Public Assessment Report

Scientific discussion

Ibuprofen Zentiva
(ibuprofen)

SE/H/2058/01-01/DC

This module reflects the scientific discussion for the approval of Ibuprofen Zentiva. The
procedure was finalised on 2021-02-24. For information on changes after this date please refer to
the module ‘Update’.

Postadress/Postal address: P.O. Box 26, SE-751 03 Uppsala, SWEDEN

Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala
Telefon/Phone: +46 (0)18 17 46 00 Fax: +46 (0)18 54 85 66
Internet: www.lakemedelsverket.se E-mail: [email protected]

Swedish MPA template version: 2020-03-13 PAR Generics

I. INTRODUCTION
The application for Ibuprofen Zentiva, 400 mg, 600 mg, film-coated tablet is a generic application
made according to Article 10(1) of Directive 2001/83/EC. The application for Ibuprofen Zentiva, 800
mg, film-coated tablet is a hybrid application made according to Article 10(3) of Directive
2001/83/EC. The applicant, Zentiva k.s., applies through the Decentralised Procedure with Sweden
acting as reference member state (RMS) and the following as concerned member states (CMS).
SE/H/2058/01/DC CMS: AT, BG, CZ, DK, FI, SK, ES, RO
SE/H/2058/02/DC CMS: AT, BG, CZ, DK, FI, SK, ES
SE/H/2058/03/DC CMS: AT, BG, CZ, FI

The reference medicinal product chosen for the purposes of establishing the expiry of the data
protection period is:
SE/H/2058/01, SE/H/2058/03 :
Brufen, 400 mg, film-coated tablet authorised in SE since year 1975, with
BGP Products AB as marketing authorisation holder.
SE/H/2058/02: Brufen, 600 mg, film-coated tablet authorised in SE since year 1982, with
BGP Products AB as marketing authorisation holder.

The reference product used in the bioequivalence study is:

- Brufen, 400 mg, film-coated tablets from Sweden with BGP Products AB as marketing
authorisation holder.
- Brufen, 200 mg, film-coated tablets, from Portugal with BGP Products, Unipessoal Lda as
marketing authorisation holder.

European Reference Product (ERP)

A European Reference Product is used in
SE/H/2058/01/DC CMS BG:
Brufen, 400 mg, film-coated tablet authorised in SE since year 1975, with
BGP Products AB as marketing authorisation holder.
SE/H/2058/02/DC CMS BG, CZ and SK:
Brufen, 600 mg, film-coated tablet authorised in SE since year 1982, with
BGP Products AB as marketing authorisation holder.
SE/H/2058/03/DC CMS FI, BG and CZ:
Brufen, 400 mg, film-coated tablet authorised in SE since year 1975, with
BGP Products AB as marketing authorisation holder.
The justification to use this product is based on RMS’s own files.

For approved indications, see the Summary of Product Characteristics.

For recommendations to the marketing authorisation not falling under Article 21a/22 of Directive
2001/83/EC and conditions to the marketing authorisation pursuant to Article 21a or 22 of Directive
2001/83/EC to the marketing authorisation, please see section VI.

II. QUALITY ASPECTS

II.1 Drug Substance

The structure of the drug substance has been adequately proven and its physico-chemical properties
are sufficiently described.

The manufacture of the drug substance has been adequately described and satisfactory specifications
have been provided for starting materials, reagents and solvents.

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The drug substance specification includes relevant tests and the limits for impurities and degradation
products have been justified. The analytical methods applied are suitably described and validated.

Stability studies confirm the retest period.

II.2 Medicinal Product

The medicinal product is formulated using excipients listed in section 6.1 in the Summary of Product
Characteristics.

The manufacturing process has been sufficiently described and critical steps identified.

The tests and limits in the specification are considered appropriate to control the quality of the finished
product in relation to its intended purpose.

Stability studies have been performed and data presented support the shelf life and special precautions
for storage claimed in the Summary of Product Characteristics, sections 6.3 and 6.4.

III. NON-CLINICAL ASPECTS

III.1 Discussion on the non-clinical aspects

Since this product has been shown to be essentially similar and refer to a product approved based on a
full application with regard to preclinical data, no further such data have been submitted or are
considered necessary.

IV. CLINICAL ASPECTS

IV.1 Pharmacokinetics
To support the marketing authorisation application the applicant has conducted two bioequivalence
studies comparing Ibuprofen film-coated tablets with the reference product Brufen. The pivotal study
was performed with the 800 mg strength, and an additional study was performed with a test batch of
the 200 mg strength with the slowest observed dissolution in order to support the suggested dissolution
specification.

