral to a speech pathologist may be appropriate for
a detailed assessment of a persons ability to swallow,
especially in a hospital or aged-care facility, and to
determine whether enteral feeding is necessary. An
inability to swallow solid-dose forms may be transient or
episodic. When clinical circumstances change, renewed
attempts should be made to encourage a person to
take unaltered dose forms. The ability of some people
to swallow can vary during the day, so that the timing
of the dose is important. When clinically acceptable,
changing to alternative dosing times might reduce the
need for product alteration.1

Review medication regimen


Individuals experiencing difficulties in swallowing soliddose forms should have their medicines regimen reviewed
to rationalise drug therapy and ensure that medicines
are being used safely and effectively. The review process
should identify any medicines that could be causing
dry mouth (xerostomia) and assess the suitability of
medicine formulations.4 Pharmacists can then determine
whether any suitable alternative formulations (e.g. liquid
preparations, transdermal patches, sublingual tablets,
suppositories or topical applications) are commercially
available, and whether certain medicines are no longer
necessary and could be ceased.1 It may be appropriate to
consider one of the following options:

Changing to an alternative drug, belonging to


the same therapeutic class, that has a prolonged
duration of action (but is still an immediate-release
formulation). This will reduce the need for multiple
daily doses.

Changing to an alternative solid-dose formulation


of the same medicine that is suitable for crushing or
otherwise modifying. If multiple brands of the same
drug are commercially available, there might be a
product available that is formulated as a dispersible
tablet, or a sustained-release capsule containing
enteric-coated pellets units that may be opened and
dispersed on food.

Changing to a liquid formulation, if one is


commercially available. The liquid formulation might
have a different bioavailability from the equivalent
solid-dose form, and it may be necessary to adjust
the dose and dosing interval to achieve the same
therapeutic response. Pharmacists should refer to the
approved product information to determine the dose
equivalency of different formulations. Excipients such
as ethanol, sorbitol or sucrose are commonly found
in liquid-dose forms and may also influence the
choice of formulation.

Assess swallowing ability


A number of factors may affect a persons ability to
swallow whole foods or orally administered medicines.
These include physical difficulties as a result of disease
or trauma (e.g. dysphagia associated with stroke,
Parkinsons disease, multiple sclerosis, decreased
consciousness, dry mouth) and psychological factors
(e.g. deteriorating cognitive state) that can cause
people to refuse to take their medicines.1 Swallowing
difficulty (dysphagia) is most common in older people
as a result of age-related changes in salivary gland
function and weakening of the muscles involved in
swallowing, and the increased prevalence of causative
diseases. Swallowing difficulties have the potential to
affect medicine adherence; increase the risk of choking,
68

Section A | Modification of oral formulations

Assess whether formulation


canbealtered
If a suitable formulation is not available but a person is
able to take medicines orally, altering a solid-dose oral
formulation may be considered. Appropriate advice
and information should be sought from the approved
product information, the manufacturer, and specialised
resources and protocols.
Issues to consider include:

risk to the safety of people preparing or


administering the product from exposure to the drug
or its constituents

reduced palatability due to destruction of sugar


coating or film coating and exposure of raw
ingredients

stability of the product once the packaging has


been opened and the drug has been exposed to the
environment.

Solid-dose forms may be removed from their original


packaging to be altered or for transfer into a doseadministration aid. In both instances, altering the
products storage conditions can pose risks to the

Types of medicines that should not be altered are


listed in Table A.3 below. Preparations that should be
swallowed whole and not crushed or otherwise altered
require cautionary advisory label A refer to Table A.1,
page 16.
There are some exceptions to the requirement that a
preparation be swallowed whole. For example, some
tablet formulations are scored and may be broken
into dosage sections, but the portions should not be
chewed or crushed. Some capsules may be opened, but
the pellets they contain should be swallowed whole.
For more detailed information on the modification
of solid-dose forms of individual medicines, refer to
Clinical monographs, Section D. A list of some common
medicines that should not be crushed is provided in
TableA.4, page 72.

Table A.3 Types of medicines that should not be altered1,4,7,8


Reason for not
altering

Types of
preparations

Mechanism

Examples

Controlled-release
(CR), sustainedrelease (SR) or
modified-release
(MR) tablets, or
pellets contained
within a capsule

MR solid-dose forms are formulated


to release the drug in a controlled
manner over a defined dosing period,
usually 12 or 24hours. Altering MR
formulations (e.g.bycrushing) affects
the pharmacokinetic properties of the
drug and may result in an unintended
large bolus dose, with excessive peak
plasma concentrations and unwanted or
exaggerated therapeutic effects, followed
by a subtherapeutic trough as the medicine
is excreted.

Crushing verapamil SR tablets results


in an increased risk of hypotension and
bradycardia.

Enteric-coated
tablets/pellets
contained within a
capsule

Enteric coating is designed to protect the


drug from degradation by gastric acid
and enhance the oral bioavailability of the
drug. It can also reduce the incidence of
gastrointestinal side effects.

Altering omeprazole tablets (e.g. by


crushing) can increase degradation of
the drug in the stomach, reducing its
bioavailability.

Film-coated tablets

Film coatings are sometimes used to protect


a solid-dose form from exposure to light
or moisture. Disruption of the coating may
cause rapid degradation of the active drug
following exposure to the environment.

Nifedipine is extremely susceptible to the


effects of light.

Altered
absorption/
release
characteristics

Altered stability

Hygroscopic or
moisture-sensitive
preparations

In general, solid-dose forms that require


cautionary advisory label 13 because of
concerns about their stability once removed
from their original packaging should not
be crushed or otherwise altered (refer to
Cautionary advisory labels, Section A, for a
more detailed explanation of the application
of label 13).

Compounding and dispensing

stability and efficacy of the product. Pharmacists


should consider any information available from the
manufacturer, and whether data on stability are
available. Removal should be restricted to short periods
and should only occur if stability data are available to
confirm that removal from the original packaging will
not adversely affect the medicines stability.6

Certain SR products cannot be crushed,


but can be halved (e.g.Tegretol CR
tablets).
Certain capsule formulations containing
MR pellets may be opened if the release
properties are built into the pellet and
not the capsule casing. The pellets can be
mixed into water, juice or milk, or sprinkled
onto a small amount of soft food. The
pellets must not be chewed or crushed,
and the mouth should be rinsed to ensure
that all pellets have been swallowed.
Examples of products with encapsulated SR
pellets are Kapanol and Reminyl capsules.

Sodium valproate tablet formulations are


hygroscopic and must be protected from
moisture. The tablets should be kept in
the original protective foil packaging until
taken.

69

Section A | Modification of oral formulations

Failure to reach
the site of
action

Enteric-coated
tablets/pellets
contained in a
capsule

Some products are formulated to


release medicine at a defined site in the
gastrointestinal tract. Crushing or otherwise
altering these formulations can result in
premature absorption, with a loss of efficacy
and increased risk of adverse effects.

Some mesalazine products are formulated


as resin-coated tablets, which are designed
to release the medicine in the lower small
intestine (Pentasa) or colon (Salofalk,
Mesasal) by disintegrating at a specified
pH. Crushing tablets causes premature
release and absorption, increasing the
risk of kidney damage and reducing the
medicines effect at the intended site of
action.

Local irritant
effect

Bisphosphonates

Some medicines cause local irritation to


the upper gastrointestinal tract (e.g. the
oesophagus or stomach). If medicines
that are potentially irritant do need to
be crushed, administration should be
accompanied by sufficient liquid to ensure
that no medicine residue is left in contact
with the oesophagus.

Some medicines (e.g. alendronate) should


not be crushed because of their potential
to cause severe upper gastrointestinal
irritation and ulceration.

Occupational
health and
safety

Cytotoxic medicines

Drug particles may be dispersed in the


air (aerosolisation) if crushed, leading
to inadvertant drug exposure for people
preparing or administering the altered
formulation.

Women who are, or may potentially be,


pregnant should not handle crushed or
broken tablets of finasteride (or handle
tablets with wet hands) because of the
possibility of absorption and the resulting
risk to a male fetus. Finasteride tablets
have a film coating to prevent contact
with the active ingredient during normal
handling, provided the tablets are intact,
and not broken or crushed.

Compounding and dispensing

Tetracyclines

Highly teratogenic
medicines
Contact irritants
Hormonal
preparations

Palatability

Sugar-coated and
film-coated tablets

Specific procedures and safety precautions


(e.g. protective clothing, dedicated
equipment) are necessary for the
handling of some medicines to minimise
contamination and exposure to potentially
hazardous powder.

Film coatings may be used to mask the taste


or odour of some medicines.

Hydroxychloroquine tablets are coated to


disguise their exceptionally bitter taste.

Such medicines may have an unacceptable


or undisguisable taste, which may
compromise patient adherence (although
crushing will not alter their effectiveness).

Other medicines with a sugar coating


to conceal an unpleasant taste include
quinine and ibuprofen.

Suitable techniques for


crushing or otherwise altering
solid-dose forms
Pharmacists should refer to Extemporaneous
dispensing, page 32, for guidance on appropriate
procedures for compounding, including the modification
of dose formulations.
The Australian Pharmaceutical Advisory Council Guidelines
for Medication Management in Residential Aged Care
Facilities1 include general guidance on suitable equipment
and methods for crushing tablets, and other special
considerations, such as compatibility issues (see Special
considerations, on the following page). Standard operating
procedures are recommended to ensure that processes
used to alter oral solid-dose forms are consistent and
address risk management issues. Factors to consider when
solid-dose forms are altered include the following.1
70

Other medicines associated with


occupational health and safety risks
if handled include cytotoxics (e.g.
methotrexate and cyclophosphamide),
isotretinoin (a teratogen), and
chlorpromazine (can cause contact
dermatitis).

Suitable equipment for crushing


Tablets can be crushed using a tablet crusher/pulveriser,
or a mortar and pestle. Equipment used to crush
tabletsshould:

enable complete and reproducible recovery of


powdered material, with minimal drug loss

be washed and thoroughly dried after use for each


resident if equipment is shared between people

for cytotoxic medicines, be a dedicated set for


eachperson.

Appropriate technique
Crushing tablets. When tablets and capsules are to be
administered at the same time, the tablets should be
crushed first. The capsule can then be opened and the
contents added to the crushed tablets. This will avoid
crushing of sustained-release or enteric-coated pellets
contained within the capsule.

Section A | Modification of oral formulations

Splitting or breaking tablets. Splitting or dividing of


tablets can facilitate oral administration by reducing
the size of the solid-dose form. However, this may lead
to dose fluctuations as a result of uneven breaking of
tablets.9 Inaccuracy in splitting tablets is of particular
concern for drugs with a narrow therapeutic index
(e.g. digoxin, phenytoin), where a small variation in
the amount ingested may cause a clinically significant
difference in therapeutic response.4,9 It is important
to consider the formulation, the shape and size of the
tablet, and the type of scoring when deciding whether
this approach is suitable.

Special considerations
Cross-contamination. Equipment used to crush more
than one persons medicines should be washed and
thoroughly dried after use for each person. This will
minimise the risk of contamination by removing
any residue of crushed medicines or excipients. For
cytotoxicmedicines, a dedicated set of equipment
must be used for each person. Specific procedures
should be implemented and safety precautions used
(e.g.protective clothing) when handling cytotoxic
medicines, to minimise exposure of the pharmacist or
patients to powderedmaterial.
Incompatibility. Crushing more than one tablet together
can make it easier to both crush and retrieve the
crushed medicines from the device used for crushing.
In most cases, the potential for chemical interaction
between medicines that are crushed and mixed together
is not great; however, to minimise the possibility of
an interaction, the medicines should be administered
as soon as possible after they are crushed and mixed
together. There are some medicines that should not
be crushed together because, when administered, one

Administration of altered medicines


People taking oral medicines should be upright, or as
close as practicable to upright, if possible. The altered
formulation may be mixed with a small amount of
semi-solid food such as jam, fruit puree or yoghurt to
disguise unpleasant taste or texture, and aid adherence.
The chemical properties (e.g. acidity) of the food used
as a carrier substance to facilitate oral ingestion of the
medicine may interfere with drug stability or absorption
in the gastrointestinal tract.10 In some cases, dairy
products such as yoghurt should not be used as a carrier
substance (see Table A.1, for medicines requiring label 4
that should not be administered with dairy products).
Crushed tablets or capsule contents should be taken
as soon as possible after altering and mixing with any
food or liquid. This minimises the risks of medicine
degradation and inadvertent administration to the wrong
person. Crushed tablets or capsule contents should not
be sprinkled onto meals because portions of the meal
may be left uneaten.
Always ensure that any solid medicines, whether altered
or not, are taken with sufficient water or other suitable
liquid to minimise the risk of oesophageal irritation.

Compounding and dispensing

Dispersing tablets. Many tablet formulations will disperse


in water, allowing administration without the need for
crushing. Refer to the approved product information
and any available solubility data to determine whether
a tablet formulation will disperse easily when placed in
water, and the volume of water necessary to allow the
tablet to disintegrate. There is often some variability in
the dispersion characteristics of different brands of the
same drug. When dispersing tablets, there is a risk that
some of the dose may be left in the container if it is not
adequately rinsed.

medicine will cause reduced absorption of the other


(e.g. calcium reduces the absorption of fluoroquinolone
antibiotics, tetracyclines and oral bisphosphonates).

Monitoring and assessment


Modifying an oral solid-dose form has the potential
to reduce the medicines efficacy through loss of drug
during the crushing, mixing and transfer process,
or through instability. There is also the potential for
increased adverse effects or toxicity if the absorption
and release characteristics of the drug are modified.
For this reason, regular monitoring and assessment of
clinical response is necessary whenever medicines are
administered following modification. To minimise the
risk of liability for the pharmacist associated with using
a medicine outside its licensing conditions, it is also
important to clearly document the reasons for altering
the medicine, any communication with other members
of the healthcare team, and the methods used to alter
and administer theproduct.

71

Section A | Modification of oral formulations

Table A.4 Examples of medicines that should not be crushed1,7,8,1113


Drug

Formulation

Reason
(refer to Table A.3)

Comments

Alendronate;
alendronate +
cholecalciferol

Tablet

D. Local irritant effect

Limited data available on crushing and administering altered


tablets; consult specialised reference source. Consider
alternative treatment options, e.g. zoledronic acid (IV infusion)
or strontium ranelate (granules for oral suspension).

Amoxycillin +
clavulanic acid

Tablet

A. Altered absorption
characteristics

Oral suspension is available.

Aspirin

Enteric-coated tablet

D. Local irritant effect

Non-enteric-coated formulations can be crushed. Soluble


aspirin is also available.

Azathioprine

Tablet

E. Occupational health
and safety

Handling of cytotoxic medicines requires special safety


precautions to minimise contamination and/or exposure to
potentially hazardous powder.

Bisacodyl

Enteric-coated tablet

D. Local irritant effect

Bisacodyl suppositories are available. Consider alternative


laxative preparations in enema or liquid form. Senna tablets can
be crushed but may be unpalatable.13

Bupropion HCl

Sustained-release tablet

A. Altered release
characteristics

Consider alternative treatment options, e.g. nicotine


replacement therapy.

Carbamazepine

Controlled-release tablet

A. Altered release
characteristics

Oral liquid is available. Immediate-release tablets may be


crushed, but carbamazepine has a narrow therapeutic index
and crushing tablets may lead to incomplete dose delivery.12
Note that tablet formulations are not bioequivalent.7

Chlorpromazine

Film-coated tablet

E. Occupational health
and safety

Oral liquid is available. Special safety precautions are necessary


when handling the tablets to avoid potential contact dermatitis
from exposure to the drug powder.1,13

Clarithromycin

Tablet

F. Palatability

Oral suspension is available. Tablets can be crushed but may be


unpalatable.

Desvenlafaxine

Extended-release tablet

A. Altered release
characteristics

Consider alternative antidepressants that are available as


immediate-release or dispersible tablets (e.g. fluoxetine).
Escitalopram is available as an oral solution.

Diclofenac

Enteric-coated tablet

D. Local irritant effect

Diclofenac suppositories and topical gel are available. Naproxen


is available as an oral suspension. Immediate-release tablets
may be crushed but should be administered with a sufficient
amount of water to ensure that no powder remains in the
gastro-oesophageal tract.

Dipyridamole;
dipyridamole + aspirin

Sustained-release capsule

A. Altered release
characteristics

Immediate-release tablets may be crushed and aspirin given


separately.

Doxycycline

Capsule containing
enteric-coated pellets

D. Local irritant effect

Limited data available on opening capsules and administering


enteric-coated pellets; consult specialised reference source.
Consider alternative treatment options, depending on the
indication for use.

Doxycycline

Tablet

D. Local irritant effect

Consider using capsule formulation instead.

Duloxetine

Capsule containing
enteric-coated pellets

A. Altered absorption
characteristics

Duloxetine is acid labile; contact with gastric acid in the


stomach can reduce oral bioavailability. Consider alternative
antidepressants in immediate-release or dispersible tablet form
(e.g. fluoxetine). Escitalopram is available as an oral solution.

Erythromycin base

Capsule containing
enteric-coated pellets

A. Altered absorption
characteristics
F. Palatability

Erythromycin base is acid labile and also has a bitter taste;


contact with gastric acid in the stomach can reduce oral
bioavailability. Limited data available on opening capsules
and administering enteric-coated pellets; consult specialised
reference source. Erythromycin ethyl succinate is available as an
oral suspension.

Compounding and dispensing

B. Altered stability1

72

Erythromycin ethyl
succinate

Tablet

F. Palatability

Oral suspension is available.

Esomeprazole

Film-coated tablet
containing enteric-coated
pellets

A. Altered absorption
characteristics

Esomeprazole is acid labile; contact with gastric acid in the


stomach can reduce oral bioavailability. Tablets can be dispersed
in half a glass of non-carbonated water. For further information
on the appropriate method of dispersing esomeprazole
tablets, see Clinical monographs, Section D. Granules for oral
suspension and powder for injection are also available.

Section A | Modification of oral formulations

Table A.4 Examples of medicines that should not be crushed1,7,8,1113 (continued)


Drug

Formulation

Reason
(refer to Table A.3)

Comments

Felodipine

Extended/modifiedrelease tablet

A. Altered release
characteristics

Consider using an alternative calcium channel blocker that is


available as immediate-release tablets (e.g. amlodipine).

Ferrous fumarate

Film-coated tablet

D. Local irritant effect

Oral solution is available.

F. Palatability
Modified-release tablet

D. Local irritant effect

Oral solution is available. Vitamin C and folic acid may be given


separately.

Ferrous sulfate + folic


acid capsule

Capsule containing
modified-release pellets

D. Local irritant effect

Limited data available on opening capsules and administering


modified-release pellets; consult specialised reference source.
Oral solution is available. Folic acid may be given separately.

Finasteride

Film-coated tablet

E. Occupational health
and safety

Finasteride is teratogenic, and special safety precautions are


necessary when handling the tablets to prevent exposure of
women who are or may potentially be pregnant to the active
ingredient.1,13

Fluvoxamine

Film-coated tablet

D. Local irritant effect

Tablets may be halved. Consider alternative antidepressants


that are available in immediate-release or dispersible tablet
form (e.g. fluoxetine). Escitalopram is available as an oral
solution.

Gliclazide

Modified-release tablet

A. Altered release
characteristics

Immediate-release tablets may be crushed.

Ibuprofen

Sugar-coated tablet

F. Palatability

Ibuprofen oral suspension and topical gel formulations are


available.

Isosorbide mononitrate

Sustained-release tablet

A. Altered release
characteristics

Tablets may be halved. Consider alternative treatment options,


e.g. glyceryl trinitrate transdermal patch.

Ketoprofen

Capsule containing
sustained-release pellets

A. Altered release
characteristics

Limited data available on opening capsules and administering


modified-release pellets; consult specialised reference source.
Ketoprofen suppositories and topical gel are available.
Naproxen is available as an oral suspension, and piroxicam as
dispersible tablets.

D. Local irritant effect

Lansoprazole

Capsule containing
enteric-coated granules

A. Altered absorption
characteristics

Capsules can be opened and the granules dispersed in water


or juice, or sprinkled onto soft food. For further information on
the appropriate method of altering lansoprazole capsules, see
Clinical monographs, SectionD. Orally dispersible tablets are
also available.

Lansoprazole

Orally dispersible tablet


containing enteric-coated
granules

A. Altered absorption
characteristics

Tablets can be placed on the tongue and gently sucked, or


swallowed whole with water.

Levodopa +
benserazide

Prolonged-release HBS
(hydrodynamically
balanced system) capsule

A. Altered release
characteristics

Dispersible tablets are available. They should be dispersed in


2550mL of water to form a milky white dispersion, which is
then stirred; the dispersion should be taken within 30minutes
of dispersing the tablets.

Levodopa + carbidopa

Controlled-release tablet

A. Altered release
characteristics

Immediate-release tablets may be crushed.

Lithium carbonate

Sustained-release tablet

A. Altered release
characteristics

Limited data available on crushing and administering


immediate-release tablets (which are film coated); consult
specialised reference source.

Melatonin

Prolonged-release tablet

A. Altered release
characteristics

Consider alternative treatment options.

Metformin

Extended-release tablet

A. Altered release
characteristics

Limited data available on crushing and administering


immediate-release tablets (which are film coated); consult
specialised reference source.

Methotrexate

Tablet

E. Occupational health
and safety

Handling of cytotoxic medicines requires special safety


precautions to minimise contamination and/or exposure to
potentially hazardous powder. Consider alternative treatment
options, e.g. parenteral methotrexate for injection.

Metoprolol

Controlled-release tablet

A. Altered release
characteristics

Tablets may be halved. Consider alternative treatment options,


e.g. carvedilol or nebivolol, which are available in immediaterelease tablet form.

Metronidazole

Tablet

D. Local irritant effect

Oral suspension is available.

Compounding and dispensing

Ferrous sulfate +/ folic


acid, vitamin C

F. Palatability

73

Section A | Modification of oral formulations

Compounding and dispensing

Table A.4 Examples of medicines that should not be crushed1,7,8,1113 (continued)

74

Drug

Formulation

Reason
(refer to Table A.3)

Comments

Minocycline

Tablet

D. Local irritant effect

Limited data available on crushing and administering altered


tablets; consult specialised reference source. Consider
alternative treatment options, depending on the indication
for use.

Mirtazapine

Tablet

F. Palatability11

Orally disintegrating tablets are available that rapidly


disintegrate when placed on the tongue and can be swallowed
with or without water.

Morphine sulfate

Sustained-release tablet

A. Altered release
characteristics

Consider alternative morphine formulations, e.g. oral liquid,


controlled-release granules for suspension, capsules containing
enteric-coated pellets that can be opened and taken without
chewing, or parenteral morphine for injection.

Morphine sulfate

Capsule containing
sustained-release pellets

A. Altered release
characteristics

Capsules can be opened and the contents sprinkled onto soft


food or dispersed in 30mL of water. The pellets should be
swallowed without chewing.

Naproxen

Sustained-release tablet

D. Local irritant effect

Limited data available on crushing and administering altered


tablets; consult specialised reference source. Oral suspension
is available.

Nifedipine

Controlled-release tablet

A. Altered release
characteristics

Limited data available on crushing and administering altered


tablets; consult specialised reference source. If crushed,
immediate-release tablets would need to be administered
immediately as the active ingredient is highly light sensitive.

B. Altered stability
Nitrofurantoin

Capsule

D. Local irritant effect1

Limited data available on opening the capsules and


administering the powder contents; consult specialised
reference source. Consider alternative treatment options.

Olanzapine

Film-coated tablet

D. Local irritant effect

Orally dispersible wafers are available that can be placed in the


mouth, or dispersed in a full glass of water, milk or juice and
taken immediately. The wafers rapidly disperse in saliva and can
then be swallowed.

Omeprazole

Tablet containing entericcoated granules

A. Altered absorption
characteristics

Omeprazole is acid labile; contact with gastric acid in


the stomach can reduce oral bioavailability. Some tablet
formulations can be dispersed in non-carbonated water or fruit
juice. Omeprazole is also available as powder for injection. For
further information on the appropriate method of dispersing
omeprazole tablets, see Clinical monographs, Section D.

Omeprazole

Capsule contain entericcoated pellets

A. Altered absorption
characteristics

Limited data available on opening capsules and administering


enteric-coated pellets; consult specialised reference source.
Consider using a dispersible tablet formulation instead.

Oxycodone +/
naloxone

Controlled-release tablet

A. Altered release
characteristics

Oxycodone suppositories and solution for injection are


available. Immediate-release tablets may be crushed.

Paliperidone

Prolonged-release tablet

A. Altered release
characteristics

Consider alternative treatment options, e.g. risperidone oral


solution or orally disintegrating tablets that can be dissolved on
the tongue and then swallowed.

Pantoprazole

Enteric-coated tablet

A. Altered absorption
characteristics

Pantoprazole granules are available. For further information on


the appropriate method of dispersing pantoprazole granules,
see Clinical monographs, SectionD.

Paracetamol

Modified-release tablet

A. Altered release
characteristics

Paracetamol oral suspension, soluble tablets and suppositories


are available. Immediate-release tablets can be crushed but may
be unpalatable.

Paroxetine

Film-coated tablet

D. Local irritant effect

Tablets may be halved. Consider alternative antidepressants


that are available in immediate-release or dispersible tablet
form (e.g. fluoxetine). Escitalopram is available as an oral
solution.

Phenytoin

Capsule

A. Altered release
characteristics

Oral suspension and chewable tablets are available.


Capsules are formulated with phenytoin sodium and are not
bioequivalent to other oral formulations, which contain the
free acid of phenytoin. Phenytoin has a narrow therapeutic
index, and opening the capsules might lead to incomplete drug
delivery.

Piroxicam

Capsule

D. Local irritant effect

Dispersible tablets and topical gel are available.

Potassium chloride

Sustained-release tablet

D. Local irritant effect

Effervescent tablets are available.

Section A | Modification of oral formulations

Table A.4 Examples of medicines that should not be crushed1,7,8,1113 (continued)


Drug

Formulation

Reason
(refer to Table A.3)

Comments

Quetiapine

Modified-release tablet

A. Altered release
characteristics

Limited data available on crushing and administering


immediate-release tablets (which are film coated); consult
specialised reference source.

Rabeprazole

Enteric-coated tablet

A. Altered absorption
characteristics

Consider using an alternative proton pump inhibitor suitable


for dispersion in water or in the mouth, e.g. lansoprazole.
Esomeprazole and omeprazole are available as powder for
injection.

Risedronate

Enteric-coated tablet

A. Altered absorption
characteristics

Consider alternative treatment options, e.g. zoledronic acid (IV


infusion) or strontium ranelate (granules for oral suspension).

Risedronate

Tablet

D. Local irritant effect

Limited data available on crushing and administering noncoated tablets; consult specialised reference source. Consider
alternative treatment options, e.g. zoledronic acid (IV infusion)
or strontium ranelate (granules for oral suspension).

Sulfasalazine

Enteric-coated tablet

A. Altered absorption
characteristics

Consider alternative treatment options, depending on


indication. Uncoated tablets can be crushed but cause
gastrointestinal side effects more frequently than the entericcoated formulation.

Sumatriptan succinate

Film-coated tablet

F. Palatability

Sumatriptan nasal spray and solution for injection are available.

Tamsulosin +/
dutasteride

Prolonged-release tablet

A. Altered release
characteristics

Consider alternative treatment options, e.g. prazosin, which is


available as immediate-release tablets.

Theophylline

Sustained-release tablet

A. Altered release
characteristics

Oral liquid is available.

Topiramate

Film-coated tablet

F. Palatability

Limited data available on crushing and administering altered


tablets; consult specialised reference source. Topiramate is
available as sprinkle capsules, which can be opened and the
contents sprinkled onto a small amount of soft food and taken
immediately without chewing.

Tramadol

Sustained-release tablet

A. Altered release
characteristics

Tramadol oral liquid and solution for injection are available.


Limited data available on opening immediate-release capsules
and administering powdered contents; consult specialised
reference source.

Trimethoprim +
sulfamethoxazole

Tablet

D. Local irritant effect

Oral suspension is available.

Valproate sodium

Enteric-coated tablet

D. Local irritant effect

Valproate syrup, sugar-free liquid and crushable tablets are


available. Because valproate has a narrow therapeutic index,
consider the risk of incomplete dose delivery when crushing
the uncoated tablets.12 Valproate is also available as powder
for injection.

Venlafaxine

Extended-release capsule

A. Altered release
characteristics

Limited data available on opening and administering capsule


contents; consult specialised reference source. Consider
alternative antidepressants that are available in immediaterelease or dispersible tablet form (e.g. fluoxetine). Escitalopram
is available as an oral solution.

Verapamil +/
trandolapril

Sustained-release tablet/
capsule

A. Altered release
characteristics

Sustained-release capsules may be opened, and the contents


sprinkled onto a small amount of soft food and taken
immediately without chewing. Limited data available on
crushing and administering immediate-release tablets (which
are film coated); consult specialised reference source.

Zolpidem

Controlled-release tablet

A. Altered release
characteristics

Limited data available on crushing and administering


immediate-release tablets (which are film coated); consult
specialised reference source. Consider alternative treatment
options.

D. Local irritant effect

Compounding and dispensing


75

Section A | Modification of oral formulations

Further information
Australian Pharmaceutical Advisory Council. Guidelines for medication
management in residential aged care facilities. 3rd edn. 2002.
At:www.health.gov.au/internet/main/publishing.nsf/Content/nmp-pdfresguide-cnt.htm.
Mitchell JF. Oral dosage forms that should not be crushed. Institute for
Safe Medication Practices. 2011. At: www.ismp.org/tools/donotcrush.pdf.
Society of Hospital Pharmacists of Australia. Australian dont rush to
crush handbook. Melbourne: SHPA; 2011.
Vincent M. Do not crush list. 2007. At: www.illawarrapa.com/ipa/
DoNotCrushListSample.pdf.

References
1. Australian Pharmaceutical Advisory Council. Guidelines for
medication management in residential aged care facilities. 3rd
edn. 2002. At: www.health.gov.au/internet/main/publishing.nsf/
Content/nmp-pdf-resguide-cnt.htm.

Compounding and dispensing

2. Paradiso LM, Roughead EE, Gilbert AL, et al. Crushing or altering


medications: whats happening in residential care facilities?
Australasian Journal on Ageing. 2002; 21(3):1237.
3. White R, Bradnam V. Handbook of drug administration via enteral
feeding tubes. 2nd edn. London: Pharmaceutical Press; 2011.
4. Wright D, Chapman N, Foundling-Miah M, et al. Consensus
guideline on the medication management of adults with
swallowing difficulties. 2006. At: www.swallowingdifficulties.com/
images/pdf/dysphagia%20full%20guideline2.pdf.
5. Wright D, Tomlin S. How to help if a patient cant swallow. The
Pharmaceutical Journal. 2011; 286:2714.
6. Church C, Smith J. How stable are medicines moved from original
packs into compliance aids? The Pharmaceutical Journal. 2006;
276:7581.
7. Product information. eMIMS [CD-ROM]. St Leonards: CMPMedica
Australia Pty Ltd; 2008.
8. Mitchell J. Oral dosage forms that should not be crushed or
chewed. Hospital Pharmacy. 2002; 37(2):21314.
9. Marriott JL, Nation RL. Splitting tablets. Australian Prescriber. 2002;
25:1335.
10. Nissen L, Steadman K. Crushing tabletsis it really a problem?
2009. At: www.webstercare.net.au/downloads/crushing_tablets.
pdf.
11. Vincent M. Do not crush listsample list. Wollongong: Pharmacy
Department, Wollongong Hospital; 2007.
12. Nissen L, Haywood A, Steadman K. Solid medication dosage form
modification at the bedside and in the pharmacy of Queensland
hospitals. Journal of Pharmacy Practice and Research. 2009;
39(2):12934.
13. Pink J. To crush or not to crush?. 2007. At: www.mndgp.org.au/
programs/documents_links/Aged%20Care/to%20crush%20or%20
not%20to%20crush.pdf.
14. Therapeutic Research Center. Medications that should not be
crushed. 2008; 24(12): At: www.pharmacistsletter.com.
15. Gowan J. Crushing tabletsissues to consider. NDGP newsletter.
Autumn 2010; 1113. At: www.nevdgp.org.au.

76

Cold chain management


The term cold chain refers to the system of transporting
and storing temperature-sensitive products (including
vaccines) within the products specified temperature
range from the place of manufacture to the point
of administration.1 Various steps in the cold chain
management process call for temperature control and
monitoring to ensure that the products move through
the supply chain under suitable conditions. This includes
the transport and storage of raw materials and products
at the site of manufacture, distribution from wholesalers
to the pharmacy premises, storage at the pharmacy
before administration, and storage after dispensing
until the point of administration. In order to maintain
the products efficacy it is essential that they be stored
within the required temperature range at all times.

Pharmacists should ensure that the cold chain


is maintained in the storage and transport of
temperaturesensitive products. This is supported by
simple, routine processes and written protocols for
monitoring and recording refrigerator temperatures and
maintenance of equipment.

Cold chain monitors are used to show if products have


been exposed to temperatures above the safe range
during transportation.

Freeze monitors are activated at the threshold


temperature (0C or below) and release dye from a
coloured bulb.2

Dual-time temperature indicators contain a


colourchange indicator that shows an estimate
of how long the temperature has exceeded a
specified threshold.

Vaccine vial monitors are heat-sensitive discs


attached to the product that register cumulative
heat exposure.

Storage of
temperaturesensitive products
Pharmacists should be familiar with and adhere to the
National Vaccine Storage Guidelines.2 The guidelines
state that for vaccine storageand for storage of other
temperature-sensitive productspharmacies require
the following:

a reliable and stable refrigerator with


adequate capacity

accurate and reliable temperature


monitoring equipment

a written process for monitoring and recording


temperatures

an appropriately placed temperature probe

education and information for everyone handling


temperature-sensitive products

Coolers are not adequate for transporting


temperature-sensitive products for longer than eight
hours or in extreme conditions. Specialised cold
boxes might be needed.

a maintenance schedule for temperature


monitoring equipment, checking the accuracy
of the thermometer and changing the batteries
where necessary

a written procedure for dealing promptly with a


cold chain breach

Unwanted freezing can occur, usually in the first two


hours after packing.

a written procedure for ordering and rotating stock

a written procedure for receiving


temperaturesensitive products

Only conditioned ice or gel packs should be usedi.e.


packs that have been left at room temperature to
allow the ice or gel at the core to rise to about 0C.

a written procedure for managing a power failure.

The product should be packed securely and should


be insulated so that it does not come into contact
with ice or gel packs.

Coolers containing temperature-sensitive products


should be stored out of direct sunlight.2

Transportation of
temperaturesensitive products
If a cooler (e.g. Esky or Willow) is to be used for storing
or transporting temperature-sensitive products requiring
+2C to +8C, pharmacists should be aware of
the following:

Compounding and dispensing

Both heat and freezing can adversely affect


temperaturesensitive products. Freezing occurs when
products are exposed to temperatures at or below 0C.
Products might not appear to be frozen but might
have been damaged at 0C. This can cause a loss of
potency of cold- or freeze-sensitive products. Exposure
to repeated episodes of heat can cause a cumulative and
irreversible loss of potency.1

Monitoring during transportation

Purpose-built refrigerators
Pharmacies wishing to comply with mandatory
Quality Care Pharmacy Program standards must
have an approved refrigerator for storage of
temperaturesensitive products. Further information is
available at www.guild.org.au/qcpp.
77

Section A | Cold chain management

Instructions for consumers


It is important for consumers to be aware that domestic
refrigerators are intended for food storage and are not
designed to meet the specialised storage requirements
of temperature-sensitive products. Domestic refrigerators
can undergo wide fluctuations in temperature, which
can affect the safety of these products.

Compounding and dispensing

Consumers receiving a vaccine should be advised to


collect it from the pharmacy immediately before their
appointment with their doctor. Alternatively, the product
could be left at the medical clinic. An insulated foil bag
can be provided when temperature-sensitive products
are to be transported in these circumstances.
Some pharmaceutical products require refrigeration
to minimise the risk of microbial growth and ensure
that they remain sterile during the course of therapy.
This includes certain ear drops, eye drops and liquid
antibiotic formulations. It is important that consumers
are informed of the proper storage method and the shelf
life of these products, according to the manufacturers
recommendations.

Management of a suspected
cold chain breach
A cold chain breach, or adverse storage event, refers
to a situation in which a temperature-sensitive product
has been exposed to temperatures outside the specified
range for the productexcluding deviations of up to
+12C for less than 15minutes, such as from opening
the refrigerator door during routine use or restocking.
If a cold chain breach occurs, isolate the product(s) in
the refrigerator and contact the manufacturer for advice.
The manufacturer might ask for information about
the following:

the minimum and maximum temperature readings

when the thermometer was last reset

when the accuracy of the thermometer was


last checked

the estimated time the product was exposed


to temperatures outside the specified range for
the product.

In cases of cold chain breaches, steps should be taken to


prevent future incidents. This includes an assessment of
cold chain processes, such as monitoring, recording and
storage procedures and equipment.

78

References
1. National Health and Medical Research Council. The Australian
immunisation handbook. 9th edn. Canberra: NHMRC, 2008.
At: www.immunise.health.gov.au.
2. Department of Health and Ageing. National Vaccine Storage
Guidelines: strive for 5. Canberra: Department of Health and
Ageing, 2005. At: www.immunise.health.gov.au/internet/
immunise/publishing.nsf/Content/provider-store.

Emulsifiers and stabilisers


Multiphase drug delivery systems such as emulsions,
creams and suspensions are stabilised to avoid unwanted
cracking, aggregation, creaming or sedimentation.
Such systems consist of a discontinuous phase and a
solid continuous phase. The discontinuous phase is
characterised by fluid droplets with at least one drug
dissolved or suspended in the fluid; the continuous
phase surrounds and encapsulates the discontinuous
phase. Stabilisation can be achieved either by the
adsorption of a surface-active agent (surfactant) at the
interface of immiscible phases (modifying the properties
of the interface) or by changing the properties of the
bulk continuous phase.

Emulsions, or liquidliquid dispersions, are formulated as


either oil-in-water or water-in-oil emulsions. Emulsifying
agentssurfactants and emulgentsare used to stabilise
the product.

Emulsifying agents
Surfactants have two distinct regions in their chemical
structure, a hydrophilic region and hydrophobic region.
Because of this, they have a tendency to accumulate
at the boundary between the two phases and can be
grouped according to the charge on the hydrophilic
portion that orients at the interface as follows:

For further information about using emulsifying agents,


see General formulary, page 38.

Oil-in-water emulsions
Multiphase preparations for internal use are generally
formulated as oil-in-water emulsions and traditionally
used gums such as acacia as the emulsifying agent.
Modern formulations use synthetic non-ionic emulgents
and cellulose derivatives such as methylcellulose or
carboxymethylcellulose (carmellose) sodium.
Oil-in-water preparations are used for the topical
application of water-soluble drugs because they are
non-occlusive and are suitable for use on weeping areas.
There is a very wide range of emulgents for oil-in-water
emulsions, and selection is often based on the chemical
compatibility between of the emulsifying agent and
the active ingredient. Anionic surfactants are used
when the active ingredients contain large anions, and
cationic surfactants are used for active ingredients with
large cations. Non-ionic surfactants are more widely
compatible, but they often contain ethylene oxide
chains, which can also bind drugs and preservatives.
The following emulgent systems and emulgents are
commonly used to stabilise oil-in-water dispersions:

anionic surfactantse.g. sodium lauryl sulfate,


sodium stearate, calcium oleate and triethanolamine

cationic surfactantse.g. cetrimide and


benzalkonium chloride

Self-emulsifying glyceryl monostearate (anionic).


Use 35% for lotions, 1015% for creams.

non-ionic surfactantse.g. polysorbates, glyceryl


monostearate and cetomacrogol 1000.

Emulsifying wax (anionic). Use 13% for lotions,


1015% for creams.

In addition to the physicochemical properties of


surfactants, extemporaneous preparation should take
into account taste, odour and toxicity, depending on the
route of administration of the emulsion.1

Cetomacrogol emulsifying wax (non-ionic). Use 13%


for lotions, 1015% for creams. Cetomacrogol is an
example of a non-ionic macrogol ether.

Cetrimide (1 part) (cationic) with cetostearyl alcohol


(9 parts). Use a total of 13% for lotions, a total of
1015% for creams.

Other non-ionic materials. These are ethoxylated


macrogol esters, poloxamers (which are a series
of polyoxyethylenepolyoxypropylene copolymers)
and sorbitan fatty acid ester derivatives that, if
ethoxylated are water soluble (polysorbates) and if
un-ethoxylated are oil soluble.2

Emulsifying agents (emulgents) stabilise the dispersion


of two immiscible liquids by adsorbing at the interface
between the two phases and reducing the interfacial
tension between the phases. The continuous phase will
be the phase in which the fine droplets are suspended
and the emulsifying agent has the greater solubility. The
type and amount of emulgent used will influence the
pharmaceutical properties of the emulsion, including
its physical stability (e.g. viscosity; risk of creaming,
flocculation and phase inversion; and cracking rate),
chemical stability (e.g. compatibility with the active
agent) and the rate of drug release from the product.2

Compounding and dispensing

Liquidliquid dispersions
(emulsions)

The most stable dispersions are produced by using


a combination of emulgents to match the phases to
be dispersed. One method of selecting surfactant
combinations is the HydrophileLipophile Balance
System, which uses numerical values to indicate the
balance between hydrophilic and lipophilic properties of
emulsifying agents.

Water-in oil emulsions


Topical water-in-oil preparations are occlusive and inhibit
the evaporation of secretions from the eccrine sweat
glands. For these emulsions, oil-soluble emulgents such
as calcium oleate, wool fat and wool alcohols have
79

Section A | Emulsifiers and stabilisers

traditionally been used. Synthetic non-ionic emulsifying


agents such as sorbitan esters are now more widely used,
obviating the variability associated with natural products.
The following emulgents are commonly used to stabilise
water-in-oil dispersions:

Soaps. Soaps of calcium, zinc or aluminium.

Wool fat. Use 510%, preferably in conjunction


with some fixed oil, which increases the emulsifying
power of the wool fat.

Wool alcohols. Use 35%, preferably in conjunction


with some fixed oil, which increases the emulsifying
power of the wool alcohols.

Sorbitan esters. Use 0.15%.

Compounding and dispensing

Solidliquid dispersions
(suspensions)
A suspension is a dispersion of finely divided, insoluble
solid particles (the disperse phase) in a fluid (the
dispersion medium, or continuous phase). Dispersed solids
tend to aggregate, settle or cream during storage and
must therefore be shaken to ensure uniformity before use.
If the shelf life of a suspension is short and the
proportion of solids low, a deflocculated system,
whereby the dispersed particles remain as discrete
units, can be used. Particles are kept discreteeither
by increasing the viscosity of the dispersing liquid or
by using of a hydrocolloid as a suspending agent. The
rate of sedimentation is also dependent on the size
of the particles and the difference in density between
the particles and the liquid.2 When the deflocculated
particles do settle, they commonly cake irreversibly on
the bottom of the container. Traditionally, tragacanthbased suspending agents were used in such systems to
increase the viscosity of the dispersing liquid by making
it a structured vehicle.
For longer shelf lives and for more concentrated
suspensions, some extent of controlled polymeric
flocculation is used. Although the larger aggregates of
floccules settle more quickly due to increased particle
size, caking is not such a problem and re-dispersion of
the solids can be achieved by normal shaking. A uniform
dispersion can be poured from the container since the
floccules and vehicle structure take time to reform.
Macromolecular suspending agents have both polymeric
flocculation and viscosity-increasing properties. These
properties, however, can be markedly influenced by ionic
strength and solvent composition. Unless the stated
grade of such agents is used, a variable product results.
The following agents are commonly used to suspend
insoluble drugs:

80

aluminium magnesium silicate, 0.52.5%

carbomer, 0.10.4%

cellulose derivatives (the amount to be used


depending on the grade)carboxymethylcellulose

(carmellose) sodium, carboxymethylcellulose


(carmellose) calcium, hydroxyethylcellulose,
hypromellose and methylcellulose

colloidal silicon dioxide, 110%

povidone (polyvinylpyrrolidone), up to 10%,


depending on grade

sodium alginate, 0.52%

tragacanth products
compound tragacanth powder, 23%
tragacanth mucilage, 1020%.

Gels and mucilages


Gels and mucilages are used as traditional emulsifying
agents, although in most cases their mode of action is
a consequence of their viscosity-increasing properties
rather than as surfactants. They are often used as
stabilisers in addition to a primary emulsifying agent.3
Gels are semi-solid systems formed when inorganic or
organic particles are interpenetrated by a liquid to form
a three-dimensional matrix. Most extemporaneously
prepared gels are semi-solid only below a certain gelling
temperature. Other ingredients in the productparticularly
electrolytes and co-solventsinfluence this temperature.
Large quantities of electrolytes can cause precipitation
of polymers.3 Gels can contract on standing and squeeze
some of the solvent out. If the solvent comes out of a
swollen gel, it is said to exhibit syneresis, or to bleed.1
Mucilages are viscous, aqueous extractions of gums such
as acacia and tragacanth traditionally used as suspending
agents and for thickening the aqueous phase of waterinoil
emulsions. They are prone to microbial contamination
and degradation, as well as depolymerisation.3
A number of common macromolecular materials are
used to form gels. The amount needed depends on
both the grade of the material and the formulation.
The following figures are a general guide only:

aluminium magnesium silicate, up to 10%

gelatin, 510%

pectin, 0.53%

tragacanth, 23%

carbomer, 0.55%

cellulose derivatives (hypromellose and


methylcellulose), 230%

povidone, 1040%.

References
1. Gennaro A ed. Remington: the science and practice of pharmacy.
21st edn. Philadelphia: Lippincott, Williams & Wilkins, 2006.
2. Aulton ME ed. Aultons pharmaceuticsthe design and
manufacture of medicines. 3rd edn. Edinburgh: Elsevier, 2007.
3. Lund W ed. The pharmaceutical codex. 12th edn. London: The
Pharmaceutical Press, 1994.

Units of concentration
Definitions
A mole is the amount of a substance that contains as
many elementary units as there are carbon atoms in
12 g of carbon-12. A millimole (mmol) is onethousandth
of this amount. The elementary unit used must be
specified when the mole is used (e.g. atoms, ions,
molecules) but for practical purposes the weight in
grams of 1 mmol of a substance is one thousandth of its
gram molecular weight.

The molality of a solution is the number of moles of


solute in 1kg of solvent. The molarity of a solution
is the number of moles of solute in 1L of solution.
Molality is generally used for very precise expressions
of concentration because it does not depend on the
solution temperature, whereas molarity does. The
molality of a substance in solution is unchanged by the
addition of a second solute, while the molarity of the
substance will be decreased because of the increase in
total volume.

The crystal forms of some compounds include water


molecules; such compounds are called hydrated salts,
or hydrates. In most cases an accurate estimation of the
number of water molecules per salt molecule is known.
In some cases, however, the name of the salt compound
does not include reference to its hydrated nature,
despite its molecular formula indicating so. This is often
a consequence of the official nomenclature adopted in
Australia from the British Pharmacopoeia. It is important
to check the molecular formula and hydration status of a
salt before doing any molecular conversion calculations.
TableA.5 provides data on ions and salts commonly used
in parenteral infusions.1

Compounding and dispensing

The gram equivalent of an ion is calculated by dividing


the molecular weight in grams by the valency of the ion.
A milli-equivalent is one thousandth of this amount. The
use of millimoles is preferred to use of milli-equivalents,
and use of milli-equivalents is to be discouraged.

Hydrated salts

When percentage is used to express concentration the


following terms are commonly used:
% w/wgrams of solute in 100 g of product
% w/vgrams of solute in 100 mL of product
% v/vmillilitres of solute in 100 mL of product
% v/wmillilitres of solute in 100 g of product.

81

Section A | Units of concentration

Table A.5 Millimoles for ions and salts


Ion
Na

Ca

Compounding and dispensing

Salt

mg of salt containing
1 mmol of ion

23.0

Sodium acid phosphate (NaH2PO4.2H2O)

156

Sodium bicarbonate (NaHCO3)

84

Sodium chloride (NaCl)

58.5

Sodium citrate (C6H5Na3O7.2H2O)

98

Sodium hydroxide (NaOH)

40

Sodium lactate (C3H5NaO3)

112

Sodium phosphate (Na2HPO4.12H2O)

179

Potassium acid phosphate (KH2PO4)

136

Potassium bicarbonate (KHCO3)

100

Potassium chloride (KCL)

74.6

Potassium citrate (C6H5K3O7.H20)

108.1

39.1

2+

Mg

2+

NH4
Cl

mg per mmol

HCO3

HPO4

H2PO4

Lactate

Potassium phosphate (K2HPO4)

87.1

40.0

Calcium chloride (CaCl2.2H2O)

147

Calcium gluconate (C12H22CaO14)

448

24.3

Magnesium chloride (MgCl2.6H2O)

203.3

Magnesium sulfate (MgSO4.7H2O)

246

18.0

Ammonium chloride (NH4Cl)

53.5

35.5

Ammonium chloride (NH4Cl)

53.5

Calcium chloride (CaCl2.2H2O)

73.5

Magnesium chloride (MgCl2.6H2O)

101.7

Potassium chloride (KCl)

74.6

Sodium chloride (NaCl)

58.5

Potassium bicarbonate (KHCO3)

100

Sodium bicarbonate (NaHCO3)

84

Sodium lactatea (C3H5NaO3)

112

Potassium phosphate (K2HPO4)

174.2

Sodium phosphate (Na2HPO4.12H2O)

358

Potassium acid phosphate (KH2PO4)

136

Sodium acid phosphate (NaH2PO4.2H2O)

156

Sodium lactatea (C3H5NaO3)

112

61.0

96.0

97.0

89.1

a. Sodium lactate is sometimes required in terms of bicarbonate because lactate is metabolised to bicarbonate.

References
1. Lund W ed. The pharmaceutical codex. 12th edn. London: The
Pharmaceutical Press, 1994;4650.

82

Isosmotic and isotonic solutions


Pharmaceutical solutions to be applied to delicate
membranes of the body are adjusted to have
approximately the same osmotic pressure as that of the
body fluid.

Osmotic pressure
Two solutions with the same osmotic pressure are
referred to as isosmotic. Aqueous solutions are
considered isosmotic with body fluids if they contain
approximately 300 milliosmoles of solute/L. An osmole
represents 1mole of osmotically active particles.1

n = molarity # P

where P is the number of osmotically active particles


formed upon the effective dissociation of a molecule
of solute.

To calculate the amount of adjusting material to be


added, the following formula can be used:
w = 0.52 - a
b

where
w = the concentration, in g/100 mL (% w/v), of the
adjusting material
a = the freezing point depression of the unadjusted
solution (i.e. the freezing point depression of the
solution of drug(s) and other substances) and
b= the FD1% of the adjusting material.
Three points should be noted:

The method assumes that freezing point depression


(FD) is directly proportional to concentration for
dilute solutions. In other words, a 2% solution of
a drug will have twice the FD of a 1% solution of
that drug, while a 0.25% solution will have onequarter of the FD of a 1% solution. This is a close
approximation for most drugs in dilute solution.

