NICARDIPINE Drug Interactions: What You Need to Know

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 hydrochloride capsules 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 hydrochloride capsules usually do not alter the plasma levels of digoxin; however, serum digoxin levels should be evaluated after concomitant therapy with nicardipine hydrochloride capsules are initiated. Maalox® Coadministration of Maalox TC had no effect on nicardipine hydrochloride capsules 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 hydrochloride capsules, an increased volume of circulating fluids might be required if such an interaction were to occur.

Cyclosporine

Concomitant administration of oral or intravenous nicardipine and cyclosporine results in elevated plasma cyclosporine levels through nicardipine inhibition of hepatic microsomal enzymes, including CYP3A4. Plasma concentrations of cyclosporine should therefore be closely monitored, and its dosage reduced accordingly, in patients treated with nicardipine. Tacrolimus: Concomitant administration of oral or intravenous nicardipine and tacrolimus may result in elevated plasma tacrolimus levels through nicardipine inhibition of hepatic microsomal enzymes, including CYP3A4. Closely monitor plasma concentrations of tacrolimus during nicardipine administration, and adjust the dose of tacrolimus accordingly. When therapeutic concentrations of furosemide, propranolol, dipyridamole, warfarin, quinidine or naproxen were added to human plasma (in vitro), the plasma protein binding of nicardipine hydrochloride capsules were 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 2 years showed a dose-dependent increase in thyroid hyperplasia and neoplasia (follicular adenoma/carcinoma). One- and 3 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 1 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 1 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

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 hydrochloride capsules 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 breastfeed 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 1 week of nicardipine hydrochloride capsules treatment at 20 mg tid. Plasma nicardipine hydrochloride capsules concentrations in elderly hypertensive subjects were similar to plasma concentrations in healthy young adult subjects when nicardipine hydrochloride capsules were administered at doses of 10, 20, and 30 mg tid, suggesting that the pharmacokinetics of nicardipine hydrochloride capsules 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.

4 CONTRAINDICATIONS

• Do not use in patients with advanced aortic stenosis (4.1).

4.1 Advanced Aortic Stenosis Nicardipine hydrochloride in sodium chloride injection is contraindicated in patients with advanced aortic stenosis because part of the effect of Nicardipine hydrochloride in sodium chloride injection is secondary to reduced afterload. Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance.

WARNINGS AND PRECAUTIONS To reduce the possibility of venous thrombosis, phlebitis, and vascular impairment, do not use small veins, such as those on the dorsum of the hand or wrist. Avoid intraarterial administration or extravasation ( 5.7 ). To minimize the risk of peripheral venous irritation, change the site of infusion of nicardipine every 12 hours ( 5.7 ). Nicardipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal. Withdraw beta-blockers gradually ( 5.8 ). Closely monitor response in patients with angina ( 5.3 ), congestive heart failure ( 5.4 ), impaired hepatic function ( 5.5 ), portal hypertension ( 5.5 ), and renal impairment ( 5.6 ) and pheochromocytoma ( 5.9 ).

5 WARNINGS AND PRECAUTIONS

5.1 Excessive Pharmacologic Effects In administrating nicardipine, close monitoring of blood pressure and heart rate is required. Nicardipine may occasionally produce symptomatic hypotension or tachycardia. Avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage.

5.2 Rapid Decreases in Blood Pressure No clinical events have been reported suggestive of a too rapid decrease in blood pressure with nicardipine. 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.

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

5.4 Use in Patients with Congestive Heart Failure Nicardipine 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, monitor vital signs carefully when using nicardipine, particularly in combination with a beta-blocker, in patients with CHF or significant left ventricular dysfunction.

5.5 Use in Patients with Impaired Hepatic Function Since nicardipine is metabolized in the liver, consider lower dosages and closely monitor response. Nicardipine administered intravenously increased hepatic venous pressure gradient by 4 mmHg in cirrhotic patients at high doses (5 mg/20 min) in one study. Use caution in patients with portal hypertension.

5.6 Use in Patients with Impaired Renal Function When nicardipine 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 patients with more than mild renal impairment.

5.7 Intravenous Infusion Site To reduce the possibility of venous thrombosis, phlebitis, local irritation, swelling, extravasation, and the rare occurrence of vascular impairment, administer drug through large peripheral veins or central veins rather than arteries or small peripheral veins, such as those on the dorsum of the hand or wrist. To minimize the risk of peripheral venous irritation, consider changing the site of the drug infusion every 12 hours.

5.8 Beta-Blocker Withdrawal Nicardipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal. Withdraw beta-blockers gradually.

5.9 Use in Patients with Pheochromocytoma Only limited clinical experience exists in use of nicardipine for patients with hypertension from pheochromocytoma.