Decentralised Procedure. Public Assessment Report. Leflunomide DE/H/2609/ /DC. Applicants: M.R. Pharma GmbH

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1 Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Leflunopharm 10 mg <20 mg> Filmtabletten Leflunomide DE/H/2609/ /DC Applicants: M.R. Pharma GmbH Reference Member State DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/9 Public AR

2 TABLE OF CONTENTS LIST OF ABBREVIATIONS AND TERMS... 4 I. INTRODUCTION... 5 II. EXECUTIVE SUMMARY... 5 II.1 Problem statement... 5 II.2 About the product... 5 II.3 General comments on the submitted dossier... 5 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles..6 III. SCIENTIFIC OVERVIEW AND DISCUSSION... 6 III.1 Quality aspects... 6 III.2 Nonclinical aspects... 7 III.3 Clinical aspects... 7 IV. BENEFIT RISK ASSESSMENT /9 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 Leflunopharm 10 mg <20 mg> Filmtabletten Leflunomide L04AA13 (Selective immunosuppressant) Film-coated tablets 10 mg / 20 mg DE/H/2609/ /DC DE DE/H/2609/ CZ, DK, EE, FI, HU, LV, NO, SE, SK M.R. Pharma GmbH Waldstrasse Tangstedt Germany Haupt Pharma Münster GmbH Schleebrüggenkamp Münster Germany A) 3/9 Public AR

4 LIST OF ABBREVIATIONS AND TERMS ACR American College of Rheumatology ADRAC Adverse Drug Reactions Advisory Committee AIDS Acquired immune deficiency syndrome ALT Alanine transaminase, also called serum glutamic pyruvic transaminase (SGPT) ANOVA Analysis of variance ASAS Assessments in Ankylosing Spondylitis (working group) AST Aspartate transaminase, also called serum glutamic oxaloacetic transaminase (SGOT) AUC Area under the concentration-time curve AUC 0-inf AUC with extrapolation to infinity AUC 0-72 AUC from administration (time 0) until 72 hours thereafter BASDAI Bath AS (ankylosing spondylitis) Disease Activity Index CAPD Chronic ambulatory peritoneal dialysis CI Confidence interval C max Maximum observed concentration (peak concentration) CMV Cytomegalovirus COX Cyclooxygenase CRP C-reactive protein CV Coefficient of variation CYP Cytochrome P450 (isoenzymes) DHODH Dihydroorotate dehydrogenase DIMDI Deutsches Institut für Medizinische Dokumentation und Information DLQI Dermatology Life Quality Index DMARD Disease-modifying antirheumatic drug EMEA European Medicines Agency ESR Erythrocyte sedimentation rate FDA Food and Drug Administration GCP Good Clinical Practice GLP Good Laboratory Practice HAQ Health Assessment Questionnaire (disability index) HPLC High performance liquid chromatography IC 50 Concentration that inhibits enzyme activity by 50% ITT Intention-to-treat (analysis/population) JRA Juvenile rheumatoid arthritis LC-MS/MS Liquid chromatography tandem mass spectrometry LDH Lactate dehydrogenase NSAID Nonsteroidal anti-inflammatory drug PASI Psoriasis Area and Severity Index PsARC Psoriatic Arthritis Response Criteria RR Relative risk rump ribonucleotide uridine monophosphate (a pyrimidine nucleotide) SD Standard deviation SmPC Summary of Product Characteristics t ½ Plasma elimination half-life TFMA 4-Trifluoromethylaniline TGF Transforming growth factor t max Time passed since administration at which the C max occurs TNF Tumour necrosis factor VAS Visual Analogue Scale vs. Versus 4/9 Public AR

