Decentralised Procedure Public Assessment report Naratriptan ...

Bundesinstitut für Arzneimittel
und Medizinprodukte
Decentralised Procedure
Public Assessment report
Naratriptan-Sandoz 2.5 mg Film-coated tablets
Naratriptan hydrochloride
DE/H/2107-2108/001/DC
Applicant: Sandoz Pharmaceuticals GmbH,
Germany
Reference Member State DE
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/7 Public AR

TABLE OF CONTENTS
I INTRODUCTION 4
II EXECUTIVE SUMMARY 4
II.1 PROBLEM STATEMENT 4
II.2 ABOUT THE PRODUCT 4
II.3 GENERAL COMMENTS ON THE SUBMITTED DOSSIER 4
II.4 GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED ETHICAL
PRINCIPLES. 4
III SCIENTIFIC OVERVIEW AND DISCUSSION 5
III.1 QUALITY ASPECTS 5
III.2 NONCLINICAL ASPECTS 5
III.3 CLINICAL ASPECTS 6
IV BENEFIT RISK ASSESSMENT 7
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Proposed name of the medicinal
product in the RMS
INN (or common name) of the active
substance(s):
Pharmaco-therapeutic group
(ATC Code):
Pharmaceutical form(s) and
strength(s):
Reference Number for the
Decentralised Procedure
ADMINISTRATIVE INFORMATION
Reference Member State: DE
Naratriptan-Sandoz 2.5 mg Filmtabletten
Naratriptan hydrochloride
N02CC02; selective serotonin (5-HT1) agonists
Film-coated tablet; 2.5 mg
DE/H/2107/001/DC
DE/H/2108/001/DC
Member States concerned: DE/H/2107/001/DC: BE, FR, NL, PL
DE/H/2108/001/DC: NL, PL
Applicant (name and address) Sandoz Pharmaceuticals GmbH
Raiffeisenstr. 11, 83607 Holzkirchen, Germany
Names and addresses of
manufacturers responsible for batch
release in the EEA
Lek Pharmaceuticals d.d.
Verovškova 57
1526 Ljubljana
Slovenia
Lek Pharmaceuticals d.d.
Trimlini 2D
9220 Lendava
Slovenia
S.C. Sandoz, S.R.L.
Str. Livezeni nr. 7A
RO-540472 Targu-Mures
Romania
Salutas Pharma GmbH
Otto-von-Guericke-Allee 1
39179 Barleben
Germany
Salutas Pharma GmbH
Dieselstrasse 5
70839 Gerlingen
Germany
Lek SA
ul. Podlipie 16
95-010 Stryków
Poland
Lek SA
ul. Domaniewska 50 C
02-672 Warszawa
Poland
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I INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the application for Naratriptan Sandoz
2.5 mg film-coated tablets, in the acute treatment of the headache phase of migraine attacks with or
without aura, is approved.
II EXECUTIVE SUMMARY
II.1 Problem statement
This decentralised application concerns a generic version of naratriptan hydrochloride, under the trade
name “Naratriptan-Sandoz 2.5 mg film-coated tablets”. In this Assessment Report, the name
naratriptan is used.
The originator product is Naramig 2.5 mg film-coated tablets by GlaxoSmithKline B.V., registered
since 01 August 1997 in The Netherlands.
With Germany acting as the Reference Member State in this Decentralised Procedure, Sandoz
Pharmaceuticals GmbH is applying for the Marketing Authorisation for Naratriptan-Sandoz 2.5 mg
film-coated tablets in Belgium, France, The Netherlands and Poland.
II.2 About the product
Naratriptan is a selective serotonin (5HT1) agonist used in acute treatment of the headache phase of
migraine attacks with or without aura. It should not be taken prophylactically. The recommended dose
of naratriptan to treat a migraine attack is 2.5 mg. If symptoms of migraine should recur, following an
initial response, a second dose may be taken provided that there is a minimum interval of four hours
between the two doses. The total dose should not exceed two 2.5 mg tablets in any 24-hour period.
