Public Assessment Report. Scientific discussion. Flecazela CR 50 mg, 100 mg, 150 mg and 200 mg, prolonged-release capsules, hard. (flecainide acetate)

Transcription

1 Public Assessment Report Scientific discussion Flecazela CR 50 mg, 100 mg, 150 mg and 200 mg, prolonged-release capsules, hard (flecainide acetate) NL/H/2996/ /DC Date: 16 February 2016 This module reflects the scientific discussion for the approval of Flecazela CR 50 mg, 100 mg, 150 mg and 200 mg, prolonged-release capsules, hard. The procedure was finalised on 25 February For information on changes after this date please refer to the steps taken after finalisation at the end of this PAR.

2 List of abbreviations C AE ASMF CEP CHMP CMD(h) CMS EDMF EDQM EEA ERA ICH MAH Ph.Eur. PL RH RMP SmPC TSE Adverse Event Active Substance Master File Certificate of Suitability to the monographs of the European Pharmacopoeia Committee for Medicinal Products for Human Use Coordination group for Mutual recognition and Decentralised procedure for human medicinal products Concerned Member State European Drug Master File European Directorate for the Quality of Medicines European Economic Area Environmental Risk Assessment International Conference of Harmonisation Marketing Authorisation Holder European Pharmacopoeia Package Leaflet Relative Humidity Risk Management Plan Summary of Product Characteristics Transmissible Spongiform Encephalopathy 2/11

3 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Medicines Evaluation Board (MEB) of the Netherlands has granted a marketing authorisation for Flecazela CR 50 mg, 100 mg, 150 mg and 200 mg, prolonged-release capsules, hard from Disphar International B.V. The product is indicated for treatment of: AV nodal reciprocating tachycardia; arrhythmias associated with Wolff-Parkinson-White Syndrome and similar conditions with accessory pathways, when other treatment has been ineffective. Severe symptomatic and life-threatening paroxysmal ventricular arrhythmia which has failed to respond to other forms of therapy. Also where other treatments have not been tolerated. Paroxysmal atrial arrhythmias (atrial fibrillation, atrial flutter and atrial tachycardia) in patients with disabling symptoms after conversion provided that there is definite need for treatment on the basis of severity of clinical symptoms, when other treatment has been ineffective. Structural heart disease and/or impaired left ventricular function should be excluded because of the increased risk for pro-arrhythmic effects. A comprehensive description of the indications and posology is given in the SmPC. This decentralised procedure concerns a generic application claiming essential similarity with the innovator product Flécaïne prolonged release capsules, which has been registered in France by Meda Pharma since 18 December In the Netherlands the innovator product is Tambocor CR 50 mg, 100 mg, 150 mg and 200 mg prolonged release capsules (NL License RVG ), registered by Meda Pharma B.V. since 10 June One concerned member state (CMS) was involved in this procedure, however the application was withdrawn in this member state before finalisation. The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Introduction Flecazela CR 50 mg is a gelatine opaque capsule with white body and white cap containing white coated pellets. Flecazela CR 100 mg is a gelatine opaque capsule with grey body and white cap containing white coated pellets. Flecazela CR 150 mg is a gelatine opaque capsule with grey body and grey cap containing white coated pellets. Flecazela CR 200 mg is a gelatine opaque capsule with grey body and pink cap containing white coated pellets. The hard capsules are packed in PVC/PVDC-Aluminium blisters. The excipients are: cellulose microcrystalline, methacrylic acid-methyl methacrylate (1:2) copolymer, macrogol 400, talc, ethanol 96%. In addition: 50 mg capsule: gelatin, titanium dioxide. 100 mg capsule: gelatin, titanium dioxide, black iron oxide. 150 mg capsule: gelatin, titanium dioxide, black iron oxide. 200 mg capsule: gelatin, titanium dioxide, black iron oxide, erythrosine The flecainide prolonged release capsules contain microgranules coated with a polymer, which enables the active substance to be released at a regular rate. The composition of the different strengths is identical, only the amount of granules is different. 3/11