5 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Leflunopharm 10 mg and 20 mg, in the treatment of adult patients with active rheumatoid arthritis and active psoriatic arthritis as a "disease-modifying antirheumatic drug" (DMARD) is approved. II. EXECUTIVE SUMMARY II.1 Problem statement Leflunomide film-coated tablets are the subject of this Marketing Authorisation Application based on Article 10 (1) of Directive 2001/83/EC. Leflunomide film-coated tablets have been developed to be essentially similar to the originator product, Arava. The pharmaceutical expert confirms a qualitative similarity and an appropriate bioequivalence study confirms the similarity of the biological availability of the Applicant s formulations to the originator product. This decentralised application concerns a generic version of leflunomide, under one trade name with two different strengths, 10mg and 20mg. In this Assessment Report, the name Leflunomide is used. The originator product is Arava film-coated tablets; Sanofi-Aventis Deutschland GmbH, Germany. First data of licensing was 2 nd September 1999, last renewal was within 2009 (EMEA/H/C/235/R/41). II.2 About the product Leflunomide primarily exhibits anti-inflammatory, antiproliferative and immunosuppressant activity. The drug is therefore used as a disease-modifying antirheumatic drug (DMARD) in the treatment of active rheumatoid arthritis but also in the treatment of active psoriatic arthritis. The intended indications, as claimed in the product information are: Leflunomide is indicated for the treatment of adult patients with active rheumatoid arthritis as a disease-modifying antirheumatic drug (DMARD), and active psoriatic arthritis. Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs (e.g., methotrexate) may result in an increased risk of serious adverse reactions; therefore, the initiation of leflunomide treatment has to be carefully considered regarding these benefit-risk aspects. Moreover, switching from leflunomide to another DMARD without following the washout procedure (see section 4.4) may also increase the risk of serious adverse reactions even for a long time after the switching. The recommended dose for a therapy with leflunomide is started with a loading dose of 100 mg once daily for 3 days. The recommended maintenance dose for rheumatoid arthritis is leflunomide 10 mg to 20 mg once daily. Patients may be started on leflunomide 10 mg or 20 mg depending on the severity (activity) of the disease. The recommended maintenance dose for patients with psoriatic arthritis is 20 mg once daily. The product information agreed for Arava during the renewal (EMEA/H/C/235/R/41) and updated during variation procedures EMEA/H/C/235/II/43 and EMEA/H/C/235/II/46 is identical to the one proposed for this application. These texts are acceptable. A user testing has been performed and accepted for the PL of Arava within the variation procedure EMEA/H/C/235/II/038. See also the joint assessment report concerning the renewal procedure for Arava. II.3 General comments on the submitted dossier Concerning the type of marketing authorisation application, see section II.1. 5/9 Public AR

6 One bioavailability study has been performed. It compared the rate and extent of absorption of Leflunomide against Arava, containing 20 mg leflunomide, by Sanofi Aventis, and is performed in accordance with the CHMP Note for Guidance on Bioavailability and Bioequivalence. A literature review about available nonclinical and clinical data has been submitted which is accepted. A risk management plan has been submitted. II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. GMP 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. Additionally, GMP certificates issued by the local district governments for the manufacturers of the finished drug product have been provided. For the active substance Leflunomide a certificate of GMP compliance of a manufacturer, issued by the local district government, following an inspection is presented. GCP Considering the submitted study documentation and reported internal quality assurance activities it can be concluded that the bioavailability study has been performed according to pertinent GCP recommendations. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The chemical-pharmaceutical documentation and the Expert Report for Leflunopharm 10 mg and 20 mg are of sufficient quality in view of the present European regulatory requirements. The active substance leflunomide is described in the European Pharmacopoeia (Ph. Eur.). The quality of the active substance leflunomide is controlled in compliance with the monograph of the European Pharmacopoeia (Ph Eur). The suitability of the monograph to test the drug substance has been verified by EDQM and is documented by the issue of a certificate of suitability. Drug Product The development of the products Leflunopharm 10 mg and 20 mg has been described, the choice of excipients is justified and their functions explained. The active ingredient and excipients used are well known and of pharmacopoeial quality. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on a sufficient number of batches of each strength. 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 without specific storage conditions for Leflunopharm 10 mg and 20 mg is accepted. Taking into account the results of the photostability stability study no instruction regarding protection of drug product from exposure to light is necessary. Conclusions on the chemical, pharmaceutical and biological aspects 6/9 Public AR

