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Public Assessment Report PUBLIC ASSESSMENT REPORT Decentralised Procedure Fraxiparine 0.3 2,850 I.U. anti-Xa/ 0.3 ml; Fraxiparine 0.4 3,800 I.U. anti-Xa/ 0.4 ml; Fraxiparine 0.6 5,700 I.U. anti-Xa/ 0.6 ml; Fraxiparine 0.8 7,600 I.U. anti-Xa/ 0.8 ml Procedure Number: DE/H/4762/002-005/DC Fraxodi 19000 UL / ml; 0.6 ml Fraxodi 19000 UL / ml; 0.8 ml Fraxodi 19000 UL / ml; 1.0 ml Procedure Number: DE/H/4763/001-003/DC Fraxiparine Multi 9,500 anti-Xa IU/ 1.0 ml Fraxiparine Multi 9,500 anti-Xa IU/ 1.0 ml Procedure Number: DE/H/4770/001-002/DC Active Substance: Nadroparin-Calcium Dosage Form: Solution for injection Marketing Authorisation Holder in the RMS, Germany: Aspen Pharma Trading Limited Publication: 19.11.2018 TABLE OF CONTENTS I. RECOMMENDATION ................................................................................................................ 4 II. EXECUTIVE SUMMARY ....................................................................................................... 4 II.1 Problem statement ..................................................................................................................... 4 II.2 About the product ..................................................................................................................... 4 II.3 General comments on the submitted dossier .......................................................................... 4 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. 5 III. SCIENTIFIC OVERVIEW AND DISCUSSION ................................................................... 5 III.1 Quality aspects ........................................................................................................................... 5 III.2 Non-clinical aspects ................................................................................................................... 9 III.3 Clinical aspects .......................................................................................................................... 9 IV. BENEFIT RISK ASSESSMENT ........................................................................................... 12 DE/H/4762/002-005/DC ; Fraxiparine DE/H/4763/001-003/DC ; Fraxodi DE/H/4770/001-002/DC ; Fraxiparine Multi Public Assessment Report Page 2/12 ADMINISTRATIVE INFORMATION Fraxiparine 0.3 2,850 I.U. anti-Xa/ 0.3 ml; 0.4 3,800 I.U. Proposed name of the medicinal anti-Xa/ 0.4 ml; 0.6 5,700 I.U. anti-Xa/ 0.6 ml; 0.8 7,600 product(s) in the RMS I.U. anti-Xa/ 0.8 ml; DE/H/4762/002-005/DC Fraxodi 19,000 I.U. / ml; DE/H/4763/01-03/DC Fraxiparine Multi 9,500 anti-Xa I.U./ 1.0 ml DE/H/4770/01-02/DC Name of the drug substance (INN Nadroparin-Calcium name): Pharmaco-therapeutic group B01AD06 (ATC Code): Pharmaceutical form(s) and Solution for injection strength(s): Reference Number(s) for the DE/H/4762/02-05/DC Decentralised Procedure DE/H/4763/01-03/DC DE/H/4770/01-02/DC Reference Member State: DE Member States concerned: IE Legal basis of application: Generic Art 10.1 and 10.2 Dir 2001/83/EC Marketing Authorisation Holder Aspen Pharma Trading Limited (name and address) 3016 Lake Drive, Citywest Business Campus DUBLIN 24 Ireland Names and addresses of all Aspen Notre Dame de Bondeville manufacturer(s) responsible for 1, rue de l’Abbaye batch release in the EEA 76960 Notre Dame de Bondeville France DE/H/4762/002-005/DC ; Fraxiparine DE/H/4763/001-003/DC ; Fraxodi DE/H/4770/001-002/DC ; Fraxiparine Multi Public Assessment Report Page 3/12 I. RECOMMENDATION Based on the review of the data and the Applicant’s response to the questions raised by RMS and CMSs on quality, safety and efficacy, the RMS considers that the application for Fraxiparine (9,500 I.U. anti-Xa / 1.0 ml solution, pre-filled syringe) in the prophylaxis and/or treatment of deep venous thrombosis, is approved. II. EXECUTIVE SUMMARY II.1 Problem statement For generic application this section is not applicable. II.2 About the product The Originator product Fraxiparine ® was first authorised in Germany in 1997 and is indicated as follows:- - Perioperative thrombosis prophylaxis: o Peri- and postoperative primary prophylaxis of deep vein thrombosis in patients with low, moderate or high thromboembolic risk. o Peri- and postoperative primary prophylaxis of deep vein thrombosis in patients undergoing larger orthopedic surgeries (e.g. elective hip surgeries) - Treatment of deep vein thrombosis. - Thrombosis prophylaxis and anticoagulation with extracorporeal circulation during hemodialysis and hemofiltration. Fraxiparine has a pharmacotherapeutic group: antithrombotic ATC code: B01 AB06 The active substance of Fraxiparine is Nadroparin Calcium. Nadroparin calcium is a low molecular weight heparin (LMWH). This LMWH is prepared by depolymerisation