LEFLUNOMIDE 10 MG TABLETS LEFLUNOMIDE 20 MG TABLETS LEFLUNOMIDE 100 MG TABLETS PL 33410/ UKPAR TABLE OF CONTENTS - PDF

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LEFLUNOMIDE 10 MG TABLETS LEFLUNOMIDE 20 MG TABLETS LEFLUNOMIDE 100 MG TABLETS PL 33410/ UKPAR TABLE OF CONTENTS Lay Summary Page 2 Scientific discussion Page 3 Steps taken for assessment Page 14
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LEFLUNOMIDE 10 MG TABLETS LEFLUNOMIDE 20 MG TABLETS LEFLUNOMIDE 100 MG TABLETS PL 33410/ UKPAR TABLE OF CONTENTS Lay Summary Page 2 Scientific discussion Page 3 Steps taken for assessment Page 14 Steps taken after authorisation summary Summary of Product Characteristics Page 15 Patient Information Leaflet Page 54 Labelling Page 69 1 LEFLUNOMIDE 10 MG TABLETS LEFLUNOMIDE 20 MG TABLETS LEFLUNOMIDE 100 MG TABLETS PL 33410/ LAY SUMMARY The Medicines and Healthcare products Regulatory Agency (MHRA) granted APSLA Limited Marketing Authorisations for the medicinal products Leflunomide 10 mg, 20 mg and 100 mg Tablets (PL 33410/0096-8) on 21 February Leflunomide Tablets are only available on prescription from your doctor and are used to treat adult patients with active: rheumatoid arthritis. Symptoms of rheumatoid arthritis include inflammation of joints, swelling, difficulty in moving and pain. Other symptoms of rheumatoid arthritis that affect the entire body include loss of appetite, fever, loss of energy and anaemia (lack of red blood cells). psoriatic arthritis. Symptoms of active psoriatic arthritis include inflammation of joints, swelling, difficulty in moving, pain and patches of red, scaly skin (skin lesions). Leflunomide Tablets contain the active ingredient leflunomide, which belongs to a group of medicines called anti-rheumatic medicines. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Leflunomide 10 mg, 20 mg and 100 mg Tablets outweigh the risks and Marketing Authorisations were granted. 2 LEFLUNOMIDE 10 MG TABLETS LEFLUNOMIDE 20 MG TABLETS LEFLUNOMIDE 100 MG TABLETS PL 33410/ SCIENTIFIC DISCUSSION TABLE OF CONTENTS Introduction Page 4 Pharmaceutical assessment Page 6 Non-clinical assessment Page 9 Clinical assessment Page 10 Overall conclusions and risk assessment Page 13 3 INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted APSLA Limited Marketing Authorisations for the medicinal products Leflunomide 10 mg, 20 mg and 100 mg Tablets (PL 33410/0096-8) on 21 February The products are prescription-only medicines used in the treatment of adult patients with: active rheumatoid arthritis as a disease-modifying anti-rheumatic drug (DMARD) 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. Switching from leflunomide to another DMARD without following the washout procedure (see section 4.4 of the SmPC) may also increase the risk of serious adverse reactions even for a long time after the switching. These applications were submitted under Article 10.1 of Directive 2001/83/EC, as amended, claiming to be generic medicinal products of Arava 10 mg, 20 mg and 100 mg film-coated tablets (Sanofi-Aventis Deutschland GmbH, Germany), which were first authorised in the EEA via the Centralised Procedure on 02 September Leflunomide is a disease-modifying anti-rheumatic agent with anti-proliferative properties (selective immunosuppressive agent ATC code: L04AA13). Leflunomide can be administered with food, since the extent of absorption is comparable in the fed and fasting state. Leflunomide is rapidly converted to the active metabolite, A771726, by first-pass metabolism in gut wall and liver. A inhibits the human enzyme dihydroorotate dehydrogenase (DHODH) and exhibits antiproliferative activity. No new non-clinical data were submitted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been in clinical use for over 10 years. Two single-dose bioequivalence studies were submitted to support these applications, comparing the test products Leflunomide 20 mg and 100 mg Tablets (APSLA Limited, Ireland) with the corresponding reference products Arava 20 mg and 100 mg film-coated tablets (Sanofi-Aventis Deutschland GmbH, Germany) under fasting conditions. The bioequivalence studies were carried out in accordance with Good Clinical Practice (GCP). With the exception of the bioequivalence studies, no new clinical data were submitted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been in clinical use for over 10 years. No new or unexpected safety concerns arose during review of information provided by the Marketing Authorisation Holder and it was, therefore, judged that the benefits of taking Leflunomide 10 mg, 20 mg and 100 mg Tablets outweigh the risks and Marketing Authorisations were granted. 