Public Assessment Report. Decentralised Procedure

Public Assessment Report Decentralised Procedure Lercanidipine hydrochloride 10 mg Film-coated Tablets Lercanidipine hydrochloride 20 mg Film-coated Tablets UK/H/4385/01-02/DC UK licence numbers: PL 00289/1438-9 Teva UK Ltd 1

LAY SUMMARY On 21 st July 2011, the MHRA granted Teva UK Ltd Marketing Authorisations (licences) for the medicinal products Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets (PL 00289/1438-9). These are prescription-only medicines (POM). The active ingredient, lercanidipine hydrochloride, belongs to a group of medicines called calcium channel blockers (dihydropyridine derivatives). Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets are used to treat high blood pressure (hypertension) in adults over the age of 18 years. The proposed products were considered to be generic versions of the UK reference products Zanidip 10 mg and 20 mg film-coated tablets (PL 04595/0005 and 0010, Recordati Industria Chimica e Farmaceutica) based on the data submitted by Teva UK Ltd. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets outweigh the risks; hence Marketing Authorisations have been granted. 2

TABLE OF CONTENTS Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflet Page 13 Module 4: Labelling Page 18 Module 5: Scientific discussion during initial procedure Page 28 I Introduction Page 28 II About the product Page 30 III Scientific Overview and discussion Page 31 III.1 Quality aspects Page 31 III.2 Non-clinical aspects Page 34 III.3 Clinical aspects Page 35 IV Overall conclusions and benefit-risk assessment Page 38 Module 6: Steps taken after initial procedure Page 39 3

Module 1 Information about Initial Procedure Product Name Lercanidipine hydrochloride 10 mg Film-coated Tablets Lercanidipine hydrochloride 20 mg Film-coated Tablets Type of Application Generic, Article 10.1 Active Substance Form Strength MA Holder Reference Member State (RMS) Concerned Member States (CMS) Procedure Number Lercanidipine hydrochloride Film-coated tablets 10 mg, 20 mg Teva UK Ltd Brampton Road, Hampden Park, Eastbourne, East Sussex, BN22 9AG, United Kingdom UK Belgium, Finland, France, Germany, Italy, Netherlands, Norway, Portugal, Romania, Spain UK/H/4385/01-02/DC Timetable End of Procedure: Day 210 22 nd June 2011 4

Module 2 Summary of Product Characteristics The UK Summary of Product Characteristics (SmPC) for Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets (PL 00289/1438-9) is as follows. Differences between the individual SmPCs are highlighted: 1 NAME OF THE MEDICINAL PRODUCT Lercanidipine hydrochloride 10 mg Film-coated Tablets Lercanidipine hydrochloride 20 mg Film-coated Tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION One tablet contains 10 / 20 mg of lercanidipine hydrochloride, which is equivalent to 9.4 / 18.8 mg of lercanidipine. Excipients 10 mg: One tablet contains 30 mg of lactose monohydrate (equivalent to 28.5 mg of lactose anhydrous) and 0.27 mg of tartrazine aluminium lake (E102). 20 mg: One tablet contains 60 mg of lactose monohydrate (equivalent to 57 mg of lactose anhydrous) and 0.711 mg of allura red AC aluminium lake (E129). For a full list of excipients, see section 6.1. 3 PHARMACEUTICAL FORM Film-coated tablet. 10 mg: Yellow to dark yellow, round convex film-coated tablet debossed with the number "10" on one side and scored on the other. 20 mg: Light pink to pink, round convex film-coated tablet debossed with the number "20" on one side and scored on the other. The tablet can be divided into equal halves. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications Lercanidipine is indicated for the treatment of mild to moderate essential hypertension. 4.2 Posology and method of administration Method of administration Oral route The tablet should be swallowed with sufficient liquid (e.g. a glass of water). Dosage The recommended dosage is 10 mg orally once a day at least 15 minutes before meals; the dose may be increased to 20 mg depending on the individual patient's response. Dose titration should be gradual, because it may take about 2 weeks before the maximal antihypertensive effect is apparent. Some individuals, not adequately controlled on a single antihypertensive agent, may benefit from the addition of lercanidipine to therapy with a beta-adrenoceptor blocking agent (atenolol), a diuretic (hydrochlorothiazide) or an angiotensin-converting enzyme inhibitor (captopril or enalapril). 5

