Public Assessment Report. Scientific discussion. Mogilarta. (Telmisartan and hydrochlorothiazide) DK/H/2306/ /DC.

Transcription

1 Public Assessment Report Scientific discussion Mogilarta 40 mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg tablets (Telmisartan and hydrochlorothiazide) DK/H/2306/ /DC 17 November 2014 This module reflects the scientific discussion for the approval of Mogilarta. The procedure was finalised on 24 January For information on changes after this date please refer to the module Update.

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Mogilarta 40 mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg tablets, from Teva Denmark A/S. The product is indicated for treatment of essential hypertension. A comprehensive description of the indications and posology is given in the SmPC. The combination of the active substances telmisartan, which is an angiotensin II antagonist, and hydrochlorothiazide, which is a diurectic, in three combinations (40 mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg) is used for treatment of essential hypertension when the blood pressure is not adequately controlled by telmisartan alone. This decentralised procedure concerns a generic application claiming essential similarity with the reference product MicardisPlus 40 mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg, which has been registered in Europe by Boehringer Ingelheim Pharma GmbH since 19 April The marketing authorisation has been granted pursuant to Article 10.1 of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Introduction Each tablet contains 40 mg telmisartan and 12.5 mg hydrochlorothiazide, 80 mg telmisartan and 12.5 mg hydrochlorothiazide or 80 mg telmisartan and 25 mg hydrochlorothiazide. The 40 mg/12.5 mg tablets are white or almost white, 6.55 x 13.6 mm oval-shaped and biconvex tablets marked with TH on one side. The 80 mg/12.5 mg tablets are white or almost white, 9.0 x 17.0 mm capsule-shaped tablets marked with TH 12.5 on both sides. The 80 mg/25 mg tablets are white or almost white, 9.0 x 17.0 mm oval-shaped and biconvex tablets marked with TH on one side and 25 on the other side. The tablets are packed in Al/Al blisters, Al/PVDC Tristar blisters and HDPE tablet containers with LDPE caps and HDPE desiccants with silica filling. The following pack sizes are available: Tablet container: 30, 90 and 250 tablets 40 mg/12.5 mg tablets: Blister: 14, 28, 56, 84 and 98 tablets 80 mg/12.5 mg and 80 mg/25 mg tablets: Blister: 14, 28 and 56 tablets However, not all pack sizes may be marketed. The excipients are: Magnesium stearate (E470b); Potassium hydroxide; Meglumine; Povidone; Sodium starch glycolate (type A); Microcrystalline cellulose and Mannitol (E421). The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place 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. 2/8

3 II.2 Drug Substance The product contains two active substances, telmisartan and hydrochlorothiazide (HCT). Both active substances are sourced from external suppliers. All manufacturers have obtained a Certificate of Suitability for their active substance. The active substance telmisartan is controlled according to the requirements of the Ph. Eur. Monograph Additional requirements for residual solvents are included in the specifications and are active substance source specific. In addition to the tests in the Ph.Eur. monograph (2154) and test in the CEP the drug substance is tested for particle size. The active substance hydrochlorothiazide is controlled according to the requirements of the Ph. Eur. Monograph Additional requirements for related substances are included in the specifications and are active substance source specific. The additional requirement is to limit any unspecified impurity to not more than 0.10% as reported in the CEP. Particle size is an additional specification parameter not covered by the CEP. II.3 Medicinal Product The product is a tablet in three fixed combination strengths of telmisartan and hydrochlorothiazide: 40 mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg of telmisartan and hydrochlorothiazide. The composition of the product is adequately described. The choice of excipients is justified and their functions explained. The containers are well known and applicability demonstrated in stability studies. The drug product is manufactured by blending of telmisartan granulate with HCT and excipients which is tabletted. The manufacturing process is controlled by in-process controls and validated. Batch sizes are presented. Satisfactory validation of the manufacturing process for these batches is provided. Additional batch sizes will be validated prior to marketing. The product specification covers appropriate parameters for this dosage form and includes relevant physicochemical, identification, assay and purity tests. Validations of the analytical methods have been presented. Batch results are provided for all three strengths. The results comply with the release requirements and confirm the consistency of the product manufacture. Stability data are provided for the proposed strengths in the packaging materials intended for marketing. Results are available for up to 18 months at long term conditions and 6 months at accelerated conditions; no significant changes, but some changes of impurity B were observed. The following shelf-life/storage conditions are accepted: Al/Al blister and HDPE container: 24 months Al/PVC/PVDC blister: 18 months Storage condition: Al/Al blister and HDPE container: No storage condition Al/PVC/PVDC blister: Do not store above 30 C 3/8