4 PHARMACEUTICAL ASSESSMENT ACTIVE SUBSTANCE INN: Leflunomide Chemical Name: 5-Methyl-N-[4-(trifluoromethyl)phenyl]isoxazole-4-carboxamide Molecular Formula: C 12 H 9 F 3 N 2 O 2 Structure Molecular mass: Appearance: g/mol White or almost white powder, practically insoluble in water, freely soluble in methanol, sparingly soluble in methylene chloride. Leflunomide is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance leflunomide, except for the proposed packaging specifications and stability data are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. Suitable specifications and Certificates of Analysis have been provided for all packaging used. The primary packaging is controlled to European Pharmacopoeia standards and complies with current legislation relating to packaging in contact with foodstuff. Appropriate stability data have been generated to support a suitable retest period for the active substance when stored in the proposed packaging. Suitable post approval stability commitments have been provided to continue stability testing on batches of the active substance. DRUG PRODUCT Other Ingredients Other ingredients consist of the pharmaceutical excipients in the tablet core and film coating, namely lactose monohydrate, lactose anhydrous, maize starch, hydroxypropyl cellulose, povidone, colloidal anhydrous silica, magnesium stearate, hypromellose (E464), titanium dioxide (E171), macrogol and purified water. In addition, the 20 mg strength tablet contains iron oxide yellow (E172). Appropriate justification for the inclusion of each excipient has been provided. All excipients comply with their respective European Pharmacopoeia monograph with the exception of hydroxypropyl cellulose and iron oxide yellow (E172), which are controlled to United States Pharmacopoeial-National Formulary specifications. In addition, the specification for iron oxide yellow (E172) is in compliance with the relevant European Directives concerning the use of colouring agents in foodstuff. Satisfactory Certificates of Analysis have been provided for all excipients. 5 With the exception of lactose monohydrate, lactose anhydrous and magnesium stearate, none of the excipients contain materials of animal or human origin. The suppliers of lactose monohydrate and lactose anhydrous have confirmed that the milk used in the production of lactose is sourced from healthy animals under the same conditions as that intended for human consumption. The supplier of the magnesium stearate has provided a declaration of compliance with current regulations concerning the minimisation of transmission of TSE/BSE. The Marketing Authorisation Holder has also confirmed that all future batches of finished product will use magnesium stearate sourced from vegetable origin. No genetically modified organisms (GMO) have been used in the preparation of these excipients. Pharmaceutical Development The objective of the development programme was to formulate safe, efficacious, stable products that could be considered generic medicinal products of the reference products Arava 10 mg, 20 mg and 100 mg film-coated tablets (Sanofi-Aventis Deutschland GmbH, Germany). Suitable pharmaceutical development data have been provided for these applications. Comparative in-vitro dissolution and impurity profiles have been provided for these products and their respective reference products. Manufacturing Process Satisfactory batch formulae have been provided for the manufacture of all strengths of the product, along with an appropriate account of the manufacturing process. Based on pilot-scale batches, the manufacturing process has been validated and has shown satisfactory results. The Marketing Authorisation Holder has committed to submitting validation data performed on full-scale batches as soon as they are available. Control of Finished Product The finished product specifications are satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specifications. Certificates of Analysis have been provided for any working standards used. Container Closure System The 10 mg and 20 mg strength tablets are packaged in white, high density polyethylene (HDPE) bottles with white polypropylene child resistant caps, in pack sizes of 30, 50 (20 mg strength only) and 100 (20 mg strength only) tablets. The 100 mg strength tablets are packaged in 3-ply aluminium/aluminium/polyvinyl chloride blisters, in a pack size of 3 tablets. Not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning materials in contact with food. 6 Stability Finished product stability studies were performed in accordance with current guidelines on batches of finished product packed in the packaging proposed for marketing. Based on the results, the