Since the dose-response curve is steep with a plateau at doses between 20-30 mg, it is unlikely that efficacy will be improved by higher doses; whereas side effects may increase. Use in the elderly Although the pharmacokinetic data and clinical experience suggest that no adjustment of the daily dosage is required, special care should be exercised when initiating treatment in the elderly. Use in children and adolescents Since there is no clinical experience in patients under the age of 18 years, use in children is not currently recommended. Use in renal or hepatic dysfunction Special care should be exercised when treatment is commenced in patients with mild to moderate renal or hepatic dysfunction. Although the usually recommended dose schedule may be tolerated by these subgroups, an increase in dose to 20 mg daily must be approached with caution. The antihypertensive effect may be enhanced in patients with hepatic impairment and consequently an adjustment of the dosage should be considered. Lercanidipine should not be used in patients with severe hepatic impairment or in patients with severe renal impairment (glomerular filtration rate < 30 ml/min) (see section 4.3). 4.3 Contraindications Hypersensitivity to the active substance, to any dihydropyridine or to any of the excipients Pregnancy and lactation Women of child-bearing potential unless effective contraception is used Left ventricular outflow tract obstruction Untreated congestive cardiac failure Unstable angina pectoris Severe renal or hepatic impairment Within 1 month of a myocardial infarction Co-administration with strong inhibitors of CYP3A4 (see section 4.5) ciclosporin (see section 4.5) grapefruit juice (see section 4.5) 4.4 Special warnings and precautions for use Special care should be exercised when lercanidipine is used in patients with sick sinus syndrome (if a pacemaker is not in situ). Although haemodynamic controlled studies revealed no impairment of ventricular function, care is also required in patients with left ventricular dysfunction. It has been suggested that some short-acting dihydropyridines may be associated with increased cardiovascular risk in patients with ischaemic heart disease. Although lercanidipine is long-acting, caution is required in such patients. Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely patients with pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks. Isolated cases of myocardial infarction may be observed (see section 4.8). Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive medicinal products (see section 4.5). Inducers of CYP3A4 like anticonvulsants (e.g. phenytoin, carbamazepine) and rifampicin may reduce lercanidipine's plasma levels and therefore the efficacy of lercanidipine may be less than expected (see section 4.5). Excipients This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take it. 6

10 mg: This medicinal product contains tartrazine aluminium lake (E102) and may cause allergic reactions. 20 mg: This medicinal product contains allura red AC aluminium lake (E129) and may cause allergic reactions. 4.5 Interaction with other medicinal products and other forms of interaction Lercanidipine is known to be metabolised by the CYP3A4 enzyme and, therefore, inhibitors and inducers of CYP3A4 administered concurrently may interact with the metabolism and elimination of lercanidipine. Co-prescription of lercanidipine with inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole) should be avoided (see section 4.3). An interaction study with a strong CYP3A4 inhibitor, ketoconazole, has shown a considerable increase in plasma levels of lercanidipine (a 15-fold increase of the area-under-the-curve (AUC) and an 8-fold increase of the peak plasma concentration (C max ) for the eutomer S-lercanidipine). Ciclosporin and lercanidipine should not be administered together (see section 4.3). Increased plasma levels of both lercanidipine and ciclosporin have been observed following concomitant administration. A study in young healthy volunteers has shown that when ciclosporin was administered 3 hours after the lercanidipine intake, the plasma levels of lercanidipine did not change, while the AUC of ciclosporin increased by 27%. However, the co-administration of lercanidipine with ciclosporin has caused a 3-fold increase of the plasma levels of lercanidipine and a 21% increase of the ciclosporin AUC. Lercanidipine should not be taken with grapefruit juice (see section 4.3). Dihydropyridines including lercanidipine are sensitive to inhibition of metabolism by grapefruit juice, with a consequent rise in their systemic availability and increased hypotensive effect. When concomitantly administered at a dose of 20 mg with midazolam per os to elderly volunteers, lercanidipine's absorption was increased (by approximately 40%) and the rate of absorption was decreased (the time to peak plasma concentration (t max ) was delayed from 1.75 to 3 hours). Midazolam concentrations were not modified. Caution should be exercised when lercanidipine is co-prescribed with other substrates of CYP3A4, like terfenadine, astemizole, class III antiarrhythmic agents such as amiodarone, quinidine. Co-administration of lercanidipine with CYP3A4 inducers like anticonvulsants (e.g. phenytoin, carbamazepine) and rifampicin should be approached with caution since the antihypertensive effect may be reduced and blood pressure should be monitored more frequently than usual. When lercanidipine was co-administered with metoprolol, a beta-blocker eliminated mainly by the liver, the bioavailability of metoprolol was not changed while that of lercanidipine was reduced by 50%. This effect may be due to the reduction in the hepatic blood flow caused by beta-blockers and may therefore occur with other medicinal products of this class. Consequently, lercanidipine may be safely administered with beta-blocking agents, but dose adjustment may be required. An interaction study with fluoxetine (an inhibitor of CYP2D6 and CYP3A4), conducted in volunteers of an age of 65 ± 7 years (mean ± standard deviation), has shown no clinically relevant modification of the pharmacokinetics of lercanidipine. Concomitant administration of cimetidine 800 mg daily does not cause significant modifications in plasma levels of lercanidipine, but at higher doses caution is required since the bioavailability and the hypotensive effect of lercanidipine may be increased. Co-administration of 20 mg lercanidipine in patients chronically treated with beta-methyldigoxin showed no evidence of pharmacokinetic interaction. Healthy volunteers treated with digoxin following dosing with 20 mg lercanidipine given fasted showed a mean increase of 33% in digoxin C max, while AUC and renal clearance were not significantly modified. Patients on concomitant digoxin treatment should be closely monitored clinically for signs of digoxin toxicity. 7

