Public Assessment Report. Scientific discussion. Leflunomide Apotex 10 mg and 20 mg, tablets. (leflunomide) NL/H/2548/ /DC

Transcription

1 Public Assessment Report Scientific discussion Leflunomide Apotex 10 mg and 20 mg, tablets (leflunomide) /DC Date: 3 August 2015 This module reflects the scientific discussion for the approval of Leflunomide Apotex 10 mg and 20 mg, tablets. The decentralised procedure was finalised on 4 October 2010 with the UK as RMS. For information on changes after this date please refer to the steps taken after finalisation at the end of this PAR.

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Leflunomide Apotex 10 mg and 20 mg, tablets from Apotex Europe BV. The product is indicated for the treatment of adult patients with: active rheumatoid arthritis as a "disease-modifying antirheumatic 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. Moreover, 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. A comprehensive description of the indications and posology is given in the SmPC. This decentralised procedure concerns a generic version of the reference medicinal product Arava 10 mg film coated tablets, which has been authorised for 10 years in at least a Member state or in the Community (Sanofi-Aventis, , EU/1/99/118/ ). The decentralised procedure was finalized with a positive outcome on 4 October The concerned member states (CMS) involved in this procedure were Belgium, Czech Republic, Hungary, Luxembourg, the Netherlands and Spain. The product was withdrawn in the UK, the initial RMS, and the role of RMS was taken over by the Netherlands (2012). The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Drug Substance INN: Chemical name: Structure: Leflunomide ɑ, ɑ, ɑ-trifluro-5-methyl-4-isoxazolecarboxy-p-toluidide; 5-methylisoxazole-4- carboxylic acid trifluoromethylanilide. N-(4'-trifluoromethylphenyl)-5 methylisoxazole-4-caboxamide. Molecular formula: C 12 H 9 F 3 N 2 O 2 Molecular mass: Appearance: leflunomide is a white to almost white crystalline powder. It is soluble in methanol, ethanol, isopropanol, acetone, methylenechloride and dimethylsulfoxide. It is practically insoluble in water and aqueous buffers within the ph range 1.2 to 7.5. No stereoisomers exist for leflunomide as there are no asymmetric carbons in its structure. Three polymorphic forms are known for leflunomide. Leflunomide is the subject of a European Pharmacopoeia monograph. 2/10

3 All aspects of the manufacture and control of the active substance leflunomide are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. II.2 Medicinal Product Other ingredients Other ingredients consist of the pharmaceutical excipients anhydrous lactose, crospovidone type B, magnesium stearate and anhydrous silica colloidal. All excipients comply with their respective European Pharmacopoeia monograph. Suitable batch analysis data have been provided for each excipient. With the exception of lactose monohydrate and magnesium stearate, none of the excipients contain materials of animal or human origin. The supplier of lactose monohydrate has confirmed that the lactose is sourced from healthy animals under the same conditions as milk for human consumption. The supplier of the magnesium stearate has provided a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability, which covers all aspects of the manufacture and control of the excipient. The marketing authorisation holder has also confirmed that all future batches of finished product will use magnesium stearate sourced from vegetable origins. No genetically modified organisms (GMO) have been used in the preparation of these product. Pharmaceutical development The objective of the development programme was to formulate safe, efficacious tablets, containing 10 mg and 20 mg leflunomide that could be considered generic medicinal products of Arava film-coated tablets (Sanofi-Aventis GmbH). A satisfactory account of the pharmaceutical development has been provided. Comparative in vitro dissolution and impurity profiles have been provided for the proposed and originator products. Manufacturing process Satisfactory batch formulas have been provided for the manufacture of all strengths of product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated and has shown satisfactory results. Quality control of drug product The finished product specifications proposed are acceptable. Test methods have been described and have been adequately validated. Batch data have been provided and comply with the release specifications. Certificates of analysis have been provided for all working standards used. Stability of drug product Stability studies were performed in accordance with current guidelines on batches of all strengths of finished product packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 2 years for the 10 mg strength and 3 years for the 20 mg strength, with the special storage conditions 'Store below 25 C'. III. NON-CLINICAL ASPECTS As the pharmacodynamic, pharmacokinetic and toxicological properties of leflunomide are well-known, no new non-clinical studies are required and none have been provided. The applicant's non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the products' pharmacology and toxicology. A suitable justification has been provided for non-submission of an environmental risk assessment. As this product is intended for generic substitution with other products already on the market, it is not considered to increase the environmental risk. Thus, the applicant's justification is accepted. 3/10

