Public Assessment Report. Scientific discussion. Mebeverine HCl Aurobindo Retard 200 mg modified release capsules, hard. (mebeverine hydrochloride)

Transcription

1 Public Assessment Report Scientific discussion ebeverine HCl Aurobindo Retard 200 mg modified release capsules, ard (mebeverine ydrocloride) NL/H/3750/001/DC Date: 18 September 2017 Tis module reflects te scientific discussion for te approval of ebeverine HCl Aurobindo Retard 200 mg modified release capsules, ard. Te procedure was finalised on 5 April For information on canges after tis date please refer to te steps taken after finalisation at te end of tis PAR.

2 List of abbreviations C B G ASF BP CD() CS EDF EDQ ERA ICH AH P.Eur. PL RH RP SmPC TSE Active Substance aster File Britis Parmacopoeia Coordination group for utual recognition and Decentralised procedure for uman medicinal products Concerned ember State European Drug aster File European Directorate for te Quality of edicines Environmental Risk Assessment International Conference of Harmonisation arketing Autorisation Holder European Parmacopoeia Package Leaflet Relative Humidity Risk anagement Plan Summary of Product Caracteristics Transmissible Spongiform Encepalopaty 2/13

3 I. INTRODUCTION Based on te review of te quality, safety and efficacy data, te ember States ave granted a marketing autorisation for ebeverine HCl Aurobindo Retard 200 mg modified release capsules, ard, from Aurobindo Parma B.V. Te product is indicated for te symptomatic relief of irritable bowel syndrome in adults and cildren over 10 years. A compreensive description of te indications and posology is given in te SmPC. Tis decentralised procedure concerns a generic application claiming essential similarity wit te innovator product Duspatal Retard 200 mg modified release capsules, ard (NL License RVG 11657) wic as been registered in te Neterlands troug a national procedure since 12 August 1987 by Abbott B.V. Te innovator product is registered in several European countries under various trade names. Te concerned member states (CS) involved in tis procedure were Poland and te United Kingdom. Te marketing autorisation as been granted pursuant to Article 10(1) of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Introduction ebeverine HCl Aurobindo Retard is a ard gelatin, modified-release capsule, filled wit wite to off wite sperical pellets. Te product as a creamy wite body and creamy wite cap. Eac capsule contains 200 mg mebeverine ydrocloride. Te capsules are packed in PVC/PVdC Aluminium blisters. Te excipients are: Capsule core - sugar speres (sucrose, maize starc), povidone and ypromellose. Sustained release coating etyl cellulose, macrogol and magnesium stearate. Capsule sell gelatin and titanium dioxide (E171). II.2 Drug Substance Te active substance is mebeverine ydrocloride, an establised active substance described in te Britis Parmacopoeia (BP). ebeverine ydrocloride is a wite or almost wite crystalline powder. Te active substance is very soluble in water and in metylene cloride, freely soluble in etanol (96%). It as a pka value of ebeverine ydrocloride as a ciral carbon in its cemical structure; ence it can exibit optical isomerism. Te substance is produced as a racemate. It as been demonstrated tat te same polymorpic form (anydrous crystalline form) is manufactured consistently. Te Active Substance aster File (ASF) procedure is used for te active substance. Te main objective of te ASF procedure, commonly known as te European Drug aster File (EDF) procedure, is to allow valuable confidential intellectual property or know-ow of te manufacturer of te active substance (AS) to be protected, wile at te same time allowing te applicant or marketing autorisation older (AH) to take full responsibility for te medicinal product, te quality and quality control of te active substance. Competent Autorities/EA tus ave access to te complete information tat is necessary to evaluate te suitability of te use of te active substance in te medicinal product. 3/13

4 anufacturing process No class-1 solvents are used in te manufacturing process. Te active substance as been adequately caracterised and acceptable specifications ave been adopted for te starting materials, solvents and reagents. Quality control of drug substance Te active substance specification is considered adequate to control te quality and meets te requirements of te monograp in te European Parmacopoeia (P.Eur.) and BP. Batc analytical data demonstrating compliance wit tis specification ave been provided for five batces. Stability of drug substance Stability data on te active substance ave been provided on tree batces stored at 25 C/60% RH (36 monts) and 40 C/75% RH (six monts). Te drug substance remains stable; tere are no significant canges or unexpected results observed. Based on te data submitted, a retest period could be granted of 48 monts wen stored in a well closed container at room temperature. II.3 edicinal Product Parmaceutical development Te product is an establised parmaceutical form and its development is adequately described in accordance wit te relevant European guidelines. Te coice of excipients is justified and teir functions are explained. Te coice of te manufacturing formula and process is also justified. Te product is designed to ave sustained release by selecting etyl cellulose as a release retarding polymer in combination wit magnesium stearate. Te parmaceutical development of te product as been adequately performed. Two bioequivalence studies ave been submitted. Te drug product batces used in te bioequivalence study were manufactured according to te finalised composition and manufacturing process. anufacturing process Te manufacturing process is described in sufficient detail and is regarded as a non-standard process. It as been validated according to relevant European/ICH guidelines. Process validation data on te product ave been presented for tree batces in accordance wit te relevant European guidelines. Control of excipients All individual excipients comply wit te P.Eur. Te ard gelatin capsules are tested according to an in-ouse specification. Tese specifications are acceptable. Quality control of drug product Te finised product specifications are adequate to control te relevant parameters for te dosage form. Te specification includes tests for appearance, identity, average fill weigt, uniformity of fill weigt, uniformity of dosage units, water content, dissolution, assay, related substances, residual solvents and microbial quality. Te release and self-life limits are identical. Limits in te specification ave been justified and are considered appropriate for adequate quality control of te product. Satisfactory validation data for te analytical metods ave been provided. Batc analytical data from tree full scale batces from te proposed production site ave been provided, demonstrating compliance wit te specification. Stability of drug product Stability data on te product ave been provided for tree full scaled batces stored at 25 C/60% RH (two batces 36 monts and one batc 12 monts), 30 C/65% RH (12 monts) and 40 C/75% RH (6 monts). Te conditions used in te stability studies are according to te ICH stability guideline. Te batces were stored in te proposed packaging. At long term and intermediate conditions te product remains stable, tere are no specific trends or out of specification results obtained. However, at accelerated conditions, significant canges and out of specification results are obtained after 6 monts for dissolution, individual unknown impurity and total impurities. Te claimed self-life of 36 monts and storage conditions Do not store above 30 C, Do not refrigerate or freeze and Store in te original package in order to protect from moisture are justified. Te drug product is not sensitive to ligt. 4/13

5 Specific measures concerning te prevention of te transmission of animal spongiform encepalopaties All excipients apart from gelatin are of non-animal origin. Scientific data and/or certificates of suitability issued by te EDQ ave been provided and compliance wit te Note for Guidance on inimising te Risk of Transmitting Animal Spongiform Encepalopaty Agents via medicinal products as been satisfactorily demonstrated. II.4 Discussion on cemical, parmaceutical and biological aspects Based on te submitted dossier, te member states consider tat ebeverine HCl Aurobindo Retard as a proven cemical-parmaceutical quality. Sufficient controls ave been laid down for te active substance and finised product. No post-approval commitments were made. III. III.1 NON-CLINICAL ASPECTS Ecotoxicity/environmental risk assessment (ERA) Since ebeverine HCl Aurobindo Retard is intended for generic substitution, tis will not lead to an increased exposure to te environment. An environmental risk assessment is terefore not deemed necessary. III.2 Discussion on te non-clinical aspects Tis product is a generic formulation of Duspatal Retard 200 mg wic is available on te European market. is made to te preclinical data obtained wit te innovator product. A non-clinical overview on te parmacology, parmacokinetics and toxicology as been provided, wic is based on up-to-date and adequate scientific literature. Te overview justifies wy tere is no need to generate additional non-clinical parmacology, parmacokinetics and toxicology data. Terefore, te member states agreed tat no furter non-clinical studies are required. IV. IV.1 CLINICAL ASPECTS Introduction ebeverine is a well-known active substance wit establised efficacy and tolerability. A clinical overview as been provided, wic is based on scientific literature. Te overview justifies wy tere is no need to generate additional clinical data. Terefore, te member states agreed tat no furter clinical studies are required. For tis generic application, te AH as submitted two bioequivalence studies, wic are discussed below. IV.2 Parmacokinetics Bioequivalence studies Te AH conducted two bioequivalence studies in wic te parmacokinetic profile of te test product ebeverine HCl Aurobindo Retard 200 mg (Aurobindo Parma B.V., Te Neterlands) is compared wit te parmacokinetic profile of te reference product Colofac retard 200 mg (Abbott Products GmbH, Austria). One bioequivalence study was carried out under fasting conditions, including a single dose treatment arm and a multiple dose treatment arm. Te oter bioequivalence study is a single dose fed study. 5/13

