Decentralised Procedure. Public Assessment Report. Allopurinol tablets 100 mg Allopurinol tablets 300 mg Allopurinol DE/H/ / /DC

Transcription

1 Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Allopurinol tablets 100 mg Allopurinol tablets 300 mg Allopurinol DE/H/ / /DC Applicant: Hexal AG Reference Member State DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/7 Public AR

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..5 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 Public AR

3 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 Alopur Hexal 100/300 mg Alopur- 1 A Pharma 100/300mg Alopur Sandoz 100/300 mg Allopurinol M04AA01 Tablets 100 mg and 300 mg DE/H/ / /DC Germany DE/H/1354/ /DC:AT (only 100mg), IE, IT DE/H/1355/ /DC: AT(only 300mg), PL DE/H/1356/ /DC: BE, CZ, DK, FI, IT, HEXAL AG Industriestr Holzkirchen Germany a) Salutas Pharma GmbH Otto-von-Guericke-Allee 1 D Barleben, Germany b) Salutas Pharma GmbH with the manufacturing site: Dieselstrasse 5 D Gerlingen, Germany 3/7 Public AR

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Allopurinol 100 and 300 mg tablets in the treatment of hyperuricaemia 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(1) of Directive 2001/83/EC for allopurinol under 39 different trade names claiming essential similarity to the European reference product. In case the strength is not registered in a country or there are differences(s) compared to the reference medicinal product (change in strength i.e. quantitative change to the active substance) this is an application in the sense of a hybrid application according to Art of the named Directive. The originator product Zyloric (100 mg, tablet), Glaxo Smith Kline (previously Wellcome) was first registered in 1966 in Finland and was subsequently licensed in various countries in the EU. II.2 About the product Allopurinol is a xanthine oxidase inhibitor (ATC code: M04AA01). Together with its metabolite oxypurinol it reduces the production of uric acid through inhibition of the enzyme xanthine oxidase, which plays an important role in the oxidation of hypoxanthine to uric acid. As a result, uric acid and urate levels in the body fluids and urine are lowered. The use of allopurinol as a hypouricaemic agent was explored in the 1960s. It is now a first-choice drug in the management of hyperuricaemia and in the prevention of acute episodes of gout and of the damage caused by tophaceous gout. It also has an important role in preventing acute, urate-induced, obstructive uropathy seen during the cytotoxic therapy of neoplastic diseases. Allopurinol (300 mg once daily) was found useful in reducing the recurrence of calcium oxalate stones in gouty or nongouty patients with hyperuricaemia or hyperuricosuria. II.3 General comments on the submitted dossier The submitted documentation in relation to the proposed products is of sufficient quality in view of the current European regulatory requirements. In order to prove the bioequivalence, a randomized, single dose, open label, 2-way crossover study was performed evaluating the bioavailability of the 300 mg tablets compared to the reference formulation. Moreover, a study of comparable design was performed evaluating the bioavailability of the 300 mg tablets compared to the European reference formulation. It could be shown that the test product is bioequivalent to the reference product. It can be concluded that all requirements for the abridged application are fulfilled and the regulatory reference to European reference product tablets is justified. Essential similarity to a European reference product has been shown. Pharmacovigilance system A pharmacovigilance system has been provided. Environmental Risk Assessment No separate environmental risk assessment has been performed by Hexal for allopurinol. No additional adverse environmental impacts are foreseen with the use and/or disposal of the Hexal drug product. 4/7 Public AR

