Decentralised Procedure. Public Assessment Report

Transcription

1 Decentralised Procedure Public Assessment Report Venlafaxin ratiopharm Venlafaxin AbZ-Pharma Venlafaxin CT-Arzneimittel prolonged-release capsule hard venlafaxine hydrochloride DE/H/ /01-03/DC Applicant: ratiopharm GmbH Reference Member State DE

2 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 Non-clinical aspects... 5 III.3 Clinical aspects... 6 IV. BENEFIT RISK ASSESSMENT... 7 DE/H/ / /DC Public AR Page 2/7

3 ADMINISTRATIVE INFORMATION Proposed name of the medicinal product(s) 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(s) for the Decentralised Procedure Reference Member State: Member States concerned: Applicant (name and address) Venlafaxin-ratiopharm Venlafaxin AbZ Venlafaxin-CT Venlafaxine N06AX16 prolonged-release capsules, hard 37.5 mg, 75 mg and 150 mg DE/H/3393/ /DC (former FI/H/0672/ /DC) DE/H/3394/ /DC (former FI/H/0674/ /DC) DE/H/3395/ /DC (former FI/H/0675/ /DC) DE AT, BE, CZ, DK, EE, FI, IT, LT, LU, LV, NL, NO, PL, SE, SK, UK DE/H/ / /DC ratiopharm GmbH, Germany DE/H/3395/ /DC CT Arzneimittel GmbH, Germany DE/H/ / /DC Public AR Page 3/7

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the for Venlafaxinratiopharm/Venlafaxin AbZ/Venlafaxin-CT 37.5 mg, 75 mg and 150 mg prolonged-release capsules, hard, in the treatment of major depressive episodes, short-term treatment of generalised anxiety disorder (according to DSM-IV), short-term treatment of social anxiety disorder/social phobia, and panic disorders, with or without agoraphobia, is approved. After changing the RMS Germany is the new RMS. The former procedure numbers were FI/H/0672/ /DC, FI/H/0674/ /DC, and FI/H/0675/ /DC. II. EXECUTIVE SUMMARY II.1 Problem statement This application for marketing authorisation for generic Venlafaxine 37.5 mg, 75 mg and 150 mg prolonged-release capsules, hard is made under Article 10 (1) of Directive 2001/83/EC as amended. The application refers to the reference product Efexor XR/XL (called also as Efectin / Effexor / Trevilor) by Wyeth. The first marketing authorisation for the original product Effexor/Trevilor within the European Community was granted on to Wyeth Pharmaceuticals in France. Consequently, data protection period is already expired and reference can be made to the non-clinical and clinical documentation of the reference product. The medicinal product Venlafaxine prolonged-release capsules, hard is a generic of the reference product Efexor XR/XL prolonged-release capsules, hard. For DE, DK, IT and UK: This application for marketing authorisation for hybrid Venlafaxine 37.5 mg prolonged-release capsules, hard is made under Article 10 (3) of Directive 2001/83/EC as amended. The application refers to the reference product Efexor XR/XL 75 mg (called also as Efectin / Effexor / Trevilor) by Wyeth. The first marketing authorisation for the original product Effexor/Trevilor within the European Community was granted on to Wyeth Pharmaceuticals in France. Consequently, data protection period is already expired and reference can be made to the non-clinical and clinical documentation of the reference product. II.2 About the product Venlafaxine is included in the pharmacological class of antidepressant drugs. Venlafaxine, a bicyclic (phenylethylamine) derivative, is a serotonin and noradrenaline reuptake inhibitor; it also inhibits weakly dopamine reuptake. It is reported to have little affinity for muscarinic, histaminergic, or a1- adrenergic receptors in vitro. Venlafaxine XR 37.5mg, 75mg and 150mg capsules is a prolonged-release, multiple unit formulation. Venlafaxine XR capsules are indicated for the treatment of depressive illness including depression accompanied by anxiety. Following an initial response Venlafaxine XR capsules are indicated for the prevention of relapses of the initial episode of depression or the prevention of the prevention of the recurrence of the new episodes Venlafaxine 75mg XR capsules are also indicated for the treatment of Generalised Anxiety Disorder (GAD). II.3 General comments on the submitted dossier The submitted documentation in relation to the proposed products is of adequate 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 (Greek) authorities as certification that acceptable standards of GMP are in place at those sites. DE/H/ / /DC Public AR Page 4/7