4 III. NON-CLINICAL ASPECTS III.1 Introduction Pharmacodynamic, pharmacokinetic and toxicological properties of telmisartan and hydrochlorothiazide are well known. As telmisartan and hydrochlorothiazide are widely used, wellknown active substances, the MAH has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. The non-clinical overview report refers 59 publications up to year The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. III.2 Ecotoxicity/environmental risk assessment (ERA) Since Mogilarta 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. IV. CLINICAL ASPECTS IV.1 Introduction Telmisartan and hydrochlorothiazide are well-known active substances with established efficacy and tolerability. As telmisartan and hydrochlorothiazide are widely used, well-known active substances, the MAH has not provided additional studies (apart from the bioequivalence study referenced below) and further studies are not required. Overview based on literature review is, thus, appropriate. The clinical overview report refers 56 publications up to year The clinical overview on the clinical pharmacology, efficacy and safety is adequate. IV.2 Pharmacokinetics To support the application, the MAH has submitted as report one pivotal bioequivalence study on telmisartan/hydrochlorothiazide 80/25 mg tablets. Biowaiver The pharmacokinetics of telmisartan are nonlinear with more than dose proportional increase in plasma concentration (C max and AUC). Hydrochlorothiazide pharmacokinetics are reported to be linear. It is therefore appropriate to conduct the bioequivalence study on the highest strength and the results of this bioequivalence study can be extrapolated to other dosage strengths. Hence, the bioequivalence results from the study on telmisartan/hydrochlorothiazide 80/25 mg can be used to waive studies on the lower strengths. Bioequivalence study The study was an open-label, randomized, two-treatment, two-sequence, four-period, two-way crossover, single-dose, fully replicate bioequivalence study conducted in 48 healthy adult subjects under fasting conditions with a wash out period of 12 days between the four administrations. A fixed dose combination of telmisartan 80 mg and hydrochlorothiazide 25 mg was administered in each period i.e. one tablet of the test product (80 mg/25 mg) or one 1 tablet of the reference product MicardisPlus 80 mg/25 mg by Boehringer Ingelheim Pharma GmbH, Germany was administered in each period. 4/8

5 The pharmacokinetic variables calculated were AUC 0-t, AUC 0-, C max, t max, K e l and t ½ el.. Data of 43 subjects were analysed. The following standards for bioequivalence were applied: The 90% confidence interval AUC 0-t and C max of hydrochlorothiazide should be within 80.00% %. The 90% confidence interval AUC 0-t of telmisartan should be within 80.00% %. The criteria for telmisartan C max was set per the observed reference intra-subject variability (ISCV) for C max parameter in the current study. If the observed ISCV (%) for C max < to 30% the 90% CI should be within 80.00% %. Results Table 1. Pharmacokinetic parameters for telmisartan Table 2. Pharmacokinetic parameters for hydrochlorothiazide The 90%CI for AUC 0-t and C max were within the acceptance criteria of %: Telmisartan AUC 0-t : % C max : % Hydrochlorothiazide AUC 0-t : % C max : % The product proposed for marketing was tolerated equally well as reference product. Conclusion on bioequivalence study: The results indicate bioequivalence between the test product Mogilarta 80 mg/25 mg and the reference product MicardisPlus 80 mg/25 mg under fasting conditions. The results of the study with the 80 mg/25 mg can be extrapolated to the two other strengths 40 mg/ 12.5mg and 80 mg/12.5 mg, according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section /8

6 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.3 Risk Management Plan The MAH has submitted a 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 Mogilarta. Summary table of safety concerns as approved in RMP 6/8

7 Summary of Safety Concerns and Planned Risk Minimisation Activities as approved in RMP V. USER CONSULTATION 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 MicardisPlus, EMEA/H/C/413. The bridging report submitted by the applicant has been found acceptable. 7/8

8 VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Mogilarta 40 mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg tablets has a proven chemicalpharmaceutical quality and is a generic form of MicardisPlus. MicardisPlus 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 what has been approved for MicardisPlus. 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 Mogilarta with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised on 24 January Mogilarta was authorised in Denmark on 13 March According to the List of Union reference dates and frequency of submission of periodic safety update reports (PSURs), no PSURs are required for this product. The date for the first renewal will be: 24 January There were no post-approval commitments made during the procedure. 8/8