Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Leflunomid Schluttig 10 mg <20 mg> <100 mg> Filmtabletten Leflunomid Pharma Resources 10 mg <20 mg> <100 mg> Filmtabletten (Leflunomide) DE/H/2571-2572/01-03/DC Applicant: Pharma Resources Dr. Schluttig GmbH Reference Member State DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/8 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...8 2/8 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 Leflunomid Schluttig 10 mg, 20 mg, 100 mg Filmtabletten Leflunomid Pharma Resources 10mg, 20 mg, 100 mg Filmtabletten Leflunomide L04AA13 (Selective immunosuppressive agent) Film-coated tablets 10 mg, 20 mg and 100 mg DE/H/2571-2572/01-03/DC DE LU Pharma Resources Dr. Schluttig GmbH Otto-Hahn-Str. 46 63303 Dreieich Germany 1.) Aliud Pharma GmbH & Co. KG Gottlieb-Daimler-Str. 19 89150 Laichingen Germany 2.) STADA Arzneimittel AG Stadastrasse 2 18 61118 Bad Vilbel Germany 3/8 Public AR
I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for LEFLUNOMID SCHLUTTIG 10 mg, 20 mg, 100 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 This decentralised application concerns a generic version of leflunomide, under 2 different trade names, LEFLUNOMID SCHLUTTIG (10 mg, 20 mg, 100 mg) and Leflunomid Pharma Resources (10mg, 20 mg, 100 mg). In this Assessment Report, the name Leflunomid Schluttig 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: Leflunomide is used as a disease-modifying antirheumatic drug (DMARD) for the treatment of adult patients with active rheumatoid arthritis, and active psoriatic arthritis. However, 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 below) may also increase the risk of serious side effects even for a long time after the switching. Pharmacologically, leflunomide is predominantly an immunomodulating agent (ATC Code: L04AA13). The exact mechanisms of action of leflunomide in the management of rheumatoid arthritis has not yet been fully elucidated but appear to principally involve regulation of autoimmune lymphocytes, such as those involved in the pathogenesis of rheumatoid arthritis. It has been suggested that leflunomide exerts its immunomodulating effects by preventing the expansion of activated autoimmune lymphocytes via interference with cell cycle progression. Administration of leflunomide in patients with rheumatoid arthritis results in progressive removal of autoimmune lymphocytes and downregulation of the autoimmune process. Leflunomide is therefore used as a DMARD primarily in the treatment of active rheumatoid arthritis but also in the treatment of active psoriatic arthritis. Leflunomide was introduced into clinical practice in the mid-1990s and has therefore been used therapeutically for more than one decade. Hence, leflunomide is well known with respect to the overall pharmaco-toxicological and clinical properties as well as its clinical use. Leflunomide tablet preparations have already been approved and are marketed (mainly under the trade name "Arava") in many European countries, in the USA and in numerous other non-european countries. II.3 General comments on the submitted dossier Concerning the type of marketing authorisation application, see section II.1. 4/8 Public AR
Two bioavailability studies have been performed (20mg and 100mg leflunomide). They compared the rate and extent of absorption of Leflunomid Schluttig against Arava by Sanofi Aventis and are performed in accordance with the CHMP Note for Guidance on Bioavailability and Bioequivalence. A literature review has been submitted which is accepted. The SmPC is identical with the SmPC of the innovator product, Arava, which was recently actualised (EMEA/H/C/235/R/41) and subsequently updated (current version: EMEA/H/C/235/II/46). The PL is identical to the PL of the innovator product, which has been user tested (EMEA/H/C/235/II/038), therefore no additional user testing is considered necessary for Leflunomid Schluttig. 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 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 authorities for the manufacturers of the finished drug product (packaging, batch release) have been provided. For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, as certification that acceptable standards of GMP are in place at those non-community sites. The bioequivalence studies were planned, conducted and reported in accordance with pertinent legal and ethical directives and guidelines of orderly study conduct and GCP. III. III.1 SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects Drug substance The chemical-pharmaceutical documentation in relation to Leflunomid Schluttig film-coated tablets 10 mg / 20 mg /100 mg is 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 manufactured by one of the manufacturers 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 certificates of suitability. For the material manufactured a re-test period of two years is confirmed on the current CEP when stored in double LDPE bags in an HDPE drum. For the drug substance leflunomide of another manufacturer details on characteristics, manufacturing process, impurity profile, specifications, analytical procedures and validations of drug substance are presented in an Active Substance Master File. The drug substance manufacturer has submitted the complete ASMF (open part and restricted part) in its current version / amendment to the regulatory authority along with a letter of access to allow the applicant to refer to their ASMF. The control tests and specifications for leflunomide are adequately drawn up. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed retest period of 3 years for leflunomide manufactured by this manufacturer is justified. Drug product The development of the products Leflunomid Schluttig film-coated tablets 10 mg / 20 mg /100 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. 5/8 Public AR