4 II.2 Drug Substance The active substance is flecainide acetate, an established active substance described in the European Pharmacopoeia (Ph.Eur.). The drug substance is soluble in water and in anhydrous ethanol. Flecainide acetate is not known to exhibit polymorphism. The CEP procedure is used for the active substance. Under the official Certification Procedures of the EDQM of the Council of Europe, manufacturers or suppliers of substances for pharmaceutical use can apply for a certificate of suitability concerning the control of the chemical purity and microbiological quality of their substance according to the corresponding specific monograph, or the evaluation of reduction of Transmissible Spongiform Encephalopathy (TSE) risk, according to the general monograph, or both. This procedure is meant to ensure that the quality of substances is guaranteed and that these substances comply with the European Pharmacopoeia. Manufacturing process A CEP has been submitted; therefore no details on the manufacturing process have been included. Quality control of drug substance The active substance specification is considered adequate to control the quality and meets the requirements of the monograph in the Ph.Eur. Batch analysis results have been provided for 5 batches of drug substance with results meeting the set drug substance specification. Stability of drug substance No re-test period is stated on the CEP. For 3 batches 5 years long-term data at 25 C/60% RH and 6 months accelerated data at 40 C/75% RH are presented with results meeting the Ph. Eur. and CEP requirements. The applied re-test period is 5 years if stored not above 25 C. II.3 Medicinal Product Pharmaceutical development The pharmaceutical development of the proposed product has been adequately described. The formulation development is strongly based on the qualitative composition of the innovator product. Data on the test and reference batches used in the bioavailability and bioequivalence studies has been provided. An overview of the batch analysis results has been given; results for assay and dissolution are comparable for the test and reference bio-batches. An adequate overview is given regarding the relation between the pellet size distribution and the resulting dissolution profile. The comparative dissolution testing between the test bio-batch and the other mg strengths of Flecazela and the reference bio-batch, at ph 1.2, ph 4.5 and ph ph 6.8, showed similarity. A bio-waiver can be granted for the mg strengths from a chemical-pharmaceutical point of view. Manufacturing process The manufacturing process is well described. The coated pellets for the mg capsules are in fact identical pellets. The non-standard manufacturing process, i.e. coating of raw pellets produced by extrusion and spheronization processes, is well under control for 3 batches of each strength manufactured at the intended production scale. Control of excipients Most of the excipients are in accordance with Ph. Eur. Iron oxide, black (E172) and Erythrosine (E127) in accordance with Commission Directive 2008/128/EC. Adequate specifications are applied for the empty hard gelatin capsules sizes Quality control of drug product In general adequate drug product specifications are proposed for description, identification of flecainide, average mass capsule content, uniformity of dosage units (content uniformity), dissolution, related substances, assay, residual ethanol, and microbial contamination. The analytical methods have been adequately described and validated. The batch analysis results of 3 batches per strength meet the set specifications. 4/11

