Public Assessment Report. Scientific discussion. Lercanidipinhydrochlorid Sandoz 10 mg and 20 mg film-coated tablets. (Lercanidipine hydrochloride)

Transcription

1 Public Assessment Report Scientific discussion Lercanidipinydroclorid Sandoz 10 mg and 20 mg film-coated tablets (Lercanidipine ydrocloride) DK/H/2360/ /DC 1 December 2015 Tis module reflects te scientific discussion for te approval of Lercanidipinydroclorid Sandoz. Te procedure was finalised on 11 February For information on canges after tis date please refer to te module Update.

2 I. INTRODUCTION Based on te review of te quality, safety and efficacy data, te Member States ave granted a marketing autorisation for Lercanidipinydroclorid Sandoz 10 mg and 20 mg film-coated tablets, from Sandoz A/S. Te product is indicated for te treatment of mild to moderate essential ypertension. A compreensive description of te indications and posology is given in te SmPC. Lercanidipine is a calcium antagonist of te diydropyridine group and inibits te transmembrane influx of calcium into cardiac and smoot muscle. Te mecanism of its antiypertensive action is due to a direct relaxant effect on vascular smoot muscle tus lowering total periperal resistance. Despite its sort parmacokinetic plasma alf-life, lercanidipine is endowed wit a prolonged antiypertensive activity because of its ig membrane partition coefficient, and is devoid of negative inotropic effects due to its ig vascular selectivity. Tis decentralised procedure concerns a generic application claiming essential similarity wit te reference product Zanidip 10 mg and 20 mg film-coated tablets, wic as been registered in Denmark by Meda A/S since 1997 and 2003, respectively. Te marketing autorisation is granted based on article 10.1 of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Introduction Eac film-coated tablet contains 10 mg or 20 mg of lercanidipine ydrocloride equivalent to 9.4 mg and 18.8 mg of lercanidipine. Te 10 mg tablets are yellow film-coated tablets of round biconvex sape (diameter 6.5 mm), scored on one side, marked 'L' on te oter side. Te 20 mg tablets are pink film-coated tablets of round biconvex sape (diameter 8.5 mm), scored on one side, marked 'L' on te oter side. Te score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses. Te tablets are packed in PVdC/PVC//Aluminium blisters in pack-sizes of 7, 10, 14, 20, 28, 30, 35, 42 (20 mg only), 50, 56, 60, 98, or 100 film-coated tablets. However, not all pack sizes may be marketed. Te tablet core contains: Magnesium stearate (E572); povidone K-30 (E1201); sodium starc glycolate (Type A); lactose monoydrate and cellulose, microcrystalline (E460). Te film-coating consists of: Macrogol 3350 (E 1521); polyvinyl alcool, partly ydrolysed; talc (E553b); titanium dioxide (E 171); iron oxide, yellow (E 172) and iron oxide, red (E 172) (20 mg only). Te RMS as been assured tat acceptable standards of GMP (see Directive 2003/94/EC) are in place for tis product type at all sites responsible for te manufacturing of te active substance as well as for te manufacturing and assembly of tis product prior to granting its national autorisation. 2/7

3 II.2 Drug Substance Te active substance lercanidipine ydrocloride is not described in te European Parmacopoeia. It is a yellow powder soluble in metanol. Lercanidipine ydrocloride, as reported in literature, exibits polymorpism. INN: Lercanidipine ydrocloride Cemical name(s): 1,4 Diydro 2,6 dimetyl 4 (3 nitropenyl) 3,5 pyridinedicarboxylic acid 2 [(3,3 dipenylpropyl)metylamino] 1,1 dimetyletyl metyl ester ydrocloride Or (±)-1,4 Diydro 2,6 dimetyl 4 (3 nitropenyl) pyridine 3,5 dicarboxylic acid 2 [N- (3,3 dipenylpropyl)-n-metylamino] 1,1 dimetyletyl metyl diester ydrocloride Structure: Molecular formula: C 36 H 4 1N 3 O 6, HCl Molecular mass: Te documentation on te drug substance is presented as a EDMF. Stability studies ave been performed wit te drug substance. No significant canges in any parameters were observed. According to te stability studies presented, an appropriate retest period as been set. II.3 Medicinal Product Te development of te product as been described, te coice of excipients is justified and teir functions explained. Te product specifications cover appropriate parameters for tis dosage form. Validations of te analytical metods ave been presented. Batc analysis as been performed on two batces for eac strengt. Te batc analysis results sow tat te finised products meet te specifications proposed. Te conditions used in te stability studies are according to te ICH stability guideline. Te control tests and specifications for te drug product are adequately drawn up. A self life of 2 years wit te storage conditions Do not store above 25 C. Store in original packaging in order to protect from moisture as been accepted. III. NON-CLINICAL ASPECTS III.1 Introduction Parmacodynamic, parmacokinetic and toxicological properties of lercanidipine ydrocloride are well known. As lercanidipine ydrocloride is a widely used, well-known active substance, te MAH 3/7

