Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Pramithon Pexogies 0,088/0,18/0,35/0,7 mg Tabletten Pramipexole DE/H/2385-2386/001-004/DC Applicant: Synthon BV 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. 5 III SCIENTIFIC OVERVIEW AND DISCUSSION 5 III.1 QUALITY ASPECTS 5 III.2 NONCLINICAL ASPECTS 6 III.3 CLINICAL ASPECTS 6 IV BENEFIT RISK ASSESSMENT 7 2/7 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 Pramithon 0,088 mg / 0,18 mg / 0,35 mg / 0,7 mg Tabletten Pexogies 0,088 mg / 0,18 mg / 0,35 mg / 0,7 mg Tabletten Pramipexole N04BC05 Dopamine agonists tablets 0.088/0.18/0.35/0.7 mg DE/H/2385/001-004/DC DE/H/2386/001-004/DC Germany (DE) AT, BE, CZ, DK, EE, EL, ES, FI, FR, IT, LT, LV, NL, RO, SE, SI, SK, UK Synthon BV Microweg 22, 6545 CM Nijmegen The Netherlands 1. Synthon Hispania S.L. Castelló 1, Polígono Las Salinas 08830 Sant Boi de Llobregat Spain 2. 2. Synthon BV Microweg 22, 6545 CM Nijmegen The Netherlands 3/7 Public AR
I INTRODUCTION This decentralised application concerns a generic version of pramipexole under the trade names Pramithon 0,088 mg / 0,18 mg / 0,35 mg / 0,7 mg Tabletten and Pexogies 0,088 mg / 0,18 mg / 0,35 mg / 0,7 mg Tabletten. Based on the review of the data on quality, safety and efficacy, the application for Pramipexol Synthon tablets in the treatment of in the suggested indications - for treatment of the signs and symptoms of idiopathic Parkinson's Disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end of dose or on off fluctuations), and for symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome in dosages up to 0.54 mg of base (0.75 mg of salt). is approved. II EXECUTIVE SUMMARY II.1 Problem statement This decentralised application concerns a generic version of pramipexole, under the trade names Pramithon 0,088 mg/0,18 mg/0,35 mg/0,7 mg Tabletten and Pexogies 0,088 mg/0,18 mg/0,35 mg/0,7 mg Tabletten. The originator product is Sifrol (0.088/0.18/0.35/0.7 mg, tablets) by Boehringer Ingelheim Int. GmbH, Germany, registered since 14.10.1997. With Germany as the Reference Member State in this Decentralised Procedure the applicant Synthon BV is applying for the Marketing Authorisations for Pramithon 0,088 mg/0,18 mg/0,35 mg/0,7 mg Tabletten in Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Italy, Lithuania, Latvia, Netherlands, Sweden, Spain and for Pexogies 0,088 mg/0,18 mg/0,35 mg/0,7 mg Tabletten in Belgium, Czech Republic, Greece, France, Italy, Romania, Slovak Republic, Slovenia, Spain, United Kingdom. But not all strengths have been submitted in the named countries in the same procedure. II.2 About the product Pramipexole is a synthetic amino-benzothiazole derivative, a non-ergot dopamine agonist (DA). It has been shown to be a selective and specific full DA receptor agonist with high affinity and selectivity for the DA D2 receptor subfamily, and particularly the D3 receptor subtype. Pramithon 0,088 mg/0,18 mg/0,35 mg/0,7 mg Tabletten and Pexogies 0,088 mg/0,18 mg/0,35 mg/0,7 mg Tabletten are indicated for treatment of the signs and symptoms of idiopathic Parkinson's Disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end of dose or on off fluctuations), and for symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome in dosages up to 0.54 mg of base (0.75 mg of salt). 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. 4/7 Public AR
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. III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects The general impression of the documentation is that it have been satisfactorily elaborated and justified in accordance with relevant guidelines. The application is straight forward with no major scientific challenges in the quality part of the dossier. The active substance is a chemical derived molecule. It has been shown to be stable. The medicinal product is formulated as immediate release tablets which are manufactured by conventional techniques using well-known excipients and packaging materials. Drug substance Pramipexole dihydrochloride monohydrate Module 3.S is submitted as EDMF. The active substance is manufactured in five main steps. The description is considered as sufficient. The proposed specifications for impurities in the active substance are in accordance with EU/ICH Q6A and Q3A guidelines. In general, the analytical methods for assay, related substances and residual solvents used for the active substance is satisfactorily described and validated in accordance with the relevant EU/ICH guidelines on Analytical validation. Reference standards are sufficiently described. Pramipexole is a stable molecule. Stability studies according to the relevant EU/ICH stability guidelines have been submitted. Significant changes are not observed at ICH conditions. Therefore, a proposed extrapolation of the retest period to 36 months with no restrictions for storage is accepted. Drug product The immediate release tablets are formulated with well-known excipients. The pharmaceutical development work is comprehensive for a generic product and in accordance with relevant EU guidelines. The manufacturing process has been satisfactorily described. Validation data as demanded in the EU guidelines on Manufacture of the finished dosage form and Process validation is provided.. The manufacturing process is conventional using standard techniques. However, the drug product has to be considered as non-standard due to its low active substance content. 5/7 Public AR
The excipients pregelatinized starch, mannitol, povidone, colloidal anhydrous silica, magnesium stearate and purified water comply with the current version of the monograph in Ph.Eur. and are tested according to the analytical methods in Ph. Eur. The proposed limits on degradation products justified according to the EU/ICH Q3B guideline. The limits for dissolution are considered as adequate. Other requirements are justified according to relevant EU/ICH guidelines and Ph.Eur. The analytical methods used for the drug product are described and validated in accordance with the relevant EU/ICH guidelines. The description and choice of container closure system is in accordance with relevant directives. The stability studies have been carried out according to relevant EU/ICH stability guidelines. Longterm stability are provided up to 24 months. A shelf life of 24 months (Al-Al blister) is accepted. III.2 Nonclinical aspects Pramipexole is a substance 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 active substance during pregnancy and lactation and preclinical safety data each contained in the proposed SPC and PL essentially reflect the current texts that were approved for the originator product Sifrol (EMEA/H/C/133/II/52). A marketing authorisation is granted. III.3 Clinical aspects In order to demonstrate bioequivalence between the Applicant s formulation and the brand leader one bioequivalence study has been conducted for pramipexole 0.18 mg IR tablets (Study number: 139/06) in healthy volunteers under fasting conditions. The investigational medicinal products used during the study were pramipexole 0.18 mg IR tablets, batch number 07A23ITA, manufactured by Synthon Hispania and Sifrol 0.18 mg IR tablets, batch number 602691U, manufactured by Boehringer Ingelheim International GmbH, Germany. Pharmacokinetics Pharmacodynamics Clinical efficacy Clinical safety Pharmacovigilance system Description of Pharmacovigilance System 6/7 Public AR
Details have been provided of the Synthon pharmacovigilance system (Version SPS.NL01.01824 (3.0) undated). 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 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 The application contains an adequate review of published clinical data and the bioequivalence has been shown. The application is approved. 7/7 Public AR