Download Decentralised Procedure Public Assessment Report (Ibuprofen) DE

Bundesinstitut für Arzneimittel
und Medizinprodukte
Decentralised Procedure
Public Assessment Report
Nurofen® Junior Fieber-und Schmerzsaft Orange
40 mg/ml Suspension zum Einnehmen
Nurofen® Junior Fieber-und Schmerzsaft Erdbeer
40 mg/ml Suspension zum Einnehmen
Nuroflex Junior Fieber- und Schmerzsaft Orange
40 mg/ml Suspension zum Einnehmen
Nuroflex Junior Fieber- und Schmerzsaft Erdbeer
40 mg/ml Suspension zum Einnehmen
(Ibuprofen)
DE/H/2204+2206/001-002/DC
Applicant: Reckitt Benckiser Germany
Reference Member State
DE
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health.
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TABLE OF CONTENTS
I
INTRODUCTION
II
4
EXECUTIVE SUMMARY
4
II.1
II.2
II.3
II.4
PROBLEM STATEMENT
ABOUT THE PRODUCT
GENERAL COMMENTS ON THE SUBMITTED DOSSIER
GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED ETHICAL
PRINCIPLES.
5
III
5
III.1
III.2
III.3
IV
SCIENTIFIC OVERVIEW AND DISCUSSION
QUALITY ASPECTS
NONCLINICAL ASPECTS
CLINICAL ASPECTS
5
5
6
BENEFIT RISK ASSESSMENT
DE/H/2204+2206/001-002/DC
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4
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ADMINISTRATIVE INFORMATION
Proposed name of the medicinal
product in the RMS
Nurofen® Junior Fieber-und Schmerzsaft Orange 40 mg/ml
Suspension zum Einnehmen (DE/H/2204/001/DC)
Nurofen® Junior Fieber-und Schmerzsaft Erdbeer
40 mg/ml Suspension zum Einnehmen
(DE/H/2204/002/DC)
Nuroflex Junior Fieber- und Schmerzsaft Orange 40 mg/ml
Suspension zum Einnehmen (DE/H2206/001/DC)
Nuroflex Junior Fieber- und Schmerzsaft Erdbeer
40 mg/ml Suspension zum Einnehmen
(DE/H/2206/002/DC)
INN (or common name) of the active
substance(s):
Ibuprofen
Pharmaco-therapeutic group
(ATC Code):
M01AE01
Pharmaceutical form(s) and
strength(s):
Oral suspension 4 %
Reference Number for the
Decentralised Procedure
DE/H/2204/001-002/DC
Reference Member State:
Germany
Member States concerned:
AT, DK, FI, IS, NO, SE (DE/H/2204/001-002/DC)
DE/H/2206/001-002/DC
BG, EE, ES, FR, LT, LV (DE/H/2206/001-002/DC)
Applicant (name and address)
Reckitt Benckiser Deutschland, GmbH, Theodor-HeussAnlage 12, 68165 Mannheim, Germany
Names and addresses of
manufacturers responsible for batch
release in the EEA
Reckitt Benckiser Healthcare UK Ltd.
DE/H/2204+2206/001-002/DC
Dansom Lane, Hull, UK
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I
INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the application for Nurofen® Junior
Fieber- und Schmerzsaft Orange/ Erdbeer 40 mg/ml Suspension zum Einnehmen (DE/H/2204/001002/DC) and for Nuroflex Junior Fieber- und Schmerzsaft Orange/Erdbeer 40 mg/ml Suspension zum
Einnehmen (DE/H2206/001-002/DC), in the short-term symptomatic treatment of mild to moderate
pain and fever is approved.
II
EXECUTIVE SUMMARY
II.1 Problem statement
Reckitt Benckiser Germany is submitting two duplicate applications for a new non-prescription
presentation of Nurofen® for Children Suspension in two different flavours (orange and strawberry).
The products have been applied for registration as an over-the-counter (OTC) medicine for the
symptomatic treatment of mild to moderate pain and fever in children in the age range of either 3
months to 12 years (BG, EE, ES, FR, LT, LV) or 6 months to 12 years (AT, DK, FI, IS, NO, SE)
depending on the market. In this document the name ´Ibuprofen 4% suspension` is used.
II.2 About the product
The product, Ibuprofen 4% Suspension, will contain 200 mg of ibuprofen per 5 ml of suspension (4%
w/v). The new presentation is simply a double strength version, in terms of the active ingredient of the
already licensed product Nurofen® for Children Suspension 2 %.
