LERCANIDIPINE HYDROCHLORIDE Film-coated tablet Ref.[6938] Active ingredients:

Sick sinus syndrome

Special care should be exercised when lercanidipine is used in patients with sick sinus syndrome (if a pacemaker is not in situ). 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 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).

This medicinal product contains lactose monohydrate and therefore should not be administered to patients with Lapp lactase insufficiency, galactosaemia or glucose/galactose malabsorption syndrome.

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.

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 AUC and an 8-fold increase of the C_max for the eutomer S-lercanidipine).

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.

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.

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 (t_max 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

Co-administration of 20 mg lercanidipine in patients chronically treated with b-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.

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.

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.

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

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.

Alcohol

Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs.

Other interactions

When lercanidipine was co-administered with metoprolol, β-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 β-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.

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 β-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. Lercanidipine has been safely administered with diuretics and ACE inhibitors.

Pregnancy

There are no adequate data from the use of lercanidipine in pregnant women. 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 child-bearing potential unless effective contraception is used.

Breastfeeding

Because of high lipophilicity of lercanidipine, distribution in milk may be expected. Therefore, it should not be administered to nursing mothers.

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.

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)

Immune system disorders

Very rare: Hypersensitivity

Psychiatric disorders

Rare: Somnolence

Nervous system disorders

Uncommon: Headache, dizziness

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

Gastrointestinal disorders

Rare: Dyspepsia, diarrhoea, abdominal pain, vomiting

Very rare: Gingival hypertrophy

Skin and subcutaneous tissue disorders

Rare: Rash

Musculoskeletal and connective tissue disorders

Rare: Myalgia

Renal and urinary disorders

Rare: Polyuria

Very rare: Urinary frequency

General disorders and administration site conditions

Rare: Asthenia, fatigue

Investigations

Very rare: Reversible increases in serum levels of hepatic transaminases

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; website: www.mhra.gov.uk/yellowcard.

Not applicable.