Direction de l Evaluation des Médicaments et des Produits Biologiques PUBLIC ASSESSMENT REPORT Scientific Discussion Olanzapine Winthrop Bloonis 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg Film coated tablets 5 mg, 10 mg, 15 mg, 20 mg Orodispersible tablets Olanzapine FR/H/404/001-010/DC FR/H/405/001-010/DC Applicant: Sanofi-Aventis France Date of the PAR: September 2010 PAR_Olanzapine Winthrop_ap commentaires Page 1 of 7
Information about the initial procedure: Application/Legal Basis Generic 10 (1) Active substance Olanzapine Pharmaceutical form and strength film coated tablet: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg Orodispersible tablet: 5 mg, 10 mg, 15 mg, 20 mg Applicant SANOFI-AVENTIS France 1-13 Boulevard Romain Rolland 75014 PARIS EU-Procedure number FR/H/404/001-010/DC FR/H/405/001-010/DC End of procedure 21 April 2010 1. INTRODUCTION Based on the review of the quality, pharmacokinetic, safety and efficacy data, the decentralised procedure for Olanzapine Winthrop / Bloonis film-coated tablets and orodispersible tablets from SANOFI-AVENTIS France was approved on 21 April 2010 for the following indications in adults: Olanzapine is indicated for the treatment of schizophrenia. Olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response. Olanzapine is indicated for the treatment of moderate to severe manic episode. In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the prevention of recurrence in patients with bipolar disorder (see section 5.1). The generic application for marketing authorisation concerns: Olanzapine Winthrop 2.5 mg, film coated tablet Olanzapine Winthrop 5 mg, film coated tablet Olanzapine Winthrop 7.5 mg, film coated tablet Olanzapine Winthrop 10 mg, film coated tablet Olanzapine Winthrop 15 mg, film coated tablet Olanzapine Winthrop 20 mg, film coated tablet Bloonis 2.5 mg, film coated tablet Bloonis 5 mg, film coated tablet Bloonis 7.5 mg, film coated tablet Bloonis 10 mg, film coated tablet Bloonis 15 mg, film coated tablet Bloonis 20 mg, film coated tablet And Olanzapine Winthrop 5 mg, orodispersible tablet Olanzapine Winthrop 10 mg, orodispersible tablet Olanzapine Winthrop 15 mg, orodispersible tablet Olanzapine Winthrop 20 mg, orodispersible tablet Bloonis 5 mg, orodispersible tablet Bloonis 10 mg, orodispersible tablet Bloonis 15 mg, orodispersible tablet Bloonis 20 mg, orodispersible tablet PAR_Olanzapine Winthrop_ap commentaires Page 2 of 7
The medicinal products are claimed to be essentially similar to Zyprexa, film coated tablet and Zyprexa Velotab, orodispersible tablet marketed in France by Eli Lilly Nederland. The applicant has submitted two bioequivalence studies: - The first one compared 10 mg olanzapine Winthrop film-coated tablet (test product) to the reference formulation Zyprexa 10 mg film-coated tablet (manufactured by Lilly S.A., Spain) under fasting condition. - The second one compared 10 mg olanzapine Winthrop orodispersible tablet (test product) to the reference formulation Zyprexa Velotab10 mg orodispersible tablet (manufactured by Lilly S.A., Spain) under fasting condition. No new preclinical or clinical studies were conducted which is acceptable for this kind of application. During the procedure, potential serious risks to public health concerns were raised regarding the drug substance. These issues have been satisfactorily resolved. 2. QUALITY ASPECTS 2.1 Introduction The drug product is an Olanzapine film coated tablets and an Olanzapine orodispersible tablet. The film-coated tablet has five different strengths: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg. The orodispersible tablet has four different strengths: 5 mg, 10 mg, 15 mg and 20 mg. Olanzapine Film Coated tablets and Olanzapine Orodispersible tablets are packed in Alu-Alu blister. 2.2 Drug substance The drug substance Olanzapine is not described in the Eur.Ph., it is a yellow to slightly yellow fine crystalline powder practically insoluble in water showing polymorphism. The drug substance can be sourced from two manufacturers. The Active Substance Master File (ASMF) procedure is used for the two active substance manufacturers. Satisfactory scientific data have been provided. The active substance specification includes relevant tests and the limits for impurities/degradation products have been justified. The analytical methods applied are suitably described and validated. Stability studies under ICH conditions have been conducted and the data provided are sufficient to confirm the retest period. 