Public Assessment Report

Scientific discussion

Montelukast Actavis
10 mg film-coated tablets

Montelukast sodium

DK/H/1712/001/DC

This module reflects the scientific discussion for the approval of Montelukast Actavis. The
procedure was finalised on 22 March 2010. For information on changes after this date please
refer to the module Update.

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I. INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Member States have granted a
marketing authorisation for Montelukast Actavis 10 mg film-coated tablets, from Actavis Group
PTC ehf. The product was authorised in Denmark on 10 June 2010. The product is indicated for the
treatment of asthma as add-on therapy in those patients 15 years of age and older with mild to
moderate persistent asthma who are inadequately controlled on inhaled corticosteroids and in whom
as-needed short acting -agonists provide inadequate clinical control of asthma. In those asthmatic
patients 15 years of age and older in whom Montelukast Actavis is indicated in asthma, Montelukast
Actavis can also provide symptomatic relief of seasonal allergic rhinitis.
Montelukast Actavis is also indicated in the prophylaxis of asthma in patients 15 years of age and
older in which the predominant component is exercise-induced bronchoconstriction.

Montelukast is used as an anti-ashmatics for systemic use. Montelukast is an orally active compound
which binds with high affinity and selectively to the CycLT1 receptor. The cycteinyl leukotrines
(LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released form various cells including mast
cells and eosinophils. These important pro-ashmatic mediator bind to cycteinly leukotriene receptors
(CysLT) found in the human airway and cause airway actions, including bronchoconstriction, mucous
secretions, vascular permeability and eosinophil recruitment. Bronchodilation was observed within 2
hours of oral administration.

This decentralised procedure concerns a generic application claiming essential similarity with the
reference product Singulair 10 mg film-coated tablets which has been authorised in the RMS since
January 20, 1998.

A bioequivalence study has been preformed with Singulair 10 mg film-coated tablets, Merck Sharp &
Dohme, from the German market, as the reference product.

The marketing authorisation is granted based on article 10.1 of Directive 2001/83/EC.

II. QUALITY ASPECTS

II.1 Introduction

Each film-coated tablet contains montelukast sodium equivalent to 10 mg of montelukast.

The tablet is a beige, square, biconvex film-coated tablet with M engraved on one side.

The product is packed in OPA-Al-PVC/Al blister packs in various pack sizes.

The excipients in the tablet core are: Cellulose, microcrystalline; hydroxypropylcellulose;

croscarmellose sodium; lactose monohydrate and magnesium stearate.

The film-coating consists of: Lactose monohydrate; hypromellose 15cP; titanium dioxide (E171);
macrogol 4000; iron oxide yellow (E172) and iron oxide red (E172).

Compliance with Good Manufacturing Practice

The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place
for this product type at all sites responsible for the manufacturing of the active substance as well as for
the manufacturing and assembly of this product prior to granting its national authorisation.

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II.2 Drug Substance

The product contains montelukast sodium as active substance which is not monographed in Ph.Eur.

INN: Montelukast sodium

Chemical name(s): [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-
methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium
salt.
Molecular formula: C35H35ClNNaO3S
Molecular mass: 608.18
Structural formula:

Montelukast sodium is a white to off white to light yellow amorphous powder. It is freely soluble in
methanol, ethanol and water and practically insoluble in acetonitrile.
Montelukast sodium has one asymmetric centre and is the R-isomer.
A crystalline and an amorphous form are known. Some solvates and mixtures thereof are also known.
Montelukast sodium is hygroscopic according to the definition in Ph.Eur.

The applicant sources the substance from two suppliers. The documentation from both suppliers is
presented in European Drug Master Files in CTD format.

Starting material synthesis is adequately described.

Specifications are satisfactory. Validation data are provided for relevant methods and are satisfactory.

The applicant specification for montelukast sodium reflects parameters and limits applied by both
ASMs. All necessary analysis methods and validations are provided.

Appropriate retest periods have been set based on the provided stability data.

