Public Assessment Report. Scientific discussion. Carbidopa/Levodopa Bristol 10 mg/100 mg, 12.5 mg/50 mg, 25 mg/100 mg and 25 mg/250 mg tablets

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1 Public Assessment Report Scientific discussion Carbidopa/Levodopa Bristol 10 mg/100 mg, 12.5 mg/50 mg, 25 mg/100 mg and 25 mg/250 mg tablets (carbidopa/levodopa) NL/H/3044/ /DC Date: 25 February 2015 Tis module reflects te scientific discussion for te approval of Carbidopa/Levodopa Bristol 10 mg/100 mg, 12.5 mg/50 mg, 25 mg/100 mg and 25 mg/250 mg tablets. Te procedure was finalised on 8 October For information on canges after tis date please refer to te module Update.

2 I. INTRODUCTION Based on te review of te quality, safety and efficacy data, te Member States ave granted a marketing autorisation for Carbidopa/Levodopa Bristol 10 mg/100 mg, 12.5 mg/50 mg, 25 mg/100 mg and 25 mg/250 mg tablets from Bristol Laboratories Ltd. Te product is indicated for treatment of Parkinson s disease. Te product is a combination of levodopa and an inibitor of dopadecarboxylase particular used in patients treated wit levodopa alone wo sowed motor fluctuations. 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 Sinemet. Te first autorisation in te EEA was obtained in te UK by Merck Sarp & Dome for Sinemet 12.5 mg/50 mg tablets in 1988, for Sinemet 10/100 mg tablets in 1973, for Sinemet Plus 25 mg/100 mg tablets in 1981 and for Sinemet 25 mg/250 mg tablets in Te innovator products in te Neterlands are Sinemet 62.5 mg tablets (NL License RVG 12858), Sinemet 110mg tablets (NL RVG 06706), Sinemet 125mg tablets (NL RVG 08740) and Sinemet 275 mg tablets (NL RVG 06707), registered by Merck Sarp & Dome BV. Te concerned member states (CMS) involved in tis procedure were Germany (25 mg/100 mg and 25 mg/250 mg), Malta (10 mg/100 mg, 12.5 mg/100 mg and 25 mg/250 mg), Spain (25 mg/100 mg and 25 mg/250 mg) and te United Kingdom (all strengts). Te marketing autorisation as been granted pursuant to Article 10(1) of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Introduction Carbidopa/Levodopa Bristol 10 mg/100 mg is a ligt blue coloured, oval saped scored tablet wit C and break line on one side and 18 on oter side. Carbidopa/Levodopa Bristol 12.5 mg/50 mg is a ligt yellow coloured, oval saped scored tablet wit C and break line on one side and 17 on oter side. Carbidopa/Levodopa Bristol 25 mg/100 mg is a yellow coloured, oval saped scored tablet wit C and break line on one side and 19 on oter side. Carbidopa/Levodopa Bristol 25 mg/250 mg is a ligt blue coloured, oval saped scored tablet wit C and break line on one side and 20 on oter side. Te tablets can be divided into equal alves. Te tablets are packed in Alu-Alu blisters. Te excipients are: crospovidone, magnesium stearate, microcrystalline cellulose, pre gelatinised starc (maize), Indigo carmine lake (E132) (10/100 mg and 25 mg/250 mg), Quinoline Yellow lake (E104) (12.5/50 mg and 25/100 mg). Te 12.5/50 mg tablet and te 25/100 mg tablet are fully dose proportional and te 10/100 mg tablets and te 25/250 mg tablets are also fully dose proportional. II.2 Drug Substances Carbidopa Te first active substance is carbidopa, an establised active substance described in te European Parmacopoeia (P.Eur.). Te active substance is a wite or yellowis-wite crystalline powder, and 2/12

