Public Assessment Report

Decentralised Procedure



IBUPROFEN 200MG EFFERVESCENT GRANULES


Procedure No: UK/H/4995/001/DC

UK Licence No: PL 18866/0059


Rockspring Healthcare Limited


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LAY SUMMARY

On 16 J anuary 2013, Austria, Belgium, Bulgaria, Czech Republic, Estonia, Finland, France, Hungary,
Ireland, Italy, Lithuania, Luxembourg, Latvia, the Netherlands, Norway, Poland, Romania, Sweden,
Slovenia, Slovakia and the UK agreed to grant a Marketing Authorisation to Rockspring Healthcare
Limited for the medicinal product Ibuprofen 200mg Effervescent Granules (PL 18866/0059;
UK/H/4995/001/DC). The licence was granted via the Decentralised Procedure (DCP), with the UK as
Reference Member State (RMS). After the national phase, a Marketing Authorisation was granted in the
UK on 22 February 2013.

This is a pharmacy product (legal status P), intended to:
- relieve pain in conditions such as toothache, period pain and headache, and
- reduce fever (high temperature) and pain when you have the common cold.

Ibuprofen belongs to a group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs).

No new or unexpected safety concerns arose from this application and it was therefore judged that the
benefits of taking Ibuprofen 200mg Effervescent Granules outweigh the risks; hence, a Marketing
Authorisation was granted.

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TABLE OF CONTENTS


Module 1: Information about initial procedure Page 4

Module 2: Summary of Product Characteristics Page 5

Module 3: Product Information Leaflets Page 6

Module 4: Labelling Page 7

Module 5: Scientific Discussion Page 11

I Introduction
II About the product
III Scientific Overview and Discussion
III.1 Quality aspects
III.2 Non-clinical aspects
III.3 Clinical aspects
IV Overall conclusions

Module 6 Steps taken after initial procedure - Summary Page 18

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Module 1
Information about initial procedure

Product Name

Ibuprofen 200mg Effervescent Granules
Type of Application

Hybrid, Article 10(3)
Active Substances

Ibuprofen
Form

Effervescent Granules
Strength

200mg ibuprofen
MA Holder

Rockspring Healthcare Limited, 38/40 Chamberlayne Road,
London, United Kingdom, NW10 3J E

Reference Member State (RMS)

UK
Concerned Member States (CMS)

Austria, Belgium, Bulgaria, Czech Republic, Estonia,
Finland, France, Hungary, Ireland, Italy, Lithuania,
Luxembourg, Latvia, the Netherlands, Norway, Poland,
Romania, Sweden, Slovenia and Slovakia

Procedure Number

UK/H/4995/001/DC
Timetable

Day 210 16 J anuary 2013

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Module 2
Summary of Product Characteristics

The current approved UK version of the Summary of Product Characteristics (SmPC) for this product is
available on the MHRA website.
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Module 3
Patient Information Leaflet

The current approved UK version of the Patient Information Leaflet (PIL) for this product is available
on the MHRA website.
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Module 4
Labelling


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Module 5
Scientific discussion during initial procedure

I INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the Member States considered that the
application for Ibuprofen 200mg Effervescent Granules (PL 18866/0059; UK/H/4995/001/DC) could be
approved. This application was submitted via the Decentralised Procedure, with the UK as Reference
Member State (RMS), and Austria, Belgium, Bulgaria, Czech Republic, Estonia, Finland, France,
Hungary, Ireland, Italy, Lithuania, Luxembourg, Latvia, Netherlands, the Norway, Poland, Romania,
Sweden, Slovenia and Slovakia as Concerned Member States (CMS).

This is a pharmacy medicine (legal status P) indicated for the symptomatic relief of mild to moderate
pain, such as headache, period pain, dental pain, and fever and pain in the common cold

This was an application made under the Decentralised Procedure (DCP), according to Article 10(3) of
Directive 2001/83/EC, as amended, a hybrid application with Brufen 600mg Tablets (Abbott
Scandinavia AB) as reference product, which was initially authorised in Sweden in 1982. This
application represents a change in strength compared to the reference product.

Ibuprofen inhibits prostaglandin synthesis by competitive inhibition of the two isomers of
cyclooxygenase, COX-1 and COX-2. It is a non-steroidal anti-inflammatory drug (NSAID) with
analgesic, anti-inflammatory and antipyretic properties.

No new non-clinical studies were conducted, which is acceptable given that the application was a hybrid
application relating to a change in strength compared to an originator product that has been licensed for
over 10 years.

