Each film-coated tablet contains lercanidipine hydrochloride 10 mg or 20 mg, respectively.
Pharmacotherapeutic Group: Dihydropyridine derivatives. ATC Code: C08CA13.
Pharmacology: Pharmacodynamics: 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 ZANIDIP 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 ZANIDIP. In a double-blind, randomized, controlled study versus placebo in patients with isolated systolic hypertension, ZANIDIP was efficacious in lowering systolic blood pressure from mean initial values of 172.6 ± 5.6 mmHg to 140.2 ± 8.7 mmHg.
Pharmacokinetics: Absorption: ZANIDIP is completely absorbed after 10-20 mg oral administration and peak plasma levels, 3.30 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 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 ZANIDIP 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 ZANIDIP is ingested up to 2 hours after a high fat meal. Accordingly, ZANIDIP 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: ZANIDIP 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 ZANIDIP 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.
Linearity/Non Linearity: Oral administration of ZANIDIP 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.
Characteristics in Patients: 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.
ZANIDIP is indicated for the treatment of mild to moderate essential hypertension. Some individuals, not adequately controlled on a single antihypertensive agent may benefit from the addition of ZANIDIP with beta-adrenoceptor blocking drug, a diuretic or an angiotensin-converting enzyme inhibitor.
The recommended dose is 10 mg orally, once a day 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. In severe hypertension, the dose titration period should be reduced.
Children: Since there is no clinical experience in patients under age of 18 years, use in children is not currently recommended.
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.
Renal or Hepatic Dysfunction: Special care should be exercised when treatment is recommenced in patients with 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. ZANIDIP is not recommended for use in patients with severe hepatic or renal dysfunction.
In the post-marketing experience, some cases of overdose were reported (from 40 up to 800 mg of lercanidipine, including reports of suicide attempt).
As with other dihydropyridines, overdosage might be expected to cause excessive peripheral vasodilatation. Symptoms associated to overdose include marked hypotension, dizziness, fatigue and reflex tachycardia. Cardiac failure, myocardial ischaemia and acute renal failure might occur. In case of severe hypotension cardiovascular support could be helpful.
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 drug 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.
Hypersensitivity to any dihydropyridine or any ingredient of the preparation. ZANIDIP is also contraindicated during pregnancy and lactation; in women of childbearing potential unless effective contraception is used. In patients with left ventricular outflow tract obstruction, untreated congestive cardiac failure, unstable angina pectoris, severe renal or hepatic dysfunction or within 1 month of a myocardial infarction.
Special care should be exercised when ZANIDIP is used in patient with sick sinus syndrome (if pacemaker is not in situ). Although hemodynamic controlled studies reveals no impairment of ventricular function, care is also required in patients with moderate to severe LV dysfunction. It has been suggested that some short-acting dihydropyridines may be associated with increase cardiovascular risk in patients with ischemic heart disease.
Data of ZANIDIP provide no evidence of teratogenic effect in the rat and the rabbit, and the reproductive performance in the rat was unimpaired. Nevertheless, since there is no clinical experience with ZANIDIP in pregnancy and lactation, and other dihydropyridine compounds have been found teratogenic in animals.
ZANIDIP should not be administered during pregnancy or to women with child-bearing potential unless effective contraception is used. Because of high lipophilicity of lercanidipine, distribution in milk may be expected. Therefore it should not be administered to nursing mothers.
Treatment with ZANIDIP is generally well tolerated. In controlled clinical trials the most commonly observed side effects were related to the vasodilatory properties of lercanidipine: Flushing, peripheral oedema, tachycardia, palpitation, headache, dizziness, asthenia. Other adverse experiences which were not clearly drug related and which occurred in less than 1% of patients were: Fatigue, gastrointestinal disturbances such as dyspepsia, nausea, vomiting, epigastric pain and diarrhea, polyuria, rash, somnolence and myalgia.
Hypotension may occur in rare cases. Although not observed in clinical trials, gingival hyperplasia may rarely occur as reported following the use of other dihydropyridines. There were reports of isolated and reversible increases in serum levels of hepatic transaminases; no other clinically significant pattern of laboratory test abnormalities related to ZANIDIP has been observed. ZANIDIP dose not appear to influence adversely blood sugar or serum lipid levels. 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.
ZANIDIP has been safely administered with diuretics and ACE inhibitors. It may also be administered safely with beta-adrenoceptor blocking drugs which are renally eliminated such as atenolol. Co-administration of ZANIDIP in patients chronically treated with cardiac glycosides showed no evidence of pharmacokinetic interaction; patients on concomitant digoxin treatment should nevertheless be closely monitored clinically for sign of digoxin toxicity. Concomitant administration of cimetidine 800 mg daily dose not cause significant modifications in plasma levels of lercanidipine, but at higher dose caution is required. As for other dihydropyridines, the main metabolic pathway for lercanidipine involves the enzyme CYP3A4. Until further evidence is available, great caution is recommended when lercanidipine is co-prescribed with inhibitors, inducers and/or substrate of CYP3A4 such as amidarone, midazolam, diazepam, metoprolol, propranolol, quinidine, erythromycin, phenytoin, rifampicin, terfenadine and cyclosporin. Dihydropyridines appear to be particularly sensitive to inhibition of metabolism by grapefruit juice, with a consequent rise in their systematic availability. Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs. Caution is required if the patient is taking anticonvulsants.
Store in the original package at temperatures not exceeding 30°C. Keep in a dry place.
Shelf-Life: 3 years.
C08CA13 - lercanidipine ; Belongs to the class of dihydropyridine derivative selective calcium-channel blockers with mainly vascular effects. Used in the treatment of cardiovascular diseases.
FC tab 10 mg (yellow, circular, biconvex, scored on one side) x 28's. 20 mg (pink, circular, biconvex, scored on one side) x 28's.