4 IV. IV.1 CLINICAL ASPECTS Pharmacokinetics In support of these applications, the marketing authorisation holder has submitted the following bioequivalence study: An open-label, randomised, single-dose, one-period, three-way, parallel-group study to compare the pharmacokinetics of the test product Leflunomide Apotex 20 mg tablets versus the reference products Arava 20 mg tablets (Sanofi-Aventis, France and Australia) in healthy adult volunteers under fasted conditions. All volunteers were dosed in a fasted state in three treatment periods. Blood samples were taken for the measurement of pharmacokinetic parameters at pre- and up to 72 hours post dose. The washout period (with cholestyramine administration) between treatment periods was at least 11 days. No values for AUC 0- were calculated due to the long half-life of A and the truncated AUC 0-t. The pharmacokinetic results for A (the active metabolite of leflunomide), for the test product versus the French reference product are presented below (non-transformed values; arithmetic mean t max median, range): Treatment AUC 0-t C max t max ng/ml/h ng/ml h Test (mean) Reference (mean) *Ratio (90% CI) 1.02 ( ) 1.01 ( ) -- AUC 0-72 area under the plasma concentration-time curve from time zero to the last quantifiable plasma concentration C max maximum plasma concentration T max time for maximum concentration *ln-transformed values Conclusion on bioequivalence study The 90% confidence intervals for AUC and C max were within the predefined acceptance range for the active metabolite A for the test versus the (French) reference product. Thus, bioequivalence was demonstrated between the test and the reference product. Biowaiver As the 10 mg and 20 mg strengths of the product meet the criteria specified in the Notes for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98), the results and conclusions of the bioequivalence study on the 20 mg strength can be extrapolated to the 10 mg strength. IV.2 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 applicant commits to submit, before marketing in any Member State, the required updated RMP addressing the safety concerns requiring risk minimisation activities and to adhere fully to the recommendations in the EPAR for Arava. Conditions of the marketing authorisation pertaining to safe and effective use of the medicinal product and other conditions pertaining to the RMP, with the 4/10

5 exception of performing additional studies, but including additional pharmacovigilance activities as needed. This commitment has been fulfilled. V. USER CONSULTATION A package leaflet has been submitted 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. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Leflunomide Apotex 10 mg and 20 mg tablets have a proven chemical-pharmaceutical quality and are a generic form of Arava. The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. The bioequivalence study supports the claim that the applicant's products and the originator products are interchangeable. Extensive clinical experience with leflunomide is considered to have demonstrated the therapeutic value of the compound. The benefitrisk is, therefore, considered to be positive. There was no discussion in the CMD(h). Agreement between member states was reached during a written procedure. The member states, on the basis of the data submitted, considered that essential similarity has been demonstrated for Leflunomide Apotex 10 mg and 20 mg with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised with a positive outcome on 4 October /10

6 STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY Scope Implementation of agreed EU warnings for leflunomide containing products. Addition of a batch release site. To add an updated Risk Management Plan. Submission of a new or updated Ph. Eur. certificate of suitability or deletion of Ph. Eur. certificate of suitability: For an excipient. Change in test procedure for the finished product. The SmPC of the innovator product Arava was updated via variations EMEA/H/C/ II/0047 and EMEA/H/C/ II/049. Via this grouped type IB variation the SmPC is updated. Update of SmPC and PL in line with recently updated SmPC and PL of the innovator product Arava. Suspension of the marketing authorisation following the European Commission Decision for authorised medicinal products for which studies have been carried out or analysed by Cetero Research, during the time period April 2005 to June The SmPC and PL of the innovator product Arava have been updated via variation EMEA/H/C/000235/ W/271. Via this type IB variation the SmPC and PL are updated accordingly, and the product information is brought in line with version 3.0 of the QRD template for MRP/DCP products. Submission updated Certificate of Suitability for the active substance. Submission of the results of an additional bioequivalence study. Procedure number UK/H/2625/ /IB/ 001 UK/H/2625/ /IA/ 002 UK/H/2625/ /IB/ /IA/ 004/G /IB/ 005/G /IB/ 006 Article 31 referral EMEA/H/A- 31/ /IB/ /IA/ /II/ 009 Type of modification Date of start of the procedure Date of end of the procedure Approval/ non approval Assessment report attached IB Approval No IA Approval No IB Approval No IA/G Approval No IB/G Approval No IB Approval No Suspension Approval Assessment report reference: EMA/691568/ 2012 IB Approval No IA Approval No II Approval Annex I 6/10