With the exception of the bioequivalence study, no new clinical studies were conducted, which is
acceptable given that the application was a hybrid application relating to a change in strength compared
to an originator product that has been licensed for over 10 years.

One bioequivalence study was performed, which compared the pharmacokinetics of Ibuprofen 600mg
Granules (the test product) versus Brufen 600mg Tablets (the reference product). The bioequivalence
study was carried out in accordance with Good Clinical Practice (GCP). A biowaiver was granted for the
200mg Granules that were the subject of this application.

The RMS has been assured that acceptable standards of Good Manufacturing Practice are in place for
these product types at all sites responsible for the manufacture, assembly and batch release of this
product.

The RMS and CMS considered that the application could be approved with the end of procedure (Day
210) on 16 J anuary 2013. After a subsequent national phase, the licence was granted in the UK on 22
February 2013.

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II. ABOUT THE PRODUCT

Name of the product in the Reference Member State

Ibuprofen 200mg Effervescent Granules
Name(s) of the active substance(s) (INN)
Ibuprofen
Pharmacotherapeutic classification
(ATC code)
Anti-inflammatory and antirheumatic
products, nonsteroids; propionic acid
derivatives. (M01AE01)
Pharmaceutical form and strength(s)
Effervescent granules 200mg
Reference numbers for the Mutual Recognition
Procedure
UK/H/4995/001/DC
Reference Member State
United Kingdom
Member States concerned Austria, Belgium, Bulgaria, Czech
Republic, Estonia, Finland, France,
Hungary, Ireland, Italy, Lithuania,
Luxembourg, Latvia, the Netherlands,
Norway, Poland, Romania, Sweden,
Slovenia and Slovakia

Marketing Authorisation Number(s)
PL 18866/0059

Name and address of the authorisation holder Rockspring Healthcare Limited, 38/40
Chamberlayne Road, London, United
Kingdom, NW10 3J E


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III SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 QUALITY ASPECTS
S. Active substance Ibuprofen
rINN: Ibuprofen
Chemical name: 2-(4-Isobutylphenyl)propionic acid
Structure:


Molecular formula: C
13
H
18
O
2

Molecular weight: 206.3
Appearance: A white to almost white, crystalline powder or colourless crystals
Solubility: Practically insoluble in water, freely soluble in acetone, methanol and in
methylene chloride. It dissolves in solutions of alkaline hydroxides and
carbonates

Ibuprofen is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of ibuprofen are covered by a European Directorate for the
Quality of Medicines and Healthcare (EDQM) certificate.

P. Medicinal Product
Other Ingredients
Other ingredients consist of the pharmaceutical excipients, namely anhydrous sodium carbonate, malic
acid, saccharin sodium, sodium hydrogen carbonate, sucrose, povidone, orange flavour and sodium
laurilsulfate.

All excipients comply with their respective European Pharmacopoeia monograph, with the exception of
orange flavour, which complies with a suitable in-house specification. Suitable batch analysis data have
been provided for all excipients, showing compliance with their respective specifications.

None of the excipients are sourced from animal or human origin. No genetically modified organisms
(GMO) have been used in the preparation of this product.

Pharmaceutical Development
The objective of the development programme was to formulate a globally acceptable, stable and
bioequivalent product that could be used in place of Brufen 600mg Tablets (Abbott Scandinavia AB) as
reference product, which were initially granted in Sweden in 1982.

A satisfactory account of the pharmaceutical development has been provided.

Comparative in vitro dissolution profiles have been provided for the proposed product and its respective
innovator product.

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Manufacturing Process
Satisfactory batch formulae have been provided for the manufacture of the finished product. The
manufacturing process has been validated using two production-scale batches and has shown
satisfactory results.

Finished Product Specification
The finished product specification proposed is acceptable. Test methods have been described and have
been adequately validated. Batch data have been provided that comply with the release specifications.
Certificates of analysis have been provided for all working standards used.

Container-Closure System
The finished product is packaged in paper/polyethylene/aluminium heat-sealed sachets, which are
packed into cartons in pack sizes of 12, 20 or 30 sachets per carton. The marketing authorisation holder
has stated that not all pack sizes are intended for marketing. However, they have committed to providing
the relevant licensing authority with the mock-ups for any pack size before marketing it in that country.

Satisfactory specifications and Certificates of Analysis have been provided for all packaging
components. All primary packaging complies with the current European regulations concerning
materials in contact with food.

Stability of the product
Stability studies were performed in accordance with current guidelines on batches of finished product
packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 2
years, with the storage conditions Store below 25C. Store in the original package in order to protect
from light and moisture.

Bioequivalence/bioavailability
Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the
bioequivalence study.

