Public Assessment Report Scientific discussion. Kagitz (quetiapine) SE/H/1589/01, 04-05/DC

Transcription

1 Public Assessment Report Scientific discussion Kagitz (quetiapine) SE/H/1589/01, 0405/DC Tis module reflects te scientific discussion for te approval of Kagitz. Te procedure was finalised on For information on canges after tis date please refer to te module Update. Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Pone: +46 (0) Fax: +46 (0) Internet: Template version:

2 I. INTRODUCTION Te application for Kagitz, 50 mg, 300 mg and 400 mg, prolonged release tablets, is a generic application made according to Article 10(1) of Directive 2001/83/EC. Te applicant, Amneal Parma Europe Limited applies troug te Decentralised Procedure wit Sweden acting as reference member state (RMS) and DE, DK, ES, FI, FR, NO and UK as concerned member states (CMS). Te applications for two additional strengts, 150 mg and 200 mg, were witdrawn by te applicant during te procedure. Te reference medicinal product cosen for te purposes of establising te expiry of te data protection period is Seroquel, 200 mg, filmcoated tablets autorised in UK since 1997, wit Zeneca Limited as marketing autorisation older. Te reference product used in te bioequivalence study is Seroquel XL 50 mg, 150 mg, 200 mg and 400 mg, prolongedrelease tablets from UK wit AstraZeneca UK Ltd as marketing autorisation older. For approved indications, see te Summary of Product Caracteristics. For recommendations to te marketing autorisation not falling under Article 21a/22 of Directive 2001/83 and conditions to te marketing autorisation pursuant to Article 21a or 22 of Directive 2001/83/EC to te marketing autorisation, please see section VI. II. II.1 QUALITY ASPECTS Drug Substance Te structure of te drug substance as been adequately proven and its pysicocemical properties are sufficiently described. Te manufacture of te drug substance as been adequately described and satisfactory specifications ave been provided for starting materials, reagents and solvents. Te drug substance specification includes relevant tests and te limits for impurities and degradation products ave been justified. Te analytical metods applied are suitably described and validated. Stability studies confirm te retest period. II.2 Medicinal Product Te medicinal product is formulated using excipients listed in section 6.1 in te Summary of Product Caracteristics. Te manufacturing process as been sufficiently described and critical steps identified. Te tests and limits in te specification are considered appropriate to control te quality of te finised product in relation to its intended purpose. 2/11

3 Stability studies ave been performed and data presented support te self life and special precautions for storage claimed in te Summary of Product Caracteristics, sections 6.3 and 6.4. III. III.1 NONCLINICAL ASPECTS Discussion on te nonclinical aspects Since tis product as been sown to be essentially similar and refer to a product approved based on a full application wit regard to preclinical data, no furter suc data ave been submitted or are considered necessary. IV. IV.1 CLINICAL ASPECTS Parmacokinetics To support te application, te applicant submitted te results from seven bioequivalence studies: 50 mg Single dose under Fasting condition (QUE/2014/1056) 50 mg Single dose under Fed condition (QUE/2014/1057) 50 mg Multiple dose steadystate under Fasting condition (ealty population) (QUE/2014/1058) 150 mg Single dose under Fasting condition (QUE/2014/1054) 200 mg Single dose under Fasting condition (QUE/2014/1052) 200 mg Single dose under Fed condition (QUE/2014/1053) 400 mg Multiple dose steadystate under Fasting condition (patients) (15VIN147) Biowaiver For a prolongedrelease singleunit formulation, wic sould be administered under fasting conditions, bioequivalence sould be demonstrated after singledose administration under fasting conditions on every strengt (or bracketing), after singledose administration under fed conditions at te igest strengt and after multipledose administration at te igest strengt (Guideline on te parmacokinetic and clinical evaluation of modified release dosage forms, EMA/CPMP/EWP/280/96). Studies on oter strengts may be waived provided tat te general biowaiver criteria as outlined in te Guideline on investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1) are fulfilled. Te 150, 200, 300 and 400 mg strengt ave proportional composition, wile te 50 mg strengt is not proportional to te oter strengts. Te 150 and 200 mg strengts were witdrawn during te procedure. A full study package as been submitted for te 50 mg strengt, wic is adequate given tat tis tablet strengt is nonproportional composition compared to te oter strengts. Single dose studies wit doses iger tan 200 mg are not feasible in ealty volunteers due to unacceptably severe adverse effects (Questions & Answers: Clinical parmacology and parmacokinetics, EMA website). 3/11