6 Te coice of te reference product Te coice of te reference product, Colofac retard 200 mg modified release capsules, in te bioequivalence studies as been justified. Colofac retard as been registered in Austria by Abbott Products GmbH since 27 January In te single dose fasting and steady state study and in te fed study a different biobatc was used, owever bot are representative for te commercial batc. Bioequivalence study under fasting conditions Design A randomised, open-label, balanced, two-treatment, two-period, two-sequence, two-way crossover, single dose and multiple-dose, oral bioequivalence study was carried out under fasted conditions in 50 ealty male subjects, aged years. Eac subject received a single dose (200 mg) of one of te two mebeverine formulations at day 1 and tereafter at day 3, twice daily for days 3-5, one in te morning and one in te evening, wit an interval of 12 ours between doses, and at day 6, once in te morning. Te tablet was orally administered wit 240 ml water under fasting conditions. Te wasout period was 6 days. At day 1, blood samples were collected pre-dose and at 0.5, 1, 1.33, 1.67, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 36 ours after administration of te products. At day 3 to 5 pre-dose (morning dose) and at day 6 at pre-dose and at 0.5, 1, 1.33, 1.67, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 6, 8, 10 and 12 ours after te administration of te products. Plasma samples were analysed for te pivotal analyte veratric acid, mebeverine acid, desmetyl mebeverine acid and desmetyl mebeverine alcool. Te design of te single and multiple dose, crossover study to assess bioequivalence is acceptable. Analytical/statistical metods Te analytical metod as been adequately validated and is considered acceptable for analysis of te plasma samples. Te metods used in tis study for te parmacokinetic calculations and statistical evaluation are considered acceptable. For all analytes, repeat analysis were carried out for parmacokinetic reasons. Tis may bias te outcome of te study. Terefore te original values were used to calculate te parmacokinetics and statistics for te pivotal analyte veratric acid (table 5 and 10). Results One subject did not report for period II. Terefore 49 subjects were eligible for parmacokinetic analysis. Single treatment arm Table 1. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of veratric acid under fasted conditions after single dose. ng./ml ± ± ( ) ng./ml ± ± ( ) 6/ ± ± ( ) 2.75 ( ) 2.50 ( ) 4.25 ± ± CV (%) area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours maximum plasma concentration time for maximum concentration alf-life

7 C B G Table 2. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of mebeverine acid under fasted conditions after single dose. ng./ml ng./ml ± ± ± ( ) ± ± ± ( ) area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours maximum plasma concentration time for maximum concentration alf-life 3.95 ± ± 1.38 Table 3. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of desmetyl mebeverine acid under fasted conditions after single dose. ng./ml ng./ml ± ± ± ( ) ± ± ± ( ) area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours maximum plasma concentration time for maximum concentration alf-life 4.33 ± ± 1.60 Table 4. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of desmetyl mebeverine alcool under fasted conditions after single dose. ng./ml ng./ml ± ± ± ( ) ± ± ± ( ) area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours maximum plasma concentration time for maximum concentration alf-life 4.61 ± ± 2.10 Table 5. Parmacokinetic parameters based on original values (non-transformed values; aritmetic mean ± SD, (median, range)) of veratric acid under fasted conditions. ng./ml ng./ml ( ) 1.01 ( ) 1.03 ( ) CV (%) /13