The value a is obtained by multiplying the FD1% of


the substance to be adjusted (i.e. the drug, or the
unadjusted substance) by the percentage strength
of this substance. In other words, a could be
considered as equal to XY, where X = FD1% of the
substance to be adjusted and Y = the percentage
strength of that substance.

Where two or more ingredients are present and


the solution requires adjustment to isotonicity, the
foregoing expression could be considered in the
following expanded form:

Isotonic solutions
A solution having the same osmotic pressure as a
particular body fluid is isotonic (of equal tone) with
that specific body fluid when all the following three
circumstances apply:

The membranes in contact with the solution are


impermeable to the solute.

The solute does not alter the permeability of


membranes to any other substance present.

No chemical reaction leads to a change in the total


concentration of dissolved ions or molecules.

Two of the common methods for adjusting the tonicity


of aqueous solutions are the freezing-point depression
method and the sodium chloride equivalent method.

Freezing point depression


The freezing point of blood serum and lachrymal
secretions is 0.52C, and any aqueous solution that
freezes at this temperature has the same osmotic
pressure.
The isotonic concentration (% w/v) of a substance is:
C ISO = 0.52
FD 1%

where FD1% is the freezing point depression of a


1% solution.

w=

Compounding and dispensing

The number (n) of osmoles per litre of solution is


calculated as follows:

Solutions that are hypotonic to blood and lachrymal


secretions can be made isotonic by the addition of a
calculated amount of a suitable substanceusually
sodium chloride or glucose.

0.52 - ^X 1 Y1 + X 2 Y2 + X 3 Y3 + fh
b

Sodium chloride equivalence


The sodium chloride equivalence (SCE) method offers an
alternative way of calculating isotonicity values. The SCE
of a substance is the mass (in grams) of sodium chloride
that will produce the same osmotic effect as 1g of
the substance.
The SCE of a substance can be calculated from the FD1%
by the relationship:
SCE = 0.9 # FD 1%
0.52

where 0.9 is the percentage strength of an isotonic


solution of sodium chloride.

83

Section A | Isosmotic and isotonic solutions

TableA.6 lists some sodium chloride equivalents and


freezing point depressions. Among other references
listing these values are the British Pharmaceutical Codex,
the USP Pharmacists Pharmacopeia and the Merck Index.

Table A.6 Isosmotic concentration, freezing


point depression and sodium chloride
equivalence for a range of substances1
Ciso
(% w/v)

FD1% (C)

SCE (g)

3.85

0.135

0.23

0.31

0.54

0.098

0.18

Aminocaproic acid

0.148

0.26

Aminophylline

0.098

0.17

Amitriptyline hydrochloride

0.10

0.17

Acetazolamide sodium
Acetic acid

Compounding and dispensing

Adrenaline acid tartrate

5.7

Ampicillin sodium

5.78

0.09

0.16

Amylobarbitone sodium

3.6

0.143

Antazoline hydrochloride
Apomorphine hydrochloride
Ascorbic acid
Atropine methonitrate
Atropine sulfate

5.04
6.52
8.85

Benzalkonium chloride

Boric acida
Calcium chloride (2H2O)

2.6
1.9
1.7

Calcium gluconate

Disodium edetate

0.132

0.23

Ecothiopate iodide

0.090

0.16

Edrophonium chloride

3.36

0.175

0.31

Ephedrine hydrochloride

3.2

0.169

0.30

Ergometrine maleate

0.089

0.16

Erythromycin lactobionate

0.04

0.07

0.05

Glucose (anhydrous)

5.05

0.100

0.18

0.17

Glucose monohydrate

5.55

0.091

0.16

Glycerola

2.6

0.202

0.35

Heparin sodium

12.2

0.042

0.07

Histamine acid phosphate

4.1

0.148

0.25

Homatropine hydrobromide

5.67

0.096

0.17

Hyoscine hydrobromide

7.85

0.068

0.12

0.110

0.20

0.144

0.25

0.041

0.07

0.10
0.074

0.13
0.16

0.101
0.10
0.225
0.241
0.283

0.18
0.18
0.39
0.42
0.5

0.298

0.51

0.091

0.16

0.118

0.2

0.041

0.07

0.095

0.17

Cephazolin sodium

0.074

0.13

Cetrimide

0.051
0.06
0.14
(calc)
0.085

Imipramine hydrochloride
Isoniazid

4.35

Kanamycin sulfate
Lactose

9.75

0.04

0.07

Lignocaine hydrochloride

4.42

0.125

0.22

Lincomycin hydrochloride

6.6

0.090

0.16

Magnesium chloride

2.02

0.26

0.45

Magnesium sulfate

6.3

0.094

0.17

Mannitol

5.07

0.099

0.17

0.101

0.18

Methadone hydrochloride
Methicillin sodium

6.0

0.099

0.18

Methoxamine hydrochloride

3.82

0.148

0.26

0.084

0.15

0.09

Metoclopramide
hydrochloride

0.10

Morphine hydrochloride

0.086

0.15

Morphine sulfate

0.078

0.14

0.24
0.15

0.058

0.10

0.098

0.18

Naloxone hydrochloride

8.07

0.083

0.14

Naphazoline hydrochloride

4.0

0.155

0.27

0.067

0.12

Neomycin sulfate
Neostigmine bromide

5.52

Cloxacillin sodium

84

0.27

0.18

4.4

Cocaine hydrochloride

0.42

0.158

0.105

Carbenicillin sodium

Citric acid monohydrate

0.245

Diphenhydramine
hydrochloride

0.31

0.36

Chlorpromazine
hydrochloride

Dimethyl sulfoxide

0.030

0.203

Chlorpheniramine maleate

0.17

0.182

2.82

Chlorbutol

0.095

3.34

Carbachol

6.83

6.75

Gentamicin sulfate

0.23

Chloramphenicol sodium
succinate

0.11

Dexamethasone sodium
phosphate

Fluorescein sodium

0.13

6.8

0.066

0.14

4.5

Cephalothin sodium

8.92

0.23

Calcium lactate

Cephaloridine

0.20

Cytarabine

0.08

0.17

Borax

0.14

0.117

0.132

0.095

3.05

0.078

5.30

0.7

Benzyl alcohol

Bethanechol chloride

7.3

Cyclopentolate hydrochloride

0.25

0.21

5.54

Codeine phosphate

0.41

0.115

Benzylpenicillin (sodium)

SCE (g)

1.28

0.09

5.48

FD1% (C)

Ethanol (dehydrated
alcohol)a

Benztropine mesylate

Benzylpenicillin (potassium)

Ciso
(% w/v)

0.08
6.3

0.091

0.16

0.123

0.22

Neostigmine methylsulfate

5.2

0.108

0.20

Nicotinamide

4.5

0.148

0.26

0.145

0.25

Nicotinic acid

Section A | Isosmotic and isotonic solutions

Ciso
(% w/v)

FD1% (C)

SCE (g)

5.94

Ciso
(% w/v)

FD1% (C)

SCE (g)

4.2

0.100

0.18

Sulfadiazine sodium

0.137

0.24

Papaverine hydrochloride

0.060

0.10

Suxamethonium chloride

0.117

0.20

Pentolinium tartrate

0.097

0.17

Tetracycline hydrochloride

0.078

0.14

0.139

0.25

0.050

0.09

Nikethamidea

Pethidine hydrochloride

4.8

0.124

0.22

Thiamine hydrochloride

Phenobarbitone sodium

3.95

0.135

0.24

Thiethylperazine maleate

Phenol

2.8

0.199

0.35

Thiopentone sodium

3.5

0.155

0.27

0.32

Thiotepa

5.67

0.090

0.16

0.141

0.25

Timolol maleate

0.077

0.13

0.038

0.07

0.194

0.34

Phenylephrine hydrochloride

3.0

Phenylethyl alcohol

0.184

4.2

0.16

Tobramycin

7.74

0.076

0.13

Tolazoline hydrochloride

Pilocarpine hydrochloride

4.08

0.134

0.24

Tubocurarine chloride

0.077

0.13

0.131

0.23

Zinc chloride

0.354

0.61

0.09

Zinc sulfate

0.085

0.15

a. Can cause haemolysis of red blood cells.

Pilocarpine nitrate
Polymyxin B sulfate

0.049

Potassium acid phosphate


(anhydrous)

2.18

0.252

0.44

Potassium chloride

1.19

0.439

0.76

Potassium iodide

2.6

0.205

0.34

Potassium nitrate

1.6

0.323

0.56

Pralidoxime chloride

2.87

0.183

0.32

0.128

0.22

0.122

0.21

Prochlorperazine edisylate

0.033

0.06

Promethazine hydrochloride

0.112

0.18

Propranolol hydrochloride

0.122

0.20

Procainamide hydrochloride
Procaine hydrochloridea

5.05

Propylene glycola

2.0

0.262

0.45

Pyridostigmine bromide

4.13

0.125

0.22

0.208

0.36

0.190

0.33

0.267

0.46

Pyridoxine hydrochloride
Silver nitrate

2.74

Sodium acetate (3H2O)


Sodium acid phosphate
(2H2O)

2.8

0.202

0.36

Sodium benzoate

2.25

0.232

0.40

Sodium bicarbonate

1.4

0.381

0.65

Sodium chloride

0.9

0.576

1.00

Sodium citrate

3.02

0.178

0.31

Sodium iodide

2.37

0.223

0.39

Sodium lactate

1.72

0.315

0.55

Sodium metabisulfite

1.38

0.389

0.67

Sodium nitrite

1.08

0.481

0.84

Sodium phosphate (12H2O)

4.45

0.126

0.22

Sodium salicylate

2.53

0.209

0.36

Sodium sulfate

3.95

0.148

0.26

Sodium thiosulfate

3.0

0.180

0.31

Spectinomycin hydrochloride

5.66

0.092

0.16

0.038

0.07

Streptomycin sulfate
Sucrose

9.25

0.047

0.08

Sulfacetamide sodium

3.8

0.133

0.23

3.05

7.65

References
1. Lund W ed. The pharmaceutical codex. 12th edn. London:
ThePharmaceutical Press, 1994;5066.

Compounding and dispensing

0.090

Physostigmine sulfate

Physostigmine salicylate

85

Buffer solutions

Compounding and dispensing

Buffer solutions minimise changes in pH value when


small amounts of acid or alkali are added. The pH of
pharmaceutical preparations is controlled in order
to increase solubility, minimise chemical instability,
standardise product colour, and protect a preparation
from microbial contamination.
Provided they are compatible with the substance to
be injected, phosphate buffers are generally used for
adjustment of parenteral preparations. Phosphates react
with calcium to form an insoluble precipitate of calcium
phosphate. They exert their maximum buffer capacity at
a pH value of about 6.8. For ophthalmic preparations,
either phosphate or borate buffers can be used,
depending on the pH value required and compatibility
with the substances present. Borate buffers are used
in topical preparations and should not be used for
injections or on abraded skin, where systemic absorption
could occur.1
Buffer solutions can be adjusted to be isotonic with
blood and lachrymal fluids by the addition of sodium
chloride. The solutions should be prepared using purified
water that has been freshly boiled and cooled, and they
should be stored in alkali-free glass and discarded within
three months of preparation. Tables A.7 to A.9 show
examples of buffers.1

Table A.7 Sorensens phosphate buffer


To obtain a solution with a particular pH value, the following solutions
are mixed in the proportions show in the table.

0.067 M potassium dihydrogen phosphate: 0.908% KH2PO4 in


aqueous solution (FD1% = 0.254C).
0.067 M disodium hydrogen phosphate: 2.39% Na2HPO4.12H2O in
aqueous solution (FD1% = 0.127C).

Table A.8 Walpoles acetate buffer (0.1 M)


To obtain a solution with a particular pH value, the following solutions
are mixed in the proportions shown in the table.

0.1 M acetic acid: 0.6% w/v CH3COOH in aqueous solution


(FD1% = 0.31C)
0.1 M sodium acetate: 1.36% CH3COONa.3H2O in aqueous
solution (FD1% = 0.163C).

0.1 M
CH3COOH
(mL)

0.1 M
CH3COONa.3H2O
(mL)

pH value at
25C

92.6

7.4

3.6

88.0

12.0

3.8

82.0

18.0

4.0

73.6

26.4

4.2

61.0

39.0

4.4

51.0

49.0

4.6

40.0

60.0

4.8

29.6

70.4

5.0

21.0

79.0

5.2

17.6

82.4

5.4

9.6

90.4

5.6

Table A.9 Isotonic phosphate buffer


To obtain a solution with a particular pH value, the following solutions
are mixed in the proportions shown in the table, and to make the
solution isotonic the specified amount of sodium chloride is added, as
shown.

0.067 M sodium acid phosphate: 1.04% NaH2PO4.2H2O in aqueous


solution (FD1% = 0.207C).
0.067 M disodium hydrogen phosphate (sodium phosphate BP):
2.39% Na2HPO4.12H2O in aqueous solution (FD1% = 0.127C).

0.067 M KH2PO4
(mL)

0.067 M
Na2HPO4.12H2O
(mL)

pH value at
25C

0.067 M
NaH2PO4.2H2O
(mL)

0.067 M
NaCl
Na2HPO4.12H2O (g)
(mL)

pH
value
at
25C

pH
value
at
37C

90.0

10.0

5.9

90

10

0.52

5.8

5.7

80.0

20.0

6.3

80

20

0.51

6.1

6.1

70.0

30.0

6.5

70

30

0.50

6.4

6.3

60.0

40.0

6.6

60

40

0.49

6.5

6.5

50.0

50.0

6.8

50

50

0.48

6.7

6.7

40.0

60.0

7.0

40

60

0.46

6.9

6.9

30.0

70.0

7.1

30

70

0.45

7.1

7.1

20.0

80.0

7.4

20

80

0.44

7.3

7.3

90

0.43

7.7

7.7

95

0.42

8.1

8.1

10.0

90.0

7.8

10

5.0

95.0

8.1

Note: If a drug is to be dissolved in the buffer system, the amount of


sodium chloride should be reduced appropriately. For pH calculations
involving phosphoric acid, pKa2 is better expressed as the practical
value of 6.8 at isotonic ionic strength, rather than the thermodynamic
value of 7.1.

86

Section A | Buffer solutions

Table A.10 Isotonic borate buffer


To obtain a solution with a particular pH value, the following solutions
are mixed in the proportions shown in the table, and to make the
solution isotonic the specified amount of sodium chloride is added, as
shown.

0.2 M boric acid: 1.24% boric acid in aqueous solution


(FD1% = 0.288C).
0.05 M borax: 1.91% borax in aqueous solution (FD1% = 0.241C).

0.2 M
boric
acid (mL)

0.05 M
borax
(mL)

NaCl
(g)

97

0.27

94

90

6.8

0.27

10

85

pH value
at 25C

15

6.8

7.1

0.27

7.1

7.4

0.26

pH
value at
37C

7.4

7.6

7.6

80

20

0.26

7.9

7.8

70

30

0.24

8.1

8.1

65

35
45

45

0.21

55

40

20
10

8.6

8.8

0.11

90

8.5

8.7

0.14

80

8.4

8.6

0.18

70

8.2

8.4

0.19

60

30

8.2

8.7

9.0

0.07

8.9

9.1

9.0

Table A.11 Isotonic citrate buffer


To obtain a solution with a particular pH value, the following solutions
are mixed in the proportions shown in the table, and to make the
solution isotonic the specified amount of sodium chloride is added, as
shown.

1.1% citric acid monohydrate in aqueous solution


(FD1% = 0.098C)
1.5% sodium citrate in aqueous solution (FD1% = 0.178C).

1.1%
citric acid
monohydrate
(mL)

1.5%
sodium
citrate
(mL)

NaCl
(g)

pH value
at 37C

32.1

67.9

0.54

5.0

29.7

70.3

0.53

5.1

24.5

75.5

0.51

5.3

17.8

82.2

0.49

5.6

10.7

89.3

0.48

5.9

6.2

93.8

0.47

6.2

3.2

96.8

0.46

6.5

To obtain a solution with a particular pH value, the amounts of


disodium phosphate (Na2HPO4.12H2O) and citric acid (C6H8O7.H2O)
shown in the table are added to 1L of water.

Na2HPO4.12H2O
(g/L)

C6H807.H2O
(g/L)

pH

1.4

20.6

2.2

4.4

19.7

2.4

7.8

18.7

2.6

11.4

17.7

2.8

14.7

16.7

3.0

17.7

15.8

3.2

20.4

15.0

3.4

23.1

14.2

3.6

25.4

13.6

3.8

27.6

12.9

4.0

29.7

12.3

4.2

31.6

11.7

4.4

33.5

11.2

4.6

35.3

10.7

4.8

36.9

10.2

5.0

38.4

9.7

5.2

39.9

9.3

5.4

41.5

8.8

5.6

43.3

8.3

5.8

45.2

7.7

6.0

47.3

7.1

6.2

49.6

6.5

6.4

52.1

5.7

6.6

55.3

4.8

6.8

59.0

3.7

7.0

62.3

2.7

7.2

65.1

1.9

7.4

67.1

1.3

7.6

68.6

0.9

7.8

69.7

0.58

8.0

Compounding and dispensing

55

0.23

Table A.12 McIlvaine universal


citratephosphate buffer

Note: Universal buffers contain two or more buffer systems and give
a buffering action over a relatively wide range of pH values. Their
buffering capacity is lower than that of the general buffers at the same
concentration. The McIlvaine citratephosphate buffer system covers
the range from pH 2.2 to pH 8.0.

References
1. Lund W ed. The pharmaceutical codex. 12th edn. London:
The Pharmaceutical Press, 1994;679.

87

pKa values
pKa is a logarithmic measure of the acid dissociation
constant and a measure of the fraction of drug available
in un-ionised form at physiological pH. TableA.13
lists the pKa values of some compounds relevant to
pharmacy practice.

Increasing urinary pH will increase renal clearance


of susceptible acidic drugs by reducing tubular
reabsorption.

Basic drugs with a pKa of their conjugate acids


in the range of about 7.5 to 10.5 have highly
variable renal clearance. Increasing urinary pH
will decrease the renal clearance for susceptible
basic drugs. Halflife, area under the plasma drug
concentrationtime curve, efficacy and toxic effects
can also be affected.

Drugs that are highly polar in their un-ionised


state or whose total body clearance is not highly
dependent on renal clearance are unlikely to
undergo significant changes in elimination when
urinary pH or the flow rate is altered.1

Acids, bases and pKa

Compounding and dispensing

Virtually all compounds are weak acids or bases


containing at least one site that can reversibly dissociate
or accept a proton (a hydrogen ion) to form a negatively
charged anion or a positively charged cation.
A compound that dissociates by releasing a proton is
termed an acid; weak acids have increased aqueous
solubility at pH values greater than their pKa. When
pH is equal to pKa, 50% of the compound is in ionised
form. Weak acids in a solution having a pH greater
than their pKa will be largely in the ionised form. The
solubility of weak acids is essentially unaffected as a
function of pH when pH is lowi.e. one to two pH units
below the pKa. At more than two pH units below the
pKa the proportion of an unionised compound increases
and precipitation can occur; the converse is true for the
solubility of compounds that are weak bases.1
Compounds having at least one acid group and one
basic group are called zwitterions. Such compounds
normally have a U- or V-shaped curve when solubility is
plotted as a function of pH, depending on how different
the pKa values are from each other.

pKa values
The middle column of Table A.13 shows the dissociation
constant of acids. A value less than 2 means the
compound is a strong acid and will be almost completely
dissociated in aqueous solutions and therefore not well
absorbed. The greater the pKa value of acids, the smaller
the extent of dissociation in acidic pH.
Compounds that accept protons are bases, and the pKa
of the corresponding protonated form of the base is
listed in the right-hand column of the table. Low values
mean the compound is a weak base.

Table A.13 pKa values of selected substances

Drug absorption
Because medicines are preferentially absorbed in
un-ionised form, the pKa value of a drug influences
absorption across biological membranes such as the
gastric mucosa, the renal tubules, the placenta and
into breast milk. Aspirin, for example, which is a weak
acid with a pKa of about 3.473.50, is preferentially
unionised in the acidic gastric juice and well absorbed
into the gastric mucosa of the stomach.

Acid
Acetazolamide

7.2

Acetic acid

4.8

Acetylcysteine

9.5 (30C)

Acitretin

5.0

Adefovir dipivoxil

4.6

Adrenaline

10.2; 12.0 (20C)

8.7

Albendazole

10.7

5.4

Alfentanil

Urinary pH and renal clearance


For some drugs, passive re-absorption in the renal
tubules, and hence renal clearance, is influenced by
the physicochemical properties of polarity and the
degree of ionisation. When a drug is in un-ionised
form it will diffuse more readily from urine back into
the bloodstream. Dietary changes, drugs and patient
characteristics (e.g. kidney failure or diarrhoea) can alter
urine pH:

88

Variation in urinary pH or flow rate can cause


marked variation in the renal clearance of acidic
drugs with pKa values between about 3.0 and 7.5.

Base

Aliskiren

6.5
12.5

9.8

Allopurinol

9.4

Alprazolam

2.4

Alprenolol

9.5 (20C)

Amantadine
Ambrisentan

10.1
1.0

2.8

Amiloride

8.7

Aminacrine

9.5

Aminophylline
Aminosalicylic acid
Amiodarone

5.0
3.6

1.8
6.6

Section A | pKa values

Table A.13 pKa values of selected substances


(continued)
Acid

Base

Amitriptyline

9.4

Dabigatran

Ammonia

9.3

Dacarbazine

7.4

Dantrolene

Amoxycillin

2.4; 9.6

Acid

Base

4.1

12.6
4.4

7.5

9.9 (20C)

Dapsone

Amphotericin B

5.5

10.0

Dasatinib

Ampicillin

2.5

7.3

Debrisoquine

Antazoline

2.5; 10.1

Deferiprone

Aprepitant

4.2

Desipramine

10.2 (24C)

Amphetamine

1.3; 2.5
10.8

3.1; 6.8
11.9

9.4

3.0

Ascorbic acid

4.2; 11.6

Desloratadine

9.4

Aspirin

3.5

Dextropropoxyphene

6.3

Atazanavir

11.1

Diazepam

Atenolol

9.6 (24C)

Diazoxide

8.5

Atomoxetine

10.1

Diclofenac

4.0

Atropine

9.9 (20C)

Dihydrocodeine

8.8

Dihydroergotamine

6.8 (24C)

Azathioprine

8.2

Baclofen

3.9

Benzoic acid

4.2

Dinoprostone

Benzylpenicillin

2.8

Diphenhydramine

Boric acid

9.2

Diphenoxylate

9.6

3.3

Diltiazem

Bromazepam

2.9; 11.0

Disopyramide

Bromocriptine

4.9

Dobutamine

Brompheniramine

3.9; 9.2

Dopamine

Bupivacaine

8.1

Doxepin

8.5

Doxorubicin

7.7
4.8
9.0
7.1
10.2

8.4
9.5

10.6

8.8
8.3
8.2; 10.2

Buprenorphine

10.0

Caffeine

14.0

Doxycyline

3.4; 7.7

9.5

Captopril

3.7, 9.8

Dronedarone

7.4

9.4

Carbonic acid

6.4; 10.4

Droperidol

Cefotaxime

2.1, 3.4, 10.9

Dutasteride

Cefuroxime

2.5

Cephalexin

5.2

Cephalothin

7.6
13.3

Ephedrine

9.6

Ergometrine

6.8

2.2 (35C)

Ergotamine

6.4 (24C)

Cephazolin

4.71

Erlotinib

5.42

Chloral hydrate

10.0

Erythromycin

Chlorambucil

5.8

Ethacrynic acid

Chloramphenicol

5.5

2.5; 7.3

8.91a
3.5 (20C)

Ethambutol

6.3; 9.5

Chloroquine

8.4; 10.8

Ethosuximide

Chlorpheniramine

9.1

Ethylnoradrenaline

8.4

Chlorpromazine

9.3 (20C)

Etravirine

1.2

Famotidine

7.1

Chlorthalidone

9.4

Cilostazol

2.2

Cimetidine

6.8

Citric acid

3.1; 4.6; 6.4

Clindamycin
Clonazepam

1.5

Clonidine

8.2

Codeine

8.2

Colchicine
Cycloserine
Cytarabine

1.7 (20C)
4.5

9.5

10.0

Fentanyl
Fingolimod

7.7
10.5

Fenoterol

2.7

Flucytosine

10.7

Flunitrazepam
Fluorouracil
Fluphenazine

8.7
9.3

Flucloxacillin

4.3

8.5
8.4

12.2

Flecainide

7.4

Compounding and dispensing

4.8

2.9
1.8

8.0; 13.0
3.9; 8.1

89

Section A | pKa values

Table A.13 pKa values of selected substances


(continued)

Compounding and dispensing

Acid
Fluvastatin

5.5

Folic acid

4.7; 6.8; 9.0

Fosamprenavir calcium

1.8

Frusemide
Fusidic acid

Acid
Mefenamic acid
Mepivacaine

1.8

7.7
7.8

3.9

Mesalazine

3.0

5.4

Metaraminol

Galantamine

7.9

Metformin

Gentamicin

8.0

Methacycline

Base

4.2

Mercaptopurine

6.0; 13.9
8.6
2.8; 11.5 (32C)

3.5; 7.6

9.2

Glibenclamide

5.3

Methadone

Gliclazide

5.8

Methicillin

2.8

Glycine

2.3

Methotrexate

3.8; 4.8

5.6

Glutethimide

4.5

Methyldopa

2.2; 10.6; 12.0

9.2

8.4 (22C)

9.8

8.3

Granisetron

10.5

Methylhydroxybenzoate

Guanethidine

8.3, 11.4

Methysergide

6.6

Haloperidol

8.3

Metoclopramide

0.6; 9.0

Homatropine

9.7 (23C)

Metoprolol

9.7

Hydralazine

0.5; 7.1

Metronidazole

2.5

Hydrochlorothiazide

7.0; 9.2

Mianserin

7.1

Hydrocortisone sodium
succinate

5.1

Miconazole

6.7

Hydromorphone

8.2

Hyoscine
Hyoscyamine
Ibuprofen

5.3

Idoxuridine

8.3

Imipramine

Midazolam

7.6 (23C)

Minocycline

9.3

Minoxidil
Morphine

6.2
2.8; 7.8

4.6
9.9

Mustine
9.5 (24C)

Naloxone

0.9

Naproxen

5.0; 9.5

8.0
6.4
7.9

4.2

Indacaterol

8.7

Indapamide

8.3

Naphazoline

10.9

4.5

Nebivolol

8.6

1.8, 3.5, 10.8

Neostigmine

12.0

Indomethacin
Isoniazid

8.6 (20C)

Nevirapine

Ketamine

7.5

Nicotinamide

Ketoconazole

2.9; 6.5

Nicotinic acid

4.8

2.0

3.5

Nitrazepam

10.8

3.2

Ketoprofen

4.8

Nitrofurantoin

7.6

Labetalol

7.4

Noradrenaline

9.8; 12.0

Lactic acid

3.9

Isoprenaline

Ketorolac

10.1; 12.0 (20C)

Lamotrigine

8.7

Orciprenaline

Lansoprazole

8.8

Orphenadrine

Levamisole

8.0

Oxazepam

Levodopa

2.3; 9.7; 13.4

Lincomycin
Liothyronine

4.2
0.5; 3.3

8.6
9.7

9.0; 11.4

10.1
8.4

11.6

1.7

8.7

Oxprenolol

9.5

7.9

Oxycodone

8.9

7.5

Palonosetron

8.5

Loperamide

12.0

Nortriptyline
5.7

Lignocaine

90

Base

9.8

Paracetamol

9.5

8.7

Pazopanib

10.2

6.1

Lorazepam

11.5

1.3

Penicillamine

1.8; 10.5

7.9

Losartan

4.2

4.3

Pethidine

8.7

Section A | pKa values

Table A.13 pKa values of selected substances


(continued)
Acid

Base

Phenethicillin

Acid
2.7

Sulfacetamide

5.4

1.8

Phenindione

4.1

Sulfadiazine

6.5

2.0

Sulfasalazine

2.4; 8.3; 11.0

0.6

Pheniramine
Phenobarbitone

Base

4.2; 9.3

Sunitinib

7.4

Phenol

10.0

Phenoxymethylpenicillin

2.7
10.1

Phentolamine
9.8

Phenytoin

8.3

Pholcodine
Phosphoric acid

10.0

Tartaric acid

3.0; 4.2

Temazepam

Phentermine

Phenylephrine

8.95

Tapentadol

9.5

1.6

Terbutaline

10.1; 11.2

8.8

7.7

Tetracycline

3.3; 7.7

9.7

8.8

Theophylline

8.6

Thiamine
9.3; 8.0

2.1; 7.12b; 12.3

4.8; 9.0

Thyroxine

2.2; 6.7

Ticarcillin

2.5; 3.4

10.1

7.9; 1.8

Timolol

8.8

Pilocarpine

6.88

Tobramycin

6.2; 7.4; 7.6; 8.6

Pindolol

8.8

Tocainide

Piroxicam

6.3

Topotecan

7.8
8.9

7.7

Pralidoxime

8.0

Tranylcypromine

8.2

Prazosin

6.5

Triamterene

6.2

11.3

Trifluoperazine

8.1

Trimethoprim

7.2

Pregabalin

4.2

Probenecid

3.4

Procainamide

9.2

Urea

Procaine

9.0

Valproic acid

4.8

Procarbazine

6.8

Varenicline

9.2

Prochlorperazine

3.7; 8.1

Venlafaxine

9.4

Promethazine

9.0

Vildagliptin

8.4

Propranolol

9.5

Vinblastine

5.4; 7.4

0.2

Propyl hydroxybenzoate

8.4 (22C)

Vincristine

Propylthiouracil

7.8

Vorinostat

9.4

9.8

Warfarin

5.0

5.0

a. Determined in 66% dimethyl formamide.

Quinine

4.1; 8.5

Ranitidine

2.3; 8.2

b. A more practical value of pKa2 of phosphoric acid at isotonic


ionic strength is 6.8.

Reserpine

6.6

Pseudoephedrine
Pyridoxine

9.0

Riboflavin

1.9, 10.2 (20C)

Rifampicin

1.7

7.9

Rivaroxaban

13.3

0.7; 1.0

Rizatriptan

9.5

Ropinirole

9.5

Rosuvastatin

4.2

Saccharin

1.6

Salbutamol

9.3

Salicylic acid

3.0; 13.4

5.0; 7.4
0.5

Note: Unless otherwise noted, the values given are at 25C and
represent the thermodynamic values taken from published data.
Values should be regarded as approximate only.27

References
1. Lund W ed. The pharmaceutical codex. 12th edn. London:
ThePharmaceutical Press, 1994.
2. SciFinder Database, American Chemical Society.
At: www.cas.org/products/sfacad/index.html.

10.3

3. Newton DW, Kluza RB. pKa values of medicinal compounds in


pharmacy practice. Drug Intelligence and Clinical Pharmacy. 1978;
12:54654.

Saxagliptin

8.3

Sertindole

9.0

4. Raymond GC, Born JL. An updated pKa listing of medicinal


compounds. Drug Intelligence and Clinical Pharmacy. 1986;
20:6835.

Solifenacin

9.0

Sotalol

8.3

Sucralfate

0.431.19

Sulfamethoxazole

5.6

Sulindac

4.5

Compounding and dispensing

Physostigmine

9.8

5. Moffat AC. Clarks analysis of drugs and poisons. London: The


Pharmaceutical Press; 2004.
6. Williams DA, Lemke TL. Foyes principles of medicinal chemistry.
5th edn. Philadelphia: Lippincott, Williams & Wilkins, 2002.
7. ChEMBL database. European Bioinformatics Institute.
At: www.ebi.ac.uk/chembldb.

91

Latin abbreviations used in prescription writing

Compounding and dispensing

One of the main causes of medication errors is the


continued use of potentially confusing abbreviations and
dose expressions. Latin was once the language of health
care and its use made medical literature universally
readable among educated people. Today English is
the predominant language of medical literature, yet
despite this many health professionals continue to use
Latin abbreviations.

92

Most of the abbreviations that follow are listed for


historical interest and teaching purposes only since
they are no longer used in prescription writing. Some,
however, are still in common use. In a document titled
Recommendations for Terminology, Abbreviations and
Symbols Used in the Prescribing and Administration of
Medicines by the New South Wales Therapeutic Advisory
Group strongly recommends the use of plain English and
the avoidance of abbreviations, including Latin ones.1
In recognition of the fact that some abbreviations are
still in use, it nevertheless includes a list of terms and
abbreviations that are commonly used and understood
and therefore considered acceptable for use. These
appear in bold script in TableA.14 below.

Table A.14 Latin abbreviations used in


prescription writing

Abbreviation

Latin

English13

brev

brevis

short

bull

bulliens

boiling

cum

with

calid

calidus

warm or hot

cap

capiat

let him take

cc

cum cibum; cum cibis

with food

cib

cibus

food

co

compositus

compound

coch

cochleare

spoonful

collut

collutorium

mouthwash

collyr

collyrium

eye lotion

conspers

conspersus

dusting powder

cort

cortex

bark

crem

cremor

cream

cyath

cyathus

glass

dies

day

deglut

deglutiatur

swallow

dest

destillatus

distilled

dexter

right

dieb altern

diebus alternis

every other day

d in p aeq

divide in partes
aequales

divide into equal parts

dol urg

dolore urgente

when the pain is severe

dolent part

dolenti parti; dolentes


partes

the painful part/s

Abbreviation

Latin

English

aa

ana

of each

ac

ante cibum; ante cibis

before food

ad

ad

make up to; to

dulc

dulcis

sweet

ah

alternis horis

every other hour

dup

duplex

double

altern d

alterno die

every other day

dura

durus

hard

altern hor

alterno hora or
alternis horis

every other hour

dur dolor

duarte dolare

while the pain lasts

emp

emplastrum

a plaster

enem

enema

enema

ext

extractum

an extract

f or ft

fiat (fiant)

let it (them) be made

13

ap

ante prandium

before dinner

applic

applicatio

an application

applicetur;
applicentur,
applicandus;

to be applied

flav

flavus

yellow

aq

aqua

water

fort

fortis

strong

aq bull

aqua bulliens

boiling water

frigid

frigidus

cold

aq calid

aqua calida

warm or hot water

fusc

fuscus

brown

aq dest

aqua destillata

distilled water

garg

gargarisma

a gargle

aq ferv

aqua fervens

boiling water

gtt

guttae

drops

aq gel

aqua gelida

cold water

guttur

aq pluv

aqua pluvialis

rainwater

appl gutturi
applicandus

to be applied to the
throat

aur

auris

the ear

hab

habeat

let him have (or take)

hac nocte

tonight

aur dextr (laev)

auris dextrae (laevae)

to right (left) ear

hac noct

aurist

auristiliae

ear drops

haust

haustus

a drink

bid

bis in die

twice a day

hd

hora decubitus

at bedtime

bd

bis die

twice a day

hs

hora somni

at bedtime

Section A | Latin abbreviations used in prescription writing

Latin

English13

Abbreviation

Latin

English13

ic

inter cibos; inter cibis

between meals

qqh

quaque quarta hora

every four hours

inf

infusum

infusion

q6h

quaque sex hora

every six hours

infric

infricetur; infricandus

to be rubbed in

qs

sufficient

inj

injectio

injection

quantum sufficiat;
quantitas sufficiens;
quantum satis

in p aeq

in partes aequales

in equal parts

quat

quater

four times

insuff

insufflatio

insufflation

quot

quotidie

daily

irrig

irrigatio

irrigation

Rx

recipio

prescription

lac

lactis

milk

sumendus

to be taken

laev

laevus

left

sem ind die

semel in die

once a day

lat

lateri dolenti

to the affected side

semih

semihora

half an hour

liq

liquor

a liquid

sig

signa

label

lot

lotio

a lotion

sinist

sinister

left

mane

in the morning

sos

si opus sit

if necessary

m; mitt

mitte

send

sp

spiritus

spirit

misce

mix

ss

semisse

half

md

more dicto

as directed

stat

statim

immediately

to be used as directed

sum; sumend

sumendus

to be taken

morning and night

supp

suppositorium

a suppository

SVM

spiritus vini
methylatus

methylated spirit

SVR

spiritus vini
rectificatus

rectified spirit

mdu
m et n

more dicto utendus


mane et nocte

mist

mistura

a mixture

moll

mollis

soft

nocte

at night

narist

naristillae

nasal drops

syr

syrupus

syrup

neb

nebula

mist

tab

tabletta

a tablet

n et m or n mque

nocte maneque

night and morning

tdd

ter de die

three times a day

tds

ter die sumendum

to be taken three times


a day

tid

ter in die

three times a day

tinct or tr

tinctura

a tincture

troch

trochiscus

a lozenge

tuss

tussis

a cough

tuss urg

tussi urgente

when the cough is


troublesome

nig

niger

black

nov

novus

new

octarius

a pint

o alt hor

omni alternis horis

every other hour

ocul

oculo

to (for) the eye

oculent

oculentum

an eye ointment

oh

omni hora

every hour

om

omni mane

every morning

urendus

to be used

on

omni nocte

every night

UEA

ung emulsif aquos

aqueous cream

paa

parti affectae
applicandus

to be applied to the
affected part

ung

unguentum

an ointment

ut dict

ut dictum

as directed

p aeq

partes aequales

equal parts

ut direct

ut directum

as directed

part effect

parti affectae

to the affected area

utend

utendus

to be used

part dolent

parti dolente

to the painful part

vap

vapor

an inhalation

pc

post cibum; post cibis

after food

pess

pessus

a pessary

pig

pigmentum

a paint

References

po

per os

by mouth

pond

ponderosus

heavy

prn

pro re nata

when necessary

pulv

pulvis

a powder

1. New South Wales Therapeutic Advisory Group Inc.


Recommendations for terminology, abbreviations and symbols
used in the prescribing and administration of medicines. Australian
Commission on Safety and Quality in Healthcare. January 2011.
At: www.health.gov.au/internet/safety/publishing.nsf/Content/compubs_NIMC-terminology/$File/32060v2.pdf.

qd

quaque die

every day

qid

quater in die

four times a day

quaque

every

Compounding and dispensing

Abbreviation

2. Harris P, Nagy S, Vardaxis N. Mosbys dictionary of medicine,


nursing and health professions. 2nd edn. Sydney: Elsevier, 2010.
3. Stedmans medical dictionary. 28th edn. Baltimore: Lippincott,
Williams & Wilkins, 2006.

93

Medical abbreviations

Compounding and dispensing

Abbreviations are commonly used in health-related


information, and new ways of truncating, abbreviating
and expressing terminology and complex terms
are continually being developed. Many identical
abbreviations can mean something completely different
depending on which health professional is using them.
An example is MMR, which can mean medication
management review; measles, mumps, rubella vaccine;
monthly morbidity reports; or multimedia resources.

Abbreviation

Expanded form

AMSE

abbreviated mental state examination

ANA

antinuclear antibodies

ANCA

antineutrophil cytoplasmic antibodies

anti-CPP

antibodies to cyclic citrullinated peptides

anti-HCV

hepatitis C antibody

APTT (aPTT)

activated partial thromboplastin time

ARA

acute respiratory acidosis

It is important to use abbreviations cautiously and avoid


them if interpretation could be ambiguous.

ARDS

acute respiratory distress syndrome

ARF

acute renal failure; acute respiratory failure

Some abbreviations used in Australia differ


from those found in international literature. An
extensive list of abbreviations is available online at
www.medicabbreviations.com.

ARB

angiotensin type 1 receptor antagonists

ARMD

age-related macular degeneration

AS

ankylosing spondylitis; aortic stenosis

ASA

acetylsalicylic acid

Table A.15 Common medical abbreviations

AST

aspartate aminotransferase

AT1

angiotensin type 1 receptor

AT1RA

angiotensin type 1 receptor antagonists

AT2

angiotensin type 2 receptor


aortic valve; atrioventricular; arteriovenous

Abbreviation

Expanded form

AAA

abdominal aortic aneurysm; ascending aortic


aneurysm; acquired aplastic anaemia

Ab

antibody

AV

ABG

arterial blood gases

AXR

abdominal x-ray

ACA

adenocarcinoma; anticardiolipin antibody;


anterior cerebral artery

Ba

barium

BAL

blood alcohol level; bronchoalveolar lavage

BBB

bundle branch block; bloodbrain barrier

BCC

basal cell carcinoma

BG

blood gases; blood glucose

BGL

blood glucose level

Bili

bilirubin

BKA

below-knee amputation

BMD

bone mineral density

BMI

body mass index


bladder neck obstruction; bowels not open

ACD

anaemia of chronic disease

ACE

angiotensin-converting enzyme

ACEI

angiotensin converting enzyme inhibitor

ACh

acetyl choline

ACR

albumincreatinine ratio

ACS
ACT
ACTH
AD

activated clotting time


adrenocorticotrophic hormone
Alzheimers disease; alternate days

ADH

antidiuretic hormone

BNO

ADHD

attention deficit hyperactivity disorder

BNP

B-type natriuretic peptide

ADP

adenosine diphosphate

BO

bowels open; bowel obstruction

ADT

adult diphtheria and tetanus vaccine

BP

blood pressure; British Pharmacopoeia

AE

air entry; adverse effect; atrial


ectopics; above elbow

BPD

bipolar disease/disorder; borderline personality


disorder; biparietal diameter

AF

atrial flutter/fibrillation

BPH

benign prostatic hypertrophy/hyperplasia

AFB

acid-fast bacilli

BS

bowel sounds; breath sounds; blood sugar

AIDS

acquired immune deficiency/immunodeficiency


syndrome

BSA

body surface area

BSE

breast self-examination

AKA

above-knee amputation

ALL

acute lymphoblastic leukaemia; acute lymphocytic


leukaemia

BSL

blood sugar level

BUN

blood urea nitrogen

ALP

alkaline phosphatase

Bx

biopsy

alanine aminotransferase

Ca

carcinoma; cancer; calcium

AMD

age-related macular degeneration

CAB

coronary artery bypass

AMI

acute myocardial infarction

CABG

coronary artery bypass graft

ALT

94

acute coronary syndrome

Section A | Medical abbreviations

Expanded form

Abbreviation

Expanded form

CAD

coronary artery disease

DBP

diastolic blood pressure

CAL

chronic airflow limitation

DDx

differential diagnosis

C-ANCA

antineutrophil cytoplasmic antibody test

DM

dermatomyositis

CAP

community acquired pneumonia

DMARD

disease-modifying antirheumatic drugs

CAPD

continual ambulatory peritoneal dialysis

DMMR

domiciliary medication management review

CAT

computerised axial tomography

DPI

dry powder inhaler

complete blood count

DRE

digital rectal examination

common bile duct

DU

duodenal ulcer

clinical breast examination; complete blood


examination

DUE

drug usage evaluation

DVT

deep vein thrombosis

CBP

complete blood picture/profile

Dx

diagnosis

CCB

calcium channel blocker

EAR

CCF

congestive cardiac failure; chronic cardiac failure

estimated average requirement; expired air


resuscitation

CDT

combined diphtheria and tetanus vaccine

EBV

EpsteinBarr virus

CE

cardiac enzymes

ECC

CEA

carotid endarterectomy; carcinogenic embryonic


antigen

emergency cardiac care; external cardiac


compression

ECG

electrocardiogram; electrocardiograph

CF

cystic fibrosis; childrens formula; cardiac failure

ECT

electroconvulsive therapy

CFU

colony-forming units

EDV

end diastolic volume

CHF

chronic heart failure; congestive heart failure

EEG

electroencephalogram; electroencephalograph

CI

confidence interval; cardiac insufficiency

EF

ejection fraction

CK

creatine kinase

eGFR

estimated glomerular filtration rate

CK-MB

creatine kinase MB isoenzyme

ELISA

enzyme-linked immunosorbent assay

CLL

chronic lymphocytic leukaemia

EN

enteral nutrition

CMI

Consumer Medicine Information

ENA

extractable nuclear antigens

CML

chronic myelocytic/myeloid leukaemia

EOM

external otitis media

CNS

central nervous system

ERCP

endoscopic retrograde cholangiopancreatography

COAD

chronic obstructive airways disease

ESR

erythrocyte sedimentation rate

COBH

change of bowel habit

ET

endotracheal

COLD

chronic obstructive lung disease

EtOH

ethyl alcohol

COPD

chronic obstructive pulmonary disease

EUC

electrolytes, urea and creatinine

CPAP

continuous positive airway pressure

FBC

full blood count or picture

CPK

creatine phosphokinase

FBE

full blood examination; full body examination

CrCl

creatinine clearance

FBG

fasting blood glucose

CREST

calcinosis, Raynauds phenomenon, (o)esophageal


dysfunction, sclerodactyly, telangiectasia

Fe

iron

FEF

forced expiratory flow

FEV

forced expiratory volume

FEV1

forced expiratory volume in one second

FH

family history
faecal occult blood test

CBC
CBD
CBE

CRF

chronic renal failure; chronic respiratory failure

CRP

C-reactive protein

CSF

colony-stimulating factor;
cerebrospinal fluid

CSU

catheter specimen urine

FOBT

CT

computerised axial tomography

FSH

follicle stimulating hormone

CTD

connective tissue disease

FUO

fever of unknown origin

cTnI

cardiac troponin I

FVC

forced vital capacity

CTnT

cardiac troponin T

GCA

giant cell arteritis

CVA

cerebrovascular accident

GCT

glucose challenge test (50 g load)

CVD

cerebrovascular disease; cardiovascular disease

GDM

gestational diabetes mellitus

CXR

chest x-ray

GERD

gastro-(o)esophageal reflux disease

D&C

dilatation and curettage

GFR

glomerular filtration rate

DAT

dementia Alzheimers type; diet as tolerated

GGT

gamma glutamyltransferase

Compounding and dispensing

Abbreviation

95

Section A | Medical abbreviations

Abbreviation

Expanded form

Abbreviation

Expanded form

GI

gastrointestinal

JVP

jugular venous pressure/pulse

GM-CSF

granulocyte-macrophage colony-stimulating
factor

JVPNE

jugular venous pressure not elevated

KJ

kilojoule

LA

left atrium; left atrial; local anaesthetic

LAA

left atrial appendage

LAC

lupus anticoagulant

LAP

laparoscopy; laparotomy; left atrial pressure;


leucocyte alkaline phosphatase; lower abdominal
pain

LBBB

left bundle branch block

LBO

lower bowel obstruction

LD50

lethal dose in 50% of the test population

LDH

lactate dehydrogenase; lactic acid dehydrogenase

LDL

low-density lipoprotein

LIF

left iliac fossa

LFT

liver function test, lung function tests

LH

luteinising hormone

LHF

left heart failure

LMWH

low-molecular-weight heparin

GORD

gastro-oesophageal reflux disease

GP

glycoprotein; general practitioner; gram positive

G6PH

glucose-6-phosphate dehydrogenase

GTT (also OGTT)

glucose tolerance test (75 g 2 hr)

GU

gastric ulcer; genito-urinary

HA

headache

HAV

hepatitis A virus

Hb
HbA1C
HBsAg
HBV

Compounding and dispensing

HCT

96

HCV

haemoglobin
glycosylated haemoglobin
hepatitis B surface antigen
hepatitis B virus
haematocrit; hydrochlorothiazide
hepatitis C virus

HD

haemodialysis; high dosage

HDL

high-density lipoprotein

HDL-C

high-density lipoprotein cholesterol

HIV

human immuno-deficiency/immuno-suppressive
virus

LOA

loss of appetite

LOC

loss of consciousness

HLA

human leucocyte antigen

LVEF

left ventricular ejection fraction

HMR

home medicines review

LVF

left ventricular failure

HR

heart rate; hazard ratio

LVH

left ventricular hypertrophy

HSA

human serum albumin

MAOI

mono-amine oxidase inhibitor

HSV

herpes simplex virus

MBA

multiple blood/biochemical analysis

HT

hypertension

MC&S

microscopy, culture and sensitivity

Hx

history

MCTD

mixed connective tissue disease

IA

intra-arterial

MCU

microculture of urine

IBD

inflammatory bowel disease

MCV

mean cell volume; mean corpuscular volume

IBS

irritable bowel syndrome

MDI

metered dose inhaler

ICH

intracranial haemorrhage

MDP

manic depressive psychosis

ICLE

intracapsular lens extraction

MI

myocardial infarction

IDDM

insulin-dependent diabetes mellitus

MIC

minimum inhibitory concentration

Ig

immunoglobulin

MMR

IgM anti-HAV

hepatitis A immunoglobulin M antibody

measles, mumps, rubella vaccine; medication


management review

IL-1

interleukin-1

MMSE

mini-mental state examination

IL-1Ra

interleukin-1 receptor antagonist

MODM

mature onset diabetes mellitus

IM

intramuscular; infectious mononucleosis

MRI

magnetic resonance imaging

INR

international normalised ratio

MRSA

methicillin/multiple resistant Staphylococcus aureus

IOL

induction of labour; insertion of lens;


intraocular lens

MS

multiple sclerosis

MSE

mental state examination

MSSU

mid-stream specimen of urine

MSU

mid-stream urine

MVA

motor vehicle accident

MVD

mitral valve disease

NAD

no abnormality detected; non-Alzheimers dementia

NBM

nil by mouth; no bowel movement; normal


bowel movement

NBS

normal bowel sounds

IOP

intraocular pressure

ISMN

isosorbide mononitrate

ITP

idiopathic thrombocytopenic purpura

IU

international unit

IUD

intra-uterine (contraceptive) device

IV

intravenous

IVP

intravenous pyelogram

IVT

intravenous transfusion

Section A | Medical abbreviations

Expanded form

Abbreviation

Expanded form

NFI

not for investigation

PPAR

peroxisome proliferator activated receptor

NFO

no further orders

PPI

proton pump inhibitor

NFR

not for resuscitation

PPM

permanent pacemaker

NG

nasogastric

PPs

peripheral pulses

NIDDM

noninsulin dependent diabetes mellitus

PR

per rectum; pulse rate; prothrombin ratio

NHL

non-Hodgkins lymphoma

PSA

prostate-specific antigen

NKA

no known allergies

PSS

progressive systemic sclerosis

NOF

neck of femur

PT

prothrombin time

NQMI

nonQ wave myocardial infarction

PTA

percutaneous transluminal angioplasty

NSA

no significant abnormality

PTCA

percutaneous transluminal coronary angioplasty

NSAID

non-steroidal anti-inflammatory drug

PTH

parathyroid hormone

NSR

normal sinus rhythm

PTSD

post-traumatic stress disorder

NSTEACS

non-ST elevation acute coronary syndrome

PTT

partial thromboplastin time

NSTEMI

non-ST elevation myocardial infarction

PU

peptic ulcer

NVD

nausea, vomiting and diarrhoea; normal


vaginal delivery

PUD

peptic ulcer disease

PUO

pyrexia of unknown origin

PV

per vagina

PVD

peripheral vascular disease

PVR

post-void residual

QALYs

quality-adjusted life-years

QMI

Q-wave myocardial infarction

RA

rheumatoid arthritis; right atrium

RAS

renal artery stenosis; renin angiotensin system

RBC

red blood count; red blood cell

RCC

red cell count

RCT

randomised controlled trial

RCV

red cell volume

RDS

respiratory distress syndrome

REM

rapid eye movement

RF

renal failure; rheumatic fever; rheumatoid factor;


respiratory failure, risk factor

RFT

respiratory function test; renal function tests

RHF

right heart failure

RIF

right iliac fossa

OA

osteoarthritis; on admission

OCD

obsessive compulsive disorder

OE

on examination; otitis externa

OGTT

oral glucose tolerance test

OR

odds ratio; oral rehydration

OTC

over-the-counter

PCI

percutaneous intervention

PCO2

partial pressure of CO2

PCOS

polycystic ovary syndrome

PCV

packed cell volume

PE

pulmonary embolus; premature ejaculation;


pre-eclampsia

PEG

percutaneous enterogastric tube; polyethylene


glycol; percutaneous endoscopic gastrostomy

PEF

peak expiratory flow

PEFR

peak expiratory flow rate

PERL

pupils equal, reacting to light

PERLA

pupils equal, reacting to light and


accommodating

PET

positron emission tomography

RMMR

residential medication management review

PFT

pulmonary function tests

RPR

rapid plasma reagin; resting pulse rate

PI

product information

RR

reference range; relative risk; respiratory rate

PIC

percutaneous intravascular catheter

RSV

respiratory syncytial virus

PKU

phenylketonuria

RUQ

right upper quadrant

PLT

platelets

RVF

right ventricular failure

PM

polymyositis; postmortem

Rx

prescription

PMH

past medical history

SA

sinoatrial

PMR

polymyalgia rheumatica

SAARD

slow-acting antirheumatic drug

PMS

premenstrual syndrome

SAE

serious adverse event

PMT

premenstrual tension

SBE

subacute bacterial endocarditis

PN

parenteral nutrition; peripheral neuropathy

SBO

small bowel obstruction

PO

per-oral; pulmonary oedema

SC

subcutaneous

PO2

partial pressure of oxygen

SCS

spinal canal stenosis

post.

posterior

SD

senile dementia; standard deviation; sudden death

Compounding and dispensing

Abbreviation

97

Compounding and dispensing

Section A | Medical abbreviations

Abbreviation

Expanded form

Abbreviation

Expanded form

SH

social history

UA

unstable angina

SIADH

syndrome of inappropriate antidiuretic hormone

UEC

urea, electrolytes, creatinine

SIDS

sudden infant death syndrome

UFH

unfractionated heparin

SL

sublingual

URTI

upper respiratory tract infection

SLE

systemic lupus erythematosus; slit lamp


examination

US

ultrasound

UTI

urinary tract infection

VaD

vascular dementia

VC

vital capacity

VD

venereal disease

VEGF

vaso-endothelial growth factor

VF

ventricular fibrillation; ventricular flutter

VIP

vaso-active intestinal peptide

VLBW

very low birth weight

VSD

ventricular septal defect

VRE

vancomycin-resistant enterococci

VT

ventricular tachycardia

WBC

white blood cell

WCC

white cell count

WNL

within normal limits

XRT

x-ray therapy/treatment

fracture

present; noted

+/-

uncertain/equivocal; plus or minus

++

present significantly

+++

present in excess

not present; no abnormality

1/7

one day

1/24

one hour

1/52

one week

1/12

one month

4/24

every four hours

5/7

five days

4/52

four weeks

3/12

three months

6/12

six months

12/12

one year

SNRI

serotonin noradrenaline re-uptake inhibitor

SOA

swelling of ankles

SOB

short of breath

SOBOE

shortness of breath on exertion

SPPS

stable plasma protein solution

SPR

see previous result

SS

Sjgrens syndrome; systemic sclerosis

SSG

split-skin graft

SSRI

selective serotonin re-uptake inhibitor

ST

sinus tachycardia

STD

sexually transmissible disease

STEMI

ST elevation myocardial infarction

STI

sexually transmitted infection; sexually


transmissible infection

SV
SVT
Sx

supraventricular tachycardia
signs; symptoms

T3

iiothyronine/triiodothyronine

T4

thyroxine

TA
TCA
TCD
TDM
TENS
TFT
THR
TIA
TIBC
TKR
TMJ

98

stroke volume

temporal arteritis
tricyclic antidepressant
transcranial Doppler
therapeutic drug monitoring
transcutaneous electrical nerve stimulation
thyroid function tests
total hip replacement; target heart rate
transient ischaemic attack
total iron-binding capacity
total knee replacement
temporomandibular joint

TNF

tumour necrosis factor

TOE

trans-oesophageal echocardiogram

TOV

trial of voiding

TPMT

thiopurine methyltransferase

TPN

total parenteral nutrition

Trig

triglycerides

TRUS

transrectal ultrasound

TSE

transmissible spongiform encephalopathy

TSH

thyroid-stimulating hormone

TURP

transurethral resection of prostate

Tx

therapy; treatment

TZD

thiazolidinediones

U&E

urea and electrolytes

Further information
Harris P, Nagy S, Vardaxis N. Mosbys dictionary of medicine,
nursing & health professions. Marrickville: Elsevier, 2006.
Williams J ed. The Australian dictionary of clinical abbreviations,
acronyms and symbols. 3rd edn. North Ryde: Health Information
Management Association, 2001.
New South Wales Therapeutic Advisory Group Inc.
Recommendations for terminology, abbreviations and symbols
used in the prescribing and administration of medicines. Australian
Commission on Safety and Quality in Healthcare. January 2011.
At: www.health.gov.au/internet/safety/publishing.nsf/Content/compubs_NIMC-terminology/$File/32060v2.pdf.