5 Stability of drug product Long-term and accelerated stability studies are carried out conform current ICH guidelines. The lowest and highest strengths (50 and 200 mg flecainide capsules, each 3 batches) are used as test samples in a bracketing design. The available stability data are 6 months at 40 C/75% RH and 24 months at 30 C/75% RH. All normal and accelerated stability results were in accordance with the specifications. Based on the available stability data and based on extrapolation, the claimed shelf-life of 3 years can be granted. Based on the results of a photostability study the product should be stored in the Alu PVC/PVDC blister packaging to protect from light. Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies There is no risk of TSE/BSE. Microcrystalline cellulose and ethanol 96% are of plant origin, methacrylic acid - methyl methacrylate copolymer (1:2) and macrogol 400 are synthetic, and talc is from mineral origin. Regarding the sourcing of the gelatin raw material adequate information is provided regarding the risk on TSE/BSE. The CEPs for the involved gelatin suppliers are valid. II.4 Discussion on chemical, pharmaceutical and biological aspects Based on the submitted dossier, the MEB considers that Flecazela CR has a proven chemicalpharmaceutical quality. Sufficient controls have been laid down for the active substance and finished product. No post-approval commitments were made. III. III.1 NON-CLINICAL ASPECTS Ecotoxicity/environmental risk assessment (ERA) Since Flecazela CR is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.2 Discussion on the non-clinical aspects This product is a generic formulation of Flécaïne prolonged release capsules, which is available on the European market. Reference is made to the preclinical data obtained with the innovator product. A non-clinical overview on the pharmacology, pharmacokinetics and toxicology has been provided, which is based on up-to-date and adequate scientific literature. The overview justifies why there is no need to generate additional non-clinical pharmacology, pharmacokinetics and toxicology data. Therefore, the Board agreed that no further non-clinical studies are required. IV. IV.1 CLINICAL ASPECTS Introduction Flecainide acetate is a well-known active substance with established efficacy and tolerability. A clinical overview has been provided, which is based on scientific literature. The overview justifies why there is no need to generate additional clinical data. Therefore, the MEB agreed that no further clinical studies are required. For this generic application, the MAH has submitted three bioequivalence studies, which are discussed below. 5/11

6 IV.2 Pharmacokinetics C The MAH conducted bioequivalence studies in which the pharmacokinetic profile of the test product Flecazela CR 200 mg (Disphar International B.V., the Netherlands) is compared with the pharmacokinetic profile of the reference product Flecaine LP 200 mg capsules (Meda Pharm, France). Three studies were performed: a single dose fasting study a single dose fed study a multiple dose study. The choice of the reference product in the bioequivalence studies has been justified. The formula and preparation of the bioequivalence batch is identical to the formula proposed for marketing. The flecainide prolonged release capsules contain microgranules coated with a polymer. Each microgranule constitutes a prolonged-release form of flecainide acetate, which enables the absorption time to be prolonged without changing the elimination parameters (the apparent elimination half-life is of the order of 12 to 13 hours). The two single-dose bioequivalence studies under fasting and fed conditions, and a multiple dose study to support this application are considered sufficient, adequate and in accordance with the guidelines, requiring such studies for prolonged-release tablets. The MEB has been assured that the bioequivalence studies have 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). Biowaiver All three studies were conducted with the highest strength (200 mg). The composition of the different strengths is identical, only the amount of granules is different and the dissolution test did not show different release characteristics. Therefore, a biowaiver for the 50, 100 and 150 mg strength is granted. Bioequivalence studies Study I single dose, fasted conditions Design A single-dose, randomised, three-way, three sequence, crossover bioequivalence study was carried out under fasted conditions in 12 healthy male subjects, aged years. Each subject received a single dose (200 mg) of one of the 3 flecainide acetate formulations. Two test products were used, Test 1 and Test 2 (different batches). The capsule was orally administered with 240 ml water after an overnight fast of 10 hours. Food was not used until 4 hours after dosing. There were 3 dosing periods, separated by a washout period of 7 days. Blood samples were collected period pre-dose and at 3, 6, 9, 12, 14, 16, 18, 19, 20, 21, 22, 24, 26, 28, 32, 36, 48 and 72 hours after administration of the products. The overall study design is considered acceptable considering the absorption rate and half-lives. Also the washout period is acceptable. Analytical/statistical methods The analytical method has been adequately validated and is considered acceptable for analysis of the plasma samples. The methods used in this study for the pharmacokinetic calculations and statistical evaluation are considered acceptable. Results The pharmacokinetic and statistical analysis was conducted on 12 subjects. Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max (median, range)) of flecainide under fasted conditions. 6/11