When a dose of 20 mg of lercanidipine was repeatedly co-administered with 40 mg of simvastatin, the AUC of lercanidipine was not significantly modified, while simvastatin's AUC increased by 56% and that of its active metabolite beta-hydroxyacid by 28%. It is unlikely that such changes are of clinical relevance. No interaction is expected when lercanidipine is administered in the morning and simvastatin in the evening, as indicated for such medicinal products. The co-administration of 20 mg lercanidipine to healthy volunteers given fasted did not alter the pharmacokinetics of warfarin. Lercanidipine has been safely administered with diuretics and angiotensin-converting enzyme inhibitors. Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive agents (see section 4.4). 4.6 Fertility, Pregnancy and lactation Fertility Reversible biochemical changes in the head of spermatozoa which can impair fecundation have been reported in some patients treated by channel blockers. In cases where repeated in vitro fertilisation is unsuccessful and where another explanation cannot be found, the possibility of calcium channel blockers as the cause should be considered. Pregnancy Animal studies with lercanidipine have not shown teratogenic effects, but these have been observed with other dihydropyridine compounds (see section 5.3). No clinical data on exposed pregnancies are available for lercanidipine, therefore it should not be used during pregnancy or in women planning to become pregnant. Lactation The excretion of lercanidipine in human milk is unknown. Consequently, it should not be used during lactation. 4.7 Effects on ability to drive and use machines Lercanidipine has no or negligible influence on the ability to drive and use machines. However, caution should be exercised because dizziness, asthenia, fatigue and rarely somnolence may occur. 4.8 Undesirable effects About 1.8% of treated patients experienced adverse reactions. The following undesirable effects have been reported in clinical studies and in the post-marketing phase. Assessment of frequencies: Very common: 1/10 Common: 1/100 to < 1/10 Uncommon: 1/1,000 to < 1/100 Rare: 1/10,000 to < 1/1,000 Very rare: < 1/10,000 Not known (cannot be estimated from the available data) As shown in the table, the most commonly occurring adverse drug reactions reported in controlled clinical trials are headache, dizziness, peripheral oedema, tachycardia, palpitations, flushing, each occurring in less than 1% of patients. 8

System organ class Adverse drug reactions Immune system disorders Very rare Hypersensitivity Psychiatric disorders Rare Somnolence Nervous system disorders Uncommon Headache, dizziness Not known An extrapyramidal syndrome has been reported with some calcium antagonists. Cardiac disorders Uncommon Tachycardia, palpitations, peripheral oedema Rare Angina pectoris Very rare Chest pain, myocardial infarction, hypotension Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely, patients with pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks. Vascular disorders Uncommon Flushing Very rare Syncope Gastrointestinal disorders Rare Dyspepsia, nausea, diarrhoea, abdominal pain, vomiting Very rare Gingival hypertrophy Skin and subcutaneous tissue Rare Rash disorders Musculoskeletal and connective Rare Myalgia tissue disorders Renal and urinary disorders Rare Polyuria Very rare Urinary frequency General disorders and Uncommon Peripheral oedema administration site conditions Rare Asthenia, fatigue In post-marketing experience, from spontaneous reports the following undesirable effects were reported very rarely: gingival hypertrophy, reversible increases in serum levels of hepatic transaminases, hypotension, urinary frequency and chest pain. Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely patients with pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks. Isolated cases of myocardial infarction may be observed. Lercanidipine does not appear to adversely influence blood sugar or serum lipid levels. 4.9 Overdose Symptoms Overdose might be expected to cause excessive peripheral vasodilatation with marked hypotension and reflex tachycardia. In post-marketing experience, three cases of overdose have been reported. The first patient developed sleepiness. The second patient developed cardiogenic shock with severe myocardial ischaemia and mild renal failure. The third patient showed vomiting and hypotension. All patients recovered without sequelae. Treatment In the above-mentioned cases, treatment consisted respectively in gastric lavage; high-dose catecholamines, furosemide, digitalis and parenteral plasma expanders; activated charchoal, laxatives and intravenous dopamine. In case of severe hypotension, bradycardia and unconsciousness, cardiovascular support can be helpful, with intravenous atropine to counteract the bradycardia. In view of the prolonged pharmacological action of lercanidipine, the cardiovascular status of patients who have taken an overdose must be monitored for at least 24 hours. There is no information on the value of dialysis. Since the substance is highly lipophilic, it is very unlikely that plasma levels will be indicative of the duration of the risk phase. Dialysis may not be effective. 9

