Public Assessment Report

Scientific discussion

Etoricoxib Alter 30 mg, 60 mg, 90 mg and 120 mg

Film-Coated Tablets

Etoricoxib

Registration number in Spain:xxx

ES/H/0411/001-004/DC

Applicant: Laboratorios Alter, S.A.

This module reflects the scientific discussion for the approval of Etoricoxib Alter 30 mg, 60
mg, 90 mg and 120 mg Film-Coated Tablets. The procedure was finalised on January 2017.
For information on changes after this date please refer to the module ‘Update’.
INTRODUCTION

This decentralised procedure concerns a generic application claiming essential similarity with
the innovator product Arcoxia® film-coated tablets (Merck Sharp & Dohme, Ltd.). Arcoxia®
film-coated tablets have been registered in Europe since 2002.

The legal basis of the application is Article 10(1) of Directive 2001/83/EC.

The Concerned Member State involved in this procedure is IT.

The efficacy and security of etoricoxib has been demonstrated in several studies conducted with
the reference product as well as with its use experience after placed in the market. Etoricoxib
Alter 30 mg, 60 mg, 90 mg and 120 mg Film-Coated Tablets are submitted under an abridged
application and no studies regarding pharmacology, pharmacokinetic, security and efficacy has
been carried out besides the bioequivalence studies against the reference product.

Etoricoxib is indicated for symptomatic pain relief of osteoarthritis, rheumatoid arthritis,

ankylosing spondylitis, acute gouty arthritis and for the short-term treatment of moderate pain
associated with dental surgery.

A comprehensive description of the product information is given in the SmPC.

RECOMMENDATION

Based on the review of the data on quality, safety and efficacy, the Member States have granted
a marketing authorisation for Etoricoxib Alter 30 mg, 60 mg, 90 mg and 120 mg Film-
Coated Tablets for Laboratorios Alter S.A.

I. SCIENTIFIC OVERVIEW AND DISCUSSION

II-1 Quality aspects

DRUG SUBSTANCE

Etoricoxib is an active substance that is not described in Ph.Eur. There is one supplier of active
substance, an Active Substance Master File (ASMF) has been submitted to support the quality
of the active ingredient. Re-test period is included in the ASMF.

DRUG PRODUCT
Description of the product
30 mg: blue-green, round-shaped, biconvex film-coated tablets.
60 mg: dark green, round-shaped, biconvex film coated tablets.
90 mg: white, round-shaped, biconvex film-coated tablets.
120 mg: pale-green, round-shaped, biconvex film-coated tablets.

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The qualitative composition of the film-coated tablets is as follows:
Core:
Etoricoxib
Microcrystalline cellulose
Calcium hydrogen phosphate anhydrous
Croscarmellose sodium
Magnesium stearate.

Tablet coating:
Hypromellose
Titanium dioxide (E171)
Glycerol triacetate.
The 30, 60 and 120 mg tablets also contain yellow ferric oxide (E172) and indigo carmine lake
(E132).

Etoricoxib film-coated tablets are packed in polyamide / aluminium / PVC-aluminum blisters.

Pharmaceutical development
The pharmaceutical development has been properly described. The function of the excipientes
has been discussed. The manufacturing process is described in detail.
The validation studies show that the manufacturing process for the product is suitable for
routine production of the medicinal product.
Excipients

The information provided is adequate. These excipients, an exception colourant excipients, are
described in European Pharmacopoeia and they are analysed according to the corresponding
monographs. The composition of Yellow iron oxide and Indigo carmin is properly described.
Product specification
Specifications proposed are adequate. The product specifications cover appropriate parameters
for this dosage form. The limits proposed for the different parameters have been adequately
justified.
All analytical methods have been correctly validated following the ICH Q2 (R1) Guideline.
Container closure system

Information about container closure system is correct. Etoricoxib film-coated tablets are packed
in polyamide / aluminium / PVC-aluminum blisters.

Stability

Stability studies have been performed following the ICH guidelines. The stability data support
the proposed shelf-life (36 months with no storage conditions).