7 Annex I C Submission of an additional bioequivalence study following suspension of the marketing authorisation ( /II/009) I. RECOMMENDATION Based on the review of the data on quality, safety and efficacy following submission of a new bioequivalence study, the Member States considers that the application for Leflunomide Apotex 10 mg and 20 mg tablets is approvable. The suspension of the marketing authorisation is lifted. II. II.1 EXECUTIVE SUMMARY Scope of the variation Following the outcome of the CHMP article 31 referral (EMEA/H/A-31/1340) on authorised medicinal products for which studies have been carried out or analysed by Cetero Research, during the time period April 2005 to June 2010 the Marketing Authorisations for Leflunomide Apotex 10 mg and 20 mg were suspended on 30 November For further details, refer to assessment report EMA/691568/2012, available on the EMA website. The following condition for lifting of the suspension was set: The National Competent Authorities of Member States, coordinated by the Reference Member State, shall ensure that the following conditions are fulfilled by the MAH: The MAH should provide adequate and satisfactory data confirming the bioequivalence of their product with the reference product within one year of the European Commission decision. Via this type II variation the results of an additional bioequivalence study was presented. III. III.1 SCIENTIFIC DISCUSSION Quality aspects Details of the clinical trial formula and that used in comparative dissolution testing are provided. The test product in the bioequivalence study is Leflunomide Apotex 20 mg, and the reference product is Arava 20 mg tablets by Sanofi-Aventis Deutschland GmbH, marketed in Germany. Sufficient batch analytical results of the biobatches have been provided. Supporting comparative dissolution profiles in QC and three different ph media were submitted. Comparative dissolution testing was not done using paddle apparatus at 50 rpm or basket apparatus at 100 rpm, which is recommended by the current guideline. A biowaiver for the 10 mg strength was however granted based on the old guideline which was in the force at the time of the assessment of the original application. At that time, a biowaiver to 10 mg tablet was accepted based on the comparative dissolution testing in three ph levels using paddle apparatus at 100 rpm. Therefore, considering that current dissolution was performed at the same conditions, this is acceptable. III.2 Clinical aspects Previously, a study (B050309) comparing Apotex Leflunomide 20 mg tablets and Arava 20 mg tablets from Sanofi-Aventis France and Australia under fasted condition has shown bioequivalence. However, due to concerns raised by the FDA and EMA over the general conduct of studies carried out by Cetero Research in the US and a subsequent CHMP Art. 31 referral, it was considered that the results of this biostudy were no longer valid. The MAH decided to conduct a second bioequivalence study (LU7898) of Leflunomide Apotex against Arava (Sanofi-Aventis Germany and Australia), which was submitted with this variation procedure. The details and results of the Australian reference product are not discussed in this report, as this is not relevant to the application. It is noted though that bioequivalence has been shown between the test and Australian reference product. 7/10

