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 in women at risk of 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 that inhibits osteoclastic with no direct effect on bone formation. Preclinical studies have shown preferential localisation of alendronate to sites of active resorption. Activity of 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 -mobilising hormone 1,25-dihydroxyvitamin D3 (calcitriol) in the 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 I.E Tabletten DE/H/4573/01-02/DC Public Assessment Report Page 5/12 The manufacturing process of the finished product consists of mixing steps, lubrication step and compression and has been sufficiently described. Holding times are adequately set. The IPCs used are acceptable specified. The validation results presented indicate that the process is robust and reproducible. The presented specification is suitable to control the quality of the drug product. The test methods have been described in detail. The validation data provided are in accordance with the requirements of the relevant ICH guidelines.. Satisfactory batch analyses have been presented. The batch analyses data together with the results obtained from the validation study and stability testing confirm consistency and uniformity of the product based on the parameters tested and indicate the reproducibility of the manufacturing process for the drug product. The information on the reference standards is sufficient. Alendronsäure Heumann plus Cholecalciferol 70 mg/2800 I.E; 70 mg/5600 I.E Tabletten are packaged in Aluminium/Aluminium (PA/ALL/PVC – Aluminium) foil blisters in a card box. The provided specifications and information for the proposed container closure systems are considered as sufficient. The conditions used in stability studies are according to the ICH stability guideline. Test results of stability testing at long-term and intermediate conditions up to 24 months and accelerated conditions up to 6 months in the proposed packaging have been provided for the new medicinal products. Based on the obtained results, a shelf-life of 24 months with no special storage conditions is proposed by the applicant. This can be granted.

III.2 Non-clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of the combination alendronic acid and cholecalciferol are well known. As alendronic acid and cholecalciferol are widely used, well- known active substances, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate.

The non-clinical overview is dated 29.07.2015. Report refers more than 100 publications up to year 2014.

The non-clinical overview on the pre-clinical pharmacology, , and toxicology is adequate.

The non-clinical sections of the SmPC and PIL are acceptable.

Environmental Risk Assessment (ERA) Since Alendronsäure Heumann plus Cholecalciferol 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.3 Clinical aspects

Pharmacokinetics The absolute of alendronate after oral doses is less than 1%. Absorption is decreased by food, especially by products containing calcium or other polyvalent cations. Bioavailability is reduced by 85 to 90% when given with food. When it was taken one hour or half an hour before a standardised breakfast the bioavailability decreased accordingly to about 0.46 and 0.39% and it was negligible when given with, or up to 2 hours after food. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by about 60%.

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 6/12 More than half of the absorbed portion is sequestered to bone; the remainder is exclusively excreted via the kidneys. Plasma protein binding is about 78%. Alendronate do not appear to be metabolised. The substance is excreted unchanged.

Cholecalciferol, a fat soluble drug, is almost completely absorbed after oral administration. Due to its lipophilic nature, cholecalciferol is rapidly distributed throughout the body. It is rapidly converted to the active form calcitriol in the liver. The plasma half-life of labelled cholecalciferol was found to be less than 3 hours.

Pharmacodynamics Synergism of the therapeutic principles of alendronate, acting by inhibiting function and therefore bone resorption resulting in a significant reduction of plasma calcium and phosphate, and of cholecalciferol, acting by a dose-related increase in calcium and phosphorus absorption from the small intestine, suppression of PTH, increase in number and activity of , reduction in the number of osteoclast precursors, regulation of remodelling of bone, and reversion of myopathy, has been demonstrated to result in an improvement of therapeutic outcome.

Clinical efficacy The applicant conducted one bioequivalence (BE) study. While the applicant seeks marketing authorisation for a tablet with 70 mg alendronate and two strengths of vitamin D3, one with 2800 IU and the other with 5600 IU, BE has been investigated only for the higher vitamin D3 content as pharmacokinetics are regarded as uncritical. This biowaiver approach for the lower strength of vitamin D3 is acceptable as vitamin D3 is not regarded as a highly variable drug.

The study was an open label, randomised, two treatment, two sequence, four period, fully replicated single dose crossover, oral bioequivalence study with a washout period of 14 days between successive dosing days. The 70 mg / 5800 IU tablet was administered after 10 hour fasting with 200 ml water. The design of the study is acceptable, with sufficient washout between periods; the sampling period is long enough, and the sampling scheme is adequate to estimate PK parameters. The reference product is acceptable. The population has been chosen according to guidelines; drops-outs and protocol deviations / violations have been documented.

Test and reference products Test Product Reference Product Formulation Alendronate Sodium / FOSAVANCE® Cholecalciferol 70 mg / 5600IU 70 mg / 5600 IU Tablets Tablets Manufactured by Merck Sharp & Dohme BV, The Netherlands Batch No 1304978 A001876 Batch Size 100,000 Tablets Retest Date 08/2014 12/2014 Storage Condition Store below 30 °C in the original blister in order to protect from moisture & light

The analytical methods are acceptable, validated (pre-study and within study), and the handling of samples is adequate. A statement on GLP compliance has been provided and protocol deviations are documented. They were minor and do not invalidate the results. The reasons for reanalysis of samples are acceptable.