7 Treatment N=12 AUC 0-t µg.h/ml AUC 0- µg.h/ml C max µg/ml t max h Test ± ± ± Test ± ± ± t 1/2 h 13.7 ± ± 4.8 Reference 5.56 ± ± ± *Ratio (90% CI) Test 1/Ref *Ratio (90% CI) Test 2/Ref CV (%) Test 1/Ref CV (%) Test 2/Ref 1.02 ( ) 0.98 ( ) ( ) ( ) 14.0 ± AUC 0- area under the plasma concentration-time curve from time zero to infinity AUC 0-t area under the plasma concentration-time curve from time zero to t hours C max maximum plasma concentration t max time for maximum concentration t 1/2 half-life CV coefficient of variation *ln-transformed values Conclusion on bioequivalence study I The pharmacokinetic variables for are comparable between the three treatments. The 90% confidence intervals for the extent and rate of absorption are within the predefined acceptance criteria of Bioequivalence is established between both batches and the reference product. The 2 test formulations and the reference product were similarly well tolerated. Two non serious adverse events (AEs) were registered in 2 subjects in the course of the study: 1 AE after administration of Test 2 product 1 AE after administration of Reference product. All adverse events were assessed as not serious and resolved completely. Study II single dose, fed conditions Design A single-dose, randomised, two-stage, two-period, crossover bioequivalence study was carried out under fasted conditions in 18 healthy male subjects, aged years. Each subject received a single dose (200 mg) of one of the 2 flecainide acetate formulations. The capsule was orally administered with 240 ml water under fed conditions, 30 min after the start of the breakfast. The breakfast consisted of 2 eggs fried in 10 g butter, 100 g sausages, 2 slices of toasted with 10 g butter, 113 g hashed brown potatoes with 10 g butter and 240 ml whole milk. There were 2 dosing periods, separated by a washout period of 7 days. Blood samples were collected period pre-dose and at 3, 6, 9, 12, 14, 16, 18, 19, 20, 21, 22, 24, 26, 28, 32, 36, 48 and 72 hours after administration of the products. The overall study design is considered acceptable considering the absorption rate and half-lives. Also the washout period is acceptable. Analytical/statistical methods 7/11

8 The analytical method has been adequately validated and is considered acceptable for analysis of the plasma samples. The methods used in this study for the pharmacokinetic calculations and statistical evaluation are considered acceptable. Results A total number of 18 volunteers were randomized. Two subjects dropped out: one before dosing with study medication on day 1 of study period 1 due to occurrence of exclusion criterion, and the second was withdrawn on day 1 of study period 1 at own request. In total 16 volunteers completed the trial according to the protocol and were subjected to statistical evaluation. Table 2. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max (median, range)) of flecainide under fed conditions. Treatment N=16 AUC 0-t µg.h/ml AUC 0- µg.h/ml C max µg/ml t max h Test 5.61 ± ± ± t 1/2 h 13.5 ± 2.4 Reference 5.23 ± ± ± *Ratio (90% CI) 1.08 ( ) ( ) 13.5 ± CV (%) AUC 0- area under the plasma concentration-time curve from time zero to infinity AUC 0-t area under the plasma concentration-time curve from time zero to t hours C max maximum plasma concentration t max time for maximum concentration t 1/2 half-life CV coefficient of variation *ln-transformed values Conclusion on bioequivalence study The pharmacokinetic variables for are comparable between both treatments. The 90% confidence intervals for the extent and rate of absorption are within the predefined acceptance criteria of Bioequivalence is established. The pharmacokinetic variables are after administration of 200 mg flecainide under fed conditions are comparable as those after administration under fasting conditions. Five adverse events were registered in 2 subjects in the course of the trial: one AE was registered in 1 subject before the administration of any study medication no AEs were observed after administration of the Test product four AEs were observed in 1 subject after administration of Reference product. All adverse events were assessed as not serious. Study III multiple dose (steady state) Design A multiple dose, randomised, two-period, crossover bioequivalence study was carried out under fasted conditions in 18 healthy male subjects, aged years. Each subject received a dose of 200 mg one of the 2 flecainide acetate formulations on 7 consecutive days, under fasting conditions. The capsule was orally administered with 240 ml water. There were 2 dosing periods, separated by a washout period of 11 days. Blood samples were collected period pre-dose on days 1, 2, 3, 4, 5, 6 and 7 as well as 2, 4, 6, 8, 10, 12, 14, 16, 18, 19, 20, 21, 22, 23, and 24 hours after the last (7th) dose. The overall study design is considered acceptable considering the absorption rate and half-lives. Also the washout period is acceptable. 8/11

