Public Assessment Report. Scientific discussion. Bloxazoc 25 mg, 50 mg, 100 mg and 200 mg prolonged-release tablets Metoprolol succinate

Transcription

1 CMDh/223/2005 February 2014 Public Assessment Report Scientific discussion Bloxazoc 25 mg, 50 mg, 100 mg and 200 mg prolonged-release tablets Metoprolol succinate HR/H/0103/ /DC Date: This module reflects the scientific discussion for the approval of Bloxazoc 25 mg, 50 mg, 100 mg and 200 mg prolonged-release tablets. The procedure was finalised at October 21 st 2015 (day 203). For information on changes after this date please refer to the module Update.

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Bloxazoc 25 mg, 50 mg, 100 mg and 200 mg prolonged-release tablets, from Krka, d.d., Novo mesto. The product is indicated in adults in: - Hypertension. - Angina pectoris. - Cardiac arrhythmias, especially including supraventricular tachycardia, reduction of ventricular rate in atrial fibrillation and in ventricular extrasystoles. - Functional heart disorders with palpitations. - Prevention of cardiac death and reinfarction after the acute phase of myocardial infarction. - Prophylaxis of migraine. - Stable chronic symptomatic heart failure with impaired systolic left ventricular function. and in children and adolescents 6-18 years of age in: - Treatment of hypertension. 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. The reference medicinal product is SelokenZOC 200 mg prolonged-release tablets authorised in Sweden since 1986, with AstraZeneca AB as marketing authorisation holder. II. QUALITY ASPECTS II.1 Introduction Bloxazoc 25 mg prolonged-release tablets are white to almost white, oval, biconvex, film coated tablets with score line on one side of the tablet (dimension 8.5 mm x 4.5 mm). On one side of the score line mark C is engraved on the other side of the score line mark 1 is Bloxazoc 50 mg prolonged-release tablets are white to almost white, oval, slightly biconvex, film coated tablets with score line on one side of the tablet (dimension 10.5 mm x 5.5 mm). On one side of the score line mark C is engraved on the other side of the score line mark 2 is Bloxazoc 100 mg prolonged-release tablets are white to almost white, oval, biconvex, film coated tablets with score line on one side of the tablet (dimension 13 mm x 8 mm). On one side of the score line mark C is engraved on the other side of the score line mark 3 is Bloxazoc 200 mg prolonged-release tablets are white to almost white, biconvex, capsule shaped film coated tablets with score line on both sides of the tablet (dimension 19 mm x 8 mm). On one side of the tablet on one side of the score line mark C is engraved on the other side of the score line mark 4 is PAR Scientific discussion 2/5

3 Bloxazoc 25 mg prolonged-release tablet can be divided into equal doses, while for Bloxazoc 50 mg, 100 mg and 200 mg prolonged-release tablets the score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses. The prolonged-release tablets are packed in PVC/PE/PVDC foil - Alu foil blisters. The other ingredients are silica, colloidal anhydrous; cellulose, microcrystalline; hypromellose; sodium laurilsulfate; polysorbate 80; glycerol; hydroxypropylcellulose; ethylcellulose; and sodium stearyl fumarate in the tablet core and hypromellose; titanium dioxide (E171); talc and propylene glycol in the film coating. Compliance with Good Manufacturing Practice (GMP) The RMS has been assured that acceptable standards of GMP are in place for this product type at all sites responsible for the manufacturing of the active substance as well as for the manufacturing and assembly of this product. II.2 Drug Substance Metoprolol succinate is described in the European Pharmacopoeia. Application is supported with CEPs from two active substance manufacturers. The re-test period and container closure system are covered by both CEPs. II.3 Medicinal Product Development of the formulation has been clearly described. Qualitative and quantitative composition of active substance in the developed drug product is identical with the originator product whereas excipients are not identical, but are similar. Development of the dissolution method has been sufficiently described. The manufacturing processes and in process control testing have been described in sufficient details. Acceptable validation data have been provided. Control of excipients is suitably addressed. The product specifications cover appropriate parameters for this dosage form and are considered acceptable. Validations of the analytical methods have been presented. Batch results demonstrate compliance with the proposed finished product specification. The container closure system is sufficiently described. Provided stability data justify the proposed shelf life of 24 months with storage condition: store below 30 C. III. NON-CLINICAL ASPECTS III.1 Introduction Pharmacodynamic, pharmacokinetic and toxicological properties of metoprolol are well known. As metoprolol is a widely used, well-known active substance, the applicant has not provided additional studies and further non clinical studies are not required. Overview based on literature review is, thus, appropriate. The provided non-clinical overview on the preclinical pharmacology, pharmacokinetics and toxicology is adequate. III.2 Ecotoxicity/environmental risk assessment (ERA) Since Bloxazoc 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. PAR Scientific discussion 3/5