3 is sligtly soluble in water. Carbidopa contains one ciral centre. Te drug substance is te pure S enantiomer. No polymorpism as been reported. Te CEP procedure is used for bot manufacturers of te active substance. Under te official Certification Procedures of te EDQM of te Council of Europe, manufacturers or suppliers of substances for parmaceutical use can apply for a certificate of suitability concerning te control of te cemical purity and microbiological quality of teir substance according to te corresponding specific monograp, or te evaluation of reduction of Transmissible Spongiform Encepalopaty (TSE) risk, according to te general monograp, or bot. Tis procedure is meant to ensure tat te quality of substances is guaranteed and tat tese substances comply wit te European Parmacopoeia. Manufacturing process CEPs ave been submitted; terefore no details on te manufacturing process ave been included. Quality control of drug substance Te drug substance specification is in line wit te P.Eur. wit additional requirements for related substances, residual solvents, particle size and microbial quality. Te specification is acceptable in view of te route of syntesis and te various European guidelines. Batc analytical data demonstrating compliance wit te respective drug substance specification ave been provided for one full-scale batc from eac source.. Stability of drug substance Te active substance is stable for 5 years wen stored under te stated conditions. Assessment tereof was part of granting te CEP and as been granted by te EDQM. Stability data on te active substance ave been provided for tree production-scale batces stored at 25 C/60% RH (35 monts) and 40 C/75% RH (6 monts). All parameters tested remain relatively stable at bot storage conditions. Based on te stability data provided te proposed re-test period of 35 monts can be granted wen stored in te original package in order to protect from ligt. Levodopa Te second active substance, levodopa, is an establised active substance described in te P.Eur. Te active substance is a wite to almost wite crystalline powder, and is sligtly soluble in water. Levodopa contains one ciral centre. Te drug substance is te pure S enantiomer. No polymorpism as been reported. For tis drug substance te CEP procedure is used. Manufacturing process A CEP as been submitted; terefore no details on te manufacturing process ave been included. Quality control of drug substance Te drug substance specification is line wit te P.Eur. monograp and te CEP wit acceptable additional requirements. Te specification is acceptable in view of te route of syntesis and te various European guidelines. Batc analytical data demonstrating compliance wit te drug substance specification ave been provided for tree production-scale batces. Stability of drug substance Stability data on te active substance ave been provided for tree production-scale batces stored at 25 C/60% RH (18 monts) and 40 C/75% RH (6 monts). All parameters tested remain relatively stable at bot storage conditions. Based on te stability data provided te proposed re-test period of 30 monts can be granted wen stored in te original package in order to protect from ligt. II.3 Medicinal Product Parmaceutical development Te development of te product as been described, te coice of excipients is justified and teir functions explained. Te main development studies were formulation trials and dissolution trials. Formulation trials were performed to investigate te effect of te addition of a disintegrant and te level of te disintegrant, te milling metod, te addition of a binder on te dissolution profile and flow properties. Te coice of manufacturing process and packaging as been adequately justified. 3/12

4 Te 25/250 mg batc and te 25/100 mg batc used in te bioequivalence studies ave te same composition and are manufactured in te same way as te future commercial batces. Te bioequivalence batces are of sufficient size in relation to te intended commercial batc size. Te studies were performed against te UK reference products. Te dissolution profiles of te batces used in te bioequivalence study are considered similar at all ph tested. Certificates of analysis as been provided for eac strengt indicating tat te batces comply wit te requirements for te subdivision of tablets described in te P.Eur. monograp for tablets. Te parmaceutical development of te product as been adequately performed. Manufacturing process Te manufacturing process is divided into te following steps: wet granulation, blending and compression. Te product is manufactured using conventional manufacturing tecniques. Adequate process validation data of tree pilot batces of eac strengt as been provided. Te manufacturing process as been adequately validated according to relevant European guidelines. Process validation for full-scale batces will be performed post autorisation. Control of excipients Te excipients comply wit relevant P.Eur. monograps, except for indigo carmine lake and quinoline yellow lake wic comply wit te in-ouse specifications. Tese specifications are acceptable. Quality control of drug product Te product specification includes tests for description, identification, average mass, uniformity of mass, disintegration time, dimension, ardness, water content, dissolution, uniformity of dosage units, related substances, ydrazine assay and microbial quality. Te release and self-life limits are identical wit te exception of related substances. Te specification is acceptable. Te analytical metods ave been adequately described and validated. Batc analytical data from te proposed production site ave been provided on tree pilot-scale batces of eac strengt, demonstrating compliance wit te release specification. Stability of drug product Stability data on te product as been provided tree pilot-scale batces of eac strengt stored at 25 C/60% 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 Al/Al blisters. Te same trends were observed in all batces at bot conditions. Te potostability data provided sow tat storage in te original package is not necessary. Based on te stability data provided te proposed self life of 24 monts witout special storage conditions can be granted. Specific measures concerning te prevention of te transmission of animal spongiform encepalopaties Tere are no substances of ruminant animal origin present in te product nor ave any been used in te manufacturing of tis product, so a teoretical risk of transmitting TSE can be excluded. Magnesium stearate is of vegetable origin. A declaration of te origin of magnesium stearate as been provided. II.4 Discussion on cemical, parmaceutical and biological aspects Based on te submitted dossier, te member states consider tat Carbidopa/Levodopa Bristol 10 mg/100 mg, 12.5 mg/50 mg, 25 mg/100 mg and 25 mg/250 mg tablets ave a proven cemicalparmaceutical quality. Sufficient controls ave been laid down for te active substance and finised product. Te following post-approval commitments were made: Te MAH committed to perform process validation on te first tree production scale batces. Te MAH committed to continue te long term stability studies for te drug substance carbidopa. Te MAH committed to continue te long term stability studies for te drug substance levodopa. Te MAH committed to continue te ongoing long-term stability studies for te drug product as per provided study design (i.e. up to 36 monts). Te MAH committed to include te first tree production-scale batces of te maximum batc size of eac strengt in accelerated and long-term stability studies. 4/12