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II-2 Non-clinical aspects

A non-clinical overview on the pharmacology, pharmacokinetics and toxicology of the active

substance has been provided, which is based on up-to-date and adequate scientific literature.
The submitted application concerns film coated tablets with the active substances in the same
form as the reference product.
The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology
is adequate and the Member States agreed that no further non-clinical studies are required.

Environmental Risk Assessment (ERA)

No ERA was submitted. The medicinal product has the same quantitative and qualitative
composition in active substances and a similar pharmaceutical form to the reference product.
The introduction on the market of this medicinal product will not mean an increased exposure to
the environment, since the generic medicinal product is intended to substitute the reference
medicinal product as well as other generic products in the market.
In accordance with the Guideline on the Environmental Risk Assessment for medicinal products
for human use (CPMP/SWP/4447/00), the absence of this Environmental Risk Assessment is
therefore justified.

II.3 Clinical aspects

Introduction

Etoricoxib is a well-known drugs with established efficacy and safety.

No new clinical efficacy or safety studies were conducted, which is acceptable for this abridged
application. A clinical overview has been provided, which is based on scientific literature. The
Member States agreed that no further clinical studies are required.

For this generic application, the MAH has submitted a bioequivalence study, which is discussed
below.

Biowaiver

The bioequivalence between test and reference products has been demonstrated for the 120 mg
strength (please refer to the section of results). These data can be extrapolated to the other
strengths since all the requirements described in section 4.1.6 of the Bioequivalence Guideline
are fulfilled.

Bioequivalence

The Applicant has submitted the bioequivalence study UECHUP-ETO/14-5 (EUDRA-CT:

2014-002450-39): “a phase I clinical trial, single oral dose, open, randomised, crossover,
replicated, 4-sequences, 4-periods to determine the bioequivalence of Etoricoxib 120 mg film-
coated tablet (Laboratorios Alter, S.A.) and Arcoxia® 120 mg film-coated tablet (Merck Sharp
& Dohme Ltd.), after oral administration to healthy adult male volunteers under fasting
conditions”.
The clinical part of the study was performed from January 23rd, 2015 to April 06th, 2015 at
Clinical Trials Unit, Hospital Universitario de la Princesa. C/ Diego de León, nº 62. Madrid,

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Spain
The analytical portion was conducted at Anapharm Europe S.L.U., C/ Encuny 22 - 08038
Barcelona (Spain) from April 14th, 2015 to April 22th, 2015.
The trial has been conducted in compliance with GCP requirements. Monitoring reports have
been submitted. QA statement of audits assuring compliance to GCP were issued by Head-QA.
The clinical, the analytical, the pharmacokinetic and the statistical sites were inspected by
Regulatory Authorities of the European Union without critical findings.

Design
A single oral dose, open, randomised, crossover, replicated, 4-sequences, 4-periods
bioequivalence study in healthy human adult subjects, under fasting conditions with a washout
period of 14 days.
The application concerns an oral immediate release formulation (film-coated tablets) with a
linear PK over the therapeutic dose for both drugs. In addition, as described in the SmPC of the
reference, etoricoxib tablets can be administered with or without food. Therefore, a single dose
bioequivalence study under fasting conditions with the 120 mg strength is considered adequate
for the application.
The wash-out period and the sampling schedule are considered acceptable for an adequate
characterisation of the systemic exposure of a drug with such a half-life and tmax.