8 Bioequivalence study LU7898 Design This was a randomized, open-label, single dose, parallel bioequivalence study under fasting conditions in 77 male subjects aged years to compare the oral bioavailability of three formulations of leflunomide. Laboratory analysts were blinded to the randomization schedule to avoid bias. Subjects reported for check-in at the clinic site on the morning prior to study period until the last blood sampling time point. After an overnight fast of at least 10 hours, the subjects received a single dose of 20 mg either test or reference tablets with 240 ml water. Water was not permitted from 2 hour before dosing and until 2 hour after dosing, only the water that was provided with dosing was allowed. Blood samples were drawn pre-dose and at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose in each period. The procedures followed for a fasting condition are agreed. Food has no effect on the rate and extent of absorption of leflunomide. Hence a study in the fasting condition is agreed as this is more sensitive to detect differences between the test and reference product. The use of 20 mg strength is also agreed as this is the highest strength and in accordance with the bioequivalence guideline. The parallel design is further agreed due to the long elimination half-life of leflunomide. Due to leflunomide s long elimination half-life, subjects were given cholestyramine powder to facilitate the rapid elimination of leflunomide after blood sampling. After 72 hour post-dose blood sample collection, the first 8 grams (2 packets of 4 gram each) of cholestyramine powder was given in the clinical facility to each dosed subject. Each subject was given 64 packets of cholestyramine at checkout and instructed to take 8 grams of cholestyramine three times a day for 11 days to wash out leflunomide from the body. All subjects were asked to return to the facility to give a blood sample for leflunomide metabolite M1 (A771726) level estimation after 14 days of leflunomide administration. The use of cholestyramine powder to facilitate the rapid elimination of leflunomide is appropriate. Bioequivalence is intended to be demonstrated based on exposure to the active metabolite A The use of the metabolite A is acceptable as leflunomide is rapidly converted into this metabolite and it is mainly responsible for the pharmacological activity of leflunomide. The start and the duration of the sampling is sufficient for an immediate-release formulation to measure pharmacokinetic parameters considering the t max and half-life (1-36 h and approximately 2 weeks, respectively) of the active metabolite A Analytical/statistical methods The analytical methods have been adequately validated and are considered acceptable for analysis of the plasma samples. The methods used in this study for the pharmacokinetic calculations and statistical evaluation are considered acceptable. Biowaiver The MAH applied for a biowaiver for the additonal 10 mg strength with the following justification: a) the pharmaceutical products are manufactured by the same manufacturing process b) the qualitative composition of the different strengths is the same c) the composition strengths are quantitatively proportional, i.e. the ratio between the amount of each excipient to the amount of active substance(s) is the same for all strengths d) in vitro dissolution data demonstrated similarity between the two strengths e) pharmacokinetic linearity of the drug s active metabolite f) lack of a narrow therapeutic window. The requirements for a biowaiver are fulfilled. 100 mg loading dose The MAH did not apply for a 100 mg strength which is used as a loading dose needed to reach steady state rapidly (if no loading dose, it will take weeks to reach steady state with 20 mg). According to the MAH this can be substituted by taking 5 times 20 mg tablets considering the linear 8/10

9 pharmacokinetics over the therapeutic dose range. According to the posology of the innovator s product, the therapy is usually started with loading dose of 100 mg once daily for 3 days and omission of the loading dose may decrease the risk of adverse events. In the proposed product, if the loading dose is taken, compliance is not expected to be a problem as this is only once daily for 3 days. Hence the absence of the 100 mg strength is acceptable. Results Twenty-six subjects were dosed for test, twenty-five subjects for the European reference and twentysix subjects for the Australian reference product. All subjects completed and were all included in the pharmacokinetic and statistical analysis. Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max (median, range)) of leflunomide metabolite M1 (A771726) under fasted conditions. Treatment AUC ng/ml /h Test ± ± (1-4) Reference (European) *Ratio (90% CI) C max ng/ml t max ± ± (1 36) 1.00 ( ) 1.00 ( ) AUC 0-72 area under the plasma concentration-time curve from time zero to the last quantifiable plasma concentration C max maximum plasma concentration t max time for maximum concentration *ln-transformed values Conclusion on the bioequivalence study Pre-dose levels were beyond detection limit and t max has not been observed in any subject in the first post- post-dose sampling time. The 90% confidence intervals calculated for AUC 0-72 and C max are within the bioequivalence acceptance range of Based on the submitted bioequivalence study Leflunomide Apotex 20 mg is considered bioequivalent with Arava 20 mg tablets. Safety A total of 10 mild adverse events occurred in eight subjects after they received the test product and 11 mild adverse events occurred in ten subjects after they received the European reference product. Out of 77 dosed subjects 62 subjects showed acceptable levels of leflunomide drug (less than 0.02 μg/ml) when estimated 14 and 28 days after leflunomide administration. The remaining 15 subjects were followed up until the leflunomide drug level went down to the acceptable level of less than 0.02 μg/ml. The MEB has been assured that the bioequivalence study has been conducted in accordance with acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC). h -- IV. UPDATED DISCUSSION, OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT Following the outcome of the CHMP article 31 referral (EMEA/H/A-31/1340) on authorised medicinal products for which studies have been carried out or analysed by Cetero Research, during the time period April 2005 to June 2010 the Marketing Authorisations for Leflunomide Apotex 10 mg and 20 mg were suspended. In order to lift the suspension, the MAH was required to provide adequate and satisfactory data confirming the bioequivalence of their product with the reference product within one year of the European Commission decision. In this type II variation the MAH provided data of a new 9/10

10 bioequivalence study between Leflunomide Apotex and the reference product Arava. As the results confirmed bioequivalence, the condition for lifting the suspension is fulfilled. The variation procedure was finalized with a positive outcome on 21 January /10