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Decentralised Procedure Public Assessment Report Modafinil

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Decentralised Procedure Public Assessment Report Modafinil Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Modafinil Efarmes 100 mg Tabletten Modafinil 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 adrafinil. It is a wakefulness-promoting agent available for oral administration that acts as central stimulant. 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 stimulants 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. Modafinil acid and modafinil
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