5 III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance Data on the chemistry, manufacturing and quality control of Venlafaxine hydrochloride is submitted via the active substance master file procedure. The drug master file (DMF) for venlafaxine hydrochloride and letters of access in respect of the DCP Applications have been submitted by the drug substance manufacturer. The specifications of the active substance venlafaxine hydrochloride are in line with the requirements of the Ph. Eur. monograph. The stability studies that have been performed with the drug substance have been provided by the drug substance manufacturer. There is 36 months of data available. The proposed retest period of 2 years, with no special storage conditions mentioned in the labels and packaged in double PE bags in a plastic container is approved. Drug Product The development of the Venlafaxine 37.5 mg, 75 mg and 150 mg prolonged-release capsules has been described. The finished product consists of a hard gelatine capsule containing one, two or three bioconvex prolonged release tablets. The goal of these formulation studies was to produce a tablet with pharmaceutical properties as close as possible to the innovator product, Efexor, Wyeth. Tabletting was the first choice for a manufacturing process because it is faster, easier, includes less steps and is the most economical manufacturing process. However, the final dosage form is a hard gelatin capsule comprised of coated tablets since the innovator company has adopted the same approach with pellets inside the hard gelatin capsule. Intensive tests were performed to the originator product since a very precise dissolution profile needed to be established as the main target characteristic for the development trials. As the content of the hard gelatine capsule is different between the applied product and the innovator s the main target was the dissolution profile. An IV- IV correlation study was performed and some correlation was established. The manufacturing process is an encapsulation of tablets which are produced as follows; First the excipients are mixed together. The granulation liquid is added to the mixture and subsequently the wet granules are dried. The dried granules are compressed into slugs. The slugs are sieved and lubricated with magnesium stearate. Then, compression into tablets is performed. Subsequently, the tablets are coated in a conventional coating pan and the coated tablets are encapsulated. Finally the capsules are packaged. The in-process controls and the sampling are described and specified acceptance criteria are set. The applicant has provided acceptable production scale process validations for three batches of each Venlafaxine 37.5 mg, 75 mg, and 150 mg prolonged release capsules. The specifications of the drug product are acceptable. E.g. the identification of colours was added, total impurities limit and water limit in release was tightened and content uniformity test was added. Also the choice of the dissolution method was justified in more detail and the method for residual solvents was replaced by new method. Batch analyses have been performed on three batches of each strength with batch sizes of one 20,000 and two 100,000 tablets. The batch analysis results show that the finished products meet the specifications proposed. The dissolution results of individual dosage units are also reported. The conditions used in the stability studies are according to the ICH stability guideline. The above mentioned three batches of each strength packed in PVC/PE/PVDC/Aluminium blisters were placed on the stability studies in long-term, intermediate and accelerated conditions. The stability studies are ongoing and data has been submitted for 36 months. All results are within specifications. The photostability study and results of the forced degradation studies have been provided. Based on the stability data, the proposed shelf-life (36 months for the product packed in PVC/PE/PVDC/Aluminium blisters with no special precaution for storage) can be accepted. III.2 Non-clinical aspects Pharmacology, Pharmacokinetics, Toxicology Pharmacodynamic, pharmacokinetic and toxicological properties of venlafaxine hydrochloride are well known. As venlafaxine hydrochloride is a widely used and well-known, the applicant has not provided additional studies and none are required. An overview based on a literature review is therefore appropriate. DE/H/ / /DC Public AR Page 5/7

6 The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. III.3 Clinical aspects To support the application, the applicant had originally submitted four bioequivalence studies and one bioequivalence study (VNN-P7-283): 1. Study VNN-P6-115: Single dose crossover comparative bioavailability study of venlafaxine 75 mg extended-release capsules in healthy male and female volunteers / Fed state 2. Study 50106: Randomized, 2-Way Crossover, Bioequivalence Study of Venlafaxine 75 mg Extended- Release Capsule And Efexor XL Following a 75 mg Dose Daily For 6 Consecutive Days in Healthy Subjects Under Fed Conditions 3. Study 50042: Randomized, 2-Way Crossover, Bioequivalence Study of Venlafaxine 75 mg Extended-Release Capsule and Efexor XL Following a 75 mg Dose in Healthy Subjects Under Fasting Conditions 4. Study 50238: Randomized, Open-Label, 2-Way Crossover, Bioequivalence Study of Venlafaxine 150 mg Extended-Release Capsule and Efexor XL Following a 150 mg Dose in Healthy Subjects under Fed Conditions 5. Study VNN-P7-283: Single dose crossover comparative bioavailability study of venlafaxine 37.5 mg extended-release capsules in healthy male and female volunteers / fasting state The primary pharmacokinetic parameters were acceptable and within the predefined acceptance range. Based on the submitted bioequivalence studies the test products can be considered bioequivalent to the reference products. No other studies were conducted to support this application. Fulfilment of the required conditions for biowaiver as defined in the Notice to Applicant and Note for Guidance CPMP/EWP/QWP/1401/98 are presented in Module 1 (1.5.2). User testing The Final readability test report is provided. The testing was performed in Finnish. Before actual testing a pilot test was performed. The test consisted of two test rounds of 10 subjects each. The success criteria used required that at least 90% out of the subjects should be are able to find the information in the leaflet at least 90% out of the subjects who found the information should also be able to understand the information in the leaflet. Interviewed population on test rounds 1 and 2 consisted of total of 20 subjects (17 women and 3 men). Test subjects represented diverse educational backgrounds. The age range of the subjects was from 29 to 75 years (mean 48.9 years). The questionnaire consisted of 12 questions. The questions are considered relevant and appropriate for testing readability. Success rate of the two test rounds was according to the Summary Outcome Report full 100%. All of the subjects were able to locate the correct information in the PL. The user test is acceptable and confirms that the PL is readable. Pharmacovigilance system The detailed description of the pharmacovigilance system complies with the current European requirements. Risk management plan The applicant consider that risk management plan is not considered applicable to the present products as they are generic products and no safety concerns have been raised for the reference medicinal products. PSUR cycle It is applied to harmonise PSUR cycle according to EU harmonised Birth Date (3 October 2006) agreed EU HPD on (Wyeth, allocated P-RMS ES). DE/H/ / /DC Public AR Page 6/7

7 IV. BENEFIT RISK ASSESSMENT Venlafaxine ratiopharm prolonged-release capsules are generic medicinal products containing venlafaxine hydrochloride as the active ingredient. The application contains an adequate review of published clinical data and the bioequivalence with the reference product Efexor XR/XL has been shown. Together with the proposed SmPC and PL the benefit/risk assessment is positive. The application is approved. For intermediate amendments see current product information. DE/H/ / /DC Public AR Page 7/7