Nicardipine Hydrochloride (Page 3 of 5)

WARNINGS

Increased Angina

About 7% of patients in short term placebo-controlled angina trials have developed increased frequency, duration or severity of angina on starting nicardipine or at the time of dosage increases, compared with 4% of patients on placebo. Comparisons with beta-blockers also show a greater frequency of increased angina, 4% vs 1%. The mechanism of this effect has not been established. (See ADVERSE REACTIONS.)

Use in Patients with Congestive Heart Failure

Although preliminary hemodynamic studies in patients with congestive heart failure have shown that nicardipine reduced afterload without impairing myocardial contractility, it has a negative inotropic effect in vitro and in some patients. Caution should be exercised when using the drug in congestive heart failure patients, particularly in combination with a beta-blocker.

Beta-Blocker Withdrawal

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 the dose of beta-blocker, preferably over 8 to 10 days.

PRECAUTIONS

General

Blood Pressure: Because nicardipine decreases peripheral resistance, careful monitoring of blood pressure during the initial administration and titration of nicardipine is suggested. Nicardipine, 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. Because of prominent effects at the time of peak blood levels, initial titration should be performed with measurements of blood pressure at peak effect (1 to 2 hours after dosing) and just before the next dose.

Use in patients with impaired hepatic function: Since the liver is the major site of biotransformation and nicardipine is subject to first pass metabolism, the drug should be used with caution in patients having impaired liver function or reduced hepatic blood flow. Patients with severe liver disease developed elevated blood levels (4-fold increase in AUC) and prolonged half-life (19 hours) of nicardipine. (See DOSAGE AND ADMINISTRATION.)

Use in patients with impaired renal function: When nicardipine hydrochloride capsules 20 mg or 30 mg TID were given to hypertensive patients with mild renal impairment, mean plasma concentrations, AUC, and Cmax were approximately 2-fold higher in renally impaired patients than in healthy controls. Doses in these patients must be adjusted. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)

Drug Interactions

Beta-Blockers

In controlled clinical studies, adrenergic beta-receptor blockers have been frequently administered concomitantly with nicardipine hydrochloride capsules. The combination is well tolerated.

Cimetidine

Cimetidine increases nicardipine plasma levels. Patients receiving the two drugs concomitantly should be carefully monitored.

Digoxin

Some calcium blockers may increase the concentration of digitalis preparations in the blood. Nicardipine usually does not alter the plasma levels of digoxin, however, serum digoxin levels should be evaluated after concomitant therapy with nicardipine hydrochloride is initiated.

Aluminum and Magnesium Hydroxides

Co-administration of an antacid containing 600 mg aluminum hydroxide and 300 mg magnesium hydroxide had no effect on nicardipine absorption.

Fentanyl Anesthesia

Severe hypotension has been reported during fentanyl anesthesia with concomitant use of a beta-blocker and a calcium channel blocker. Even though such interactions were not seen during clinical studies with nicardipine, an increased volume of circulating fluids might be required if such an interaction were to occur.

Cyclosporine

Concomitant administration of nicardipine and cyclosporine results in elevated plasma cyclosporine levels. Plasma concentrations of cyclosporine should therefore be closely monitored, and its dosage reduced accordingly, in patients treated with nicardipine.

When therapeutic concentrations of furosemide, propranolol, dipyridamole, warfarin, quinidine, or naproxen were added to human plasma (in vitro), the plasma protein binding of nicardipine was not altered.

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 TID maximum recommended antianginal or antihypertensive dose in man, assuming a patient weight of 60 kg).

Pregnancy

Pregnancy Category C

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 antianginal or antihypertensive 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. Nicardipine 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 following oral administration. For this reason it is recommended that women who wish to breast-feed should not take this drug.

Pediatric use

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

Geriatric use

Pharmacokinetic parameters did not differ between elderly hypertensive patients (≥65 years) and healthy controls after one week of nicardipine hydrochloride treatment at 20 mg TID. Plasma nicardipine concentrations in elderly hypertensive patients were similar to plasma concentrations in healthy young adult subjects when nicardipine hydrochloride was administered at doses of 10, 20 and 30 mg TID, suggesting that the pharmacokinetics of nicardipine are similar in young and elderly hypertensive patients.

Clinical studies of nicardipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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