Public Assessment Report

Scientific discussion

Riseteva

75 mg film-coated tablets

Risedronate sodium

DK/H/2020/001/DC

This module reflects the scientific discussion for the approval of Riseteva. The procedure was finalised on 18 May 2011. For information on changes after this date please refer to the module ‘Update’.

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I. INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Riseteva 75 mg film-coated tablets, from Teva Denmark A/S. The product was authorised in Denmark on 28 June 2011. The product is indicated for treatment of in postmenopausal women at increased risk of fractures.

Risedronate sodium belongs to the pharmaco-therapeutic group of (ATC code: M05 BA07). It is a pyridinyl that inhibits osteoclast-mediated bone resorption by binding to bone hydroxyapatite.

This decentralised procedure concerns a generic application claiming essential similarity with the reference product Optinate/Optinate Septimum/Actonel which has been registered in the EEA by Aventis Pharma/ and Procter & Gamble since 1998. In Denmark Optinate film-coated tablets and Optinate Septimum 35 mg film-coated tablets, Sanofi- Aventis, have been registered since 1999 and 2004, respectively.

The marketing authorisation is granted based on article 10.1 of Directive 2001/83/EC.

II. QUALITY ASPECTS

II.1 Introduction

Each film-coated tablet contains 75 mg risedronate sodium (equivalent to 69.6 mg risedronic acid).

The tablets are pink, round, biconvex, film-coated tablets engraved “R 75” on one side and plain on the other.

The tablets are packed in transparent PVC/PVdC – Aluminium blister packs in a cardboard carton in pack sizes of 2, 4, 6, 8 or 12 tablets. However, not all pack sizes may be marketed.

Compliance with Good Manufacturing Practice The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) 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 prior to granting its national authorisation.

II.2 Drug Substance rINN: Risedronate sodium Compendial names: Risedronate sodium (USP) Chemical name(s): [1-hydroxy-2-(3-pyridinyl)ethylidene]bis[phosphonic acid]monosodium salt Molecular formula: C7H10NO7P2Na.H2O Molecular mass: 323.10

Structural formula:

2/7 Risedronate soidum is a white to pale yellow (or off-white) solid. It is soluble in water and in aqueous solutions, and essentially insoluble in common organic solvents. Several crystal forms of risedronate sodium are known from the literature.

Risedronate sodium is not monographed in Ph.Eur. The applicant sources the substance from a single supplier. The documentation on the active substance risedronate sodium is presented as a European Drug Master File/Active Substance Master File (DMF). The Applicant’s Part of the DMF has been forwarded by the Applicant. The Applicant’s and Restricted Part plus a LoA have been forwarded by the ASM.

Details on the synthesis, starting materials, methods of analysis and their validations are all satisfactory. Impurities are adequately controlled. Specifications are satisfactory and test methods have been presented in adequate detail. Validation data are satisfactory.

Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed retest period is justified.

The applicant specification for risedronate sodium reflects parameters and limits applied by the ASM and the same analytical methods are employed.

II.3 Medicinal Product

The drug product is film-coated tablets containing 75 mg risedronate sodium. The product is to be marketed in transparent PVC/PVdC/Al blisters. The product composition is adequately described. The development of the product has been satisfactorily performed and explained. No incompatibilities between the active substance and the excipients are observed. Excipients are those commonly used for manufacture of a film-coated tablet. The packaging material is standard and shown suitable by the presented stability studies.

Product manufacture is by standard processing and employs a wet granulation process followed by tabletting and film-coating.

Validation data are provided for small production scale batches. The results obtained show that the process is adequately controlled, reproducible and robust.

The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on two batches of the lower range of the proposed production scale batch size. The batch analysis results show that the finished products meet the proposed specifications.

The conditions used in the stability studies are according to the ICH stability guideline.

The control tests and specifications for drug product are adequately drawn up.

A shelf-life of 24 months when packaged in transparent PVC/PVdC – aluminium blisters is considered acceptable.

III. NON-CLINICAL ASPECTS

This product is a generic formulation of Optinate/Optinate Septimum/Actonel, which is available on the European market. No new preclinical data have been submitted, and therefore the application has not undergone preclinical assessment. This is acceptable for this type of application

Environmental risk assessment

3/7 The product is intended as a substitute for other identical products on the market. The approval of this product will not result in an increase in the total quantity of risedronate sodium released into the environment. It does not contain any component, which results in an additional hazard to the environment during storage, distribution, use and disposal.

IV. CLINICAL ASPECTS

IV.1 Introduction

Risedronate sodium is a well-known active substance with established efficacy and tolerability.

