Bundesinstitut für Arzneimittel und Medizinprodukte

Decentralised Procedure

Public Assessment Report

Modafinil Efarmes 100 mg Tabletten Runiam 100 mg Tabletten

Modafinil

DE/H/2481, 2508/001/DC

Applicant: Efarmes S.A.U., Spain

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

2/7 Public AR ADMINISTRATIVE INFORMATION

Proposed name of the medicinal Modafinil Efarmes 100 mg Tabetten product in the RMS Modafinil Runiam 100 mg Tabletten INN (or common name) of the active Modafinil substance(s): Pharmaco-therapeutic group N06BA07 (ATC Code): Pharmaceutical form(s) and Tablets; 100 mg strength(s): Reference Number for the DE/H/2481/001/DC Decentralised Procedure DE/H/2508/001/DC Reference Member State: DE Member States concerned: DE/H/2481/001/DC: FR, SI, UK DE/H/2508/001/DC: FR Applicant (name and address) Efarmes S.A.U. Sardenya 350, 08025 Barcelona, Spain Names and addresses of Lacer S.A. manufacturers responsible for batch C/Boters 5, Parc Tecnológic del Vallès release in the EEA 08290 Cerdanyola del Vallès, Barcelona, Spain

3/7 Public AR I. INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the application for “Modafinil Efarmes 100 mg Tabletten” and “Modafinil Runiam 100 mg Tabletten” in the treatment of narcolepsy with or without cataplexy is approved.

II. EXECUTIVE SUMMARY

II.1 Problem statement This decentralised application in accordance with Art. 10(1) of Dir. 2001/83/EC concerns a generic version of Modafinil, under the trade names “Modafinil Efarmes 100 mg Tabletten” and ”Modafinil Runiam 100 mg Tabletten”. In this Assessment Report, the name “Modafinil” is used.

The originator product is “Modiodal 100 mg tablets” by Cephalon France (obtained from the Spanish market), registered since 1st September 1997 in Spain.

With Germany as the Reference Member State in this Decentralised Procedure, Efarmes S.A.U is applying for the Marketing Authorisations for “Modafinil Efarmes 100 mg Tabletten” and ”Modafinil Runiam 100 mg Tabletten” in France, Slovenia and The United Kingdom.

II.2 About the product Modafinil is a racemic compound chemically related to . It is a wakefulness-promoting agent available for oral administration that acts as central . The precise pharmacological mechanism of modafinil is unknown. Although similar to conventional sympathomimetic agents like amphetamine, the wake-promoting activity of modafinil is not identical to these drugs. Modafinil is not a direct- or indirect-acting dopamine receptor agonist. However, in vitro, modafinil binds to the dopamine transporter and inhibits dopamine reuptake. This activity has been associated in vivo with increased extracellular dopamine levels in certain brain regions of narcoleptic animals. Moreover, the stimulation of alertness by modafinil seems to involve the increase of noradrenergic and the decrease of GABAergic neurotransmission in areas of the brain that regulate wakefulness. In addition to its wake-promoting effects and ability to increase locomotor activity in animals, modafinil produces psychoactive and euphoric effects, alterations in mood, perception thinking, and feelings typical of other CNS in humans.

Modafinil is indicated in: - Narcolepsy with and without cataplexia. - Moderately severe to severe obstructive sleep apnoea syndrome with excessive sleepiness during the day in spite of adequate CPAP treatment. - Moderately severe to severe chronic shift work syndrome with excessive sleepiness in patients when switching to night shift if other sleep-hygiene measures have not led to a satisfactory improvement.

II.3 General comments on the submitted dossier The non-clinical overview is afflicted by several shortcomings and hardly meets the standards outlined for a generic application in Annex I of Dir. 2001/83/EC as amended and NTA Vol. 2B. The document is only accepted based on the long-standing non-clinical and clinical experience with Modafinil.

II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. The RMS has 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.

4/7 Public AR 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. For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.

III. SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 Quality aspects

Drug substance The drug substance Modafinil is described in the current Ph.Eur. A single source of Modafinil is proposed. Information on the active substance is presented in form of an ASMF (German ASMF No. 2311, version 07/08). Furthermore, the applicant provides a valid Certificate of Suitability (No. R0- CEP 2008-199-Rev 00) that has been granted during DCP procedure. The chemical-pharmaceutical documentation is of sufficient quality in view of the present European regulatory requirements. The manufacturing process has been adequately described in the restricted part of the ASMF. The control tests and specifications for the drug substance are in accordance with in-house requirements and justified according to the EU/ICH guidelines. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed retest period of five years is justified. No special storage condition is necessary.