9 Analytical/statistical methods The analytical method has been adequately validated and is considered acceptable for analysis of the plasma samples. The methods used in this study for the pharmacokinetic calculations and statistical evaluation are considered acceptable. Results A total number of 18 volunteers completed the trial according to the protocol. The statistical evaluation was based on the data of these 18 volunteers. Table 3. Pharmacokinetic parameters in steady-state (non-transformed values; arithmetic mean ± SD) Treatment N=18 AUC,ss µg.h/ml C max,ss µg/ml C min,ss µg/ml t max h Test 5.92 ± ± ± (0-24) Reference 5.53 ± ± ± ) *Ratio (90% CI) 1.05 ( ) 1.07 ( ) CV (%) AUC area under the plasma concentration-time curve over the dosing interval C max,ss maximum plasma concentration C min,ss minimum plasma concentration t max time for maximum concentration CV coefficient of variation Conclusion on bioequivalence study III The pharmacokinetic variables for are comparable between both treatments. The 90% confidence intervals for C max, ss, and AUC 0-t, ss are within the predefined acceptance criteria of Based on the submitted multiple dose bioequivalence study, Flecazela CR 200 mg is considered bioequivalent with Flecaine LP 200 mg capsules. The test and reference products were well tolerated. Only 1 non-serious adverse event was registered in 1 subject after administration of the test product in the course of the trial. The single AE (a case of palpitations) was judged by the investigator with a possible causal relationship to study drug administration. It resolved completely. IV.3 Risk Management Plan The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Flecazela CR. - Summary table of safety concerns as approved in RMP Important identified risks Proarrhythmic effects Adverse hemodynamic effects, including cardiac failure Important potential risks None Missing information Exposure during pregnancy and lactation Use in the paediatric population <12 years old The MEB agreed that routine pharmacovigilance activities and routine risk minimisation measures are sufficient for the risks and areas of missing information. 9/11

10 IV.4 Discussion on the clinical aspects C For this authorisation, reference is made to the clinical studies and experience with the innovator product Flecaine LP. No new clinical studies were conducted. The MAH demonstrated through bioequivalence studies that the pharmacokinetic profile of the product is similar to the pharmacokinetic profile of this reference product. This was shown after a single dose under both fasted and fed conditions, and at steady state (multiple dose). Risk management is adequately addressed. This generic medicinal product can be used instead of the reference product. V. USER CONSULTATION The package leaflet has not been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The MAH submitted a bridging report to the outcome of the readability test for the leaflet of Flecaïnideacetaat Teva, (NL/H/2471/ ). This approach is acceptable as the wordings of both leaflets are nearly identical. The lay-out and design of the leaflet of Flecazela CR are the same as the leaflet for Losibere 2 mg/125 mg tablets approved in procedure NL/H/2730/001/DC. The bridging report submitted by the MAH has been found acceptable. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Flecazela CR 50 mg, 100 mg, 150 mg and 200 mg have a proven chemical-pharmaceutical quality and are generic forms of Flécaïne prolonged release capsules. Flécaïne prolonged release capsules is a well-known medicinal product with an established favourable efficacy and safety profile. Bioequivalence has been shown to be in compliance with the requirements of European guidance documents. The Board followed the advice of the assessors. On the basis of the data submitted, the MEB considered that essential similarity has been demonstrated for Flecazela CR with the reference product, and has therefore granted a marketing authorisation. The decentralised procedure was finalised with a positive outcome on 25 February /11

11 STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY Scope Procedure number Type of modification Date of start of the procedure Date of end of the procedure Approval/ non approval Assessment report attached 11/11