4 as not provided additional studies and furter studies are not required. Overview based on literature review is, tus, appropriate. Te non-clinical overview report refers 45 publications up to year Te non-clinical overview on te pre-clinical parmacology, parmacokinetics and toxicology is adequate. III.2 Ecotoxicity/environmental risk assessment (ERA) Since Lercanidipinydroclorid Sandoz is intended for generic substitution, tis will not lead to an increased exposure to te environment. An environmental risk assessment is terefore not deemed necessary. IV. CLINICAL ASPECTS IV.1 Introduction Lercanidipine ydrocloride is a well-known active substance wit establised efficacy and tolerability. As lercanidipine ydrocloride is a widely used, well-known active substance, te MAH as not provided additional studies (apart from a supportive bioequivalence study referenced below) and furter studies are not required. Overview based on literature review is, tus, appropriate. Te clinical overview on te clinical parmacology, efficacy and safety is adequate. IV.2 Parmacokinetics Biowaiver Te application concerns 2 dosage strengts, 10 mg and 20 mg. Te study was carried out wit te 20 mg strengt. Justification for biowaiver for te 10 mg strengt was provided. Biowaiver criteria cf. Guideline on te Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1/Corr*) section were met. Bioequivalence To support te application, te MAH submitted as report one bioequivalence study, in wic Lercanidipinydroclorid Sandoz 20 mg film-coated tablets was compared wit Corifeo 20 mg filmcoated tablets, UCB GmbH, Germany. Te study was an open-label, randomized, two-treatment, two-sequence, four-period, replicated, crossover, single-dose bioavailability study conducted under fasting conditions wit a was out period of 7 days between te two administrations. 20 mg was administered in eac period. 34 ealty male subjects participated in te study. 27 subjects completed te study. Te primary variables for conclusion of bioequivalence were: AUC 0-t, AUC 0- and C max in. Te 90% confidence intervals of te ratio (test/reference) of least-squares means for log-transformed AUC 0-t and C max sould be witin 80% and 125% for (+)-S-lercanidipine in order to conclude bioequivalence. 4/7

5 Results Table 1. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max median, range) for (+)-S-lercanidipine Treatment AUC 0-t pg/ml AUC 0- C max Test ( ) ( ) ( ) Test ( ) ( ) ( ) Mean Test ( ) ( ) ( ) Reference ( ) ( ) ( ) Reference ( ) ( ) ( ) Mean Reference ( ) ( ) ( ) *Ratio (90% CI) t max ( ) ( ) 2.00 ( ) 2.00 T 1/ (6.24) (4.74) (4.50) (5.59) (7.02) (4.71) AUC0- AUC0-t Cmax Tmax T1/2 alf-life * log-transformed values area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours maximum plasma concentration time for maximum concentration Table 2. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max median, range) for (-)-R-lercanidipine Treatment AUC 0-t pg/ml AUC 0- C max Test ( ) ( ) ( ) Test ( ) ( ) ( ) Mean Test ( ) ( ) ( ) Reference ( ) ( ) ( ) Reference ( ) ( ) ( ) Mean Reference ( ) ( ) ( ) *Ratio (90% CI) t max ( ) ( ) 2.00 ( ) ( ) ( ) T 1/ (5.15) (3.55) (3.35) (5.05) (6.53) (4.72) AUC0- AUC0-t Cmax Tmax T1/2 alf-life * log-transformed values area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours maximum plasma concentration time for maximum concentration 5/7

6 Parmacokinetic conclusion 90% confidence intervals of te ratio (test/reference) of least-squares means for log-transformed AUC 0- t and C max were witin 80% and 125% for (+)-S-lercanidipine and for (-)-R-lercanidipine. Te 90% CI of AUC 0-t and C max demonstrate bioequivalence between te test product, Lercanidipinydroclorid Sandoz 20 mg film-coated tablets, and te reference product, Corifeo 20 mg film-coated tablets. Te results from te 20 mg film-coated tablet can be extrapolated to te 10 mg film-coated tablet, according to conditions in Note for Guidance on te Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98, section 5.4. Te RMS as been assured tat te bioequivalence study as been conducted in accordance wit 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 Te MAH as submitted a risk management plan, in accordance wit te requirements of Directive 2001/83/EC as amended, describing te parmacovigilance activities and interventions designed to identify, caracterise, prevent or minimise risks relating to Lercanidipinydroclorid Sandoz. Te following summary list of safety concerns wit no additional parmacovigilance measures or risk minimisation measures as been agreed: Table 3. Summary table of safety concerns as approved in RMP V. USER CONSULTATION A user consultation wit target patient groups on te package information leaflet (PIL) as been performed on te basis of a bridging report making reference to Zanidip Novum 8 mg and 16 mg filmcoated tablets, UK/H/0132/ /DC. Te bridging report submitted by te MAH as been found acceptable. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Lercanidipinydroclorid Sandoz 10 mg and 20 mg film-coated tablets as a proven cemicalparmaceutical quality and is a generic form of Zanidip. Zanidip is a well-known medicinal product wit an establised favourable efficacy and safety profile. 6/7

7 Bioequivalence as been sown to be in compliance wit te requirements of European guidance documents. Te MAH as presented a risk management plan summarising te safety concerns. Tere are no additional parmacovigilance or risk minimisation measures. Agreement between Member States was reaced during a written procedure. Tere was no discussion in te CMD(). Te Concerned Member States, on te basis of te data submitted, considered tat essential similarity as been demonstrated for Lercanidipinydroclorid Sandoz wit te reference product, and ave terefore granted a marketing autorisation. Te decentralised procedure was finalised on 11 February Lercanidipinydroclorid Sandoz was autorised in Denmark on 11 Marc According to te List of Union reference dates and frequency of submission of periodic safety update reports (PSURs), no routine PSURs are required for tis product. Te date for te first renewal will be: 11 February Te following post-approval commitments ave been made during te procedure: Te MAH sall perform te required parmacovigilance activities and interventions detailed in te agreed RMP presented in Module of te Marketing Autorisation and any agreed subsequent updates of te RMP. An updated RMP sould be submitted: - At te request of te RMS; - Wenever te risk management system is modified, especially as te result of new information being received tat may lead to a significant cange to te benefit/risk profile or as te result of an important (parmacovigilance or risk minimisation) milestone being reaced. If te dates for submission of a PSUR and te update of a RMP coincide, tey can be submitted at te same time. 7/7