The main advantage that this product will have is that it has been formulated for children (6 months to
12 years). A reduced volume of product will need to be administrated compared to Nurofen® for
Children Suspension (2% w/v). This offers greater convenience to both the parent/carer and the child.
In addition, by reducing the dose to one syringe of medicine it becomes easier for the child to take
which improves dosing compliance and therefore generates a superior quality of relief.
In some countries, the formulation will also be used for infants (3 months to 12 years) based on the
double concentration benefit. As with older children, the reduced dose volume makes dosing easier, in
terms of it being difficult to administer medicine to a sick child. This again offers greater convenience
to both the parent/carer and the child, and, by reducing the dose to one syringe of medicine it becomes
easier for the child to take which improves dosing compliance and therefore results in a superior
quality of relief.
Ibuprofen was first approved in the UK in 1969 and first became available as an OTC medicine in the
UK in 1983. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that is used OTC for the
treatment of mild to moderate painful conditions and fever.
II.3 General comments on the submitted dossier
The application is submitted under the legal basis Article 8 (3) of Directive 2001/83, for a known
active substance. The applicant has submitted bibliographic data to document clinical pharmacology,
efficacy and safety. Since clinical pharmacology, efficacy and safety of ibuprofen are well-known this
is considered acceptable.
The applicant already holds a number of other marketing authorisations for non-prescription products
containing ibuprofen. In particular the applicant holds marketing authorisations for Ibuprofen 2%
Suspension under a number of different trade names across the EU. The subject of the present
application, Ibuprofen 4 % Suspension, is considered a line extension of the previously authorised
Ibuprofen 2 % Suspension.
The submitted documentation is adequate as far as the indications mild to moderate pain and fever are
concerned.
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II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical
principles.
No clinical efficacy study reports are provided.
Since Nurofen® for Children 4% oral Suspension is an ibuprofen formulation, justification for
bioavailability either by own or published data for this formulation has to be provided.
Module 5 contains one clinical report of a bioavailability study which has been carried out to compare
the pharmacokinetics of Ibuprofen 4% Suspension with Ibuprofen 2% suspension (Junifen®): Study
IBU-2001/015 by Ruiz Antoran B: Randomized crossover study on relative bioavailability of three
ibuprofen formulations after a 400 mg single dose to healthy volunteers. Farmalider S.A., 2001.
The study was conducted to Good Clinical Practice (GCP) standards in the Clinical Trials Division of
the Puerta de Hierro Clinic, Madrid. The protocol was approved by the Clinic Ethics Committee and
authorisation obtained from the Spanish Drug Agency.
III
SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 Quality aspects
Drug substance
The active substance ibuprofen is described in the current European Pharmacopoeia (Ph Eur).
The quality of ibuprofen, which is sourced from two different manufacturers is controlled in
compliance with the corresponding monograph of the European Pharmacopoeia. The suitability of the
monograph to test the drug substance has been verified by EDQM.
As far as the stability of ibuprofen is concerned, a re-test period of 3 years is listed in the Certificate of
Suitability for ibuprofen manufactured by manufacturer A.
For ibuprofen sourced from manufacturer B, stability studies have been performed with the drug
substance. No significant changes in any parameters were observed. The proposed re-test period of 5
years is justified.
Drug Product
Relevant quality characteristics of the drug substance and the drug products are specified. The
proposed limits are accepted.
The development of the product has been described, the choice of excipients is justified and their
functions explained.
The ingredients and the manufacturing process of the drug product are considered to be suitable to
produce pharmaceutical products of the appropriate quality. Descriptions of the analytical methods
used to analyse the drug substance and drug products are adequate, the validation results are plausible.
The batch analysis results show that the finished products meet the specifications proposed.
The stability data presently available are sufficient to justify the shelf-life of 24 months with the
storage condition “Do not store above 25°C” and an in-use stability of 6 months.
III.2 Nonclinical aspects
Pharmacology, Pharmacokinetics. Toxicology
Pharmacodynamic, pharmacokinetic and toxicological properties of ibuprofen are well known. As
ibuprofen is a widely used, well-known active substance, no further non-clinical studies are required
and the applicant provides none. Overview based on literature review is thus appropriate.
Environmental Risk Assessment
A final conclusion on the environmental risk could not be reached, because a Phase II environmental
fate and effect analysis was not provided by the applicant. However, the RMS appreciates that the
applicant commits to provide a Phase II environmental risk assessment until November the 15th 2010.
Therefore, this issue is considered resolved.
Conclusions
A marketing authorisation is granted.