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Selective calcium channel blockers with mainly vascular effects ATC code: C08C A13 Lercanidipine is a calcium antagonist of the dihydropyridine group and inhibits the transmembrane influx of calcium into cardiac and smooth muscle. The mechanism of its antihypertensive action is due to a direct relaxant effect on vascular smooth muscle thus lowering total peripheral resistance. Despite its short pharmacokinetic plasma half-life, lercanidipine is endowed with a prolonged antihypertensive activity because of its high membrane partition coefficient, and is devoid of negative inotropic effects due to its high vascular selectivity. Since the vasodilatation induced by lercanidipine is gradual in onset, acute hypotension with reflex tachycardia has rarely been observed in hypertensive patients. As for other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due to its S-enantiomer. 5.2 Pharmacokinetic properties Lercanidipine is completely absorbed after oral administration of 10-20 mg lercanidipine hydrochloride and peak plasma levels, 3.30 ng/ml ± 2.09 standard deviation and 7.66 ng/ml ± 5.90 standard deviation respectively, occur about 1.5-3 hours after dosing. The two enantiomers of lercanidipine show a similar plasma level profile: the time to peak plasma concentration is the same, the peak plasma concentration and AUC are, on average, 1.2-fold higher for the S-enantiomer and the elimination half-lives of the two enantiomers are essentially the same. No in vivo interconversion of enantiomers is observed. Due to the high first-pass metabolism, the absolute bioavailability of lercanidipine orally administered to patients under fed conditions is around 10%, although it is reduced to 1/3 when administered to healthy volunteers under fasting conditions. Oral availability of lercanidipine increases 4-fold when it is ingested up to 2 hours after a high-fat meal. Accordingly, lercanidipine should be taken before meals. Distribution from plasma to tissues and organs is rapid and extensive. The degree of serum protein binding of lercanidipine exceeds 98%. Since plasma protein levels are reduced in patients with severe renal or hepatic dysfunction, the free fraction of the drug may be increased. Lercanidipine is extensively metabolised by CYP3A4; no parent substance is found in the urine or the faeces. It is predominantly converted to inactive metabolites and about 50% of the dose is excreted in the urine. In vitro experiments with human liver microsomes have demonstrated that lercanidipine shows some degree of inhibition of CYP3A4 and CYP2D6, at concentrations 160- and 40-fold, respectively, higher than those reached at peak in the plasma after the dose of 20 mg. Moreover, interaction studies in humans have shown that lercanidipine did not modify the plasma levels of midazolam, a typical substrate of CYP3A4, or of metoprolol, a typical substrate of CYP2D6. Therefore, inhibition of biotransformation of substances metabolised by CYP3A4 and CYP2D6 by lercanidipine is not expected at therapeutic doses. Elimination occurs essentially by biotransformation. A mean terminal elimination half life of 8-10 hours was calculated and the therapeutical activity lasts for 24 hours because of its high binding to lipid membrane. No accumulation was seen upon repeated administration. 10

Oral administration leads to plasma levels of lercanidipine not directly proportional to dosage (non-linear kinetics). After 10, 20 or 40 mg, peak plasma concentrations observed were in the ratio 1:3:8 and areas under plasma concentration-time curves in the ratio 1:4:18, suggesting a progressive saturation of first pass metabolism. Accordingly, availability increases with dosage elevation. In elderly patients and in patients with mild to moderate renal dysfunction or mild to moderate hepatic impairment the pharmacokinetic behaviour of lercanidipine was shown to be similar to that observed in the general patient population; patients with severe renal dysfunction or dialysis-dependent patients showed higher levels (about 70%) of the substance. In patients with moderate to severe hepatic impairment, the systemic bioavailability of lercanidipine is likely to be increased since it is normally metabolised extensively in the liver. 5.3 Preclinical safety data Safety pharmacological studies in animals have shown no effects on the autonomic nervous system, the central nervous system or on gastrointestinal function at antihypertensive doses. The relevant effects which have been observed in long-term studies in rats and dogs were related, directly or indirectly, to the known effects of high doses of calcium antagonists, predominantly reflecting exaggerated pharmacodynamic activity. Lercanidipine was not genotoxic and showed no evidence of carcinogenic hazard. Fertility and general reproductive performance in rats were unaffected by treatment with lercanidipine. There was no evidence of any teratogenic effect in rats and rabbits; however, in rats, lercanidipine at high dose levels induced pre- and post-implantation losses and delay in fetal development. Lercanidipine hydrochloride, when administered at high dose (12 mg/kg/day) during labour, induced dystocia. The distribution of lercanidipine and/or its metabolites in pregnant animals and their excretion in breast milk have not been investigated. Metabolites have not been evaluated separately in toxicity studies. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Core: Lactose monohydrate Sodium starch glycolate (potato) Microcrystalline cellulose Povidone Magnesium stearate 10 mg: Film-coating: Opadry 03F32418 yellow containing hypromellose (E464), titanium dioxide (E171), tartrazine aluminium lake (E102), macrogol 6000, talc, iron oxide yellow (E172) 20 mg: Film-coating: Opadry 03F34650 pink containing hypromellose (E464), titanium dioxide (E171), allura red AC aluminium lake (E129), macrogol 6000, talc, indigo carmine aluminium lake (E132) 11