8 area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours maximum plasma concentration C B G After single dose, based on te parmacokinetic parameters of te pivotal analyte veratric acid, te reference and test product are considered bioequivalent wit respect to te extent and rate of absorption. Te 90% confidence intervals calculated for and were inside te normal range of acceptability ( ). For mebeverine acid, desmetyl mebeverine acid and desmetyl mebeverine alcool bioequivalence could also be proven, supporting te results of veratric acid. Steady state (multiple dose) arm Table 6. Parmacokinetic parameters of veratric acid in steady-state (non-transformed values; aritmetic mean ± SD) AUC / ± ± ( ) ± C PTF% ± ± ± ± ± ± ( ) 1.07 ( ) % CV (%) AUC area under te plasma concentration-time curve over te dosing interval maximum plasma concentration C plasma concentration over de dosing interval PTF% fluctuation index Table 7. Parmacokinetic parameters of mebeverine acid in steady-state (non-transformed values; aritmetic mean ± SD) AUC / C tmax PTF% ± ± ± ± ± ± ± ± ± ± AUC C PTF% area under te plasma concentration-time curve over te dosing interval maximum plasma concentration plasma concentration over de dosing interval fluctuation index Table 8. Parmacokinetic parameters of desmetyl mebeverine acid in steady-state (nontransformed values; aritmetic mean ± SD) AUC C PTF% / % ± ± ± ± ± ± ± ± ± ± AUC area under te plasma concentration-time curve over te dosing interval maximum plasma concentration C plasma concentration over de dosing interval PTF% fluctuation index % 8/13

9 Table 9. Parmacokinetic parameters of desmetyl mebeverine alcool in steady-state (nontransformed values; aritmetic mean ± SD) AUC / C PTF% % ± ± ± ± ± ± ± ± ± ± 44.3 AUC area under te plasma concentration-time curve over te dosing interval maximum plasma concentration C minimum plasma concentration PTF% fluctuation index Table 10. Parmacokinetic parameters of veratric acid in steady-state (non-transformed values; aritmetic mean ± SD) AUC / ( ) 0.99 ( ) C 1.07 ( ) CV (%) AUC area under te plasma concentration-time curve over te dosing interval maximum plasma concentration C minimum plasma concentration At steady state, based on te parmacokinetic parameters of te pivotal analyte veratric acid, te reference and test products are considered bioequivalent wit respect to te extent and rate of absorption. Te 90% confidence intervals calculated for AUC, C and were inside te normal range of acceptability ( ). Bioequivalence study under fed conditions Design An open-label, balanced, randomised, two-treatment, two-period, two-sequence, single-dose crossover oral bioequivalence study was carried out under fed conditions in 40 ealty male subjects, aged years. Eac subject received a single dose (200 mg) of one of te two mebeverine formulations. Te tablet was orally administered wit 240 ml water 30 minutes after te start of intake of a ig fat ig caloric breakfast. Te wasout period was seven days. Blood samples were collected pre-dose and at 0.5, 1, 1.33, 1.67, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 6, 8, 10, 12, 24 and 36 ours after administration of te products. Plasma samples were analysed for te pivotal analyte veratric acid, mebeverine acid, desmetyl mebeverine acid and desmetyl mebeverine alcool. Te design of te single dose, crossover study to assess bioequivalence under fed conditions is considered adequate. Analytical/statistical metods Te analytical metod as been adequately validated and is considered acceptable for analysis of te plasma samples. Te metods used in tis study for te parmacokinetic calculations and statistical evaluation are considered acceptable. 9/13