Pharmacokinetic properties of the active substance

Absorption: Ibuprofen has an oral bioavailability of 80-90 %. Following an oral dose of ibuprofen
maximal plasma concentrations occur at approximately 1-2 hours.

If administered with food, peak serum concentrations are lower and achieved more slowly than when
taken on an empty stomach. Food does not affect markedly total bioavailability. In order to achieve a
faster onset of action, the dose may be taken on an empty stomach. It is recommended that patients
with sensitive stomachs take ibuprofen with food.

Linearity: The pharmacokinetics of ibuprofen is linear within the dose range 200-800 mg.

Elimination: The terminal half-life is 2 hours.

Study IBUPRL09206/ZNV-P0-163
Methods
This was a single-dose, two-way crossover study conducted in 22 healthy volunteers, comparing

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Ibuprofen, 800 mg, film-coated tablets with Brufen, 2x400 mg, film-coated tablets under fasting
conditions. Blood samples for concentration analysis were collected pre-dose and up to 12 hours post-
dose. Plasma concentrations of ibuprofen were determined with an HPLC-MS/MS method. Analysis
of variance (ANOVA) was performed on the log-transformed data for AUC0-t and Cmax. The study was
conducted between 2019-03-15 and 2019-04-17.

Results
The results from the pharmacokinetic and statistical analysis are presented in Table 1 below.

Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax

median, range) for ibuprofen, n=20.
Treatment AUC0-t Cmax tmax
µg*h/ml µg/ml h
Test 238.851 ± 52.235 60.381 ± 10.468 1.63
(0.50-3.50)
Reference 235.235 ± 44.674 62.771 ± 14.540 1.63
(0.75-4.00)
*Ratio (90% CI) 101.48 97.76 -
(98.53 – 104.51) (89.77 – 104.30)
AUC0-t area under the plasma concentration-time curve from time zero to t hours
Cmax maximum plasma concentration
tmax time for maximum plasma concentration
*calculated based on ln-transformed data

For AUC0-t and Cmax the 90 % confidence interval for the ratio of the test and reference products fell
within the conventional acceptance range of 80.00-125.00 %. Comparable median and range for tmax
was shown for the test and reference product.

A biowaiver was sought for the additional strengths of 200, 400, 600 mg.

Study IBUPRL27419/2020-4819
Since a decrease in dissolution rate was observed for all strengths of the drug product during the
stability testing, an additional bioequivalence study was conducted to justify the proposed dissolution
limit for all strengths.

Methods
This was a single-dose, two-way crossover study conducted in 22 healthy volunteers, comparing
Ibuprofen, 200 mg, film-coated tablets (test batch with lowest observed dissolution rate) with Brufen,
200 mg, film-coated tablets under fasting conditions. Blood samples for concentration analysis were
collected pre-dose and up to 12 hours post-dose. Plasma concentrations of ibuprofen were determined
with an LC-MS/MS method. Analysis of variance (ANOVA) was performed on the log-transformed
data for AUC0-t and Cmax. The study was conducted between 2020-02-26 and 2020-03-18.

Results
The results from the pharmacokinetic and statistical analysis are presented in Table 2 below.

Table 2. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax

median, range) for ibuprofen, n=22.

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Treatment AUC0-t Cmax tmax
µg*h/ml µg/ml h
Test 77.4583 ± 21.1227 ± 1.38
15.7780 4.5263 (0.75-4.02)
Reference 79.5622 ± 21.9473 ± 1.38
16.6601 5.9118 (0.75-5.00)
*Ratio (90% CI) 97.60 97.83 -
(94.59-100.70) (90.17-106.14)
AUC0-t area under the plasma concentration-time curve from time zero to t hours
Cmax maximum plasma concentration
tmax time for maximum plasma concentration
*calculated based on ln-transformed data

For AUC0-t and Cmax the 90 % confidence interval for the ratio of the test and reference products fell
within the conventional acceptance range of 80.00-125.00 %.

Discussion and overall conclusion

The pivotal bioequivalence study and its statistical evaluation were in accordance with accepted
standards for bioequivalence testing, as stated in the Guideline on the investigation of bioequivalence
(CPMP/EWP/QWP/1401/98 Rev 1/Corr) and Ibuprofen oral use immediate release formulations 200-
800 mg product-specific bioequivalence guidance (EMA/CHMP/356876/2017). The bioanalytical
methods were adequately validated.