6.2 Incompatibilities Not applicable. 6.3 Shelf life Blisters: 3 years Bottles: 2 years Bottles (after first opening container): 30 days 6.4 Special precautions for storage Blisters Store in the original package in order to protect from light. Bottles Store in the original package in order to protect from light. Bottles (after first opening container) Store in the original package in order to protect from light. 6.5 Nature and contents of container Blisters White opaque PVC/PVdC aluminium blisters 14 (10 mg strength only), 15, 28, 30, 50, 56, 60, 90, 98, 100 tablets and Hospital pack: 50x1 tablets - Calendar packs of 28 tablets. Not all pack sizes may be marketed. Bottles 40 ml white HDPE bottle with 33 mm child-resistant white polypropylene closure and 1 g silica gel desiccant 30 tablets 6.6 Special precautions for disposal No special requirements. 7 MARKETING AUTHORISATION HOLDER Teva UK Ltd Brampton Road, Hampden Park, Eastbourne, East Sussex, BN22 9AG, United Kingdom 8 MARKETING AUTHORISATION NUMBER(S) PL 00289/1438 PL 00289/1439 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 21/07/2011 10 DATE OF REVISION OF THE TEXT 21/07/2011 12

Module 3 Patient Information Leaflet - text 13

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Module 4 Labelling - text Lercanidipine hydrochloride 10 mg Film-coated Tablets 18

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Lercanidipine hydrochloride 20 mg Film-coated Tablets 23

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Module 5 Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted Teva UK Ltd Marketing Authorisations for the medicinal products Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets () on 21 st July 2011. The products are prescription-only medicines. These are generic applications for Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets, submitted under Article 10.1 of Directive 2001/83 EC, as amended. The applications refer to the UK products, Zanidip 10 mg and 20 mg film-coated tablets (PL 04595/0005 and 0010), authorised to Recordati Industria Chimica e Farmaceutica on 22 nd March 1996 and 9 th August 2002 respectively. Zanedip 20 mg film-coated tablets was first authorised to Recordati Industria Chimica e Farmaceutica in Italy in March 1997. The originator products have been authorised in the EU for more than 10 years, thus the period of data exclusivity has expired. With the UK as the Reference Member State (RMS) in this Decentralised Procedure, Teva UK Ltd applied for Marketing Authorisations for Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets in Belgium, Finland, France, Germany, Italy, Netherlands, Norway, Portugal, Romania and Spain. Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets are indicated for the treatment of mild to moderate essential hypertension. Lercanidipine is a calcium channel blocker of the dihydropyridine group (ATC code C08C A13) and inhibits the transmembrane influx of calcium into cardiac and smooth muscle. The mechanism of its antihypertensive action is due to a direct relaxant effect on vascular smooth muscle thus lowering total peripheral resistance. Despite its short pharmacokinetic plasma half-life, lercanidipine is endowed with a prolonged antihypertensive activity because of its high membrane partition coefficient, and is devoid of negative inotropic effects due to its high vascular selectivity. As for other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due to its S-enantiomer. No new non-clinical or clinical efficacy studies were conducted for these applications, which is acceptable given that the applications were for generic versions of products that have been licensed for over 10 years. The applications are supported by a bioequivalence study comparing the pharmacokinetic profile of the test product, Lercanidipine hydrochloride 20 mg Film-coated Tablets, to that of the reference product, Zanedip 20 mg film-coated tablets (Recordati Industria Chimica e Farmaceutica, Italy). The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). The Reference Member State (RMS) has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for this product type at all sites responsible for the manufacture and assembly of these products. 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 28

GMP are in place at those sites. For manufacturing sites outside the community, the RMS has accepted copies of current GMP Certificates or satisfactory inspection summary reports, close-out letters or exchange of information issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-community sites. The RMS considers that the pharmacovigilance system as described by the Marketing Authorisation Holder (MAH) fulfils the requirements and provides adequate evidence that the MAH has the services of a Qualified Person (QP) responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. The MAH has provided adequate justification for not submitting a Risk Management Plan (RMP). As the applications are for generic versions of already authorised reference products, for which new safety concerns requiring additional risk minimisation have not been identified, routine pharmacovigilance activities are proposed and a risk minimisation system is not considered necessary. The reference products have been in use for many years and the safety profile of the active is well-established. The MAH has provided adequate justification for not submitting a detailed Environmental Risk Assessment (ERA). These were applications for generic products and there is no reason to conclude that marketing of these products will change the overall use pattern of the existing market. There are no environmental concerns associated with the method of manufacture or formulation of the products. 29

II. ABOUT THE PRODUCT Name of the product in the Reference Member State Name(s) of the active substance(s) (INN) Pharmacotherapeutic classification (ATC code) Lercanidipine hydrochloride 10 mg Film-coated Tablets Lercanidipine hydrochloride 20 mg Film-coated Tablets Lercanidipine hydrochloride Selective calcium channel blockers with mainly vascular effects (C08CA13) Pharmaceutical form and strength(s) Reference numbers for the Decentralised Procedure Reference Member State Member States concerned Film-coated tablets 10 mg, 20 mg UK/H/4385/01-02/DC United Kingdom BE, DE, ES, FI, FR, IT, NL, NO, PT and RO Marketing Authorisation Number(s) PL 00289/1438-9 Name and address of the authorisation holder Teva UK Ltd Brampton Road, Hampden Park, Eastbourne, East Sussex, BN22 9AG, United Kingdom 30

