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Bosentan BASICS 62.5 Mg & 125Mg

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Bosentan BASICS 62.5 Mg & 125Mg PUBLIC ASSESSMENT REPORT Decentralised Procedure Bosentan BASICS 62.5 mg & 125mg Procedure Number: DE/H/4181/001-002/DC Active Substance Bosentan Dosage Form Film Coated Tablets Marketing Autorisation Holder Basics GmbH, Hemmelrather Weg 201 D- 51377 Leverkusen, Germany Publication: 12.10.2016 TABLE OF CONTENTS I. EXECUTIVE SUMMARY................................................................................................. 3 I.1 Problem statement ......................................................................................................... 3 This is a generic application ...................................................................................................... 3 I.2 About the product .......................................................................................................... 3 I.3 General comments on the submitted dossier................................................................... 4 I.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.4 II. SCIENTIFIC OVERVIEW AND DISCUSSION ............................................................ 5 II.1 Quality aspects ............................................................................................................... 5 II.2 Non-clinical aspects ........................................................................................................ 5 II.3 Clinical aspects ............................................................................................................... 7 III. BENEFIT RISK ASSESSMENT .................................................................................. 12 IV. PROPOSED LIST OF OUTSTANDING ISSUES ........................................................ 12 IV.1 Quality aspects ............................................................................................................. 12 IV.2 Non-clinical aspects ...................................................................................................... 12 IV.3 Clinical aspects ............................................................................................................. 13 V. PROPOSED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT INFORMATION ..................................................................................................................... 13 V.1 Legal Status.................................................................................................................. 13 V.2 (Draft) final list of recommendations not falling under Article 21a/22 of Directive 2001/83 in case of a positive benefit risk assessment ................................................................ 13 V.3 Proposed list of conditions pursuant to Article 21a or 22 of Directive 2001/83/EC ....... 13 V.4 Summary of Product Characteristics (SmPC) .............................................................. 14 V.5 Package Leaflet (PL) .................................................................................................... 14 V.5.1 Package Leaflet.................................................................................................... 14 V.5.2 Assessment of User Testing .................................................................................. 14 V.6 Labelling ...................................................................................................................... 14 VI. APPENDIX .................................................................................................................. 15 QRD GUIDANCE AND CHECKLIST FOR THE REVIEW OF USER TESTING RESULTS ................................................................................................................................................ 15 Guidance regarding Recruitment .......................................................................................... 18 DE/H/4148/001-002/DC Public Assessment Report Page 2/21 RECOMMENDATION Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Bosentan Basics, in the treatment of Treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class III. Efficacy has been shown in: • Primary (idiopathic and heritable) pulmonary arterial hypertension • Pulmonary arterial hypertension secondary to scleroderma without significant interstitial pulmonary disease • Pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts and Eisenmenger’s physiology. Some improvements have also been shown in patients with pulmonary arterial hypertension WHO functional class II (see section 5.1). Bosentan film-coated tablets are also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease (see section 5.1) is approvable provided that the applicant commits to perform a number of post authorisation follow- up measures to be reported back to the RMS and CMS within predefined timeframes. A list of such follow-up measures is in section VI of this report. There is no need for an additional expert involvement or a GCP inspection. I. EXECUTIVE SUMMARY I.1 Problem statement This is a generic application I.2 About the product This decentralised application concerns a generic version of Bosentan, under 1 trade name (Bosentan Basics 62,5mg & 125 mg). In this Assessment Report, the name Bosentan Basics is used. The originator product is Tracleer (62.5 and 125 mg film-coated tablets) by Actelion Pharmaceuticals, registered since 2002-05-15. With Germany as the Reference Member State in this Decentralized Procedure, Basics GmbH is applying for the Marketing Authorisations for Bosentan Basics in FR, IT, ES. Bosentan 62.5/125 mg film-coated tablets is a dual endothelin A and B (ETA and ETB) receptor antagonist that is indicated for the treatment of patients with primary or secondary pulmonary arterial hypertension. Endothelin 1 (ET 1) is a potent vascular paracrine and autocrine peptide whose actions are mediated through ETA receptors present on smooth muscle cells and endothelin B (ETB) receptors present on endothelial cells. Predominant actions of ET 1 binding to ETA receptors are vasoconstriction and vascular remodeling, while binding to ETB receptors results in ET 1 clearance and vasodilatory and antiproliferative effects due in part to nitric oxide and prostacyclin release. ET 1 concentrations are DE/H/4148/001-002/DC Public Assessment Report Page 3/21 elevated in plasma and lung tissue of patients with PAH. ETA and ETB receptors play a key role in regulating vascular resistance in the lung by directly stimulating vasoconstriction and pulmonary vascular remodeling and this ultimately leads to progressive right heart failure. The proposed indications are: Treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class III. Efficacy has been shown in: • Primary (idiopathic and heritable) pulmonary arterial hypertension • Pulmonary arterial hypertension secondary to scleroderma without significant interstitial pulmonary disease • Pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts and Eisenmenger’s physiology. Some improvements have also been shown in patients with pulmonary arterial hypertension WHO functional class II (see section 5.1). Bosentan film-coated tablets are also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease (see section 5.1) I.3 General comments on the submitted dossier This decentralised application concerns a generic version of Bosentan, under one trade name. The originator product is Tracleer (62.5 and 125 mg film-coated tablets) by Actelion Pharmaceuticals, registered since 2002-05-15. With Germany as the Reference Member State in this Decentralized Procedure, Basics GmbH is applying for the Marketing Authorisations for Bosentan Basics in FR, IT, ES. No scientific advice has been given. The strategy was in accordance with the relevant guideline CPMP/QWP/EWP/1401/98 Rev. 1, January 2010 (bioequivalence guideline). Sections 1.6.1-3 of the paediatric regulation EC No 1901/2006 are not applicable for a generic medicinal product. No PIP has been submitted I.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. According to the Applicant the bioequivalence study and the validation of the methods were conducted in accordance to the principles of GCP and GLP. The BE study has been approved by a local ethics committee prior to the conduct of the study. The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. Valid GMP certificates for all proposed manufacturing sites, which are responsible for bulk manufacture, packaging step, testing and batch release, are presented. A QP declaration is applicable to the following registered MIAH(s), that use the active substance as a starting material and/or is responsible for QP certification of the finished batch of a human or veterinary medicinal product, where the active substance is registered as a starting material and is manufactured at the sites listed in Part A. DE/H/4148/001-002/DC Public Assessment Report Page 4/21 II. SCIENTIFIC OVERVIEW AND DISCUSSION This is a generic application. II.1 Quality aspects Drug substance Bosentan monohydrate contained in the drug products applied for is manufactured
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