2.3 Medicinal product The pharmaceutical development of Olanzapine Film Coated tablets and of Olanzapine Orodispersible tablets has demonstrated the feasibility of direct compression of a common blend. All the tablet strengths presented are homothetic. The choice of qualitative and quantitative composition is well justified. The excipients used in the manufacture of the drug product comply with the corresponding Eur. Ph.or with in-house monographs. Comparative in vitro dissolution profiles and impurities profiles of the generic product and the reference product support the essentially similar character. PAR_Olanzapine Winthrop_ap commentaires Page 3 of 7
Critical steps of manufacturing processes are defined and process parameters are well justified Results from the process validation studies confirm that the process is under control and ensure both batch to batch reproducibility and compliance with the product specification. The tests and limits in the specification are considered appropriate to control the quality of the finished product in relation to its intended purpose. Stability studies under ICH conditions have been performed. The data support the shelf life claimed in the SPC for Olanzapine Film Coated tablets and Olanzapine Orodispersible tablets: 21 months with storage mention store in the original package in order to protect from moisture 3. NON-CLINICAL ASPECTS 3.1 Discussion on the non-clinical aspects These products are generic formulations of Zyprexa and Zyprexa Velotab on the European market. No new preclinical data have been submitted and no preclinical assessment has been performed. The product is intended as a substitute for identical products on the European market. Evaluation of the potential environmental risk posed by the medicinal product has not been provided. As olanzapine is a well-known substance, generic and authorise, such an evaluation is deemed unnecessary. Approval of this product will not result in an increase in the total quantity of the active substance released into the environment, since it is intended as a substitute for other identical products on the market. 4. CLINICAL ASPECTS 4.1 Introduction Olanzapine is an atypical antipsychotic agent used for the symptomatic management of psychotic disorders such as schizophrenia and, in addition, for acute mixed or manic episodes associated with bipolar I disorder, for longer-term maintenance monotherapy in this disorder, and for the management of acute agitation in patients with bipolar disorder or schizophrenia. Olanzapine is a well-known active substance with established efficacy and tolerability. 4.2 Discussion on the clinical aspects The BE of the product under consideration to an adequate comparator has been demonstrated. Taking into account the pharmaceutical characteristics a single BE study has been performed: open-label, randomised, single-dose, two-period, two-sequence crossover, with 240 ml low carbonated water. No new preclinical and clinical studies were conducted, which is acceptable for this kind of application. Product Zyprexa was approved in EU in 1996, and therefore with more than 10 years of experience. The safety profile can be considered as well-established and no product-specific pharmacovigilance issues were identified which are not adequately covered by the current SPC. Additional risk minimisation activities have not been identified for the reference medicinal product. A detailed Risk management Plan is not necessary for this product. PAR_Olanzapine Winthrop_ap commentaires Page 4 of 7
4.3 Pharmacokinetics Bioequivalence study with film-coated tablets: In support of the present application, a single dose bioequivalence study was submitted comparing 10 mg olanzapine Winthrop film-coated tablet (test product) to the reference formulation Zyprexa 10 mg film-coated tablet (Lilly) under fasting condition. The study was designed according to an open-label, randomised, single-dose, two-period, twosequence crossover. Doses were separated by a 14-day washout period. Thirty-six adult healthy male volunteers were enrolled. Among them 32 subjects completed all the clinical phases of the study. The bio-batch is considered representative of the full scale production of the generic product under review. The plasma concentrations of olanzapine were monitored over 192 h time period after drug administration and samples were assayed for olanzapine by the means of a validated LC-MS-MS technique. The primary pharmacokinetic parameters of olanzapine assessed were AUC0-t, AUC0-inf, Cmax and Tmax. The statistical analysis of the data was conducted according to up to date methods. The analysis consisted in an ANOVA and estimation of 90% Confidence intervals of the ratios T/R for each PK parameter of interest Based on the submitted bioequivalence study, olanzapine Winthrop 10 mg could be considered bioequivalent with Zyprexa 10 mg. Olanzapine: Pharmacokinetic parameters (AUC and Cmax: arithmetic mean ± SD, tmax: median, range): Single 10 mg oral dose (n=31). Treatment AUC 0-t AUC 0- C max t max Test Reference *Ratio (90% CI) Point estimate 538.5 (193.8) 533.9 (194.9) [96; 107]% 100.4 % 564.7 (197) 559.6 (197.9) [96; 106]% 101 % ng/ml 16.69 (5.71) 16.4 (4.3) [93; 108]% 100.5 % Intra-subject CV (%) 12.2 % 10.7 % 16.9 % 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 time for maximum concentration : mediane, min and max T max *log-transformed values h 3 (1.5-6.5) 4.0 (2-6.5) NS The bioequivalence study could be extrapolated to the other strengths as all criteria for biowaiver are fulfilled according to the Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98, section 5.4. Bioequivalence study with orodispersible tablets: PAR_Olanzapine Winthrop_ap commentaires Page 5 of 7
In support of the present application, a single dose bioequivalence study was submitted comparing 10 mg olanzapine Winthrop orodispersible tablet (test product) to the reference formulation Zyprexa Velotab10 mg orodispersible tablet (Lilly) under fasting condition. The study was designed according to an open-label, randomised, single-dose, two-period, twosequence crossover. Doses were separated by a 14-day washout period. Thirty-six adult healthy male volunteers were enrolled. Among them 32 subjects completed all the clinical phases of the study. Both study products - the test and reference formulations were placed entirely on the subject's tongue, where it rapidly dispersed in saliva, so it was easily swallowed. Once disintegrated, 240 ml of bottled still water were swallowed and a mouth check was performed to ensure consumption of the medication. The bio-batch is considered representative of the full scale production of the generic product under review. The plasma concentrations of olanzapine were monitored over 192 h time period after drug administration and samples were assayed for olanzapine by the means of a validated LC-MS-MS technique. The primary pharmacokinetic parameters of olanzapine assessed were AUC0-t, AUC0-inf, Cmax and Tmax. The statistical analysis of the data was conducted according to up to date methods. The analysis consisted in an ANOVA and estimation of 90% Confidence intervals of the ratios T/R for each PK parameter of interest Based on the submitted bioequivalence study, olanzapine Winthrop 10 mg orodispersible could be considered bioequivalent with Zyprexa Velotab10 mg. Olanzapine: Pharmacokinetic parameters (AUC and Cmax: arithmetic mean ± SD, tmax: median, range): Single 10 mg oral dose (n=32). Treatment AUC 0-t AUC 0- C max t max Test Reference *Ratio (90% CI) Point estimate 441.7 (168.9) 450.6 (173.1) [96; 101]% 101 % 465.6 (171.3) 475.6 (174.6) [95; 101]% 100.9 % ng/ml 15.43 (5.20) 15.69 (5.83) [96; 104]% 104.4 % Intra-subject CV (%) 6.6 % 6.8 % 10.5 % 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 time for maximum concentration : mediane, min and max T max *log-transformed values h 3 (1.5-6.5) 2.5 (1.5-5.5) NS The bioequivalence study could be extrapolated to the other strengths as all criteria for biowaiver are fulfilled according to the Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98, section 5.4. PAR_Olanzapine Winthrop_ap commentaires Page 6 of 7
5. OVERALL DISCUSSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION The chemical-pharmaceutical quality of Olanzapine Film Coated tablets and of Olanzapine Orodispersible tablets is demonstrated. Bioequivalence has been shown to be in compliance with the European guidance documents. The SPC is consistent with that of the reference product. The SPC, Package Leaflet (PL) and Labelling are in the agreed template. The Member States mutually recognised the French evaluation of the marketing authorisation. There was no discussion in the CMD(h). Agreement between Member States was reached through a written procedure. The decentralised procedure was positively ended on 21 st April 2010. PAR_Olanzapine Winthrop_ap commentaires Page 7 of 7