LERCANIDIPINE 10 MG FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Lercanidipine Hydrochloride10 mg film-coated tablet

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 10 mg lercanidipine hydrochloride, equivalent to 9.4 mg lercanidipine.

Excipient with known effect:

Each 10 mg film-coated tablet contains 30mg Lactose monohydrate

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

Yellow, round, biconvex 6.5 mm film-coated tablets, scored on one side, marked ‚L‘ on the other side.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4.1 Therapeutic indications

Lercinigen is indicated in adults for the treatment of mild to moderate essential hypertension.

4.2 Posology and method of administration

Posology

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 lercandipine to therapy with a beta-adrenoreceptor blocking drug, (atenolol) a diuretic (hydrochlorot­hiazide) or an angiotensin converting enzyme inhibitor (captopril or enalapril).

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.

Elderly patients

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.

Paediatric population

The safety and efficacy in children and adolescents below the 18 years of age has not been established. No data are available.

Renal or hepatic insufficiency

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 is not recommended for use in patients with severe hepatic impairment or with severe renal impairment (GFR < 30 ml/min).

Method of administration

For oral use.

Precautions to be taken before handling or administrating the medicinal product:

Treatment should be preferably administered in the morning at least 15 minutes before breakfast.

This product should not be administered with grapefruit (see section 4.3 and section 4.5)

4.3 Contraindications

– Hypersensitivity to the active substance, to any dihydropyridine or to any of the excipients listed in section 6.1.

– Left ventricular outflow tract obstruction.

– Untreated congestive cardiac failure.

– Unstable angina pectoris.

– Within 1 month of a myocardial infarction.

– Severe renal or hepatic impairment.

– Co-administration with:

strong inhibitors of CYP3A4 (see section 4.5), cyclosporin (see section 4.5),

grapefruit juice (see section 4.5).

– Pregnancy and lactation (see section 4.6).

– Women of child-bearing potential unless effective contraception is used.

4.4 Special warnings and precautions for use

Sick sinus syndrome

Special care should be exercised when lercanidipine is used in patients with sick sinus syndrome (without pacemaker).

Left ventricular dysfunction and ischaemic heart disease

Although hemodynamic 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.

Angina pectoris

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).

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 is not recommended for use in patients with severe hepatic impairment or in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.2).

Alcohol

Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs (see section 4.5).

CYP3A4 inducers

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).

Paediatric population

The safety and efficacy of lercanidipine has not been demonstrated in children.

Excipients with known effects

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the total-lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction Interaction studies have only been performed in adults

Metabolic interactions

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.

CYP3A4 inhibitors

Co-administration of lercanidipine with inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) should be avoided (see section 4.3). An interaction study with a strongCYP3A4 inhibitor, ketoconazole, has shown a considerable increase in plasma levels of lercanidipine (a 15-fold increase of the AUC and an 8-fold increase of the Cmax for the eutomer S- lercanidipine).

Ciclosporin

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. Ciclosporin and lercanidipine should not be administered together (see section 4.3).

Grapefruit juice

As for other dihydropyridines, lercanidipine is sensitive to inhibition of metabolism by grapefruit juice, with a consequent rise in its systemic availability and increased hypotensive effect. Lercanidipine should not be taken with grapefruit juice (see section 4.3).

Midazolm

When concomitantly administered at a dose of 20 mg with midazolam p.o. to elderly volunteers, lercanidipine's ab­sorption was increased (by approximately 40%) and the rate of absorption was decreased (tmax was delayed from 1.75 to 3 hours). Midazolam concentrations were not modified. CYP3A4 inducers 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.

CYP3A4 substrates

Caution should be exercised when lercanidipine is co-prescribed with other substrates of CYP3A4, like terfenadine, astemizole, class III antiarrhythmic drugs such as amiodarone, quinidine.

Digoxin

Co-administration of 20 mg lercanidipine in patients chronically treated with P— 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 Cmax, while AUC and renal clearance were not significantly modified. Patients on concomitant digoxin treatment should be closely monitored clinically for signs of digoxin toxicity.

Cimetidine

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.

Fluoxetine

An interaction study with fluoxetine (an inhibitor of CYP2D6 and CYP3A4), conducted in volunteers of an age of 65 ± 7 years (mean ± s.d.), has shown no clinically relevant modification of the pharmacokinetics of lercanidipine.

Warfarin

The co-administration of 20 mg lercanidipine to healthy volunteers given fasted did not alter the pharmacokinetics of warfarin.

Alcohol

Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs (see section 4.4).

Metoprolol

When lercanidipine was co-administered with metoprolol, P-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 P-blockers and may therefore occur with other drugs of this class. Consequently, lercanidipine may be safely administered with beta- adrenoceptor blocking drugs, but dose adjustment may be required.

Simvastatin

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 P-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 drug.

Diuretics and ACE inhibitors

Lercanidipine has been safely administered with diuretics and ACE inhibitors.