Section B
Principles of drug therapy

Pharmacokinetics (the effects of the body on the drug including drug absorption, distribution, metabolism and
excretion) and pharmacodynamics (the effects of the drug on the body including the nature, magnitude and duration
of the pharmacological response to the drug) are fundamental principles of drug therapy. This section includes
information for pharmacists and pharmacy students on the application of these principles in their everyday pharmacy
practice and studies, to inform and support clinical decision-making, including appropriate drug selection, dosing
regimens and monitoring of drug responses.

Pharmacokinetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Pharmacokinetic data. . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Therapeutic drug monitoring . . . . . . . . . . . . . . . . . . . . 117
Drugs commonly monitored in clinical practice. . . . 119
Antineoplastics and immuno-suppressives
recommended therapeutic concentration ranges. . 122
Drug interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Potentially serious drug interactions . . . . . . . . . . . . . . 129
Cytochrome P450 substrates, inhibitors & inducers . 131
Drugs affecting or transported by P-glycoprotein. . 133
Medicines in older people. . . . . . . . . . . . . . . . . . . . . . . . 134
Dose calculations for children. . . . . . . . . . . . . . . . . . . . 138
Physiological differences in children that influence
the pharmacokinetic characteristics of medicines. . 139
Average weights, heights and body surface
areas for children from birth to 14 years . . . . . . . . . . 140
Dosing in renal impairment . . . . . . . . . . . . . . . . . . . . . . 142
CockcroftGault equation. . . . . . . . . . . . . . . . . . . . . . . . 142
Modification of Diet in Renal Disease equation. . . . 142
CKD Epidemiology Collaboration formula. . . . . . . . . 143
Medicines in breast milk. . . . . . . . . . . . . . . . . . . . . . . . . . 146
Individualised medicine . . . . . . . . . . . . . . . . . . . . . . . . . . 149

99

Pharmacokinetics
Pharmacokinetics describes the relationship between the
dose of a medicine, the unbound drug concentration at
the site of action (the drug receptor) and the time course
of drug concentration in the body.1 The pharmacokinetic
properties of individual drugs influence pharmacists
decisions on issues such as dosage adjustment in certain
disease states and assessment of the clinical significance
of a possible drug interaction.

Principles of drug therapy

Half-life
The half-life (t1/2) of a medicine is defined as the time
required for half of the medicine to be eliminated from
the body. It is governed by the volume of distribution
and clearance of the drug, in accordance with
the following:
half-life = 0.693 # volume of distribution
clearance

The volume of distribution (Vd) is a measure of the


extent to which a medicine distributes out of the
bloodstream and into the tissues of the body (i.e. the
site of the drug receptors). It is a function of the relative
binding to plasma proteins and tissue components: the
greater the binding to the tissues relative to the plasma
proteins, the higher the volume of distribution. Since
it takes longer for organs eliminating drugs to access
molecules that are distributed extensively throughout
the body, half-life tends to increase as the volume of
distribution increases. Clearance is a measure of how
efficiently a medicine is removed from the bloodstream
by the organs of elimination (generally the liver and
kidneys). For any given drug, a reduction in clearance
(e.g. resulting from impaired liver or kidney function)
will result in an increase in half-life unless there is also a
compensatory change in the volume of distribution.
The half-life of a medicine is clinically important because
it determines the frequency of dosing, the time to reach
steady-state with constant dosing, and the duration of
action after a single dose.1

daily dosing is usually adequate for medicines with a


half-life of days (e.g. digoxin).

Time taken to reach steady-state


with constant dosing
The half-life of a medicine dictates when the medicine
must be administered in order for the plasma
concentrations to reach steady-state, which, as a
general rule, takes about four to five half-lives. This has
important implications for drugs with long halflives.
Similarly, once a person stops taking a medicine it
will take about four to five half-lives before very low
or negligible drug concentrations are achieved. If the
dose is increased or decreased, it will take four to five
halflives to reach the new steady-state.

Duration of action after a


single dose
Generally, for a single dose of a medicine the longer
the half-life the longer the plasma concentration will
remain in the effective range. The decrease in duration
is logarithmic rather than linear, increasing the dose
by a certain percentage does not result in an identical
increase in the duration of action.
In some instances the onset and offset of the clinical
effects of a medicine will not be related to that
medicines half-life. This usually occurs in the following
circumstances:

The drug acts via an irreversible mechanism


e.g.aspirins effect on platelets.

The drug acts via an indirect mechanism


e.g.warfarins effect on the synthesis of blood
coagulation factors.

The medicine is a pro-drugin which case it is the


half-life of the active species that is important.

The medicine is converted to an active metabolite


possessing a long half-life. For example, allopurinol
(t1/2 = 0.52 hours) has a primary metabolite
(oxypurinol) with the same pharmacological effects
but a half-life of 1830 hours. Allopurinol is
therefore suitable for once-a-day dosing despite its
short half-life.

Frequency of dosing
It might be necessary, for example, to administer a
medicine with a short half-life (e.g. morphine in non
sustained release formulations, which has a half-life of
two to three hours) up to four times a day to achieve
a constant therapeutic effect and avoid undesirably
large fluctuations in plasma levels. Sustained-release
formulations can allow the dosage interval to be
extended to once or twice daily, especially if the
medicine has a narrow safety margin. In contrast, once100

Pharmacists use a medicines half-life to guide


recommendations on things such as:

the timing of administration

the likely impact of missing a dose

assessing when a person starting a new medicine


(or changing dosage) might be expected to reach a
steady-state plasma level

Section B | Pharmacokinetics

the optimal timing to obtain blood samples for


therapeutic drug monitoring

interpreting the likely onset and offset of a


potential medicine interaction.

The stated half-life shown in TableB.1 should


be regarded as a population average. Within the
population there might be a two-fold to four-fold
variation in halflife (or more in some cases), and in
most cases it is not possible to predict what the halflife of a medicine will be in an individual.

Clearance

total clearance =
CI (metabolic) + Cl (renal) + CI (other)

Clearance can be defined as the volume of plasma


from which the drug is completely removed per unit
of time (e.g. mL per minute or L per hour).
Clearance can also be normalised for body size; it is
then expressed as mL/minute/kg.2 Table B.1 shows
clearance values that have been normalised in
thisway.
Along with the volume of distribution, clearance is
an important determinant of a medicines half-life.
Its clinical importance of clearance stems from
the pharmacokinetic relationship described by
thefollowing:
plasma concentration =

rate of drug input into body


clearance

For a given dosage rate, therefore, the plasma


concentration of a medicine will double if the
clearance of the medicine is halved.
The clearance of some medicines will decrease
in certain disease states. Such a decrease might
necessitate a change in dosing. For examples see
Dosing in renal impairment, page 142.
For an individual, clearance will be influenced by
genetic, physiological and pathological factors.
In some disease states, however, such as renal or

In summary, clearance is an important parameter in


determining the maintenance dose required to achieve
a particular target average concentration such that:
maintenance dose rate = C ss # Cl
F

where Css is the average steady-state concentration


associated with optimal drug effects and F is the
bioavailability.
The clearance of a medicine is usually independent of
dose, and a doubling of the dose will usually result
in a doubling of the steady-state concentration. For
some drugs at usual therapeutic doses, however, or
for many drugs in overdosage, the clearance changes
as the dose or plasma concentration changes. In this
case the medicine is said to exhibit dose-dependent
pharmacokinetics. An important clinical example of
this is phenytoin.

Principles of drug therapy

The clearance (Cl) of a medicine is a measure of


how efficiently the body irreversibly eliminates the
medicine from the systemic circulation. The higher
the clearance the more efficiently the medicine
is removed. The term refers to excretion of the
unchanged drug from the body via the urine and
gastrointestinal contents, expelled in exhaled air and
in sweat, and metabolic conversion into a different
chemical entity, most commonly by the liver. The total
body clearance is the sum of the individual organ
clearances contributing to the clearance of the drug:

hepatic failure, clearance and volume of distribution


can sometimes change in the same direction, exerting
opposing effects on a drugs half-life, which can
remain unchanged. Changes in clearance might
not necessarily be reflected in changes in half-life
if there is a compensating change in the volume of
distribution. Environmental factors such as diet and
other medicines can also alter the clearance value.
Indeed, many clinically important interactions occur
because one medicine alters the clearance of another.

Fraction excreted unchanged


Elimination of unchanged drug via the kidneys is the
net result of three processesglomerular filtration,
tubular secretion and tubular reabsorption. The
fraction of a dose excreted unchanged in urine
(e) is a quantitative measure of the contribution
of renal excretion to overall drug elimination. The
relative importance of the kidney as an organ of
elimination for a medicine increases as the e value
approaches1, whereas other (non-renal) mechanisms
become dominant as e approaches zero. For a drug
that is predominantly metabolised, a low e value
is to be expected. For a drug that is filtered and not
reabsorbed or secreted, renal clearance is determined
only by the fraction of drug unbound to plasma
protein and the glomerular filtration rate.
A drugs e value shows whether a reduced dose
is likely to be necessary to maintain a safe and
effective plasma concentration in renal impairment.
Even if a medicine is predominantly metabolised
(i.e. has a lowe), its dosage might still need to
be reduced in renal impairment if the metabolites
are active and predominantly renally excreted
(e.g.morphine). Dosage adjustment in patients
with impaired renal function is discussed in greater
detail in Dosing in renal impairment, page142.
101

Section B | Pharmacokinetics

Fraction unbound in plasma


Drugs tend to bind reversibly to plasma proteins such
as albumin, alpha1-acid glycoprotein and lipoproteins;
the fraction unbound in plasma (u) represents the
fraction of drug in plasma that exists in the unbound
(free) form. Among the extensively bound medicines are
the nonsteroidal anti-inflammatory agents, whereas
paracetamol and L-dopa are examples of poorly
bound medicines.

Principles of drug therapy

For a highly bound drug (u less than 0.2) the u value


can increase in disease states that are associated with
a reduction in plasma proteins (e.g. liver or kidney
disease). Similarly, co-administration of two medicines
that compete for common plasma-binding sites can lead
to an increase in u of one or both drugs. As discussed
in Drug interactions, page 124, these changes in u
are rarely of clinical importance.

Protein binding
An understanding of protein binding is important when
interpreting plasma concentrations of extensively bound
medicines. There is a demonstrated benefit in monitoring
drug concentrations for some medicines and these are
identified in Table B.2 and B.3. Readers should refer
to Therapeutic drug monitoring, page 117, and the
relevant clinical monograph for more comprehensive
information about a specific medicine.

Removal of drugs by haemodialysis


A knowledge of protein binding assists in determining
the extent to which medicines are removed from the
body during haemodialysis. The following relationship
provides some guide to the extent of clearance of a
medicine by dialysis3:
R=

u # 100
Vd

where R is a comparative index of the effectiveness with


which a drug can be removed from the body through
haemodialysis. If R<20 the medicine is not significantly
removed by haemodialysis; if R>80 the medicine is
significantly removed by haemodialysis; if R is between
20 and 80 a variable amount of medicine is removed by
haemodialysis.

Oral bioavailability
The oral bioavailability (F) of a medicine is the fraction
of a dose that reaches the systemic circulation intact.
The fraction that is not bioavailable might have remained
unabsorbed within the intestinal lumen or might have
been metabolised by the liver (and occasionally the
intestinal tract) during the initial passage (the first
pass) through that organ. With medicines that have
low oral bioavailability (e.g. morphine), the dose used
102

orally might need to be much greater than that for


intravenous administration. Generally, medicines with
low bioavailability because of high hepatic extraction
(e.g.diltiazem, verapamil, propranolol and morphine) will
also have a more variable bioavailability (referred to as a
highly variable medicines), and the dosage requirements
can vary more significantly among individuals. Similarly,
for those medicines with low bioavailability because
of poor absorption (e.g.griseofulvin) the extent of
absorption is more likely to be affected by the ingestion
of foods and the timing of the dose. Such medicines
are also more likely to be involved in interactions at the
level of absorption (seeDrug interactions, page 124).
The rate at which and the extent to which a formulation
dissolves in the gastrointestinal fluids (i.e. its dissolution)
can be an important determinant of the formulations
oral bioavailability. The dissolution can be influenced by
dietary factors or concomitant administration of other
drugs. For example, increasing gastric pH (with, say,
proton pump inhibitors or H2-antagonists) decreases
the dissolution and hence the oral bioavailability of
ketoconazole.

References
1. Birkett DJ. Pharmacokinetics made easy. Rev. edn. Sydney: McGraw
Hill, 2002.
2. Helms RA, Quan DJ eds. Textbook of therapeutics: drug and
disease management. 8th edn. Philadelphia: Lippincott, Williams &
Wilkins, 2006.
3. Gwilt PR, Perrier D. Clinical pharmacology and therapeutics. 1978;
24:15461.
4. Moffat AC, Osselton MD, Waddup B. Clarkes analysis of drugs and
poisons. 3rd edn. London: Pharmaceutical Press, 2004.
5. Product information. eMIMS St Leonards: CMPMedica Australia Pty
Ltd; 2011.
6. Lacy CF, Armstrong LL, Goldman MP et al. Drug information
handbook international. 14th edn. Lexi-Comp: Ohio, 2006.

Section B | Pharmacokinetics

1316 days

0.004

Acetazolamide

13

0.5

0.70.9

Acetylcysteine

2.65

Aciclovir

4.5

0.6

Adalimumab

1020 days

0.003

Adefovir

7.5

0.6

Adrenaline

510 min

Agomelatine

1.5

Albendazole

812*

Alendronate

10.5 years*

Aliskiren

40

Allopurinol

0.52
(allopurinol)*

10

Oral
bioavailability (F)

Clearance (Cl)
(mL/min/kg)

Abatacept

Medicine

Fraction
unbound (u)

Half-life (hours)

Fraction excreted
unchanged (e)

Table B.1 Pharmacokinetic data46

Comments

<0.01
0.1
0.2

16

4.8

0.2

0.95

0.59

<0.1

0.5

Negligible

0.05

<0.01*

0.3

0.33

0.22

<0.01

0.01
* Active metabolite

0.5

0.03

<0.1
(single dose)

>0.95
(allopurinol)

0.9

0.3 (regular
dosing)

>0.8
(oxypurinol)

0.9

0.3

0.03

0.01

Amantadine

16

Ambrisentan

15

Amikacin

1.3

0.9

>0.9

Amiloride

7.4

0.6

0.6

0.5

Amiodarone

50 days

<0.05

0.01

0.5

Amisulpride

12

5.6

0.5

0.84

0.48

Amitriptyline

24

10

<0.02

0.05

0.5

* Alendronate is irreversibly
incorporated in bone

* Active metabolite (oxypurinol)


has a half-life of about 24 hours

>0.9

Principles of drug therapy

1240
(oxypurinol)

0.8

See Table B.2, in Therapeutic drug


monitoring

Active metabolite (nortriptyline).


See Table B.2, in Therapeutic drug
monitoring

Amlodipine

3550

<0.1

0.03

0.6

Amoxycillin

<0. 75

0.8

0.9

Amphotericin B

28

0.4

<0.05

0.05

<0.1

Ampicillin

3.5

0.9

0.8

Anastrozole

50*

<0.1

0.6

Apomorphine

0.5

65

Aprepitant

913

Aprotinin

0.6

0.05

0.2

Aripiprazole

75*

0.7

<0.01

0.01

Artemether

2 (artemether
and dihydroartemisinin)

Asparaginase

830

<0.05

0.7

Aspirin

0.5*

10

<0.02

0.50.9

Atazanavir

6.4

0.07

0.14

Atenolol

7.5

2.7

0.4

0.95

<0.05

* Active metabolites with half-lives


of up to 37 hours

0.6

Weakly active metabolites

0.87

* Active metabolite
(dehydroaripiprazole) has a
halflife of 4 days

0.5

Active metabolite
(dihydroartemisinin)

0.7

* Pro-drug, rapidly hydrolysed to


active metabolite (salicylic acid)

0.5

Note: For some values clearance has been calculated using the half-life and volume of distribution.

103

Section B | Pharmacokinetics

Clearance (Cl)
(mL/min/kg)

Fraction excreted
unchanged (e)

Fraction
unbound (u)

Oral
bioavailability (F)

0.03

0.01

0.630.93*

<0.02

0.02

0.14

<0.01

<0.01

<0.01

0.2

0.3

0.5

0.5

0.1

0.15

0.4

0.25

57

<0.1

0.7

>0.8

* Rapidly converted to active


metabolite (6-mercaptopurine)

22 (56*)

7.6

0.13

0.12 (0.03*)

0.2

* Active metabolite
(desmethylazelastine)

Azithromycin

70

0.06

0.070.51*

0.37

* Protein binding dependent


on plasma azithromycin
concentration

Aztreonam

0.6

0.6

0.3

Baclofen

0.8

0.7

0.70.8

<0.01

0.01

0.01

0.13

0.1

Medicine

Half-life (hours)

Principles of drug therapy

Table B.1 Pharmacokinetic data46 (continued)

Atomoxetine

3.6

Atorvastatin

14

Atovaquone

6070

Atracurium besylate

0.3

Atropine

Auranofin

40 days

Azathioprine

10 min (2*)

Azelastine

0.15

Balsalazide
Beclomethasone
dipropionate

15

Benzhexol

Benzylpenicillin

0.5

Betamethasone

Bimatoprost

0.75

25

Bisoprolol

1012

3.7

Bleomycin

Bosentan

Brinzolamide

111 days

Bromazepam

17

Bromhexine

Bromocriptine

Budesonide

15

Bumetanide

1.5

Bupivacaine
Buprenorphine

* 710% of Caucasians are


poor metabolisers; see product
information for further
information

<0.05

0.05

10

0.75

0.4

<0.05

0.3

0.7

0.1

very low

0.5

0.65

0.9

No active metabolites

0.4

0.99

<0.03

0.02

0.4

Clearance is non-linear and


autoinducible

>0.9

0.4

0.02

0.3

<0.01

0.05

0.70.8

<0.05

0.05

0.07

<0.01

0.1

0.33

0.5

0.05

>0.9

<0.05

0.05

35*

13

<0.1

0.04

Bupropion

20

50

<0.01

0.16

Buspirone

211 (average
2.4)

30

<0.01

0.05

Busulfan

2.5

4.5

<0.01

Cabergoline

60110

Calcitonin

0.5

0.02

0.6

<0.02

0.60.7

Active metabolite (N-desethyl


brinzolamide)

0.4 (SL)

Note: For some values clearance has been calculated using the half-life and volume of distribution.

104

Comments

Nasal bioavailability is 0.2

* Elimination half-life is long


with considerable variation.
Sublingual/transdermal half-life
of 2036 hours

Section B | Pharmacokinetics

Fraction
unbound (u)

Oral
bioavailability (F)

<0.01*

0.14*

0.4

0.7

0.7

<0.05

0.25

>0.7

Clearance (Cl)
(mL/min/kg)

0.3*

Medicine

Half-life (hours)

Fraction excreted
unchanged (e)

Table B.1 Pharmacokinetic data46 (continued)

Calcitriol

4.5

Candesartan cilexetil

9*

0.37*

Capreomycin

46

0.95

0.5

Captopril

1.5

13

Carbamazepine

15

1.3

Comments

Pharmacological half-life of 4 days


* Pro-drug of candesartan;
parameters are for candesartan
formed from the pro-drug

Induces its own metabolism


values are for chronic therapy.
Value for oral bioavailability is for
conventional formulation.
See Table B.2, in Therapeutic drug
monitoring

0.85

<0.05

>0.9

Rapidly hydrolysed to methimazole,


which has a half-life of 35 hours

Carboplatin

1.5

1.5

0.7

Carmustine

0.3

60

<0.01

0.2

Cefaclor

0.75

0.85

0.75

Cefepime

1.7

0.9

0.8

Cefotaxime

1.3

0.5

0.7

Cefoxitin

0.8

0.3

Ceftazidime

1.6

0.8

0.9

Ceftriaxone

7.3

0.3

0.5

0.1

Celecoxib

11

<0.01

0.03

Cephalexin

4.3

0.9

0.85

Cephalothin

0.8

0.5

0.8

Cephazolin

1.8

0.8

0.2

Chlorambucil

1.3

2.6

<0.01

0.01

>0.7

Chloramphenicol

4.5

0.3

0.5

0.9

Chlorpheniramine
maleate

30

1.7

0.2

0.3

Chlorpromazine

1530

<0.01

0.05

Chlorthalidone

50

1.4

0.3

0.25

Cholecalciferol

18 days*

Ciclesonide

0.94

Cilostazol

10

Cimetidine

Cinacalcet

35

Ciprofloxacin
Cisplatin

0.9

Available only as intramuscular


injection for systemic use

0.6

<0.01
35

Principles of drug therapy

Carbimazole

* Stored in fat deposits throughout


the body for long periods
0.01

<0.01

<0.05

0.02

0.7

0.8

0.7

<0.05

0.03

0.25

0.45

0.6

0.7

0.5 (unbound
cisplatin),
65 (proteinbound
platinum)

6.3

0.2

<0.1

Note: For some values clearance has been calculated using the half-life and volume of distribution.

105

Section B | Pharmacokinetics

Fraction excreted
unchanged (e)

Fraction
unbound (u)

Oral
bioavailability (F)

Citalopram

36
(citalopram),
up to
96 (active
metabolites)

0.120.23

0.2

0.8

Cladribine

15

0.15

0.8

Clarithromycin

0.3

0.2

Clavulanic acid

3.6

0.23

0.70.9

Clindamycin

4.7

0.1

0.05

Clobazam

25

0.6

Clonazepam

25

1.5

<0.02

0.14

0.9

Clonidine

15

0.4

0.7

0.95

Clopidogrel

0.5

0.02

>0.5

Clozapine

12

<0.01

0.05

0.5

Active metabolite (norclozapine)

Codeine

12

0.1

0.9

0.5

Converted to active metabolite


(morphine)

Colchicine

4.4

0.15

0.5

0.250.5

Colistin

0.8

0.5

Cromoglycate

1.3

<0.05

0.35

<0.05

Cyclophosphamide

1.3

0.25

0.8

>0.75

Cyclosporin

620

<0.001

0.1

0.10.9

Cytarabine

13

<0.1

0.9

Dabigatran

1217

1.4

0.85

0.65

Dacarbazine

0.5

>0.9

Dactinomycin

36

0.1

Dantrolene

Darunavir

15
(in presence
of ritonavir)

Dasatinib

Daunorubicin

26

0.2

Deferiprone

13

10

0.05

>0.9

Delavirdine

0.03

<0.02

Desloratadine

27

Desmopressin

23

1.3

0.45

Desvenlafaxine

11

0.45

0.7

0.8

Dexamethasone

3.7

<0.05

0.3

0.9

Diazepam

2040
(diazepam)
96
(nordiazepam)

0.4

<0.01

0.01

>0.95

Diazoxide

30

0.05

0.4

0.1

Diclofenac

1.5

<0.01

<0.01

Principles of drug therapy

Medicine

Half-life (hours)

Clearance (Cl)
(mL/min/kg)

Table B.1 Pharmacokinetic data46 (continued)

8
1.5
(in presence
of ritonavir)

Active metabolites
(demethylcitalopram,
didemethylcitalopram,
citalopramN-oxide)

0.55

0.9

0.2

<0.01

0.1

0.07

0.05

See Table B.2, in Therapeutic drug


monitoring

See Table B.3, in Therapeutic drug


monitoring

0.06

0.4
0.8
(in presence
of ritonavir)

0.001

0.15
0.0008

0.55

Note: For some values clearance has been calculated using the half-life and volume of distribution.

106

Comments

Values for oral tablets

Active metabolites
(hydroxydiazepam (temazepam),
nordiazepam, oxazepam)

Section B | Pharmacokinetics

Fraction excreted
unchanged (e)

Fraction
unbound (u)

Oral
bioavailability (F)

Dicloxacillin

0.7

0.5

0.02

0.6

Didanosine

1.5

16

0.20.5

>0.95

0.20.4

Digoxin

40

0.7

0.8

0.7

Dihydrocodeine

0.3

15

<0.11

<0.1

<0.1

15

<0.05

0.2

0.4

Dihydroergotamine

Clearance (Cl)
(mL/min/kg)

Medicine

Half-life (hours)

Table B.1 Pharmacokinetic data46 (continued)

Comments

See Table B.2, in Therapeutic drug


monitoring

0.21

Diltiazem

Diphenoxylate

4*

Dipyridamole

10

2.5

<0.05

<0.05

0.40.7

Disopyramide

0.5

0.5

0.75

Dobutamine

2 min

60

<0.1

Docetaxel

11

0.05

<0.05

Dolasetron

8*

50

<0.05

0.3

0.75

Domperidone

0.01

0.1

0.15

Donepezil

70

0.17

0.04

>0.95

Dopamine

2 min

60

<0.01

Dothiepin

51

25

0.01

0.16

Doxepin

20

15

<0.01

0.2

Doxorubicin

30

17

<0.05

0.2

Doxycycline

16

0.5

0.4

0.1

0.9

Dronedarone

2530

<0.01

0.02

0.05 fasting,
0.15 with
food

Duloxetine

12

25

<0.01

<0.1

Dutasteride

35 weeks

<0.01

<0.01

0.6

Eltrombopag

30

<0.01

0.01

0.5

Emtricitabine

10

0.7

>0.95

0.93

Adjust dose in renal impairment

Enalapril

30*

0.4*

0.5*

0.4*

* Active metabolite (enalaprilat)

Enfuvirtide

3.8

Ephedrine

4.5

Epirubicin

36

19

0.1

Eplerenone

<0.05

Epoetin

0.1

0.05

Eprosartan

2.2

0.05

Ergotamine

10

<0.05

Erlotinib

36

<0.05

0.05

0.6

Erythromycin

1.5

<0.1

0.25

0.4

Esomeprazole

1.5

2.2

<0.01

0.03

0.50.9

Ethacrynic acid

Ethambutol

12

0.10.4

0.8

0.1*

0.4

* Active metabolite
(hydrodolasetron)

Active metabolites

Active metabolite
(desmethyldothiepin)

Principles of drug therapy

* Active metabolite (diphenoxylic


acid)

0.3
Pegylated liposomal formulation of
doxorubicin has a terminal half-life
of 55 hours

0.08
0.65

0.5

0.7

0.02

0.13
<0.05

0.2
9

0.5

Note: For some values clearance has been calculated using the half-life and volume of distribution.

107

Section B | Pharmacokinetics

Medicine

Half-life (hours)

Clearance (Cl)
(mL/min/kg)

Fraction excreted
unchanged (e)

Fraction
unbound (u)

Oral
bioavailability (F)

Principles of drug therapy

Table B.1 Pharmacokinetic data46 (continued)

Ethinyloestradiol

25

<0.05

<0.05

0.5

Ethosuximide

50

0.2

0.2

>0.9

Etidronate

6*

2.4

0.5

Etoposide

11.5

0.5

0.25

0.05

0.55

Etoricoxib

22

0.8

<0.01

0.08

Etravirine

35

<0.01

0.01

Everolimus

28

0.25

Exemestane

24

<0.01

0.1

Exenatide

23

Famciclovir

2*

>0.8*

0.8*

Famotidine

0.7

0.8

0.5

Felodipine

14

15

<0.01

0.01

0.2

Fentanyl

12

<0.1

0.2

0.5*

Fexofenadine

15

16

0.1

0.35

0.3

Finasteride

2.5

0.07

0.8

Fingolimod

69 days

1.4

<0.01

<0.01

0.9

Flecainide

15

10

0.3

0.5

>0.9

Flucloxacillin

0.5

0.08

Fluconazole

30

0.3

0.8

0.9

>0.9

Flucytosine

3.5

0.9

>0.95

0.8

Fludarabine

20

0.5

>0.95

0.6

Flunitrazepam

25

1.5

<0.01

0.2

0.9

Fluorouracil

10 min

16

<0.2

0.9

0.3

Fluoxetine

5 days

2.5

<0.1

0.05

0.6

Fluphenazine

710 days*

Flutamide

Fluticasone

Fluvastatin
Fluvoxamine

8.8

0.05

* Binds irreversibly to bone

See Table B.3, in Therapeutic drug


monitoring

1
* Active metabolite (penciclovir)

* Sublingual formulation of
fentanyl

Active metabolite (norfluoxetine)


has a half-life of 9 days

<0.1

* Fluphenazine decanoate available


in Australia

<0.06

0.05

Active metabolite
(hydroxyflutamide)

14

<0.05

0.1

0.10.3*

25

<0.01

0.02

0.2

20

12

<0.04

0.2

0.5

Fosamprenavir

7.7*

<0.01

0.1*

Foscarnet

0.8

0.85

Fosinopril

4 (12*)

0.12 (0.75*)

0.05*

Fotemustine

83

<0.01

0.7

Frusemide

0.7

0.03

Fusidic acid

<0.01

0.05

Gabapentin

0.8

>0.9

0.6

Galantamine

0.2

0.8

0.9

0.5*

* Systemic bioavailability following


inhalation

Pro-drug; values are for amprenavir

* Pro-drug; rapidly converted to


active metabolite (fosinoprilat)

0.6

Note: For some values clearance has been calculated using the half-life and volume of distribution.

108

Comments

Section B | Pharmacokinetics

Medicine

Half-life (hours)

Clearance (Cl)
(mL/min/kg)

Fraction excreted
unchanged (e)

Fraction
unbound (u)

Oral
bioavailability (F)

Table B.1 Pharmacokinetic data46 (continued)

Ganciclovir

0.9

0.98

Gemfibrozil

1.5

<0.02

0.01

Gentamicin

2.5

1.3

0.8

>0.7

Glibenclamide

0.5

<0.01

<0.01

Gliclazide

11

<0.05

0.1

Glimepiride

6.5

<0.01

<0.01

Glipizide

0.04

0.05

>0.9

Glucagon

0.1

10

Glyceryl trinitrate

2 min

300

<0.01

0.4

Glycopyrrolate

1.5

20

>0.8

Granisetron

0.12

0.35

Griseofulvin

17

0.01

0.16

Haloperidol

20

12

0.01

0.1

0.6

Hydralazine

2.5

50

<0.1

0.1

0.2

Hydrochlorothiazide

10

0.65

0.4

0.7

Hydrocortisone

1.5

<0.01

<0.1

Hydromorphone

2.5

25

<0.1

Hydroxyurea

3.5

Hyoscine

Hyoscyamine

2.5

Ibandronate

1060

12

0.5

0.15

0.01

Ibuprofen

0.75

<0.1

0.01

>0.9

Icatibant

12

<0.1

0.66

0.97

Idarubicin

20

25

0.03

0.03

0.3

Iloprost

525 min

20

Imatinib

18

2.5

0.05

0.05

Imipenem

2.9

0.7

0.8

Imipramine

12

16

<0.1

0.1

0.5

See Table B.2, in Therapeutic drug


monitoring

Indacaterol

45125

5.5

0.02

0.05

0.43

* Fraction of inhaled dose


absorbed is 0.57

Indapamide

15

0.3

0.05

0.2

>0.9

Indinavir

0.1

0.4

Indomethacin

0.05

0.05

Ipratropium

0.03

0.8

0.7

Comments

>0.9
See Table B.2, in Therapeutic drug
monitoring
0.85

Half-life can increase at higher


doses

0.6
Bioavailability influenced by fat
content of mealsi.e. requires
high fat content for adequate
absorption

0.25

Principles of drug therapy

Bioavailability depends on route of


administration

Active 3-glucuronide accumulates


in renal failure

0.8
1

<0.1

0.2

<0.05

1.5

Elimination half-life of active


metabolite (idarubicinol) is
>45 hours.

0.4
0.98

1
Fraction of inhaled dose absorbed
through gastrointestinal tract is
~0.05

Note: For some values clearance has been calculated using the half-life and volume of distribution.

109

Section B | Pharmacokinetics

Medicine

Half-life (hours)

Clearance (Cl)
(mL/min/kg)

Fraction excreted
unchanged (e)

Fraction
unbound (u)

Oral
bioavailability (F)

Principles of drug therapy

Table B.1 Pharmacokinetic data46 (continued)

Irbesartan

14

2.2

0.02

0.1

0.7

Irinotecan

12.5

0.2

0.35

Isoniazid

0.1

0.85

0.8

Isosorbide dinitrate

34

<0.01

0.7

0.25

Isosorbide mononitrate

10

0.02

>0.95

0.9

Isotretinoin

1020

<0.1

0.01

Itraconazole

>20

0.01

0.55

Ivabradine

0.04

0.3

0.4

Ketoconazole

<0.01

0.01

Ketoprofen

1.5

<0.01

0.05

0.9

Labetalol

20

0.05

0.5

0.3

Lamivudine

>0.7

>0.65

0.8

Lamotrigine

27

0.6

<0.1

0.45

>0.95

Lansoprazole

1.5

<0.05

0.02

>0.8

Lanthanum

>26 weeks

<0.01

<0.01

<0.01

Lapatinib

24

<0.01

<0.01

Lenalidomide

3 (CL/F)

0.65

0.7

Letrozole

48

0.5

0.06

0.4

Leucovorin

0.5

0.1

0.6

Parameters are for the active


() isomer

Levodopa

1.5

<0.1

0.8

Value for oral bioavailability is for


conventional oral formulation

Lignocaine

10

<0.1

0.4

Lincomycin

0.04

0.35

Linezolid

0.35

0.7

Liraglutide

13

0.3

<0.01

0.02

Lisinopril

13

0.7

>0.9

>0.9

0.4

Lithium carbonate

24

0.4

>0.95

Loperamide

10

<0.05

0.03

0.4

Loratadine

12

Lorazepam

15

<0.05

0.1

0.95

Losartan

2 (69*)

8 (0.7*)

0.05

0.01

0.33

Lumefantrine

25 days

Active metabolite SN-38 has a


halflife of 630 hours

0.25

<0.05

0.01

0.1

0.2

Converted to active metabolite*


(E3174), which has a half-life of
8 hours
N-demethyl lumefantrine is active

0.23

Mefenamic acid

3.5

Melphalan

1.5

Mepivacaine

2.5

Mercaptopurine

11

<0.05

0.8

0.15

Mesna

0.3

20

0.4

0.3

0.5

0.2

Note: For some values clearance has been calculated using the half-life and volume of distribution.

110

See Table B.2, in Therapeutic drug


monitoring

Active metabolite (desloratidine)


has a half-life of >17 hours

0.001
0.08

See Table B.2, in Therapeutic drug


monitoring

0.4

0.02

Maraviroc

Comments

Section B | Pharmacokinetics

Medicine

Half-life (hours)

Clearance (Cl)
(mL/min/kg)

Fraction excreted
unchanged (e)

Fraction
unbound (u)

Oral
bioavailability (F)

Table B.1 Pharmacokinetic data46 (continued)

Metformin

6.5

0.4

>0.9

0.5

Methadone

20

1.4

<0.33

0.1

0.9

Methotrexate

>0.7

0.4

>0.75

Methyldopa

0.25

>0.8

0.4

Methylnaltrexone

0.5

0.9

0.8

Methylprednisolone

6.5

0.05

0.2

Metoclopramide

11

0.3

0.6

0.8

Metoprolol

16

<0.05

0.9

0.5

Metronidazole

1.3

0.1

>0.8

Mianserin

16

10

0.05

0.05

0.2

Miconazole

24

<0.01

0.1

0.25

Midazolam

<0.01

0.05

Milrinone

0.8

0.3

Minocycline

16

<0.1

0.25

Minoxidil

10

<0.1

>0.9

Misoprostol

<0.5*

Mitomycin C

50 min

Mitozantrone

12 days

0.05

0.2

Moclobemide

1.5

0.01

0.5

0.6 after
single dose
0.8 after
multiple
doses

Montelukast

36

0.5

<0.01

0.01

0.64

Morphine

20

<0.1

0.7

0.3

Active metabolite
morphine6glucuronide

Mycophenolate

18*

2.5

<0.01

0.03*

0.94*

* Data are for mycophenolic acid

Naloxone

22

<0.01

0.6

0.03

Naltrexone

22

<0.01

0.8

0.2

Naproxen

14

0.1

<0.1

0.01

0.99

Natalizumab

11 days

0.004

Nebivolol

10 (fast
metabolisers)
3050 (slow
metabolisers)

<0.01

0.02

0.13 (fast
metabolisers)
1 (slow
metabolisers)

Nedocromil

0.7

0.15

Neomycin

2.5

Neostigmine

Nevirapine

2545

<0.03

0.4

0.9

Nicorandil

0.01

0.75

0.75

Nicotinic acid

0.75

0.4

Nifedipine

0.04

0.5

20

Systemic absorption can occur after


buccal or vaginal delivery

>0.8*

Rapidly converted to the active


metabolite* (misoprostol acid)

Principles of drug therapy

0.2*

Comments

0.1

Fraction of inhaled dose absorbed


~0.05

0.01
11

0.4

<0.01

Note: For some values clearance has been calculated using the half-life and volume of distribution.

111

Section B | Pharmacokinetics

Fraction excreted
unchanged (e)

Fraction
unbound (u)

Oral
bioavailability (F)

Comments

Nilotinib

17

<0.1

0.02

0.3

Blood/serum = 0.68

Nitrazepam

26

<0.04

0.15

0.8

Nitrofurantoin

10

0.4

<0.4

Nizatidine

1.6

10

0.6

0.7

>0.7

Norfloxacin

0.3

0.85

0.35

Nortriptyline

30

7.2

0.02

0.1

0.6

Octreotide

1.5

0.10.3

0.35

Olanzapine

33

<0.1

0.07

0.8

Olmesartan

13

0.4

<0.01

0.26

Omeprazole

7.5

<0.05

0.05

0.5

Ondansetron

7.5

<0.05

0.25

0.6

Clearance (Cl)
(mL/min/kg)

Medicine

Half-life (hours)

Principles of drug therapy

Table B.1 Pharmacokinetic data46 (continued)

Orlistat

See Table B.2, in Therapeutic drug


monitoring

Pro-drug which is rapidly


converted to the active metabolite
(olmesartan)

Minimal absorption

Orphenadrine

14

0.04

0.8

Oseltamivir

7.5

>0.99

>0.9

Oxaliplatin

270*

2*

>0.5

Oxazepam

<0.05

0.1

Oxcarbazepine

2 (12*)

0.85*

<0.01

0.6*

Oxpentifylline

<0.05

>0.9

Oxprenolol

2.5

<0.05

0.2

0.5

Oxybutynin

<0.001

<0.001

0.06

Oxycodone

10

<0.1

0.50

0.87

Paclitaxel

350*

<0.1

<0.1

Low

Paliperidone

24

0.6

0.25

0.28

Palonosetron

40

2.5

Pamidronate

0.4

0.46

Pantoprazole

<0.01

0.03

0.8

Paracetamol

<0.05

Negligible

0.8

0.75

Data presented for active


metabolite
* Ultrafiltrable platinum

* Active monohydroxy-metabolite,
which has a half-life of 9 hours is
cleared hepatically and renally

Active metabolite (N-desethyl-)

* Non-linear pharmacokinetics,
independent of dose and wide
inter-patient variability

0.4
Extensive uptake into bone

F = 0.35 after rectal administration.


See Table B.2, in Therapeutic
drug monitoring in the event of
suspected toxicity

Paroxetine

24

Pazopanib

30

Penicillamine

90*

0.07

0.02

0.05

0.04

0.01

0.1

0.2

0.140.4

Note: For some values clearance has been calculated using the half-life and volume of distribution.

112

* Half-life of stored D-penicillamine

Section B | Pharmacokinetics

0.7 (poor
metaboliser),
7.2 (extensive
metaboliser),
17.2 9 ultraextensive
metaboliser)

Oral
bioavailability (F)

Fraction
unbound (u)

26 days*

Fraction excreted
unchanged (e)

Perhexiline

Clearance (Cl)
(mL/min/kg)

Medicine

Half-life (hours)

Table B.1 Pharmacokinetic data46 (continued)

<0.1

Comments

* Half-life highly variable.


Metabolised by CYP2D6. In poor
metabolisers can have a half-life
of greater than 30 days so require
reduced dose.
See Table B.2, in Therapeutic drug
monitoring

Perindopril

2 (28*)

10*

0.7*

>0.8*

Pethidine

3 (20*)

15

<0.1

0.35

Phenobarbitone

96

0.05

0.3

0.5

Phenoxybenzamine

24

24

Phenoxymethylpenicillin

0.5

0.5

0.3

0.2

0.6

Phenytoin

22
(range 742)

0.3

<0.05

0.1

0.9

Pindolol

3.5

0.4

0.6

0.9

Pioglitazone

0.01

<0.02

0.85

Piperacillin

2.6

0.7

0.8

Piroxicam

45

0.04

<0.05

0.01

Posaconazole

35

<0.01

<0.02

Pramipexole

10

0.9

0.85

0.9

Pravastatin

0.08

0.5

0.2

Prazosin

0.05

<0.1

0.6

Prednisolone

3.5

<0.2

0.1

Prednisone*

3.5*

<0.2*

0.1*

Pregabalin

0.95

>0.9

Dose adjustment may be required


in renal impairment

Primidone

10

0.8

0.4

<0.8

>0.9

Metabolised to phenobarbitone

Probenecid

0.075

0.1

Prochlorperazine

24

<0.01

Promethazine

12

16

0.02

Propantheline

20

0.05

Propofol

20

Propranolol

15

<0.01

0.1

0.35

Propylthiouracil

1.5

<0.1

<0.2

>0.8

Pseudoephedrine

10

0.1

0.7

Pyridostigmine

12

0.9

Quetiapine

Quinapril

1 (25*)

2*

* Active metabolite (perindoprilat)


* Active metabolite (norpethidine)
can accumulate and cause
toxicity

0.8

See Table B.2, in Therapeutic drug


monitoring

<0.01

See Table B.2, in Therapeutic drug


monitoring

Principles of drug therapy

0.25

Bioavailability increases significantly


when administered with food
Erythrocyte/plasma ratio = 2

* Pro-drug; rapidly converted


to the active metabolite
(prednisolone)

0.2
0.15

0.25

<0.05

0.15

0.01

0.17

0.09

>0.9*

0.03

>0.6

* Active metabolite (quinaprilat)


has a prolonged apparent
terminal half-life thought to
reflect the slow release of
quinalaprat from ACE

Note: For some values clearance has been calculated using the half-life and volume of distribution.

113

Section B | Pharmacokinetics

Medicine

Half-life (hours)

Clearance (Cl)
(mL/min/kg)

Fraction excreted
unchanged (e)

Fraction
unbound (u)

Oral
bioavailability (F)

Table B.1 Pharmacokinetic data46 (continued)

Quinine

11

<0.05

<0.3

0.8

Rabeprazole

<0.01

0.03

0.5

Raloxifene

28

Negligible

0.01

0.02

0.1

0.17

>0.3

Principles of drug therapy

Raltegravir
Raltitrexed

8 days

0.7

0.5

0.07

Ramipril

12*

1*

<0.02
(>0.6*)

0.5*

0.3

Ranitidine

2.5

10

0.7

0.85

0.5

Repaglinide

<0.08

0.02

0.63

Ribavirin

28

0.3

0.55*

* Bioavailability increased after a


high-fat meal

Rifabutin

40

0.05

0.15

0.2

Possibly induces its own


metabolism

Rifampicin

3.5

3.5

0.15

0.2

Risedronate

1.5 (initial)

1.7

0.85

0.75

<0.01

4 (extensive
metaboliser),
0.5 (slow
metaboliser)

0.2

0.1 (0.2*)

0.66
(extensive
metaboliser),
0.82 (slow
metaboliser)

<0.01

0.6

0.4

0.3

0.05

0.9

0.14

0.86

0.45

5.0

* Active metabolite (ramaprilat)

480 (terminal)
Risperidone

3 (extensive
metaboliser),
19 (slow
metaboliser)

Rivastigmine

1.5

Rivaroxaban

513

Rizatriptan

2.5

Ropinirole

15

<0.1

0.75

0.45

Rosiglitazone

34

0.71

<0.01

<0.01

0.99

Rosuvastatin

20

1.1

<0.1

0.1

0.2

Rotigotine

<0.02

0.08

0.37

Roxithromycin

12

0.07

0.05

0.5

Salbutamol

0.25

>0.9

0.44

Salcatonin

12*

<0.02

0.65

0.7
(SC and IM)

Saxagliptin

2.5

0.25

0.99

>0.75

Selegiline

1825

<0.01

0.1

0.1*

Sertindole

3 days

<0.01

<0.01

Sertraline

26

0.1

0.02

0.88

Active metabolite
(N-desmethylsertraline)

Simvastatin

2 (1.9*)

<0.01

0.02 (0.06*)

0.05

* Pro-drug; extensively converted


to active metabolite (simvastatin
b-hydroxy acid analogue) after
oral dosing

Sitagliptin

12

0.8

0.6

0.87

Solifenacin

4070

2.6

0.1

0.02

0.9

2.4

12.8

0.3

* Active metabolite
(9-hydroxyrisperidone),
with a half-life of 24 hours

* Transdermal bioavailability 0.37

* The apparent biological half-life


is several hours

* Oral bioavailability increases up


to threefold when administered
with a high-fat meal
Cardiac monitoring required

Note: For some values clearance has been calculated using the half-life and volume of distribution.