10 Repeat analyses were carried out for parmacokinetic reasons. Tis may bias te outcome of te study. For te pivotal analyte veratric acid no repeat analysis is carried out. Te original values were be used for calculation of parmacokinetics and statistics. Results Two subjects were witdrawn due to protocol violation, two subjects did not report for period II and one subject was witdrawn as e was found positive for drug abuse. Terefore 35 subjects were eligible for parmacokinetic analysis. Table 11. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of veratric acid under fed conditions after single dose. N=35 ng./ml ± ± ( ) ng./ml ± ± ( ) ± ± ( ) 4.50 ± ± ± ± CV (%) area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours maximum plasma concentration time for maximum concentration alf-life Table 12. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of mebeverine acid under fed conditions after single dose. N=35 ng./ml ± ± ( ) ng./ml ± ± ( ) ± ± ± ± ( ) 4.50 ± ± CV (%) area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours maximum plasma concentration time for maximum concentration alf-life Table 13. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of desmetyl mebeverine acid under fed conditions after single dose. N=35 ng./ml ± ± ng./ml ± ± ± ± ± ± ± ± /13

11 0.96 ( ) 0.98 ( ) 0.91 ( ) C B G CV (%) area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours maximum plasma concentration time for maximum concentration alf-life Table 14. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of desmetyl mebeverine alcool under fed conditions after single dose. N=35 ng./ml ng./ml ± ± ± ± ± ± ± ± ± ± ( ) 1.09 ( ) 0.86 ( ) CV (%) area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours maximum plasma concentration time for maximum concentration alf-life Based on te parmacokinetic parameters of veratric acid, te reference and test product are considered bioequivalent wit respect to te extent and rate of absorption. Te 90% confidence intervals calculated for, and were inside te normal range of acceptability ( ). For mebeverine acid bioequivalence could not be proven for, and, and for desmetyl-mebeverine alcool bioequivalence could not be proven for. However tese parameters are not considered pivotal. In addition, considering te confidence intervals, it does not contradict te conclusion for veratric acid. Conclusion on bioequivalence studies Te 90% confidence intervals calculated for, and are witin te bioequivalence acceptance range of Based on te submitted bioequivalence studies ebeverine HCl Aurobindo Retard 200 mg is considered bioequivalent wit Colofac retard 200 mg. Te EB as been assured tat te bioequivalence studies ave been conducted in accordance wit 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). IV.3 Risk anagement Plan Te AH as submitted a risk management plan, in accordance wit te requirements of Directive 2001/83/EC as amended, describing te parmacovigilance activities and interventions designed to identify, caracterise, prevent or minimise risks relating to ebeverine HCl Aurobindo Retard. Summary table of safety concerns as approved in RP: 11/13

12 Important identified risks Hypersensitivity Important potential risks None issing information Use in pregnancy C B G Te member states agreed tat routine parmacovigilance activities and routine risk minimisation measures are sufficient for te risks and areas of missing information. IV.4 Discussion on te clinical aspects For tis autorisation, reference is made to te clinical studies and experience wit te innovator product Duspatal Retard. No new clinical studies were conducted. Te AH demonstrated troug bioequivalence studies tat te parmacokinetic profile of te product is similar to te parmacokinetic profile of tis reference product. Risk management is adequately addressed. Tis generic medicinal product can be used instead of te reference product. V. USER CONSULTATION Te package leaflet as (PL) been evaluated via a user consultation study in accordance wit te requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. Te test consisted of: a pilot test wit two participants, followed by two rounds wit ten participants eac. Te questions covered te following areas sufficiently: traceability, compreensibility and applicability. Te results sow tat te PL meets te criteria for readability as set out in te Guideline on te readability of te label and PL of medicinal products for uman use. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSENT AND RECOENDATION ebeverine HCl Aurobindo Retard 200 mg modified release capsules, ard as a proven cemicalparmaceutical quality and is a generic form of Duspatal Retard 200 mg modified release capsules. Duspatal Retard is a well-known medicinal product wit an establised favourable efficacy and safety profile. Bioequivalence as been sown to be in compliance wit te requirements of European guidance documents. Te Board followed te advice of te assessors. Tere was no discussion in te CD(). Agreement between member states was reaced during a written procedure. Te member states, on te basis of te data submitted, considered tat essential similarity as been demonstrated for ebeverine HCl Aurobindo Retard wit te reference product, and ave terefore granted a marketing autorisation. Te decentralised procedure was finalised wit a positive outcome on 5 April /13

13 STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE SUARY Scope Procedure number Type of modification Date of start of te procedure Date of end of te procedure Approval/ non approval Assessment report attaced 13/13