III III.1 SCIENTIFIC OVERVIEW AND DISCUSSION QUALITY ASPECTS ACTIVE SUBSTANCE Lercanidipine hydrochloride Nomenclature: INN: Lercanidipine hydrochloride Chemical names: i) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5- pyridinedicarboxylic acid-2-[(3,3-diphenylpropyl)methylamino]-1,1- dimethylethyl methyl ester hydrochloride ii) (+/-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) pyridine-3,5- dicarboxylic acid-2-[n-(3,3-diphenylpropyl)n-methylamino]-1,1- dimethylethyl methyl diester hydrochloride Structure: Molecular formula: C 36 H 41 N 3 O 6. HCl Molecular weight: 648.19 g/mol CAS No: 132866-11-6 Physical form: Yellow powder Solubility: Soluble in methanol and practically insoluble in water Melting range: 165.0 to 180.0 C The active substance, lercanidipine hydrochloride, is not the subject of a European Pharmacopeia (Ph. Eur.) or British Pharmacopeia (B.P.) monograph. Synthesis of the active substance from the designated starting materials has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specifications are in place for all starting materials and reagents and these are supported by relevant Certificates of Analysis. Confirmation has been provided that the raw materials, intermediates and auxiliary agents used in synthesis of the active are not of animal, biological or genetically modified origin. Appropriate specifications have been provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Batch analysis data are provided and comply with the proposed specifications. Satisfactory Certificates of Analysis have been provided for reference standards used by the active substance manufacturer during validation studies. 31

The active substance is stored in appropriate packaging. Specifications and Certificates of Analysis have been provided for the packaging materials used. The primary packaging in direct contact with the active substance complies with relevant Ph. Eur. requirements and satisfies Directive 2002/72/EC (as amended); it is suitable for contact with foodstuffs. Appropriate stability data have been generated for the active substance stored in the proposed commercial packaging. These data demonstrate the stability of the active substance and support the 36-month retest period that has been applied. MEDICINAL PRODUCT Description and Composition Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets are presented as yellow to dark yellow (10 mg) and light pink to pink (20 mg) round, convex, film-coated tablets debossed with 10 / 20 on one side and scored on the other side. The tablets can be divided into equal halves. Each tablet contains 10 mg or 20 mg of the active ingredient, lercanidipine hydrochloride. Other ingredients consist of pharmaceutical excipients, namely lactose monohydrate, sodium starch glycolate (potato), microcrystalline cellulose, povidone and magnesium stearate making up the tablet cores; and Opadry 03F32418 yellow (10 mg) and Opadry 03F34650 pink (20 mg) film-coatings (see SmPCs for full details). Appropriate justification for the inclusion of each excipient has been provided. All excipients of the tablet cores comply with their respective European Pharmacopoeia monographs. The Opadry formulations used for film-coating comply with satisfactory inhouse specifications; they are constituted from pharmacopoeial ingredients along with pigments that comply with the requirements of the US Pharmacopoeia. Satisfactory Certificates of Analysis have been provided for all excipients. The magnesium stearate has been confirmed as being of vegetable origin. The only excipient used that contains material of animal or human origin is lactose monohydrate. The applicant has provided a declaration that milk used in the production of lactose monohydrate is sourced from healthy animals under the same conditions as that for human consumption. None of the excipients are sourced from genetically modified organisms. There were no novel excipients used and no overages. Pharmaceutical development Details of the pharmaceutical development of the medicinal products have been supplied and are satisfactory. The objective was to develop stable, immediate-release, tablet formulations of lercanidipine hydrochloride 10 mg and 20 mg, qualitatively and quantitatively equivalent and bioequivalent to the reference products, Zanidip 10 mg and 20 mg film-coated tablets (Recordati Industria Chimica e Farmaceutica). Comparative dissolution and impurity data were provided for batches of the test products and appropriate reference products. The dissolution and impurity profiles were satisfactory. Manufacture A description and flow-chart of the manufacturing method has been provided. 32