114

Comments

Section B | Pharmacokinetics

Fraction
unbound (u)
0.01

0.45 (tablets
relative to
oral solution)

0.75

>0.9

Low

<0.1

>0.9

0.5

0.4

>0.95

0.86

0.3

<0.25

0.4

>0.9

610

0.05

<0.1

Sulindac

7*

<0.20

0.05

0.9

Sumatriptan

16

0.2

0.8

0.15

Sunitinib

4060
(80110*)

2 (Cl/F)

<0.1

0.05 (0.1*)

Tacrolimus

43 (whole
blood) in
healthy
subjects
1115 in
transplant
patients

0.5 in healthy
subjects
12 in
transplant
patients

<0.01

0.01

Tamoxifen

57 days
(1014 days*)

1.4

<0.01

<0.02

Tamsulosin

16

0.3

0.05

0.01

0.55

Tapentadol

22

0.03

0.8

0.32

Teicoplanin

34 days

0.18

0.8

0.05

Telbivudine

40

0.42

0.95

Temazepam

10

0.9

<0.02

0.04

Teniposide

20

0.4

0.1

<0.01

Terazosin

12

0.1

<0.1

0.92

Terbutaline

15

<0.5

0.8

0.15

Testosterone

70 min

25

<0.05

0.02

<0.05

Transdermal bioavailability = 0.1

Tetracycline

10

1.7

0.6

0.070.77

Thalidomide

2.5

<0.01

0.4

Theophylline

312 (mean
7)*

0.6

0.1

0.4

>0.9

* Half-life is shortened by smoking.

Thiopental

<0.01

0.15

Thiotepa

0.9

>0.6

Thyroxine

67 days

0.01

<0.01

Tiaprofenic acid

2.5

1.4

0.55

0.02

Tibolone

Very short

Ticarcillin

1.3

Sorafenib

2448

Sotalol

12

Spironolactone

1.5

Stavudine

1.5

Sulfamethoxazole

912

Sulfasalazine

Clearance (Cl)
(mL/min/kg)

<0.01

Medicine

Half-life (hours)

Fraction excreted
unchanged (e)

Oral
bioavailability (F)

Table B.1 Pharmacokinetic data46 (continued)

2.5

Comments

High-fat meal reduces


bioavailability

Active metabolite (canrenone) has a


half-life of up to 24 hours

Metabolised in colon to
sulfapyridine and 5-amino
salicylic acid

* Active metabolite (SU12662)


0.2

See Table B.3, in Therapeutic drug


monitoring

Principles of drug therapy

* Metabolised to active sulfide,


which has a long half-life
(16 hours)

* Active metabolite
(N-desmethyltamoxifen)

0.9

See Table B.2, in Therapeutic drug


monitoring

Unreliable absorption through


bladder mucosa (0.11)

0.04
2

0.65

Effect due to active metabolites


with half-lives of 7 hours

0.5

Note: For some values clearance has been calculated using the half-life and volume of distribution.

115

Section B | Pharmacokinetics

Medicine

Half-life (hours)

Clearance (Cl)
(mL/min/kg)

Fraction excreted
unchanged (e)

Fraction
unbound (u)

Oral
bioavailability (F)

Principles of drug therapy

Table B.1 Pharmacokinetic data46 (continued)

Timolol

0.2

0.4

0.6

Tobramycin

23

1.5

>0.9

>0.9

Tocilizumab

>10 days

0.2

Topiramate

2030

0.5

0.6

>0.8

>0.8

Topotecan

14

0.4

0.65

0.4

Toremifene

5 days

<0.1

<0.01

Trandolapril

1 (22*)

<0.01 (0.15*)

<0.2 (0.05*)

(0.1) 0.5*

* Pro-drug, rapidly converted to


active metabolite (trandolaprilat)

Triamterene

20

0.05

0.33 (0.1*)

0.5

* Active metabolite
(p-hydroxytriamterene sulfate)

Triazolam

10

<0.02

0.1

>0.95

Trimethoprim

11

0.6

0.40

Trimipramine

24

15

0.01

0.05

0.4

Tropisetron

7
(intravenous)
8.6 (oral) in
extensive
metabolisers

1.0

<0.1

0.45

0.6

Valaciclovir

<0.01

0.85

0.6

Valproate

14

0.12

<0.05

0.1

>0.95

Vancomycin

1.5

0.85

0.45

Varenicline

24

0.9

>0.8

>0.9

Venlafaxine

5 (10*)

15

0.05

0.7

0.45

Verapamil

15

<0.05

0.1

0.2

Verteporfin

<0.01

<0.05

Vigabatrin

1.7

0.7

>0.8

Vildagliptin

10

0.25

0.9

Vinblastine

24

Vincristine

50

0.05

0.25

Vorinostat

0.01

0.3

Warfarin

40

<0.01

0.02

Zafirlukast

10

<0.01

<0.01

Zidovudine

25

0.15

0.6

Zoledronic acid

6 days

0.4

0.8

Zolpidem

2.4*

Low

0.1

0.7

Zonisamide

60

0.2

0.5

See Table B.2, in Therapeutic


drug monitoring

0.3

See Table B.2, in Therapeutic drug


monitoring

* Active metabolite
(o-desmethylvenlafaxine)

0.85
Active metabolite
(desacetylvinblastine)

1
Bioavailability reduced (by about
40%) when taken with food
0.6
Extensive uptake into bone

Note: For some values clearance has been calculated using the half-life and volume of distribution.

116

8% of Caucasians are poor


metabolisers and half-life can be
extended to 45 hours

See Table B.2, in Therapeutic drug


monitoring

0.01

0.04

Comments

* Half-life increased in individuals


with cirrhosis to 10 hours

Therapeutic drug monitoring


Therapeutic drug monitoring (TDM) involves an array of
practitioners, among them doctors, pharmacists, nurses
and medical scientists. Its clinical value is dependent
on suitable laboratory methods for measuring drug
concentrations in biological specimens and interpretation
of drug levels; it can be of limited value or even
potentially detrimental to patient outcomes if not
properly done or if misinterpreted.1

Indications for monitoring

Clinical need
Although there is no clear consensus on when TDM is
indicated, there are a range of clinical situations in which
drug concentration measurements in relation to the
following are of value:

toxicity
detecting or confirming suspected toxicity
minimising toxicity and the associated risk of
adverse effects (e.g. aminoglycosides, cyclosporin)

If the measurement of drug concentrations is to


be useful there needs to be a relationship between
the dose, plasma or blood concentrations and
pharmacological effects.
Drug concentrations can be useful surrogates for drug
effects when these cannot easily be assessed clinically
and can help with determining individual patients
dosage requirements. Monitoring concentrations is
most useful when drugs are used to prevent an adverse
outcome (e.g. graft rejection) or to avoid toxicity.3
Drugs that are monitored tend to have a narrow
therapeutic index, whereby the drug level required for
effectiveness is close to the level that causes significant
side effects or toxicity, or both.1
To be suitable for therapeutic drug monitoring, a drug
should satisfy criteria such as the following:

a defined measurable therapeutic concentration range

a narrow therapeutic index

significant pharmacokinetic variability between


patientsi.e. an unpredictable doseresponse
relationship

an established relationship between plasma


concentrations and clinical effect

lack of an easily observable, safe or desirable clinical


endpoint, therapeutic and/or toxic effects being
difficult to measure directlye.g. the early toxic effects
of paracetamol are clinically difficult to ascertain

the drug not having active metabolites (unless the


active metabolites are included in the assay)

complex kineticse.g. non-linear, as in cases with


phenytoin and theophylline

availability of a reliable, cost-effective drug assay and


any relevant active metabolites.1,3,4

guiding treatment in overdose situations


(e.g. paracetamol)

dosing
monitoring the effects of dose adjustment (after
allowing time to reach steady-state)
assessing therapeutic concentrations after
administration of a loading dose (e.g. phenytoin)
dose forecasting to help make predictions
of an individuals dosage requirements
(e.g. aminoglycosides)
guiding dosage adjustment when a potentially
interacting drug is added to or removed from the
patients drug regimen
guiding dosage adjustment when there are
significant changes in a patients weight, fluid
status, renal or liver function

monitoring
assessing patient adherence
diagnosing under treatment
assessing treatment failurecan help distinguish
between non-adherence, absorption problems,
adverse effects mimicking the underlying disease,
or ineffective drug therapy.1,3,4

Principles of drug therapy

Therapeutic drug monitoring refers to the measurement


of drug concentrations in biologic fluids (plasma, blood
or serum) with the aim of optimising the efficacy and
minimising the toxicity of drug therapy in an individual
patient.25 The results obtained can be used to adjust the
dosage for each patient and so keep concentrations within
a target range for the particular drug(s) being monitored.

Characteristics of drugs suitable


for monitoring

Tables B.2 and B.3 show some medicines that meet these
criteria and are therefore suitable for TDM, along with
their target or therapeutic ranges.

Limitations
There are a number of limitations associated with the
use of TDM:

Only a small number of medicines are able to


be assayed.

There are inter-laboratory variations in reporting and


assay methodology.

There is varying assay test reliability and


result variability.
117

Section B | Therapeutic drug monitoring

Target ranges might not be relevant to


specific individuals.

Consideration of clinical efficacy and/or toxicity must


include the contribution of any active metabolite(s).3

Most medicines have a wide therapeutic indexi.e. they


are effective across a wide concentration range with a
low risk of toxicityand so can be prescribed according
to pre-established dosage regimens and evaluated on
the basis of clinical signs and symptoms. Adjustments to
dosing are made according to the clinical response when
the effects can be readily assessede.g. heart rate,
blood pressure and serum cholesterol.1,4

groups of patients. When they are applied to the broader


population there is an assumption that patients are
representative of the study population used to define the
therapeutic range. Consequently, the principle of treat
the patient, not the number should always be considered
when using TDM results in clinical practice.1,3,4
Table B.2 shows the target concentration ranges for
some commonly monitored medicines. The following
should be noted:

Concentrations are expressed as total (bound plus


unbound) concentration ranges unless specifically
noted as unbound.

For some medicines, reported optimal concentrations


can vary between laboratories, depending on assay
methods (e.g. cyclosporin and tacrolimus) or local
interpretation of the literature.

Recommended concentrations might not be


appropriate for very young or very old patients,
who can be more sensitive to the effects of
specific medications.

Principles of drug therapy

Therapeutic range
The therapeutic range represents a target drug
concentration range that correlates with probable
treatment success without a major risk of toxicity in
most patients.3 For most drugs, concentrations above
the upper limit will be associated with an increased risk
of toxicity, while concentrations below the range will be
associated with an increased likelihood of inadequate
treatment.2,4 The therapeutic range is used as a tool
for optimising treatment. Monitoring for signs and
symptoms of toxicity and for disease response should
also be used to indicate the appropriateness of a dose.
Although the ranges shown in Table B.2 and B.3 are
based on available evidence in the literature and centres
of best practice in Australia, they should serve as a guide
only and should not replace clinical judgment.
The optimal therapeutic range can depend on
several factors:

the condition being treated and its severity

alterations in tissue or receptor responsiveness


pharmacodynamic changes

the extent of plasma protein binding and the


amount of unbound drug

electrolyte concentrations.

Achieving a desired target range is not always as


simple as giving a standard dose of medication.
Pharmacokinetic, pharmacodynamic and
pharmacogenomic variations between individuals
mean there is much variability between a dose and
the clinical response.4 Adjusting doses to keep plasma
drug concentrations within a target range reduces the
effect of inter-individual variations. Among the factors
contributing to this variability are adherence, patient
age, physiology (e.g. gender, pregnancy), comorbidities,
renal or hepatic impairment, drug interactions, effects of
genetic polymorphisms on hepatic drug metabolism, and
environmental influences.
In most cases the target ranges have been derived
from population data from clinical trials and are based
on observed therapeutic and adverse effects in small
118

Sample timing
At steady-state
Unless monitoring is being done because toxicity is
suspected, samples should be taken after a sufficient
amount of time has elapsed for the steady-state plasma
concentration to be reachedi.e. the state of equilibrium
at which the rate of drug input into the systemic
circulation is the same as the rate of elimination.1 Except
in circumstances where a loading dose has been given,
this requires a period of about four to five half-lives after
the beginning of therapy or a change in dosage.
Some drugs (such as perhexiline) have, however, very
long half-lives in individuals who are poor metabolisers,
and after several initial doses (i.e. before steady-state is
reached) monitoring can be used to predict the potential
for toxicity.3
Early monitoring might also be useful after
administration of loading doses to give a preliminary
indication of adequate dosing.3

Within the dosing interval


The time of sample collection is important because the
drug concentration will vary during the dosing interval.
The least variable point is just before the next dose is
due, so a pre-dose or trough concentration is generally
preferred. This is of particular importance for drugs with
short half-livese.g. vancomycin. For drugs with longer
half-lives (more than 24hours), such as amiodarone, there
will be less variation in serum concentrations and samples
can be collected at any point in the dosing interval.3

Section B | Therapeutic drug monitoring

The time required for absorption and distribution also


needs to be taken into account. For example, digoxin
levels should not be taken until more than six hours after
administration in order to ensure that the distribution
phase is complete and serum and myocardial tissue
concentrations are at equilibrium.5 Levels drawn after
absorption but prior to equilibrium can be very high but
are clinically unimportant.

Other factors
Sample timing can also be determined by the method
of monitoring. For example, for once-daily dosing
of aminoglycosides the sample should be taken
614 hours post-dose if nomogram methods are used,
while computerised area-under-the-curve methods
require two samples within the dosing interval.3

Samples sent for TDM are accompanied by


documentation detailing the time of the last dose,
the time of sample collection, the dosage regimen,
and the reasons for drug monitoring.

Dosage adjustment
Concentration levels should always be interpreted
in the context of the individual patient. Changes to

Before dosage adjustments are made in response to


levels outside the target range, the clinical relevance of
the result needs to be assessed. Among the factors to
consider are the following:

the prescribed dose

whether the sample was taken at the correct time

the biological fluid assayedwhole blood,


plasma or serum

the duration of therapy and whether steady-state


had been reached

whether the patient adhered to their


treatment regimen

the patients clinical status and co-morbidities, as


well as parameters such as age, sex and weight

the condition being treated

drug-specific parameterse.g. renal and/or hepatic


function, serum albumin for highly protein bound
drugs such as phenytoin, and serum potassium in
patients on digoxin

possible drug interactions.1,3,4

Principles of drug therapy

Occasionally, to assess the possibility of toxicity related to


peak serum concentrations, the sample can be timed to
match the occurrence of specific symptoms.

therapy should not be initiated solely on the basis of the


numerical results obtained. For example, for a person
who is being treated with an anticonvulsant and is
responding adequately to therapy (i.e. is seizure-free),
a value just below the target range would generally not
require a dosage change.3

Table B.2 Drugs commonly monitored in clinical practicea


Medicine

Paracetamol10

Therapeutic range1,69
Gravimetric units1,9

Molar units (SI)5,9

1030 mg/L

65200 micromol/L

Toxic
concentration1,612

Time to
steadystate1,4,8,9,13,14

Comments1,4,8,9

>150 mg/L
4 hours after
ingestion.

1020 hours

Paracetamol levels are indicated only in


cases of overdose. The time of ingestion
must be obtained in order to assess
whether or not the level is toxic.
In liver dysfunction, marked increases in
halflife have been observed in overdose
patients.

100 mg/L 4 hours


after ingestion for
those with risk
factors for toxicity
(e.g. alcoholism,
fasting/anorexia;
taking enzyme
inducing drugs, or
with HIV/AIDS).
Salicylate

150300 mg/L
(anti-inflammatory)

1.02.5 mmol/L
(anti-inflammatory)

300400 mg/L
(rheumatic fever)

2.530 mmol/L
(rheumatic fever)

>3.6 mmol/L
(>500 mg/L)

If patient is seen >8 hours post-ingestion,


treatment should not be delayed while
waiting for serum levels.

57 days

Dose and urinary pH-dependent halflife.


May exhibit non-linear behaviour, especially
at higher levels.
If dose changed, re-test after 57 days.

Anticonvulsants (to monitor seizure control and adherence)


Carbamazepine

512 mg/L

1750 micromol/L

>12 mg/L

411 days
(initially)
24 days
(ongoing
therapy)

Induces its own metabolism. Pre-dose


testing not as critical with slow-release
formulations.

119

Section B | Therapeutic drug monitoring

Table B.2 Drugs commonly monitored in clinical practicea (continued)


Medicine

Lamotrigine

Therapeutic range1,69

Gravimetric units1,9

Molar units (SI)5,9

3.014 mg/L

1256 micromol/L

Toxic
concentration1,612

Time to
steadystate1,4,8,9,13,14

Comments1,4,8,9

57 days

Levels can be significantly changed during


pregnancy or use of the OCP due to
increased clearance.
Half-life can double in combination with
valproate (from 30 to 60 hours).
Half-life reduces to about 15 hours in
combination with enzyme inducers.

Phenobarbitone

1040 mg/L (adult)


1030 mg/L (child)

65180 micromol/L
(adult)

>40 mg/L

1525 days

While half-life in children (excluding


neonates) is approximately half that of
adults, the time to stead-state is cited as
equivalent across all ages.

>20 mg/L

57 days

Phenytoin is strongly protein bound (~90%)


to albumin. Tests generally measure total
phenytoin, though only free phenytoin is
the active portion. Target ranges and doses
might need adjustment when albumin is
decreased.

65135 micromol/L
(child)

Principles of drug therapy

Phenytoin

1020 mg/L
trough (total)

4080 micromol/L
trough (total)

12 mg/L
trough (unbound)

48 micromol/L
trough (unbound)

Half-life is concentration dependent. Time


to steady-state may be prolonged. If dose
changed, retest after 57 days.
Monitor for adverse effects.
Valproate

50100 mg/L
(up to 150 mg/L in
some patients)

350700 micromol/L

In some patients
from >100 mg/L

24 days

Multiple daily
dosing:
>2 mg/L
(trough)

1020 hours
(adult);

Baseline serum creatinine should always be


measured.

1525 hours
(infant);

Half-life may be significantly increased


(>10-fold) in severe renal dysfunction.

2040 hours
(neonate)

Clearance decreased by concomitant


administration of other nephrotoxic
drugs. Serum concentrations and dosage
requirements can be influenced by
numerous factors (e.g. dehydration,
obesity, burns and cystic fibrosis).

(longer in
neonates)

There is a poor correlation between


concentration and effect and routine
monitoring is not recommended.
Monitoring can be useful to confirm
toxicity, assess compliance, or adjust dose
in the setting of possible drug interactions.
If dose changed, retest after 3 days.

Anti-infectives
Gentamicin12,15

Monitoring is not required for short-term


empirical use (<48 hours).
Monitoring of plasma concentrations is
recommended for all patients receiving directed
aminoglycoside therapy, the monitoring starting
with the first dose of directed therapy.

Daily dosing:
Computerised methods using AUC calculations >0.5 mg/L
(trough)
should be used. Graphical (nomogram)
methods of monitoring have been omitted
from current Australian guidelines.
Tobramycin12,15

Monitoring is not required for short-term


empiric use (<48 hours).
Monitoring of plasma concentrations is
recommended for all patients receiving
directed aminoglycoside therapy, monitoring
starting with the first dose of directed therapy.
Computerised methods using area under the
curve AUC calculations should be used. Graphical
(nomogram) methods of monitoring have been
omitted from current Australian guidelines.

Vancomycin12,16

15 3 mg/L
(trough level for
12hourly, 24-hourly,
and 48-hourly
dosing)

Multiple daily
dosing:
>2 mg/L
(trough)
Daily dosing:
>0.5 mg/L
(trough)

>20 mg/L
(trough)

1020 hours
(adult);
1525 hours
(infant);
2040 hours
(neonate)

2555 hours
(adult);
1020 hours
(child);
30-50 hours
(neonate)

Peak levels do not correlate with efficacy


or toxicity and checking peak levels is not
necessary.
Half-life can be significantly increased
(>25-fold) in severe renal dysfunction.
Rare cause of nephrotoxicity, but the
relationship is unclear. Mighty contribute to
toxicity of other nephrotoxic drugs.

Bronchodilators and respiratory stimulants


Theophylline

120

Adult: 1020 mg/L


(24 hours
postdosei.e.
steady-state peak
levels).

55110 micromol/L
Neonates:
3580 micromol/L
(for neonatal apnoea)

>20 mg/L

2 days

Theophylline clearance reduced by factors


such as heart failure, liver disease and some
medicines (e.g. carbamazepine, cimetidine,
ciprofloxacin, erythromycin). Clearance is
increased by smoking.

Section B | Therapeutic drug monitoring

Table B.2 Drugs commonly monitored in clinical practicea (continued)


Medicine

Therapeutic range1,69
Gravimetric units1,9

Molar units (SI)5,9

Toxic
concentration1,612

Time to
steadystate1,4,8,9,13,14

Comments1,4,8,9

Cardiovascular drugs
Amiodarone

0.52.5 mg/L
(pre-dose)
(same range for
desethylamiodarone)

1.54.0 micromol/L

from >2 mg/L

5 months

Average half-life is about 50days. After


any change in dosage levels will not reach
the new steady-state for 3 months.

Digoxin

0.51.8 microgram/L

0.62.0 nanomol/L
(atrial fibrillation)

>2.0 microgram/L

711 days
(up to 20
days in end
stage renal
failure)

Samples should be taken pre-dose or


>6 hours post-dose. If dose is changed,
retest after 6 days.

0.61.0 nanomol/L
(heart failure)

Toxicity-induced irregular rhythms can


mimic atrial fibrillation. Monitoring can help
to clarify whether excessive or inadequate
dosing is the problem.

Only unbound levels are interpretable after


administration of Digibind. Assess visual
disturbances.
Perhexiline

0.150.60 mg/L
0.601.2 mg/L for
non-responders

0.52.0 micromol/L

>0.6 mg/L

(612 hours
postdose)

30 hours for
extensive
metabolisers,
longer
in poor
metabolisers

Non-linear pharmacokinetics.
Take initial levels 7296 hours after
initiation. If below 2.0 micromol/L, repeat in
14 days, by which time steady-state should
have been reached. Poor metabolisers have
longer half-lives and greater risk of toxicity.
If dosage adjustment is required, measure
levels 14days later, keeping in mind that
it might take slow metabolisers up to
3months to reach steady-state.

Principles of drug therapy

Patients with renal dysfunction are


especially prone to toxicity. Toxicity is also
more likely in the context of hypokalaemia
and hypercalcaemia, even when digoxin
levels are within the target range.

Psychopharmacological
Amitriptyline/
nortriptyline

Imipramine/
desipramine

60250 microgram/L
(amitriptyline)

210900 nanomol/L
(amitriptyline)

50170 microgram/L
(nortriptyline)

185650 nanomol/L
(nortriptyline)

100300
microgram/L
(imipramine)

3501000 nanomol/L
(imipramine)

90250 microgram/L
(desipramine)
Clonazepam
Lithium

1550 microgram/L

>500
microgram/L

410 days

Tricyclic antidepressant levels are indicated


only in cases of overdose to aid diagnosis
and treatment. Both the parent drug
and the active metabolites should be
interpreted as a combined level.

>500
microgram/L

710 days

50160 nanomol/L

>80 microgram/L

57 days

Relationship between serum concentration


and seizure control is not well established.

0.81.2 mmol/L
(Acute mania)

>1.5 mmol/L
(adult)

45 days

Assess renal function: half-life can double


in severe renal dysfunction.

0.41.0 mmol/L
(prophylaxis)

>1.2 mmol/L
(elderly)

150550 nanomol/L
(desipramine)

If dosage changed, re-test in 510 days.


Therapeutic levels influenced by indication.
Levels increase with renal failure, diuretics,
low sodium diets, pregnancy and
infection.
Factors pre-disposing to toxicity include
dehydration, age >50, thyroid dysfunction,
pre-existing renal dysfunction, some drugs.

a. Some variations in recommended concentration ranges will occur between laboratories depending on technology and assay methods in use.
Note: Data are based on available evidence in the literature and centres of best practice in Australia; they should serve as a guide only and should not replace
clinical judgment. Trough concentration ranges are measured in serum or plasma unless otherwise specified. Medicines other than those included in the table
might be monitored by hospital and specialist laboratories in specific situations or patient groups, although the clinical benefit of monitoring might not have
been definitively established.

121

Section B | Therapeutic drug monitoring

Table B.3 Antineoplastics and immuno-suppressives recommended therapeutic


concentration rangesa
Medicine

Recommended concentration rangesa

Time to
steadystate1,4,8,9,13,14

Comments1,4,8,9

Cyclosporin

Recommended concentration ranges in microgram/L (trough, pre-dose)

30 hours

Transplant type

<3 months

36 months

612 months >12 months

EDTAwhole blood is
used.

Heart

225300

150225

110200

80110

Lung

225300

190260

190260

150225

Kidney*

80150

80150

60150

60150

Bone Marrow

80225

80225

Time to
steadystate
can be
longer
soon after
transplant
or if patient
has hepatic
impairment.

Principles of drug therapy

Recommended concentration ranges 2 hours post-dose microgram/L (*preferred


measurement method for kidney transplantation)
Transplant type

<3 months

36 months

612 months >12 months

Heart

7501000

450750

450750

300600

Lung

6001100

530900

450700

450600

Kidney*

7501000

600750

400600

400600

Multiple interactions
caution needed.
Monitoring concentration
at 2 hours post-dose is
preferred method for
renal transplants.

Ranges for other conditions not establishede.g. when used as an


immunosuppressive agent for auto-immune or similar conditions.
Everolimus

Sirolimus

Transplant type

microgram/L

Heart (de novo, without


calcineurin inhibitors)

812

Heart (with calcineurin


inhibitors)

38

Lung

613

Kidney

38

Heart and lung


transplantation (with
calcineurin inhibitors)

38

Transplant type

microgram/L

Heart (<12 months)

1015

Heart (>12 months)

3.510

Lung

613

Kidney (with cyclosporin)

412

Kidney (after cyclosporin


withdrawal)

1220

Bone marrow

510

45 days

EDTAwhole blood is
used.
Multiple interactions
caution needed.
Interactions with CYP3A4
inhibitors and inducers
can affect concentrations.

14 days
Lower concentration
ranges for heart and
lung when used with
calcineurin Inhibitors.

EDTAwhole blood is
used.
Minimise calcineurin
inhibitor 24 months post
transplant due to risk of
synergistic nephrotoxicity.
Exhibits wide
pharmacokinetic
variability, with low
bioavailability and
unpredictable clearance.
Monitoring trough
concentration aids
treatment optimisation.

Tacrolimus

Transplant type

microgram/L

Liver

215

Heart or lung (<12 months)

1520

Heart or lung (>12 months)

1015

Kidney (<3 months)

1020

Kidney (>3 months)

515

Bone marrow

510

22.5 days

EDTAwhole blood
is used.
Substances that alter
the activity of CYP3A4
will affect plasma
concentration.

a. Some variations in recommended concentration ranges will occur between laboratories depending on technology and assay methods in use.
Note: Data are based on available evidence in the literature and centres of best practice in Australia; they should serve as a guide only and should not replace
clinical judgment. Concentrations are measured in serum or plasma unless otherwise specified. Medicines other than those included in the table might be
monitored by hospital and specialist laboratories in specific situations or patient groups, although the clinical benefit of monitoring might not have been
definitively established.

122

Section B | Therapeutic drug monitoring

Further information
Doogue MP, Martin JH. Whither therapeutic drug monitoring [editorial].
Internal Medicine Journal. 2010; 40:6712.
Rybak M, Lomaestro B, Rotschafer JC et al. Therapeutic monitoring
of vancomycin in adult patients: a consensus review of the American
Society of Health-System Pharmacists, the Infectious Diseases Society of
America, and the Society of Infectious Diseases Pharmacists. American
Journal of Health-System Pharmacy. 2009; 66:8298.
Rybak M, Lomaestro B, Rotschafer JC et al. Vancomycin therapeutic
guidelines: a summary of consensus recommendations from the
Infectious Diseases Society of America, the American Society of HealthSystem Pharmacists, and the Society of Infectious Diseases Pharmacists.
Clinical Infectious Diseases. 2009; 49:3257.
Schiff J, Cole E, Cantarovich M. Therapeutic monitoring of calcineurin
inhibitors for the nephrologist. Clinical Journal of the American Society
of Nephrology 2007; 2:37484.
Tomson T, Dahl ML, Kimland E. Therapeutic monitoring of antiepileptic
drugs for epilepsy. Cochrane Database of Systematic Reviews 2007,
Issue 2. Art No.: CD002216. DOI: 10.1002/14651858.CD002216.pub2.
Trevillian P. Therapeutic drug monitoring. Nephrology. 2007; 12,
S57-S65.

References
1. Lee M. Basic skills in interpreting laboratory data. 4th edn.
Maryland: American Society of Health-System Pharmacists, 2009.
2. Alderman C, ed. Therapeutic drug monitoring. RGH Pharmacy
E-Bulletin. 1March, 2010; 37(4).
3. Ghiculescu RA. Therapeutic drug monitoring: which drugs, why,
when and how to do it. Australian Prescriber. 2008; 31:424.
4. Birkett DJ. Pharmacokinetics made easytherapeutic drug
monitoring. Australian Prescriber. 1997; 20:911.

Principles of drug therapy

Vadja FJE. Monitoring antiepileptic drugs therapy with serum level


measurements. Medical Journal of Australia 2007; 187:581.

5. Winter ME. Basic clinical pharmacokinetics. 5th edn. Baltimore:


Lippincott Williams & Wilkins, 2010.
6. SydPath Pathology. Test Information. 2010. At: www.sydpath.com.
au/test-information.htm.
7. Alfred Pathology Service. Bayside Health Pathology Handbook.
14th edn. 2004.
8. Auckland and District Health Board. LabPLUS Test Guide. 2011.
At: http://testguide.adhb.govt.nz/EGuide/.
9. Evans WE, Oellerich M, Holt DW eds. Therapeutic drug monitoring
clinical guide. 2nd edn. Sydney: Abbott Laboratories Diagnostic
Division, 1994.
10. Daly FFS, Fountain JS, Murray L et al. Guidelines for the management
of paracetamol poisoning in Australia and New Zealand
explanation and elaboration. A consensus statement from clinical
toxicologists consulting to the Australasian poisons information
centres. Medical Journal of Australia. 2008; 188:296301.
11. Emergency Medicine Expert Group. Therapeutic guidelines:
emergency medicine, version 1. Melbourne: Therapeutic Guidelines
Ltd, 2008.
12. Antibiotic Expert Group. Therapeutic guidelines: antibiotic, version
14. Melbourne: Therapeutic Guidelines Ltd, 2010.
13. Calgary Laboratory Services. Half-life and time to steady state
(T to SS). 2009. At: www.calgarylabservices.com/files/LabTests/
HalfLifeTime.pdf.
14. Ashley C, Currie A eds. The renal drug handbook. 3rd edn. Oxford:
Radcliffe Publishing Ltd, 2009.
15. Moulds RFW, Jeyasingham MS. Gentamicin: a great way to start.
Australian Prescriber. 2010; 33:1345.
16. Rybak M, Lomaestro B, Rotschafer JC et al. Therapeutic monitoring
of vancomycin in adult patients: a consensus review of the
American Society of Health-System Pharmacists, the Infectious
Diseases Society of America, and the Society of Infectious Diseases
Pharmacists. American Journal of Health-System Pharmacy. 2009;
66:8298.

123

Drug interactions
A drugdrug interaction occurs when the effect
of a drug is modified by previous or concomitant
administration of another drug. Drug activity can
also be modified by complementary medicines, food,
smoking or alcohol.1 Interactions can result in decreased
efficacyeven therapeutic failureor an increased
pharmacodynamic response causing adverse effects.

Principles of drug therapy

Clinically important
interactions
Because of the increasing complexity of medication
regimens and widespread polypharmacy, pharmacists
are often required to make informed recommendations
on managing potential interactions. Understanding the
mechanism of interaction and the characteristics of the
substances involved can provide insight into the clinical
relevance of an interaction and how the interaction
might be avoided (e.g. by changing in medication) or
how to minimise the potential clinical impact of the
interaction (e.g. by changing the dose or by changing
the timing of doses).
In recent years there has been enormous growth in
the number of published potential interactions,
and there is a danger that the relatively small
number of wellestablished and clinically significant
interactions could become buried within exhaustive
interaction tables.
This entry discusses some of the pharmacodynamic
and pharmacokinetic mechanisms involved in drug
interactions, the potential clinical significance of these
interactions, and how the interactions can be managed.
Some examples of clinically important drug interactions
are included, but the list is by no means exhaustive.
Furthermore, the entry does not specifically discuss
herbdrug interactions (see Complementary medicines
monographs, Section E).

Pharmacodynamic interactions
Pharmacodynamic interactions occur when the ability
of a drug to interact with its target site of action (e.g.
receptor) and the subsequent clinical response are
modified by the co-administration of another drug.2
Drugs can compete for particular receptors either
directly or indirectly, by interfering with physiological
mechanisms. Pharmacodynamic interactions can often
be predicted when the pharmacological properties and
mechanisms of action of the individual medicines are
understood.
124

Additive and synergistic interactions


Additive or synergistic interactions can occur when
two drugs with common pharmacological effects are
taken concomitantly. The interaction is additive when
the observed effect is equal to the sum of the two
medicines individual effects and synergistic if the
combined effect is greater than the sum of the individual
effects. Synergistic interactions have the potential to be
more harmful than additive interactions. The following
are examples of interactions leading to additive or
synergistic toxicity:

alcohol with central nervous system (CNS)


depressantsincreased CNS depression

verapamil with beta-blockersadditive cardiodepressant effects

anticholinergics with tricyclic antidepressants


or some antipsychoticsincreased
anticholinergic effects

non-steroidal anti-inflammatory drugs with


angiotensin-converting enzyme inhibitorsincreased
risk of renal impairment and hyperkalaemia

ACE inhibitors with potassium supplements or


potassium-sparing diuretics (e.g. spironolactone)
can lead to hyperkalaemia

antibiotics with warfarinincreased risk of bleeding


because of reduced vitamin K production by
bowel flora

NSAIDs with warfarinincreased risk of


gastrointestinal bleeding

antiplatelet agents or selective serotonin reuptake


inhibitors (SSRIs) with anticoagulantsincreased risk
of bleeding

methotrexate with co-trimoxazoleadditive


antifolate activity and increased toxicity

tramadol with SSRIsincreased risk of serotonin


syndrome.1,3,4

Antagonistic or opposing
interactions
A drug can neutralise or oppose the desirable actions of
another drug. This can occur through direct antagonism
at a receptor site or when drugs have opposing
pharmacological effects mediated via different actions.
The following are examples:

Non-selective beta-blockers (e.g. sotalol) antagonise


the effects of beta-agonist bronchodilators
(e.g. salbutamol).

Vitamin K opposes the anticoagulant activity


of warfarin.

Section B | Drug interactions

Oral hypoglycaemics and glucocorticoids have


opposing effects on blood glucose levels.

NSAID-induced fluid retention can oppose the


desirable actions of antihypertensive, diuretic or
heart failure drugs.

Metoclopramide antagonises the effects of


dopaminergic agents in Parkinsons disease.

Caffeine antagonises the sedative effects of


benzodiazepines.1,3,4

Interactions caused by fluid or


electrolyte disturbances

Pharmacokinetic interactions
Pharmacokinetic interactions occur when one drug alters
the absorption, distribution, metabolism and/or excretion
of another drug, modifying the concentration of the
second drug at its site of action. Only a small percentage
of theoretical pharmacokinetic interactions actually lead
to adverse clinical outcomes.
To assess the potential clinical importance of a
pharmacokinetic interaction, several factors need to be
considered:

Clinically important interactions are more likely


to occur when the affected drug has a narrow
therapeutic index or a steep doseresponse curve.

Any drug that has the potential to adversely affect


kidney function can influence the pharmacokinetics
of other medicines that are renally excreted.

Only a relatively small number of drugs inhibit or


induce hepatic metabolism to a significant extent.

There is significant inter-patient variability in


response to potential pharmacokinetic drug
interactions. Adverse outcomes from interactions
are more likely in older patients, in those with liver
or kidney dysfunction and in those taking a large
number of medicines.1,2,5

An understanding of the mechanisms whereby one


medicine can influence the pharmacokinetics of
another will help pharmacists assess the likelihood of a
pharmacokinetic interaction, the potential significance of
such an interaction, and how a potential interaction can
be avoided.

Absorption
One drug can affect the absorption of another through a
number of different mechanisms1,2,5 as follows.

Antacids and acid-suppression therapy (proton


pump inhibitors, H2-antagonists) increase gastric pH,
which can:

increase the gastric solubility of drugs that are poorly


soluble weak acids

decrease the solubility of drugs that are weak bases

increase the stability of acid-labile drugs

potentially cause the premature release of drugs


from enteric-coated formulations if gastric pH
becomes sufficiently high.

For example, the reduced solubility of ketoconazole in


elevated gastric pH results in a substantial decrease in
the rate and extent of the drugs absorption.

Complexation, chelation and adsorption


Certain metal ions (e.g. those present in antacids,
ferrous sulfate, sucralfate and dairy products), ion
exchange resins (cholestyramine) and non-digested
substances (e.g. orlistat, kaolin, pectin and dietary fibre)
can form poorly soluble complexes with drugs such as
tetracyclines, fluoroquinolones, thyroxine, cyclosporin,
warfarin and digoxin. To avoid an interaction and ensure
that a substance susceptible to complexation has moved
from the stomach into the intestine, the drug should
be administered 3060 minutes before administering
a complexing agent. Once the complexing agent has
been taken, it is advisable to wait at least two to three
hours before taking medicines that are susceptible to
complexation or adsorption (see Label 4 in Counselling
and cautionary advisory labels, in Section A).

Principles of drug therapy

Pharmacodynamic interactions can also occur when


one drug causes alterations to the environment
necessary for the safe and effective use of another drug;
e.g.loop diuretics causing potassium loss sensitise the
myocardium to the effects of digoxin, without altering
plasma concentrations of the latter.5

Modification of gastric pH

Effects on gastrointestinal motility


Most drugs are largely absorbed in the upper part of the
small intestine, so any modification of gastrointestinal
motility and gastric emptying can affect the rate
of absorption.1 For example, opioid analgesics and
anticholinergic agents that slow gastric emptying
prolong the exposure of the drugs to stomach acid
and increase the degradation of acid-labile drugs (e.g.
penicillin V), effectively reducing their absorption.
Conversely, metoclopramide increases the rate of gastric
emptying and can increase the rate of absorption of
drugs such as paracetamol and diazepam.
For many drugs, however, the clinical significance of this
effect is unclear and the total amount of drug absorbed
might not be altered.

Pathological changes to the


gastrointestinal tract
Some drugs, such as antibiotics, colchicine and
antineoplastic agents can cause reversible pathological
changes to the gastrointestinal tracte.g. mucosal
damage and epithelial barrier dysfunction. Such changes
125

Section B | Drug interactions

can alter gastrointestinal permeability and the absorption


of other medicines.

Clinical relevance of changes


in absorption

Modification of bacterial flora

An interaction mediated through altered


absorption can change the rate or extent of
absorption, or both, of an affected drug. Changes
in the rate of absorption are not necessarily
clinically important if the total amount of drug
absorbed is unaffected. For drugs with a short
half-life or those required to achieve high
concentrations rapidly (e.g.analgesics, antiemetics and hypnotics), changes in the absorption
rate may affect the onset of drug action.

Principles of drug therapy

Gastrointestinal bacterial flora are occasionally involved


in drug metabolism. This metabolism can be affected if
the flora are modified by antibiotic use, although it is
unlikely that the clinical importance of this effect extends
beyond the well-documented interaction involving the
oestrogen component of combined oral contraceptives
and antibiotics. Oestrogen undergoes enterohepatic
recirculation and is repeatedly secreted in the bile as
steroid conjugates. It is thought that antibiotics reduce
the efficacy of oral contraceptives by inhibiting the
hydrolysis of these conjugates by gut bacteria before
re-absorption into the bloodstream, lowering the
concentrations of circulating oestrogen.1
Elevated digoxin plasma levels in some individuals treated
with antibiotics, particularly macrolides, were thought to
be caused by a reduction in pre-systemic metabolism by
gut flora. More recent evidence suggests, however, that
inhibition of P-glycoprotein in the intestinal wall might
be responsible.7,8

Effects on metabolising enzymes and


transporters in the intestinal wall
Within the intestinal wall enzymes and drug transporter
proteins (particularly CYP3A4 and P-glycoprotein, or
Pgp) are thought to work together to reduce drug
absorption. Pgp is present in significant levels along the
length of the gastrointestinal tract and is associated with
the ejection of some drug molecules that have diffused
across the gut lining and have been re-absorbed into
the intestine, thus reducing the total amount of drug
absorbed. Inhibiting the function of intestinal Pgp results
in increased absorption, while inducing the function of
Pgp results in an enhanced defensive mechanism and
decreased absorption of certain drugs that are substrates
for Pgp.6 Intestinal CYP3A4 iso-enzymes work to
metabolise drugs removed from systemic circulation by
Pgp. If one or both of these are induced or inhibited by
co-administered drugs, herbs or food, there is potential
for altered bioavailability of a range of drugs. In the case
of inhibition, the consequences are more likely to be
clinically relevant when the drug has low bioavailability.
The following are clinically significant examples of
these interactions:

down-regulation of intestinal CYP3A4 by grapefruit


juice causing felodipine bioavailability to significantly
increase (from 14% to 25%)9, whereas changes in
amlodipine bioavailability are relatively minor (81%
up to 88%).10

induction of intestinal Pgp by medicines such


as rifampicin and St Johns wort resulting in a
significant reduction in the bioavailability of drugs
such as digoxin.7

(See Table B.6 and also St Johns wort in Section E.)


126

In the case of drugs taken chronically it is important


to focus on interactions that alter the extent (rather
than the rate) of absorption because this will
influence average plasma concentrations. Drugs
with low to medium bioavailability are most likely
to exhibit significantly affected plasma levels, while
those with oral bioavailability close to 100% under
normal circumstances are generally less susceptible
to changes in the extent of absorption.

Distribution
Most drugs reversibly bind to plasma proteins, and
competition for binding sites is common. Sometimes
this competition can result in one drug (e.g. warfarin)
being displaced, causing an increase in the fraction
unbound in plasma. An increase in the unbound
fraction, however, rarely leads to an increase in
the unbound concentration in plasma and, if it
does, it is usually transient (a few hours). For most
medicines, an increase in the unbound fraction will
mean the medicine distributes more extensively and
is eliminated more readily. This explains why there
are very few documented examples of clinically
significant displacement interactions. Clinically
significant changes would be expected only when
there is displacement from plasma proteins occurring
alongside a change in the intrinsic clearance of
unbound drug. An example of such an interaction is
valproate displacing phenytoin from plasma proteins
and also inhibiting its metabolism.1 In such cases
any change in drug therapy should be guided by
unbound plasma concentration rather than total
(i.e.bound plus unbound) plasma concentration.
There is potential for altered distribution into the
CNS via carrier-mediated processes if a drug that is
a substrate for transporter proteins (specifically Pgp)
at the bloodbrain barrier is co-administered with
an inhibitor or an inducer of Pgp.7,8 Generally, Pgp
inhibition will result in only mild increases in serum
concentrations of orally administered Pgp substrates,
but toxic CNS concentrations can develop4 and in
situations of unexplained CNS side effects or toxicity
this mechanism should be considered (see Table B.6).

Section B | Drug interactions

Metabolism
A range of microsomal enzymes mediate the metabolism
of drugs by chemically changing them into less lipid
soluble products, facilitating their elimination via the
kidneys or bile. Details of specific enzyme systems,
the medicines they metabolise (i.e. substrates), and
the medicines that cause inhibition and induction
are provided in Table B.5. Interactions resulting from
inhibition or induction of hepatic enzyme metabolism
cannot generally be avoided by changing the timing of
administration of one medicine relative to the other.
Individual variations in enzyme activity also play an
important role: this is covered in detail in Individualised
medicine, page 149.

Enzyme induction

Enzyme inhibition
Unlike enzyme induction, enzyme inhibition can occur
within two or three days of starting therapy and can
result in rapid development of toxicity.1 The time taken
for the affected medicine to reach a new steady-state
plasma level after the start of therapy with an enzyme
inhibitor depends on the half-life of the affected
medicine. As a general rule, it takes about three to
four half-lives for the full impact of an inhibition
interaction to emerge. The clinical significance of many
enzyme inhibition interactions depends on the extent
to which the serum levels of the drug rise. Inhibition
of metabolism is probably the most common cause
of clinically important pharmacokinetic interactions
because it can lead to a dramatic increase in the plasma
concentrations of the affected drug, even though
there are relatively few drugs that significantly inhibit
metabolism (see Table B.5). Caution should be exercised
whenever an enzyme inhibitor is added to or withdrawn
from a dosage regimen that includes medicines that are
primarily eliminated by hepatic metabolism.

Effects on the metabolic process


Saturation of the process of metabolism can occur
when two or more drugs that are the substrates of
the same enzyme are present, causing an increased
pharmacological effect of one or more of the drugs.

Renal excretion
Interactions involving renal excretion mechanisms
(secretion, filtration and re-absorption) are generally
important only in the case of drugs with a narrow
therapeutic index that are primarily excreted unchanged in
urine (e >0.7; see e in Pharmacokinetics, page 101).
Among such drugs are the aminoglycosides, vancomycin,
methotrexate, digoxin and lithium.

Changes in secretion
Some drugs are secreted into the urine by active
transport systems found in the renal tubules. There
are separate systems for weak acids and weak bases.
Competition between two weak acids (e.g. probenecid
and penicillin or NSAIDs and high-dose methotrexate)
can cause an increase in the plasma concentration of the
affected drug (penicillin and methotrexate respectively).

Principles of drug therapy

Enzyme induction occurs when one drug induces the


synthesis of enzymes involved in the metabolism of
another. Increasing the extent of metabolism of the
affected drug decreases plasma concentrations and the
pharmacological effect. Conversely, when an inducing
agent is withdrawn from the regimen of a patient
receiving multiple medicines, there is a possibility that
the plasma levels of other drugs will increase. It can
take a week or more for enzyme induction to occur and
several weeks for enzyme levels to return to normal once
the inducer drug is ceased. Caution is needed whenever
enzyme inducers are initiated or ceased.

Induction or inhibition of the metabolism of a pro-drug


or a drug with active metabolites will result in a different
pharmacological response compared with that produced
by an active drug. When the metabolism of a prodrug
is inhibited less of the active moiety is produced,
reducing the pharmacological effect (and vice versa).
Inhibition of the conversion of clopidogrel to its active
metabolite by omeprazole is an example of this type of
pro-drug interaction.

Changes in filtration
Drugs that influence renal blood flow can affect the
excretion of renally cleared medicines by decreasing
the filtration rate. See Dosing in renal impairment,
page142.

Changes in re-absorption
Drugs that are relatively non-polar can undergo passive
tubular re-absorption, the drug passing from tubular
urine back into blood. For a given rate of administration,
therefore, the plasma concentration will increase if
reabsorption is increased, and vice versa.
The re-absorption of relatively non-polar weak acids and
bases (e.g. salicylates and amphetamines) can be altered
by changes in urinary pH. For example, an increase in
urinary pH tends to favour tubular re-absorption of
amphetamine, nicotine and morphine derivatives
because a greater proportion of the drug will be in
the non-ionised, lipid-soluble form and therefore able
to diffuse back through the lipid membranes of the
tubule cellsand this can lead to an increase in the
plasma concentrations. The clinical significance of this
mechanism is limited, however, because, although
many drugs are weak acids or bases, almost all are
largely metabolised in the liver to inactive compounds
and few are excreted unchanged in the urine. In cases
of overdose, urinary alkalinisation has been used to
increase the excretion of drugs such as phenobarbitone
and salicylates.1
127

Section B | Drug interactions

Other causes
Complex renal drug interactions can also occur, as is
the case when thiazide diuretics increase serum lithium
levels and the risk of toxicity by increasing renal tubular
re-absorption of lithium, secondary to impairing sodium
re-absorption.

The clinical importance of


pharmacokinetic interactions
In making a judgment about whether a reported
pharmacokinetic interaction is likely to be clinically
important in a particular setting, several factors need to
be taken into consideration, as follows.

Principles of drug therapy

Therapeutic index
An interaction is likely to be clinically important when
a relatively small change in the plasma concentration is
associated with a substantial change in the therapeutic
or toxic responsei.e. if the medicine has a narrow
therapeutic index or a steep doseresponse curve
(e.g. cyclosporin, digoxin, lithium, warfarin, theophylline,
phenytoin and aminoglycosides).
Drugs with a narrow therapeutic index often need to be
monitored in order to guide therapy (see Therapeutic
drug monitoring, page 117), and individuals should be
monitored whenever a drug is added to or removed from
a regimen involving drugs with a narrow therapeutic
index.

The magnitude of the change in


plasma concentration
The consequences of an interaction will probably be
minor if the change in the plasma concentration is small
relative to the changes normally observed between
individuals. For example, a 20% reduction in the rate of
absorption will not generally be clinically significant if
there is normally a two-fold variation in the absorption
rate. Similarly, if there is normally a two-fold to threefold variation in the plasma concentrations between
individuals, an interaction leading to a 20% reduction in
clearance would not normally be expected to be clinically
important. For drugs with a narrow therapeutic index,
such as digoxin, however, an interaction resulting in
20% reduction in clearance might precipitate toxicity.

Temporal considerations
The consequences of a pharmacokinetic interaction can
depend on the sequence in which the drugs are started
or stopped, or both. For example, if an enzyme inhibitor
is introduced in a patient who is stabilised on phenytoin,
the plasma concentration of phenytoin might increase
and cause toxicity. If, however, a medicine that inhibits
the metabolism of phenytoin is withdrawn from the
128

regimen of a patient already stabilised on phenytoin, the


outcome could be a reduction in plasma phenytoin levels
and an associated loss of seizure control. The potential
for an interaction should therefore be considered
not only when a new medicine is introduced but also
whenever a patients drug regimen is altered.

The effect of ageing


Interactions tend to be much more prevalent in older
people, who have an increased likelihood of receiving
multiple medications for multiple conditions. In general,
older people are also more susceptible to the effects
of drug interactions because their homeostatic reflexes
are less able to respond to additive pharmacological
effects. Reduced renal function and drug elimination
capacity can reduce their ability to metabolise drugs
(see Medicines in older people, after this entry, for
further information).

Genetic factors
There is considerable inter-patient variability in responses
to drug interactions. An interaction might manifest
clinically with adverse outcomes in one patient but
not in another. Some CYP iso-enzymes are subject to
genetic polymorphism, meaning that a proportion
of the population have a variant of a CYP iso-enzyme
with altered (usually poor) activity. These individuals
are classified as poor metabolisers and have impaired
metabolism of some drugs as a result of diminished
functioning of the affected iso-enzyme. There is some
variation among the iso-enzymes and population groups
affected1,5 (see Individualised medicines, page 149).
At present it is not possible to predict which individuals
will be more susceptible to pharmacokinetic interactions.
If, however, there is evidence that the dosage in a
particular person might already be too high (e.g. from
therapeutic monitoring data or signs of adverse events)
or too low (e.g. from breakthrough bleeding in a
woman taking the contraceptive pill) special care would
obviously need to be taken.