Pharmacokinetic variables are adequate. Standard non-compartmental pharmacokinetic parameters were derived for alendronate and cholecalciferol. The 90% confidence intervals were calculated for ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ alendronate and baseline uncorrected and baseline corrected data of cholecalciferol. Descriptive statistics were calculated and reported for all pharmacokinetic parameters of alendronate and baseline uncorrected and baseline 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 7/12 corrected data of cholecalciferol. ANOVA, power and ratio analysis for ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ were calculated.

Statistics are described adequately and the methods are acceptable. ANOVA, power and ratio analysis for ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ were calculated and reported for alendronate and baseline uncorrected and baseline corrected data of cholecalciferol. Acceptance criteria for Cmax were if the 90% confidence interval falls within the acceptance range of 80.00 to 125.00% for ln-transformed pharmacokinetic parameter Cmax for alendronate and baseline corrected data of cholecalciferol. Acceptance criteria for AUC0-t: were if the 90% confidence interval of geometric least squares mean ratio of test to reference falls within the acceptance range of 80.00 to 125.00% for ln-transformed pharmacokinetic parameter AUC0-t for alendronate and baseline corrected data of cholecalciferol.

Results of this trial demonstrated BE between the test product Alendronsäure Heumann plus Cholecalciferol and the reference product Fosavance.

Table 1a: Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax median, range) for Alendronate

Table 1b: Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax median, range) for Vitamin D3 (Baseline corrected values)

Table 2a: Relative Bioavailability Results for Alendronate (N = 55)

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 8/12 Table 2b: Relative Bioavailability Results for Cholecalciferol (Baseline Corrected Data) (N = 55)

Figure 1a: Mean Plasma Concentration vs. Time Curve for Alendronate [Test Product-T (N = 110 observations), Reference Product- R (N = 110 observations)]

Figure 1b: Mean Plasma Concentration vs. Time Curve for Cholecalciferol (Baseline Corrected Data) [Test Product-T (N = 110 observations), Reference Product- R (N = 110 observations)]

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 9/12 Figure 1c: Mean Plasma Concentration vs. Time Curve for Cholecalciferol (Baseline Uncorrected Data) [Test Product-T (N = 110 observations), Reference Product- R (N = 110 observations)]

Clinical safety In the BE study the investigational products were well tolerated by subjects as a single dose administration. Eleven (11) adverse events (AEs) were reported by 10 subjects during the conduct of the study. One (1) AE was moderate in nature and 10 AEs were mild in nature. All AEs resolved.

Both active substances as well as the combination product Fosavance have a positive benefit risk ration in the applied indication.

Summary Pharmacovigilance system The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.

Risk Management Plan The MAH has submitted an updated 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 Alendronsäure Heumann plus Cholecalciferol, Alendronic acid & cholecalciferol

Summary of safety concerns Important identified risks Oesophageal adverse reactions Important potential risks Atypical femur fracture Missing information Use in patients below 18 years of age Use in patients with severe renal insufficiency (GFR  35 ml/min) Use during and lactation

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 10/12 - Summary of Safety Concerns and Planned Risk Minimisation Activities as proposed in RMP

Safety concern Routine risk minimisation measures Additional risk minimisation measures

Important identified risks Oesophageal adverse reactions Information is included in labelling (SmPC None proposed sections 4.3, 4.4 and 4.8) Prescription-only medicine Osteonecrosis of the jaw Information is included in labelling (SmPC None proposed sections 4.4 and 4.8) Prescription-only medicine

Important potential risks Atypical femur fracture Information is included in labelling (SmPC None proposed sections 4.4 and 4.8) Prescription-only medicine

Missing information Use in patients below 18 years Information is included in labelling (SmPC None proposed of age section 4.2)

Prescription-only medicine Use in patients with severe renal Information is included in labelling (SmPC None proposed insufficiency (GFR  35 sections 4.2 and 4.4) ml/min) Prescription-only medicine Use during pregnancy and Information is included in labelling (SmPC None proposed lactation section 4.6)

Prescription-only medicine

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.

Periodic Safety Update Report (PSUR) With regard to PSUR submission, the MAH should take the following into account: • PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall 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 11/12 continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR.

• For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list.

• For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.

Common renewal date A proposed common renewal date of 5 years after finalization of the procedure was accepted.

Legal status Medicinal product subject to medical prescription.

User Test Assessment of the User Testing has been performed and found to be acceptable.

IV. BENEFIT RISK ASSESSMENT

From the quality point of the application contains sufficient data on quality aspects and is approvable.

The application contains an adequate review of published clinical data and the bioequivalence has been shown. Approval is recommended from the non-clinical, pharmacovigilance and clinical point of view.

The application is approved. For intermediate amendments see current product information.

V. PROPOSED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT INFORMATION

V.1 Final list of recommendations not falling under Article 21a/22 of Directive 2001/83 / a positive benefit risk assessment

Proposed list of recommendations not falling under Article 21a/22 of Directive 2001/83/EC

In this section post approval commitments not falling under Article 21a or 22 should be included, e.g. as follows:

Description Due date The MAH commits to update RMP in Part "Risk minimizations measures by 3 months after safety concerns”, important potential risk of atypical femur fracture, in accordance closure DCP with information already included in Part III.

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