5 III. NON-CLINICAL ASPECTS III.1 Ecotoxicity/environmental risk assessment (ERA) Since Carbidopa/Levodopa Bristol 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 Sinemet, wic is available on te European market. Reference 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-todate 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. CLINICAL ASPECTS IV.1 Introduction Levodopa and carbidopa are well-known active substances 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 MAH as submitted two bioequivalence studies, wic are discussed below. IV.2 Parmacokinetics Te MAH conducted a bioequivalence study in wic te parmacokinetic profile of te test product Carbidopa/Levodopa Bristol 25/250 mg (Bristol Laboratories Ltd, UK) is compared wit te parmacokinetic profile of te reference product Sinemet 25/250 mg tablets (Merck Sarp & Dome Limited, UK). In addition a bioequivalence study was conducted wit Carbidopa/Levodopa Bristol 25 mg/100 mg (Bristol Laboratories Ltd, UK) versus Sinemet Plus 25 mg/100 mg tablets (Merck Sarp & Dome Limited, UK). Te coice of te reference products in te bioequivalence study as been justified. Te formula and preparation of te bioequivalence batc is identical to te formula proposed for marketing. Analytical/statistical metods Te analytical metods in bot studies ave been adequately validated and are considered acceptable for analysis of te plasma samples. Te metods used for te parmacokinetic calculations and statistical evaluation are considered acceptable. Biowaiver Te 25 mg/250 mg strengt and 10 mg/100 mg strengt are dose-proportional, as well as te 12.5/50 mg tablet and te 25/100 mg tablet. All criteria for granting a biowaiver ave been fulfilled. Terefore te results obtained in te bioequivalence studies wit te 25/250 mg and 25/100 mg strengts can be extrapolated to te oter strengts. Bioequivalence studies 5/12

6 Bioequivalence study I 25 mg/250 mg strengt Design A single-dose, randomised, two-period, two-treatment, two-sequence, crossover bioequivalence study was carried out under fasted conditions in 54 ealty male subjects, aged years. Eac subject received a single dose (25 mg/250 mg) of one of te 2 carbidopa/levodopa formulations. Te tablet was orally administered wit 240 ml water after an overnigt fast of 10 ours. Tere were 2 dosing periods, separated by a wasout period of 7 days. Blood samples were collected pre-dose and at 0.17, 0.33, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12 and 16 ours after administration of te products. Te innovator product can be taken wit or witout food. Hence, it is agreed tat te study was performed under fasted conditions. Te procedures followed for a fasted condition and a was-out period of 7 days (i.e. at least 5 terminal alf-lives to exclude carry-over effects) is also agreed. Results Forty (40) subjects completed te study. Fourteen (14) subjects were witdrawn/dropped out: one subject did not report for Period II and 13 subjects were discontinued by te investigator due to adverse events (vomiting) in Period 1 (6 from test and 7 from reference). Te blood samples of te witdrawn/dropped- out subjects were analyzed but not included in te statistical analysis. Tis is in accordance wit te applicable guideline. Table 1. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of carbidopa under fasted conditions. Treatment N=40 AUC 0-t AUC 0- C max ng/ml t max Test 158 ± ± ± (0.8 6) Reference 155 ± ± ± (0.8 6) t 1/2 1.8 ± ± 0.5 *Ratio (90% CI) 0.99 ( ) ( ) CV (%) AUC 0- area under te plasma concentration-time curve from time zero to infinity AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life *ln-transformed values Table 2. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of levodopa under fasted conditions. Treatment N=40 AUC 0-t AUC 0- C max ng/ml t max Test 5667 ± ± ± Reference 5699 ± ± ± t 1/2 1.6 ± ± 0.2 *Ratio (90% CI) 1.00 ( ) ( ) CV (%) /12

