Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Clozapin Regiomedica 50 mg/ml Suspension zum Einnehmen Clozamedica 50 mg/ml Suspension zum Einnehmen Clozapine DE/H/1668-1669/001/DC Applicant: Regiomedica GmbH Reference Member State DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/6 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... 5 IV. BENEFIT RISK ASSESSMENT... 6 2/6 Public AR
ADMINISTRATIVE INFORMATION 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 Reference Member State: Member States concerned: Applicant (name and address) Names and addresses of manufacturers responsible for batch release in the EEA Clozapin Regiomedica 50 mg/ml Suspension zum Einnehmen Clozamedica 50 mg/ml Suspension zum Einnehmen Clozapine N05A H02 Antipsychotic Oral suspension 50 mg/ml DE/H/1668-1669/001/DC Germany LU Regiomedica GmbH, Teichstr. 66, D-79539 Lörrach Regiomedica GmbH, Teichstr. 66, D-79539 Lörrach 3/6 Public AR
I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Clozapin Regiomedica 50 mg/ml Suspension zum Einnehmen and Clozamedica 50 mg/ml Suspension zum Einnehmen in the treatment of treatment-resistant schizophrenic patients and in schizophrenia patients who have severe, untreatable neurological adverse reactions to other antipsychotic agents, including atypical antipsychotics and in the treatment of psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed, is approved. II. EXECUTIVE SUMMARY II.1 Problem statement These are decentralised applications with Germany as the reference member state (RMS) submitted in accordance with article 10(3) of Directive 2001/83/EC as amended (hybrid application) for Clozapine 50 mg/ml suspension claiming essential similarity to Clozaril 25 mg Tablets, manufactured by Novartis Pharmaceuticals UK Limited. The originator product is Leponex, a tablet available in 25 mg, 50 mg, and 100 mg (Marketing Authorisation Holder: Novartis). Leponex 25 mg tablets and Leponex 100 mg tablets are registered in Germany since 01 January 1978. With Germany as the Reference Member State in this Decentralised Procedures, Regiomedica GmbH is applying for the Marketing Authorisations for Clozapin Regiomedica 50 mg/ml and Clozamedica 50 mg/ml in Luxembourg. II.2 About the product Clozapine is a tricyclic dibenzodiazepine derivative with a pharmacological and therapeutic profile quite different from that of the classic antipsychotics. Clinically clozapine is regarded as an atypical antipsychotic on account of its low propensity to induce extrapyramidal motor side effects (EPMS) and the lack of stimulatory effect on prolactin secretion. Despite its therapeutical potential, the relatively high incidence of clozapine-induced agranulocytosis is a major factor restricting the wider use of clozapine in psychiatric practice. The reference medicinal product is a conventional tablet whereas this application refers to an oral suspension. The clozapine suspension should allow a more flexible dosing schedule according to the patient's individual needs. Furthermore, a liquid formulation means an advantage for patients with difficulties in swallowing tablets (e.g., with Parkinson's disease). It is supplied with dosing syringes calibrated to deliver the required dose when dispensed according to instruction. To demonstrate adequate bioavailability of clozapine from the generic product submitted for approval, a bioequivalence study has been conducted investigating the bioequivalence between Clozapine 50 mg/ml suspension and the innovator product Clozaril. II.3 General comments on the submitted dossier The submitted documentation in relation to the proposed products is of sufficient high quality in view of the current European regulatory requirements. 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. 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 4/6 Public AR
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. III.1 SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects Drug substance The drug substance Clozapine is described in the current European Pharmacopoeia. 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 drug substance product are adequately drawn up. Drug Product The development of the product has been described, the choice of excipients is justified and their functions explained. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on three 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. A shelf-life of 24 months with the labelled storage condition Store in original container is accepted. III.2 Nonclinical aspects Clozapine is a substance of widespread clinical use with well-known pharmacodynamic, pharmacokinetic and toxicological properties that have been adequately described in the non-clinical overview. The instructions regarding the use of the substance during pregnancy and lactation and preclinical safety data contained in the proposed SPC and PL are considered acceptable. A marketing authorisation is granted. III.3 Clinical aspects Pharmacokinetics According to the current Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98), a bioequivalence study was conducted on healthy volunteers to investigate the bioavailability and bioequivalence of Clozapine 50 mg/ml Oral Suspension developed by Douglas Pharmaceuticals Ltd, New Zealand, in comparison with the reference product Clozaril 25 mg tablets from Novartis Pharma, UK. Pharmacodynamics Not applicable Clinical efficacy and safety Safety and efficacy of Clozapine are regarded as well established in the published literature. Despite its therapeutical potential, the relatively high incidence of clozapine-induced agranulocytosis is a major factor restricting the wider use of clozapine in psychiatric practice. 5/6 Public AR
Description of Pharmacovigilance System The applicant has provided documents that set out a detailed description of the system of pharmacovigilance. A statement signed by the applicant and the qualified person for pharmacovigilance, indicating that the applicant has the services of a qualified 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 now 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 Efficacy and safety of clozapine are considered well documented in the medical literature. The application is approved. 6/6 Public AR