The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on 5 batches for 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. Results from a photostability study have been submitted in the revised Module 3. According to the results obtained a storage advice is proposed: Store in the original package in order to protect from moisture. A shelf-life of 36 months with the storage advise Store in the original package in order to protect from moisture for the drug product is accepted. Conclusion There is no outstanding issue regarding the pharmaceutical quality. III.2 Nonclinical aspects Pharmacology, pharmacokinetics and toxicology 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 and the applicant provides none. Overview based on literature review is appropriate. The submitted nonclinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is considered adequate. The non-clinical properties of leflunomide are adequately summarized in the SmPC which is identical to the SmPC of the reference medicinal product, Arava. Environmental Risk Assessment The applicant did not present an environmental risk assessment (ERA) in the application by justifying that an increase in the environmental exposure is not expected and an environmental risk assessment was deemed not necessary. This is agreed by the RMS. Conclusion A marketing authorisation is granted. III.3 Clinical aspects Clinical efficacy As this is a medicinal product with a systemic effect, there is the need of appropriate bioequivalence studies to justify efficacy. To support the application for Leflunomid Schluttig film-coated tablets 10 / 20 / 100 mg, the applicant has submitted two bioequivalence studies, i.e. for the 20 mg and 100 mg strengths. Bioequivalence Leflunomide is considered a prodrug since it is rapidly and almost completely metabolised to the active metabolite A771726, which is responsible for essentially all the in vivo activity. Moreover, it has to be considered that studies using multiple doses (5-25 mg/d) of leflunomide indicate that plasma levels of A771726 are dose-proportional, i.e., A771726 plasma concentrations are dose-proportional over a dose range of 5 to 25 mg once daily (Rozman 2002; Silva & Morris 1997; for more pharmacokinetic data, see Section 2.5.3.2.). Accordingly, the two clinical trials have been conducted - as generally recommended - with the higher 100-mg and 20-mg strengths to demonstrate adequate bioavailability and bioequivalence of these tablet formulations in comparison with the corresponding strength of the reference (innovator) product Arava. Due to the very long elimination half-life of A771726, a parallel-group design was chosen for both studies. 6/8 Public AR
The studies were planned, conducted and reported in accordance with pertinent legal and ethical directives and guidelines of orderly study conduct and GCP. Pharmacokinetic conclusion Based on the two submitted bioequivalence studies (results see below) the 20 and 100 mg test products are considered bioequivalent to the innovator product. I. Study on the bioequivalence of a 20 mg leflunomide film-coated tablet as compared to a market standard (Arava ) as reference after single dose administration in healthy male subjects. Pharmacokinetic data for the main metabolite A771726 and results of the ANOVA (after a single oral dose of 20 mg leflunomide; n = 80) Parameters Test product: Geom. mean (Geom. SD) Mean ± SD (CV) C max [ng/ml] 1792 (1.21) 1824 ± 343 (18.80) AUC 0-72 [ng/ml h] 92919 (1.20) 94298 ± 15396 (16.33) Reference product: Geom. mean (Geom. SD) Mean ± SD (CV) 1795 (1.25) 1834 ± 357 (19.49) 91809 (1.22) 93451 ± 16961 (18.15) Point estimate test/ref. ratio 90% confidence interval 99.84 92.42-107.87 101.21 94.31-108.61 t max [h] 3.00 (Median) 1.52 (Median) - - II. Study on the bioequivalence of a 100 mg leflunomide film-coated tablet as compared to a market standard (Arava ) as reference after single dose administration in healthy male subjects. Pharmacokinetic data for the main metabolite A771726 and results of the ANOVA (after a single oral dose of 100 mg leflunomide; n = 80) Parameters Test product: Geom. mean (Geom. SD) Mean ± SD (CV) C max [ng/ml] 10988 (1.19) 11153 ± 1990 (17.85) AUC 0-72 [ng/ml h] 557331 (1.18) 565060 ± 97170 (17.20) Reference product: Geom. mean (Geom. SD) Mean ± SD (CV) 10462 (1.21) 10654 ± 2043 (19.17) 508806 (1.18) 515801 ± 85874 (16.65) Point estimate test/ref. ratio 90% confidence interval 105.02 98.06-112.48 109.54 102.92-116.58 t max [h] 3.00 (Median) 3.02 (Median) - - All issues raised concerning the bioequivalence studies by the RMS have been sufficiently solved. Pharmacodynamics The pharmacodynamic profile of leflunomide is established and sufficiently characterized in literature. No new data are required. Clinical efficacy and safety 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. 7/8 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 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 The applicant has submitted an updated Risk Management Plan. The RMP 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, however some parts including the safety specification are considerably abridged compared to a full presentation. In particular all important risks, the pharmacovigilance plan and the risk minimization plan are identical to those outlined in the originator s RMP. Following the RMS s previous comments the RMP has been updated to include a warning regarding progressive multifocal leucoencephalopathy (PML) in section 4.4 of the SmPC as a risk management activity. The RMP is therefore endorsed. In addition the applicant has supplied updated wordings for the physician leaflet and the patient information sheet. These now contain all relevant information outlined in the SmPC regarding the key messages set out in the conditions of the marketing authorisation for the reference medical product and are therefore endorsed. Additionally the applicant commits to ensure that - prior to launch, all physicians who are expected to prescribe/use the product are provided with a physician educational pack containing the following: SmPC, physician leaflet - that any changes to the safety profile of the reference medicinal product requiring changes to the RMP, product information, physician leaflet or patient information sheet are immediately implemented for the applicant s medicinal product. IV. BENEFIT RISK ASSESSMENT The application contains an adequate review of published nonclinical and clinical data. With regard to the efficacy and safety analysis, the characteristics of the innovator have been reassessed repeatedly after the first marketing authorisation and at last actualised within a finalised renewal procedure in 2009 (EMEA/H/C/235/R/41). 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. Based on the two submitted bioequivalence studies, Leflunomid Schluttig 20 mg, 100 mg is considered bioequivalent with Arava, the innovator product.. The applicant has submitted a RMP 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. The application is approved. 8/8 Public AR