Drug Product The development of the Modafinil 100 mg tablets has been described, the choice of excipients is justified and their functions explained. The product specification cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on three pilot scale batches. The batch analysis results show that the finished products meet the specifications proposed. The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. The shelf-life of 36 months without any labelled storage condition for the drug product is justified by stability data provided.

III.2 Nonclinical aspects

Pharmacology Modafinil is a benzhydrylsulfinylacetamide derivative with wakefulness-promoting activity that is pharmacologically distinct from conventional CNS stimulants like amphetamine or methylphenidate. It is a racemic compound. The two isomers do not interconvert and have the same pharmacological activity as the racemate. The precise mechanism of action of modafinil is unknown, but seems to include the interaction with glutamatergic, GABAergic, noradrenergic, serotonergic, histaminergic and orexinergic pathways. In particular, modafinil diminishes GABAergic transmission in areas of the brain that regulate alertness. Furthermore, modafinil inhibits dopamine reuptake and hence increases extracellular dopamine levels by binding to the dopamine transporter. This action has been linked to effective stimulation of wakefulness in narcoleptic animals, because it was abolished in dopamine transporter knockout mice.

Pharmacokinetics Modafinil is well absorbed from the gastrointestinal tract after oral administration and rapidly

5/7 Public AR distributes throughout all tissues. Terminal half-lifes are 1-3 h in mice and rats and 1.5-6 h in dogs. Plasma protein binding is about 60%. Modafinil is predominantly metabolised in the liver by hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation and glucuronide conjugation. and modafinil sulfone are the major metabolites, neither appears to be pharmacologically active. Excretion is mainly through the kidneys with less than 10% of the dose being eliminated unchanged. Modafinil moderately and reversibly inhibits the cytochrome P450 2C19 isoenzyme. In addition, it modestly induces CYP1A2, CYP3A4/5 and CYP2B6 and suppresses CYP2C9 activity. This implicates that modafinil might interact with other drugs.

Toxicology Modafinil did not significantly influence cardiovascular and cerebrovascular parameters (heart rate, blood pressure, cerebral blood flow) in rats, dogs and rhesus monkeys. In subchronic toxicity studies, haematological changes and increased liver weights were detected in mice and rats. Additionally, elevated weights of spleen and kidneys were also observed in rats, while thymus weight was decreased. In dogs, levels of blood parameters, cholesterol and alkaline phosphatase were increased. Moreover, stereotypical locomotion (head movement, agitation), panting and sometimes hypotension were apparent. The investigation of chronic toxicity over 52 weeks in rats revealed comparable findings as previously seen in the subchronic toxicity study. Modafinil did not show any mutagenic, clastogenic or carcinogenic potential. It should be noted however, that the dosages applied in the carcinogenicity studies to mice and rats were not representative of a maximum tolerated dose. In reproduction toxicity studies, modafinil was not teratogenic and did not affect fertility at doses up to 100 mg/kg in rats and rabbits. At higher doses, embryotoxicity, hydronephrosis and skeletal variations as well as an increased number of resorptions and stillbirths was evident.

Although the submitted non-clinical overview poorly summarises the characteristics of the active substance, the document is accepted based on the extensive non-clinical and clinical experience with Modafinil. SmPC and PL have been harmonised with the texts approved in other recent European procedures (e.g. DE/H/1521/001/DC) as requested by the RMS and UK. A marketing authorisation is granted.

III.3 Clinical aspects

Pharmacokinetics This application concerns the 100 mg strength (film-coated tablet) of the active substance modafinil. A single bioequivalence study was performed with the single dose of 100 mg under fasting conditions.

Based on the submitted bioequivalence study, Modafinil 100 mg tablets of Efarmes/Qualix and Modiodal (Modafinil) 100 mg tablets of Noventure/Cephalon (France), are considered bioequivalent in healthy human adults under fasting conditions.

Pharmacodynamics No new data.

Clinical efficacy and safety The proposed indications for Modafinil are considered to be approvable:

- Narcolepsy with and without cataplexia.(…)

Pharmacovigilance system The applicant has provided documents that set out a detailed description of the Lacer Group system of pharmacovigilance (Version 2.0 dated 12 January 2010). A statement signed by the applicant and the qualified person for pharmacovigilance, indicating that the applicant has the services of a qualified

6/7 Public AR 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.

IV. BENEFIT RISK ASSESSMENT

Bioequivalence has been shown. The application is approved.

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