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels
The SmPC, PIL and labels are pharmaceutically acceptable.

A package leaflet has been submitted to the MHRA along with results of consultations with target
patient groups (user testing), in accordance with Article 59 of Council Directive 2001/83/EC, as
amended. The results indicate that the package 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.

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

Quality Overall Summary (Expert report)
The pharmaceutical expert report has been written by an appropriately qualified person and is a suitable
summary of the pharmaceutical dossier.

Conclusion
The grant of a Marketing Authorisation is recommended.

III.2 NON-CLINICAL ASPECTS
As the pharmacodynamic, pharmacokinetic and toxicological properties of ibuprofen are well-known,
no further non-clinical studies are required and none have been provided.

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The applicants non-clinical expert report has been written by an appropriately qualified person and is
satisfactory, providing an appropriate review of the products pharmacology and toxicology.

Suitable data have been submitted for the environmental risk assessment for this medicinal product. The
overall conclusion was that in view of its inherent bioavailability and low likelihood for
bioaccumulation, the therapeutic use of ibuprofen represents an insignificant risk to the environment.
Also, as this product is intended for substitution with products that are currently marketed, no increase in
environmental burden is expected.

There are no objections to the approval of this product from a non-clinical viewpoint.

III.3 CLINICAL ASPECTS
Pharmacokinetics
In support of this application, the Marketing Authorisation Holder has submitted the following
bioequivalence study:

An open-label, randomised, four-way, single-dose, crossover study to compare the
pharmacokinetics of the test product (A & B) Ibuprofen 600mg Effervescent Granules
(Rockspring Healthcare Limited), under fed and fasted conditions, versus the reference product
(D) Brufen 600mg Tablets (Abbott Scandinavia AB) in healthy adult subjects under fasted
conditions. The study also included a second test product (C) that is not relevant to this
application.

Volunteers were dosed with 600mg of the test or reference product after an overnight fast of at least 10
hours or after a high-fat breakfast. Blood samples were taken for the measurement of pharmacokinetic
parameters at pre- and up to 14 hours post-dose. The two treatment arms were separated by a 7-day
washout period.

The pharmacokinetic results (presented as geometric least-squares means, ratios and 90% confidence
intervals) for plasma levels of ibuprofen are presented below:


The 90% confidence intervals for C
max
and AUC for test versus reference products are within predefined
acceptance criteria under fasted conditions (A versus D). The data support the claim that the test product
is bioequivalent to the reference product.

The relative bioavailability under both fed and fasted conditions were also analysed and the results are
presented below:
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Analysis of the relative bioavailability showed that C
max
was reduced in the fed state versus fasted,
although the AUC was comparable between fed and fasted states.

A biowaiver was granted to link the 600mg test dose to the 200mg market presentation.

Efficacy
No new data on the efficacy have been submitted and none are required for this type of application.

Safety
With the exception of the data submitted during the bioequivalence study, no new safety data were
submitted and none were required. No new or unexpected safety issues were raised by the
bioequivalence data.

SmPC, PIL and Labels
The SmPC, PIL and labels are medically acceptable. The SmPC is consistent with that for the originator
product.

Pharmacovigilance System and Risk Management Plan
The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides
adequate evidence that the applicant has the services of a qualified person responsible for
pharmacovigilance, and has the necessary means for the notification of any adverse reaction suspected
of occurring either in the Community or in a third country.

Suitable justification has been provided for not submitting a risk management plan for this product. As
Ibuprofen is a well-known active substance, which has been in clinical use for many years, this is
accepted.

Clinical Expert Report
The clinical expert report has been written by an appropriately qualified physician and is a suitable
summary of the clinical aspects of the dossier.

Conclusion
The grant of a Marketing Authorisation is recommended.

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IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT
QUALITY
The important quality characteristics of Ibuprofen 200mg Effervescent Granules 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
No new non-clinical data were submitted and none are required for an application of this type.

CLINICAL
Bioequivalence has been demonstrated between the applicants product and the reference product
Brufen Tablets (Abbott Scandinavia AB) at a dose of 600mg. A biowaiver has been granted to link the
600mg test dose to the 200mg market presentation.

No new or unexpected safety concerns arose from this application.

The SmPC, PIL and labelling are satisfactory and consistent with those for the reference product.

BENEFIT-RISK ASSESSMENT
The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been
identified. The bioequivalence study supports the claim that the applicants product and the originator
product are interchangeable. Extensive clinical experience with ibuprofen is considered to have
demonstrated the therapeutic value of the compound. The benefit-risk is therefore considered to be
positive.

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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date
submitted
Application
type
Scope Outcome