Beta-Blocker Withdrawl

Nicardipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of dose of beta-blocker.

Rapid Decreases In Blood Pressure

No clinical events have been reported suggestive of a too rapid decrease in blood pressure with Cardene® I.V. However, as with any antihypertensive agent, blood pressure lowering should be accomplished over as long a time as is compatible with the patient's clinical status.

Use In Patients With Angina

Increases in frequency, duration, or severity of angina have been seen in chronic oral therapy with Cardene® capsules. Induction or exacerbation of angina has been seen in less than 1% of coronary artery disease patients treated with Cardene® I.V. The mechanism of this effect has not been established.

Use In Patients With Congestive Heart Failure

Cardene® I.V. reduced afterload without impairing myocardial contractility in preliminary hemodynamic studies of CHF patients. However, in vitro and in some patients, a negative inotropic effect has been observed. Therefore, caution should be exercised when using Cardene® I.V., particularly in combination with a beta-blocker, in patients with CHF or significant left ventricular dysfunction.

Use In Patients With Pheochromocytoma

Only limited clinical experience exists in use of Cardene® I.V. for patients with hypertension associated with pheochromocytoma. Caution should therefore be exercised when using the drug in these patients.

Peripheral Vein Infusion Site

To minimize the risk of peripheral venous irritation, it is recommended that the site of infusion of Cardene® I.V. be changed every 12 hours.

General

Blood Pressure: Because Cardene® I.V. decreases peripheral resistance, monitoring of blood pressure during administration is required. Cardene® I.V., like other calcium channel blockers, may occasionally produce symptomatic hypotension. Caution is advised to avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage.

Use in Patients with Impaired Hepatic Function: Since nicardipine is metabolized in the liver, the drug should be used with caution in patients with impaired liver function or reduced hepatic blood flow. The use of lower dosages should be considered.

Nicardipine administered intravenously has been reported to increase hepatic venous pressure gradient by 4 mmHg in cirrhotic patients at high doses (5 mg/20 min). Cardene® I.V. should therefore be used with caution in patients with portal hypertension.

Use in Patients with Impaired Renal Function: When Cardene® I.V. was given to mild-to-moderate hypertensive patients with moderate renal impairment, a significantly lower systemic clearance and higher AUC was observed. These results are consistent with those seen after oral administration of nicardipine. Careful dose titration is advised when treating renal impaired patients.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Rats treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of 5, 15, or 45 mg/kg/day) for two years showed a dose-dependent increase in thyroid hyperplasia and neoplasia (follicular adenoma/carcinoma). One- and three-month studies in the rat have suggested that these results are linked to a nicardipine-induced reduction in plasma thyroxine (T4) levels with a consequent increase in plasma levels of thyroid stimulating hormone (TSH). Chronic elevation of TSH is known to cause hyperstimulation of the thyroid. In rats on an iodine deficient diet, nicardipine administration for one month was associated with thyroid hyperplasia that was prevented by T4 supplementation. Mice treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of up to 100 mg/kg/day) for up to 18 months showed no evidence of neoplasia of any tissue and no evidence of thyroid changes. There was no evidence of thyroid pathology in dogs treated with up to 25 mg nicardipine/kg/day for one year and no evidence of effects of nicardipine on thyroid function (plasma T4 and TSH) in man. There was no evidence of a mutagenic potential of nicardipine in a battery of genotoxicity tests conducted on microbial indicator organisms, in micronucleus tests in mice and hamsters, or in a sister chromatid exchange study in hamsters. No impairment of fertility was seen in male or female rats administered nicardipine at oral doses as high as 100 mg/kg/day (50 times the 40 mg TlD maximum recommended dose in man, assuming a patient weight of 60 kg).

Pregnancy Category C: Cardene® I.V. at doses up to 5 mg/kg/day to pregnant rats and up to 0.5 mg/kg/day to pregnant rabbits produced no embryotoxicity or teratogenicity. Embryotoxicity was seen at 10 mg/kg/day in rats and at 1 mg/kg/day in rabbits, but no teratogenicity was observed at these doses. Nicardipine was embryocidal when administered orally to pregnant Japanese White rabbits, during organogenesis, at 150 mg/kg/day (a dose associated with marked body weight gain suppression in the treated doe), but not at 50 mg/kg/day (25 times the maximum recommended dose in man). No adverse effects on the fetus were observed when New Zealand albino rabbits were treated, during organogenesis, with up to 100 mg nicardipine/kg/day (a dose associated with significant mortality in the treated doe). In pregnant rats administered nicardipine orally at up to 100 mg/kg/day (50 times the maximum recommended human dose) there was no evidence of embryolethality or teratogenicity. However, dystocia, reduced birth weights, reduced neonatal survival, and reduced neonatal weight gain were noted. There are no adequate and well-controlled studies in pregnant women. Cardene® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Studies in rats have shown significant concentrations of nicardipine in maternal milk. For this reason, it is recommended that women who wish to breastfeed should not be given this drug.

Pediatric Use

Safety and efficacy in patients under the age of 18 have not been established.

Use In The Elderly

No significant difference has been observed in the antihypertensive effect of Cardene® I.V. in elderly patients (≥65 years) compared with other adult patients in clinical studies.

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