PUBLIC ASSESSMENT REPORT Decentralised Procedure Alendronsäure Heumann plus Colecalciferol 70 mg/2800 & 70 mg/5600 I.E. Tabletten Procedure number: DE/H/4573/01-02/DC Active Substance: Alendronic acid & cholecalciferol Dosage Form: Tablet Marketing Authorisation Holder in the RMS, Germany: Heumann Pharma GmbH & Co. Generica KG Publication: 27.06.2019 TABLE OF CONTENTS I. INTRODCUTION ....................................................................................................................... 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 ................................................................................................................. 6 III.3 Clinical aspects ........................................................................................................................ 6 IV. BENEFIT RISK ASSESSMENT ......................................................................................... 12 V. PROPOSED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT INFORMATION ............................................................................................................................... 12 V.1 Final list of recommendations not falling under Article 21a/22 of Directive 2001/83 / a positive benefit risk assessment ........................................................................................................ 12 Alendronsäure Heumann plus Cholecalciferol 70 mg / 2800 I.E and 70 mg / 5600 I.E Tabletten DE/H/4573/01-02/DC Public Assessment Report Page 2/12 ADMINISTRATIVE INFORMATION Proposed name of the medicinal Alendronsäure Heumann plus Colecalciferol 70 mg/2800 product(s) in the RMS I.E. Tabletten; Alendronsäure Heumann plus Colecalciferol 70 mg/5600 I.E. Tabletten Name of the drug substance (INN Alendronic acid & cholecalciferol name): Pharmaco-therapeutic group M05BB03 (ATC Code): Pharmaceutical form(s) and Tablet 70 mg / 2800 IU strength(s): Tablet 70 mg / 5600 IU Reference Number(s) for the DE/H/4573/01-02/DC Decentralised Procedure Reference Member State: DE Member States concerned: no CMS Heumann Pharma GmbH & Co. Generica KG Marketing Authorisation Holder Südwestpark 50 (name and address) 90449 Nürnberg Germany Heumann Pharma GmbH & Co. Generica KG Names and addresses of all Südwestpark 50 manufacturer(s) responsible for 90449 Nürnberg batch release in the EEA Germany Pharmathen International S.A Industrial Park Sapes, Rodopi Prefecture, Block No 5, Rodopi 69300, Ellas Greece Pharmathen S.A. Dervenakion 6 Pallini 15351 Attikis Greece Alendronsäure Heumann plus Cholecalciferol 70 mg / 2800 I.E and 70 mg / 5600 I.E Tabletten DE/H/4573/01-02/DC Public Assessment Report Page 3/12 I. INTRODCUTION Based on the review of the data and the Applicant’s response to the questions raised by RMS and CMSs on quality, the RMS considers that the application for Alendronsäure Heumann plus Cholecalciferol 70 mg / 2800 I.E and 70 mg / 5600 I.E Tabletten in the treatment of postmenopausal osteoporosis in women at risk of vitamin D insufficiency is approved. II. EXECUTIVE SUMMARY II.1 Problem statement N/A II.2 About the product This application for marketing authorisation concerns a generic application of a centrally authorised medicinal product according to article 10(1) of Directive 2001/83/EC for “Alendronsäure Heumann plus Cholecalciferol 70 mg / 2800 I.E Tabletten” and “Alendronsäure Heumann plus Cholecalciferol 70 mg / 5600 I.E. Tabletten”. The reference products are Fosavance 70 mg / 2,800 IU and 70 mg / 5,600 IU tablets of Merck Sharp & Dohme Ltd. which have been authorised in the EU since 24.08.2005. Alendronate is a bisphosphonate that inhibits osteoclastic bone resorption with no direct effect on bone formation. Preclinical studies have shown preferential localisation of alendronate to sites of active resorption. Activity of osteoclasts is inhibited, but recruitment or attachment of osteoclasts is not affected. The bone formed during treatment with alendronate is of normal quality. Cholecalciferol (vitamin D3) is produced in the skin by conversion of 7-dehydrocholesterol to vitamin D3 by ultraviolet light, which is then converted to 25-hydroxyvitamin D3 in the liver and stored until needed. Conversion to the active calcium-mobilising hormone 1,25-dihydroxyvitamin D3 (calcitriol) in the kidney is tightly regulated. The principal action of 1,25-dihydroxyvitamin D3 is to increase intestinal absorption of both calcium and phosphate as well as regulate serum calcium, renal calcium and phosphate excretion, bone formation and bone resorption, which results in reducing the risks from abnormal bone formation. The combination of alendronate and cholecalciferol is indicated for the treatment of postmenopausal osteoporosis in women at risk of vitamin D insufficiency. Alendronsäure Heumann plus Cholecalciferol reduces the risk of vertebral and hip fractures. II.3 General comments on the submitted dossier This decentralised application concerns a generic version of Alendronic acid & cholecalciferol. The drug products have been developed as generic medicinal products with respect to the innovator European reference product Fosavance® tablets marketed by MSD Ltd. Both active substances are well known and described by monographs in the European Pharmacopoeia. Alendronsäure Heumann plus Cholecalciferol 70 mg / 2800 I.E and 70 mg / 5600 I.E Tabletten DE/H/4573/01-02/DC Public Assessment Report Page 4/12 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles 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. For manufacturing sites within the Community the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For the Drug substance manufacturing site outside the communitythe RMS has accepted a copy of current a GMP Certificate as certification that acceptable standards of GMP are in place at those non- Community sites. GMP active substance Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU. As regards GCP the applicant has provided appropriate documents of GCP standards for the clinical trial and GCP documents for the bioanalytical determination of alendronate and vitamin D3. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance Two drug substances are used for the manufacture of the drug product Alendronsäure Heumann plus Cholecalciferol 70 mg/2800 I.E; 70 mg/5600 I.E Tabletten: Sodium alendronate trihydrate and Cholecalciferol concentrate (powder form). Both drug substances are monographed in the Ph. Eur. For Sodium alendronate trihydrate a Certificate of Suitability has been granted for Cholecalciferol concentrate (powder form) an ASMF is provided. In the ASMF for Cholecalciferol concentrate (powder form) the synthesis is sufficiently described; all requirements of the ASMF Guideline are fulfilled. Cholecalciferol concentrate (powder form) and its identified impurities have been sufficiently characterised. The possible impurity profile of drug substance has been discussed. The active substance specification is in line with the Ph. Eur. monograph for from Cholecalciferol concentrate (powder form). The test methods used are described in detail. The validation data provided are in accordance with the requirements of the relevant ICH guidelines. The information about reference standards and container closure system is considered adequate. The stability program is carried out according to ICH guidelines on stability testing. Results of three production batches were all within specifications and no significant changes are observed. The re-test period of the substance is 18 months in in the proposed marketing packaging material is acceptable. Drug Product Alendronsäure Heumann plus Cholecalciferol 70 mg/2800 I.E; 70 mg/5600 I.E Tabletten are the generic form of the MSD Ltd. product Fosavance® tablets. The aim was to develop a product that would be essentially similar to the originator. The dissolution method has been sufficiently developed. The discriminatory power of the dissolution test method has been evaluated. Sufficient dissolution profiles of the reference and the test products of all strengths have been presented. All dissolution profiles are comparable. The composition of the drug product is satisfactorily described. Alendronsäure Heumann plus Cholecalciferol 70 mg / 2800 I.E and 70 mg / 5600