4 Te results from te singledose studies wit te 200 mg strengt are terefore waived to te 300 and 400 mg strengts. Te results from te multipledose study wit te 400 mg strengt can be waived to te 300 mg strengt. Parmacokinetic studies Te design of te bioequivalence studies was adequate. Plasma concentrations of quetiapine were determined wit validated LC/MS/MS metods. Bioequivalence study: single dose, fasting conditions, 50 mg (QUE/2014/1056) Tis was a singledose, twoway crossover study conducted in 45 ealty volunteers, comparing Quetiapine Amneal, 50 mg, prolongedrelease tablet wit Seroquel XL, 50 mg, prolongedrelease tablet, under fasting conditions. Blood samples were collected predose and up to 48 ours postdose. For AUC 0t, AUC inf and C max te 90% confidence interval for te ratio of te test and reference products fell witin te conventional acceptance range of %. Table 1. Parmacokinetic parameters (nontransformed values; aritmetic mean ± SD, t max median, range) for quetiapine after single dose administration of 50 mg under fasting conditions, n=41. Treatment AUC 0t C max t max AUC 0 Test ± ± ± Reference ± ± ± *Ratio (90% CI) ( ) ( ) ( ) AUC 0t area under te plasma concentrationtime curve from time zero to t ours AUC 0 area under te plasma concentrationtime curve from time zero to infinity C max maximum plasma concentration t max time for maximum plasma concentration *calculated based on lntransformed data Bioequivalence study: single dose, fed conditions, 50 mg (QUE/2014/1057) Tis was a singledose, twoway crossover study conducted in 46 ealty volunteers, comparing Quetiapine Amneal, 50 mg, prolongedrelease tablet wit Seroquel XL, 50 mg, prolongedrelease tablet under fed conditions (igfat meal). Blood samples were collected predose and up to 48 ours postdose. For AUC 0t, AUC inf and C max te 90% confidence interval for te ratio of te test and reference products fell witin te conventional acceptance range of %. 4/11

5 Table 2. Parmacokinetic parameters (nontransformed values; aritmetic mean ± SD, t max median, range) for quetiapine after singledose administration of 50 mg under fed conditions, n=45. Treatment AUC 0t C max AUC 0 Test ± ± ± Reference ± ± ± *Ratio (90% CI) ( ) ( ) ( ) AUC 0t area under te plasma concentrationtime curve from time zero to t ours AUC 0 area under te plasma concentrationtime curve from time zero to infinity C max maximum plasma concentration t max time for maximum plasma concentration *calculated based on lntransformed data Bioequivalence study: multiple dose, fasting conditions, 50 mg (QUE/2014/1058) Tis was a multipledose, twoway crossover study conducted in 46 ealty volunteers, comparing Quetiapine Amneal, 50 mg, prolongedrelease tablet wit Seroquel XL, 50 mg, prolongedrelease tablet under fasting conditions for five days in eac study period. Bloodsamples were collected predose on day 1 to 5 of eac period and up to 48 ours postdose on day 5 of eac period. For AUC,, C max,ss and C,ss te 90% confidence interval for te ratio of te test and reference products fell witin te conventional acceptance range of %. Table 3. Parmacokinetic parameters in steadystate (nontransformed values; aritmetic mean ± SD, tmax median, range) for quetiapine after multiple dose administration of 50 mg under fasting conditions, n=41. Treatment AUC 0τ C max,ss **C,ss t max,ss Test ± ± ± Reference ± ± ± *Ratio (90% CI) ( ) ( ) ( ) AUC 0τ area under te plasma concentrationtime curve during one dosing interval C max,ss maximum plasma concentration at steady state concentration at te end of te dosing interval at steady state C,ss t max, ss time for maximum plasma concentration at steady state *calculated based on lntransformed data **n=40 Bioequivalence study: Single dose, fasting conditions, 150 mg (QUE/2014/1054) Tis was a singledose, twoway crossover study conducted in 46 ealty volunteers, comparing Quetiapine Amneal, 150 mg, prolongedrelease tablet wit Seroquel XL, 150 mg, t max 5/11