In-process controls are appropriate considering the nature of the products and the method of manufacture. Process validation studies were conducted on pilot-scale batches and the results were satisfactory. The validation data demonstrated consistency of the manufacturing process. A commitment has been made by the MAH that full process validation will be conducted on commercial scale batches in accordance with the process validation protocol. Finished product specification The finished product specifications are provided for both release and shelf-life and are satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and have been adequately validated, as appropriate. Satisfactory batch analysis data are provided and accepted. The data demonstrate that the batches are compliant with the proposed specifications. Certificates of Analysis have been provided for any reference standards used. Container Closure System Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets are packed in bulk packs for repackaging into marketable packs. The bulk packaging consists of transparent polyethylene bags as a primary packaging material, which are placed inside black polyethylene bags and finally into High-Density Polyethylene (HDPE) drums. The medicinal products are licensed for marketing in white, opaque polyvinylchloride (PVC) - polyvinylidene chloride (PVdC) / aluminium foil blister strips, which are packaged with the Patient Information Leaflet (PIL) into cardboard outer cartons in pack sizes of 14 (10 mg strength only), 15, 28, 30, 50, 56, 60, 90, 98 and 100 film-coated tablets. The products are also licensed in hospital packs of 50 x 1 and calendar packs of 28, as well as HDPE bottles of 30 tablets. The MAH has stated that not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis for all packaging components used have been provided. All primary product packaging complies with EU legislation, Directive 2002/72/EC (as amended), and is suitable for contact with foodstuffs. Stability Finished product stability studies have been conducted in accordance with current guidelines, using product stored in the packaging proposed for marketing. These data support the applied shelf-lives of 3 years for the blister packs and 2 years for the HDPE bottles. Once opened, the shelf-life of the HDPE bottles is 30 days. Storage instructions are Store in the original package in order to protect from light. Quality Overall Summary A satisfactory quality overall summary is provided, and has been prepared by an appropriately qualified expert. The CV of the expert has been supplied. Product Information The approved Summaries of Product Characteristics (SmPCs), and Patient Information Leaflet (PIL) and labelling texts are satisfactory. The labelling texts fulfil the statutory requirements for Braille. The user-testing of the PIL text has been evaluated and is accepted. The MAH has submitted text versions only and has committed to submitting mock-up livery to the relevant regulatory authorities for approval before packs are marketed. 33

Conclusion All pharmaceutical issues have been resolved and the quality grounds for these applications are considered adequate. There are no objections to approval of Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets from a pharmaceutical point of view. III.2 NON-CLINICAL ASPECTS Specific non-clinical studies have not been performed, which is acceptable considering that these are applications for generic versions of products that have been licensed for over 10 years. The non-clinical overview provides a satisfactory review of the pharmacodynamic, pharmacokinetic and toxicological properties of lercanidipine hydrochloride, a widely used and well-known active substance. The overview, dated June 2010, cites 2 references from the published literature dated up to year 2000. The CV of the non-clinical expert has been supplied. For generic applications of this nature, the need for repetitive tests on animals and humans is avoided. Reference is made to the UK products, Zanidip 10 mg and 20 mg filmcoated tablets (Recordati Industria Chimica e Farmaceutica). There are no objections to approval of Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets from a non-clinical point of view. 34

III.3 CLINICAL ASPECTS INDICATIONS Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets are indicated for the treatment of mild to moderate essential hypertension. The indications are in line with those for the reference products and are satisfactory. POSOLOGY AND METHOD OF ADMINISTRATION The recommended dosage is 10 mg orally once a day at least 15 minutes before meals; the dose may be increased to 20 mg depending on the individual patient's response. Full details concerning the posology are provided in the SmPCs. The posology is consistent with that for the reference products and is satisfactory. TOXICOLOGY The toxicology of lercanidipine hydrochloride is well-known. No new data have been submitted and none are required for applications of this type. CLINICAL PHARMACOLOGY The clinical pharmacology of lercanidipine hydrochloride is well-known. With the exception of the bioequivalence study, no new pharmacodynamic or pharmacokinetic data are supplied and none are required for these applications. The antihypertensive activity of lercanidipine is mainly due to its S-enantiomer. Pharmacokinetics bioequivalence study The applications are supported by the bioequivalence study presented by the applicant comparing the pharmacokinetic profile of the test product, Lercanidipine hydrochloride 20 mg Film-coated Tablets, to that of the reference product, Zanedip 20 mg film-coated tablets (Recordati Industria Chimica e Farmaceutica, Italy). The study was of an appropriate design and was conducted to principles of Good Clinical Practice (GCP). Certificates of Analysis were provided for both the test and reference products. The UK reference product, Zanidip 20 mg film-coated tablets, is considered to be equivalent to the originator and clinical reference product, Zanedip 20 mg film-coated tablets (Recordati Industria Chimica e Farmaceutica). This was an open-label, randomised, four-period, two-sequence, two-treatment, replicate single-dose crossover bioequivalence study conducted in 40 healthy adult human subjects under fasting conditions. A single dose of the investigational products was administered orally to each subject in each period. A satisfactory washout period of 7 days was maintained between the dosing days in each group. Blood samples were taken pre-dose (0.0) and at specified time points up to 24.0 hours after administration of test or reference product. Plasma levels of (S)-lercanidipine hydrochloride were quantified by a validated LC-MS / MS method. The primary pharmacokinetic parameters for this study were C max, AUC 0-t, and AUC 0-. Bioequivalence of the test product versus the reference product was concluded if the 90% Confidence Intervals (CI) fell within the acceptance range, 0.80-1.25 (80.00%-125.00%), for log-transformed C max, AUC 0-t, and AUC 0- for (S)-lercanidipine hydrochloride. 35