II.3 General comments on the submitted dossier
The present DC procedure concerns a generic single strength of an immediate release film-coated
tablet. Therefore, a bioavailability study was conducted to show bioequivalence of the 2.5 mg
NARATRIPTAN TABLETS test product versus the approved reference product Naramig® 2.5 mg
naratriptan film-coated tablets manufactured by GlaxoSmithKline GmbH & Co.KG, Germany.
This was a single centre, bioequivalence, open-label, single dose, randomized, 2-way crossover study,
performed under fasting conditions (Project No. 70362, Anapharm Inc.).
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical
principles.
The RMS has been assured that acceptable standards of GMP are in place for these product types at all
sites responsible for the manufacture and assembly of this product.
For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer
authorisations issued by inspection services of the competent authorities as certification that
acceptable standards of GMP are in place at those sites.
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III SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 Quality aspects
Drug substance
The active substance naratriptan hydrochloride is a known drug substance which is not
described in the European Pharmacopoeia. An ASMF procedure has been. Letter of Access has
been provided for the ASMF procedures. All questions regarding Applicant’s part and restricted
part have been sufficiently answered. The claimed re-test period of 12 months is acceptable.
Drug Product
The goal of the formulation of the Naratriptan Hydrochloride Tablets, 2.5 mg was the
development of a stable, product essentially similar to the brand leader. The brand leader product is
marketed in a 2.5 mg Tablets under brand name Naramig®.
The marketing authorisation holder of the brand leader product is GlaxoSmithKline.
After characterization of brand product, the desired product specifications were set. After evaluating
qualitative composition of innovator, API properties and development trials, the following excipients
were selected for Naratriptan Hydrochloride Tablets:
Cellulose, Microcrystalline Ph Eur and Lactose Anhydrous Ph Eur are used as diluent.
Croscarmellose Sodium Ph Eur is used as disintegrant. Magnesium stearate Ph Eur is used as
lubricant.
All relevant quality characteristics of the active substance and the finished product (release and shelflife)
are specified.
The proposed limits are accepted. The description of the analytical methods used to analyse the drug
product are adequate, the validation results are plausible. The questions raised during assessment have
been sufficiently answered. The stability data obtained cover the shelf life of 24 months for the drug
product.
III.2 Nonclinical aspects
Pharmacology
Naratriptan ((N-methyl-3-1-methyl-4-piperidinyl)-1H-indole-5-ethanesulphonamide hydrochloride) is
a highly selective agonist for serotonergic 5-HT1B/1D/1F receptors with lower affinity for 5-HT1A/1E
receptors and minor or no affinity for other serotonine receptors. The anti-migraine activity of
naratriptan involves the dose-dependent counteraction of painful vasodilatation predominantly in the
cranial vasculature, whereas peripheral blood vessels are barely affected. This reflects the different
distribution of serotonergic 5-HT receptors. In addition, naratriptan inhibits the extravasation of
vasoactive neuropeptides by trigeminal sensory neurons, which innervate intracranial vessels and dura
mater and also interferes with nociceptive neurotransmission within brainstem and spinal cord.
Pharmacokinetics
Naratriptan demonstrated high oral bioavailability in rats and dogs (71 and 95 %, respectively), which
could be clinically confirmed (63 % in men, 74 % in women). The elimination half-life was 1.7 h in
rats and dogs, whereas 5-6 h was determined in humans. Tmax was reached in humans after 2-3 h, but
was extended to 4 h during a migraine attack. Following oral doses between 2.5 and 10 mg, Cmax
amounted to 12.6-46.1 ng/ml. Naratriptan shows a high tissue distribution volume of 170 l. It is
metabolised by a variety of cytochrome P450 isoenzymes to numerous inactive metabolites. Excretion
mainly occurs by the renal route with half of the dose being recovered unchanged in the urine, while
about 30 % is eliminated as metabolites. The renal clearance of naratriptan (220 ml/min) exceeds the
glomerular filtration rate indicating active tubular secretion.