6 prolongedrelease tablet under fasting conditions. Blood samples were collected predose and up to 48 ours postdose. For AUC 0t, AUC inf and C max te 90% confidence interval for te ratio of te test and reference products fell witin te conventional acceptance range of %. Table 4. Parmacokinetic parameters (nontransformed values; aritmetic mean ± SD, t max median, range) for quetiapine after single dose administration of 150 mg, n=43. Treatment AUC 0t AUC 0 Test ± ± ± Reference ± ± ± *Ratio (90% CI) ( ) ( ) C max ( ) AUC 0t area under te plasma concentrationtime curve from time zero to t ours AUC 0 area under te plasma concentrationtime curve from time zero to infinity C max maximum plasma concentration t max time for maximum plasma concentration *calculated based on lntransformed data Bioequivalence study: Single dose, fasting conditions, 200 mg (QUE/2014/1052) Tis was a singledose, twoway crossover study conducted in 46 ealty volunteers, comparing Quetiapine Amneal, 200 mg, prolongedrelease tablet wit Seroquel XL, 200 mg, prolongedrelease tablet under fasting conditions. Blood samples were collected predose and up to 48 ours postdose. For AUC 0t, AUC inf and C max te 90% confidence interval for te ratio of te test and reference products fell witin te conventional acceptance range of %. Table 5. Parmacokinetic parameters (nontransformed values; aritmetic mean ± SD, t max median, range) for quetiapine after single dose administration of 200 mg under fasting conditions, n=40. Treatment AUC 0t AUC 0 Test ± ± ± Reference ± ± ± *Ratio (90% CI) ( ) ( ) C max ( ) AUC 0t area under te plasma concentrationtime curve from time zero to t ours AUC 0 area under te plasma concentrationtime curve from time zero to infinity C max maximum plasma concentration t max time for maximum plasma concentration *calculated based on lntransformed data t max t max 6/11

7 Bioequivalence study: Single dose, fed conditions, 200 mg (QUE/2014/1053) Tis was a singledose, twoway crossover study conducted in 48 ealty volunteers, comparing Quetiapine Amneal, 200 mg, prolongedrelease tablet wit Seroquel XL, 200 mg, prolongedrelease tablet under fed conditions (igfat meal). Blood samples were collected predose and up to 48 ours postdose. For AUC 0t, AUC inf and C max te 90% confidence interval for te ratio of te test and reference products fell witin te conventional acceptance range of %. Table 6. Parmacokinetic parameters (nontransformed values; aritmetic mean ± SD, t max median, range) for quetiapine after single dose administration of 200 mg under fed conditions, n=38. Treatment AUC 0t AUC 0 Test ± ± ± Reference ± ± ± *Ratio (90% CI) ( ) ( ) C max ( ) AUC 0t area under te plasma concentrationtime curve from time zero to t ours AUC 0 area under te plasma concentrationtime curve from time zero to infinity C max maximum plasma concentration t max time for maximum plasma concentration *calculated based on lntransformed data Bioequivalence study: Multiple dose, fasting conditions. 400 mg (15VIN147) Tis was a multipledose, twoway crossover study conducted in 64 patients wit scizoprenia, comparing Quetiapine Amneal, 400 mg, prolongedrelease tablet wit Seroquel XL, 400 mg, prolongedrelease tablet under fasting conditions for five days in eac study period. Blood samples were collected predose on all study days and predose and up to 24 ours postdose on day 5 in eac period. Subjects for wom steadystate could not be demonstrated were excluded from te statistical analysis in accordance wit te study protocol. For AUC,, C max,ss and C,ss te 90% confidence interval for te ratio of te test and reference products fell witin te conventional acceptance range of %. t max 7/11