Results: 40 subjects were enrolled in the study; 37 of these completed the study and were included in the pharmacokinetic evaluation and statistical analysis. The discontinuation, and noninclusion in the pharmacokinetic analysis, of 3 subjects was satisfactorily justified. Safety - There were no deaths or serious or significant adverse events reported in the study. The summary of the results of the bioequivalence study are tabulated below: Pharmacokinetic results for (S)-lercanidipine hydrochloride for a randomised, four-period, two-treatment, replicate, single-dose crossover study between the test and reference products. n=38 (first administration) and 37 (second administration) healthy subjects, dosed fasted; t=24 hours. Wash-out period: 7 days. Parameters C max (ng/ml) AUC 0-t (ng.h/ml) AUC 0- (ng.h/ml) Reference Product (X) Geometric Least Squares Mean Test Product (Y) Ratio (Y/X) % 90% CI (Parametric) 3500.74 3899.67 4317.64 4374.02 102.58 92.47-113.80% 13624.03 13367.73 15095.08 15772.89 97.66 90.46-105.43% 14075.25 13831.62 15667.41 16321.53 97.58 90.70-104.98% - First administration, n=38 - Second administration, n=37 AUC 0- AUC 0-t C max area under the plasma concentration-time curve from time zero to infinity area under the plasma concentration-time curve from time zero to t hours maximum plasma concentration Conclusion on Bioequivalence The results of the bioequivalence study show that the test and reference products are bioequivalent under fasting conditions, as the confidence intervals for C max, AUC 0-t, and AUC 0- for (S)-lercanidipine hydrochloride fall within the acceptance criteria ranges of 80.00-125.00%, in line with current guidelines. Satisfactory justification is provided for a bio-waiver for Lercanidipine hydrochloride 10 mg Film-coated Tablets. As Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets meet the criteria specified in the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 rev. 1/Corr), the results and conclusions of the bioequivalence study on the 20 mg strength can be extrapolated to the 10 mg strength tablets. Clinical efficacy No new data have been submitted and none are required. The reference products are established and the applications depend upon the ability to demonstrate bioequivalence. Efficacy is reviewed in the clinical overview. The efficacy of lercanidipine hydrochloride is well-established from its extensive use in clinical practice. Clinical safety No new data have been submitted and none are required for applications of this type. No new or unexpected safety concerns arose from these applications. Safety is reviewed in the clinical overview. The safety profile of lercanidipine hydrochloride is well-known. 36

PRODUCT INFORMATION: Summary of Product Characteristics (SmPC) The approved SmPCs are consistent with those of the UK reference products and are acceptable. Patient Information Leaflet The final PIL texts are in line with the approved SmPCs and are satisfactory. The PIL usertesting has been evaluated and is accepted. Labelling The labelling texts are satisfactory. Clinical overview A satisfactory clinical overview is provided, and has been prepared by an appropriately qualified expert. The overview, dated February 2010, cites 6 references from the published literature dated up to year 2008. The CV of the clinical expert has been supplied. CONCLUSIONS Sufficient clinical information has been submitted to support these applications. The riskbenefit of the products is considered favourable from a clinical perspective. The grant of Marketing Authorisations was, therefore, recommended on medical grounds. 37

IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for applications of this type. CLINICAL Bioequivalence has been demonstrated between the applicant s Lercanidipine hydrochloride 20 mg Film-coated Tablets and the reference product, Zanedip 20 mg film-coated tablets (Recordati Industria Chimica e Farmaceutica). The UK reference product, Zanidip 20 mg film-coated tablets, is considered to be equivalent to the originator and clinical reference product, Zanedip 20 mg film-coated tablets (Recordati Industria Chimica e Farmaceutica). As the proposed products, Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets, meet the criteria specified in the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 rev. 1/Corr), the results and conclusions of the bioequivalence study on the 20 mg strength were extrapolated to the 10 mg strength tablets, and omission of further bioequivalence studies on the lower strength can be accepted. No new or unexpected safety concerns arise from these applications. PRODUCT LITERATURE The approved SmPCs are consistent with those of the UK reference products and are satisfactory. The PIL text is in line with the SmPCs and is satisfactory. The leaflet text has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The results show that the leaflet text meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. The approved labelling texts are satisfactory and fulfil the statutory requirements for Braille. The MAH has submitted text versions only for the PIL and labelling and has committed to submitting mock-up livery to the relevant regulatory authorities for approval before packs are marketed. BENEFIT-RISK ASSESSMENT The quality of the products is acceptable and no new non-clinical or clinical safety concerns have been identified. The bioequivalence study and its conclusions support the claim that the applicant s Lercanidipine hydrochloride 10 mg and 20 mg Film-coated Tablets are generic versions of the reference products, Zanidip 10 mg and 20 mg film-coated tablets (Recordati Industria Chimica e Farmaceutica). Extensive clinical experience with lercanidipine hydrochloride is considered to have demonstrated the therapeutic value of the active substance. The benefit: risk ratio is considered to be positive. 38

Module 6 STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY Date submitted Application type Scope Outcome 39