Examples of clinically important


drug interactions
Table B.4 lists some of the drug interactions that have
the greatest potential for serious effects. A study
of Australian war veterans found that, in practice,
relatively few drugs account for the majority of clinically
significant interactions.11 It was found that people
taking amiodarone, cyclosporin, itraconazole, lithium,
methotrexate, verapamil and warfarin should be the
focus of medication review services in order to avoid
potentially serious adverse drug events.

Section B | Drug interactions

Table B.4 Potentially serious drug


interactions: some examples1,4,11
ACE inhibitors and potassium salts
Allopurinol and azathioprine
Allopurinol and mercaptopurine
Amiloride and ACE inhibitors
Amiloride and potassium salts
Amiloride and tacrolimus
Amiodarone and digoxin
Amiodarone and haloperidol
Amiodarone and phenothiazines
Amiodarone and sotalol
Amiodarone and thioridazine
Carbamazepine and dextropropoxyphene
Cyclosporin and orlistat

Fluoxetine and moclobemide


Fluoxetine and selegiline
Imipramine and clonidine
Imipramine and entacapone
Imipramine and moclobemide
Itraconazole and simvastatin or atorvastatin
Itraconazole and tacrolimus or sirolimus
Lithium and ACE inhibitors or AIIR blockers
Lithium and frusemide
Lithium and haloperidol
Lithium and thiazides
Lithium and phenothiazines
Methotrexate and aspirin
Methotrexate and NSAIDs
Pravastatin and gemfibrozil
Sildenafil, tadalafil, vardenafil and nitrates
Spironolactone and ACE inhibitors
Spironolactone and amiloride
Spironolactone and lithium
Spironolactone and potassium salts
Spironolactone and tacrolimus or sirolimus
Tramadol and mono-amine oxidase inhibitors
Triptan and ergot alkaloids
Triptan and methysergide
Triptan and mono-amine oxidase inhibitors
Triptan and SSRIs
Verapamil and beta-adrenoceptor blockers
Warfarin and anti-platelet medicines
Warfarin and miconazole (or other imidazoles)
Warfarin and NSAIDs

The following examples illustrate the diverse ways


medicines can interact. Also included is a discussion of
the strategies a pharmacist might adopt when faced with
such interactions.

Metabolism of warfarin is susceptible to inhibition by


a number of medicines, among them fluvoxamine,
ketoconazole, metronidazole, amiodarone, miconazole,
omeprazole and cimetidine. Warfarin has a narrow
therapeutic index and is almost exclusively metabolised
by hepatic microsomal enzymes and then excreted
into the urine and, to a lesser extent, the bile. Drugs
that inhibit the metabolism of warfarin reduce drug
excretion and increase the risk of bleeding.4
When a pharmacist is faced with a prescription for one
of these medicines in a patient stabilised on warfarin,
the first course of action would be to consider the
use of a similar medicine that is unlikely to interact
e.g.using ranitidine instead of cimetidine. Another
option would be to decrease the dose of warfarin and
closely monitor the patients clotting status (INR). Either
way, it is important that the prescriber is consulted to
determine the most appropriate action. Whether or not
a dose reduction is implemented, the patient should
be advised about the signs of abnormal bleeding and
what action to take if this occurs. Warfarin has a halflife of about a day, so a new steady-state plasma level
should be achieved within a few days. The effect on
INR depends on the half-lives of the clotting factors
and lags behind the effect on warfarin plasma levels.

Principles of drug therapy

Cyclosporin and statins

Example 1: medicines that inhibit


warfarin metabolism

Example 2: medicines that


reduce the effectiveness of oral
contraceptives
Pharmacists need to be particularly diligent about
providing advice when dispensing a medicine that
can alter the pharmacokinetics of oral contraceptives
because the consequences of even a transient
reduction in efficacy are significanti.e. an unintended
pregnancy. Drug interactions can impair the efficacy
of oral contraceptives via two pharmacokinetic
interactions.

Enzyme-inducing medicines
Hepatic enzyme CYP3A4-inducing medicines such
as phenytoin, carbamazepine, St Johns wort and
rifampicin increase the rate of metabolism of both
oestrogens and progestogens, hastening their
clearance and lowering systemic blood levels.
This can cause irregular bleeding and reduced
contraceptive efficacy with both combined and
progestogen-only contraceptive pills. For women
taking a hepatic enzymeinducing medicine, a
high-dose contraceptivepill with 50 micrograms
of ethinyloestradiol or an alternative form of
contraception (such as depot injection or a
copper or progestogen intra-uterine device) could
beconsidered.12
129

Principles of drug therapy

Section B | Drug interactions

Antibiotic therapy

Clinically important alterations in drug metabolism

It is thought that broad-spectrum antibiotics


temporarily decrease colonic bacteria, interfering with
enzymes essential for enterohepatic recirculation of
oestrogens and potentially decreasing the effectiveness
of combined oral contraceptives in a small percentage
of women. The documentation and case reports of
oral contraceptive failure resulting in pregnancy during
concurrent antibiotic therapy are limited.1 Often it
is difficult to identify which women are at risk of
oral contraceptive failure. The timing and duration
of the course of antibiotics are, however, thought
to be important. Because of the potentially serious
consequences of unintended pregnancy, additional
contraception protection is recommended for women
taking combined oral contraceptives during a short
course of a non-liver enzyme-inducing antibiotic (less
than three weeks) and for seven days after stopping
treatment.12 On the basis that flora recover three weeks
after starting antibiotics, women taking an established
course of antibiotics (three weeks or more) do not
require additional protection when starting a combined
oral contraceptive. For enzyme-inducing antibiotics
such as rifampicin and rifabutin, however, additional
contraception is necessary during use and for 28 days
after the enzyme inducer is stopped. Progestogens do
not undergo enterohepatic recirculation, so nonliver
enzyme-inducing antibiotics do not interact with the
progestogen-only pill.

and plasma concentrations occur more frequently in

Example 3: cigarette smoking and


drug therapy
Cigarette smoking can potentially alter the
pharmacokinetics and pharmacodynamics of numerous
drugs by a range of mechanisms, and dosage
adjustment can be necessary in individuals who start or
stop smoking.

Enzyme induction
Some constituents of cigarette smoke are capable of
liver enzyme induction while others act as enzyme
inhibitors. The most common mechanism is through
induction of liver enzymes (CYP1A1 and CYP1A2),
increasing drug metabolism and dosage requirements
in patients receiving drugs affected by this mechanism.
Clozapine and olanzapine are examples of drugs
mainly metabolised via CYP1A2, and non-smokers
might need a 50% lower starting dose than smokers;
if a patient who smokes and is on a stable clozapine
regimen ceases smoking, the clozapine plasma level
can increase by up to oneandahalf times during the
following two to four weeks.
The effect of smoking on drug metabolism is more
pronounced in smokers aged less than 40 years
and can persist for months after smoking cessation.
130

people who smoke more than 20 cigarettes a day.


The effects of drugs can be increased or antagonised
by the pharmacological effects of nicotine. This can
also be clinically relevant in individuals using nicotine
replacement therapy.2

Caffeine
Cigarette smoking is known to accelerate the
metabolism of caffeine and related medicines such
as theophylline. Studies have found that cessation of
smoking can be associated with a three-fold increase
in the plasma concentration of caffeine, despite no
change in caffeine consumption. It has been suggested
that these increased levels and the stimulant effects of
caffeine could contribute to the perceived symptoms
of tobacco withdrawal syndromeincluding headache
and agitation. When counselling a patient who plans
to stop smoking, it is wise to suggest that they also
reduce their caffeine intake.

Example 4: NSAIDs, COX2


inhibitors, ACE inhibitors,
angiotensin II receptor antagonists
and renal haemodynamics
NSAIDs, COX-2 inhibitors, ACE inhibitors and
angiotension II receptor antagonists can potentially
cause serious deterioration in renal function via several
different pharmacodynamic mechanisms.

The triple whammy


The risk of drug-induced renal impairment is
cumulative and is more likely in patients with underperfused kidneys (e.g. congestive cardiac failure) or
with preexisting renal disease (including age-related
renal decline). Renal function should therefore be
checked before an NSAID or a COX-2 inhibitor is
started in patients taking ACE inhibitors or angiotensin
II receptor antagonists. The risk is further increased if
the patient is also taking a diuretic.3 This combination
can result in what is commonly referred to as the triple
whammy effect. For further information, see Dosing
in renal impairment, page 142.

Antihypertensive therapies
NSAIDs and COX-2 inhibitors can also reduce the
antihypertensive effects of ACE inhibitors, angiotensin
II receptor antagonists and other antihypertensives
and the effects of drugs in treating heart failure. ACE
inhibitors and angiotensin II antagonists can increase
potassium concentrations4 and increase the risk of
hyperkalaemia when used in combination with other
drugs that cause elevated potassium levels.

Section B | Drug interactions

Table B.5 Medicines that are substrates for or inhibitors or inducers of the cytochrome P450
family of iso-enzymes: some examples1,3,4
Substrates

Inhibitors

Inducers

CYP1A2

Amitriptyline, caffeine, clozapine, diazepam, flutamide, fluvoxamine,


haloperidol, imipramine, mirtazapine, naproxen, oestradiol,
olanzapine, ondansetron, paracetamol, propranolol, ropinirole,
tacrine, tamoxifen, theophylline, terbinafine, verapamil, R-warfarin,
zolmitriptan

Amiodarone,
anastrozole, cimetidine,
clarithromycin,
erythromycin,
fluvoxamine, grapefruit
juice, isoniazid,
paroxetine, propranolol,
quinolone antibiotics
(ciprofloxacin,
norfloxacin), tacrine

Carbamazepine,
cruciferous vegetables
(e.g. broccoli, brussels
sprouts), lansoprazole,
omeprazole, phenytoin,
polycyclic aromatic
hydrocarbons (e.g. meat
cooked over charcoal,
tobacco smoking)

CYP2C9

Amitriptyline, carvedilol, celecoxib, diclofenac, fluoxetine, fluvastatin,


glibenclamide, glimepiride, glipizide, ibuprofen, imipramine,
indomethacin, irbesartan, losartan, meloxicam, montelukast,
naproxen, phenytoin, piroxicam, rosiglitazone, rosuvastatin,
tamoxifen, terbinafine, tetrahydrocannabinol, voriconazole,
S-warfarin, zafirlukast

Amiodarone,
cimetidine, diclofenac,
fenofibrate, fluconazole,
fluoxetine, fluvoxamine,
imatinib, isoniazid,
sertraline, sitaxentan,
sulfamethoxazole,
trimethoprim,
voriconazole, zafirlukast

Aprepitant, bosentan,
carbamazepine,
phenytoin, rifampicin,
St Johns wort

CYP2C19

Amitriptyline, citalopram, clomipramine, cyclophosphamide,


diazepam, escitalopram, esomeprazole, imipramine, indomethacin,
lansoprazole, moclobemide, nelfinavir, omeprazole, pantoprazole,
pentamidine, phenytoin, propranolol, rabeprazole, terbinafine,
topiramate, R-warfarin

Cimetidine, fluoxetine,
fluvoxamine,
indomethacin,
ketoconazole, letrozole,
modafinil, omeprazole,
oxcarbazepine,
topiramate, voriconazole

Carbamazepine,
phenytoin, prednisone,
rifampicin

CYP2D6

Amitriptyline, aripiprazole, atomoxetine, carvedilol, chlorpromazine,


citalopram, clomipramine, clozapine, codeine, dextromethorphan,
dolasetron, donepezil, doxepin, escitalopram, flecainide, fluoxetine,
fluphenazine, galantamine, haloperidol, hydrocodone, imipramine,
labetalol, methadone, metoclopramide, metoprolol, mianserin,
mirtazapine, morphine, nortriptyline, olanzapine, ondansetron,
oxprenolol, oxycodone, paroxetine, perhexiline, pethidine,
promethazine, propranolol, quetiapine, risperidone, tamoxifen,
thioridazine, tramadol, trimipramine, venlafaxine

Amiodarone,
bupropion, celecoxib,
chloroquine, cimetidine,
clomipramine,
diphenhydramine,
escitalopram,
haloperidol, methadone,
metoclopramide,
ritonavir, selective
serotonin reuptake
inhibitors (all SSRIs
inhibit 2D6, with
fluoxetine and paroxetine
the most potent),
terbinafine, thioridazine

Carbamazepine,
dexamethasone,
phenytoin, rifampicin,
ritonavir

CYP2E1

Enflurane, ethanol, halothane, isoflurane, methoxyflurane,


paracetamol, sevoflurane, theophylline

Disulfiram

Ethanol, isoniazid

CYP3A4

Alfentanil, alprazolam, amiodarone, amitriptyline, amlodipine,


aprepitant, aripiprazole, atazanavir, atorvastatin, bosentan,
bromocriptine, budesonide, buprenorphine, busulfan, carbamazepine,
citalopram, clarithromycin, clindamycin, clomipramine, clonazepam,
cocaine, cyclophosphamide, cyclosporin, dapsone, dexamethasone,
dextromethorphan, diazepam, diltiazem, donepezil, doxorubicin,
eplerenone, ergot alkaloids, escitalopram, everolimus, erythromycin,
esomeprazole, ethinyloestradiol, ethosuximide, etoposide, felodipine,
fentanyl, fexofenadine, finasteride, flutamide, galantamine,
haloperidol, hydrocortisone, ifosfamide, imatinib, imipramine,
indinavir, irinotecan, itraconazole, ivabradine, ketoconazole,
lansoprazole, lapatinib, lercanidipine, lignocaine, lopinavir, loratadine,
losartan, methadone, miconazole, midazolam, mirtazapine,
montelukast, nelfinavir, nevirapine, nifedipine, nimodipine, oestradiol,
omeprazole, ondansetron, paclitaxel, pioglitazone, quetiapine,
reboxetine, repaglinide, ritonavir, saquinavir, sertraline, sildenafil,
simvastatin, sirolimus, sodium valproate, sunitinib, tacrolimus,
tadalafil, tamoxifen, teniposide, tetrahydrocannabinol, theophylline,
tiagabine, tolterodine, tramadol, trazodone, triazolam, vardenafil,
venlafaxine, verapamil, vinblastine, vincristine, voriconazole,
R-warfarin, zolpidem

Amiodarone, aprepitant,
cannabinoids,
cimetidine, ciprofloxacin,
clarithromycin, diltiazem,
efavirenz, erythromycin,
fluconazole, fluoxetine
(due to norfluoxetine
metabolite), fluvoxamine,
grapefruit juice, imatinib,
indinavir, itraconazole,
ketoconazole,
metronidazole,
miconazole, protease
inhibitors (all inhibit 3A4,
with ritonavir the most
potent), verapamil

Bosentan, carbamazepine,
efavirenz, glucocorticoids,
modafinil, nevirapine,
phenobarbitone,
phenytoin, primidone,
rifabutin, rifampicin,
StJohns wort

Principles of drug therapy

Cytochrome
P450

131

Section B | Drug interactions

Example 5: NSAIDs and impaired


renal drug clearance
Methotrexate

Principles of drug therapy

There are a number of case reports of increased


methotrexate toxicityin some situations
lifethreateningin patients also taking NSAIDs.
The signs and symptoms of methotrexate toxicity can
become evident one to two weeks after the start of
coadministration. The risk of a serious interaction
appears to be dose-related, with more frequent case
reports among people taking high-dose methotrexate
(150 mg or more daily to treat neoplastic disease)
and among patients with renal impairment. Toxicity
is less likely to occur with weekly low-dose regimens
(5 to 25mg weekly) for rheumatoid arthritis and other
inflammatory diseases.1,2
Methotrexate is primarily cleared unchanged from the
body by renal excretion. Although the exact mechanism
of the interaction is unclear, NSAIDs might inhibit the
renal clearance of methotrexate through competition
for renal secretion or, alternatively, might have a direct
effect on renal blood flow (via inhibition of prostaglandin
synthesis).1 Monitoring of renal function and full
blood counts are recommended in patients receiving
this combination.

Lithium
NSAIDs can also decrease the renal clearance of lithium,
and monitoring of lithium levels is essential during
initiation of NSAID therapy.3

Cytochrome P450 interactions


Many medicines are metabolised by the cytochrome
P450 family of iso-enzymes. Although humans can
produce up to 50 individual P450 enzymes, only a few
specific subfamilies are responsible for about 90% of
the metabolism of commonly used medicines. The term
cytochrome P450 is a generic term for the entire family
of enzymes. The iso-enzymes are named using the root
symbol CYP followed by an arabic numeral designating
the family, a letter denoting the subfamily, and a further
arabic numeral designating the individual enzymes.
The activity of metabolising enzymes such as the
cytochrome P450s can be influenced by a variety
of factors, among them genetic variations, enzyme
inhibition and induction, diet, health status, gender and
age. A large number of clinically important interactions
arise from inhibition or induction of cytochrome
P450mediated metabolism.
Substrates are medicines that are significantly
metabolised by the given enzyme, while inhibitors
are compounds that are generally capable of inhibiting
132

the metabolism of the various substrates (as a result,


administration of the inhibitor can lead to an increased
plasma concentration of the listed substrate). Inducers
of the specified P450 have the capacity to increase the
activity of the designated enzyme and therefore reduce
the plasma concentrations of the listed substrates.
Table B.5 shows some common medicines that
are substrates for or inhibitors or inducers of the
cytochrome P450 iso-enzymes. The table is subject to the
following limitations:

It is not comprehensive. Information about the


metabolism of many medicines is still lacking.

Medicines can be metabolised by multiple P450


enzymes and might be listed under more than
one enzyme.

The listing of two medicines under the same P450


does not indicate a definite interaction of clinical
significance.

Information about substrates for and inhibitors


and inducers of cytochrome P450 is continuously
being updated. An up-to-date, comprehensive list is
available at www.medicine.iupui.edu/flockhart.

Antiretroviral agents used for the treatment of HIV


infection are involved in a large number of drug
interactions; interaction information for these agents is
available from www.hiv-druginteractions.org.

Drug transporter proteins


Drugs and endogenous substances are known to cross
biological membranes by active transport with the
involvement of various transporter proteins through
carrier-mediated processes. The most widely recognised
transporter is Pgp (P-glycoprotein), a plasma membrane
glycoprotein belonging to the ATP-binding cassette
(ABC) family of efflux transporters, whose involvement
in drug interactions is shown in Table B.6. Other
transporters involved in drug interactions are the organic
anion transporters (OATs), through the renal excretion of
a number of drugs (e.g. probenecid).1
Some drug interactions occur through interference with
the activity of Pgp, which is found in the membranes
of some cells and can influence the extent of drug
absorption (in the intestine), distribution (to the brain or
placenta) and elimination (in the urine and bile). Drug
transporter proteins can act as a barrier to absorption,
and in the bloodbrain barrier they can have a protective
function by ejecting certain drugs and limiting central
nervous system penetration. The activity of Pgp can be
stimulated or inhibited by exposure to particular drugs.
Inhibition of Pgp is thought to have a greater impact
on drug distribution (e.g. into the brain) than on drug
absorption (e.g. plasma levels).1

Section B | Drug interactions

There is considerable overlap between the drugs that act


as CYP3A4 and Pgp inhibitors, inducers and substrates,
and both mechanisms might be involved in many of the
drug interactions traditionally thought to be the result of
changes in CYP3A4.1,5

Table B.6 Drugs affecting or transported by


P-glycoprotein1,6
Inhibitors

Inducers

Substrates

cyclosporin

digoxin

clarithromycin

protease inhibitors
(ritonavir, tipranavir)

erythromycin

rifampicin

colchicine

itraconazole

St Johns wort

cyclosporin

ketoconazole

carbamazepine

fexofenadine

loperamide

quinidine

indinavir

verapamil

morphine

amiodarone

sirolimus

References
1. Baxter K ed. Stockleys Drug Interactions. 9th edn. London:
Pharmaceutical Press, 2010.
2. Tatro DS. Drug interaction facts. St Louis: Wolters Kluwer Health,
2011.
3. Rossi S ed. Australian medicines handbook. Adelaide: Australian
Medicines Handbook Pty Ltd, 2011.
4. Product information. eMIMs [CD-ROM]. St Leonards: CMPMedica
Australia Pty Ltd, 2010 August.

Principles of drug therapy

saquinavir

5. Bachmann KA ed. Lexi-Comps drug interactions handbook. 2nd


edn. Ohio: Lexi-Comp, 2004.
6. Horn JR, Hansten P. Drug transporters: the final frontier for drug
interactions. Pharmacy Times. 2008. At: www.pharmacytimes.com/
issues/articles/2008-12_029.asp.
7. Marchetti S, Mazzanti R, Beijnen JH et al. Concise review: clinical
relevance of drug drug and herb drug interactions mediated by the
ABC transporter ABCB1 (MDR1, P-glycoprotein). Oncologist 2007,
12:92741.
8. Lee CA, Cook JA, Reyner EL et al. P-glycoprotein related drug
interactions: clinical importance and a consideration of disease
states. Expert Opinion on Drug Metabolism and Toxicology 2010;
6:60319.
9. Lundahl J, Regardh CG, Edgar B et al. Effects of grapefruit juice
ingestionpharmacokinetics and haemodynamics of intravenously
and orally administered felodipine in healthy men. European
Journal of Clinical Pharmacology. 1997; 52:13945.
10. Vincent J, Harris SI, Foulds G et al. Lack of effect of grapefruit juice
on the pharmacokinetics and pharmacodynamics of amlodipine.
British Journal of Clinical Pharmacology. 2000; 50:45563.
11. Roughead EE, Kalisch LM, Barratt JD et al. Prevalence of potentially
hazardous drug interactions amongst Australian veterans. British
Journal of Clinical Pharmacology. 2010; 70:2527.
12. Cowie R, Woolcock K. Contraception essential CPE. Canberra:
Pharmaceutical Society of Australia, 2010.

133

Medicines in older people

Principles of drug therapy

There is no widely accepted definition of an older


person. The terminology used to describe older people
is also variablee.g. aged, elderly, frail elderly, geriatric,
and so on. Although chronological age on its own
might not offer a suitable way of categorising people,
in general those people who are aged over 65 years
(or over 50 years for Aboriginal and Torres Strait Islander
peoples) are described as aged, older or elderly.
People aged over 65 years account for about 13% of the
Australian population but use a disproportionate number
of prescription and other medicines when compared with
younger Australians.1 Older people are more likely to
have multiple medical problems and be taking multiple
medications. As a result of this and age-related changes
in physiology, older people experience higher rates of
medication-related problems, including adverse events.2,3
Pharmacists can play a central role in improving the safety
and efficacy of drug therapy and promoting quality use of
medicines by older people.

Pharmacokinetic effects
A number of physiological changes that occur with
ageing can modify the absorption, distribution, hepatic
metabolism and renal excretion of medicines, leading
to changes in serum drug concentrations and clinical
response.38 Older people often need smaller drug doses
than younger people, but dosage regimens must be
individualised and re-assessed over time, according to
the clinical response: increasing physiological variability
between individuals occurs with age.4,6

Absorption
Age-related atrophic gastritis and an associated
decrease in the secretion of pepsin and hydrochloric acid
(hypochlorhydria) can reduce the extent of absorption
and the efficacy of some medications (e.g. ketoconazole).
These changes can also contribute to malabsorption
of some dietary nutrients that rely on gastric acid for
absorption, among them vitamin B12, iron and calcium.
Chronic acid-suppressive therapy (e.g. proton pump
inhibitors) can further increase the risk of vitamin B12
deficiency in older people.9
Reduced tissue blood perfusion can diminish the rate
of transdermal drug absorption, as well as absorption
from subcutaneous and muscular tissue in older people,
although the clinical consequences of this are unclear.4

Distribution
Lean body mass progressively declines with age, and there
is a reduction in total body water content and an increase
in total body fat. As a consequence, changes in the volume
of distribution can occur for certain drugs.46 Adecrease
134

in the volume of distribution for hydrophilic drugs (e.g.


gentamicin and digoxin) can produce higher plasma
concentrations for normal adult doses in older people.
The use of diuretics can lead to a further reduction in
extracellular space and an increased risk of drug toxicity. A
higher proportion of body fat associated with ageing causes
an increase in the volume of distribution for some lipophilic
drugs (e.g. diazepam). This can increase the plasma half-life
of some drugs and therefore the time required to reach
steady-state concentrations during multiple dosing. In frail
older people, however, the proportion of fat and muscle
mass decreases, causing a reduction in body weight and an
increased risk of overmedication (particularly for lipophilic
drugs), with an unpredictable effect on the efficacy and
safety of medicines.3,4,7

Metabolism
The age-related effect on hepatic drug biotransformation
and metabolism is probably the result of a decline in
liver mass and liver blood flow.3,8 First-pass metabolism
and hepatic clearance can decrease with age. The
bioavailability of drugs that undergo extensive first-pass
metabolism (e.g. metoprolol) can be greatly increased,
while the livers bioactivation of some pro-drugs
(e.g. perindopril) can be slowed or reduced in some older
patients. Although the metabolic clearance of some
drugs is significantly reduced, this is thought to be more
dependent on inter-individual variation in metabolic
drug clearance by CYP enzymes than the result of a
decline in activity of CYP microsomal enzymes associated
with ageing.3,8

Renal excretion
Age-related decline in kidney functiona result of
reductions in both renal blood flow and glomerular
filtration ratehas a fundamental impact on drug
elimination. The glomerular filtration rate and renal
clearance of drugs decline by up to 50% between the
ages of 25 and 85 years.10 Some medical conditions that
are common in older peoplesuch as hypertension and
diabetescan also adversely affect renal function. In the
case of drugs that are predominantly eliminated by the
kidneys (e.g. digoxin and lithium) or have renally cleared
active metabolites (e.g. allopurinol and morphine), reduced
clearance by the kidneys can lead to increased drug serum
concentrations and adverse effects, particularly in the case
of drugs with a narrow therapeutic index.6

Pharmacodynamic effects
Data on the influence of age on pharmacodynamics are
limited, but it is known that age-related changes can
amplify or reduce the sensitivity and clinical response
to some medicines.4 Increased sensitivity can result
from an altered therapeutic response to a particular

Section B | Medicines in older people

serum concentration or impairment of homeostatic


mechanisms, producing an increased susceptibility to
adverse reactions.3,7,8

Receptor properties

Orthostatic hypotension
Older people are more susceptible to the orthostatic
hypotension that occurs in response to drugs that lower
arterial blood pressure, increasing the risk of syncope and
falls.3,4,8 The baroreceptor reflex that normally maintains
blood pressure control is impaired, and the reflex
tachycardia that normally occurs on standing in response
to vasodilatation is diminished in older people.10
Among the medicines that have a greater propensity to
cause hypotension in older people are antihypertensives
and drugs that cause the blockade of alpha-adrenergic
receptors (e.g. prazosin, tricyclic antidepressants and
phenothiazines). Co-existing illness (e.g. Parkinsons disease,
diabetes mellitus or aortic stenosis) can also contribute to
age-related impairment of the homeostatic mechanism that
protects against orthostatic hypotension.8,11
Orthostatic hypotension can affect a persons confidence
in their mobility and is associated with considerable
morbidity and mortality in older people, there being an
increased risk of falls and fractures and a reduction in
quality of life.8

Hyponatraemia
Changes associated with the normal ageing process can
compromise the homeostatic systems involved in the
regulation of fluid and electrolyte balanceincluding
thirst perception, renal function, and regulation of
antidiuretic hormone, atrial natriuretic hormone and the
renin-angiotensin-aldosterone system.12
Disturbances of water and electrolyte balance
(particularly hyponatraemia) are common in older
people. The most common cause of hyponatraemia in
older people is an increase in extracellular water relative
to sodium (i.e. dilutional hyponatraemia), most often as
a result of the syndrome of inappropriate antidiuretic
hormone secretion (SIADH). Sodium depletion can

Medical conditions (e.g. chronic heart failure and


vomiting) and medicines can precipitate hyponatraemia
in older people. Among the medicines associated with
hyponatraemia are diuretics (particularly frequent use of
thiazide diuretics) and medicines associated with SIADH (e.g.
selective serotonin re-uptake inhibitors and carbamazepine).
Among the symptoms of diureticinduced hyponatraemia are
nausea and vomiting, confusion and seizures. The condition
is particularly common in older women.13
Hyponatraemia can present insidiously and, if undetected,
can lead to serious morbiditye.g. lethargy, apathy,
confusion, agitation, disorientation, muscle twitching and
cramps, irritability, convulsions and comaand death.13
The signs are not generally seen until the serum sodium
concentration falls below 125 mmol/L (see Sodium in
Section C Normal physiological values).

Central nervous system effects


Older people are more sensitive to the pharmacological
effects of CNS-active drugs such as sedatives
and hypnotics, analgesics, antidepressants and
antipsychotics.10 This increased sensitivity is a result
of structural and neurochemical changes in the CNS,
including neuronal loss in several regions of the brain,
increased permeability of the bloodbrain barrier, and a
depletion of central neurotransmitters such as dopamine,
acetylcholine and serotonin, causing an increase in target
tissue responsiveness. Age-related neuronal loss resulting
from reduced CNS blood flow caused by atherosclerotic
vessel narrowing can also contribute to changes at
the target site.10 For example, there is an increased
frequency and severity of extrapyramidal symptoms and
a higher incidence of tardive dyskinesia with long-term
antipsychotic therapy in older people.4

Principles of drug therapy

Altered sensitivity to medicines in older people can


be caused by a change in receptor properties and the
response and size of the effect of a drug at its target
site. This can be associated with a change in the
number of receptors and receptor responsiveness, as
well as cells response to receptor activation and the
levels of circulating neurotransmitters. An example of
this age-related change in response is the decreased
sensitivity and response to beta-adrenergic agonists in
older people. This is thought to result from a reduction
in beta-adrenoreceptor density and down-regulation
of beta-adrenoreceptors in old age from increased
serum noradrenaline levelspossibly from diminished
presynaptic alpha2-adrenoreceptor activity and increased
noradrenaline release.4,5

also result from increased loss of sodium from the


gastrointestinal tract, increased urinary loss and sweat.

People taking dopamine agonists (e.g. pergolide or


ropinirole) can experience episodes of uncontrollable
somnolence. Medicines with CNS-depressant effects (e.g.
hypnotics and anxiolytics) can cause confusion, incontinence
and unsteady gait, contributing to falls and fractures.14
Older people are also more susceptible to the central
anticholinergic effects of medicines because of the decline
in cholinergic transmission with ageing. Such effects
include drowsiness, memory impairment, restlessness,
confusion, and delirium. Medicines with anticholinergic
activity can also exacerbate cognitive impairment in
people with dementia.8,10

Anticholinergic effects
Medicines with anticholinergic activity can cause a number
of adverse effects in older people.15 As well as the central
nervous system effects just mentioned, there are a number
of peripheral adverse effectse.g.constipation, dry
mouth, dry eyes, blurred vision, and urinary hesitancy and
retention. These can, however, be mistaken for the effects
of aging or age-related diseases.
135

Section B | Medicines in older people

Principles of drug therapy

In addition to medicines with known anticholinergic


effects (e.g. oxybutynin and tricyclic antidepressants),
there are many medicines with low but detectable
anticholinergic activity (e.g. paroxetine and ranitidine)16,
and when several of these drugs are co-administered the
cumulative anticholinergic activity can become significant.

anti-inflammatory drugs (NSAIDs), including selective


COX-2 inhibitors, with a higher incidence of intestinal
bleeding in older patients. Older people treated
with NSAIDs can also experience CNS effects such
as dizziness, confusion and psychosis. These agents
should be used with great care in older patients.

The overall anticholinergic activity of a patients


medication regimen is described as the anticholinergic
load, or anticholinergic burden.15,17 Although the
anticholinergic activity of some drugs might not be
readily apparent, the addition of a medicine with even
low anticholinergic activity (such as paroxetine) can raise
the total anticholinergic load to a level where symptoms
become evident. A higher anticholinergic load has been
associated with an increased risk of adverse effects,
including disturbance of gait and a greater risk of falls.

Age-dependent impairment of glucose


counterregulation means that advanced age is a risk
factor for hypoglycaemia caused by sulfonylureas.

A number of medicines, including certain


antidepressants and neuroleptics, have been
associated with adverse cardiac effects, causing
prolongation of the QT interval and possible lifethreatening ventricular tachyarrhythmias. Advancing
age, as well as bradycardia, heart failure, and
multiple drug use are risk factors for these effects.4

The following medicines pose a high risk of anticholinergic


effects:

Adverse drug reactions and precautions associated with


the use of some medicines in older people are detailed in
Section D, Clinical monographs.

amitriptyline
atropine
benztropine
chlorpheniramine
chlorpromazine
clomipramine
cyproheptadine
diphenhydramine
doxepin
hyoscyamine
imipramine
nortriptyline
oxybutynin
promethazine
trifluoperazine
trimipramine.16,1820

Despite the problems associated with using drugs with


anticholinergic properties in elderly patients, such drugs
are not always contraindicated. Urinary retention is of
special concern in older males who might have prostate
problems, and the symptom of urinary frequency or
urgency can be relieved by using oxybutynin, a drug with
an anticholinergic effect. Tricyclic antidepressants can also
be valuable adjuncts in the management of neuropathic
pain. When a medicine with anticholinergic properties is
indicated, there should be careful monitoring for adverse
effects and regular review of the efficacy of the medicine.

Multiple diseases and multiple


medicines
Many older people have several chronic diseases, and
this has a number of potential consequences:

The increased number of chronic conditions


necessitates the use of multiple medicines, with an
exponential rise in adverse effects and the potential
for drug interactions.

The diseases themselves can further modify the


pharmacokinetic and pharmacodynamic changes
that occur with ageing.

More than one medicine might be needed to


manage each condition, and as more medicines are
added to the medication regimen the increased pill
burden increases the risk of poor adherence.

Taking multiple medicines that have anticholinergic


properties increases the risk of adverse
anticholinergic effects.17

It might not always be appropriate to treat


a condition associated with normal ageing
(e.g. inability to sleep through the night) or an
adverse effect of a medicine already being taken by
the patient (e.g. mental confusion or incontinence).
The potential for using more medicines than are
clinically indicated (called polypharmacy) needs to
be considered.21,22

Ceasing medicines needs to be done cautiously, with


gradual dose reductions and careful monitoring.23

Other effects
A number of other pharmacodynamic effects can occur3,8:

136

Medicines causing the blockade of alpha-adrenergic


receptors (e.g. prazosin) might affect bladder control
(especially in older women) and lead to urinary
incontinence.

Advanced age is an independent risk factor for


myopathy and rhabdomyolysis in patients taking
HMG-CoA reductase inhibitors.

Under-use of medicines

There is a substantial increase in the frequency of


adverse gastrointestinal, renal and cardiovascular
effects associated with the use of non-steroidal

Increasingly, it is recognised that under-treatment


failure to prescribe an indicated drug without good
reasonposes at least as much risk for older patients

Use of medicines

Section B | Medicines in older people

as the use of multiple medicines.21,24 Many instances


of under-use of appropriate drug therapies have been
documentedparticularly in the treatment of chronic
atrial fibrillation, hypertension, hyperlipidaemia, chronic
heart failure, asthma, depression, pain and osteoporosis.
Among the possible factors contributing to undertreatment are insufficient evidence of clinical benefit as a
result of under-representation of older patients in clinical
trials, doctors concerns about polypharmacy (in terms of
treatment burden, cost and compliance), and a lack of
effective coordination between hospitals and aged care
facilities when patients move from one to the other.
Under-prescribing on the basis of age alone can result in
sub-optimal patient care. Analysis of the net benefit versus
the risk of a drug for a particular patient is important so
that a persons drug regimen is rationalised and a decision
can be made about whether treatment is warranted.

As the number of prescribed medicines increases, the


rate of adherence decreases. Not taking medicines as
directed can result in sub-optimal clinical outcomes or an
increased risk of adverse drug reactions, or both.
Many factors compromise older peoples ability to use
their medicines as intended:

Impaired physical dexterity associated with muscle


weakness, joint deformity or poor coordination and
impaired hearing and sight can lead to difficulties
reading labels, opening jars, operating certain
devices (e.g. metered-dose aerosols), halving tablets
and swallowing.21,25

Cognitive impairment, memory loss or confusion


can affect an older persons ability to understand
the advice of health care providers and written
instructions on labels, causing misunderstanding
about medication regimens.21,25

People can unintentionally use different brands


of the same medicine at the same time by not
recognising proprietary as opposed to generic drug
names. Medication duplication is a particular risk
when patients return to their community health care
providers after a stay in hospital or a residential aged
care facility or are given multiple generic brands. The
pharmacist has a fundamental role in ensuring that
patients, carers and nursing staff are well informed
about the different brands of medicines.

Older people can also choose not to adhere to


their medication regimen because of distrust of
the prescriber, concern about the number and
effectiveness of their medicines, or the cost.

See Medicines review in Section C for information


about quality use of medicines and assessing
medication regimens.

Further information
Hughes J, Tenni P, Peterson G. The Australian pharmacist aged care
primer. Canberra: Pharmaceutical Society of Australia, 2007.
Beers MH, ed. Merck manual of geriatrics. 3rd edn.
At: www.merck.com/mkgr/mmg/home.jsp.

References
1. Australian Institute of Health and Welfare. Australias health 2010.
Canberra: AIHW, 2010. At: www.aihw.gov.au/publications/aus/ah10/
ah10.pdf.
2. Easton K, Morgan T, Williamson M. Medication safety in the
community: a review of the literature. Sydney: National Prescribing
Service, 2009.
3. McLean AJ, Le Couteur DG. Aging biology and geriatric clinical
pharmacology. Pharmacological Reviews. 2004; 56(2):16384.
4. Turnheim K. When drug therapy gets old: pharmacokinetics and
pharmacodynamics in the elderly. Experimental Gerontology. 2003;
(38)9:84353.
5. Walker R, Edwards C. Clinical pharmacy and therapeutics. 4th edn.
Edinburgh: Churchill Livingstone, 2008.
6. Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics
and pharmacodynamics: basic principles and practical applications.
British Journal of Clinical Pharmacology. 2004; 57(1):614.
7. McLachlan AJ, Hilmer SN, Le Couteur DG. Variability in response to
medicines in older people: phenotypic and genotypic factors. Clinical
Pharmacology and Therapeutics. 2009; 85(4):4313.
8. Hilmer SN, McLachlan AJ, Le Couteur DG. Clinical pharmacology in
the geriatric patient. Fundamental and Clinical Pharmacology. 2007;
21(3):21730.
9. Kapadia A, Wynn D, Salzman B. Potential adverse effects of proton
pump inhibitors in the elderly. Clinical Geriatrics. 2010; 18(7):2431.
10. Hughes J, Donnelly R, James-Chatgilaou G eds. Clinical pharmacy:
a practical approach. 2nd edn. Melbourne: The Society of Hospital
Pharmacists of Australia, 2001.
11. Tinetti ME, Kumar C. The patient who falls: Its always a trade-off.
Journal of the American Medical Association. 2010; 303(3):25866.
12. Miller M. Hyponatraemia in the elderly: risk factors, clinical
consequences, and management. Clinical Geriatrics. 2009; 17(9):349.
13. Haskal R. Current issues for nurse practitioners: hyponatremia. Journal
of the American Academy of Nurse Practitioners. 2007; 19(11):56379.
14. Woolcott JC, Richardson KJ, Wiens MO et al. Meta-analysis of the
impact of 9 medication classes on falls in elderly persons. Archives of
Internal Medicine 2009; 169(21):195260.
15. Hilmer SN, Mager DE, Simonsick EM et al. A drug burden index to
define the functional burden of medications in older people. Archives
of Internal Medicine. 2007; 167(8):7817.
16. Rudolph JL, Salow MJ, Angelini MC et al. The anticholinergic risk scale
and anticholinergic adverse effects in older persons. Archives of Internal
Medicine. 2008; 168(5):50813.
17. Elliott R, Lee CY. Anticholinergic load and adverse outcomes in older
people. Australian Pharmacist. 2009; 28(11):9705.
18. Nishtala PS, Fois RA, McLachlan AJ et al. Anticholinergic activity of
commonly prescribed medications and neuropsychiatric adverse events in
older people. Journal of Clinical Pharmacology. 2009; 49(10):117684.
19. Carnahan RM, Lund BC, Perry PJ et al. The anticholinergic drug scale
as a measure of drug-related anticholinergic burden: associations with
serum anticholinergic activity. Journal of Clinical Pharmacology. 2006;
46(12):14816.
20. Baxter K ed. Stockleys drug interactions. London: Pharmaceutical Press,
2011. At: www.medicinescomplete.com.
21. Holbeach E, Yates P. Prescribing in the elderly. Australian Family
Physician. 2010; 39(10):72833
22. Hilmer SN, Gnjidic D. The effects of polypharmacy in older adults.
Clinical Pharmacology and Therapeutics. 2009; 85(1):868.
23. Iyer S, Naganathan V, McLachlan AJ et al. Medication withdrawal trials
in people aged 65 years and older: a systematic review. Drugs Aging.
2008; 25(12):102131.
24. Peterson GM. Continuing evidence of inappropriate medication usage
in the elderly. Australian Pharmacist. 2004; 23(7):5336.
25. Olsen C, Tindall W, Casen M eds. Geriatric pharmacotherapy: a guide
for the helping professional. Washington: American Pharmacists
Association, 2007.

Principles of drug therapy

Medication adherence

Bochner F, Buckley N, Curtis J et al. eds. Australian medicines


handbook drug choice companion: aged care. 3rd edn. Adelaide:
Australian Medicines Handbook Pty Ltd, 2010.
RACGP. The medical care of older persons in residential aged care
facilities. (The silver book.) 4th edn. Melbourne: Royal Australian
College of General Practitioners, 2006. At: www.racgp.org.au/
guidelines/silverbook.
Australian Government Department of Health and Ageing. Medication
management reviews. Canberra: DoHA. At: www.health.gov.au/
internet/main/publishing.nsf/Content/medication_management_
reviews.htm.
Many of the Pharmaceutical Society of Australias Self Care Fact Cards
might also be of particular relevance to older peoplee.g. Dry mouth
and Preventing Falls.

137

Dose calculations for children


Childrenparticularly neonatesdiffer from adults
in their responses to medicines. They do not always
represent small adults, so a scaling-down of doses is
not always appropriate. Their physiological systems are
not fully developed, and there can be differences in
metabolism and excretion capabilities as children progress
from birth to adulthood. Childrens doses of medicines
can be calculated using the childs age, body weight, body
surface area or any combination of these parameters.16

Principles of drug therapy

Considerations when
calculating doses
Terminology
The age of an infant or child greatly affects their
bodys ability to efficiently process medicines. Several
accepted terms are used to describe ages and stages in
child development:

preterm newborn infantborn before


37 weeks gestation or weighing less than about
10001500 grams

term newborn infant neonatethe period from birth


(0 days) to 28 days

infant28 days to 1 year

young child

TableB.7 shows some of the physiological changes in


children that can affect the pharmacokinetic properties
of particular medicines.

Reference sources for doses


in children
Dose calculation and confirmation in children can
be difficult and can necessitate an extensive search
for information.14 The following sources might be
useful if pharmacists need detailed information about
paediatric dosing:

a drug information service

the Paediatric Pharmacopoeia (Pharmacy Department,


The Royal Childrens Hospital, Melbourne)

Drug Doses for Children (The Childrens Hospital


at Westmead)

British National Formulary for Children

therapeutic guidelines.

When consulting reference sources dealing with the


use of medicines in children, it is important to note
the following:

Failure to observe a listed contraindication for use


in children might have very serious implications.

Some medicines administered to children are used


off label i.e. the indication, formulation, age
range or route differs from that in the approved
product information. Off-label use of registered
medicines may be necessary when there is a lack of
research evidence to support licensing applications
for paediatric use of a product. Off-label use is
not necessarily illegal and in some cases may
be clinically appropriate if there is high-quality
evidence supporting its use in children (which may
have become available post-marketing, or where
there are exceptional individual circumstances and
informed consent has been obtained).

toddler1 to 3 years
pre-schoolers3 to 5 years

older child5 to 12 years

adultover 12 years or weighing 4050 kg is


generally considered an adult for the purposes of
dose calculations.1,2,7

Age-related pharmacokinetic and


pharmacodynamic differences

Note that off-label use refers to the prescribing


of registered medicines for a use not included in
the product information. The use of unlicensed
or unregistered medicines might occur where
there are technical difficulties in the marketing or
registration of a paediatric dose form in Australia.

As children mature physically their physiological systems


develop at varying rates. These deviations from adult
metabolism and excretion capabilities have clinically
relevant implications for the pharmacokinetic and
pharmacodynamic characteristics of medicines. It is
important that pharmacists consider these factors because
they can influence the dosing of medicines in children.
In general, absorption, plasma protein binding,
metabolism and excretion in children are reduced and
the volume of distribution is increased. The effect is,
however, highly variable and depends on both age
and drug characteristics. Further, it cannot be assumed
that the same plasma concentration of a drug or its
metabolites will have the same pharmacological effect in
adults and paediatric patients.
138

As with all therapy, patients prescribed off label


medicines should receive a consumer medicines
information leaflet and relevant counselling,
including a discussion of off label use.

General principles
There are a number of general principles for calculating
doses in children:

Neonatal doses should be carefully calculated


if specific doses are not available because the

Section B | Dose calculations for children

Table B.7 Physiological differences in children that influence the pharmacokinetic characteristics
of medicines: some examples2,411
Pharmacokinetic
parameter

Physiological differences in children

Approximate age at which


adult levels are reached

Absorption

Reduced acid production and increased gastric pH, with increased absorption of
acid-labile drugs and reduced absorption of weak acids

2 years

Delayed gastric emptying as a result of immature intestinal mucosa and reduced


gastric motility, although effect on absorption varies according to age

68 months

Immature pancreatic fluid and bile salt production and activity, with reduced
absorption of some fat-soluble drugs

9 months

Thinner stratum corneum; larger % body surface area and hydration with increased
topical absorption

812 months

Variations in intestinal microbial colonisation possibly causing decreased


bioavailability of some drugs

6 months to adolescence

Increased body water %, with larger volume of distribution for water-soluble medicines

Adolescence

Lower albumin concentration with reduced plasma protein binding and increases in
unbound fraction of drug

1012 months

Distribution

Metabolism

Immature liver function, with reduced blood flow and lower levels of
drugmetabolising enzymes. First pass effect altered but highly variable between
neonate, infant and child. Clearance and half-life affected differently in each age
group
Not all CYP450 iso-enzymes present at birth

Elimination

Immature renal function with reduced renal blood flow and glomerular filtration rate
producing variable and complex effects on drug elimination depending on both the
drug and age
Creatinine clearance increasing rapidly with agefrom about 510 mL/min/m
preterm to adult range by age 6 months.

pharmacokinetics of medicines can vary markedly


between this group and older children and adults.

The childs weight or body surface area (BSA)


should generally be noted on the prescription to
enable pharmacists to recheck the calculated dose.
Read all childrens doses carefully. They can
be expressed in different reference sources
in various ways, among them units/kg/dose,
units/kg/day, units/dose (not per kg) and units/m2/day
(bodysurfacearea). Infusions can be expressed as
units/kg/hour or units/kg/min. It is important to seek
further advice if there is any uncertainty.

In general, the maximum dose for a child should


not exceed the usual adult dose. The adult dose
can be used once a child reaches 12 years of age
and weighs over 40 kg.

Calculated doses of liquid medicines should be


rounded down to the nearest whole number,
where appropriate, for ease of measuring.

Recommended doses for children, whether


calculated on a weight or a BSA basis, are averages
that provide guidance for starting treatment. The
clinical response, therapeutic drug monitoring,
the severity of the medical condition and other
comorbidities will all influence determination of
the final dose.13,12

12 months to 12 years
Individual CYP iso-enzymes reach
adult levels at various times
e.g.CYP3A4 at 2 years; CYP2D6
adolescence
Glomerular filtration: 36 months
Tubular secretion: 812 months
Renal tubular re-absorption: 3 years

Principles of drug therapy

Immature bloodbrain barrier and resultant increased membrane permeability and


increased levels passing through the bloodbrain barrier

Methods of calculation
Weight-based dosing
Weight-based dose calculations are most commonly used
for calculating an accurate dose for a child.

It is recommended that dose calculations be made


from an accurate measurement of the childs weight
whenever possibleparticularly in infants under
12 months of age.

If the childs weight cannot be accurately measured,


an approximation can be gained by using the data
shown in Table B.8. The age and gender of a child
are used as a reference for the average weight, the
average height and an approximation of average
BSA in the table.

In oedematous or obese children, the ideal body


weight (IBW) can be used to calculate doses of some
medicines (e.g. paracetamol). IBW takes into account
changes in body composition in obese patients
which can alter drug distribution. Note however,
that not all doses are adjusted for obesity (e.g. most
anaesthetic doses are titrated according to clinical
response). In general, lipophilicity determines the
extent to which obesity influences the volume of
distribution and whether dosing should be based on
actual or adjusted body weight.
139

Section B | Dose calculations for children

Table B.8 Average weights, heights and body surface areas for children from birth to 14 years1516

Principles of drug therapy

Boys

Girls

Age last
birthday

Average body
weight (kg)

Average height
(cm)

Average surface
area (m2)

Average body
weight (kg)

Average height
(cm)

Average surface
area (m2)

Term

3.3

50

0.22

3.2

49

0.21

2 months

5.6

58

0.30

5.1

57

0.29

4 months

64

0.35

6.4

62

0.33

6 months

7.9

68

0.39

7.3

66

0.37

9.6

76

0.45

8.9

74

0.43

12.2

88

0.54

11.5

86

0.52

14.4

95

0.62

13.9

94

0.60

16.3

103

0.68

15.9

101

0.67

18.5

109

0.75

18

108

0.74

20.8

116

0.82

20.3

115

0.81

23.2

122

0.89

22.9

122

0.88

25.8

128

0.96

25.8

128

0.96

28.7

134

1.03

29.1

133

1.04

10

32.1

139

1.11

33.1

138

1.13

11

36.1

144

1.20

37.4

144

1.22

12

40.7

149

1.30

41.8

151

1.33

13

45.8

156

1.41

46

157

1.42

14

51.2

164

1.53

49.5

160

1.49

Children are classified as being obese when their


BMI is at or above the 95th percentile on a BMI-forage reference chart (i.e. their BMI is the same or
more than 95% of the reference population for the
same age).
Note that Body Mass Index (BMI) =

weight (kg)
height (m) 2

The IBW, based on the childs height, can be


calculated using the following formula:13
6height (cm)@2 # 1.65
Ideal body weight (kg) =
1000

This formula is suitable for use with children aged


1 to 18 years.

Body surface areabased dosing


Body surface area (BSA) dose calculations are
generally considered more accurate than body
weight for calculating doses in children since many
of the physiological changes that occur in childhood
(e.g. changes in cardiac output, fluid requirements
and renal function) correlate more closely with BSA.
In practice, however, BSA-based dosing is limited in
use because it is relatively difficult to calculate BSA
accurately and the BSA can increase by 12% a day in a
young child.13,7
BSA can be estimated by using a body surface
nomogram or by using Mostellers equation, as follows14:
Body surface area (m 2) =

140

height (cm) # weight (kg)


3600

The approximate BSAs for each age and gender in


TableB.8 have been calculated using Mostellers formula
and the specified average weight and height for that age
andgender.