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Toxicology
After oral and intravenous administration of naratriptan to rodents, maximum non-lethal doses of
1000 mg/kg and 30-40 mg/kg were determined, respectively. Like all 5-HT1 agonists, naratriptan
elevates the blood pressure and has the potential to elicit vasospasms. Therefore, patients may be at
some risk for cerebral, perivascular and colonic ischemia. This is appropriately reflected in the
informative texts.
Naratriptan was not mutagenic or clastogenic when analysed in vitro (Ames test, mouse lymphoma
assay, human lymphocytes) or in vivo (mouse micronucleus assay). In carcinogenicity studies over
104 weeks, tumour formation was not influenced in mice administered up to 200 mg/kg/d oral doses,
whereas hyperplasia and follicular adenomas of the thyroids were found in rats of the high dose group.
The relevance of these findings for human therapy is unclear, because this dose is approximately 200fold
the maximum recommended human exposure and no carcinogenic potential could be detected in
mice or clinically. Hence, a species-specific effect seems plausible.
In reproduction toxicity investigations, effects on male and female reproduction were apparent at
doses well above the maximum recommended daily dose in humans. Reduced foetal viability and
skeletal malformation were observed in pregnant rats and rabbits at maternal exposures of
approximately 11- to 470-times and 2.5- to 140-times the human exposure at the maximum
recommended daily dose, respectively. Naratriptan was excreted into the milk of rats. Postnatally,
tremors and decreased survival of the offspring were found at 11-times the maximum recommended
daily dose in humans. As no adequate data from human pregnancies exists, naratriptan should only be
used by pregnant women after a careful benefit-risk assessment and mothers should abstain from
breast-feeding for one day after treatment.
Altogether, the pharmacodynamic, pharmacokinetic and toxicological properties of naratriptan are
well-known and have been satisfactorily considered for the informative texts. The toxicologically
relevant sections of SPC and PL have been harmonised with the wordings approved for the originator
“Naramig” (SE/H/131/001/R/02) and are hence acceptable.
Environmental Risk Assessment
On the basis of a worst case scenario calculation the PECsurfacewater would be 4.5 ng/L, which is
below the action limit of 10 ng/L. Hence, no further environmental risk assessment is necessary.
III.3 Clinical aspects
Naratriptan has been available since 1997 for the acute treatment of the headache phase of migraine
attacks. It is not indicated for prophylaxis of migraine attacks. The therapeutic activity of naratriptan
in migraine is attributed to agonist effects at 5-HT1B/1D receptors on the extracerebral, intracranial
blood vessels that become dilated during a migraine attack and on nerve terminals in the trigeminal
system. This causes vasoconstriction of the meningeal vasculature, a block of neuropeptide release and
an inhibition of the processing of pain signals in the nucleus caudalis thereby relieving headache pain
as well as the associated symptoms.
The pharmacodynamic properties as well as the clinical efficacy/safety profile of naratriptan are well
established. As naratriptan is widely used, the applicant has not provided additional clinical studies
and further studies are not required. The clinical overview based on literature review is, thus,
appropriate.
The submitted bioequivalence study demonstrates that Naratriptan Sandoz 2.5 mg film-coated tablets
can be considered bioequivalent with Naramig 2.5 mg tablets (GlaxoSmithKline, Germany) with
respect to both rate and extent of absorption.
Pharmacovigilance system
Description of Pharmacovigilance System
The applicant has provided documents that set out a detailed description of the system of
pharmacovigilance (Version 7.0 effective 15 July 2008). 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
N/A
IV BENEFIT RISK ASSESSMENT
The application contains an adequate review of published clinical data. Bioequivalence between the
Naratriptan Sandoz 2.5 mg film-coated tablets and the originator Naramig 2.5 mg film-coated tablets
(GlaxoSmithKline, Germany) has clearly been shown after single dose fasted conditions.
The application is approved.
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