8 Table 7. Parmacokinetic parameters in steadystate (nontransformed values; aritmetic mean ± SD, tmax median, range) for quetiapine after multiple dose administration of 400 mg under fasting conditions, excluding subject No B07, B10, C 04, C07, D01, D05 and D06, n=53. Treatment **AUC 0τ C max,ss C,ss t max,ss Test ± ± ± Reference ± ± ± *Ratio (90% CI) ( ) ( ) ( ) AUC 0τ area under te plasma concentrationtime curve during one dosing interval C max,ss maximum plasma concentration at steady state C,ss concentration at te end of te dosing interval at steady state t max, ss time for maximum plasma concentration at steady state *calculated based on lntransformed data **For Test product (T) N= 52 Overall parmacokinetic conclusion Bioequivalence as been demonstrated after singledose administration under fasting condition wit te 50 mg, 150 mg and 200 mg strengt, after singledose administration under fed conditions wit te 50 mg and 200 mg strengt and after multipledose administration under fasting conditions wit te 50 mg and 400 mg strengt. Te results from te submitted bioequivalence studies are considered sufficient to conclude bioequivalence between Quetiapine Amneal 50 mg, Quetiapine Amneal 300 mg and Quetiapine Amneal 400 mg wit te corresponding strengts of te reference product. IV.2 Discussion on te clinical aspects Since tis product as been sown to be essentially similar and refer to a product approved based on a full application wit regard to clinical efficacy/safety data, no furter suc data ave been submitted or are considered necessary. IV.3 Risk Management Plan Te MAH as submitted a an updated risk management plan in line wit te latest RMP version of te originator, 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 quetiapine. 8/11

9 Safety specification Routine parmacovigilance is suggested and no additional parmacovigilance/risk minimisation activities are proposed by te applicant, wic is endorsed. Summary of te RMP Te Applicant as satisfactory responded to te questions raised and updated te RMP accordingly. Te RMP is approved Te MAH sall perform te required parmacovigilance activities and interventions detailed in te agreed RMP presented in Module of te Marketing Autorisation and any agreed subsequent updates of te RMP. An updated RMP sould be submitted: At te request of te RMS; Wenever te risk management system is modified, especially as te result of new information being received tat may lead to a significant cange to te benefit/risk profile or as te result of an important (parmacovigilance or risk minimisation) milestone being reaced. 9/11

10 If te dates for submission of a PSUR and te update of a RMP coincide, tey can be submitted at te same time, but via different procedures. V. USER CONSULTATION Te package leaflet 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 language used for te purpose of user testing te PIL was Englis. 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 Te quality of te generic product, Kagitz, is found adequate. Tere are no objections to approval of Kagitz, from a nonclinical and clinical point of view. Bioequivalence between te test and reference product as been adequately demonstrated. Te product information is acceptable. Te application is terefore recommended for approval. An agreed specific obligation to complete additional risk minimisation measures (educational material) is specified in section VIII of tis report. List of recommendations not falling under Article 21a/22 of Directive 2001/83 in case of a positive benefit risk assessment N/A List of conditions pursuant to Article 21a or 22 of Directive 2001/83/EC Additional risk minimisation measures (including educational material) Te educational material sould contain te following key elements: Te innovator (and reference product) as additional risk minimisation measures concerning te bipolar depression indication for te safety concerns EPS and somnolence, metabolic risk factors and te potential for offlabel use and misdosing for te bipolar depression indication (in te form of approved keyelements for educational material). As is stated in te GVP RMP Module V, te RMP of generic products sould be in line wit te reference product. VII. APPROVAL Te Decentralised procedure for Kagitz, 50 mg, 300 mg and 400 mg, prolonged release tablets was positively finalised on /11

11 Public Assessment Report Update Procedure number* Scope Product Information affected Date of end of procedure Approval/ non approval Summary/ Justification for refuse *Only procedure qualifier, cronological number and grouping qualifier (wen applicable) Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Pone: +46 (0) Fax: +46 (0) Internet: Template version: