Public Assessment Report

National Procedure

Codipar 15mg/500mg Capsules

Co-Codamol 15mg/500mg Capsules

UK licence no: PL 12762/0413

Mercury Pharmaceuticals Limited

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LAY SUMMARY
This is a summary of the Public Assessment Report (PAR) for Codipar 15mg/500mg
Capsules/Co-Codamol 15mg/500mg Capsules (PL 12762/0413). It explains how these
products were assessed and their authorisation recommended, as well as their conditions of
use. It is not intended to provide practical advice on how to use this product. Throughout this
report, these products will be referred to as Codipar Capsules, for ease of reading.

For practical information about using Codipar Capsules, patients should read the Package
Leaflet or contact their doctor or pharmacist.

What are Codipar Capsules and what are they used for?
Codipar Capsules are used for the short-term relief of moderate pain that is not relieved by
other painkillers, such as paracetamol or ibuprofen, alone.

How do Codipar Capsules work?

Codipar Capsules contains the active substances codeine and paracetamol. Codeine belongs
to a group of medicines called opioid analgesics, which act to relieve pain. Paracetamol is an
analgesic (relieves pain) and an antipyretic (lowers raised temperatures).

How are Codipar Capsules used?

Always take Codipar Capsules exactly as your doctor has told you. Check with your doctor
or pharmacist if you are not sure.

Swallow your capsules whole with a glass of water. Do not bite or chew the capsules.

The usual dosage is one to two capsules every four hours, as needed. You should not take more
than 8 capsules in 24 hours. Children aged 12 years and over should take one capsule every 6
hours, as needed. Do not take more than 6 capsules in 24 hours. A lower dose may be required in
the elderly or those with other medical problems.

This medicine should not be taken longer than 3 days. If symptoms do not improve in this time,
speak to your doctor or pharmacist.

How have Codipar Capsules been studied?

Both codeine and paracetamol are well-known, as separate active substances and in
combination. For this reason, the data submitted for this product licence was based on
literature references.

What are the possible side effects of Codipar Capsules?

Because these are well-known active substances, the side-effect profile is the same as that
other products containing these in combination.

For further information, please see Section 4 the Package Leaflet.

Why are Codipar Capsules approved?

Based on the data submitted, it was concluded that Codipar Capsules could be granted a
product licence, with the same benefit/risk profile as other similar products.

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What measures are being taken to ensure the safe and effective use of Codipar
Capsules?
A risk management plan (RMP) has been developed to ensure that Codipar Capsules are used
as safely as possible. Based on this plan, safety information has been included in the
Summary of Product Characteristics and the package leaflet for Codipar Capsules, including
the appropriate precautions to be followed by healthcare professionals and patients.

Known side-effects are continuously monitored. Furthermore new safety signals reported by
patients and healthcare professionals will be monitored and reviewed continuously as well.

Other information about Codipar Capsules

The UK first granted a marketing authorisation for this product on 06 September 2010.

The full PAR for Codipar Capsules follows this summary.

For more information about treatment with Codipar Capsules, read the Package Leaflet or
contact your doctor or pharmacist.

This summary was last updated in April 2016.

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TABLE OF CONTENTS

I Introduction Page 5
II Quality aspects Page 7
III Non-clinical aspects Page 8
IV Clinical aspects Page 9
V User consultation Page 13
VI Overall conclusion, benefit/risk assessment Page 13
and recommendation

Table of content of the PAR update Page 17

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I INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the UK granted a marketing
authorisation for Codipar Capsules to Mercury Pharmaceuticals Limited, for use in patients
older than 12 years of age for the treatment of acute moderate pain, which is not considered
to be relieved by other analgesics (such as paracetamol or ibuprofen) alone.

This is an application made under Article 10a of 2001/83 EC, as amended, for Codipar
Capsules, a bibliographic application for the well-established active substances codeine and
paracetamol.

Paracetamol, a para-aminophenol derivative, is only a weak inhibitor of prostaglandin

synthesis, but it is known to inhibit substance P-induced hyperalgesia and also reduces nitric
oxide generation in response to NMDA receptor activation and substance P. Codeine
phosphate, a phenanthrene derivative, is much less potent as an analgesic than morphine and
has relatively mild sedative properties. Codeine is a pure agonist and is particularly selective
for receptors. However, overall, codeine has a low affinity for opioid receptors and its
analgesic effect is due to its conversion to morphine.

As this product is a bibliographic application for two well-known active substances, no new
non-clinical or clinical data have been submitted with this application, and none are required.

Since this product will be used in place of other products that are currently on the market, no
increase in environmental exposure is anticipated. An Environmental Risk Assessment
(ERA) is, therefore, not deemed necessary.

The Reference Member State (RMS) has been assured that acceptable standards of Good
Manufacturing Practice (GMP) are in place for these product types at all sites responsible for
the manufacture and assembly of this product.

The pharmaceutical, non-clinical and clinical expert reports have been written by
appropriately qualified persons and are suitable summaries of the data submitted.

The Marketing Authorisation Application (MAA) form submitted is satisfactory.

The UK granted a marketing authorisation for this product on 06 September 2010

(PL 12762/0413).

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II. QUALITY ASPECTS

II.1 INTRODUCTION
This is an abridged application for Codipar Capsules, submitted under Article 10a of
Directive 2001/83/EC, a so-called bibliographic application. The proposed MA holder is
Mercury Pharmaceuticals Ltd, Capital House, 85 King William Street, London, EC4N 7BL,
UK.

Each capsule contains 500mg paracetamol and 15mg codeine phosphate.

Other ingredients consist of pharmaceutical excipients maize starch, sodium lauryl sulfate,
crosscarmellose sodium, purified talc, magnesium stearate, gelatin, titanium dioxide (E171),
erythrosine (E127) and red iron oxide (E172).

Polyvinylidene chloride/polyvinylchloride/aluminium blisters, with 10 capsules per strip,

packaged into cardboard boxes in pack sizes of 30, 32 or 100 capsules. Not all pack sizes
may be marketed.

Specifications and certificates of analysis for all packaging have been provided. These are
satisfactory. The primary packaging has been shown to comply with relevant regulations
regarding the contact of materials with foodstuff.

II.2 DRUG SUBSTANCE

Paracetamol
INN/Ph Eur Name: Paracetamol
Chemical name: Acetaminophen
N-Acetyl-p-aminophenol
N-(4-hydroxyphenyl)acetamide
Structure:

Formula: C8H9NO2
Molecular Weight: 151.2
Appearance: Almost white or white crystalline powder, sparingly soluble in water,
freely soluble in alcohol and very slightly soluble in methylene chloride.

Paracetamol is the subject of a European Pharmacopoeia monograph.

The manufacture and control of the active substance paracetamol is covered by a European
Directorate for the Quality of Medicines (EDQM) Certificate of Suitability

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Codeine Phosphate
INN/Ph Eur Name: Codeine phosphate
Chemical name: 7, 8-Didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol
phosphate hemihydrate
Structure:

Formula: C18H24NO7P, H2O

Molecular Weight: 406.4
Appearance: White or almost white, crystalline powder or small colourless crystals,
freely soluble in water, slightly or very slightly soluble in ethanol.

Codeine phosphate is the subject of a European Pharmacopoeia monograph.

The manufacture and control of the active substance codeine phosphate is covered by a
European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability.

II.3 DRUG PRODUCT

Pharmaceutical development
The objective of the pharmaceutical development programme was to produce safe,
efficacious capsules containing 500mg paracetamol and 15mg codeine phosphate.

Satisfactory product development data were submitted with this application.

With the exception of erythromysine (E127) and red iron oxide (E172), all excipients comply
with their respective European Pharmacopoeia monograph. Erythromysine (E127) and red
iron oxide (E172) comply with suitable in-house specifications. Suitable certificates of
analysis have been provided for all excipients, showing compliance with the respective
specification.

The only excipient used that contains material of animal origin is gelatin. The suppliers of
gelatin have provided Certificates of Suitability from the European Directorate for the
Quality of Medicines (EDQM) to show that they are manufactured in-line with current
European guidelines concerning the minimising of risk of transmission of Bovine
Spongiform Encephalopathy/transmissible Spongiform Encephalopathies (BSE/TSE).

Manufacture
A satisfactory batch formula has been provided for the manufacture of the product, along
with an appropriate account of the manufacturing process.

In-process controls are appropriate considering the nature of the product and the method of
manufacture.

The manufacturing process has been validated and has shown satisfactory results.

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Finished product specification

The finished product specification is satisfactory. Test methods have been described and have
been adequately validated, as appropriate. Batch data have been provided and comply with
the release specification. Satisfactory certificates of analysis have been provided for all
working standards used.

Stability
Finished product stability studies have been conducted in accordance with current guidelines.
Based on the results, a shelf-life of 24 months, with the storage conditions Do not store
above 25C have been accepted.

II.4 Discussion on chemical, pharmaceutical and biological aspects

It is recommended that a Marketing Authorisation is granted for this application.

III NON-CLINICAL ASPECTS

III.1 Introduction
This is a bibliographic application submitted under Article 10a of Directive 2001/83/EC. As
both codeine and paracetamol are well-known active substances, no further studies are
required.

III.2 Pharmacology
III.3 Pharmacokinetics
III.4 Toxicology
No new data have been submitted and none are required.

III.5 Environmental Risk Assessment

Since this product will be used in place of other products that are currently on the market, no
increase in environmental exposure is anticipated. An Environmental Risk Assessment
(ERA) is, therefore, not deemed necessary.

III.6 Discussion on non-clinical aspects

It is recommended that a Marketing Authorisation is granted for this application.

IV CLINICAL ASPECTS
IV.1 Introduction
This is a bibliographic application submitted under Article 10a of Directive 2001/83/EC. As
both codeine and paracetamol are well-known active substances, no further studies are
required.

IV. 2 Pharmacokinetics
No new data have been submitted and none are required.

IV.3 Pharmacodynamics
No new data have been submitted and none are required.

IV.4 Clinical efficacy

No new data have been submitted and none are required.

IV.5 Clinical safety

No new data have been submitted and none are required.

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IV.6 Risk Management Plan (RMP)

The marketing authorisation holder has submitted an RMP in accordance with the
requirements of Directive 2001/83/EC, as amended, describing the pharmacovigilance
activities and interventions designed to identify, characterise, prevent or minimise risks
relating to these products.

A summary of safety concerns and planned risk minimisation activities, as approved in the
RMP, are listed below.

IV.7 Discussion on the clinical aspects

It is recommended that a Marketing Authorisation is granted for this application.

V USER CONSULATATION
A user consultation with target patient groups on the PIL has been performed and the results
submitted in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The
results indicate that the patient information leaflet is well-structured and organised, easy to
understand and written in a comprehensive manner. The test shows that the patients/users are
able to act upon the information that it contains.

IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT

QUALITY
The important quality characteristics of Codipar Capsules are well-defined and controlled.
The specifications and batch analytical results indicate consistency from batch to batch.
There are no outstanding quality issues that would have a negative impact on the benefit/risk
balance.

NON-CLINICAL/CLINICAL
No new non-clinical or clinical data were submitted and none were required for an
application of this type. No new or unexpected safety concerns arise from this application.

PRODUCT LITERATURE
The summary of product characteristics (SmPC), patient information leaflet (PIL) and
labelling are satisfactory, and consistent with that for other similar products. The current
approved UK labelling is provided below.

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BENEFIT-RISK ASSESSMENT
The quality of the product is acceptable and no new non-clinical or clinical safety concerns
have been identified. Extensive clinical experience with codeine phosphate and paracetamol
is considered to have demonstrated the therapeutic value of the compound. The benefit-risk
is, therefore, considered to be positive.

Table of content of the PAR update

Steps taken after the initial procedure with an influence on the Public Assessment Report
(Type II variations, PSURs, commitments)

Scope Procedure Product Date of start of Date of end of Approval/ Assessment

number information the procedure procedure non report
affected approval attached
Y/N
(version)
IB N/A SmPC/PIL 15/12/2015 29/02/2016 Approval Yes
(Annex 1)

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ANNEX 1

Our Reference: PL 12762/0413-0035

Product: Codipar 15mg/500mg Capsules

Marketing Authorisation Holder: Mercury Pharmaceuticals Limited

Active Ingredient(s): Codeine phosphate, paracetamol

Type of Procedure: National

Submission Type: Variation
Submission Category: Type IB
Submission Complexity: Standard
EU Procedure Number (if applicable): Not applicable

Reason:
To register an additional generic name, Co-Codamol 15mg/500mg Capsules.
Consequentially, sections 1, 4.3, 4.4, 4.5, 4.6, 4.7 and 4.8 of the SmPC, label and leaflet have
been updated.

Supporting Evidence
Revised SmPC fragments, PIL and labels.

Evaluation
The proposed changes to the SmPC and PIL are acceptable. The updated SmPC fragments
and PIL have been incorporated into the Marketing Authorisation.

Conclusion
The proposed changes are acceptable. The updated labelling for the additional generic name
is presented below.

Decision- Approved on 29 February 2016.

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