Further information

BMI-for-age reference charts available at:


www.rch.org.au/emplibrary/genmed/cdc_bmigirls.pdf.
www.rch.org.au/emplibrary/genmed/cdc_bmiboys.pdf.

An online body surface nomogram is available at:


www.pediatriccareonline.org/pco/ub/view/Pediatric-DrugLookup/153885/0/body_surface_area_of_children_and_adults.

The Royal Childrens Hospital, Melbourne, publishes clinical practice


guidelines: www.rch.org.au/clinicalguide/index.cfm.

An online BSA calculator that shows comparative calculated BSA


values using different equations is available at: www.globalrph.
com/bsa2.cgi.

The WHO growth standards charts and tablesheight-for-age,


weight-for-agesuitable for use with children from birth to 5 years
are available at: www.cdc.gov/growthcharts/who_charts.htm.

An online paediatric drug dose calculator is available at:


www.ugapharmd.com/calculators/peds.htm.

References
1. Kemp CA, McDowell JM ed. Paediatric pharmacopoeia. 13th edn.
Melbourne: Royal Childrens Hospital, 2002.
2. Rossi S ed. Australian medicines handbook. Adelaide: Australian
Medicines Handbook Pty Ltd, 2011.
3. Paediatric Formulary Committee. BNF for children. London: RPS
Publishing, 2008.
4. Azzopardi LM. Lecture notes in pharmacy practice. London:
Pharmaceutical Press, 2010.
5. McKenna L, Mirkov S. Australia New Zealand nursing and
midwifery drug handbook. 5th edn. Sydney: Lippincott, Williams
and Wilkins, 2010.
6. Kirkpatrick C, Gardiner S, McCrae E ed. The dispensing guide.
Wellington: Pharmaceutical Society of New Zealand, 2001.

Section B | Dose calculations for children

Principles of drug therapy

7. Marriott JF, Wilson KA, Langley CA et al. Pharmaceutical


compounding and dispensing. London: Pharmaceutical Press, 2006.
8. Bartelink IH, Rademaker CMA, Schobben A et al. Guidelines on
paediatric dosing on the basis of developmental physiology and
pharmacokinetic considerations. Clinical Pharmacokinetics. 2006;
45(11):107797.
9. Long SS, Pickering LK, Prober CG. Principles and practice of
paediatric infectious disease. Rev. reprint, 3rd edn. Philadelphia:
Churchill Livingstone, 2009.
10. Berkow R ed. The Merck manual of diagnosis and therapy. 18th
edn. New Jersey: Merck & Co. 2006.
11. Blackburn ST. Maternal and neonatal physiology: a clinical
perspective. Missouri: Saunders Elsevier, 2007.
12. Kilham H, Alexander S, Wood N, et al. Paediatrics manual: The
Childrens Hospital at Westmead handbook. 2nd edn. Sydney:
McGraw-Hill, 2009.
13. Traub SL, Johnson CE. Comparison of methods of estimating
creatinine clearance in children. American Journal of Hospital
Pharmacy. 1980; 37(2):195201.
14. Mosteller RD. Simplified calculation of body surface area. New
England Journal of Medicine. 1987; 317(17):1098.
15. WHO Multicentre Growth Reference Study Group: WHO
growth standards: height-for-age, weight-for-age: methods of
development. Geneva: World Health Organisation, 2006.
At: www.cdc.gov/growthcharts/who_charts.htm.
16. Centres for Disease Control and Prevention. CDC Clinical growth
charts: set 1: Children 2 to 20 years (5th95th percentile): staturefor-age, weight-for-age. Atlanta: CDC & National Centre for Health
Statistics, 2000. At: www.cdc.gov/growthcharts/clinical_charts.
htm#Summary.

141

Dosing in renal impairment

Principles of drug therapy

Renal excretion is the main route of elimination for


many medicines and their metabolites, via filtration at
the glomerulus or secretion and re-absorption in renal
tubules. This clearance is influenced by the extent of
protein binding, renal blood flow, and genetic variation
in the expression of drug transporters. Renal function
reduces with certain disease states and with increasing
age. A reduction in drug and metabolite elimination
can increase the pharmacological effect of medicines,
and severe impairment of renal function will affect the
absorption, distribution and metabolism of some drugs.
Dose adjustment might therefore be necessary for
patients with renal impairment, in keeping with degree of
remaining kidney function and the pharmacodynamic and
pharmacokinetic characteristics of the particular medicine.

Estimation of renal function


Despite its wide use by many clinicians, serum creatinine
concentration on its own is a poor measure of renal
function and can lead to significant underestimation of
an individuals actual renal function. For a description
of the role of creatinine as a biochemical marker and
further information about the measurement of serum
creatinine, see Renal function in Normal physiological
values, in Section C.
A range of formulae have been used to calculate an
estimate of residual kidney function, the two most
commonly used for adults being the CockcroftGault1 and
the Modification of Diet in Renal Disease2,3 equations.

The CockcroftGault equation


The CockcroftGault equation is used to calculate
an individuals creatinine clearance (CrCl), which is
considered to approximate the glomerular filtration
rate (GFR) in people with stable renal dysfunction.4,5
The equation assumes that the renal clearance of a
drug is directly proportional to this measure of kidney
function. It continues to be the accepted method for
assessing renal function for the purpose of drug dosage
adjustment and is particularly suitable when drugs that
are predominantly renally excreted are involved.
Creatinine clearance in mL/min =

^140 age ^years hh # ideal body weight ^kg h


0.815 # serum creatinine concentration ^micromol/Lh

For females, multiply by 0.85 to account for the reduced


muscle to ideal body weight ratio in comparison
with males.
Ideal body weight for males =
50 kg + 0.9 kg/for each cm above 152 cm
Ideal body weight for females =
45.5 kg + 0.9 kg/for each cm above 152 cm

142

If the patients actual weight is less than ideal body


weight, the actual weight should be used.

When measured creatinine serum concentration


is <60 micromol/L. If the measured creatinine
concentration is less than the minimum value
reported by the laboratory reference range
(<60 micromol/L), this could be a reflection of
decreased production as opposed to enhanced
clearance of creatinine. To prevent overestimation
of the GFR, use the minimum value of the reference
range (60 micromol/L) rather than the actual
creatinine concentration.

In cases of renal replacement therapy.


(e.g.haemodialysis). Do not use this equation if
renal replacement therapy is being used: instead,
assume that the GFR is <10 mL/min.

The Modification of Diet in Renal


Disease equation
The Modification of Diet in Renal Disease (MDRD)
equation offers a method of estimating GFR using serum
creatinine concentration and age and, if applicable,
modified for gender (female). It does not directly assess
weight, lean body mass or ethnicity.
The majority of Australasian laboratories currently report
an estimated glomerular filtration rate (eGFR) based
on the MDRD formula with results of serum creatinine
measurement in people aged 18 or more years.3,6 This
is possible because the equation does not require a
measure of body weight or height. Increasingly, the
measure is being used to detect patients with chronic
kidney disease in the community and guide prescribing
in out-of-hospital settings where an eGFR based on the
MDRD formula is the only readily accessible measure
of renal function. There are, however, conflicting
opinions about the use of eGFR based on the MDRD
formula in people from different ethnic backgrounds
and specific patient groups (e.g. paediatrics, frail older
people and pregnant women) and the value, safety
and costeffectiveness of this method as a screening
test or to help with decision making in relation to
drug dosing.7,8
The revised MDRD formulathe 175 formula
isas follows:

eGFR ^mL/ min /1.73 m 2h =


175 # ^serum creatinine ^micromol/Lh # 0.0113 h1.154
# ^ageh0.203 # ^0.742 6if female@h

The eGFR upper reporting limit is currently


90 mL/min/1.73 m2, values greater than this being reported
as >90 mL/min/1.73 m2, rather than a precise figure.
Readers will note that the MDRD reports the estimated
GFR corrected for a specific body surface area. Use of the

Section B | Dosing in renal impairment

eGFR to calculate or interpret dosing regimens requires


calculation of body surface area and calculation of the
uncorrected eGFR dose.

The CKD Epidemiology


Collaboration formula
The CKD Epidemiology Collaboration (CKD-EPI) formula
was published in 2009. It is claimed that it more
accurately estimates GFR than the MDRD equation,
which might underestimate the true GFR for the
hightonormal range of kidney function and therefore
has the potential for false-positive diagnoses of early
chronic kidney disease.9
eGFR = 141 # min ^SCr/K, 1ha # max ^SCr/K, 1h1.209
# 0.993 Age # 61.018 if female@ # 61.159 if Afro-American@

In the future it is possible that the CKD-EPI


equation, instead of the MDRD formula, will be
used for the automatic reporting of eGFR through
Australian laboratories.

Although the CockcroftGault formula continues


to be the preferred method for determining renal
dosage adjustments, the preferred method for
estimating kidney function in order to detect renal
impairment and diagnose chronic kidney disease is
yet to bedetermined.
Section I, Information from the internet, provides a
listof online clinical calculators.

Dose adjustment
It is important to consider other processes that can
change drug disposition, apart from reductions in
renal clearance. Drug disposition is influenced by a
drugs pharmacodynamics in the presence of renal
dysfunction, as well as altered pharmacokinetic
processes such as drug absorption and bioavailability,
distribution, metabolism or elimination. For drugs
that are extensively metabolised or highly protein

Interpreting laboratory results

bound, a more complex strategy of dosage

Pharmacists should note that the equations rely on


a series of assumptions and have been validated in
differing clinical contexts and with differing patient
characteristics. The CockroftGault equation estimates
a persons creatinine clearance, whereas the MDRD and
CKD-EPI equations estimate glomerular filtration rate.

drug monitoring, for example, is used to guide

It is of note that the three measures of renal function are


not interchangeable, that all three equations provide an
estimate rather than a direct measure of renal function,
and that underestimation or overestimation is possible.
Among the clinical situations in which estimated
renal function can be unreliable or misleading are
the following:

adjustment might be necessary. Therapeutic


dosage adjustment for drugs whose plasma drug
concentrations correlate with toxicity or efficacy.10
Inappropriate dosing can cause toxicity or result in
ineffective therapy. For this reason it is important
to consider patient outcomes by asking several
basic questions:

Is the drug having the desired effect?

Are side effects evident?

Is the outcome optimal?

Clearance of some medicines and metabolites is

acute changes in kidney functione.g. acute


kidney failure

strongly influenced by a reduction in renal function.

dialysis-dependent patients

adjusting the usual dosage regimen by reducing the

exceptional dietary intakee.g. vegetarian diet,


high-protein diet, recent consumption of cooked
meat, and creatine supplementation

maintenance dose or prolonging the dosing interval,

extremes of body size

diseases of skeletal muscle, paraplegia or


amputees (can underestimate) or high muscle mass
(can overestimate)

Principles of drug therapy

where SCr is serum creatinine (mg/dL), K is 0.7 for


females and 0.9 for males, a is 0.329 for females and
0.411 for males, min indicates the minimum of SCr/k
or 1, and max indicates the maximum of SCr/k or 1.

Dose adjustments based on these formulas should


always take account of a patients individual treatment
requirements, as well as the safety margin and the
potential toxicity of the drug treatment.

In these instances consideration must be given to

or both, particularly when the medicine or any active


metabolites have a narrow therapeutic index.11
Adjustment of the dosing interval is importantfor
drugs whose efficacy is dependent on adequate
peak concentrations (e.g. aminoglycosides and
cephalosporins) or area under the curve, while the
dosage might need to be reduced when a rapid

children under the age of 18 years

severe liver disease

toxicity.5 For most drugs a combined approach is

frail older people.4

recommended.10

increase in plasma concentration correlates with

143

Section B | Dosing in renal impairment

Dose adjustment using creatinine


clearance
The CockroftGault equation is the method generally

Other considerations affecting


dosing in renal impairment

used to estimate renal function for the purpose of drug


dosage adjustment in renal impairment. The extent of
renal impairment based on creatinine clearance is used
to guide the decision about whether dosage adjustment
of renally excreted drugs is necessary, and the degree
of impairment is often categorised to facilitate this
process. The Australian Medicines Handbook defines the
following categories12 of CrCl for dosage adjustments:

mild impairmentCrCl 2550 mL/min

moderate impairmentCrCl 1025 mL/min

severe impairmentCrCl <10 mL/min or dialysis.

Principles of drug therapy

Most medicines in clinical use do not routinely


require dosage adjustment until CrCl falls to below
3060 mL/min. Dosage reduction considerations include
the following:

If more than 2550% of the active component is


excreted unchanged by the kidney, a dose reduction
should be considered.

Renally eliminated drugs with narrow therapeutic


indexes (e.g. aminoglycosides and digoxin)
might warrant dose adjustment at a lesser level
of impairment.

When an active or toxic metabolite is produced the


clearance of the metabolite might also need to be
considered. If metabolites are pharmacologically
active or toxic, further dosage adjustment will be
necessary; e.g. norpethidine is a toxic metabolite

Calculating loading doses


When a loading dose is recommended as part of a
dosage regimen it is usually the same in patients with
renal impairment. This is because the size of the loading
dose is dependent on the desired drug concentration
in the blood and the volume of distribution and is
independent of drug clearance.13 In a few cases it
might be necessary to adjust the loading dose in
renal impairment when there is a smaller volume of
distribution because of changes in renal protein excretion
or tissue binding, or both. This can be particularly
important for drugs with a narrow therapeutic index,
such as digoxin.
For further information about effective dose selection
and avoidance of toxicity, see Therapeutic drug
monitoring, page 117.

Changes in plasma protein binding


Renal impairment might necessitate a dose adjustment
of highly protein bound drugs such as phenytoin.
Hypoalbuminaemia can be induced by renal disease and
can increase the unbound (active) fraction of the drug.
In such cases dosing is preferably based on unbound
phenytoin levels, rather than total drug concentration.
If dosing is based on total drug concentration, however,
the therapeutic range should be reduced; e.g. the
therapeutic range in normal renal function is 1020 mg/L
and in renal failure it is 510 mg/L.

of pethidine and will accumulate in patients with


impaired renal function.

If a medicine or metabolite is nephrotoxic and the

Drug-induced renal impairment

estimated CrCl is less than 30 mL/min, it is advisable


to use an alternative medicine where possible.13
For further information about renally excreted drugs
and the relative importance of the kidney for a drugs
excretion, see Fraction excreted unchanged (fe) values
in Pharmacokinetics, page 101.

Summary
At present there are no specific guidelines on dosage
adjustment of medicines based on the use of the eGFR
values derived from the MDRD formula, although an
eGFR value can be used to indicate the need for drug
dosage adjustment. Dosage reduction or cessation of
renally excreted drugs is recommended once the eGFR
(MDRD) falls below 60 mL/min/1.73 m2, although
how this adjustment is then calculated has not yet
been determined.4
144

Although many different drugs can potentially cause


kidney damage, pharmacists should be especially aware
of the potential for acute nephrotoxicity with some
commonly used agents. NSAIDs (including selective
COX2 inhibitors), ACE inhibitors and angiotensin II
receptor antagonists can all cause an acute decline
in renal function. Patients with renal hypoperfusion
(in situations of dehydration, cardiac failure, excess
diuretic effect, hypotension, blood loss and infection)
orpreexisting renal impairment are at increased risk.13
Patients undergoing therapy with any of these medicines
should be well hydrated before surgery and be warned
of situations where dehydration may occure.g.when
vomiting or diarrhoea occurs or in hot weather.
When renal impairment is present, ACE inhibitors and
angiotensin II receptor antagonists should generally be
initiated at lower doses and titrated with care.

Section B | Dosing in renal impairment

The potential for nephrotoxicity with an ACE inhibitor


or angiotensin II receptor antagonist is further increased
with co-administration of other hypertensives or diuretics
or NSAIDs. The combined use of ACE inhibitors, NSAIDs
and diureticscalled the triple whammyhas been
implicated in a large number of reports of drug-induced
renal failure.14

Drug therapy in chronic


kidney disease
Maintenance of residual
renal function

Renal replacement therapies


Renal replacement therapies refers to life-supporting
treatments for patients with renal failure; this includes
dialysis (haemodialysis and peritoneal dialysis),
haemofiltration and renal transplantation.
Dialysis-based therapies are premised on passive
diffusion (from a region of high concentration to one
of lower concentration) or convection (movement as
a solute in water being sucked across a membrane) of
waste products across a semi-permeable membrane.
This membrane can be manufactured (as used in
haemodialysis) or it can be the patients own peritoneal
lining (peritoneal dialysis). The waste products contained
in the blood side of the membrane are bathed against a
dialysis fluid on the other side of the membrane.
The ability to dialyse a medicine and its metabolites
can be predicted by molecular size, protein binding and
volume of distribution:

Molecular size. The larger the molecule, the more


slowly it moves and the less likely it is to be removed
by passive diffusion. Many centres now use high-flux
(large membrane pore size) dialysis in conjunction
with high blood flow rates, minimising the impact of
molecular size on clearance.

Protein binding. This essentially makes medicine


molecules too large to be dialysed; only unbound
drug is dialysed.

Volume of distribution. The larger the volume of


distribution of a medicine with respect to plasma,
the less medicine is available to be dialysed at
any time.15

Diuretics are used in the management of patients with


renal impairment and transplantation, cardiac failure and
other conditions associated with fluid overload.13
The pharmacokinetic and pharmacodynamic properties
of diuretics can change in patients with renal
impairment. For diuretics to be clinically effective they
must be able to achieve adequate concentrations at their
site of action (the renal tubule). In renal impairment,
loop diuretics are the preferred diuretic agents, but they
often require an increased dose to achieve an adequate
concentration at the site of action.13

Further information
For further information about methods of calculating glomerular
filtration rate for diagnostic purposes and screening of chronic kidney
disease, see Renal function, in Normal Physiological values in
SectionC, or Kidney Health Australia, www.kidney.org.au.

References
1. Cockcroft DW, Gault MH. Prediction of creatinine clearance from
serum creatinine. Nephron. 1976; 16:3141.
2. Levey AS, Greene T, Kusek JW et al. A simplified equation to
predict glomerular filtration rate from serum creatinine. Abstract.
Journal of the American Society of Nephrology. 2000; 11:155A.
3. Levey AS, Bosch JP, Breyer Lewis J et al. A more accurate method
to estimate glomerular filtration rate from serum creatinine:
anew prediction equation. Annals of Internal Medicine. 1999;
130(6):46170.

Principles of drug therapy

In patients with declining renal function, preservation of


the remaining renal function is paramount. This is the
case even when renal replacement therapy (e.g. dialysis)
has been initiated. It is important to avoid nephrotoxic
agents, and maintain optimal blood pressure, cholesterol
concentrations, fluid balance and blood glucose
concentration (if diabetic).13

Diuretics in people with


renal disease

4. Kidney Health Australia. Chronic kidney disease (CKD)


management in general practice. Melbourne: KHA. 2007.
At:www.kidney.org.au.
5. Roberts GW. Dosing of key renally cleared drugs in the elderly
time to be wary of the eGFR. Journal of Pharmacy Practice and
Research. 2006; 3:2049.
6. Australasian Creatinine Consensus Working Group. Chronic kidney
disease and automatic reporting of estimated glomerular filtration
rate: revised recommendations. Medical Journal of Australia.
2007;1 87:45963.
7. Martin JH, Fay MF, Ungerer JP. eGFRuse beyond the evidence.
Medical Journal of Australia. 2009; 190(4):1979.
8. Automatic eGFR reportingits role in screening for kidney disease
and drug-dosing decisions. NPS Radar: National Prescribing Service.
August 2008. At: www.nps.org.au.
9. White SL, Polkinghorne KR, Atkins RC, et al. Comparison of the
prevalence and mortality risk of CKD in Australia using the CKD
Epidemiology Collaboration (CKD-EPI) and modification of diet in
renal disease (MRDR) study GFR estimating equations: the AusDiab
(Australian Diabetes, Obesity and Lifestyle) study. American Journal
of Kidney Disease. (April) 2010; 55(4):66070.
10. Olyaei AJ, Bennett WM. Drug dosing in the elderly patients
with chronic kidney disease. Clinics in Geriatric Medicine. 2009;
25:459527.
11. Verbeeck RK, Musuamba FT. Pharmacokinetics and dosage
adjustment in patients with renal dysfunction. The European
Journal of Clinical Pharmacology. 2009; 65:75773.
12. Rossi S ed. Australian medicines handbook. Adelaide: Australian
Medicines Handbook Pty Ltd, 2011.
13. Cervelli, M ed. The renal drug reference guide. 1st edn. Adelaide:
Kidney Health Australia, 2007.
14. Australian Adverse Drug Reactions Advisory Committee. Australian
Adverse Drug Reactions Bulletin. 2003; 22(4). At: www.tga.gov.au.
15. Walker R, Edwards C. eds. Clinical pharmacy and therapeutics. 3rd
edn. Edinburgh: Churchill Livingstone, 2003.

145

Medicines in breast milk

Principles of drug therapy

Most prescription and over-the-counter medicines are


considered safe to use during breastfeeding. The amount
of medicine that passes to the infant through breast milk
is generally negligible, equating to less than 1% of an
infant dose.1 If the medicine is considered safe to use
in infants, generally it is also safe for the breastfeeding
mother. If there is a risk of adverse effects in the infant,
the decision to use the medicine calls for an assessment
of the potential risks and benefits to both the mother
and infant.
Managing the risks of medicine use in breastfeeding
involves evaluating the need to treat the breastfeeding
mother for a medical condition whilst supporting
breastfeeding of the infant. Pharmacists can provide to
breastfeeding mothers and prescribers advice on the safe
and effective use of medicines in breastfeeding.
Medicines that have been widely used in breastfeeding
and for which evidence-based data are available are
generally preferred over newer medicines that have
had little use in clinical practice. There are limited
data available to support the effectiveness or safety
of most complementary and alternative medicines in
breastfeeding.1

Principles of safe medicine use


If advice is to be provided about the safety of continuing
to breastfeed when taking medicines, the risks and
benefits should have been thoroughly assessed. The
advantages of breastfeeding are widely recognised,
and the benefits of the practice should always be
emphasised where appropriate.2 Pharmacists should
provide counselling to support the safe and correct use
of medicines.
Among the factors influencing the choice and safety of
medicines used while breastfeeding are the following:

the age and weight of the infant

the drugs pharmacokinetic properties, such as:


the drugs half-life
the lipid solubility of the drug and the fat content
of milk
maternal plasma concentrations
maternal plasma protein binding
the molecular weight of the drug
the drugs oral bioavailability to the infant.1,3

The financial costs associated with formula feeding and


the potential difficulty of re-establishing the milk supply
should also be considered.
146

Topical or local treatments (e.g. inhalers, creams and eye


drops) are generally considered safe during breastfeeding
and might be preferred.2
If a medicine is to be used during breastfeeding, mothers
should be advised to watch for any suspected adverse
effects on the infant and to contact their doctor or
pharmacist if they are concerned. Use of antibiotics, for
example, can be associated with changes to the infants
gastrointestinal flora, this having the potential to cause
diarrhoea, vomiting or thrush.1

The infants gestational or


postnatal age
Infants ability to metabolise and excrete drugs increases
from about 33% at birth to 100% at 78 months of age.
Premature infants have reduced capacity to metabolise
and excrete medicines and might be at increased risk of
adverse effects.

Specific medicines
Medicines that are contraindicated during
breastfeeding are those that have the potential to
cause more than minor adverse effects in the breastfed
infant or can decrease the mothers milk supply
(e.g.pseudoephedrine and oestrogens). It is important
to note that some of the recommendations are based
on limited data or refer to the use of medicines in
higher than usual doses.
Use of social or recreational drugs when breastfeeding
can also affect the infant. Alcohol, amphetamines,
cannabis and nicotine are all transferred into
breast milk. Use of nicotine replacement therapies
(e.g.patches or gums) when breastfeeding produces
lower nicotine levels in breast milk and is preferable
tosmoking.1

Factors determining the


infants exposure to medicines
in breast milk
Infant dose
The following parameters can be used to determine an
infants exposure to a medicine as a result of excretion
into breast milk:2

Absolute infant dose. This is the total amount of


drug ingested via breast milk over 24 hours. It can
be directly compared with known safe doses of a
drug in infants or neonates.

Section B | Medicines in breast milk

Relative infant dose. This is the percentage of the


weight-adjusted maternal daily dose.
RID =

Absolute infant dose ^mg/kg/dayh # 100


Maternal dose ^mg/kg/dayh

Values less than 10% are generally considered safe


if the drug does not produce serious side effects
and is taken within the usual dose range. The 10%
notional level of concern is less in preterm infants,
who have reduced clearance capacity.
Drug concentration in infant plasma. Expressed as a
percentage of known therapeutic concentrations of
a particular drug, this figure may give an estimation
of likely drug effects in the infant.

Reported adverse effects after breast milk ingestion.


A literature search can be undertaken to determine
if reactions to a drug have been reported after an
infant has ingested the drug via breast milk.

Milk to plasma ratio. This is a numerical value,


expressed as a single number or range, that
represents the drug concentration in breast milk
relative to the maternal plasma concentrations.
A ratio greater than 1.0 suggests the drug might
appear in breast milk in high concentrations. The
ratio has, however, little value for assessing the
safety of a drug in breastfeeding if the maternal
plasma concentration is unknown: the actual
dose of the drug ingested by the baby is the
important factor.3,4
Oral bioavailability of the drug in the infant.2,3
This refers to the amount of drug that reaches
the infants systemic circulation after ingestion
of the drug through breast milk and absorption
through the infants highly acidic gastrointestinal
tract. Acid-labile drugs and drugs that undergo
firstpass hepatic metabolism generally have low oral
bioavailability. The frequency of breastfeeding and
the volume of breast milk ingested also need to be
taken into account.
The volume of milk ingested by the infant. It is
estimated that an infant who is exclusively breastfed
(e.g. eight or more times a day) ingests 150 mL of
milk/kg/day. This allows for estimating the drug
per kilogram the infant would ingest. The risk
of exposure to maternal medicines is reduced in
children who are breastfed only once or twice a day
and receive supplemental nutrition.1,3

Molecular weight of drug. Drugs with a high


molecular weight, such as proteins (e.g. heparin and
insulin), generally do not transfer into breast milk.

Plasma protein binding. Drugs circulate in maternal


plasma bound to plasma protein or albumin or they
remain freely soluble in the plasma. Highly protein
bound drugs (e.g. warfarin and ibuprofen) are
transferred into breast milk in limited amounts since
only the unbound fraction can be transferred.2,3
A drug with more than 90% protein binding is
considered significantly protein bound.

The pKa of the drug and the pH of milk. The pKa of


a drug is the pH at which the drug exists equally in
ionised and un-ionised states. Weakly basic drugs,
which have a pKa less than 7.2, can appear in breast
milk in higher concentrations than drugs with a
lower pKa. The un-ionised drug molecules diffuse
into breast milk but can quickly become trapped
in their ionised form and then accumulate in breast
milk. This is because the milk is slightly more acidic
than the mothers plasma.2,3 (See Appendix A5
pKavalues for further information.)

Lipid solubility and the fat content of milk. Fat


facilitates the transfer of highly lipidsoluble drugs.
Colostrum, which is the first stage of breast milk and
is produced for several days from birth, has a low fat
content. Mature milk, which is produced from about
two weeks after birth, has a higher fat content, and
increased concentrations of lipid-soluble drugs can
appear in breast milk given more than two weeks
post-partum.3

Minimising the transfer of


medicine to an infant
When a breastfeeding mother needs medicine, there
are a number of strategies for minimising potential
transfer of the medicine into breast milk and consequent
infant exposure:

consideration of alternative routes of administration


and alternative productse.g. nasal drops in
preference to an oral decongestant

use of medicines only for essential treatment of the


mothers condition and at the lowest appropriate dose

timing breastfeeding so that it occurs immediately


before the mother takes the medicine, thus generally
minimising the babys drug exposure and reassuring
the mother. This is useful in the case of drugs with
short half-lives or once-daily dosing; it is of limited

Drug transfer

Maternal plasma concentration of the drug. The


concentration of a drug in breast milk directly
relates to the concentration of the drug in maternal
plasma. Drugs are mostly excreted into breast milk
by passive diffusion, which involves movement
of the drug from a body compartment of high
concentration (the plasma) to a compartment of

Principles of drug therapy

lower concentration (the breast milk). The milk to


plasma ratio can be used to provide an estimate of
a drugs distribution between maternal milk and
plasma where the maternal plasma concentration
is known.3,4

147

Section B | Medicines in breast milk

value for drugs with long half-lives, particularly in


the neonatal period, when infants feed frequently

choice of a drug within a specific therapeutic class


that has desirable pharmacokinetic properties in
breastfeeding and minimises the infants exposure
but is still clinically suitable for the mother
e.g.sertraline rather than fluoxetine and ibuprofen
rather than naproxen
temporary suspension of breastfeeding in the
case of some drugs that are administered in a
single dose or intermittentlye.g. radio-isotopes
or chemotherapy.1 Milk should be expressed and
discarded while breastfeeding is withheld.

Principles of drug therapy

Medicines information centres


Professional judgment is needed when interpreting
the clinical relevance of product information
recommendations. Pharmacists should understand the
factors influencing drug transfer and, where necessary,
contact specialist medicines information centres for
clarification.
ACT
ACT Drug Information Service
The Canberra Hospital
Tel: 02 6244 3333

NT
Royal Darwin Hospital
Tel: 08 8922 8424

SA
Womens and Childrens Hospital
Tel: 08 8161 7222
Email: cywhs.druginfocentre@health.sa.gov.au

VIC
The Royal Womens Hospital
Tel: 03 8345 3190
Email: drug.information@thewomens.org.au

NSW
MotherSafe
Tel: 02 9382 6539
Toll free (NSW): 1800 647 848
or
NSW Medicines Information Centre
Tel: 02 8382 2136
Email: nswmic@stvincents.com.au

QLD
Queensland Drug Information Centre
Tel: 07 3636 7098 or 07 3636 7599
Email: Queensland_Drug_Information_Centre@health.qld.gov.au

TAS
Royal Hobart Hospital
Tel: 03 6222 8737

WA
Women and Newborn Health Service
Tel: 08 9340 2723

148

Further information
Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation.7th
edn. Philadelphia: Lippincott, Williams and Wilkins, 2005.
Motherisk: The Hospital for Sick Children. Breastfeeding and drugs.
At: www.motherisk.org/women/breastfeeding.jsp.
Pharmacy Department ed. Drugs and breastfeeding. Melbourne: The
Royal Womens Hospital, 2004.
TOXNET LactMed database, US National Library of Medicine (vendor),
updated when required. At: www.toxnet.nlm.nih.gov.

References
1. Amir LH, Pirotta MV, Raval M. Breastfeeding: evidence
based guidelines for the use of medicines. Australian Family
Physician. 2011; 40(9):68490. At: www.racgp.org.au/
afp/201109/201109Amir.pdf.
2. Hale TW, Hartmann PE, eds. Textbook of human lactation. Amarillo,
Texas: Hale Publishing, 2007.
3. Marks JM, Spatz DL. Medications and lactation: what PNPs need to
know. Journal of Pediatric Health Care. 2003; 17(6):3117.
At: www.medscape.com/viewarticle/464551.
4. Loke YC ed. Pregnancy and breastfeeding medicines
guide. Melbourne: The Royal Womens Hospital, Pharmacy
Department, 2010.

Individualised medicine
Pharmacogenetics is the study of the effect of genetic
factors on individuals or population subgroups
response to specific drugs. Completion of the mapping
of the human genome and the introduction of new
technologies have made it possible to analyse multiple
genes simultaneously, giving rise to the science of
pharmacogenomics.

Although the genomes of individuals are 99.9%


identical, the 0.1% difference can represent as
many as 3 million polymorphisms (DNA sequence
variations), the most common allelic variations being
single nucleotide polymorphisms (SNPs), which are
interindividual variations in the genetic code at the level
of one nucleotide.2 SNPs are scattered throughout the
human genome and are major determinants of many
pharmacokinetic and pharmacodynamic variations in
drug response.

Identifying genes involved in


drug responses
Clinical observation of the variation in drug responses can
enable identification of the genes involved in several ways:

The traditional approach involves delineation of


drug pathways to identify any gene that might
influence the clinical pharmacology of a particular
druge.g. genes encoding proteins likely to modify
pharmacokinetics, such as drugmetabolising
enzymes and drug transporters, or genes
involved in the pathogenesis of the condition
being treated. This approach has been used for
many drugs (e.g. perhexiline, 5-fluorouracil and
irinotecan) but is limited by our understanding of
a drugs pharmacological, pharmacokinetic and
toxicological pathways.
A newer approach involves studying the entire
genome to identify genetic differences in a
population that explain specific observed responses
to a drug or susceptibility to a health problem.
Although use of this approach to date has been

A third approach involves gene expression profiling,


which provides a snapshot of gene activity in a
specific tissue at a specific time. By comparing the
gene expression profiles of patients with different
responses to a drug, it is possible to identify genes
whose regulation might be linked to differential
drug outcomes. This approach is particularly useful
in oncology and has been used in breast cancer
patients to identify a group of 70 genes (the gene
signature) that can be used to predict the probable
prognosis.4

Once candidate genes have been selected for


pharmacogenomic analysis, they are assessed for
variability across ethnically diverse population groups.
A number of technologies have emerged, among them
gene chip technology that enables rapid detection
of multiple SNPs. Chips for some cytochrome P450
genes have been introduced into clinical practice in the
United States and are among commercially available
pharmacogenomic tests that can be used to optimise the
use of particular medications.

Principles of drug therapy

The term pharmacogenetics is usually used to describe


a single-gene approach, whereas pharmacogenomics
is used to define multi-gene interactions and pathways
that determine a drug response, allowing the broader
application of genomic technologies to new drug
development and prediction of patient responses to
drugs.1 The aim of pharmacogenomics is to allow for
the selection of genetically guided, individualised drug
and dose regimens, thereby optimising a medicines
effectiveness and minimising the risk of possible adverse
side effects.

limited by cost, an example of its value is the


identification of HLA-B57 as a determinant of
hypersensitivity to the antiretroviral drug abacavir.3

Important projects are under way in most large


pharmaceutical companies and major research institutes
with a view to assigning priority to those SNPs that are
predictive of drug and health outcomes. At present
the main challenges to be overcome are assessment of
the potential clinical relevance of the large number of
emerging SNPs and development of cost-effective SNP
detection methods for use in diagnostic laboratories.

Genetic variation in
drug responses
For a given drug, the pharmacokinetic and
pharmacodynamic consequences of polymorphisms
are a result of the specific proteins involved and how
the altered expression or function of these proteins
contributes to pharmacological activity. Among these
proteins are enzymes (e.g. cytochrome P450 enzymes),
drug transporters (e.g. P-glycoprotein), receptors and
structural components of the cell that are involved in
the metabolism, transport and mechanism of action of
medications. For more information about the mechanisms
of pharmacokinetic and pharmacodynamic drug
responses, see Drug interactions, page 124.

Drug metabolism
Until recently most examples of genetic polymorphisms
involved genes encoding drug-metabolising enzymes
149

Section B | Individualised medicine

(DMEs), some of them producing marked variations


in enzyme activity.5 The resulting differences in drug
metabolism could be due to variations in genes encoding
DMEs that are:

structurala polymorphism in the region of a DME


gene that influences the structure of the encoded
protein, potentially altering its enzyme activity

regulatoryvariability in regulatory regions of DME


genes, an important determinant of individual
drugmetabolising capacity.

Principles of drug therapy

As more variability in DME genes is identified, it is


becoming increasingly apparent that each person
possesses a distinct genetically determined complement
of DMEssomething that might be described as a
metabolic fingerprint.
Genetic variability in DMEs is thought to be an important
contributor to the incidence of adverse drug reactions.5
Increasingly, however, it is recognised that the role of
polymorphism of the genes encoding transporters,
receptors and signalling pathways can also alter
drug response.

Variations in the cytochrome P450 genes


Drug metabolism performed by polymorphic enzymes
particularly many forms of cytochrome P450 (CYP)can
lead to variations in the clearance (i.e. the efficacy of
drug elimination) of many drugs and their metabolites.
The following are three clinically important examples of
genetic polymorphisms in metabolising enzymes.
CYP2D6
The cytochrome P450 2D6 (CYP2D6) gene is responsible
for at least the partial metabolism of about 25% of
all drugs, including anti-arrhythmics, antidepressants
and antipsychotics. Many of these drugs have a narrow
therapeutic index, and genetic variations in the level of
expression or function of CYP2D6 can have important
effects on their efficacy and toxicity.
Individuals are broadly classified as poor metabolisers
or extensive metabolisers of CYP2D6 substrates. The
proportion of poor (or slow) metabolisers varies with
ethnicity but is 510% in Caucasian populations. These
individuals are considered to be at increased risk of
adverse reactions. For example, nortriptyline is dosed
in most patients at a range of 75150 mg, but in poor
CYP2D6 metabolisers the effective tolerable dose is
1020mg.2 Individuals can, however, also experience
therapeutic failuree.g. poor metabolisers do not achieve
adequate analgesia when treated with codeine, which
requires metabolic activation to morphine via CYP2D6.
A small number of individuals (12% of Caucasians)
are classified as having extensive (or ultra-rapid) drug
metabolism mediated by CYP2D6. In this instance a
genetic variation results in the inheritance of as many
as 13 copies of the gene. These extensive metabolisers

150

are generally considered to be at risk of therapeutic


failuree.g. they metabolise nortriptyline so quickly they
might require a dose of more than 500 mg to achieve
therapeutic effect.2 When treated with pro-drugs such as
codeine, however, they can experience an exaggerated
response. The impact of this might not be immediately
obviouse.g. a nursing mother who is an ultra-rapid
metaboliser might not be aware of experiencing an
exaggerated response to codeine, but there could be
profound consequences, such as respiratory depression
in the infant.
CYP2C19
More than 20 alleles have been defined for CYP2C19,
but only two allelesCYP2C19*2 and CYP2C19*3
are responsible for the majority of poor metabolisers.
About 5% of Caucasians and 20% of Asians will
carry two of these defective alleles.6 More recently, a
variant, CYP2C19*17, has been identified: it confers
an elevated CYP2C19 protein level and enhanced
metabolic activity.7
Although CYP2C19 is known to be involved in the
metabolism of a number of drugsamong them
omeprazole, diazepam, sertraline and citalopramthe
clinical significance of the CYP2C19 polymorphisms
remains uncertain. This can be attributed to two main
factors: many of the drugs metabolised predominantly
by CYP2C19 (such as proton pump inhibitors) have
relatively large therapeutic indices, which limits
the potential clinical toxicity associated with poor
metabolisers; and for some substrates (such as sertraline
and citalopram) the doseeffect relationship is not well
defined. There are, however, some situations in which
CYP2C19 polymorphisms can be of clinical significance.
For example, it has been demonstrated that the poor
metaboliser phenotype is associated with enhanced
Helicobacter pylori eradication rates relative to extensive
metabolisers following treatment with standard doses
of proton pump inhibitor as part of triple therapy.8 The
difference in eradication success rates between extensive
metabolisers and poor metabolisers has prompted
suggestions that proton pump inhibitor dosage should
be adjusted for CYP2C19 metaboliser status.
It has been shown that individuals with one or two
CYP2C19 reduced-function alleles are reduced
metabolisers of clopidogrel, which requires conversion
to an active metabolite to cause inhibition of adenosine
diphosphate (ADP)-stimulated platelet aggregation.9
Individuals with the CYP2C19*2 genotype were shown
to experience an increased risk of ischaemic events and
have poorer clinical outcomes.10 The relative contribution
of CYP2C19 to the variability in response to clopidogrel
is, however, uncertain. It has been shown to account
for about 12% of the variation in clopidogrel response,
although the strength of effect of the CYP2C19*2
variant on clopidogrel response could depend on other
factors, such as genetic background or environmental

Section B | Individualised medicine

exposures.9 Although the effect is substantial and highly


significant, the majority of the variation in response to
clopidogrel might be explained by other unmeasured
factors (e.g. additional genetic variants) that remain to
be identified. The CYP2C19 genotype does not appear
to have a major effect on the risk of ischaemic events
with the use of prasugrel, which inhibits ADP-stimulated
platelet aggregation but is not as dependent on
CYP2C19 for activation.11 CYP2C19 genotyping could,
however, have the potential to guide the choice of
antiplatelet therapy.
CYP2C9

Drug transport
Many drugs are substrates of active transporters, which
are membrane proteins that influence the absorption,
bioavailability and elimination of numerous drugs.
Genetic polymorphism can affect the expression of these
proteins or alter their affinity for substrates. Among the
transporters of particular interest are ABCB1 (MDR1),
MRPs, OATPs, OCTs, OATs and nucleoside transporters.5
An average eight- to ten-fold difference in P-glycoprotein
(Pgpthe product of ABCB1) expression in tissues has
been shown. The relevance of ABCB1 polymorphism
to dose requirements, blood concentrations, chronic
rejection and chronic nephrotoxicity in renal transplant
patients receiving the calcineurin inhibitors cyclosporin
and tacrolimus continues to be investigated. Animal
studies have linked low expression of Pgp in renal tissue
with chronic cyclosporin nephrotoxicity.
Another area of interest is the influence of genetic
polymorphism on responses to HIV therapy. Because
all currently used HIV protease inhibitors are Pgp
substrates, studies have examined whether differences
in the expression of Pgp could provide some explanation
for the variability observed in CD4 cell recovery. The
consequences of genetic polymorphism have been
assessed in vivo for another transporter of relevance
for drug therapy, OATP-C (SCP1B1), which facilitates

Drug targets
Genes determine how many drug targets (receptors) are
produced on or within cells. Genetic variations cause
some people to produce a greater number of receptor
sites, influencing the drug response.12
For example, the HER2 receptor, which is encoded by
the HER2 gene, is amplified in 1530% of patients
with breast cancer and has been shown to correlate
with rapid cell proliferation and a poor prognosis.
The monoclonal antibody trastuzumab (Herceptin)
is approved for use in patients who test positive for
overexpression of HER2 receptors on the cell surface.
Blocking the HER2 receptor with trastuzumab has
significantly improved the clinical outcomes for a
subset of patients with HER2 overexpression. Testing
for overexpression of HER2 receptors is used to identify
patients likely to respond to the drug and determine
whether they qualify for subsidised treatment.13
Genetic polymorphism of the beta2-adrenoceptor
(ADBR2) is associated with altered expression,
downregulation or coupling of ADBR2. A subset of
patients with a genetic variation of ADBR2 experience
an altered response to regular beta-agonist therapy.
Desensitisation of ADBR2 can lead to exacerbation of
asthma symptoms with chronic use of salbutamol.1416

Principles of drug therapy

Individuals response to warfarin can vary unpredictably.


People who carry at least one variant CYP2C9 allele
have been found to require lower maintenance doses
and experience a much higher risk of bleeding.5
Warfarin is a racemate, and its S-enantiomer is
five times more potent than its R-enantiomer. The
S-enantiomer is predominantly metabolised by CYP2C9
to the inactive 7-hydroxywarfarin, meaning that
changes in the activity of CYP2C9 have the potential to
alter the anticoagulative response. Additional variability
in warfarins anticoagulant effects can also be caused
by polymorphisms in genes that encode clotting factors
and warfarin targets. Polymorphisms in the gene
encoding a protein of the vitamin K cycle (VKROC), for
example, have been found to explain about 25% of the
variation in warfarin response, compared with 610%
for CYP2C9 alone.5

the uptake of drug substrates from the blood into


hepatocytes. For more information about drug
transporter proteins, see Drug interactions, page 124.

Pharmacogenomics and
clinical practice
Although the contribution of multiple genetic (polygenic)
determinants of drug effects is still not fully understood,
pharmacogenomics has a number of applications
relevant to pharmacy practice. There is a growing list
of polymorphisms found in genes encoding drugmetabolising enzymes, drug transporters and drug
targets, as well as disease-modifying genes that have
been linked to drug effects in humans. Table B.9 provides
examples of identified genetic polymorphisms that
influence drug responses. It is important that pharmacists
recognise the potential for genetic determinants to
produce inter-individual variations in treatment response
and the risk of adverse effects.

Pharmacogenomic testing
The availability of genetic testing and tools for
determining drug responses (i.e. molecular diagnostics)
in order to individualise and optimise drug therapy
is expected to expand in the future. It is important
to understand that the pharmacological effects of
most drugs are determined by numerous proteins.
A drug response can be determined by composite
151

Section B | Individualised medicine

Principles of drug therapy

Table B.9 Examples of pharmacogenomic associations5,21,22

152

Drug

Gene

Protein

Clinical significance

Abacavir

HLA

Human leucocyte
antigen (HLA)

Individuals with HLA-B*5701, HLA-DR7 and HLA-DQ3 haplotype


are at increased risk of experiencing potentially life threatening
hypersensitivity reactions.

ACE inhibitors

BKB2R

Bradykinin B2
receptor (BKB2R)

Individuals with polymorphism in promoter region C-58T are more


susceptible to ACE inhibitor-induced cough, although data are inconsistent.

Azathioprine,
6-mercaptopurine

TPMT

TPMT enzyme

There are three variations in TPMT activity that account for the majority
of cases with low or intermediate activity. Homozygous TPMT-deficient
individuals (with two non-functional TPMT alleles) have low or undetectable
TPMT activity and experience greater risk of severe myelosuppression.

Carbamazepine

SCN1A

Sodium channel
1-subunit
(SCN1A)

Polymorphism of the gene encoding neuronal SCN1A alters channel


activation with a potential loss of channel function. Carbamazepine
binds to voltage-gated sodium channels; mutations of SCN1A can alter
dosage requirements.

Cetuximab

KRAS

KRAS (also known


as Kras, K-RAS or
KRAS2)

Genetic alterations of the intracellular effectors involved in epidermal


growth factor receptor (EGFR)related signalling pathways alter the response
to EGFR inhibitors such as cetuximab and are a predictor of resistance
to therapy.

Clopidogrel

CYP2C19

CYP2C19 enzyme

Carriers of reduced function alleles (*2 and *3) are resistant to the
antiplatelet effects of clopidogrel, with an increased risk of ischaemic events,
particularly postcoronary artery stent insertion.

Codeine

CYP2D6

CYP2D6 enzyme

Individuals with two inactive alleles do not achieve analgesia.

Diuretics (thiazide
and loop diuretics)

ADDA

Alpha-adducin
(ADDA)

The gene variant Gly460Trp has been associated with a saltsensitive form of
hypertension, renal sodium retention and plasma renin activity. Individuals
with Gly460Trp mutation can have significantly greater reductions in blood
pressure and their blood pressure can also be more susceptible to changes
in salt balance.

Fluorouracil (5-FU)

DPYD

Dihydropyrimidine
dehydrogenase
(DPYD)

Deficiency in DPYD enzymatic activity is an autosomal recessive trait


that leads to a prolonged half-life and risk of 5-FU toxicity (neutropenia,
thrombocytopenia, neurological damage).

Irinotecan

UGT1A9

UGT1A9

Individuals with low metabolic activity phenotypes (UGT1A7*2 or


UGT1A7*3) display a higher response rate and are more likely to experience
severe irinotecan-induced neutropoenia compared with other patients.

Isoniazid

NAT2

N-acetyltransferase
2 enzyme (NAT2)

Rapid acetylator phenotypes activate and metabolise isoniazid faster, with


higher dosage requirements.

Protease inhibitors

ABCB1 (MDR1)

P-glycoprotein
(Pgp)

Differences in the expression of Pgp lead to variability in intracellular


concentrations and antiretroviral efficacy, based on CD4 cell count and
viral load.

Proton pump
inhibitors

CYP2C19

CYP2C19 enzyme

Genetic polymorphism displays three distinct phenotypes: poor metaboliser,


heterozygous extensive metaboliser and extensive metaboliser. Variation in
hepatic metabolism leads to differences in drug concentration and inhibition
of gastric acid secretion, with variations in rates of H. pylori eradication.

Salbutamol

ADRB2

Beta2-adrenergic
receptor

Individuals with variant forms of the ADRB2 gene display variations in


beta2-adrenergic receptor function. People with the Gly16 genotype may
demonstrate an altered response to beta2-agonist drugs with enhanced
receptor down-regulation after prolonged exposure and a decline in
respiratory function with regular use (e.g. of salbutamol).

Trastuzumab

HER2

Human epidermal
growth factor
receptor type II
(HER2)

Tumours not over-expressing the transmembrane glycoprotein receptor


p185HER2 will not respond to trastuzumab. Tumour regression with
trastuzumab therapy occurs in up to 35% of patients with tumours that
strongly over-express HER2.

Vemurafenib

BRAF

BRAF

There is a high frequency of BRAF gene mutations in melanoma, as well


as some solid tumours. BRAF is a mediator of cell growth and is involved
in the activation of growth signals in melanocytes. Vemurafenib is used in
the treatment of patients with metastatic melanoma who test positive for
BRAFV600E mutation.

Warfarin

CYP2C9

CYP2C9 enzyme

Potent S-enantiomer is mostly metabolised by CYP2C9 to the inactive


7-hydroxywarfarin. Individuals with defective alleles (*2 and *3 alleles)
require significantly lower maintenance doses and are at higher risk of
serious bleeding.

Warfarin

VKORC

Vitamin K epoxide
reductase complex
1 (VKORC)

Variants stratify patients into low-, intermediate- and high-sensitivity groups.


Haplotype (expression of a set of alleles) encodes clotting factors and
warfarin targets.

Section B | Individualised medicine

genetic polymorphisms in multiple genes, as well as


environmental (non-genetic) factors such as drug
interactions, diet and smoking, which are difficult to
control for. This means the relative contribution of the
genotype to the variability in response would need to
be determined, and testing for single polymorphiwsms
might account for only part of the variability in drug
response. For a given drug, identifying polygenic
determinants of the drug response necessitates
identification of the multiple relevant genes and genetic
polymorphisms and the complex pathways and processes
in their interaction.

the small number of laboratories offering


pharmacogenomic testing for clinical use

the limited number of fast, reliable and affordable


assays for routine pharmacogenomic testing

a lack of diagnostic test criteria, including the


processes required to interpret genotype information
and how to use that information

the fact that testing involves interpretation of


genotypes, potentially requiring clinicians to receive
further training in molecular biology or genetics

concern about test costs and reimbursements

a lack of specific guidelines on how to adjust


medications on the basis of genetic test results

a lack of scientific evidence to demonstrate


the clinical relevance of genetic variations in
pharmacokinetics and improvement in patient
outcomes as a result of pharmacogenomic
testing.1719

Standards and guidelines


The Clinical Pharmacogenetics Implementation
Consortium has developed a framework for the types
and levels of evidence required to justify incorporation of
pharmacogenomics in clinical practice.18 The framework
takes account of the need for evidence to demonstrate a
clear scientific rationale linking genomic variability with
drug effects, the therapeutic index of the medications
involved, the severity of the underlying disease, the
availability of alternative dosages or drugs for patients
with high-risk genotypes, the availability of approved
laboratory tests, and peer-reviewed clinical practice
guidelines that incorporate pharmacogenomics in their
recommendations.