7 Based on the review of the data the application for Leflunopharm 10 mg and 20 mg is approvable regarding to quality aspects. III.2 Nonclinical aspects Nonclinical pharmacodynamic, pharmacokinetic and toxicological properties of leflunomide are well known. As leflunomide is a widely used, well-known active substance, no further nonclinical studies are required. Overview based on literature review is appropriate. An environmental risk assessment was not submitted for Leflunomide. However, the Applicant has provided sufficient evidence that no additional environmental risks as compared to those of the originator s product have to be considered for Leflunomide. From a nonclinical point of view, marketing authorization is recommended. III.3 Clinical aspects Pharmacodynamics The pharmacodynamic profile of leflunomide is established and sufficiently characterized in literature. No new data are required. Clinical efficacy and safety As this is a medicinal product with a systemic effect, there is the need of an appropriate bioequivalence study to justify efficacy. To support the application for Leflunomide film-coated tablets 10 mg/ 20 mg, the applicant has submitted one bioequivalence study for the 20 mg strength. The efficacy and safety of leflunomide is well established. The efficacy and safety characteristics of the innovator have been reassessed repeatedly after the first marketing authorisation and at last within a renewal procedure in 2009 (EMEA/H/C/235/R/41). The efficacy and safety are adequately reflected in the approved SmPC. No new safety concern was detected in this review. Overview based on literature review is thus appropriate. With the exception of pharmaceutical and administrative data, the SmPC of Leflunomide is identical to the SmPC of the reference product Arava and the PL submitted for the generic product corresponds to the PL of the reference product. PL structure follows the QRD template. A user testing has been performed and accepted for the PL of Arava within the variation procedure EMEA/H/C/235/II/38. Insofar no additional user testing is considered necessary. Bioequivalence The applicant has developed Leflunomide Tablets, 10 mg and 20 mg. In order to obtain marketing authorisation, bioequivalence of the new Leflunomide Tablets 20 mg (herein further called Test ) with a previously marketed reference product (Arava, containing 20 mg leflunomide, by Sanofi Aventis, herein further called Reference ) had to be shown by an appropriately designed bioequivalence study as shown in this Report In accordance with the Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98 (Rev 1)) the applicant provided a justification for the extrapolation of the bioequivalence study results to the 10 mg strength. Batch control results of the test and reference products were presented in the documentation of the pharmaceutical quality showing comparable assayed contents of the test and reference product. According to the data available to the undersigned expert, the study was planned, designed, conducted and basically reported according to ICH/GCP recommendations. Particulars of the study design have been discussed and justified. As demonstrated, the estimated 90% confidence intervals were safely 7/9 Public AR

8 within the preset acceptance range, i.e %, for AUC 0-168h and C max. Based on the reported data, both formulations can be considered bioequivalent and expected to behave similarly in vivo. All the published clinical and nonclinical experience on leflunomide can be therefore transferred to the new Leflunomide Tablets (for further details see clin+nonclin AR). M1 (A771726) true values (geometric means + SD), ratios of least-square means and acceptance ranges for 90% confidence intervals for C max and AUC 0-168h (80% - 125%) Parameter Geometric means + SD (True data) Ratios Test Reference Point Estimator 90% Confidence Interval C max [ng/ml] % % to % T max [h] AUC 0-168h [ng. h/ml] n.d. n.d % % % Pharmacokinetic Conclusion The estimated 90%-confidence intervals are within the preset acceptance range, i.e %, for AUC 0-168h and C max. Based on the reported data, both formulations can be considered bioequivalent and expected to behave similarly in vivo following a single dose of 20 mg in the fasted state. Both formulations were well tolerated, no SAE were reported during the study. All events corresponded to the known safety profile of the drug. No pathological findings were recorded in the post-study physical examinations. Based on the provided dossier the bioequivalence study using a parallel design has been performed according to current standards and adequately reported. Adequate methods have been employed for bioanalytical and statistical measurements and evaluations, respectively. In-study validation data are described in a separate report including information on respective quality assurance activities. The report comprises relevant calibration curve parameters, back-calculated concentrations of calibration standards, and between-run accuracy and precision. No deviations from the study plan occurred. Overall study results are in line with published data on leflunomide. The justification for the extrapolation of the bioequivalence study results to the 10 mg strength by the applicant is accepted, the requirements according to the Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98 (Rev 1)) are fulfilled. Pharmacovigilance system The applicant has provided documents that set out a detailed description of the pharmacovigilance system 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. Risk Management Plan 8/9 Public AR

9 The applicant has submitted a RMP dated May 2010 which meets the formal requirements of the Guideline on Risk Management Systems for Medicinal Products for Human Use and Annex C: Template for EU Risk Management Plan. With regard to contents the RMP is largely consistent with the originator s RMP. In particular all important risks, the pharmacovigilance plan and the risk minimization plan are identical to those outlined in the originator s RMP. The RMP is therefore endorsed. IV. BENEFIT RISK ASSESSMENT Leflunomide is a known immunomodulating substance used in the treatment of rheumatoid arthritis as disease modifying antirheumatic drug (DMARD). The application contains an adequate review of published non-clinical and clinical data. The SmPC/PIL is identical to the texts of Arava which were agreed within a renewal procedure in 2009 (EMEA/H/C/235/R/41) and updated in recent variation procedures. As this product adapts the approved actualised SmPC/PL of the innovator, the efficacy and safety is considered adequately reflected. No new safety concern was detected in this review. A user testing has been performed and accepted for the PL of Arava within the variation procedure EMEA/H/C /II/0038. Insofar no additional user test is considered necessary. Based on the submitted bioequivalence study, Leflunomide 20 mg is considered bioequivalent with the innovator product, Arava. No additional bioequivalence data is required. The application is approved. 9/9 Public AR