II.3 Medicinal Product

The product is a film-coated tablet and its composition is adequately described. The development of
the product has been satisfactorily performed and explained. No incompatibilities between the active
substance and the excipients are observed. Excipients are those commonly used for manufacture of a
film coated tablet. The packaging material is standard and shown suitable by the presented stability
studies.

Product manufacture is by standard processing and employs a wet granulation process followed by
tabletting and film coating. Manufacture is suitably described. Validation data are provided for three
pilot scale batches. The manufacturing instructions describe sub-lot processing for granulation with
subsequent blending to a large homogeneous batch blend. This aspect of manufacture will be fully
validated on commercial batches and the number of sublots limited in line with the validation data.
The data provided at a pilot scale otherwise support a reproducible product manufacture when sub-lot
granulation is not employed.

The finished product specification is standard for the pharmaceutical form and includes relevant
physicochemical, ID, assay and purity tests. Separate release and shelf-life specifications are provided

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where the latter employ slightly wider related substances limits. Stability data provided to date support
widening of the sulphoxide and total impurities limits to the extent suggested.

Batch analysis data are provided for three pilot scale batches showing compliance with the release
requirements and confirming consistency of product manufacture.

Stability data are provided for 2 batches of each strength stored in the proposed market packaging. A
shelf-life of 3 years when stored in the original package in order to protect from light and moisture is
accepted.

III. NON-CLINICAL ASPECTS

This product is a generic formulation of Singulair 10 mg film-coated tablets, which is available on the
European market. No new preclinical data have been submitted, and therefore the application has not
undergone preclinical assessment. This is acceptable for this type of application

Environmental risk assessment

The product is intended as a substitute for other identical products on the market. The approval of this
product will not result in an increase in the total quantity of montelukast sodium released into the
environment. It does not contain any component, which results in an additional hazard to the
environment during storage, distribution, use and disposal.

IV. CLINICAL ASPECTS

IV.1 Introduction

Montelukast sodium is a well-known active substance with established efficacy and tolerability.

For this generic application, the MAH has submitted three single dose bioequivalence studies, though
two of these relate to alternative dosage forms and are therefore not directly relevant to the application
and hence will not be reviewed here. The single dose study on the 10 mg film-coated tablets under
fasting conditions compares the pharmacokinetic profile of the test product Montelukast Actavis 10
mg film-coated tablets with the pharmacokinetic profile of the reference product Singulair 10 mg film-
coated tablets, Merck Sharp & Dohme, from the German market.

The study was a single centre, open label, randomised, single dose, two-way crossover study
conducted under fasting conditions with a wash out period of 7 days between administrations. 10 mg
was administered in each period with 240 ml water under yellow monochromatic light, after an
overnight fast of at least 10 hours. Subjects were confined to the clinical research centre from at least
13 hours prior to drug administration until after the 24 hour post-dose blood draw in each period.
Water was permitted ad lib until 1 hour before dosing and again 2 hours after dosing, otherwise ad
libitum. Standardised meals were provided at 4, 8 and 12 hours post dose in each period.
Blood sampling was performed predosing (within 1 hour) and at 0.5, 1.0, 1.333, 1.667, 2.0, 2.25, 2.5,
2.75, 3.0, 3.5, 3.75, 4.0, 5.0, 6.0, 7.0, 8.0, 12.0, 16.0 and 24.0 hours post-dose in each period under
yellow monochromatic light.
36 healthy volunteers were randomised into the study and 33 completed.

Primary pharmacokinetic variables were AUC0-t, AUC0- and Cmax. Secondary parameters were AUC0-
t/AUC0-, tmax,
Kel, and t. Safety was also analysed.

90% CIs for AUC0-t and Cmax are to be within 80-125% in order to conclude bioequivalence.