The study result from IBUPRL09206 can be extrapolated to the other strengths 200 mg, 400 mg and
600 mg, as all conditions for biowaiver for additional strengths, as described in the Guideline on the
investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr) are fulfilled and since the
pharmacokinetics of ibuprofen is linear between 200 mg and 800 mg. The study was performed with
the highest strength in accordance with guideline recommendations.

Based on the submitted bioequivalence study, Ibuprofen is considered bioequivalent with Brufen.

The additional study (IBUPRL27419/2020-4819), using a test batch with lowest observed dissolution
rate, was also performed in accordance with standards for bioequivalence testing and demonstrates
bioequivalence compared to Brufen 200 mg. Although it is not optimal from a PK perspective that the
study was performed with a lower strength, it is agreed that the study can be used to support the
dissolution limit for all strengths. Thus, the suggested dissolution specification limit has been
adequately justified.

IV.2 Discussion on the clinical aspects

Since this product has been shown to be essentially similar and refer to a product approved based on a
full application with regard to clinical efficacy/safety data, no further such data have been submitted or
are considered necessary. Ibuprofen has been studied extensively in adults and children in a variety of
painful and inflammatory conditions where its therapeutic effects are comparable to other NSAIDs. A
number of large clinical trials have focused on the clinical uses, safety and pharmacological properties
of ibuprofen given at prescription level doses (<2,400 mg/day using e.g. 600 mg and 800 mg tablets of
ibuprofen) compared with other NSAIDs (including coxibs). In many of these studies, ibuprofen was
used as a reference drug.

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IV.3 Risk Management Plan

The MAH has submitted an updated risk management plan (version 0.2, signed 04 August 2020), 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 Ibuprofen Zentiva, 400 mg, 600 mg, 800 mg, film-coated tablet.

Since this type of application (article 10 (1) generic; article 10 (3) hybrid) has no PSUR requirements,
the applicant has agreed with comments from CMS CZ to delete such statements in the RMP. The
applicant is committed to provide a final updated version of the RMP by EoP.

Safety specification

Summary of safety concerns

Important identified risks None

Important potential risks None
Missing information None

Pharmacovigilance Plan

Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed

by the applicant, which is endorsed.

Risk minimisation measures

Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by
the applicant, which is endorsed.

Summary of the RMP

The submitted Risk Management Plan, version 0.2 signed 04 August 2020 is considered acceptable. It
is in line with the RMP of the reference product.

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent
updates of the RMP.

An updated RMP should be submitted:

- At the request of the RMS;
- Whenever the risk management system is modified, especially as the result of new
information being received that may lead to a significant change to the benefit/risk profile or
as the result of an important (pharmacovigilance or risk minimisation) milestone being
reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the
same time, but via different procedures.

V. USER CONSULTATION
The package leaflet has been evaluated via a user consultation study in accordance with the
requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose
of user testing the PIL was English.

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The results show that the package leaflet meets the criteria for readability as set out in the Guideline
on the readability of the label and package leaflet of medicinal products for human use.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION
The quality of the products, Ibuprofen Zentiva are found adequate. There are no objections to approval
of Ibuprofen Zentiva from a non-clinical and clinical point of view. The submitted bioequivalence data
show that bioequivalence between the test and reference product has been adequately demonstrated.
The product information is acceptable. The application is therefore recommended for approval.

List of recommendations not falling under Article 21a/22 of Directive 2001/83/EC in case of a
positive benefit risk assessment

N/A

List of conditions pursuant to Article 21a or 22 of Directive 2001/83/EC

N/A

VII. APPROVAL
The decentralised procedure for Ibuprofen Zentiva, 400 mg, 600 mg, 800 mg, film-coated tablet was
positively finalised on 2021-02-24.

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Public Assessment Report – Update
Procedure number* Scope Product Date of Approval/ Summary/
Information end of non approval Justification
affected procedure for refuse
(Yes/No)

*Only procedure qualifier, chronological number and grouping qualifier (when applicable)

Postadress/Postal address: P.O. Box 26, SE-751 03 Uppsala, SWEDEN

Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala
Telefon/Phone: +46 (0)18 17 46 00 Fax: +46 (0)18 54 85 66
Internet: www.lakemedelsverket.se E-mail: [email protected]

Swedish MPA template version: 2020-03-13 PAR Generics