Test Product: Etoricoxib 120 mg film-coated tablets manufactured by Laboratorios Alter, S.A.,
Spain. Batch number: ETX120‐13. Batch size: 100,000 film-coated tablets. Expiry date (re-test
date): September 2017. Assay (content): 102.0 % of label claim.
Reference Product: Arcoxia® 120 mg tablets, manufactured by Merck Sharp & Dohme, Ltd.
(from the Spanish market). Batch number: 1012247. Expiry date: March 2016. Assay (content):
101.5% of label claim.
The reference product is adequate with regards to expiry date, content and it was obtained from
Spanish market.
All batches were tested before expiry date and a similar content of active substance is shown.
Therefore, content correction is not necessary.
Twenty-four (24) healthy volunteers (12 men and 12 women) were included to have an enough
number in case there are 2-4 subjects withdrawing the trial, and 23 of them completed the study.
Subjects were randomised to one of the four treatment sequences, TRTR, TRRT, RTRT or
RTTR, where T = Etoricoxib Alter and R = Arcoxia®; the treatments were allocated in a
balanced manner on every inclusion day (blocks of 4 subjects).
Subject number 2 withdrew from the study for personal reason in the second period just after
receiving the dose but no samples were taken in this period.
The study population is considered acceptable with regards to demographic characteristics. The
inclusion and exclusion criteria are considered to be acceptable.

Analytical methods
The analytical method has been adequately validated before the conduct of the study and during
the analysis of the subject samples. Therefore, the analytical method is considered acceptable
for analysis of the plasma samples..

Pharmacokinetic data analysis

Pharmacokinetic parameters were calculated using a non-compartmental method with
acceptable software. AUC was calculated by the trapezoidal rule. The methods used in this
study for the pharmacokinetic calculations are considered acceptable

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Statistical analysis
Following EMA criteria, the two formulations were classified as bioequivalent if the standard
90% confidence intervals of the pharmacokinetic parameters (AUC0-72 and Cmax) with log
transformation are within the 80.00-125.00 range.
According to the guidelines published by the EU authorities, if the within-subject variability for
Cmax of the reference product is ≥30% based on the log-transformed parameters from both
groups, the following criteria was used to evaluate the bioequivalence between the test and
reference products for etoricoxib:
- The 90% confidence interval of the relative mean AUC0-72 of the test to reference products
should be between 80-125%.
- The 90% confidence interval of the relative mean Cmax of the test to reference products should
be widened to a maximum of 69.84-143.19%.
The within-subject variability of etoricoxib for the reference product was calculated using the
data from an ANOVA of the reference and test products separately. The error mean square from
ANOVA was used to estimate the intra-subject variability according to the formula:

The methods used in this study for the statistical evaluation are considered acceptable. ANOVA
was performed on log-transformed pharmacokinetic parameters Cmax and AUC0-t were
considered as the primary pharmacokinetic parameters. The analysis of variance model included
the following factors: sequence, subjects nested within sequence, period and treatment.

Results
The 90% confidence intervals mean treatment T/R ratios are shown in the following table:

PK Parameter 90% Confidence Intervals

Point estimate% Lowe limit % Upper Limit % Intra-subject
CV%1
Cmax 98.22 92.39 104.41 15.85
AUC0-72 98.63 95.31 102.06 10.84
1
Estimated from the Residual Mean Squares. For replicate design studies report the within-subject CV% using only
the reference product data.

The 90% confidence intervals calculated for AUC0-t and Cmax are within the bioequivalence
acceptance range of 0.80 – 1.25 and therefore bioequivalence has been proven. No clinically
significant differences were observed between the median tmax of test and reference products.

Risk Management Plan

A risk management plan in accordance with the requirements of Directive 2001/83/EC as

amended has been submitted.

No additional risk minimization activities were required beyond those included in the product
information.

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Discussion on the clinical aspects

Based on the statistical analysis submitted by the Applicant the test product is equivalent to the
reference product.

Efficacy and safety of the active substances etoricoxib are well documented for the reference
medicinal product. The design of the submitted bioequivalence study is adequate and the results
allow us to conclude bioequivalence with the reference.

III OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION

Bioequivalence has been shown to be in compliance with the requirements of European Union
guidance documents.

The SmPC, PIL and labelling are considered satisfactory and consistent with the information for
the reference medicinal product. The user testing of the Package Information Leaflet has been
tested in accordance with Article 59(3) of Directive 2001/83/EC, as amended by Directive
2004/27/EC.

The benefit/risk balance was considered to be positive.

Agreement between Member States was reached during the procedure. The decentralised
procedure was finalised with a positive outcome in January 2017.

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