7 AUC 0- area under te plasma concentration-time curve from time zero to infinity AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life *ln-transformed values C Safety A total of 19 adverse events were reported in 19 subjects during te entire duration of te study: 7 vomiting, 2 dizziness and 2 nausea cases considered probably related to te oral administration of Sinemet 25/250 mg tablets; 6 vomiting, 1 dizziness and 1 nausea cases considered probable related to te oral administration of Carbidopa/Levodopa Bristol 25/250 mg tablets. Overall, te test and reference drugs were well tolerated. Bioequivalence study II 25 mg/100 mg strengt Design A single-dose, randomised, two-period, two-treatment, two-sequence, crossover bioequivalence study was carried out under fasted conditions in 50 ealty male subjects, wit a mean age of 30 years. Eac subject received a single dose (25 mg/100 mg) of one of te 2 carbidopa/levodopa formulations. Te tablet was orally administered wit 240 ml water after an overnigt fast of 10 ours. Tere were 2 dosing periods, separated by a wasout period of 8 days. Blood samples were collected pre-dose and at 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, and ours after administration of te products. Te procedures followed for a fasted condition and a was-out period of 8 days (i.e. at least 5 terminal alf-lives to exclude carry-over effects) are agreed. Results Fifty subjects were dosed in period I and 48 subjects were dosed in period II. Two subjects were witdrawn in period-i as tey met te witdrawal criteria, i.e. vomiting at or before 2 times te median Tmax of carbidopa and levodopa in any period. One subject was voluntarily witdrawn in period-ii and ad missed two samples. As per protocol tese tree subjects were not considered for statistical analysis. Plasma concentrations of 47 subjects were included in parmacokinetic analysis of carbidopa and levodopa. Table 3. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of carbidopa under fasted conditions. Treatment N=47 AUC 0-t AUC 0- C max ng/ml t max Test ± ± 80** 44.0 ± ( ) Reference ± ± 98*** 48.3 ± ( ) t 1/ *Ratio (90% CI) 0.98 ( ) ( ) - -- CV (%) AUC 0- area under te plasma concentration-time curve from time zero to infinity AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life *ln-transformed values **N=46, ***N=45 7/12

8 Table 4. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of levodopa under fasted conditions. Treatment N=47 AUC 0-t AUC 0- C max ng/ml t max Test ± ± ± ( ) Reference ± ± ± ( ) t 1/ *Ratio (90% CI) 0.93 ( ) ( ) - -- CV (%) AUC 0- area under te plasma concentration-time curve from time zero to infinity AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life *ln-transformed values Safety All te subject s vital signs were witin normal range. Two of forty nine subjects experienced a total of two adverse events (4.08%) after administration of single dose of test product, and two of forty nine subjects experienced two adverse events (4.08%) after administration te reference product. No serious adverse events were reported during te entire duration of te study. Conclusion on bioequivalence studies Te 90% confidence intervals calculated for AUC 0-t and C max are witin te bioequivalence acceptance range of Based on te submitted bioequivalence studies Carbidopa/Levodopa Bristol 25 mg/250 mg and 25 mg/100 mg are considered bioequivalent wit Sinemet 25 mg/250 mg and Sinemet Plus 25 mg/100 mg tablets respectively. Te MEB 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 Management Plan Te MAH 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 Carbidopa/Levodopa Bristol. Summary of Safety Concerns and Planned Risk Minimisation Activities as approved in RMP Safety concern Concomitant use of monoamine oxidase inibitors Routine risk minimisation measures Important identified risks Te risks associated wit te concomitant use of monoamine oxidase inibitors are described in te SmPC, and appropriate advice is provided to te 8/12 Additional risk minimisation measures