4.6 Fertility, pregnancy and lactation

Pregnancy

Non- clinical data provide no evidence of a teratogenic effect in the rat and the rabbit and reproductive performance in the rat was unimpaired. Since other dihydropyridine compounds have been found teratogenic in animals, lercanidipine should not be administered during pregnancy or to women with childbearingpo­tential unless effective contraception is used.

Breast-feeding

It is unknown whether lercanidipine/me­tabolites are excreted in human milk. A risk in the newborns /infants cannot be excluded. Lercaindipine is contraindicated during breast-feeding (see section 4.3)

Fertility

No clinical data are available with lercanidipine. 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.

4.7 Effects on ability to drive and use machines

Lercanidipine has minorinfluence 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 table below shows the incidence of adverse drug reactions, at least possibly causally related, grouped by MedDRA System Organ Class classification, and ranked by frequency: 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 (frequency cannot be estimated from available data).

Within each frequency grouping the observed adverse reactions are presents in order of decreasing seriousness.

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.

In post-marketing experience, from spontaneous reports the following undesirable effects were reported very rarely (<1/10,000): 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 influence adversely blood sugar or serum lipid levels.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: www.mhra.gov.uk/yellowcard

4.9 Overdose

In the post-marketing experience, some cases of overdose were reported (from 40 up to 800 mg of lercanidipine, including reports of suicide attempt.

Symptoms

As with other dihydropyridines, over dosage might be expected to cause excessive peripheral vasodilatation, Symptoms associated to overdose include marked hypotension and reflex tachycardia.

Treatment

In case of severe hypotension, bradycardia and unconsciousness, cardiovascular support could be helpful, with intravenous atropine for bradycardia.

In view of the prolonged pharmacological effect of lercanidipine, it is essential that the cardiovascular status of patients who take an overdose is monitored for

24 hours at least. There is no information on the value of dialysis. Since the active substance is highly lipophilic, it is most probable that plasma levels are no guide to the duration of the period of risk and dialysis may not be effective.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Selective calcium channel blockers with mainly vascular effects- Dihydropyridine derivatives ATC Code: C08CA13

Mechanism of action

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.

Pharmacodynamic effects

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.

Clinical efficacy and safety

In addition to the clinical studies conducted to support the therapeutic indications, a further small uncontrolled but randomised study of patients with severe hypertension (mean ± SD diastolic blood pressure of 114.5 ± 3.7 mmHg) showed that blood pressure was normalised in 40% of the 25 patients on 20 mg once daily dose and in 56% of 25 patients on 10 mg twice daily doses of lercanidipine. In a double-blind, randomized, controlled study versus placebo in patients with isolated systolic hypertension lercanidipine was efficacious in lowering systolic blood pressure

from mean initial values of 172.6 ± 5.6 mmHg to 140.2 ± 8.7 mmHg.

5.2 Pharmacokinetic properties

Absorption

Lercanidipine is completely absorbed after 10–20 mg oral administration and peak plasma levels,

3.3 0 ng/ml ± 2.09 s.d. and 7.66 ng/ml ± 5.90 s.d. 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 halflives 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.

Linearity/non-linearity

Oral administration of lercanidipine 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.

Oral availability of lercanidipine increases 4-fold when lercanidipine is ingested up to 2 hours after a high fat meal. Accordingly, lercanidipine should be taken before meals.

Distribution

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.

Biotransformation

Lercanidipine is extensively metabolised by CYP3A4; no parent drug 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 drugs metabolised by CYP3A4 and CYP2D6 by lercanidipine is not expected at therapeutic doses.

Elimination

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.

Elderly, renal and hepatic insufficiency

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 drug. In patients with moderate to severe hepatic impairment, the systemic bioavailability of lercanidipine is likely to be increased

since the drug is normally metabolised extensively in the liver.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for human based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

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 Ca-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 foetal development.

Lercinigen, 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

Tablet core:

Magnesium stearate

Povidone

Sodium starch glycolate (type A)

Lactose monohydrate

Cellulose, microcrystalline

Film-coating:

Macrogol

Polyvinyl alcohol, partly hydrolysed

Talc

Titanium dioxide (E-171)

Iron oxide yellow (E-172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Al/PVC blister: Do not store above 25°C. Store in the original package in order to protect from moisture.

HDPE bottles: Do not store above 25°C. Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

Blister pack (Aluminium/PVC) with push-through foil.

Blister pack (Aluminium/PVdC) with push-through foil.

Bottle (HDPE pack) with LDPE caps

Pack sizes:

Blisters:

14, 20, 28, 30, 50, 56, 98, 100 film-coated tablets

Bottles

14, 25, 28, 30, 50, 56, 84, 90, 98, 100, 112 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan, Station Close, Potters Bar, Hertfordshire EN6 1TL

8 MARKETING AUTHORISATION NUMBER(S)

PL 04569/1097

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

03/04/2014