following shelf-life/storage conditions were accepted: - 2 years for product packaged in HDPE tablet containers, with the storage conditions, Keep the container tightly closed. - 2 years for product packaged in blister packs, with the storage conditions Store in the original package. Suitable post approval stability commitments have been provided to continue stability testing on batches of finished product. Bioequivalence/Bioavailability Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the bioequivalence studies. Summaries of Product Characteristics (SmPCs), Patient Information Leaflets (PILs) and Labelling The SmPCs, PILs and labelling are satisfactory from a pharmaceutical perspective. The Marketing Authorisation Holder has committed to submitting mock-ups to the relevant competent authorities for approval before marketing any pack size. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ( user testing ), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. MAA (Marketing Authorisation Application) Forms The MAA forms are pharmaceutically satisfactory. Expert Report (Quality Overall Summary) The quality overall summary is written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion The grant of Marketing Authorisations is recommended. 7 NON-CLINICAL ASSESSMENT PHARMACODYNAMICS, PHARMACOKINETICS AND TOXICOLOGY As the pharmacodynamic, pharmacokinetic and toxicological properties of leflunomide are well-known, no further non-clinical studies are required and none have been provided. NON-CLINICAL EXPERT REPORT (NON-CLINICAL OVERVIEW) The non-clinical overview has been written by an appropriately qualified person and is a suitable summary of the non-clinical aspects of the dossier. ENVIRONMENTAL RISK ASSESSMENT Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As these products are intended for generic substitution with products that are already marketed, no increase in environmental burden is anticipated. Thus, the justification for non-submission of an Environmental Risk Assessment is accepted. CONCLUSION The grant of Marketing Authorisations is recommended. 8 CLINICAL ASSESSMENT CLINICAL PHARMACOLOGY The clinical pharmacology of leflunomide is well-known. With the exception of data from the bioequivalence studies described below, no new pharmacodynamic or pharmacokinetic data were provided or required for these applications. Pharmacokinetics In support of the applications, the Marketing Authorisation Holder submitted the following bioequivalence studies: Study 1 A randomised, single-dose, open-label, parallel study comparing the pharmacokinetics of the test product Leflunomide 20 mg Tablets (APSLA Limited, Ireland) and the reference product Arava 20 mg film-coated tablets (Sanofi-Aventis Deutschland GmbH, Germany ) in healthy adult male subjects under fasting conditions. The subjects were administered one tablet of either the test or the reference product with 240 ml of water, after an overnight fast. Blood samples were collected before and up to 72 hours after each administration. Leflunomide is rapidly converted to the active metabolite A771726; therefore analysis of leflunomide for the determination of bioequivalence is not possible. Measurement of the active metabolite is appropriate. As the active leflunomide metabolite (A771726) has a long half-life, subjects were later given cholestyramine to eliminate the metabolite from blood.the pharmacokinetic results for active leflunomide metabolite (A771726) are presented below: Pharmacokinetic parameters (arithmetic mean±sd, ratios and confidence intervals [CI]) of active leflunomide metabolite (A771726) Parameters Leflunomide 20 mg Arava 20 mg Test/Ref 90% CI (units) (Test) (Reference) Ratio (%) AUC ± ± (ng hr/ml) C max ± ± (ng/ml) AUC 0-72 area under the plasma concentration-time curve from time zero to 72 hours C max maximum plasma concentration SD=standard deviation Ratios and 90% CI calculated from log-transformed data The Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98) defines the confidence limits for ratio of geometric means for acceptance of bioequivalence as 80.00% to % for AUC and C max values. The 90% confidence intervals for AUC 0-72 and C max lie within the acceptable limits for the active metabolite A for the test versus the reference products. Thus, the data support the claim that the test product Leflunomide 20 mg Tablets (APSLA Limited, Ireland) is bioequivalent to the reference product Arava 20 mg film-coated tablets (Sanofi-Aventis Deutschland GmbH, Germany). 