brufen granules.pdf

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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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PAR Ibuprofen 200mg Effervescent Granules UK/H/4995/001/DC

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LAY SUMMARY

On 16 January 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 IntroductionII 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 3JE

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 January 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 beapproved. 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. Thisapplication 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 thisproduct.

The RMS and CMS considered that the application could be approved with the end of procedure (Day

210) on 16 January 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 acidderivatives. (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 3JE


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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: C13H18O2

Molecular weight: 206.3

Appearance: A white to almost white, crystalline powder or colourless crystalsSolubility: 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 havebeen 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 thebioequivalence 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 ASPECTSAs 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 inenvironmental 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 Cmax 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 Cmax 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-CLINICALNo 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

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