9 Safety concern Use in patients wit glaucoma Use in patients wit suspicious undiagnosed skin lesions or a istory of melanoma Use in patients wit mental disorders Dyskinesia Use in patients wit cardiovascular disorders Laboratory test interference Routine risk minimisation measures prescriber to minimise tese risks. Te risks associated wit te use of te drug product in patients wit glaucoma are described in te SmPC, and appropriate advice is provided to te prescriber to minimise tese risks. Te risks associated wit te use of te drug product in patients wit suspicious undiagnosed skin lesions or a istory of melanoma are described in te SmPC, and appropriate advice is provided to te prescriber to minimise tese risks. Te risks associated wit te use of te drug product in patients wit mental disorders are described in te SmPC, and appropriate advice is provided to te prescriber to minimise tese risks. Te risks of dyskinesia associated wit te use of te drug product is described in te SmPC, and appropriate advice is provided to te prescriber to minimise tis risk. Te risks associated wit te use of te drug product in patients wit cardiovascular disorders are described in te SmPC, and appropriate advice is provided to te prescriber to minimise tese risks. Te risk of laboratory test interference associated wit te use of te drug product is described in te SmPC, and appropriate advice is provided to te prescriber to minimise tese risks. Important potential risks C Additional risk minimisation measures none 9/12

10 Safety concern Use in patients wit pulmonary disease; broncial astma; renal, epatic or endocrine disease; and istory of peptic ulcer disease or convulsions Somnolence Use in patients receiving general aneastetesia Use in pregnancy and breastfeeding Use in patients below 18 years of age Routine risk minimisation measures Te risks associated wit te use of te drug product in patients wit pulmonary disease; broncial astma; renal, epatic or endocrine disease; and istory of peptic ulcer disease or convulsions are described in te SmPC, and appropriate advice is provided to te prescriber to minimise tese risks. Te risk of somnolence and episodes of sudden sleep onset associated wit te use of te drug product are described in te SmPC, and appropriate advice is provided to te prescriber to minimise tese risks. Te risks associated wit te use of te drug product in patients receiving general aneastetesia are described in te SmPC, and appropriate advice is provided to te prescriber to minimise tese risks. Important missing information Te SmPC states tat no information is available regarding te use of drug product during pregnancy and breastfeeding, and suggests tat drug product sould be used during pregnancy and breastfeeding only if anticipated benefits outweig te risks. Te SmPC states tat te safety of te drug product in patients under 18 years of age as not been establised and its use in patients below te age of 18 years is not recommended. C Additional risk minimisation measures Not applicable Not applicable Te member states agreed tat routine parmacovigilance activities and routine risk minimisation measures are sufficient for te risks and areas of missing information. 10/12

11 IV.4 Discussion on te clinical aspects C For tis autorisation, reference is made to te clinical studies and experience wit te innovator product Sinemet. No new clinical studies were conducted. Te MAH 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 (PL) as 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 results sow tat te package leaflet meets te criteria for readability as set out in te Guideline on te readability of te label and package leaflet of medicinal products for uman use. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Carbidopa/Levodopa Bristol 10 mg/100 mg, 12.5 mg/50 mg, 25 mg/100 mg and 25 mg/250 mg tablets ave a proven cemical-parmaceutical quality and are generic forms of Sinemet 10 mg/100 mg, 12.5 mg/50 mg, 25 mg/100 mg and 25 mg/250 mg. Sinemet 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 CMD(). 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 Carbidopa/Levodopa Bristol wit te reference product, and ave terefore granted a marketing autorisation. Te decentralised procedure was finalised wit a positive outcome on 8 October /12

12 STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY Scope Procedure number Type of modification Date of start of te procedure Date of end of te procedure Approval/ non approval Assessment report attaced 12/12