9 STUDY 2 An open-label, randomised, balanced, single-dose, two treatment, parallel-group study to compare the pharmacokinetics of the test product Leflunomide 100 mg Tablets (APSLA Limited, Ireland) versus the reference product Arava 100mg film-coated tablets (Sanofi-Aventis Deutschland GmbH, Germany) in healthy adult male volunteers under fasted conditions. The subjects were administered one tablet of either the test or the reference product with 240 ml of water, after an overnight fast.blood samples were collected before and up to 72 hours after each administration. As the active leflunomide metabolite (A771726) has a long half-life, subjects were later given cholestyramine to eliminate the metabolite from blood. The pharmacokinetic results for active leflunomide metabolite are presented below: Pharmacokinetic parameters (arithmetic mean±sd, ratios and confidence intervals [CI]) of active leflunomide metabolite (A771726) Parameters Leflunomide 100 mg Arava 100 mg Test/Ref Ratio 90% CI (units) (Test) (Reference) (%) AUC ± ± (ng hr/ml) C max ± ± (ng/ml) AUC 0-72 area under the plasma concentration-time curve from time zero to 72 hours C max maximum plasma concentration SD=standard deviation Ratios and 90% CI calculated from log-transformed data The Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98) defines the confidence limits for ratio of geometric means for acceptance of bioequivalence as 80.00% to % AUC and C max values. The 90% confidence intervals for AUC 0-72 and C max lie within the acceptable limits for the active metabloite A for the test versus the reference products. Thus, the data support the claim that the test product Leflunomide 100 mg Tablets (APSLA Limited, Ireland) is bioequivalent to the reference product Arava 100 mg film-coated tablets (Sanofi-Aventis Deutschland GmbH, Germany). As the 10 mg, 20 mg and 100 mg strengths of the product meet the criteria specified in the Notes for Guidance on the Investigation of Bioavailability and Bioequivalence for a biowaiver (CPMP/EWP/QWP/1401/98), the results and conclusions of the bioequivalence studies on the 20mg and 100 mg strengths can be extrapolated to the 10 mg strength. EFFICACY The efficacy of leflunomide is well-known. No new efficacy data have been submitted and none are required for applications of this type. 10 SAFETY With the exception of the safety data generated during the bioequivalence studies, no new safety data were submitted and none are required for applications of this type. No new or unexpected safety issues were raised by the bioequivalence data. PHARMACOVIGILANCE SYSTEM AND RISK MANAGEMENT PLAN The Pharmacovigilance System, as described by the applicant, fulfils the requirements 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. The Risk Management Plan proposed by the applicant is acceptable. The applicant has made a commitment to ensure that any changes to the safety profile of the reference medicinal product requiring changes to the Risk Management Plan or product information are implemented for the generic product in an appropriately timely fashion. Conditions or restrictions regarding supply and use imposed on the Marketing Authorisation Holder (MAH) These are medicinal product subjects to restricted medical prescription (Summary of Product Characteristics, section 4.2). Conditions or restrictions with regard to the safe and effective use of the medicinal product Prior to placing the product on the market, the Marketing Authorisation Holder (MAH) shall ensure that all physicians who are expected to prescribe/use leflunomide are provided with a physician educational pack containing the following: o The Summary of Product Characteristics o Physician Leaflet The Physician Leaflet should contain the following key messages: That there is a risk of severe liver injury and so regular measurement of ALT (SGPT) levels to monitor liver function is important. The information provided in the Physician Leaflet should provide information on dose reduction, discontinuation and wash out procedures. The identified risk of synergistic hepato- or haematotoxicity associated with combination therapy with another Disease-Modifying Antirheumatic Drug (e.g. methotrexate). That there is a risk of teratogenicity and so pregnancy must be avoided until leflunomide plasma levels are at an appropriate level. Physicians and patients should be made aware that there is an ad-hoc advisory service available to provide information on leflunomide plasma level laboratory testing. The risk of infections, including opportunistic infections, and the contraindication for use in immunocompromised patients. The need to counsel patients on important risks associated with leflunomide therapy and appropriate precautions when using the medicine. 11 SUMMARIES OF PRODUCT CHARACTERISTICS (SmPCs
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