Public Assessment Report. Scientific discussion. Levosimendan. Date:

Transcription

1 CMDh/223/2005 February 2014 Public Assessment Report Scientific discussion Zimino 2,5 mg/ml Konzentrat zur Herstellung einer Infusionslösung Levosimendan Date: This module reflects the scientific discussion for the approval of Zimino 2,5 mg/ml Konzentrat zur Herstellung einer Infusionslösung. The procedure was finalised at of day 173. For information on changes after this date please refer to the module Update. Bundesamt für Sicherheit im Gesundheitswesen

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Zimino 2,5 mg/ml Konzentrat zur Herstellung einer Infusionslösung, from Orion Corporation. The product is indicated for: the short-term treatment of acutely decompensated severe chronic heart failure (ADHF) in situations where conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate. A comprehensive description of the indications and posology is given in the SmPC. The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC. Levosimendan enhances the calcium sensitivity of contractile proteins by binding to cardiac troponin C in a calcium-dependent manner. Levosimendan increases the contraction force but does not impair ventricular relaxation. In addition, levosimendan opens ATP-sensitive potassium channels in vascular smooth muscle, thus inducing vasodilatation of systemic and coronary arterial resistance vessels and systemic venous capacitance vessels. Levosimendan is a selective phosphodiesterase III inhibitor in vitro. The relevance of this at therapeutic concentrations is unclear. In patients with heart failure, the positive inotropic and vasodilatory actions of levosimendan result in an increased contractile force, and a reduction in both preload and afterload, without adversely affecting diastolic function. Levosimendan activates stunned myocardium in patients after PTCA (percutaneous transluminal coronary angioplasty) or thrombolysis. II. II.1 QUALITY ASPECTS Introduction Zimino 2,5 mg/ml Konzentrat zur Herstellung einer Infusionslösung is a concentrate for solution for infusion which is presented in a type I glass vial. II.2 Drug Substance The active substance in Zimino 2,5 mg/ml Konzentrat zur Herstellung einer Infusionslösung is levosimendan. The specification of the active substance meets the current scientific requirements. The adequate quality of the active substance has been shown by submitting the appropriate control data. The stability of the active substance has been tested under ICH conditions. The results of the stability studies support the established retest-period. Bundesamt für Sicherheit im Gesundheitswesen

3 II.3 Medicinal Product Zimino 2,5 mg/ml Konzentrat zur Herstellung einer Infusionslösung contains the following excipients: - Povidone (Kollidon PF12) - Citric Acid, anhydrous - Ethanol, anhydrous: this medicinal product contains 785 mg/ml ethanol. The manufacturer responsible for batch release is Orion Corporation, Orionintie 1, Espoo, Finland. The development of the product has been sufficiently made and deemed appropriate. The usage of all the excipients has been described. The release specification includes the check of all parameters relevant to this pharmaceutical form. Appropriate data concerning the control of the finished product support the compliance with the release specifications. The packaging of the medicinal product complies with the current legal requirements. Stability studies under ICH conditions have been performed and data presented support the shelf life claimed in the SmPC, with a shelf life of 36 months when stored in a refrigerator (2 C-8 C). The product must not be frozen. The pharmaceutical quality of Zimino 2,5 mg/ml Konzentrat zur Herstellung einer Infusionslösung has been adequately shown. II.4 Discussion on chemical, pharmaceutical and biological aspects Information on development, manufacture and control of active substance and medicinal product has been presented in a satisfactory manner. The results of tests carried out indicate satisfactory consistency and uniformity of important product quality characteristics. III. III.1 NON-CLINICAL ASPECTS Introduction Abundant data on levosimendan non-clinical pharmacodynamics is available in the public literature. The applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. III.2 Pharmacokinetics Only scarce information is available on levosimendan pharmacokinetics in experimental animals, but the human pharmacokinetics of i.v. levosimendan is well established in different patient groups. Bundesamt für Sicherheit im Gesundheitswesen

4 III.3 Toxicology Only one publicly available article reports results on toxicity studies with levosimendan. These studies on general toxicity and genotoxicity revealed no special hazard for humans in short term use. III.4 Ecotoxicity/environmental risk assessment (ERA) Since Zimino is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.5 Discussion on the non-clinical aspects The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is deemed adequate. IV. IV.1 CLINICAL ASPECTS Pharmacokinetics No new data have been submitted and none are required for this application. According to CPMP guidelines, the applicant is not required to submit a bioequivalence study if the product is to be administered as an aqueous intravenous solution containing the same active substance in the same concentration as the currently authorised product. (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**, APPENDIX II, Parenteral solutions). IV.2 Pharmacodynamics Abundant data on levosimendan clinical pharmacodynamics is available in the public literature. The applicant has not provided additional studies and further studies are not required. IV.3 Clinical efficacy/safety No new efficacy and safety data have been submitted and none are required for this generic application. Bibliographical data demonstrate a sufficient level of efficacy and safety of levosimendan in the claimed indication. IV.4 Risk Management Plan The MAH has submitted a RMP Version 1.3 dated , according to GVP Module V Bundesamt für Sicherheit im Gesundheitswesen

5 - Risk management systems, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Zimino 2,5 mg/ml Konzentrat zur Herstellung einer Infusionslösung. - Summary table of safety concerns as approved in RMP Bundesamt für Sicherheit im Gesundheitswesen

6 - Summary of Safety Concerns and Planned Risk Minimisation Activities as approved in RMP Bundesamt für Sicherheit im Gesundheitswesen

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13 IV.5 Discussion on the clinical aspects According to the current Guideline on the Investigation of Bioequivalence no bioequivalence study is required for the present formulation. The clinical overview on the clinical pharmacology, efficacy and safety is deemed adequate. 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 Simdax 2.5 mg/ml concentrate for solution for infusion. The bridging report submitted by the applicant has been found acceptable. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION The pharmaceutical quality of Zimino 2,5 mg/ml Konzentrat zur Herstellung einer Infusionslösung has been adequately shown. The benefit/risk ratio is considered positive. Bundesamt für Sicherheit im Gesundheitswesen

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15 Public Assessment Report Update Zimino 2,5 mg/ml Konzentrat zur Herstellung einer Infusionslösung Levosimendan This module reflects the procedural steps and scientific information after the finalisation of the initial procedure. Bundesamt für Sicherheit im Gesundheitswesen

16 Scope Procedure number Product Information affected Date of start of the procedure Date of end of procedure Approval/ non approval Assessment report attached Y/N (version) PAR Scientific discussion 16/16