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III.3 Clinical aspects
Pharmacokinetics and Pharmacodynamics
Pharmacodynamic and pharmacokinetic properties of ibuprofen are well-known. Justification for
extrapolation of pharmacokinetic parameters from adults to children is given. Individual literature
references are provided in Module 5.4.
Clinical efficacy
No clinical efficacy study reports are provided.
In support of this application the clinical overview reviews the evidence available about the clinical
efficacy of ibuprofen in various painful states and in fever control. The efficacy and safety sections
included in this report provide evidence that ibuprofen administration as an OTC medicine has been
well established for use in mild to moderate painful conditions and fever in children in the age range
from 3 months to 12 years. However, for the specification post immunization pyrexia insufficient
literature or other study data was provided by the applicant, which cannot be accepted within the legal
basis of an article 8 (3) application. In consequence, this indication has bee removed by the applicant.
Since Ibuprofen 4% suspension is an ibuprofen formulation, justification for bioavailability was
necessary and provided by means of the clincial report of Study IBU-2001/015 by Ruiz Antoran B:
Randomized crossover study on relative bioavailability of three ibuprofen formulations after a 400 mg
single dose to healthy volunteers. Farmalider S.A., 2001.
The results of the comparison of an ibuprofen 4% suspension, considered to be essentially similar to
the Ibuprofen 4% suspension to be marketed based on quality and in vitro dissolution data, and
Junifen® 2% (ibuprofen suspension 2%) demonstrate that:
The ibuprofen 4% suspension had a similar extent of absorption as the reference product
Junifen®) The values for AUC and the respective 90% C.I. fell within the limits of 80.0 - 125.0
%, as defined for bioequivalence by the CPMP Note for Guidance on the Investigation of
Bioavailability and Bioequivalence 2001 (CPMP/EWP/QWP/1401/ 98);
The ratio of the AUC0-∞ for ibuprofen 4% suspension to that of Junifen® was 108.5%, and the
90% C.I. for this ratio was 102.90-114.40; for AUC 0-t, the ratio was 108.01, and the 90% C.I
was 102.17-114.20 (log transformed data);
The mean peak plasma concentrations (Cmax) of the ibuprofen 4% suspension and of Junifen®
are 43.02 ug/ml and 36.45 ug/ml, respectively, with a mean ratio of 118.2% and a 90% C.I. of
105.55 to 132.37 (log transformed data).
The time parameters were closely similar for the two formulations being compared. The median
Tmax was the same for the ibuprofen 4% suspension and, Junifen® (1.38 hours); the 90%
confidence interval for the Tmax was within the range 56.5 – 114.5%; this was not unexpected
given the large interindividual variability in Tmax, both with the ibuprofen 4% suspension
(coefficient of variation 58%) and with Junifen® (Nurofen® for Children Suspension 2%)
(coefficient of variation 61%).
For Cmax, the 90% confidence intervals (106 – 132%) fell slightly outside the usually required range
of 80-125%, with mean Cmax levels being slightly higher (118%) for the ibuprofen 4% suspension
than for Junifen®. However, the applicant has provided a literature review, showing that this small
difference is not expected to be associated with any relevant difference in clinical efficacy or safety.
It is to be noted that the `Note for Guidance on the Investigation of Bioavailability and
Bioequivalence` states that in cases of higher individual variability and a wide therapeutic window, the
confidence limits may be extended (0.75-1.33) (CPMP/EWP/QWP/1401/98).
Clinical safety
No clinical safety study reports are provided. Literature references to support clinical safety of
Ibuprofen 4 % Suspension in the proposed paediatric indications are adequately reviewed in the
clinical overview.
Pharmacovigilance system
The applicant has provided documents that set out a detailed description of the system of
pharmacovigilance (Version 1 dated November 2009). A statement signed by the applicant and the
qualified person for pharmacovigilance, indicating that the applicant has the services of a qualified
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person responsible for pharmacovigilance and the necessary means for the notification of any adverse
reaction occurring either in the Community or in a third country has been provided.
The Pharmacovigilance system as described by the applicant fulfils the requirements as described in
Volume 9A of the Rules Governing Medicinal Products in the European Union 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.
Risk Management Plan
The Risk Management Plan provided by the Applicant is accepted.
IV
BENEFIT RISK ASSESSMENT
The application is submitted under the legal basis of Article 8 (3) of Directive 2001/83, for a known
active substance. It contains an adequate review of published nonclinical and clinical data for the
indications mild to moderate pain and fever.
The application is approved.
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