Candesartan Amlodipin Zentiva, DE/H/3677/001 + 003/DC Public AR Page 1/12 PUBLI

Candesartan Amlodipin Zentiva, DE/H/3677/001 + 003/DC Public AR Page 1/12 PUBLIC ASSESSMENT REPORT Decentralised Procedure Candesartan Amlodipin Zentiva DE/H/3677/001 + 003/DC Candesartan Amlodipin Zentiva DE/H/3677/02/DC - withdrawn Marketing authorisation holder in the Reference Member State, Germany : Zentiva Pharma GmbH Date: 09.04.2015 Bundesinstitut für Arzneimittel und Medizinprodukte Candesartan Amlodipin Zentiva, DE/H/3677/001 + 003/DC Public AR Page 2/12 ADMINISTRATIVE INFORMATION Proposed name of the medicinal product in the RMS Candersartan Amlodipin Zentiva 8 mg / 5 mg Candersartan Amlodipin Zentiva 16 mg / 10 mg (withdrawn: Candersartan Amlodipin Zentiva 16 mg / 5 mg) INN (or common name) of the active substance(s): Candesartan-cilexetil & amlodipine besilate Pharmaco-therapeutic group (ATC Code): C09DB Pharmaceutical form(s) and strength(s): Tablet, 8mg/5mg; 16mg/10mg (withdrawn:Tablet, 16 mg / 5 mg) Reference Number for the Decentralised Procedure DE/H/3677/001/DC, DE/H/3677/003/DC withdrawn : DE/H/3677/002/DC Reference Member State: DE Member States concerned: BG; CY; CZ; EE; EL; HU; LT; LV; PL; PT; RO ; SK Applicant (name and address) Zentiva k.s. U. Kabelovny 130 Dolni Mecholupy, 102 37 Prague 10, Czech Republic Names and addresses of manufacturers responsible for batch release in the EEA Zentiva k.s. U. Kabelovny 130 Dolni Mecholupy, 102 37 Prague 10, Czech Republic Candesartan Amlodipin Zentiva, DE/H/3677/001 + 003/DC Public AR Page 3/12 TABLE OF CONTENTS 1. INTRODUCTION ....................................................................................................................... 4 2. Quality aspects ............................................................................................................................. 6 2.1 Drug substances ....................................................................................................................... 6 2.1.1 Candesartan cilexetil ..................................................................................................... 6 2.1.2 Amlodipine besilate ....................................................................................................... 6 2.2 Drug Product ........................................................................................................................... 6 3. Non-clinical aspects ..................................................................................................................... 7 3.1 Pharmacology .......................................................................................................................... 7 3.2 Pharmacokinetics .................................................................................................................... 7 3.3 Toxicology ................................................................................................................................ 8 3.3.1 Candesartan cilexetil ..................................................................................................... 8 3.3.2 Amlodipine .................................................................................................................... 9 4. Clinical aspects ............................................................................................................................ 9 4.1 Pharmacokinetics .................................................................................................................... 9 4.2 Pharmacodynamics ............................................................................................................... 10 4.3 Clinical efficacy...................................................................................................................... 11 4.4 Clinical safety ......................................................................................................................... 11 4.5 Pharmacovigilance system .................................................................................................... 11 4.6 Risk Management Plan ......................................................................................................... 11 5. Overall discussion, benefit/risk assessment and recommendation ....................................... 11 Candesartan Amlodipin Zentiva, DE/H/3677/001 + 003/DC Public AR Page 4/12 Scientific discussion during the initial procedure This assessment report is published by BfArM following Article 21 (3) and (4) of Directive 2001/83/EC. The report comments on the registration dossier that was submitted to BfArM as Reference Member State (RMS) and the national competent authorities in the Concerned Member States (CMS). It reflects the scientific conclusion reached at the end of the evaluation process and provides a summary of the grounds for approval of a marketing authorisation. This report is intended for all those involved with the safe and proper use of the medicinal product, i.e. healthcare professionals, patients and their family and carers. Some knowledge of medicines and diseases is expected of the latter category as the language in this report may be difficult for laymen to understand. This assessment report shall be updated by a following addendum whenever new information becomes available. General information on the Public Assessment Reports can be found on the website of the BfArM (www.bfarm.de). To the best of the BfArM`s knowledge, this report does not contain any information that should not have been made available to the public. The MAH has checked this report for the absence of any confidential information. EU-procedure number: DE/H/3677/001 + 003/DC (withdrawn: DE/H/3677/002/DC) Registration number in Germany: 88639.00.00, 88641.00.00 Pharmacotherapeutic group: Angiotensin II antagonists and calcium channel blockers ATC code: C09DB Route of administration: Oral use Therapeutic indication: “Candersartan Amlodipin Zentiva is indicated as substitution therapy in adult patients with essential hypertension whose blood pressure is adequately controlled with amlodipine and candesartan given concurrently at the same dose level” Prescription status: subject to medical prescription For product information for healthcare professionals and users, including information on pack sizes and presentations, see SPC, PL and labelling. 