Absorption of risedronate after an oral dose is rapid (tmax approx. 1 hour), and occurs throughout the upper gastrointestinal tract. Linear kinetics in the dose range of 35-75 mg is demonstrated in relation with a biowaiver.

The mean oral of the tablet formulation is 0.63% and is bioequivalent to a solution. Risedronate is excreted unchanged primarily via the kidney. Since it is not metabolised, risedronate does not induce or inhibit hepatic cytochrome P450 enzymes.

The absorption of risedronate is significantly inhibited by food. The extent of absorption when administered 30 minutes before breakfast is reduced by 55% compared to dosing in the fasting state (i.e. no food or drink for 10 hours prior to or 4 hours after dosing). Dosing 1 hour prior to breakfast reduces extent of absorption by 30% compared to dosing in the fasting state. Dosing either 30 minutes prior to breakfast or 2 hours after a meal results in a similar extent of absorption.

Approximately half of the absorbed dose is excreted in urine within 24 hours, and 85% of an intravenous dose is recovered in the urine over 28 days. Once risedronate is absorbed, the serum concentration-time profile is multiphasic with an initial half-life of about 1.5 hours and a terminal exponential half-life of 480 hours. Although the elimination rate of bisphosphonates from human bone is unknown, the 480-hour half-life is hypothesized to represent the dissociation of risedronate from the surface of the bone.

For this generic application, the MAH has submitted two bioequivalence studies under fasting conditions in which the pharmacokinetic profile of the test product Risedronatnatrium “Teva” 35 mg film-coated tablets is compared with the pharmacokinetic profile of the reference product Actonel 35 mg film-coated tablets, Aventis Pharma, from the German market. It is suggested to claim bioequivalence of Riseteva 75 mg film-coated tablets with Actonel 75 mg film-coated tablets based on the two bioequivalence studies performed on the 35 mg tablets. The second study was a confirmatory study, since in the first study the 90% CI for Cmax was just outside the general acceptance limits of 80-125% (79.09-103.50%). The number and type of bioequivalence studies are considered sufficient for the present application for an immediate release formulation.

Main study The main study was performed as a single centre, randomized, single dose, 2-period, 2-sequence, crossover study conducted under fasting conditions with a wash out period of 7 days between administrations. 1x35 mg film-coated tablet was administered in each period with 240 ml water after an overnight fast of at least 10 hours. Blood samples were collected pre-dosing and at various time- points up to 24 hours post administration of a single-dose 35 mg tablet with 240 ml of water for the analyses of risedronic acid.

80 healthy non-smoking male subjects (19-53 years; 62 Caucasians, 10 Black and 3 Asian (of the 75 included in data analysis)) participated in the study. 75 subjects completed the study and were used for the pharmacokinetic and statistical analysis.

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The primary pharmacokinetic variables evaluated were AUC0-t, AUC0-∞, and Cmax and bioequivalence was determined based on limits of 80-125% for AUC0-t and AUC0-∞, and 75-133% for Cmax. The 90% confidence interval for both AUC parameters was within the acceptance range of 80-125%, whereas the 90% confidence interval for Cmax was just outside the lower limit of the acceptance range (79.09- 103.5%).

Results Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax median, range): N=75

Treatment AUC0-t AUC0-∞ Cmax tmax t½ ng.h/ml ng.h/ml ng/ml h h Test 47.705 51.527 14.305 1.26 7.58 (S.D.) (36.063) (39.190) (11.452) (0.25-4.00) (5.47) Reference 49.104 53.000 14.923 1.19 8.66 (S.D.) (32.484) (35.182) (9.830) (0.25-4.00) (6.78) *Ratio (90% 94.15% 94.22% 90.48% - - CI) (83.20- (83.12- (79.09- 106.53%) 106.82%) 103.50%) Intra-subject 48 48 53 - - CV (%)

A widening of the limits is not considered acceptable, however taking into account the additional confirmative study (see below), bioequivalence between the test and reference product can be concluded.

Confirmative study The confirmative study was performed as a single centre, randomized, single dose, 2-period, 2- sequence, crossover study conducted under fasting conditions with a wash out period of 7 days between administrations. 1x35 mg film-coated tablet was administered in each period with 240 ml water after an overnight fast of at least 10 hours. Blood samples were collected pre-dosing and at various time-points up to 36 hours post administration of a single-dose 35 mg tablet with 240 ml of water for the analyses of risedronic acid.

117 healthy male subjects (20-55 years; 77 Caucasian, 23 Black and 13 Asian (of the 113 completing the study)) participated in the study. 113 subjects completed the study and were used in the pharmacokinetic and statistical analysis.

The primary pharmacokinetic variables evaluated were AUC0-t, AUC0-∞, and Cmax and bioequivalence was determined based on limits of 80-125% for AUC0-t and AUC0-∞, and 75-133% for Cmax. The 90% confidence intervals for all primary parameters lay within the normal acceptance range of 80-125%.

Results Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax median, range): N=113

Treatment AUC0-t AUC0-∞ Cmax tmax t½ pg.h/ml pg.h/ml pg/ml h h Test 19287.56 20188.56 7462.65 1.06 2.58 (S.D.) (20991.53) 21869.92 (7838.68) (0.33-3.00) (2.30) Reference 21622.33 22534.06 8256.96 1.01 3.21 (S.D.) (28383.19) (30183.49) (10531.44) (0.33-3.00) (4.95) *Ratio (90% 95.66% 97.91% 96.81% - - CI) (85.17- (87.48- (86.04- 107.46%) 109.60%) 108.93%)

5/7 Intra-subject 57 52 57 - - CV (%)

A widening of the 90% CI for Cmax is not acceptable although the drug exhibits high intra-subject variability. However, since the results are within the general acceptance range of 80-125%, no concern was raised.

The results obtained demonstrate that the 35 mg test product is bioequivalent with Actonel/ Optinate 35 mg film-coated tablets from Aventis Pharma. Test product was tolerated equally well as reference product. The conditions for accepting the biowaiver on the 75 mg strength have been fulfilled. Based on the two bioequivalence studies performed on the 35 mg tablets and the dissolution and kinetics data provided by the applicant, bioequivalence between Riseteva 75 mg film-coated tablets and the reference product has been concluded.

The RMS has been assured that the bioequivalence study has been conducted in accordance with acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC).

IV.2 Risk management plan & Pharmacovigilance system

Risedronate was first approved in 1998, and there is now more than 10 years post-authorisation experience with the active substance. The safety profile of risedronate can be considered to be well established and no product specific pharmacovigilance issues were identified pre- or postauthorisation which are not adequately covered by the current SPC. Additional risk minimisation activities have not been identified for the reference medicinal product. The MAH has a pharmacovigilance system at their disposal, which is based on the current European legislation.

The Pharmacovigilance system described fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the identification and notification of any potential risks occurring either in the Community or in a third country.

V. PRODUCT INFORMATION

SmPC and Package leaflet As this is a application for a generic product of a reference medicinal product (brand leader) authorised by the Community, the SPC must in all relevant aspects be consistent with that of the brand leader, according to Regulation (EC) no. 726/2004 of the European Parliament and of the Council.

The content of the SmPC and package leaflet approved during the decentralised procedure is in accordance with that accepted for the reference product Optinate/Optinate Septimum/Actonel marketed by Aventis Pharma/Sanofi and Procter & Gamble.

Readability test 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 Risedronatnatrium “Teva” 35 mg film-coated tablets, DK/H/1338/001/DC. The bridging report submitted by the applicant has been found acceptable.

6/7 VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

Riseteva 75 mg film-coated tablets has a proven chemical-pharmaceutical quality and is a generic form of Optinate 75 mg film-coated tablets, Sanofi-Aventis. Optinate is a well-known medicinal product with an established favourable efficacy and safety profile.

Bioequivalence has been shown to be in compliance with the requirements of European guidance documents.

The MAH 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 that accepted for the reference product.

Agreement between Member States was reached during a written procedure. There was no discussion in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that essential similarity has been demonstrated for Riseteva 75 mg film-coated tablets with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised on 18 May 2011. Riseteva 75 mg film-coated tablets was authorised in Denmark on 28 June 2011.

A European harmonised birth date has been allocated (31 March 1998) and the next data lock point for risedronate sodium is March 2012, after which the PSUR submission cycle is yearly.

The date for the first renewal will be: 18 May 2016.

The following post-approval commitments have been made during the procedure:

 The finished product manufacturer commits to perform process validation when batches larger than 200,000 tablets are produced.

 The finished product manufacturer commits to provide batch analysis data for one batch of 400,000 tablets as soon as available.

 The enclosed stability studies will be continued.

 The first 3 production batches of each strength will be put on stability and tested according to the stability protocol as presented in section P.8.1.

 It is committed to perform bulk stability test from two validation batches and a bulk storage time of 3-month is applied until the results of the two validation batches support the 6-month bulk storage time.

 It is committed that one batch of finished product will be prepared from bulk tablets stored for 6 months at 15-25°C/70% RH. This finished product batch will be placed in stability under ICH conditions and will be followed until end of shelf-life.

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