Public Assessment Report Scientific discussion. Levodopa/Carbidopa/Entacapone Mylan (levodopa, carbidopa, entacapone) SE/H/1548/01-06/DC

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1 Public Assessment Report Scientific discussion Levodopa/Carbidopa/Entacapone Mylan (levodopa, carbidopa, entacapone) SE/H/1548/01-06/DC This module reflects the scientific discussion for the approval of Levodopa/Carbidopa/Entacapone Mylan. The procedure was finalised on For information on changes after this date please refer to the module Update. Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: Template version:

2 I. INTRODUCTION The application for Levodopa/Carbidopa/Entacapone Mylan, 50 mg/12.5 mg/200 mg; 75 mg/18.75 mg/200 mg; 100 mg/25 mg/200 mg; 125 mg/31.25 mg/200 mg; 150 mg/37.5 mg/200 mg and 200 mg/50 mg/200 mg, film-coated tablets, is a generic application made according to Article 10(1) of Directive 2001/83/EC. The applicant, Mylan AB applies through the Decentralised Procedure with Sweden acting as reference member state (RMS) and DE, HU, RO, SI as concerned member states (CMS). The reference medicinal product chosen for the purposes of establishing the expiry of the data protection period is Stalevo, 50 mg/12.5 mg/200 mg; 75 mg/18.75 mg/200 mg; 100 mg/25 mg/200 mg; 125 mg/31.25 mg/200 mg; 150 mg/37.5 mg/200 mg and 200 mg/50 mg/200 mg, film-coated tablets authorised in Union since 2003, with Orion Corporation as marketing authorisation holder. The reference product used in the bioequivalence study is Stalevo 50 mg/12.5 mg/200 mg film-coated tablets and Stalevo 200 mg/50 mg/200 mg film-coated tablets from EU with Orion Corporation as marketing authorisation holder. Similarity to medicinal products with orphan drug status According to Article 8.1 of Regulation (EC) No 141/2000, where a marketing authorization in respect of an orphan medicinal product is granted, the Community and the Member States shall not, for a period of 10 years, accept another application for a marketing authorisation, or grant a marketing authorisation, accept an application to extend an existing marketing authorisation, for the same therapeutic indication, in respect of a similar medicinal product (so-called 10 year market exclusivity). According to Article 3 of Commission Regulation (EC) No 847/2000 a similar medicinal product means a medicinal product containing a similar active substance or substances (active substance(s) with the same principal molecular, structural features and which acts via the same mechanism) as contained in a currently authorised orphan medicinal product, and which is intended for the same therapeutic indication. The Applicant has completed module (report addressing the possible similarity with authorised orphan medicinal products). At the time of submission of the application, Duodopa (levodopa/carbidopa, intestinal gel), has been designated as orphan medicinal product and has a marketing authorisation. Duodopa was approved through the mutual recognition procedure in 25 member states on 18 November Duodopa was granted Orphan Drug Market Exclusivity on 18 November, 2005 but is no longer an orphan medicine since the 10-year period has expired. RMS position on similarity of Levodopa/Carbidopa/Entacapone Mylan film-coated tablets, with Duodopa is concluded below: Molecular structure None of the three active substances, levodopa, carbidopa and entacapone, are new active substances and levdopa and carbidopa have the same principal molecular and structural features as the active substances included in Duodopa intestinal gel. 2/8

3 Therapeutic indication Duodopa has been granted a marketing authorization for the following indication Treatment of advanced levodopa-responsive Parkinson's disease with severe motor fluctuations and hyper-/dyskinesia when available combinations of Parkinson medicinal products have not given satisfactory results. Levodopa/Carbidopa/Entacapone Mylan suggests the following indication: treatment of adult patients with Parkinson s disease and end-of-dose motor fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment. The Duodopa indication is a highly advanced disease target population who no longer experience symptomatic relief from current levodopa/carbidopa formulations, also including oral products such as Levodopa/Carbidopa/Entacapone Mylan. Duodopa was granted Orphan Drug Market Exclusivity on 18 November 2005 when other oral levodopa-containing products were already commercially available, some for decades. The basis of the Orphan Drug Market Exclusivity was that Duodopa would only be administered via a PEG-J tube to the most severe Parkinson s patients who do not get relief from the existing levodopa-containing products. Levodopa/Carbidopa/Entacapone Mylan target population encompasses those patients taking already existing oral levodopa-containing products and thus would not overlap with the Duodopa target population. Mechanism of action The active substances Levodopa/Carbidopa, in Levodopa/Carbidopa/Entacapone Mylan, and Duodopa are identical and have therefore the same mechanism of action. Conclusion The indication for Levodopa/Carbidopa/Entacapone Mylan is a broad one covering treatment of adult patients with Parkinson s disease and end-of-dose motor fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment. However, the target population for Duodopa is patients with severe motor fluctuations who no longer experience symptomatic relief from current levodopa/carbidopa formulations, including oral products as Levodopa/Carbidopa/Entacapone Mylan. To conclude, the mechanism of action and molecular structure of Levodopa/Carbidopa, in Levodopa/Carbidopa/Entacapone Mylan, and Duodopa intestinal gel are considered similar in the context of orphan medicinal products. However, the therapeutic indication of Levodopa/Carbidopa/Entacapone Mylan and Duodopa intestinal gel are considered non-similar in the context of orphan medicinal products. Therefore, with reference to Article 8 of Regulation (EC) No 141/2000, Levodopa/Carbidopa/Entacapone Mylan is considered not similar (as defined in Article 3 of Commission Regulation (EC) No. 847/2000) to Duodopa intestinal gel. Therefore, with reference to article 8 of Regulation (EC) No. 141/2000, the existence of any market exclusivity for Duodopa intestinal gel in the Treatment of advanced levodoparesponsive Parkinson's disease with severe motor fluctuations and hyper-/dyskinesia when available combinations of Parkinson medicinal products have not given satisfactory results does not prevent the granting of the marketing authorisation of Levodopa/Carbidopa/Entacapone Mylan. This finding is without prejudice to the outcome of the scientific assessment of the marketing authorisation application. For approved indications, see the Summary of Product Characteristics. For recommendations to the marketing authorisation not falling under Article 21a/22 of Directive 2001/83 and conditions to the marketing authorisation pursuant to Article 21a or 22 of Directive 2001/83/EC to the marketing authorisation, please see section VI. 3/8