1. INTRODUCTION These applications concern a fixed dose combination (FDC) which is not yet authorised in the EU. A substitution indication in the treatment of essential hypertension is applied for. Candesartan is an angiotensin II (Ang-II) receptor antagonist acting on the AT1 receptor subtype thus blocking the effect of Ang-II in the renin angiotensin system (RAS) cascade. It is administered orally as the inactive prodrug candesartan cilexetil which is rapidly and completely converted to candesartan during gastrointestinal absorption. Amlodipine is a L-type Ca2+ channel blocker of the dihydropyridine group with a long-lasting effect on the L-type Ca2+ channel. By inhibiting the transmembrane influx of calcium ions into vascular smooth muscle, the intracellular Ca2+ concentration is decreased, leading to vasodilatation. Candesartan Amlodipin Zentiva tablets were developed as immediate release formulations containing the drug substances candesartan cilexetil and amlodipine as besilate in the following strengths: 16mg / 10 mg and 8mg / 5 mg. It should be noted that the applicant has withdrawn the Marketing Candesartan Amlodipin Zentiva, DE/H/3677/001 + 003/DC Public AR Page 5/12 Authorisation Application for the 16mg / 5mg dose strength after conducting a new bioequivalence study (code 12/13/CAA/BSD) in response to the major objection raised by the RMS in the Day70 Assessment Report. In this study no bioequivalence between the test product (Candesartan Amlodipin Zentiva 16mg/5mg) and the reference products Atacand 16mg / Norvasc 5 mg tablets could be achieved and subsequently the application for the 16mg/5mg dosage was withdrawn. The proposed indication is: “Candesartan Amlodipin Zentiva is indicated as substitution therapy in adult patients with essential hypertension whose blood pressure is adequately controlled with amlodipine and candesartan given concurrently at the same dose level”. Currently, no fixed combination of amlodipine and candesartan has been approved in the EU. However, in Japan, 2 fixed combinations containing candesartan and amlodipine (8mg/5mg and 8mg/2.5mg) were approved in 2010. This decentralised application concerns an abridged application, according to article 10b of Directive 2001/83/EC, so called fixed combination application, as amended. The dossier submitted provides the scientific basis for this application of fixed combinations of candesartan cilexetil + amlodipine as besilate (i.e. 16mg / 10mg and 8mg / 5 mg) tablets under Candesartan Amlodipin Zentiva trade names. Marketing authorisation is applied for with DE as the Reference Member State and with BG, CY, CZ, EE, EL, HU, LT, LV, PL, PT, RO and SK as the Concerned Member States. Overall, the submitted dossier is considered adequate. Since the indication applied for is substitution of a free combination by the respective fixed combination, it is necessary - in terms of pharmaceutical / clinical equivalence - to show that the components of the FDC products applied for are bioquivalent to the respective approved monocomponent innovator products (Guideline on the investigation of bioequivalence: CPMP/QWP/EWP/1401/98 Rev.1). Therefore, one bioequivalence study (Code: 45/11/CAA/BSD) has been submitted. This study is presented as “final integrated and statistical report” (dated 2012-07- 03), as well as in the clinical overview and summary and as tabulated study report. The test product was the highest strength of the fixed combination Candesartan Amlodipin Zentiva (16mg / 10 mg). The reference products used in this bioequivalence study was the free combination of Atacand® (16mg) by Astra Zeneca GmbH (registered since 03.12.1997 / 26.04.2007 in Germany) and Norvasc® (10mg) by Pfizer (registered since 11.05.1993 / 03.03.2004 in Germany). For the other Candesartan Amlodipin Zentiva dose-strenght 8mg / 5mg a biowaiver has been applied for. The applicant has withdrawn the Marketing Authorisation Application for the originally submitted application for the 16mg/5mg dose strength as in the subsequently conducted BE study no bioequivalence with the originators Atacand 16mg and Norvasc 5mg could be shown. The applicant has also conducted a PK interaction study (code 11/13/CAA/TP1) in response to the major objection raised by the RMS in the Day70 Assessment Report. The clinical overview (dated May 2012) is clearly written and is based on comprehensive literature (approx. 100 publications). It provides a review of the findings on the pharmacodynamic and pharmacokinetic properties, as well as of the efficacy and safety of candesartan and amlodipine as individual therapeutics. In addition numerous publications on combined therapies of amlodipine and other angiotensin II (Ang-II) receptor antagonist acting on the AT1 receptor subtype are adequately reviewed.Overall, the bibliographical data submitted are eligible to support the efficacy and safety of the combined use of Candesartan and Amlodipin in the treatment of essential hypertension. The applicant has submitted a risk management plan. The active substances are not considered new active substances. 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 Candesartan Amlodipin Zentiva, DE/H/3677/001 + 003/DC Public AR Page 6/12 manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. According to the applicant, the bioequivalence study (Code: 45/11/CAA/BSD) and the interaction study (code 11/13/CAA/TP1) were conducted in compliance with Good Clinical Practice (GCP). During review, there was no indication for GCP non-compliance. 2. QUALITY ASPECTS 2.1 Drug substances 2.1.1 Candesartan cilexetil Candesartan cilexetil is an ester prodrug that is hydrolysed to the active form candesartan during absorption from the gastrointestinal tract. Candesartan is an angiotensin II receptor antagonist with actions similar to those of losartan. It uploads/S4/de-h-3677-001-par.pdf

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• Publié le Mai 27, 2021
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