Pharmacogenomics
in the future
The study of pharmacogenomics facilitates drug
discovery and development by identifying drug targets
and subpopulation-specific drug development. In drug
development, pharmacogenomics has the potential to
identify the size of markets for new drugs, potentially
ending the era of blockbuster drugs and leading to
market segmentation.17 It might also result in dramatic
cost savings by streamlining clinical trials and decreasing
drug failure rates. Genetically informed clinical trials
will probably be much smaller because populations are
chosen specifically on the basis of a greater likelihood of
response or a reduced risk of toxicity.

Principles of drug therapy

In recent years a number of commercially available


pharmacogenomic tests have been approved, although
their adoption in routine clinical practice has been
relatively limited. Among the barriers to incorporation
of pharmacogenomics in clinical practice are not only
prevailing attitudes and prescribing practices but also
a variety of technical, economic, ethical, regulatory
and educational factors. The following are some of the
challenges for developing and implementing clinical
applications of pharmacogenomics:

The dosing recommendations for azathioprine,


mercaptopurine and thioguanine based on the thiopurine
methyltransferase (TPMT) phenotype constitute one
of the first genedrug guidelines to be developed and
provide an example of how pharmacogenomics can guide
decision making in relation to drug therapy.20 The TPMT
genotype test can be used to guide dosing adjustments
and reduce thiopurine-induced adverse effects. TableB.9
provides an explanation of the clinical significance of
TPMT activity. Three TPMT SNPs account for more than
90% of inactivating alleles, allowing genotype testing to
detect most variant alleles.

Future uses of pharmacogenomics in clinical practice


include the prevention of toxicity and treatment
optimisation, therapy selection and population-wide
screening. Pharmacogenomics can be used to identify
genetic polymorphisms that predispose patients to
adverse drug effects. One approach is to obtain genomic
DNA from patients in large phase III clinical trials of a
new agent and then to search retrospectively for genetic
polymorphisms that predispose a small subset to severe
toxicities. Screening for these genetic variations will
help to identify individuals at risk of toxicity from the
new agent and will help guide drug dosage adjustments
based on the presence of gene variants.
Pharmacogenomics has been advocated as a new
therapeutic paradigm, moving us from a populationbased
approach to medicine to an individualised one. Its
uptake into routine clinical practice is still limited, so it is
incumbent on pharmacists to be aware of the science, its
potential impact on therapeutics, and the various practical
considerations related to its implementation.

References
1. Bleeker E. Pharmacogenomics and asthma. Rethinking
asthma control: implementing the new guidelines. 2007.
At: www.rethinkasthma.com/eBulletin6_bleeker.htm.
2. Norton R. Pharmacogenomics and individualized drug therapy.
Medscape Pharmacists. 2001; 3(1). At: www.medscape.com/
viewarticle/408606_1.

153

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3. Roses AD. Genome-based pharmacogenetics and the


pharmaceutical industry. Nature Reviews Drug Discovery. 2002;
1:5419.
4. Vant Veer LJ, Hongyue D, Van de Vijver MJ et al. Gene expression
profiling predicts clinical outcome of breast cancer. Nature. 2002;
415:5306.
5. Eichelbaum M, Ingelman-Sundberg M, Evans WE.
Pharmacogenomics and individualized drug therapy. Annual Review
of Medicine. 2006; 57:11937.
6. Desta Z, Zhao X, Shin JG et al. Clinical significance of the
cytochrome P450 2C19 genetic polymorphism. Clinical
Pharmacokinetics. 2002; 41: 91358.
7. Sim SC, Risinger C, Dahl ML et al. A common novel CYP2C19 gene
variant causes ultrarapid drug metabolism relevant for the drug
response to proton pump inhibitors and antidepressants. Clinical
Pharmacology and Therapeutics. 2006; 79:10313.

Principles of drug therapy

8. Padol S, Yuan Y, Thabane M et al. The effect of CYP2C19


polymorphisms on H.pylori eradication rate in dual and triple
first-line PPI therapies: a meta-analysis. American Journal of
Gastroenterology. 2006; 101(7):14768.
9. Shuldiner AR, OConnell JR, Bliden KP et al. Association of
cytochrome P450 2C19 genotype with the antiplatelet effect and
clinical efficacy of clopidogrel therapy. Journal of the American
Medical Association. 2009; 302(8):84958.
10. Mega JL, Close SL, Wiviott SD et al. Cytochrome P-450
polymorphisms and response to clopidogrel. New England Journal
of Medicine. 2009; 360:35462.
11. Mega JL, Close SL, Wiviott SD et al. Cytochrome P450 genetic
polymorphisms and the response to prasugrel: relationship to
pharmacokinetic, pharmacodynamic, and clinical outcomes.
Circulation. 2009; 119:255360.
12. Pharmacogenetics/pharmacogenomics. The Australasian
geneticsresource book fact sheet 25. Sydney: Centre for
GeneticsEducation. 2007. At: www.genetics.com.au/pdf/
factsheets/fs25.pdf.
13. Pharmaceutical Benefits Scheme. Schedule of Pharmaceutical
Benefits. 1 March 2011. At: www.pbs.gov.au.
14. Israel E, Drazen JM, Liggett SB et al. The effect of polymorphisms
of the beta2-adrenergic receptor on the response to regular use of
albuterol in asthma. American Journal of Respiratory and Critical
Care Medicine. 2000; 162(1):7580.
15. Weschler ME, Lehman E, Lazarus SC et al. Beta-adrenergic receptor
polymorphisms and response to salmeterol. American Journal of
Respiratory and Critical Care Medicine. 2006; 173:51926. At:
http://ajrccm.atsjournals.org/cgi/reprint/173/5/519.pdf.
16. Bleecker ER, Yancey SW, Baitinger LA et al. Salmeterol response
is not affected by beta2-adrenergic receptor genotype in subjects
with persistent asthma. Journal of Allergy and Clinical Immunology.
2006; 118(4):80916.
17. Swen JJ, Huizinga TW, Gelderblom H et al. Translating
pharmacogenomics: challenges on the road to the clinic. PLoS
Medicine. 2007; 4(8):e209. At: www.plosmedicine.org.
18. Relling MV, Klein TE. CPIC: Clinical Pharmacogenetics
Implementation Consortium of the Pharmacogenomics Research
Network. Clinical Pharmacology and Therapeutics. 2011;
89(3):4647.
19. Zanger UM. Pharmacogeneticschallenges and opportunities
ahead. Frontiers in Pharmacology. 2010; 1(112):12.
20. Relling MV, Gardner EE, Sandborn WJ et al. Clinical
Pharmacogenetics Implementation Consortium guidelines for
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Clinical Pharmacology and Therapeutics. 2011; 89:38791.
21. Cavallari LM, Ellingrod VL, Kolesar JM. Lexi-Comps
pharmacogenomics handbook. 2nd edn. Ohio: Lexi-Comp Inc.,
2005.
22. Pharmacogenomics Knowledge Base. 2011. At: www.pharmgkb.org.

154

Section C
Therapeutic management

This section covers some of the key areas of therapeutic management relevant to pharmacy practice. The information
can assist pharmacists identify drug-related issues and advise on appropriate drug therapy and optimise health
outcomes for patients. The topics focus on the role of the pharmacist in promoting safe, rational drug therapy.

Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

Wound management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

HIV and antiretroviral therapy . . . . . . . . . . . . . . . . . . . 160

Wound cleansing and antiseptics. . . . . . . . . . . . . . . . . 225


Classification of wound tissue. . . . . . . . . . . . . . . . . . . . 226
Types of wound dressings. . . . . . . . . . . . . . . . . . . . . . . . 228

Insulin preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164


Medicines review. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
Medicine-induced discoloration. . . . . . . . . . . . . . . . . . 169
Medicines and urinary incontinence . . . . . . . . . . . . . 172
Missed doses of oral contraceptives . . . . . . . . . . . . . 175
Normal physiological values . . . . . . . . . . . (see over page)
Opioid conversion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
Opioid conversion: equi-analgesic doses . . . . . . . . . . 202
Conversion from morphine to
transdermal fentanyl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Opioid-induced constipation. . . . . . . . . . . . . . . . . . . . . 205
Opioid substitution pharmacotherapy. . . . . . . . . . . 207
Methadone diluent APF. . . . . . . . . . . . . . . . . . . . . . . . . . 209

Gauze. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Non-adherent dressings. . . . . . . . . . . . . . . . . . . . . . . .
Paraffin gauze dressings. . . . . . . . . . . . . . . . . . . . . . . .
Plastic strips. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Film dressings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Foam dressings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hydrocolloid dressings . . . . . . . . . . . . . . . . . . . . . . . . .
Hydroactive dressings. . . . . . . . . . . . . . . . . . . . . . . . . .
Alginate dressings. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hydrofibre dressings. . . . . . . . . . . . . . . . . . . . . . . . . . .
Combined bioactive dressings. . . . . . . . . . . . . . . . . . .
Anti-infective dressings . . . . . . . . . . . . . . . . . . . . . . . .
Hypertonic saline dressings. . . . . . . . . . . . . . . . . . . . .
Silicone-based dressings . . . . . . . . . . . . . . . . . . . . . . .
Bandages and bandaging . . . . . . . . . . . . . . . . . . . . . .

228
228
228
229
229
229
230
231
231
232
232
232
233
234
234
234

Palliative care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212


Breakthrough analgesia. . . . . . . . . . . . . . . . . . . . . . . . . . 216
Management of nausea and vomiting
in palliative care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
Weight management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

155

Normal physiological values


Blood cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Erythrocyte count (RCC). . . . . . . . . . . . . . . . . . . . . . . . . .
Erythrocyte sedimentation rate (ESR). . . . . . . . . . . . . .
Haematocrit (packed cell volume). . . . . . . . . . . . . . . . .
Haemoglobin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Leucocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Mean cell haemoglobin concentration. . . . . . . . . . . .
Mean cell volume. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Red cell distribution width. . . . . . . . . . . . . . . . . . . . . . . .
Reticulocyte count. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

177
177
178
178
178
179
179
179
179

Therapeutic management

Blood clotting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179


Activated partial thromboplastin time (APTT). . . . . .
Anti-Factor Xa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
International normalised ratio (INR). . . . . . . . . . . . . . .
Platelet count. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Prothrombin time (PT). . . . . . . . . . . . . . . . . . . . . . . . . . . .

179
179
179
180
180

Catecholamines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
Cerebrospinal fluid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

Ferritin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Iron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Iron-binding capacity. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Transferrin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ketones

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

187
187
188
188
188

Hydroxybutyrate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
High-density lipoprotein (HDL). . . . . . . . . . . . . . . . . . . .
Low-density lipoprotein (LDL). . . . . . . . . . . . . . . . . . . . .
Total cholesterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Triglycerides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Faecal fat. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

188
188
188
189
189

Liver function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189


Alkaline phosphatase (AP). . . . . . . . . . . . . . . . . . . . . . . .
Aminotransferases (ALT and AST). . . . . . . . . . . . . . . . .
Bilirubin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Gamma glutamyltransferase (GGT) . . . . . . . . . . . . . . .

189
189
190
190

Electrolytes, other minerals and trace elements . . 181

Metabolic function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

Aluminium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Anion gap. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Bicarbonate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Calcium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Chloride. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Copper. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Lead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Magnesium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Phosphate (inorganic). . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Potassium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Sodium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Zinc. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

Ammonium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
Arterial blood gases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
Beta-hydroxybutyrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Osmolality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Uric acid (urate). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Alpha1-antitrypsin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Amylase. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Creatine kinase. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Lactate dehydrogenase . . . . . . . . . . . . . . . . . . . . . . . . . .

184
184
184
184

Glucose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

Oxalate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Porphyrins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Proteins

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

191

Albumin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C-reactive protein. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Globulins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Rheumatoid factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Total protein. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Troponin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

191
192
192
193
193
193

Renal function

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

194

Creatinine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
Creatinine clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
Cystatin C. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

Glucose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Glucose tolerance test . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Glycosylated haemoglobin (HbA1C) . . . . . . . . . . . . . . . 184

Thyroid function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

Urine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

Cortisol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Erythropoietin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
FSH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
LH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
Oestrogens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
Parathyroid hormone . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
Testosterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

156

Iron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

Urea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Folic acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Vitamin B12. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

Corticosteroids
Corticosteroids are used in the treatment of adrenal
insufficiency and a number of immune-mediated diseases
such as asthma and rheumatoid arthritis. They vary in
their glucocorticoid and mineralocorticoid properties
and can be administered orally, nasally or topically,
depending on the condition being treated.

Systemic corticosteroids
Dose equivalence
Table C.1 provides information about the relative
potencies and equivalent doses of oral corticosteroids.

response and tolerance of dose reductions and is


dependent on the dose, the duration of treatment and
the underlying disease state.4
For people requiring long-term corticosteroid therapy,
changing therapy from a daily to an alternate day
regimen can reduce the risk of adverse reactions and
toxicity and allow recovery of the HPA axis function.
This calls for careful monitoring of the response to dose
adjustments.1 At times of concomitant illness, trauma
or surgical stress, additional glucocorticoid replacement
(or stress-dose therapy) is also necessary for people on
longterm pharmacological doses of corticosteroids.1

To minimise toxicity and related adverse reactions,


corticosteroids are used in the lowest effective dose for
the shortest time. Systemic corticosteroid therapy can
cause suppression of the hypothalamicpituitaryadrenal
(HPA) axis. Adrenal suppression is more likely to occur
with pharmacological doses (greater than 10 mg of
prednisone or prednisolone daily or the equivalent dose of
glucocorticoid) used for longer than two to three weeks.1
Glucocorticoid doses should not be discontinued
abruptly if there is a risk of clinically significant adrenal
suppression.13 Tapering of doses minimises exacerbation
of precipitating disease or other corticosteroid
withdrawal symptoms (anorexia, fatigue, nausea,
vomiting, fever, orthostatic hypotension, dizziness or
syncope). Tapering is individualised according to clinical

Dose equivalence
Table C.2 summarises the approximate dose equivalence
and normal dose ranges for inhaled corticosteroids
in adults.
The additional therapeutic response to doses of inhaled
corticosteroid diminishes as the daily dose approaches
and exceeds the normal adult high-dose rangei.e.
there is a flat doseresponse curve.

Therapeutic management

Inhaled corticosteroids

Tapering therapy

Adverse effects
Adverse systemic effects can occur with inhaled
corticosteroids, particularly when they are used in high
doses for prolonged periods. The risk of systemic effects

Table C.1 Systemic corticosteroids: relative potencies and equivalent doses15


Compound

Anti-inflammatory
potency
(glucocorticoid
activity)

Sodium-retaining
potency
(mineralo-corticoid
activity)

Duration of actiona

Approximate
equivalent dose
(mg)b

Hydrocortisone (cortisol)

20

Cortisone

0.8

0.8

25

Prednisone

3.5

0.8

Prednisolone

0.8

Methylprednisolone

0.5

Triamcinolone

Fludrocortisone

10

125

Betamethasone

25

0.6

Dexamethasone

30

0.75

a. Sshort or 812 hour biological half-life; Iintermediate or 1236 hour biological half-life; Llong or 3672 hour biological half-life.
b. Relationships apply only to oral or intravenous administration: relative glucocorticoid potencies can differ greatly when injected intramuscularly
or into joint spaces. Fludrocortisone is not used for glucocorticoid effects.
Note: Oral budesonide is not included here because it is used in inflammatory bowel disease for local gastrointestinal effects. Systemic absorption
of budesonide is reduced by high first-pass metabolism, but some systemic effects can occur.

157

Section C | Corticosteroids

Table C.2 Inhaled corticosteroids: approximate dose equivalence and normal adult dose ranges68
Compound

Dose equivalence

Low dose (mcg/day)

Medium dose (mcg/day)

High dose (mcg/day)

Beclomethasone

1.0

100200

200400

400+

Fluticasone

1.0

100200

200400

400+

Budesonide

2.0

200400

400800

800+

Ciclesonide

0.8

80160

160320

320+

Therapeutic management

is influenced by the potency of the corticosteroid, the


patients inhaler technique and the delivery device
used, and subsequent absorption of the drug from
oropharyngeal deposition, although this is subject to
considerable first-pass hepatic metabolism.2
Use of high doses of inhaled corticosteroids for long
periods in children can be associated with growth failure
as well as adrenal suppression.6 Growth failure is not
considered a reliable indicator of adrenal suppression,
however, and monitoring growth cannot be used as a
screening test for adrenal function.7,8 Despite any initial
delay in growth (which is usually limited to a maximum
of 1 cm), full adult height is eventually achieved in
most individuals whose asthma is properly controlled.6
Uncontrolled asthma itself is a risk factor for children
not achieving full adult height, and children with
mild to severe persistent asthma benefit from inhaled
corticosteroid therapy, experiencing improvement in lung
function, a reduction in exacerbations and less frequent
use of oral corticosteroids.
The dose and duration of inhaled steroid treatment that
will place a child at risk of clinical adrenal insufficiency are
unknown. Daily administration of inhaled corticosteroids
at or above 200 mcg of beclomethasone (BDPHFA) or
equivalent might be associated with systemic effects.6
A meta-analysis of paediatric asthma studies showed,
however, no evidence of growth suppression with doses
of inhaled BDPHFA at less than 800 mcg a day.9 Clinical
adrenal insufficiency has been identified in a small
number of children who were mostly treated with high
doses of inhaled corticosteroids and became acutely
unwell at the time of concomitant illness.7

Dosing and back-titration


Reductions in inhaled corticosteroid doses to the
minimum dose needed to maintain adequate asthma
control should be considered after two to three months
of effective symptom controli.e. few symptoms,
minimal use of short-acting beta2-agonists, and no
exercise limitation. This approach is called downward
titration, or back-titration, of corticosteroid therapy.2,6
A one-quarter reduction in total daily dose should
be considered, further reductions being dependent
on individual circumstances. Cessation of inhaled
corticosteroid therapy can be considered once a patient
has been stabilised on low-dose treatment.10
158

Topical corticosteroids
Topical corticosteroids play an important part in the
management of dermatological conditions because
of their anti-inflammatory and immunosuppressive
effects, as well as their anti-proliferative effects on
keratinocytes.10

General principles of use


Cutaneous penetrationand therefore efficacy and
potential for adverse effectsdepends on the potency
and concentration of the topical corticosteroid, the
product formulation (vehicle and certain excipients),
the application method, the skin condition, and the
site of application. The extent of systemic absorption
is also influenced by the application method, including
the frequency, duration and use under occlusion,
application to damaged or thin skin, the fat content of
the formulation (ointment), and skin hydration.1 When
the product is used correctly there is a low risk of side
effects: prolonged therapy with mild or moderately
potent preparations rarely leads to complications.

Corticosteroid potency and


vehicle used
In general, acute inflammatory eruptions respond well
to mild or moderate topical corticosteroids. Potent or
very potent products are reserved for chronic, thickened
dermatoses. For a given strength of steroid, ointments
are more potent than creams; this is because of the
occlusive nature of ointment bases, which facilitates
penetration into the skin. Creams are suitable for moist
and hair-bearing areas, while ointments are useful for
their moisturising effect on dry and scaly areas. Other
agents, such as propylene glycol, can be added to
increase penetration and improve delivery of the topical
steroid. For the scalp, steroids are often delivered in a
lotion or gel.
TableC.3 provides information about the relative
potencies of topical corticosteroids. The vasoconstrictor
assay is the primary method of classifying the potency of
topical steroids and correlates with clinical efficacy.11 The
greater the corticosteroid potency, the greater the risk of
adverse effects and rebound on cessation of treatment.

Section C | Corticosteroids

Table C.3 Topical corticosteroids: potency of


commonly used preparations2,5
Compound

Strength

Mild
Desonide

0.05%

Hydrocortisone

0.51.0%

Hydrocortisone acetate

0.51.0%

Moderate
Betamethasone valerate

0.020.05%

Triamcinolone acetonide

0.02%

Potent
0.05%

Betamethasone valerate

0.1%

Methylprednisolone aceponate

0.1%

Mometasone furoate

0.1%

Triamcinolone acetonide

0.1%

Very potent
Betamethasone dipropionate

0.05% (optimised vehicleOV)

The application method


Initial treatment might warrant a more potent
corticosteroid and higher frequency of application, but
as the condition improves both potency and frequency
should be reduced. Once the condition has resolved,
topical corticosteroids should be ceased: they are not
used as preventive therapy. Prolonged use should be
avoided wherever possible: intermittent therapy is
preferred to continuous application for long-term use.
Patients should also be advised that treatment should
not exceed the prescribed quantities. If doses are tapered
following long-term therapy, the chance of rebound
flare and adverse effects will be reduced. Among the risk
factors for adverse systemic effects with topical steroids
are use in infants and children, prolonged and extensive
use, use of highpotency compounds, use over large
areas, and use under occlusion.1113
In the view of the British Dermatology Working
Group, the current advice to patients to apply topical
corticosteroid preparations sparingly or thinly
contributes to steroid phobia, increasing the risk of a
poor clinical response and treatment failure. Most patients
are prescribed topical corticosteroids of mild potency, for
which the evidence suggests the risk of harm is minimal.11
It is recommended that topical corticosteroids be applied
according to the fingertip unit (FTU) rule.14 One FTU (the
distance between the tip of the finger and the crease
of the first joint) should cover an area equivalent to two
palmar surfaces on the patients body. One FTU in an adult
is approximately 0.5g.
Use under occlusive dressings (including gloves or
plastic film) greatly increases corticosteroid absorption,
potentially increasing the risk of adverse effects. This

The application site


The thickness of the skin and local occlusive factors
are important considerations for safe use of topical
corticosteroids. Penetration effectiveness is as follows, in
decreasing order: mucous membranes, scrotum, axillae
and perineal flexures, eyelids and face, chest and back,
upper arms and legs, lower arms and legs, dorsum of
hands and feet, and palms, soles and nails.11,12
Mild corticosteroids are preferred for the face and
flexures, moderate agents being used short-term if
necessary. Potent or very potent agents are often required
for the management of disease on palms and soles.

The patients age


An increased bodysurface-to-weight ratio in infants and
the relatively thin skin of older patients place these two
groups at particular risk of adverse effects when topical
corticosteroids are not used appropriately. In these
instances the lower potency corticosteroids are preferred
as first-line treatment. Particular care should be taken if
application involves a large area or an infants nappy area.10

Therapeutic management

Betamethasone dipropionate

approach is generally reserved for use on areas of


thickened skin such as the palms and the soles of
the feet.

References
1. Helms RA, Herfindal ET, Quan DJ et al. eds. Textbook of
therapeutics: drug and disease management. 8th edn. Philadelphia:
Lippincott, Williams & Wilkins, 2006.
2. Therapeutic Guidelines Limited. eTG complete. Melbourne:
Therapeutic Guidelines Limited, 2009.
3. Schimmer BP, Parker KL. Adrenocorticotropic hormone
adrenocortical steroids and their synthetic analogues: inhibitors of
the synthesis and actions of adrenocortical hormones. In: Hardman
JG, Limbird LE, Molinoff PB et al. eds. Goodman and Gilmans
the pharmacological basis of therapeutics. 9th edn. New York:
McGraw-Hill, 1996.
4. Hall BM. Corticosteroids in autoimmune diseases. Australian
Prescriber. 1999 (22):911.
5. Rossi S ed. Australian Medicines Handbook. Adelaide: Australian
Medicines Handbook Pty Ltd, 2011.
6. National Asthma Council Australia.Asthma management
handbook 2006. Melbourne; 2006.7. British Thoracic Society.
British guideline on the management of asthma: a national clinical
guideline. 2009. At: www.sign.ac.uk/pdf/sign101.pdf.
8. Jenkins C. Starting steroids for asthma. Australian Prescriber. 2006;
29:636.
9. Mellis C. Inhaled steroids work in childhood asthma. Australian
Prescriber. 1997; 20:567.
10. ODriscoll BR, Kaira S, Wilson M, Pickering CA, Carral KB,
Woodcock AA. Double blind trial of steroid tapering in acute
asthma. Lancet. 1993; 341:3247.
11. Lee M, Marks R. The role of corticosteroids in dermatology.
Australian Prescriber. 1998; (21):911.
12. Bellingham C. Proper use of topical corticosteroids. Pharmaceutical
Journal. 2001; (267):377.
13. Bewley A, Dermatology Working Group. Expert consensus: time
for a change in the way we advise our patients to use topical
corticosteroids. British Journal of Dermatology. 2008; Feb 22.
14. Fingertip units for topical steroids. United Kingdom: Patient UK.
2005. At: www.patient.co.uk/showdoc/27000762.

159

HIV and antiretroviral therapy

Therapeutic management

The human immunodeficiency virus (HIV) is a


retrovirus that infects cells of the immune system,
destroying or impairing their function. As the infection
progresses, the immune system becomes weaker, and
the person becomes more susceptible to infections.
The most advanced stage of HIV infection is acquired
immunodeficiency syndrome (AIDS). It can take
1015 years for an HIV-infected person to develop
AIDS; antiretroviral drugs can slow down the process
even further.1
AIDS was first clinically observed in the United States
between late 1980 and early 1981. Intravenous drug
users and homosexual men with no history of immune
impairment began presenting with Pneumocystis carinii
pneumonia and Kaposis sarcoma, both of which are rare
opportunistic infections typically found in individuals
with severely compromised immune systems.2 A great
deal is now known about HIV infection, and this
knowledge allows us to optimise identification and
treatment of the disease and its manifestations. The four
stages of HIV infectionprimary infection, asymptomatic
HIV, symptomatic HIV, and advanced immune
deficiencyare clinically monitored, and the response
to therapy is assessed by measuring viral load and CD4+
T-cell count (referred to as CD4 count).35

Human immunodeficiency virus


The human immunodeficiency virus is a blood-borne
RNA retrovirus most commonly transmitted through
unprotected sexual intercourse, direct blood contact (e.g.
needlestick injury or intravenous drug use), transfusion
of blood and blood products, and motherchild transfer.
About 7585% of HIV cases worldwide are acquired
through unprotected sexual intercourse, transmission
occurring at the genital mucosa.
The probability of HIV transmission and subsequent
infection varies according to the type and route of
exposure, as well as the presence of other factors, such
as genital ulceration. Many individuals are diagnosed with
HIV when they present for screening after participation in
an activity deemed to be high risk, such as male-to-male
sex, unprotected sex or needle sharing. The diagnosis of
HIV is based on detection of anti-HIV antibodies using
an enzyme-linked immuno-sorbent assay (ELISA) and is
usually confirmed by a positive Western Blot assay, which
is more sensitive and specific.37
HIV seroconversioni.e. the development of antiHIV antibodiesusually occurs about one to three
months after initial infection and is accompanied by
characteristic symptoms caused by the initial effects of
the virus on the immune system. It is thought that about
160

4090% of individuals infected with HIV experience


clinical symptoms during seroconversion; these can
include acute fever, mucocutaneous rash, headache,
night sweats, generalised myalgia, oral ulceration and
swelling of the cervical lymph nodes. Recognition of
these clinical signs and prompt investigation can lead to
early diagnosis, treatment and counselling, which in turn
can prevent further spread of the virus in the community.
On initial diagnosis, individuals should be given
information and support to help them deal with their
diagnosis. Baseline CD4 counts and viral load assays are
essential on diagnosis, and screening for opportunistic
and other associated infections should also be done at
this time.
Management of individuals with HIV infection is
based on treatment with antiretrovirals, prevention
of opportunistic infections by using prophylactic
antiinfective agents, and maintenance of good health,
both physical (through diet, exercise and vaccination)
and psychological.35,7,911

Antiretroviral medicines for


HIV infection
To date, six categories of antiretroviral medicines have
revolutionised the treatment of individuals with HIV
infection. Treatment has continued to evolve since
the introduction of zidovudine in 1987, the most
important advance occurring in 1995 with the licensing
of protease inhibitors and the successful use of highly
active antiretroviral therapy, or HAART. For the first
time medicines were able to reduce the viral load to
undetectable levels. For now, however, the goal of total
eradication of HIV infection remains elusive.9

Principles of therapy
Since there is as yet no effective cure or vaccination for
HIV infection, the aim of therapy is to reduce the viral
load and increase the CD4 count. Complete eradication
of the infection is extremely difficult because latently
infected T-lymphocytes have an extremely long half-life
(usually a minimum of six months) and are able to
archive the virus and allow it to emerge and propagate
again after antiretroviral therapy ceases.35,9
The basic principles of antiretroviral therapy are to
use a combination of therapies, aim for maximal
suppression of the viral load, optimise adherence, and
tailor treatment in order to avoid toxicity or resistance.
Initiation of antiretroviral therapy is recommended
once the CD4 count falls below 350 cells per mm3 but
before it falls below 200 cells per mm3, when there is

Section C | HIV and anti-retroviral therapy

a significant risk of the development of AIDS. Starting


treatment at a lower CD4 count is associated with an
impaired immunological response to therapy.
Therapy with antiretroviral medicines should be initiated
only by a specialist in HIV medicine.3,5,8,10,11 More
information about the current guidelines for treatment
of HIV infection can be found through the AIDSinfo
website and therapeutic guidelinessee Further
information, at the end of this entry.
Changes in antiretroviral therapy might be necessary if
virological failure is detected (i.e. there is a significant
rise in viral load over 810 weeks), if drug toxicity or
intolerance is suspected, if adherence is problematic or if
the individual becomes pregnant. If medication changes
are called for there should be a full review, and the
complete combination should be changednot just a
single agent.

Prolonged antiretroviral therapy is associated with


adverse reactions such as the following:

lipodystrophy and insulin resistance

mitochondrial toxicity, lactic acidosis and


hepatic stenosis

osteopeniawhich can lead to increased risk


of fractures

peripheral neuropathy

myopathy

nephrolithiasisthe presence of calculi (stones)


in the kidney.5,89

Drug interactions
Drug interactions with antiretroviral medicines are
numerous and often significant. Pharmacists need to
be aware of the potential for drug interactions with
all antiretroviral medicines because such interactions
can result in toxicity or reduced efficacy.5,8,9 For more
information about drug interactions with antiviral
medicines, see Drug interactions, in Section B.

Combination therapy
Combination antiretroviral therapy is indicated for all
patients with symptomatic HIV infection because it has
been shown to reduce the risk of disease progression.
HAART involves the combination of three or more
antiretroviral agents, one or more of them penetrating
the bloodbrain barrier. Through the use of HAART
individuals have achieved a sustained improvement in
viral load and CD4 count, which in turn has improved
clinical outcomes, reduced hospitalisation rates,
and reduced morbidity and mortality from AIDSrelated illness. There have also been signs of partial
immune restoration during HAART, enabling the safe
withdrawal of prophylactic anti-infective medicines.
When CD4 counts are stabilised above 200 cells per
mm3, prophylactic medicines used for opportunistic
infectionse.g. Pneumocystis jirovecii pneumonia
(PCP), Mycobacterium avium complex infection and
cytomegaloviruscan safely be withdrawn. The use of
HAART, which should be initiated with at least three
antiretroviral agents, has seen patients remaining on
multiple therapies for longer periods.3,5,711

Adverse effects of antiretrovirals


Less toxic antiretroviral medicines are now being
used for the treatment of HIV infection, and this has
led to a decline in adverse effects and toxicity, and
subsequent discontinuation of therapy. It is important
to provide to individuals starting antiretroviral therapy
advice about common adverse effects such as rashes

Therapeutic management

These principles will improve quality of life, symptom


control and suppression of AIDS-associated illnesses
such as pneumonia, central nervous system disease and
secondary malignancies. Despite optimal treatment with
combination therapy and the therapys demonstrated
ability to prolong the time to antiretroviral resistance,
eventually all combinations and salvage therapy will be
exhausted.3,5,711

and gastrointestinal discomfort. Antiretroviralinduced rashes should not be prevented by using


antihistamines or systemic corticosteroids: these are
ineffective and can increase the likelihood of a rash
occurring.3,5,711

Antiretroviral medicines
The aim of therapy using antiretroviral medicines is to
achieve maximum potency against the HIV retrovirus,
with high thresholds for development of resistance,
activity against resistant strains, convenient dosing
schedules and fewer adverse effects.5,8,9 At present six
classes of antiretroviral medicines are licensed for use in
Australia (see FigureC.1).

Nucleoside reverse transcriptase


inhibitors
The nucleoside reverse transcriptase inhibitor (NRTI)
class can be further divided into nucleoside reverse
transcriptase inhibitors and nucleotide analogue
reverse transcriptase inhibitors (NtRTIs). These types of
antiretrovirals are converted by cellular enzymes into
an active (phosphorylated) metabolite that inhibits
reverse transcriptase and viral DNA synthesis, leading
to prevention of HIV replication. Abacavir, didanosine,
emtricitabine, lamivudine, stavudine, tenofovir and
zidovudine are examples of NRTIs.5

Non-nucleoside reverse
transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
have a mechanism similar to that of the NRTIs in their
161

Section C | HIV and anti-retroviral therapy

ability to bind to and reversibly inhibit HIV-1 reverse


transcriptase, thereby reducing viral DNA synthesis.
NNRTIs are hepatically metabolised, and the potential for
significant interactions needs to be taken into account
when they are prescribed or dispensed. Efavirenz,
etravirine and nevirapine are examples of NNRTIs.5

Protease inhibitors

Therapeutic management

Protease inhibitors (PIs) inhibit both HIV-1 and HIV-2


proteases, preventing viral maturation and replication of
newly-formed viral particles. This results in the generation
of immature and non-infectious virus. Protease inhibitors
are extensively hepatically metabolised, so there is the
potential for many clinically significant drug interactions,

which need to be considered. Atazanavir, darunavir,


indinavir, lopinavir, ritonavir and tipranavir are examples
of protease inhibitors.5

Entry inhibitors
Entry inhibitors, also known as fusion inhibitors, are the
first class of antiretroviral medicine that target a site of
replication other than reverse transcriptase or protease
enzymes. Entry inhibitors work by binding to the HIV
virus and blocking the viruss fusion to the CD4 receptor
of the host cell, thereby preventing the virus from
entering the cell and replicating. At present the sole
entry inhibitor available in Australia is enfuvirtide, which
is produced only as an injectable formulation.5,12

Figure C.1 HIV life cycle and sites of antiretroviral action

Copyright Furtado MR, Callaway DS, John P. Phair JP et al. Persistence of HIV-1 Transcription in Peripheral-Blood Mononuclear Cells in Patients
Receiving Potent Antiretroviral Therapy. NEJM 1999; 340:161422. Reproduced by permission.

162

Section C | HIV and anti-retroviral therapy

Integrase inhibitors
Integrase inhibitors inhibit HIV integrase, which
prevents replication of the HIV virus by stopping the
insertion of viral DNA into the host DNA. Viral DNA
that is not integrated into the host DNA is unable to
direct the production of new infectious virus particles,
and so propagation of the viral infection is prevented.
At present the only integrase inhibitor available in
Australia is raltegravir.5

Human chemokine co-receptor


5 inhibitor

Management of exposure
The risk of both occupational transmission
(e.g. as a result of a needlestick injury or exposure
to body fluids) and non-occupational transmission
(e.g. as a consequence of assault) of HIV following a
single exposure is very lowestimated at 0.090.3%.
The risk increases if there is a deep injury, if blood is
present on the needle or if the source is an individual
with confirmed HIV infection. Because there are major
risks associated with post-exposure prophylaxis (PEP)
for HIV, such action is recommended only if the risk of
infection is considered high.

Further information
The most recent guidelines for HIV management are available from
AIDSinfo, at www.AIDSinfo.nih.gov.
Information is also available from:

Australasian Society for HIV Medicine (ASHM), at www.ashm.org.au

Multilingual information about HIV infection can be found


on the HIV/AIDS and hepatitis C information website, at
www.multiculturalhivhepc.net.au

Antibiotic Expert Group Therapeutic Guidelines: antibiotics.


Version14. Melbourne: Therapeutic Guidelines Ltd, 2010.

References
1. World Health Organization. Health topics: HIV/AIDS. 2011.
At: www.who.int/topics/hiv_aids/en/.
2. Centers for Disease Control. A cluster of Kaposis sarcoma and
pneumocystis carinii pneumonia among homosexual male residents
of Los Angeles and Orange Counties, California. Morbidity and
Mortality Weekly Report. 1982, 31(23):3057.
3. Murtagh J. John Murtaghs general practice. 5th edn. Sydney:
McGraw-Hill, 2011.
4. Davey P. Medicine at a glance. 2nd edn. Carlton: Blackwell
Publishing, 2006.
5. Rossi S ed. Australian medicines handbook. Adelaide: Australian
Medicines Handbook Pty Ltd, 2011.
6. Royce RA, Sena A, Cates W et al. Sexual transmission of HIV. New
England Journal of Medicine. 1997; 336:10728.
7. Palliative Care Expert Group. Therapeutic guidelines: palliative care.
Melbourne: Therapeutic Guidelines Ltd, 2010.

Therapeutic management

The HIV virus enters CD4 cells by binding to either or


both of the chemokine receptors CCR5 and CXCR4,
which are found on the cell membrane. The human
chemokine co-receptor 5 inhibitors block the entry of
HIV virus strains that use only the chemokine CCR5
receptor to enter the host cell. Strains of the HIV virus
that can enter the host cell using the CXCR4 receptor
or that can use both CXCR4 and CCR5 receptors
are unaffected. A test can be used to detect CCR5tropism, which enables determination of whether the
drug will be effective for a particular individual. It is
important to start therapy with a CCR5 inhibitor as
soon as possible after the result is confirmed because
tropism can change. At present the only CCR5 inhibitor
available in Australia is maraviroc.5

high-risk sexual behaviour. Screening and treatment for


other sexually transmissible infections (such as hepatitis B
andC) should also be carried out.5

8. Post JJ, Kelly MD. New developments in antiretroviral therapy for


HIV infection. Australian Prescriber. 2005; 28:1469.
9. Palmer C. HIV treatments and highly active antiretroviral therapy.
Australian Prescriber. 2003; 26:5961.
10. Panel on Antiretroviral Guidelines for Adults and Adolescents.
Guidelines for the use of antiretroviral agents in HIV-1-infected
adults and adolescents. Department of Health and Human Services.
Updated 10 January 2011. At: www.aidsinfo.nih.gov/ContentFiles/
AdultandAdolescentGL.pdf.
11. World Health Organization. Antiretroviral therapy for HIV
infection in adults and adolescents: recommendations for a
public health approach. Rev. 2010. At: http://whqlibdoc.who.int/
publications/2010/9789241599764_eng.pdf.
12. Boyd M, Pett S. HIV fusion inhibitors: a review. Australian
Prescriber. 2008; 31:669.

Administration of zidovudine has been shown to


reduce transmission rates by over 80%, so this
antiretroviral is usually included in most PEP regimes.
The choice of antiretroviral medicines used for PEP
depends on whether the exposed person is pregnant
or taking other medicines. A two-NRTI combination
is generally used for low-risk exposures; a protease
inhibitor is added for higher risk exposures. Treatment
should be initiated as soon as practical, preferably
within one or two hours, and under the advice of a
specialist in infectious diseases. PEP should continue
for four weeks along with routine counselling and
follow-up. Non-occupational post-exposure prophylaxis
(nPEP) can be offered following sexual exposure or

163

Insulin preparations
People with type 1 diabetes need insulin from the
time of diagnosis. Type 2 diabetes is associated with
progressive beta cell decline, and more than 50% of
patients with the condition will eventually need insulin.
In type 2 diabetes, insulin is often initially combined
with oral glucose-lowering agents, especially metformin.
Regular blood glucose monitoring is necessary to
determine insulin doses and dose regimens. Insulin is
regarded as a high-risk medicine.

Therapeutic management

Types of insulin preparations


Rapid- and short-acting insulins are known as prandial
insulins and are generally administered before breakfast,
lunch and dinner in order to manage mealtime glucose
levels. Intermediate- and long-acting insulins are known
as basal insulins and act to reduce fasting glucose
levels and contribute to a reduction in postprandial
(after eating) glucose levels.
Five groups of insulin preparations are available for
clinical use:

Short-acting insulins. These are clear solutions


that can be used intravenously (usually in
continuous infusions) as well as subcutaneously.
Subcutaneous doses should be administered no
more than 30 minutes before a meal. An example is
insulinneutral.

Intermediate-acting insulins. These are cloudy


suspensions and they should be gently rolled
between the palms of the hands before use. Many
have an increased duration of action achieved
by combining the insulin with a protein such as
protamine (e.g. Neutral Protamine Hagedorn (NPH)/
isophane insulin). Intermediate-acting insulins do not
need to be injected close to meal times. An example
is isophane insulin.

164

Rapid-acting (ultra-short) insulins. These are human


insulin analogues. They are clear solutions and
have a rapid onset of action when administered
subcutaneously. They can be used immediately
before (but no more than 15 minutes before) or
soon after meals when necessary. Examples are
insulin aspart, insulin lispro and insulin glulisine.

Long-acting insulins. These are human insulin


analogues and are clear solutions. Their delayed
action is a result of insulin glargine having low
solubility at neutral pH and insulin detemir, although
soluble at neutral pH, binding reversibly to albumin.
Long-acting insulins can be injected regardless of
meal times. Examples are insulin detemir and insulin
glargine.

Pre-mixed insulins. These are also known as biphasic


insulins. They are cloudy in appearance and should
be gently rolled between the palms of the hands
before use. Various pre-mixed combinations of
intermediate- and rapid- or short-acting insulins are
available (see Table C.4).

Mixing insulins
It is generally recommended that proprietary
preparations of pre-mixed insulins be used if the insulin
ratio is suited to the patients requirements.1 There
might, however, be circumstances in which it is better to
mix insulins in a single syringe.
On mixing, physicochemical changes in the insulin mixture
can occur, either immediately or over time. As a result, the
physiological response to the insulin mixture can differ from
that produced when the different insulins are administered
separately. No other medication or diluent should be mixed
with any insulin product without specialist advice.1
Patients who are well controlled on a particular regimen
of more than one insulin product should maintain their
standard procedure for preparing insulin doses.1

Considerations
Several considerations for mixing specific insulins should
be borne in mind:

Rapid-acting insulin. When rapid-acting and


intermediate or isophane insulins are mixed, a slight
decrease in the absorption rate, but not the total
bioavailability, can occur. The mixture should be
injected no more than 15 minutes before a meal.1
The rapid-acting insulin glulisine can only be mixed
with the intermediate-acting NPH insulin. No data
are available on whether glulisine can be mixed with
other insulins or diluents when using an infusion
pump.2

Short-acting insulin. Short-acting (insulin-neutral)


and intermediate (NPH) insulins can be mixed. They
should preferably be used immediately.1,3

Long-acting insulin. The manufacturer of insulin


glargine recommends that the product not be mixed
with other insulins.1,4 Insulin detemir has a neutral
pH, but it should not be mixed with a rapid-acting
insulin.5-7 Insulin detemir and insulin glargine should
not be administered intravenously, used in insulin
infusion pumps or injected intramuscularly.5

The current recommendations state that insulin


glargine and insulin detemir should not be injected
into the same site as other insulins. Insulin glargine
and insulin detemir can be administered at any time
of the day but should be administered at the same
time each day.

Section C | Insulin preparations

Table C.4 Activity characteristics of insulins


Brand name

Onset of action
(hrs)

Time to peak
(hrs)

Duration of
action (hrs)

Insulin lispro

Humalog

0.25

45

Insulin glulisine

Apidra

0.25

45

Insulin aspart

NovoRapid

0.25

45

Short acting

Neutral insulin

Actrapid, Humulin R,
Hypurin Neutral

0.5

23

68

Intermediate acting
(non-mixed)

Isophane (NPH)
insulin

Humulin NPH,
Hypurin Isophane,
Protaphane

12.5

412

1624

Humalog Mix 25
(lispro 25%/lispro
protamine 75%)

0.25

1618

Humalog Mix 50
(lispro 50%/lispro
protamine 50%)

0.5

24

2224

Mixtard (30/70
or 50/50 neutral/
isophane)

0.51

212

1624

NovoMix 30 (aspart
soluble 30%/aspart
protamine 70%)

0.25

1618

Humulin 30/70
neutral/isophane)

0.51

212

1624

Rapid (ultra-short)
acting

Intermediate acting
(pre-mixed biphasic)

Long acting

Insulin glarginea

Lantus

12

No peak

24

Insulin detemir

Levemir

34

1224

a. It is recommended that this not be mixed with or injected into the same site as other insulins.

Preparation
For all insulin suspensions (pre-mixed insulins and
nonmixed isophane NPH insulins), the vial, pen or
syringe should be gently rolled in the palms of the hands
at least 20 timesnot shakento resuspend the insulin
before administration.1
When mixing rapid- or short-acting insulin with
intermediate-acting insulin, the former should be drawn
into the syringe first.1 If a cloudy insulin is drawn up first
and the suspension is allowed to enter the short-acting
insulin vial, the short-acting insulin can become cloudy.
It would therefore be impossible to know whether the
short-acting insulin was cloudy as a result of introduction
of the insulin suspension or a problem had developed
with the short-acting insulin.8

Storage
Pre-drawn insulin syringes can be prepared for patients
to administer at home. If a health professional decides to
use such syringes, cold storage for the shortest possible
period is recommended. The syringes should be stored in
a vertical position, with the needle (protected by a plastic
cap) pointing upward, so that suspended insulin particles
do not clog the needle. Pre-drawn syringes containing
suspensions should be rolled between the hands at least
20 times to resuspend the insulin before administration.1
Pre-mixed insulin syringes must be clearly labelled with
the time the dose should be administered. Storage of

Therapeutic management

Insulin type

pre-mixed insulin syringes is not recommended in a


hospital setting.

Stability
Manufacturers do not guarantee the stability of insulin
mixtures when they are stored in pre-mixed syringes and
recommend, where appropriate, the use of a proprietary
pre-mixed insulin with documented stability.
Syringes pre-drawn with a single insulin prepared under
aseptic conditions are known to be stable for up to
30 days when stored between 2 C and 30 C in a
refrigerator.1

References
1. American Diabetic Association. Insulin administration. Diabetes
Care. 2004; 27(Supplement 1):S1069.
2. Insulin glulisine FDA label revised April 2007. At: www.fda.gov/
cder/foi/label/2007/021629s010lbl.pdf.
3. Insulin Monograph Drugdex Database. Micromedex Healthcare
Series 6/2003.
4. Lantus. Product information. eMIMS. St Leonards: CMPMedica
Australia Pty Ltd, 2010.
5. Insulin detemir new medicines profile. UK Medicines Information
Centre issue no. 0503, produced by Guys Hospital, London.
6. Jones MC, Patel M. Insulin detemir: a long-acting insulin product.
American Journal of Health-System Pharmacy. 2006; 63:246672.
7. Peterson GE. Intermediate and long-acting insulins: a review of
NPH insulin, insulin glargine and insulin detemir. Current Medical
Research and Opinion. 2006; 22(12):26139.
8. Drugs for diabetes. Insulins. In: Rossi S ed. Australian medicines
handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2011.

165

Medicines review

Therapeutic management

Pharmacists review medication regimens as part of their


routine professional practice. The aim of assessing a
consumers medicines is to identify, prevent and resolve
potential medication-related problems and optimise
health outcomes within the framework of quality use
of medicines (QUM). This can involve an opportunistic
discussion with a customer about their medication
regimen, review of a persons medication history during
the dispensing process, or more systematic review
services such as home medicines reviews (HMRs) that
warrant a suitable level of training and involve an
accreditation process for pharmacists.

Improving the quality use


of medicines
Quality use of medicines is one of the central objectives
of Australias National Medicines Policy.1 Pharmacists can
contribute to QUM by promoting the most appropriate
treatment option (including nondrug therapy) and
conveying to people the knowledge and skills to
use their medicinesprescription, over-thecounter,
vitamins, and herbal and natural medicinessafely and
effectively.2
Pharmacists can help ensure that therapy is appropriate
for the persons condition, is the most effective available,
is the safest possible and can be used as intended. They
can also bring potential or actual medication-related
problems to the attention of the prescriber.
Research continues to highlight that good communication
between all members of the multidisciplinary health care
team is essential if we are to achieve QUM.

with the aim of optimising consumer health outcomes


and identifying potential medication-related issues within
the framework of the quality use of medicines.2 The
standards further describe medication review services
as being on a continuum of increasing complexity, with
a comprehensive and proactive review identified as an
HMR and a RMMR (residential medication management
review) with consumer involvement.2 See figure C.2.
A comprehensive review is a structured, critical
examination of a persons medicines. The aim is
to identify, resolve or prevent actual or potential
medication-related problems and improve the
individuals quality of life and health outcomes. The
consumer's values and preferences are an essential part
of shared decision making, and patient-centred care is
fundamental to the review.

A systematic approach
The review process needs to be consistent, regardless of
the environment or context in which the review is taking
place. The purpose is to gather information, identify
potential problems, and determine whether changes to
therapy are necessary.

Therapeutic necessity
The following are some of the questions a pharmacist
might consider:



Opportunities for medicines


review

The Professional Practice Standards describe medication


review as a systematic assessment of a consumers
medications and the management of those medications,

Is the medicine really necessary?


What is the medical indication?
Have non-drug options for treatment been
investigated or tried?
Might a single agent be as effective as a
combination of multiple medications?
Is the condition being treated an adverse reaction to
another medicine?
Is the condition being treated an untreatable
manifestation of normal ageing?
Do the possible benefits of drug treatment outweigh
the risk of harm?

Figure C.2 Medication review services: a continuum of increasing complexity2


Opportunistic
Reactive
review
e.g. medication history
review at the time of
dispensing

166

Systematic

Medication
chart review
e.g. hospital or residential
care facility inpatient
medication chart review

Treatment
review
e.g. medicines
use review (MUR),
medication
profilingservice

Proactive
review
e.g. HMR and RMMR with
consumer involvement

Section C | Medicines review

Selection of medicine and


formulation
If a medicine is necessary, the choice of medicine and
formulation should be aligned with the needs of the
individual. Among the factors to consider are the different
side effect profiles and characteristics of drugs in the same
therapeutic class, the cost, the complexity of the dosage
regimen, and individual characteristics such as coexisting
conditions and previous treatments. These considerations
are particularly important for high-risk groupsolder
people, children, people with multiple co-morbidities
(including renal or hepatic impairment), and so on.

Some people have difficulty swallowing oral formulations.


The cause of the difficulty should be investigated because
this knowledge will help with deciding on the best
strategy. For example, after a stroke many people are at
risk of aspirating liquids when trying to swallow them. If
someone has difficulty swallowing a solid dose form, an
alternative formulation can be usede.g. an oral liquid or
a transdermal patch.
Cost considerations, such as a medicines availability on the
Pharmaceutical Benefits Scheme, can also influence the
choice of medicine and formulation. In some situations this
might necessitate modification of a solid dosage form by
crushing a tablet or opening a capsule and dispersing the
powdered material in a small amount of soft food or another
suitable medium. This approach is, however, not appropriate
for some medicines and formulations (see Modification
of oral formulations, in Section A, and, for individual
medicines, see Clinical monographs, Section D).