5 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 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. The principles of GCP like ethical approval and informed consent of the volunteers were observed and the study was performed in fully accordance to the applicable guidelines and regulations valid at the time of study conduct. III. III.1 SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects Drug substance The supplier of active substance allopurinol possesses a Certificate of European Pharmacopoeia (CEP) which assures that the testing methods of the pharmacopoeia monograph together with additional tests named in the certificate allows an appropriate testing of the active substance. As a result of the presented CEP, part 3.2.S. is short and does only present the fundamental information on the active substance because the evaluation of the production and quality control of the active substance was done by the European Directorate for the Quality of Medicines & HealthCare in Strasbourg (France) for the CEP certification. No risk to public health is seen in part 3.2.S and therefore with view to the quality of the active substance the grant of a marketing authorisation is recommended. Drug Product In general the generic medicinal product Allopurinol Tablets with 100 mg or 300 mg allopurinol is from the pharmaceutical point of view a simple drug product in tablet form for oral use. With view to the simple composition and the typical excipients used to form a stable and in water disintegrating tablet no real problems in the production of the drug product are expected. Dissolution tests in water in comparison to the reference product, shows that it is possible to produce a generic product with a comparable disintegration behaviour. Therefore with view to the production of the tablet no real problems have been identified, because a standard tablet, using standard excipients is produced. III.2 Nonclinical aspects Pharmacodynamic, pharmacokinetic and toxicological properties of allopurinol are well known. As allopurinol is a widely used, well-known active substance, no further nonclinical studies are required and the applicant provides none. 5/7 Public AR

6 An adequate non-clinical overview on the preclinical pharmacology, pharmacokinetics and toxicology of allopurinol is included in the application. There are no objections to approval of Alopurinol100 mg/300 mg tablets from a nonclinical point of view. III.3 Clinical aspects As allopurinol is a widely used, well-known active substance, no further clinical efficacy and safety studies are required for this application and the applicant provides none. Overview based on literature review is, thus, appropriate. To support this application, the applicant has submitted data of two bioequivalence studies. One study is a randomized, single dose, open label, 2-way crossover study which was performed to evaluate the bioavailability of the 300 mg tablets compared to the reference formulation (tablets containing 300 mg allopurinol). For regulatory reasons a study of comparable design was provided evaluating the bioavailability of the 300 mg tablets compared to the European reference formulation (tablets containing 300 mg allopurinol). Based on the pharmacokinetic parameters of allopurinol, the reference and test are considered bioequivalent with respect to the extent and rate of absorption. The 90% confidence intervals calculated for AUC (0-t), AUC (0-inf) and C max of allopurinol were very well inside the normal range of acceptability ( ). On the basis of the comparable composition (qualitatively identical and quantitatively proportional) of the 100 mg and 300 mg formulations and their identical dissolution profiles the results obtained with the 300 mg formulation can be safely transferred to the 100 mg strength, also in view of the dose proportionality of allopurinol absorption. Bioequivalence of the 100 mg strength can therefore be assumed. The applicant provided dissolution profiles and data to show dose proportionality of allopurinol absorption in the range of mg. Batch size information was given. With regard to the safety analysis, there was no significant difference between the test and reference preparation. Pharmacovigilance system and Risk Management Plan The applicant has provided documents that set out a detailed description of the system of pharmacovigilance (Version 7.0 effective 15 July 2008). 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. 6/7 Public AR

7 IV. BENEFIT RISK ASSESSMENT From the clinical point of view the application contains an adequate review of published clinical data and bioequivalence has been shown. Based on this it can be concluded that the formulations of Alopur Hexal will be efficacious and safe in the treatment of adult patients with All forms of hyperuricaemia not controllable by diet, with serum uric acid values in the range of 535 µmol/l (9 mg/100 ml) and above and in clinical complications of hyperuricaemic states, particularly manifest gout, urate nephropathy, for the dissolution and prevention of uric acid stones as well as for the prevention of the formation of calcium oxalate stones in concurrent hyperuricaemia Adults, children and adolescents 15 kg/ 45 kg bodyweight (for 100/300 mg) Secondary hyperuricaemia of differing origin Children and adolescents 15 kg// 45 kg bodyweight (for 100/300 mg) Uric acid nephropathy during treatment of leukaemia Hereditary enzyme deficiency disorders, Lesch-Nyhan syndrome (partial or total hypoxanthinguanin phosphoribosyl transferase deficiency) and adenine phosophoribosyl transferase deficiency. No undesirable effects other than those already previously known are to be expected. The application is approved. 7/7 Public AR