of unfractionated porcine heparin sodium (UFH) by means of nitrous acid, followed by extraction/purification, then conversion to the calcium salt. Nadroparin calcium consists of fragments of the glycosaminoglycan, heparin, in which the relative molecular mass of the major species is between 4000 and 5000 Da. The degree of sulphation is approximately 2 per disaccharide unit. Most of the constituents have a 2-O-sulpho-δ-L- idopyranosuronic acid structure at the non-reducing end, and a 6-O-sulpho-2,5-anhydro-D-mannitol structure at the reducing end of the chains. II.3 General comments on the submitted dossier The application concerns a Marketing Authorisation Application under the Decentralised Procedure in accordance with Article 10(1) of Directive 2001/83/EC (abridged, “generic” application) with Fraxiparine ® as the reference medicinal product (RMP). The applicant, Aspen, is also the current MAH for Fraxiparine 0.3 2,850 I.U. anti-Xa/ 0.3 ml, Fraxiparine 0.4 3,800 I.U. anti-Xa/ 0.4 ml, Fraxiparine 0.6 5,700 I.U. anti-Xa/ 0.6 ml and Fraxiparine 0.8 7,600 I.U. anti-Xa/ 0.8 ml. The use of the “generic” Article 10(1) basis rather than biosimilar10(4) for the current application was chosen by the Applicant on the basis that Fraxiparine (i.e. Fraxiparine 0.3 2,850 I.U. anti-Xa/ 0.3 ml, Fraxiparine 0.4 3,800 I.U. anti-Xa/ 0.4 ml, Fraxiparine 0.6 5,700 I.U. anti-Xa/ 0.6 ml and Fraxiparine 0.8 7,600 I.U. anti-Xa/ 0.8 ml) is identical to Fraxiparine ® in all but invented name and packaging. An application according to Article 10(1) (abridged, “generic” application) is based on the information provided by the Applicant, i.e. the identical qualitative and quantitative composition in drug substance and excipients and the same pharmaceutical forms and strengths between the two products and that for DE/H/4762/002-005/DC ; Fraxiparine DE/H/4763/001-003/DC ; Fraxodi DE/H/4770/001-002/DC ; Fraxiparine Multi Public Assessment Report Page 4/12 both, there would be no change in the manufacturing process, manufacturer or manufacturing site that could lead to differences regarding safety or efficacy compared to Fraxiparine ®. The MAH needs to ensure that the new product is kept updated to reflect any changes to the reference medicinal product, including changes concerning quality of the medicinal product, throughout the life cycle of the two products. This application contains no new clinical or preclinical data, other than supporting literature where necessary. II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. All relevant sites have valid manufacturing authorizations or valid GMP certificates as appropriate. Hence, no GMP inspections are deemed necessary at this stage within the scope of this MAA evaluation procedure. GLP, GCP and agreed ethical principles: N/A as no clinical studies are submitted. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance Nadroparin calcium is the calcium salt of a low molecular-mass heparin prepared by nitrous acid fragmentation of heparin obtained from porcine intestinal mucosa. Nadroparin calcium is manufactured and released by Aspen Notre Dame de Bondeville, 1, rue de l’Abbaye, 76960 Notre Dame de Bondeville, France. Manufacturing Process and Process Controls In the manufacturing process description for nadroparin calcium a reference is now included that refers to the heparin sodium manufacturing process starting from pooled porcine mucosa. This is in accordance with the classification of pooled porcine intestinal mucosa as starting material for heparin and heparin derivatives (EMA/CHMPBWP/429241/2013). The conversion of heparin sodium to nadroparin calcium is performed by controlled depolymerisation of porcine heparin sodium by means of nitrous acid. The solution is then purified and converted to the calcium salt. The product is filtered, precipitated and washed with ethanol, and finally dried. The depolymerisation process is guided by pH, sodium nitrite concentration, temperature and time. Critical parameter and tests have been defined and included in the application. The depolymerisation product is purified at various operations to comply with predefined quality attributes, in particular presence of reducing groups and molecular weight distribution. Reprocessing is restricted to performed in exceptional circumstances, e.g. in case of technical failure. This is considered appropriate. The batch size of a nadroparin calcium batch derived from heparin sodium is approximately 80kg. Control of Materials Materials used in the manufacturing process are either controlled by compendial standards, standards adapted to a compendial monograph or by in-house specifications. For sodium heparin from the intended suppliers respective CoAs have been provided. Furthermore,
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