Dose
For some medicines, it might be preferable to use a low
starting dose and increase the dose gradually to reduce
the risk of adverse events. A useful dictum with many
medicines is start low and go slow, particularly for
older patients.

Provision of information
To optimise health outcomes, it is important to ensure
adequate written and verbal instructions for the correct
and safe use of a medicine are provided. Information
on what each medicine is for, how to use it, and the
precautions to take when using it should be provided.
Levels of education, language barriers and cultural beliefs
can affect the understanding of instructions.

Using the smallest possible number of medicines in a


simple medication regimen can increase the likelihood
that the prescribed dosage and dosing interval are
followed (adherence), and that the treatment is
continued for the prescribed duration (persistence),
as well as minimising the risk of adverse effects.5
Acompartmentalised medication organiser and a daily
medication planner may be helpful.
If an individual has difficulty opening containers with
child-resistant closures, consider suggesting that they use
a different type of container, and be sure to discuss the
safe storage of medicines.
Among other potential barriers to adherence are impaired
cognitive function, hearing impairment (beingunable to hear
instructions), cost, health beliefs and perceptions, lack of
motivation, and concerns about potential adverseeffects.
The use of therapeutic devices can also compromise
adherence, particularly in the case of older people. For
example, it might be difficult to activate a metered-dose
aerosol and coordinate the steps necessary for optimal
use of inhalation devices. In such a situation the use of
an inhaler aid that facilitates aerosol activation or a largevolume spacer might be helpful, or the prescriber might
consider substituting a dry powder inhalation device
ornebuliser.

Medication profile

Therapeutic management

Some medicines might be more appropriate than others in


a particular class. In older people, for example, the choice
of a tricyclic antidepressant for neuropathic pain might
be influenced by the drugs anticholinergic properties
and the risk of postural hypotension with different drugs;
nortriptyline might be preferred over amitriptyline because
it has fewer anticholinergic effects and is less likely to
cause postural hypotension. In older people with type 2
diabetes, shorter acting agents (e.g. gliclazide) might be
preferred over glibenclamide, which has a long half-life
and is renally cleared, with greater risk of hypoglycaemia.

Medication-taking behaviour

Encourage individuals to keep an up-to-date medication


profile that contains important details about their
prescribed and over-the-counter medicines, including
complementary medicines.

Medicine-related issues
In reviewing an individuals medication regimen, be
mindful of potential and actual medicine-related issues
and their possible causes:
the need for additional therapyfor an untreated
indication; for a synergistic effect or to potentiate
therapy; as preventative or prophylactic therapy
unwarranted therapyno medical indication;
non-medicine therapy indicated; use of multiple
medications where a single agent would be effective;
treating an avoidable adverse reaction caused by
another medicine; duplication of therapy; different
brands of the same medicine
medicine considerationsinappropriate dosage form;
more effective medication available; contraindication
present; not cost effective; safety concerns;
condition not responding to therapy; medication not
indicated for the condition being treated; medication
administration error
dosage considerationsgreater or less than
recommended dose; pharmacogenomics
(seeIndividualised medicine, in SectionB) and
genetic polymorphism; escalating use of medicines
167

Section C | Medicines review

that cause dependence; over- or under-use;


inappropriate frequency; inappropriate duration;
medical condition significantly influencing
pharmacokinetics; inappropriate route or
administration time; poor administration technique
adverse drug reactionundesirable or excessive
effect; allergic reaction; contraindications; drug
drug interaction; drugdisease interaction; dosage
change too rapid; inadequate monitoring; effect
of concomitant food or alcohol and other drinks
e.g.grapefruit juice
other factors:

Therapeutic management

effects related to duration of therapy; duplication


of different brands of the same medicine; or
different medicines from the same pharmacological
or therapeutic class
changes in the clinical status of the patient;
for medicines or their active metabolites that
are renally eliminated, appropriate age-related
adjustments in dosages
biochemical parameters (e.g. serum electrolyte levels
or indicators of renal or hepatic function) that should
be monitored, either to determine drug dosage needs
or to monitor for adverse drug effects.4
A classification systemcalled the DOCUMENT DRP
systemhas been developed to help pharmacists identify
and classify medicine-related concerns and choose
suitable clinical interventions. The Pharmaceutical Society
of Australias Standard and Guidelines for Pharmacists
Performing Clinical Interventions6 outlines DOCUMENT
DRP and how to incorporate a systematic approach to
assessing drug-related concerns in daily practice.

Services requiring accreditation


The general principles outlined here apply to medication
management reviews regardless of where they are
conducted, be it in an aged care home (a residential
medication management review, or RMMR) or in the
domiciliary setting (a home medicines review, or HMR,
also previously known as a domiciliary medication
management review, or DMMR).
Pharmacists who are accredited to conduct medication
management reviews are entitled to conduct reviews
in both these settings and to be paid for their reviews,
but different obligations and business rules apply in
eachsetting.
Pharmacists who are conducting medication reviews can
be guided by the following publications:

168

Standard 4: Medication review. In: Professional


Practice Standards.

Guidelines for pharmacists providing home medicines


review (HMR) services. Pharmaceutical Society of
Australia.

Guidelines for pharmacists providing residential


medication management review (RMMR) and quality
use of medicines (QUM) services to aged care homes.
Pharmaceutical Society of Australia.
Home Medicines Review Checklist (T3F). In: Quality
Care Pharmacy Program. Pharmacy Guild of
Australia, 2006.

Further information is available from a number of


other sources, including the Pharmaceutical Society of
Australia (www.psa.org.au/supporting-practice), the
Australian Association of Consultant Pharmacy website
(http://aacp.moodle.com.au) and the Society of Hospital
Pharmacists of Australia website (www.shpa.org.au).

Further information
1. Disease state management

Therapeutic information is available from the National Prescribing
Service, Australian Prescriber, Adverse Drug Reactions Advisory
Committee bulletins and the Medical Journal of Australia
(free online). Other texts that can be purchased are:
Bochner F ed. Australian medicines handbook drug choice
companion: Aged care. 3rd edn. Adelaide: Australian Medicines
Handbook Pty Ltd, 2010.
Nissen L, Rigby DA. Home medicines review disease state
management guide, 3rd edn. Brisbane: Pharmacy Guild of
Australia, 2005.
The Therapeutic Guidelines series.
2. Medication review process
The 5th Community Pharmacy Agreement website,
www.5cpa.com.au
The Society of Hospital Pharmacists of Australia Standards
of Practice for Clinical Pharmacy, on the societys website,
www.shpa.org.au, or in the Journal of Pharmacy Practice and
Research (2005; 35(2):12246).
The Australian Association of Consultant Pharmacy website,
http://aacp.moodle.com.au/login/index.php.
The Pharmacy Guild of Australia website, www.guild.org.au.
Hughes J, Tenni P, Peterson G, Jackson S et al. The Australian
Pharmacist aged care primer. Canberra: Pharmaceutical Society
of Australia, 2007.
Hughes J, Tenni P, Soulsby N. Case studies in clinical practice.
Use of laboratory test data: process guide and reference for
health care professionals. 2nd edn. Canberra: Pharmaceutical
Society of Australia, June 2009.
3. Communication and collaboration
Rigby DA. Collaboration between doctors and pharmacists in
the community. Australian Prescriber. 20w10; 33:1913.

References
1. Australian Government Department of Health and Ageing.
National Medicines Policy. Canberra: DoHA, 2000.
2. Standard 4: Medication review. Professional Practice Standards.
Version 4. Canberra: Pharmaceutical Society of Australia, 2010.
3. Cipole RJ, Strand LM, Morley PC. Pharmaceutical care practice. New
York: McGraw Hill, 1998.
4. Strand LM, Morley PC, Cipolle RJ et al. Drug-related problems: their
structure and function. DICP, Annals of Pharmacotherapy. 1990;
24:10937.
5. Cramer JA, Roy A, Burrell A et al. Medication compliance and
persistence: terminology and definitions. International Society for
Pharmacoecnomics and Outcomes Research. 2008.
At: www.ispor.org/workpaper/research_practices/Cramer.pdf.
6. Pharmaceutical Society of Australia. Standard and guidelines for
pharmacists performing clinical interventions. Canberra: PSA. March
2011.

Medicine-induced discolouration
Some medicinesincluding complementary medicines
and vitaminscan cause discolouration of urine, faeces
or bodily secretions. Medicines can also cause changes
in the colour or pigmentation of the skin, nails and eyes.
To allay unnecessary concern for patients who buy or are
prescribed these medicines, pharmacists should advise
them of this possibility.

Variations in urine colour



The appearance and colour of urine are studied
during routine urinalysis. The range of colours for
normal urine extends from pale yellow to dark amber,
depending on the concentration. The yellow colouration
is caused by the pigment urochrome, a product of
bilirubin metabolism. Medicines can also cause urine
discolouration only at particular pH levels: pH might be
lower at night and might be raised after meals high in
protein or carbohydrates.

Dark yellow or orange urine can be a result


of low fluid intake, dehydration or excessive
carotene intake.
Dark red urine can indicate bleeding from the
kidney, while bleeding from the lower urinary tract
generally causes bright red or pink urine.
Purple colouration of urine can indicate infection
with Providencia stuartii, Klebsiella pneumoniae,
P. aeruginosa, Escherichia coli and enterococcus
species. In alkaline urine these bacteria can degrade
indoxyl sulfate (indican), a metabolite of dietary
tryptophan, into indigo (blue colour) and indirubin
(red colour).3
Dark-coloured urine can be a sign of cholestasis or
acute viral hepatitis.
Cloudy, murky or turbid urine can be caused by the
presence of necrotic white blood cells, red blood
cells or bacteria (e.g. in a urinary tract infection)
or the ingestion of large amounts of fat, urates
or phosphates.
Green, odorous urine can indicate Pseudomonas
infection.
Variations in the colour of urine can also be caused
by the excipients used when preparing medications.

Medicines that produce abnormal urine colours can


affect the accuracy of urinalysis reagent strips. They can
also cause discolouration of other bodily fluids, such as
sweat, tears and saliva.

Therapeutic management

Some foods, such as blackberries and rhubarb, and dyes


used in confectionery or diagnostic testing can also
cause discolouration. Additionally, changes in the colour
of urine and faeces can be the result of an underlying
medical condition. Any colour changes that are not
diet or drug related should be reported to a medical
practitioner, particularly if they are associated with
symptoms such as urinary urgency, dysuria or abdominal
colic or have persisted for several days.1,2

Table C.5 lists examples of medicines that can cause


discolouration of urine.

Table C.5 Medicines that can cause discolouration of urine16


Colour of urine

Medicine

Yellow

Fluorescein (IV), flutamide (amber), nitrofurantoin (rust yellow), primaquine (rust yellow), riboflavin, senna,
sulfasalazine (in alkaline urine), trimethoprim with sulfamethoxazole (dark rust yellow), warfarin

Yellowgreen

Flutamide

Yellowbrown

Cascara (in acidic urine), senna laxatives

Orange

Ascorbic acid (vitamin C), dantrolene, fluorescein (IV), rifampicin, sulfasalazine, warfarin

Pink

Phenolphthalein, phenothiazines, phenytoin, propofol, salicylates

Red

Cascara (in alkaline urine), dantrolene, daunorubicin, desferrioxamine, doxorubicin, epirubicin, levodopa (red on
voiding, darkens on standinga), mesalazinea, olsalazinea, phenolphthalein, phenothiazines, phenytoin, senna

Redorange

Rifabutin, rifampicin

Redbrown

Bismuth, deferiprone, entacapone (reddish brown), phenolphthalein (in alkaline urine), phenothiazines, phenytoin,
rhubarb (rust), senna

Bluegreen

Amitriptyline, indomethacin (green), methylene blue, mitozantrone, propofol (green), thalidomide (green),
triamterene (blue)

Brown

Methyldopa (darkens on standinga), metronidazole (dark brown), nitrates (brownblack), nitrofurantoin,


paracetamol (dark brown in overdosage), phenytoin, primaquine, quinine, trimethoprim with sulfamethoxazole

Black

Ferrous salts, iron dextran (black on standing), nitrates (brown-black), quinine, trimethoprim with sulfamethoxazole

Unspecified discolouration

Clofazimine, loratadine, tinidazole (dark)

a. With prolonged contact with hypochlorite bleach in the toilet.

169

Section C | Medicine-induced discolouration

Therapeutic management

Table C.6 Medicines that can cause discolouration of faeces26


Colour of faeces

Medicine

White speckling

Aluminium hydroxide, barium (oral)

Yellow

Gold, rhubarb, senna

Yellowgreen

Cascara

Pink

Aspirina, clopidogrela, corticosteroidsa, ergot alkaloidsa, heparina, indomethacina, NSAIDs (COX-1 and COX-2)a,
phenindionea, salicylatesa, warfarina

Redorange

Rifabutin, rifampicin

Red

Aspirina, clofazimine, clopidogrela, corticosteroidsa, ergot alkaloidsa, heparina, indomethacina, NSAIDs (COX-1 and
COX-2)a, phenindionea, phenolphthalein, salicylatesa, warfarina

Green

Bismuth, gold, indomethacin, medroxyprogesterone, rhubarb, senna

Blue

Chloramphenicol (unlikely with ocular use)

Brownblack

Clofazimine

Grey

Colchicine

Black

Acetazolamide, aminophylline, amphotericin b, aspirina, bismuth, charcoal, chloramphenicol (unlikely with ocular
use), clindamycin, clopidogrela, corticosteroidsa, ergot alkaloidsa, ethacrynic acid, ferrous salts, fluorouracil,
heparina, hydralazine, indomethacina, iodine preparations, levodopa, mesalazine, methotrexate, nitrates,
NSAIDs (COX-1 and COX-2) a, olsalazine, phenindionea, phenolphthalein, salicylatesa, tetracyclines, theophylline,
triamterene, warfarina

Unspecified discolouration

Aripiprazole, omeprazole, orlistat, pantoprazole, risperidone, saquinavir, tinidazole

a. The colour can indicate medicine-induced gastrointestinal bleeding.

Variations in faeces colour


The normal brown colour of faeces is due to the
presence of bile salts.

Diseases that affect the pancreas, gall bladder or


liver can cause light-coloured faeces.

Black or tarry faeces can be a result of ingested


iron supplements or bleeding from an ulcer in
the oesophagus or stomach (the blood remains in
the intestines long enough to be broken down by
digestive enzymes).

Pink, red or maroon faeces can be a result of


the presence of undigested blood, either from a
profusely bleeding site in the upper digestive tract
or from lower down in the digestive tract.

Silver, white, grey or yellow faeces can be


associated with cholestasis or acute viral hepatitis.

Yellowing of faeces can occur in giardiasis.

In infants digesting solid food for the first time,


greenish faeces that have an altered consistency
can be caused by the presence of cells discarded
during development of the digestive tract.

Variations in the colour of faeces can also be


caused by the excipients used when preparing
medications.

Table C.6 lists examples of medicines that can cause


discolouration of faeces.

170

Variations in the colour of the


skin, nails and eyes
Some medicines can cause variations in the colour
of the skin, nails and eyes. Medicine-induced skin
discolouration tends to be cumulative and can become
more apparent over time as the individual has further
exposure to the medicine. A pharmacist might be able
to identify the most likely cause of the discolouration by
finding out when the discolouration began in relation
to the taking up of any new medicines. A person has a
greater chance of experiencing medicine-induced skin
discolouration if they have a personal or family history of
previous reactions to medicines.
Recent exposure to sunlight or artificial ultraviolet light
can lead to an exacerbation of medicine-related skin
discolouration. Medicine-induced skin discolouration
usually has a characteristic distribution pattern and can
cause prominent discolouration in sun-exposed areas,
mucous membranes, sclerae, cartilage or nails. Most
changes in the colour of skin are reversible, and the
colour usually fades with time after use of the causative
agent is discontinued.7
The following are examples of medicines that relatively
commonly cause skin discolouration:

Amiodarone, when taken in doses greater than


200 mg daily, can cause bluegrey discolouration of
the skin in up to 25% of individuals, particularly in
sunexposed areas.

Section C | Medicine-induced discolouration

Hydroxychloroquine, when used for longer than four


weeks, has been reported to cause bluishgrey or
purple discolouration of the skin.

Clofazimine has been reported to cause


reddishbrown discolouration of the skin and on the
sites of lesions (particularly for light-skinned people
in sunexposed areas) and discolouration of the hair,
the conjunctiva, and corneal and lacrimal fluid.7

References
1. Terris MK. The significance of abnormal urine color. Palo Alto, CA:
Stanford School of Medicine, Department of Urology.
At: http://urology.stanford.edu/about/articles/abnormal_urine.html.
2. Mason P. Tests on specimens of urine or stools. Pharmaceutical
Journal. 1 May 2004; 272. At: www.pharmj.com/pdf/cpd/
pj_20040501_clinicaltesting04.pdf.
3 Lee J. Images in clinical medicine: purple urine. New England
Journal of Medicine. 2007; 357:13.

5. Product information. eMIMs [CD-ROM]. St Leonards: CMPMedica


Australia Pty Ltd, 2011.
6. Lacy CF, Armstrong LL, Goldman MP et al. Drug information
handbook international. United States: Lexi-Comp, 2006.
7. Butler DF, Henderson DZ. Drug-induced pigmentation. Texas:
eMedicine Dermatology; June 2010. At: http://emedicine.
medscape.com/article/1069686-overview.

Therapeutic management

4. Anderson PO, Knoben JE, Troutman WG. Handbook of clinical drug


data. New York: McGraw-Hill, 2001.

171

Medicines and urinary incontinence

Therapeutic management

Urinary incontinence is defined as the involuntary


leakage of urine.1 It is a common condition, especially
among women and older people.2 Age-related changes
in bladder functionsuch as a decrease in the urinary
sphincters closure pressure, frequent involuntary muscle
contractions in the bladder wall, and a reduction in
urine flow through the urethraincrease the risk of
developing the condition.3 Urinary incontinence can also
be associated with neurological problems, constipation,
urinary tract infection, delirium and immobility.
In addition, many commonly used medicines can
cause or exacerbate urinary incontinence. Pharmacists
can play an important role in identifying medicines
that might be contributing to urinary incontinence
(e.g. cyclophosphamide, vincristine and cisplatin) and
advising on whether the patient should cease taking a
particular medicine or replace it with a different medicine
or whether the dosing regimen should be altered.

Types of incontinence
Urinary incontinence occurs when there is dysfunction
in either the storage function of the bladder or the
emptying function of the lower urinary tract. It is
classified according to the presentation and cause
(see Table C.7). In women, stress incontinence and
urge incontinence are the two most common types of
the condition; in men, overflow incontinence and urge
incontinence are the most common.

Stress incontinence
Stress incontinence involves involuntary loss of
urine from the urethra in association with raised
intraabdominal pressure (e.g. through coughing,
sneezing or exercise).1,4 The increased pressure
overcomes the closed urinary sphincters resistance,
allowing urine to flow through the urethra. The
condition results from weakening of the urinary
sphincter and pelvic floor muscles, which support the
bladder and urethra. It can be caused by trauma or
surgery (such as hysterectomy or prostatectomy), vaginal
birth delivery, or post-menopausal atrophic urethritis
caused by a loss of fibrous connective tissue as a result
of a decline in oestrogen.2 It can also be associated with
obesity and pregnancy.
This type of incontinence mostly occurs in women.
The failure of the sphincter to maintain closure pressure
is generally a consequence of muscle or nerve damage,
age-related denervation of muscle, changes in collagen
and elastin as a result of birth-related damage, genetic
factors or declining hormonal status.
172

Urge incontinence
Urge incontinence involves an abrupt and intense
urge to urinate followed by involuntary loss of urine.
It is often associated with frequent voiding and
increased urination during the night (nocturia). Urgency
accompanied by frequency and nocturia is referred to
as overactive bladder and can occur with or without
urge incontinence.2 Overactive bladder is caused by
uncontrolled muscle contractions in the bladder wall
(detrusor muscle overactivity) that overcome urethral
resistance. It can be associated with conditions that
affect the ability of the brain or spinal cord to inhibit
bladder contractions; among these conditions are some
neurological disorders (e.g. spinal cord injury, multiple
sclerosis and stroke), impaired functional status and
bladder symptoms in childhood.
Urge incontinence is the most common type of persistent
incontinence in the elderly and can increase the risk of
falls because of the sense of urgency about getting to
the bathroom in time.3 In older women atrophic vaginitis
contributes to urge incontinence because of thinning
and irritation of the urethra. Other conditions that
irritate the bladder, such as urinary tract infection and
diabetes, can also cause urge incontinence. The volumes
of urine involuntarily voided can be moderate to large.

Mixed incontinence
More than one type of incontinence can be present. Mixed
incontinence describes a combination of incontinence that
occurs following a strong urge to urinate and involuntary
voiding on exertion, coughing or sneezing.1,5 In older
women incontinence occurs commonly as a combination
of urge and stress incontinence.

Overflow incontinence
Overflow incontinence involves the involuntary loss of
urine associated with impaired bladder emptying and
an over-distended bladder. Continuous or intermittent
leakage can occur, as well other urinary symptoms such
as hesitancy, frequency and nocturia. The volume of urine
remaining after urination (residual urine) is increased,
the incomplete bladder emptying being caused by
outlet obstruction (e.g. as a result of benign prostatic
hypertrophy or constipation) or ineffective contraction of
the detrusor muscle (e.g. neurogenic bladder).3,4

Functional incontinence
Functional incontinence occurs in otherwise continent
individuals who are unable or unwilling to get to the
toilet in time. It often accompanies urge or stress
incontinence and can occur as a result of impaired
mobility (e.g. caused by arthritis or muscle weakness);
medicines that affect balance, cognition or mental
alertness; or severe cognitive impairment.3

Section C | Medicines and urinary incontinence

Table C.7 Classification of urinary incontinence14,7


Stress

Involuntary leakage of urine caused by abrupt increases in intra-abdominal pressuree.g. on exertion or with sneezing or coughing

Urge

Involuntary leakage of urine accompanied by or immediately preceded by urgency

Mixed

Involuntary leakage of urine occurring following a strong urge to urinate and also on exertion or with coughing or sneezing

Overflow

Urine leakage caused by bladder outflow obstruction or ineffective contraction of the detrusor muscle, resulting in impaired
bladder emptying and elevated levels of residual urine

Functional

Incontinence resulting from an inability to reach or use the toilet in timee.g. as a result of poor mobility or cognitive impairment

Table C.8 Medicines that can cause or exacerbate urinary incontinence3,6


Medicine

Mechanism

Type of incontinence

Inhibit voiding reflex, reduce


detrusor activity, urinary retention,
constipation, confusion

Overflow, functional

Reduce detrusor activity, voiding difficulty,


urinary retention, constipation

Overflow

Antihypertensives (all)

Postural hypotension (unsteadiness)

Functional

ACE inhibitors

Cough-induced sphincter weakness

Stress

Diuretics

Polyuria, constipation, frequency

Urge

Verapamil

Reduced detrusor activity, constipation

Overflow

Enhanced detrusor activity


(instability), urgency

Urge

Amisulpride, clozapine, olanzapine,


quetiapine, risperidone

Constipation, confusion, sedation,


Parkinsonism

Overflow, functional, stress

Benzodiazepines

Sedation, impaired mobility

Functional

Chlorpromazine, haloperidol, pericyazine,


trifluoperazine

Anticholinergic, sedation, confusion,


Parkinsonism, impaired mobility

Overflow, functional

Lithium

Polydipsia, nocturia, frequency

Functional

SSRIsb, duloxetine, moclobemide,


venlafaxine

Enhanced detrusor activity (instability),


sedation, impaired mobility

Urge, functional

TCAsc, mianserin, mirtazapine, reboxetine

Anticholinergic, sedation,
impaired mobility

Overflow, functional

Sphincter relaxation, unconscious


dribbling of urine

Stress

Donepezil, galantamine, rivastigmine

Cholinergic effect, detrusor instability,


frequency, urgency

Urge, overflow

Pseudoephedrine

Enhanced sphincter activity, retention,


voiding difficulty

Overflow

Tiaprofenic acid

Enhanced detrusor activity,


frequency, urgency

Urge, cystitis-like symptoms

Analgesics
Opioidse.g. morphine, tramadol

Oxybutynin, propantheline, tolterodine,


solfenacin, etc.
Antihypertensives

Cholinergic agents
Bethanechola

Therapeutic management

Anticholinergic agents

Psychotropics

Selective alpha blockersd


Alfuzosin, prazosin, tamsulosin, terazosin
Other

a. Bethanechol increases bladder contraction. It is used to treat urinary retention and overflow incontinence, has limited efficacy and is
not recommended.
b. Paroxetine has some anticholinergic effects.
c. These relax the bladder and increase its capacity and are used for urge incontinence. They include medicines with significant anticholinergic
effects (e.g. first-generation antihistamines). Older people are more sensitive to their adverse effects.
d. These block receptors in the bladder neck and urethra. They can help to reduce outflow obstruction in males but can exacerbate or precipitate
incontinence in women.

173

Section C | Medicines and urinary incontinence

Medicines contributing to
urinary incontinence

Therapeutic management

Medicines can affect urinary continence by increasing


urine production, acting directly on the lower urinary
tract, impairing cognitive function or mobility, or causing
constipation.3 Any medicine that acts on adrenergic
or cholinergic receptors or that affects cognition
has the potential to affect urinary continence.3 The
risk of incontinence is cumulative and increases with
the number of such medicines being used. This is of
particular concern in older people, who often take
multiple medicines.

Some complementary medicines have the potential


to aggravate urinary incontinencee.g. those that
have a possible diuretic effect, sedative properties or
antidepressant action.

Some medicinese.g. cyclophosphamide, vincristine


and cisplatinexert a cytotoxic effect on the bladder
wall, leading to cystitis. Urinary symptoms associated
with cystitis can manifest as urinary incontinence.

Some medicines used to treat a particular type of


urinary incontinence can contribute to other types of
urinary incontinence.

Table C.8 lists some commonly used medicines that can


cause or exacerbate urinary incontinence.

Further information
PSA Pharmacy Self Care Fact Card Bladder and Urine Control.
Continence Foundation of Australiawww.continence.org.au.
National Continence Helpline1800 33 00 66.

References
1. Abrams P, Cardozo L, Fall M et al. The standardisation of
terminology of lower urinary tract function: report from the
Standardisation Sub-committee of the International Continence
Society. Neurourology and Urodynamics. 2002; 21:16778.
2. Urinary INCONTINENCE [revised August 2007]. In Merck manual of
diagnosis and therapy. At: www.merckmanuals.com.
3. Australian Government Department of Veterans Affairs. The
impact of commonly used medicines on urinary incontinence.
Veterans Mates Therapeutic Brief 26. March 2011.
At: www.veteransmates.net.au/VeteransMATES/documents/
module_materials/M26_TherBrief.pdf.
4. Harris P, Nagy S, Vardaxis N. Mosbys dictionary of medicine,
nursing and health professions. 2nd edn. Sydney: Elsevier, 2010.
5. National Prescribing Service. Managing urinary incontinence
in primary care. NPS News 66. 2009. At: www.nps.org.au/
health_professionals/publications/nps_news/current/nps_news_66_
managing_urinary_incontinence_in_primary_care.
6. National Prescribing Service, Medicines that may cause or make
incontinence worse. NPS News 66. 2009. At: www.nps.org.au/
health_professionals/publications/nps_news/current/nps_news_66_
managing_urinary_incontinence_in_primary_care/insert.
7. Bereznicki, L. Urinary incontinence. Australian Pharmacist. 2011;
30(4):31822.

174

Missed doses of oral contraceptives


The counselling advice presented in this entry is in
accordance with the recommendations of Sexual
Health and Family Planning Australia and its member
organisations, the Australian Medicines Handbook
and the Therapeutic Guidelines. Recommendations
from other sources might differ and be less or
more conservative.
Pharmacists should use the information here as a
general guide only and should treat each case on an
individual basis, using their clinical knowledge and
professional judgment to recommend the most suitable
course of action.

Contraceptive efficacy
To encourage consistent daily intake, combined oral
contraceptive (COC) active pills should be taken at
about the same time each day. The sugar tablet, or
hormonefree phase of the contraceptive cycle should
not exceed seven days.1
Contraceptive efficacy is affected in several
circumstances:

if two or more active pills are missedi.e. the period


between active pills is greater than 48 hours

if additional medicines or natural therapies are taken


and interfere with the pills effectiveness

if severe vomiting or diarrhoea persists for more than


24 hours.2,3

The progestogen-only pill (POP or minipill) is taken


continuouslyi.e. without a hormone-free interval. Its
efficacy depends largely on its effect on thickening the
cervical mucus. The thickening is maximal between three
and 21 hours after ingestion, so POPs should be taken
at the same time each day, and not more than three
hours late.6
The recommendations for situations where the POP is
more than three hours overdue, when vomiting occurs
within two to three hours after taking a pill, or when
severe vomiting or diarrhoea persists for more than
24 hours are as follows:

Take one pill as soon as possible.

Take the next pill at the usual time.

Continue taking pills regularly, at the same time


each day.

Use extra contraception (such as condoms) or


abstain from sexual intercourse for the next
48 hours.

Consider using emergency contraception if sexual


intercourse has occurred after any of these events
and before three consecutive pills have been taken
to restore contraceptive effect.2,3

Therapeutic management

The combined oral


contraceptive pill

The progestogen-only pill

The risk of pregnancy depends not only on how many


pills are missed but also on when those pills are missed.
The risk is greatest when active pills are missed at the
beginning or end of the active pillsi.e. when the
hormone-free interval extends beyond seven days. The
rationale for this is summarised in the seven-day rule:

Seven consecutive days of active pills are necessary


to reliably prevent ovulation.

Seven active pills can be omitted from an established


course without ovulationas happens in the pillfree, or inactive pill, week.

Missing more than seven consecutive active pills


poses a risk that ovulation will occur.1,4

See Table C.9.

175

Section C | Missed doses of oral contraceptives

Managing missed doses of oral contraceptives


Table C.9 Missed combined oral contraceptive pills: counselling recommendations2,3,5
Scenario

Advice

One active pill is missed (i.e. >24 hours


but <48 hours between active pills) or
vomiting occurs within 2 hours of taking
an active pill.

Take an active pill as soon as possible.


Take the next pill at the usual time.a
Continue taking active pills as usual.

Therapeutic management

Contraception will not be affected, and there is no need for emergency contraception.
Pack is started more than a day late or
2 or more pills in a row are missed, or
severe vomiting or diarrhoea for >24 hours
in the first week of active pills.

Take an active pill as soon as possible and continue taking pills as usual.a

Two or more pills are missed or severe


vomiting or diarrhoea is experienced for
>24 hours in the middle week of
active pills.

Take an active pill as soon as possible, and continue taking pills as usual.a

Two or more pills are missed or severe


vomiting or diarrhoea is experienced for
>24 hours in the last week of active pills.

Take an active pill as soon as possible, and continue taking pills as usual.a

An inactive tablet is missed.

Contraception will not be affected.

Emergency contraception is used.

Start taking active pills within 12 hours of the emergency contraceptive dose and use an extra
method of contraception until 7 active tablets have been taken.

Use an extra method of contraception or avoid sexual intercourse for the next 7 days.
Consider using emergency contraception if unprotected sexual intercourse has occurred since
the end of the preceding packet of pills or in the 7 days after re-starting the pill.

Use extra method of contraception or avoid sexual intercourse for the next 7 days.

Use an extra method of contraception or avoid sexual intercourse for the next 7 days.
On finishing the active pills in the present pack immediately start on the active pills
in the new pack; i.e. do not have a break from the active pills.

a. Depending on when the missed pill is remembered, 2 pills can be taken on the same dayone at the moment of remembering and the other
at the regular time.4
Note: The information in this table does not apply to the combined oral contraceptive Qlaira, which has different recommendations for
management of missed pills.

References
1. Guillebaud J. Contraception. 4th edn. London: Churchill
Livingstone, 2004.
2. Rossi S ed. Australian medicines handbook. Adelaide: AMH Pty Ltd,
2011.
3. Sexual Health & Family Planning Australia. Contraception: an
Australian clinical practice handbook. 2nd edn. Canberra: SH&FPA,
2008.
4. WHO Department of Reproductive Health and Research. Selected
practice recommendations for contraceptive use. 2nd edn. Geneva:
WHO, 2004. At: www.who.int/reproductivehealth/publications/
family_planning/9241562846index/en/.
5. Endocrinology Expert Group. Therapeutic guidelines:
endocrinology. Version 4. Melbourne: Therapeutic Guidelines Ltd,
2009.

176

Normal physiological values


The results of laboratory tests performed on body fluids
such as blood and urine are commonly used in the
monitoring of disease severity, screening and diagnosis,
and in therapeutic management.
This section discusses some common laboratory tests in
terms of their clinical uses, how they relate to disease
pathophysiology, and how to correctly interpret test
results. Unless otherwise specified, reference ranges
and terminology are standardised to comply with those
found in the manual published by the Royal College of
Pathologists of Australasia.1

Laboratory data

Reference ranges, or reference intervals, are a


statistical calculation of the range of results expected
to be found in 95% of healthy individuals unless
otherwise specified.1 Although most laboratory methods
are standardised, inter-laboratory differences can
occur as a result of differences in the methods used
for specimen collection and analysis. Laboratory test
results can also be influenced by characteristics such as
age, gender, genetics, ethnicity, body mass and factors
such as time of collection, exercise, and the presence
of food or some drugs. Information about the effect of
drugs on laboratory tests results can be found under
the individual tests at www.labtestsonline.org.au and
www.rcpamanual.edu.au.
Reference ranges are generally expressed in SI (Systme
Internationale) units. The litre is the standard unit of
volume, and mole is preferred to gram whenever
possible for describing values of concentration. Readers
might note some North American textbooks use
conventional units (e.g. g/100 mL) when discussing
laboratory results. Conversion tables are available in
most medical dictionaries.
Values of concentration are expressed in gram units
rather than moles when the analyte being measured
is a heterogenous group of compounds with differing
molecular weights and the molecular weight of the
analyte being measured is not precisely known.

Individual results should ideally be interpreted using the


reference intervals of the pathology laboratory performing
the test in the context of the patient, including their
clinical status, the presence or absence of signs and
symptoms, and baseline results. The sensitivity (ability of
the test to identify positive results in patients who actually
have the disease), specificity (the percentage of negative
results in people without the disease) and predictive value
(reproducibility of test results) of individual laboratory
tests influence the interpretation and clinical significance
of test results.2
When interpreting laboratory test results, pharmacists should
consider the combined results of several analytes, as well as
the health status and medication profile of the patient.

Blood cells
Erythrocyte count (red cell count)
Red blood cell count (adult female): ....... 3.85.8 1012/L
Red blood cell count (adult male): .......... 4.56.5 1012/L

Therapeutic management

Reference ranges

Interpreting laboratory data

The main function of erythrocytes (red blood cells, or


RBCs) is to carry oxygen to the tissues and to transfer
carbon dioxide to the lungs.

A high red cell count (RCC) can indicate polycythaemia


rubra vera or low oxygen tension in the blood from
diseases that produce chronic hypoxia (congenital
heart disease, cor pulmonale or pulmonary fibrosis).3
Dehydration can provide a falsely high RCC as a result of
a contraction in total blood volume.

A low RCC indicates anaemia, which can be caused


by haemorrhage (gastrointestinal bleeding or trauma),
bone marrow failure (leukaemia, multiple myeloma
or chemotherapy), renal disease or haemolysis. Low
levels can also be caused by nutritional deficiencies of
iron, folate, vitamin B12 and vitamin B6. Overhydration
(e.g. from intravenous fluids) also causes a reduced
RCC because of the diluted blood concentration.

Erythrocyte sedimentation rate

The accepted SI unit where functional activity rather


than molecular mass is measured (e.g. enzymatic
activity) is the International Unit (IU), defined as the
quantity of that enzyme that will catalyse the reaction of
1micromole of substrate per minute.

(Westergren method)

Some of the reference ranges provided are for specific


age groups. Unless specified, an additional information
source should be used to confirm that the reference
range is the same for adults and individuals aged less
than 18 years.

Adult male.................... 1750 years: ........... 110 mm/hr

Adult female................. 1750 years:............ 319 mm/hr


.................................... 5170 years:............. <20 mm/hr
....................................... >70 years: ............ <35 mm/hr
.................................... 5170 years: ............ <14 mm/hr
....................................... >70 years: ............ <30 mm/hr
Child............................................................ 215 mm/hr
177

Section C | Normal physiological values

The erythrocyte sedimentation rate (ESR) is a


measurement of the rate at which RBCs settle in saline
solution or plasma over a specified time period.

An increased total white blood cell (WBC) count usually


indicates the presence of infection, inflammation, tissue
necrosis, or leukaemic neoplasma. Trauma or stress
can also increase WBC count. Serum total WBC and
differential counts can be diagnostic and prognostic.3
Leucocyte differential count (adult):
Neutrophils............................................. 2.07.5 109/L
Basophils......................................................<0.1 109/L
Eosinophils............................................ 0.040.4 109/L
Lymphocytes........................................... 1.54.0 109/L
Monocytes.............................................. 0.20.8 109/L

Haematocrit (packed cell volume)


Adult female: ................................. 0.370.47 (3747%)

Neutrophilia (neutrophil count >7.5 109/L) can


be caused by acute bacterial infection, trauma,
myocardial infarction, chronic bacterial infection,
leukaemia and certain drugs, notably corticosteroids,
lithium and colony-stimulating factors.5

Neutropenia (neutrophil count <1.5 109/L) and


agranulocytosis (neutrophil count <0.25 109/L)
place the patient at increased risk of infection.
Depression of the neutrophil count can occur as a
result of drugs (e.g. cytotoxic agents, ticlopidine,
antithyroid agents, ganciclovir and clozapine),
overwhelming bacterial infection, vitamin B12 and
folate deficiency, salmonellosis and pertussis.

Lower than normal levels occur with congestive


heart failure, hyperviscosity, hypofibrinogenaemia,
low plasma proteins, polycythaemia and sickle
cell anaemia.

Adult male: .................................... 0.400.54 (4054%)


Haematocrit (Hct) is the measure of the fraction
or percentage of red blood cells in whole blood.
It is an important indicator of anaemia (decreased),
polycythaemia (elevated), dehydration (elevated),
increased red blood cell breakdown in the spleen
(decreased) or possible overhydration (decreased).

Haemoglobin
Adult female............................................... 115165 g/L
Adult male.................................................. 130180 g/L
Infant at term (cord blood)........................... 135195 g/L
Child 1 year................................................. 105135 g/L
Child 36 years........................................... 105140 g/L
Child 1012 years........................................ 115145 g/L
Haemoglobin is the main transporter of oxygen
and carbon dioxide in the blood. It consists of
globin (a protein) and haem, which contains iron atoms
and the red pigment porphyrin.
When used in conjunction with the haematocrit value,
haemoglobin level is an important indicator of anaemia
(decreased haemoglobin), dehydration (increased
haemoglobin), polycythaemia (increased haemoglobin),
poor diet or nutrition, or possible malabsorption.
Haemoglobin target levels for erythropoietin stimulating
agent (ESA) therapy remain controversial. Initially the
target was set at an upper limit of 100 g/L, but reports
of improved quality of life and physical performance
with higher levels have seen the target increased to
120130g/L.4
178

Leucocyte count, total, blood (adults): ......... 411 109/L

Neutrophils, also known as granulocytes, or segmented


neutrophils, are the main defender of the body against
infection and antigens. High levels can indicate an active
infection; a low count can indicate a compromised
immune system or depressed bone marrow (low
neutrophil production).

Therapeutic management

An elevated ESR is indicative of organic pathology,


but a normal ESR does not exclude the presence
of disease. The ESR is a non-specific indicator of
inflammation and malignancy. Elevated values occur
with alcoholic liver disease, inflammatory bowel
disease, kidney disease, pregnancy, rheumatic
fever, rheumatoid arthritis, severe anaemia,
syphilis, systemic lupus erythematosus, thyroid
disease and tuberculosis. Markedly elevated values
occur with giant cell (temporal, cranial) arteritis,
multiple myeloma, macroglobulinaemiaprimary,
hyperfibrinogenaemia, necrotising vasculitis and
polymyalgia rheumatica.

Leucocytes

Lymphocytes are involved in protecting the body from


viral infections such as measles, influenza, rubella and
chickenpox or infectious mononucleosis. Lymphocytosis,
and an elevation of the lymphocyte count (>4 109/L),
can occur in pertussis, tuberculosis, lymphoma and
syphilis. Lymphopenia, a reduction in the lymphocyte
count (<1 109/L), can occur in patients with HIV/AIDS,
Hodgkins lymphoma or aplastic anaemia and following
radiation exposure.
Monocytes are helpful in fighting severe infection and
are considered the bodys second line of defence against
infection. They are the largest cells in the bloodstream.
Elevated levels (>0.8 109/L) occur in the recovery phase
after acute bacterial infection, leukaemia (monocytic),
disseminated tuberculosis, endocarditis, and protozoal or
rickettsial infection.
Eosinophilia is usually associated with allergic disorders
(e.g. asthma and drug reactions) and parasitic infections.
A low eosinophil count (eosinopenia, <0.04 109/L) can
be seen in acute infections.

Section C | Normal physiological values

Basophilic activity is not fully understood, but these cells


are known to carry histamine, heparin and serotonin.
Basophils are probably involved in immediate as well as
delayed hypersensitivity reactions. High levels are found
in chronic inflammation and certain leukaemias.

decreased MCVanaemia of chronic disease,


thalassaemia (heterozygous).

Increased RDW

Mean cell haemoglobin


concentration

increased MCVvitamin B12 deficiency, folate


deficiency, immune haemolytic anaemia, liver disease

normal MCVearly stage of vitamin B12, folate and


iron deficiency anaemias, anaemic globinopathy

Adults and children...................................... 300350 g/L

The mean cell haemoglobin concentration (MCHC) is a


measure of the average concentration (or percentage) of
haemoglobin in a single RBC, derived by dividing the total
haemoglobin concentration by the haematocrit measure.3

decreased MCViron deficiency anaemia, RBC


fragmentation, HbH disease.

Reticulocyte count

A low MCHC is described as hypochromic, a normal


MCHC as normochromic, and an elevated MCHC
as hyperchromic.

By flow cytometry...........................................................
....... 30140 109/L (0.73.2% of total number of RBCs)

Adult.............................................................. 80100 fL
Mean cell volume (MCV) is a measure of the average
volume, or size, of a single RBC and is used in the
classification of anaemias.
A low MCV (<80 fL) is described as microcytic, a normal
MCV as normocytic and an elevated MCV (>100 fL) as
macrocytic.
Anaemias are classified according to the size of the RBC
and then the MCHC:

The reticulocyte count gives an indication of the bone


marrows ability to respond to anaemia and produce
RBCs. The count will be reduced in untreated anaemia
arising from iron, folate or vitamin B12 deficiency and
elevated in acute bleeding and haemolysis.

Blood clotting
Activated partial thromboplastin
time (APTT)
Normal (baseline) range: .......................... 2535 seconds

normocytic and normochromicacute blood loss,


aplastic anaemia, prosthetic heart valves, sepsis
and tumours

microcytic and normochromicerythropoietin


deficiency secondary to renal disease

The APTT test is used to monitor the efficacy of


unfractionated continuous infusion heparin therapy.
The reference interval and therapeutic interval vary
depending on the reagents and method used, consult
the laboratory.

microcytic and hypochromiciron deficiency, lead


poisoning, thalassaemia

Anti-factor Xa

macrocytic and normochromicvitamin B12 and


folate deficiencies and chemotherapy.

Continuous IV infusion.............. 0.51.0 anti-Xa units/mL


Subcutaneous injection...... >0.3 anti-Xa units/mL (trough)

Red cell distribution width

...........................................<1.0 anti-Xa units/mL (peak)

For a reference range consult the individual laboratory as


results vary according to the instrument used for testing,
although a common result might be 1115%.

The recommended test for monitoring for therapeutic


dosing of low molecular weight heparin (LMWH) is an
anti-factor Xa (anti-Xa) assay. Unlike unfractionated
heparin, LMWH does not affect the activated partial
thromboplastin time (APTT). Patients with renal failure,
extremes of body weight, or in situations where there
is an increased risk of bleeding can have their dose of
LMWH adjusted for a given anti-factor Xa result.

The red cell distribution width (RDW) is an indication of


the variation in RBC size. It is therefore helpful in further
classifying the types of anaemia. The RDW can become
abnormal before the MCV changes.

Therapeutic management

Mean cell volume

By microscopy................................................................
.......... 10100 109/L (0.22% of total number of RBCs)

Normal RDW

increased MCVaplastic anaemia, pre-leukaemia

normal MCVanaemia of chronic disease, acute


blood loss, haemolysis, chronic lymphocytic
leukaemia, chronic myelogenous leukaemia,
haemoglobinopathy, normal variant

International normalised ratio


Normal (baseline) range.......................................0.91.3
The international normalised ratio (INR) is a marker of
the activity of the extrinsic coagulation pathway and
becomes elevated in response to the same conditions
179

Section C | Normal physiological values

affecting prothrombin time.3 INR is used as the standard


monitoring parameter for patients taking some oral
anticoagulants (warfarin or phenindione).
Target range for oral anticoagulation
for all indications.................................................2.03.0

Adrenaline (urine)......................... <80 nanomol/24 hours

except for:

Dopamine (urine)...................... <3500 nanomol/24 hours

thrombosis associated with antiphospholipid


antibodies.................................................... 2.03.5

bileaflet mechanical heart valves


(aortic)......................................................... 2.53.5

mechanical prosthetic heart valve


(high risk).................................................... 3.04.5

Urinary catecholamine levels (adrenaline and/


or noradrenaline) are raised in patients with
phaeochromocytoma and are used in the diagnosis
of that condition. Increased dopamine can indicate
neuroblastoma and ganglioneuroma.1 Urinary
catecholamines can also increase as a result of
physiological stress (e.g. acute myocardial infarction),
drugs, strenuous exercise and food (e.g. bananas). Plasma
catecholamine levels have different reference intervals and
can be used as an alternative to urine studies.

Therapeutic management

The designated target INR will also be determined


by individual risk factors for increased sensitivity to
anticoagulants (e.g. age and a history of bleeding).

Platelet count
Normal range........................................ 150400 109/L
Some diseases affect platelet numbers and cause an
abnormal platelet count (thrombocythaemia).

Stress and infection are associated with an elevated


platelet count (thrombocytosis), as is splenectomy,
trauma, asphyxiation, rheumatoid arthritis, iron
deficiency anaemia, haemorrhage, cirrhosis, chronic
pancreatitis, tuberculosis and recovery following
bone marrow transplantation. In these cases the
values rarely exceed 500800 109/L. Platelet counts
>800 109/L occur in primary thrombocythaemia,
polycythaemia rubra vera, chronic myelogenous
leukaemia and myelosclerosis.
Thrombocytopenia is defined as a platelet count
<150 109/L and can be associated with reduced
production of platelets (bone marrow failure,
tumour), platelet loss from bleeding (trauma), or
accelerated destruction of platelets (infections
and numerous drugs especially heparin, quinine
and antineoplastic agents).3 Platelet counts
<20 109/L are associated with an increased
risk of spontaneous bleeding. Thrombocytopenia
caused by rapid destruction of platelets occurs
in diseases such as idiopathic thrombocytopenic
purpura, thrombotic thrombocytopenic purpura,
disseminated intravascular coagulation and
haemolyticuraemic syndrome.

Prothrombin time
Normal (baseline) range: .......................... 1115 seconds
Prothrombin time (PT) is an indicator of the activity
of the extrinsic coagulation pathway and can be used
to monitor oral anticoagulants, expressed as an INR
value.2 It is elevated (prolonged time to clot formation)
in patients with poor dietary intake of vitamin K,
malabsorption of fat-soluble vitamins and chronic
liver disease.
180

Catecholamines

Noradrenaline (urine).................. <780 nanomol/24 hours

Cerebrospinal fluid
Opening pressure...................................50195 mm H20
Cell count......................................................................
.........<5106/L mononuclears; no neutrophils or red cells
Glucose..........................................................................
........... 6070% of plasma levels; usually 2.84.4 mmol/L
Lactate....................................................1.22.8 mmol/L
Protein (adult)........................................... 0.150.45 g/L
Protein (full term neonate)............................. 0.11.2 g/L
Cerebrospinal fluid (CSF) is normally clear and colourless;
a cloudy appearance is often a result of the presence of
white blood cells, protein and bacteria. CSF examination
is used in the diagnosis of encephalitis, disorders
with local immunoglobulin production in the central
nervous system (e.g. multiple sclerosis), subarachnoid
haemorrhage, and spinal canal blockage.1
The white cell count is increased when there is
inflammation of the central nervous system, particularly
the meninges. In patients with meningitis, the CSF
protein and lactate concentrations can be elevated and
the CSF glucose concentration decreased because of
disruption of the bloodbrain barrier.2
CSF protein levels falls during the first year of life from
<1.94 g/L in neonates to <0.36 g/L in children aged
110 years. They can be elevated in CNS infections,
chronic inflammatory conditions of the central nervous
system (e.g. tuberculosis, syphilis), multiple sclerosis,
with increased bloodbrain barrier permeability
(chronic alcoholism, GuillainBarr syndrome) or blood
contamination.
The glucose concentration of CSF is usually lower than
for plasma glucose, so it is important to measure the
plasma glucose to allow accurate interpretation of the CSF
level. The CSF glucose concentration will fall as a result

Section C | Normal physiological values

of hypoglycaemia or central nervous system infection.


A reduction in the CSF glucose associated with an
elevation in CSF white cell count (particularly neutrophils)
and an elevated protein level is suggestive of bacterial
meningitis. A normal CSF glucose in the presence of an
elevated CSF lymphocyte count and normal or moderately
elevated protein suggests viral meningitis.

with an elevated serum potassium, whereas an elevated


bicarbonate is usually associated with a low serum
potassium. These changes in potassium levels occur as
a result of potassium movement into and out of cells in
response to extracellular hydrogen ion concentrations.

Calcium
Serum, total........................................ 2.102.60 mmol/L

Electrolytes, other minerals


and trace elements
Aluminium
Serum.................................................. <0.30 micromol/L
Serum, toxic level................................... >7.4 micromol/L

Aluminium can accumulate in patients with chronic


renal failure undergoing long-term haemodialysis,
causing dialysis dementia and osteodystrophy. In
dialysis patients, aluminium levels should not exceed
2.0 micromol/L.1 Serum aluminium >7.4 micromol/L
generally causes clinical symptoms of aluminium
toxicity; levels >3.7 micromol/L are of clinical
concern and close surveillance is required.

Anion gap
..................................................................816 mmol/L
if potassium not included.............................413 mmol/L
The calculated anion gap (AG) is the difference between
the cations and the anions in the extracellular space.
It is equal to (Na + K) (Cl + HCO3), although some
laboratories do not include K in the equation. AG is used
to investigate the cause of metabolic acidosis.
Increased AG occurs in lactic acidosis, diabetic
ketoacidosis, renal failure and alcohol intoxication.
Lithium toxicity reduces the anion gap.1,3

Bicarbonate
................................................................2232 mmol/L
When used with the other electrolytes, bic