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

Treatment AUC0-t AUC0- Cmax tmax T1/2

ng.h/ml ng.h/ml ng/ml h h
Test 3081.133 3183.654 502.622 3.50 4.82
(S.D.) (893.562) (939.577) (140.727) (2.25-6.00) (0.87)
Reference 3072.972 3178.813 474.541 2.67 4.55
(S.D.) (938.166) (982.893) (160.197) (1.67-8.00) (1.10)
*Ratio (90% CI) 99 99 108 -0.500 -
92 -108 92 -107 96 -121 -1.500 to
0.750
Intra-subject CV (%) 19.81% 18.96% 28.37% - -

AUC0- area under the plasma concentration-time curve from time zero to infinity
AUC0-t area under the plasma concentration-time curve from time zero to t hours
Cmax maximum plasma concentration
Tmax time for maximum concentration
T1/2 half-life
*log-transformed values

The 90% confidence intervals for AUC0-t, AUC0- and Cmax are within the acceptance range of 80-
125%.

Based on the submitted bioequivalence studies, Montelukast Actavis 10 mg film-coated tablets are
considered bioequivalent with Singulair 10 mg film-coated tablets.

Tolerability of the test products is acceptable and not significantly different from reference products.

The RMS has been assured that the bioequivalence study has been conducted in accordance with
acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good
Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC).

IV.2 Risk management plan & Pharmacovigilance system

Montelukast was first approved in 1997, and there is now more than 10 years post-authorisation
experience with the active substance. The safety profile of montelukast can be considered to be well
established and no product specific pharmacovigilance issues were identified pre- or postauthorisation
which are not adequately covered by the current SPC. Additional risk minimisation activities have not
been identified for the reference medicinal product. The MAH has a pharmacovigilance system at their
disposal, which is based on the current European legislation.

The Pharmacovigilance system described 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 identification and notification of any potential risks occurring either in the
Community or in a third country.

V. PRODUCT INFORMATION
SmPC and Package leaflet

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The content of the SmPC and package leaflet approved during the decentralised procedure is in
accordance with that accepted for the reference product Singulair film-coated tablets marketed by
Merck Sharp & Dohme.

Readability test
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 package leaflet was English. The test consisted of a pilot test with 3 participants,
followed by one round with 10 participants only, since the package leaflet for the Montelukast
chewable tablets had already been user tested and the applicant had submitted a table of comparison of
the package leaflet for the chewable tablets and the 10 mg film-coated tablets. Based on the
comparison it was deemed necessary to test 10 subjects and present the results of the test (the results
of the user test of the package leaflet for the 10 mg film-coated tablets were presented as an addendum
to that of the chewable tablets).
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
Montelukast Actavis 10 mg film-coated tablets have a proven chemical-pharmaceutical quality and
are generic forms of Singulair 10 mg film-coated tablets. Singulair is a well-known medicinal product
with an established favourable efficacy and safety profile.

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

The MAH has provided written confirmation that systems and services are in place to ensure
compliance with their pharmacovigilance obligations.

The SmPC, package leaflet and labelling are in the agreed templates and are in agreement with other
montelukast containing products.

Agreement between Member States was reached during a written procedure. There was no discussion
in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that
essential similarity has been demonstrated for Montelukast Actavis with the reference product, and
have therefore granted a marketing authorisation. The decentralised procedure was finalised on 22
March 2010. Montelukast Actavis is authorised in Denmark on 10 June 2010.

A European harmonised birth date has been allocated (1997-06-25) and subsequently the first data
lock point for montelukast is July 2012, after which the PSUR submission cycle is 3 years.

The date for the first renewal will be: 22 March 2015.

The following post-approval commitments have been made during the procedure:

a) The EDMF for montelukast sodium will be harmonised following completion of this DC
procedure.

b) A commitment is made that all commercial batches will be fully validated and sublots limited
in line with validation data for commercial batches.

c) A commitment is made to perform assay and related substances HPLC testing at the 24
months and 36 months time points with an extended run time of up to 40 minutes.

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d) Stability data supporting the proposed holding times of one month for powder blend, one
month for tablet cores and 3 months for bulk coated tablets will be generated on the first
production scale batches and will be submitted when available.

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