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 Lercadip 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 randomized study of patients with severe hypertension (mean±SD diastolic blood pressure of 114.5±3.7 mmHg) showed that blood pressure was normalized 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 Lercadip. In a double-blind, randomized, controlled study versus placebo in patients with isolated systolic hypertension, Lercadip was efficacious in lowering systolic blood pressure from mean initial values of 172.6±5.6 to 140.2±8.7 mmHg.
Pharmacokinetics: Absorption: Lercadip 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 ± 5.9 s.d. respectively, occur about 1.5-3 hrs after dosing.
The 2 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 2 enantiomers are essentially the same. No in vivo interconversion of enantiomers is observed.
Due to the high 1st pass metabolism, the absolute bioavailability of Lercadip 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 Lercadip is ingested up to 2 hrs after a high fat meal. Accordingly, Lercadip 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: Lercadip is extensively metabolized by CYP3A4; no parent drug is found in the urine or the feces. 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 metabolized by CYP3A4 and CYP2D6 by Lercadip is not expected at therapeutic doses.
Elimination: Elimination occurs essentially by biotransformation.
A mean terminal elimination half-life of 8-10 hrs was calculated and the therapeutic activity lasts for 24 hrs because of its high binding to lipid membrane. No accumulation was seen upon repeated administration.
Linearity/Non Linearity: Oral administration of Lercadip 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 1st pass metabolism. Accordingly, availability increases with dosage elevation.
Special Populations: 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 metabolized extensively in the liver.
Treatment of mild to moderate essential hypertension. Some individuals, not adequately controlled on a single antihypertensive agent may benefit from the addition of Lercadip with β-adrenoceptor blocking drug, a diuretic or an angiotension-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.
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.
Children: Since there is no clinical experience in patients <18 years, use in children is not currently recommended.
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 the dose to 20 mg daily must be approached with caution. Lercadip 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 40-800 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 ischemia 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 hrs 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. Lercadip is also contraindicated during pregnancy and lactation; in woman 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 dysfunctions or within 1 month of a myocardial infarction.
Special care should be exercised when Lercadip is used in patient with sick sinus syndrome (if pacemaker is not in situ). Although hemodynamic controlled studies reveal no impairment of ventricular function, care is also required in patients with moderate to severe left ventricular dysfunction. It has been suggested that some short-acting dihydropyridines may be associated with increased cardiovascular risk in patients with ischemic heart disease.
Lercadip is contraindicated during pregnancy and lactation; in woman of childbearing potential unless effective contraception is used.
Treatment with Lercadip is generally well tolerated. In controlled clinical trials, the most commonly observed side effects were related to the vasodilatory properties of lercanidipine: Flushing, peripheral edema, tachycardia, palpitation, headache, dizziness, asthenia. Other adverse experiences which were not clearly drug related and which occurred in <1% of patients were: Fatigue, gastrointestinal disturbances eg, 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 Lercadip has been observed. Lercadip does 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 preexisting angina pectoris may experience increased frequency, duration or severity of these attacks. Isolated cases of myocardial infarction may be observed.
Lercadip has been safely administered with diuretics and ACE inhibitors. It may also be administered safely with β-adrenoceptor blocking drugs which are renally eliminated eg, atenolol. Co-administration of Lercadip 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 does 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 eg, amiodarone, 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 systemic availability. Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs. Caution is required if you are taking anticonvulsants.
Use in Pregnancy & Lactation: Data of Lercadip 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 Lercadip in pregnancy and lactation, and other dihydropyridine compounds have been found teratogenic in animals.
Lercadip should not be administered during pregnancy or to women with childbearing 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.
Store in the original package at a temperature 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.