4 IV. CLINICAL ASPECTS IV.1 Pharmacokinetics Bioequivalence studies To support the application, the applicant has submitted three bioequivalence studies: 1) Comparative, Randomised, Single-Dose, 2-Way Crossover Bioavailability Study of Two Metoprolol Succinate 190 mg Products in Healthy Adult Volunteers Under Fasting Conditions 2) Comparative, Randomised, Single-Dose, 2-Way Crossover Bioavailability Study of Two Metoprolol Succinate 190 mg Products in Healthy Adult Volunteers Under Fed Conditions 3) Multiple Dose Crossover Comparative Bioavailability Study of Metoprolol Succinate 190 mg Sustained-Release Tablets in Healthy Male Volunteers / Fasting State According to the Note for guidance on modified release oral and transdermal dosage forms: Section II (pharmacokinetic and clinical evaluation) CPMP/EWP/280/96 Corr * the set of BE studies provided by the Applicant is sufficient for the applied product with respect to the pharmaceutical form (prolonged release). Bioequivalence studies were conducted with the highest strength (190 mg) which is acceptable according to the Note for Guidance on Modified Release Oral and Transdermal Dosage Forms: Section II (Pharmacokinetic and Clinical Evaluation) CPMP/EWP/280/96 Corr* and The Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/ 1401/98 Rev.1/Corr**. A biowaiver is requested for other strengths (95 mg, 47.5 mg and mg) since Metoprolol prolonged-release tablets are multiple unit formulations and comply with the requirements of the current guideline for biowaiver (same manufacturer, same qualitative composition, proportional compositions of the strengths, comparable in vitro dissolution profile). Dissolution profiles are provided on acceptable batch size of all strengths (minimal production batch size). The biowaiver request for other strengths (95 mg, 47.5 mg and mg) is acceptable. Conclusion on bioequivalence studies: Based on the submitted bioequivalence studies Bloxazoc is considered bioequivalent with Beloc-Zoc forte. IV.2 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 Bloxazoc. - Summary table of safety concerns as approved in RMP PAR Scientific discussion 4/5

5 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 Bisoprolol Krka (bisoprolol fumarate) 2.5, 5 mg and 10 mg film-coated tablets, CZ/H/0427/ /DC. The bridging report submitted by the applicant has been found acceptable. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Bloxazoc 25 mg, 50 mg, 100 mg and 200 mg prolonged-released tablets have a proven chemical-pharmaceutical quality and are generic form of SelokenZOC (Betaloc ZOK, Beloc- Zoc) 25 mg, 50 mg, 100 mg and 200 mg prolonged-release tablets, respectively. Metoprolol succinate is a well-known active substance with an established favourable efficacy and safety profile. Bioequivalence has been shown to be in compliance with the requirements of European guidance documents. The marketing authorisation holder has provided written confirmation that systems and services are in place to ensure compliance with their pharmacovigilance obligations. The SmPC, package leaflet and labelling are in the agreed templates and are in agreement with other metoprolol containing products. Agreement between Member States was reached during a written procedure. There was no discussion in the CMD(h). The member states, on the basis of the data submitted, considered that essential similarity has been demonstrated with the reference product and the application was approved. The decentralised procedure was finalized with a positive outcome on 21 st October PAR Scientific discussion 5/5