4 II. II.1 QUALITY ASPECTS Drug Substance The structure of the drug substance has been adequately proven and its physico-chemical properties are sufficiently described. The manufacture of the drug substance has been adequately described and satisfactory specifications have been provided for starting materials, reagents and solvents. The drug substance specification includes relevant tests and the limits for impurities and degradation products have been justified. The analytical methods applied are suitably described and validated. Stability studies confirm the retest period. II.2 Medicinal Product The medicinal product is formulated using excipients listed in section 6.1 in the Summary of Product Characteristics. The manufacturing process has been sufficiently described and critical steps identified. 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 have been performed and data presented support the shelf life and special precautions for storage claimed in the Summary of Product Characteristics, sections 6.3 and 6.4. III. III.1 NON-CLINICAL ASPECTS Discussion on the non-clinical aspects Since this product has been shown to be essentially similar and refer to a product approved based on a full application with regard to preclinical data, no further such data have been submitted or are considered necessary. IV. IV.1 CLINICAL ASPECTS Pharmacokinetics To support the application, the applicant has submitted two pivotal bioequivalence studies in the fasted state. In addition there were two pilot studies conducted to assess the formulation performance and to estimate the sample size and type of study design for the pivotal studies. The pivotal studies are described below: 4/8

5 PHARMACOKINETIC STUDY WITH THE 50MG/12.5MG/200MG STRENGTH (STUDY NUMBER: 14-VIN-514) Bioequivalence was evaluated in one randomised, two-treatment, four-period, two-sequence, single-dose replicate crossover study. The study was conducted in 48 (+2 extra subjects up to dosing in period 1) healthy volunteers, comparing Levodopa/Carbidopa/Entacapone Mylan, 50/12.5/200mg, film coated tablets with Stalevo, 50/12.5/200mg, film coated tablets under fasting conditions. The study was conducted at Veeda Clinical Research in India between and Blood samples were collected pre-dose and up to12 hours postdose. The study design is considered acceptable. Plasma concentrations of levodopa, carbidopa and entacapone were determined with an adequately validated LC/MS/MS method. For AUC 0-t and C max the 90% confidence interval for the ratio of the test and reference products fell within the conventional acceptance range of % for all three substances. PHARMACOKINETIC STUDY WITH THE 200MG/50MG/200MG STRENGTH (STUDY NUMBER: 14-VIN-515) Bioequivalence was evaluated in one randomised, two-treatment, four-period, two-sequence, replicate single-dose crossover study. The study was conducted in 48 (+02 extra subjects up to dosing in period 01) healthy volunteers, comparing Levodopa/Carbidopa/Entacapone Mylan, 200/50/200 mg, Film Coated Tablets with Stalevo, 200/50/200mg, film-coated tablets under fasting conditions. The study was conducted at Veeda Clinical Research in India between and Blood samples were collected pre-dose and up to 12 hours postdose. The study design is considered acceptable. Plasma concentrations of levodopa, carbidopa and entacapone were determined with an adequately validated LC/MS/MS method. For AUC 0-t and C max the 90% confidence interval for the ratio of the test and reference products fell within the conventional acceptance range of % for all three substances. Both the highest and the lowest strength of levodopa and carbidopa have been studied as well as the only strength of entacapone. The tested strengths are considered sufficient regardless of any non-linearity in pharmacokinetics for the active substances. Thus, the absence of studies with the additional strengths is acceptable from a pharmacokinetic point of view. IV.2 Discussion on the clinical aspects Since this product has been shown to be essentially similar and refer to a product approved based on a full application with regard to clinical efficacy/safety data, no further such data have been submitted or are considered necessary. 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 Levodopa/Carbidopa/Entacapone Mylan. Safety specification Summary table of safety concerns as approved in RMP 5/8

6 Pharmacovigilance Plan Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed. Risk minimisation measures Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed. Summary of the RMP The MAH has satisfactory responded to the questions raised and updated the RMP accordingly. Issue is resolved. The RMP is approved The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures. 6/8

7 V. USER CONSULTATION A user consultation with target patient groups on the package information leaflet (PIL) has been performed on the basis of a bridging report making reference to Stalevo 200 mg/50 mg/200 mg film-coated tablets, EMEA/H/C/ (content) and Duloxetine Mylan 30 mg hard gastro-resistant capsules, EMEA/H/C/ (layout). The bridging report submitted by the applicant has been found acceptable. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION The quality of the generic product, Levodopa/Carbidopa/Entacapone Mylan is found adequate. There are no objections to approval of product name, from a non-clinical and clinical point of view. Bioequivalence between the test and reference product has been adequately demonstrated. The product information is acceptable. The application is therefore recommended for approval. 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 N/A VII. APPROVAL The Decentralised procedure for Levodopa/Carbidopa/Entacapone Mylan, 50 mg/12.5 mg/200 mg; 75 mg/18.75 mg/200 mg; 100 mg/25 mg/200 mg; 125 mg/31.25 mg/200 mg; 150 mg/37.5 mg/200 mg and 200 mg/50 mg/200 mg, film-coated tablets was positively finalised on /8

8 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, chronological number and grouping qualifier (when applicable) Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: Template version: