Nicardipine

I. Stable Angina Nicardipine hydrochloride capsules are indicated for the management of patients with chronic stable angina (effort-associated angina). Nicardipine hydrochloride capsules may be used alone or in combination with beta-blockers. II. Hypertension Nicardipine hydrochloride capsules are indicated for the treatment of hypertension. Nicardipine hydrochloride capsules may be used alone or in combination with other antihypertensive drugs. In administering nicardipine it is important to be aware of the relatively large peak to trough differences in blood pressure effect (see DOSAGE AND ADMINISTRATION ).

Nicardipine hydrochloride capsules are contraindicated in patients with hypersensitivity to the drug. Because part of the effect of nicardipine hydrochloride capsules are secondary to reduced afterload, the drug is also contraindicated in patients with advanced aortic stenosis. Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance.

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 hydrochloride 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 hydrochloride 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 hydrochloride 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 days to 10 days.

General Blood Pressure Because nicardipine hydrochloride decreases peripheral resistance, careful monitoring of blood pressure during the initial administration and titration of nicardipine hydrochloride is suggested. Nicardipine hydrochloride, 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 hour 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 since nicardipine hydrochloride 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 (fourfold increase in AUC) and prolonged half-life (19 hours) of nicardipine hydrochloride (see DOSAGE AND ADMINISTRATION ). Use in Patients with Impaired Renal Function When nicardipine hydrochloride 20 mg or 30 mg tid was given to hypertensive patients with mild renal impairment, mean plasma concentrations, AUC and C max were approximately twofold 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. The combination is well tolerated. Cimetidine Cimetidine increases nicardipine hydrochloride 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 usually does not alter the plasma levels of digoxin; however, serum digoxin levels should be evaluated after concomitant therapy with nicardipine hydrochloride is initiated. Maalox ® 2 Co-administration of Maalox TC had no effect on nicardipine hydrochloride 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, 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 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 mg/kg/day, 15 mg/kg/day 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 (T 4 ) 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 T 4 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 T 4 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 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 hydrochloride 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 treatment at 20 mg tid. Plasma nicardipine hydrochloride concentrations in elderly hypertensive subjects were similar to plasma concentrations in healthy young adult subjects when nicardipine hydrochloride was administered at doses of 10 mg, 20 mg, and 30 mg tid, suggesting that the pharmacokinetics of nicardipine hydrochloride 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.

In multiple-dose US and foreign controlled short-term (up to 3 months) studies 1,910 patients received nicardipine hydrochloride alone or in combination with other drugs. In these studies adverse events were reported spontaneously; adverse experiences were generally not serious but occasionally required dosage adjustment and about 10% of patients left the studies prematurely because of them. Peak responses were not observed to be associated with adverse effects during clinical trials, but physicians should be aware that adverse effects associated with decreases in blood pressure (tachycardia, hypotension, etc.) could occur around the time of the peak effect. Most adverse effects were expected consequences of the vasodilator effects of nicardipine hydrochloride. Angina The incidence rates of adverse effects in anginal patients were derived from multicenter, controlled clinical trials. Following are the rates of adverse effects for nicardipine hydrochloride (n = 520) and placebo (n = 310), respectively, that occurred in 0.4% of patients or more. These represent events considered probably drug-related by the investigator (except for certain cardiovascular events that were recorded in a different category). Where the frequency of adverse effects for nicardipine hydrochloride and placebo is similar, causal relationship is uncertain. The only dose-related effects were pedal edema and increased angina. Percent of Patients with Adverse Effects in Controlled Studies (Incidence of Discontinuations Shown in Parentheses) Adverse Experience NICARDIPINE HYDROCHLORIDE (n = 520) PLACEBO(n = 310) Pedal Edema 7.1 (0) 0.3 (0) Dizziness 6.9 (1.2) 0.6 (0) Headache 6.4 (0.6) 2.6 (0) Asthenia 5.8 (0.4) 2.6 (0) Flushing 5.6 (0.4) 1.0 (0) Increased Angina 5.6 (3.5) 4.2 (1.9) Palpitations 3.3 (0.4) 0.0 (0) Nausea 1.9 (0) 0.3 (0) Dyspepsia 1.5 (0.6) 0.6 (0.3) Dry Mouth 1.4 (0) 0.3 (0) Somnolence 1.4 (0) 1.0 (0) Rash 1.2 (0.2) 0.3 (0) Tachycardia 1.2 (0.2) 0.6 (0) Myalgia 1.0 (0) 0.0 (0) Other Edema 1.0 (0) 0.0 (0) Paresthesia 1.0 (0.2) 0.3 (0) Sustained Tachycardia 0.8 (0.6) 0.0 (0) Syncope 0.8 (0.2) 0.0 (0) Constipation 0.6 (0.2) 0.6 (0) Dyspnea 0.6 (0) 0.0 (0) Abnormal ECG 0.6 (0.6) 0.0 (0) Malaise 0.6 (0) 0.0 (0) Nervousness 0.6 (0) 0.3 (0) Tremor 0.6 (0) 0.0 (0) In addition, adverse events were observed that are not readily distinguishable from the natural history of the atherosclerotic vascular disease in these patients. Adverse events in this category each occurred in < 0.4% of patients receiving nicardipine hydrochloride and included myocardial infarction, atrial fibrillation, exertional hypotension, pericarditis, heart block, cerebral ischemia, and ventricular tachycardia. It is possible that some of these events were drug-related. Hypertension The incidence rates of adverse effects in hypertensive patients were derived from multicenter, controlled clinical trials. Following are the rates of adverse effects for nicardipine hydrochloride (n = 1,390) and placebo (n = 211), respectively, that occurred in 0.4% of patients or more. These represent events considered probably drug‑related by the investigator. Where the frequency of adverse effects for nicardipine hydrochloride and placebo is similar, causal relationship is uncertain. The only dose-related effect was pedal edema. Percent of Patients with Adverse Effects in Controlled Studies (Incidence of Discontinuations Shown in Parentheses) Adverse Experience NICARDIPINE HYDROCHLORIDE (n = 1,390) PLACEBO(n = 211) Flushing 9.7 (2.1) 2.8 (0) Headache 8.2 (2.6) 4.7 (0) Pedal Edema 8.0 (1.8) 0.9 (0) Asthenia 4.2 (1.7) 0.5 (0) Palpitations 4.1 (1.0) 0.0 (0) Dizziness 4.0 (1.8) 0.0 (0) Tachycardia 3.4 (1.2) 0.5 (0) Nausea 2.2 (0.9) 0.9 (0) Somnolence 1.1 (0.1) 0.0 (0) Dyspepsia 0.8 (0.3) 0.5 (0) Insomnia 0.6 (0.1) 0.0 (0) Malaise 0.6 (0.1) 0.0 (0) Other Edema 0.6 (0.3) 1.4 (0) Abnormal Dreams 0.4 (0) 0.0 (0) Dry Mouth 0.4 (0.1) 0.0 (0) Nocturia 0.4 (0) 0.0 (0) Rash 0.4 (0.4) 0.0 (0) Vomiting 0.4 (0.4) 0.0 (0) Rare Events The following rare adverse events have been reported in clinical trials or the literature: Body as a Whole: infection, allergic reaction Cardiovascular: hypotension, postural hypotension, atypical chest pain, peripheral vascular disorder, ventricular extrasystoles, ventricular tachycardia Digestive: sore throat, abnormal liver chemistries Musculoskeletal: arthralgia Nervous: hot flashes, vertigo, hyperkinesia, impotence, depression, confusion, anxiety Respiratory: rhinitis, sinusitis Special Senses: tinnitus, abnormal vision, blurred vision Urogenital: increased urinary frequency To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Beta-Blockers In controlled clinical studies, adrenergic beta-receptor blockers have been frequently administered concomitantly with nicardipine hydrochloride. The combination is well tolerated. Cimetidine Cimetidine increases nicardipine hydrochloride 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 usually does not alter the plasma levels of digoxin; however, serum digoxin levels should be evaluated after concomitant therapy with nicardipine hydrochloride is initiated. Maalox ® 2 Co-administration of Maalox TC had no effect on nicardipine hydrochloride 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, 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 was not altered.

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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Studies in rats have shown significant concentrations of nicardipine hydrochloride in maternal milk following oral administration. For this reason it is recommended that women who wish to breastfeed should not take this drug.

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

Pharmacokinetic parameters did not differ between elderly hypertensive patients (≥ 65 years) and healthy controls after 1 week of nicardipine hydrochloride treatment at 20 mg tid. Plasma nicardipine hydrochloride concentrations in elderly hypertensive subjects were similar to plasma concentrations in healthy young adult subjects when nicardipine hydrochloride was administered at doses of 10 mg, 20 mg, and 30 mg tid, suggesting that the pharmacokinetics of nicardipine hydrochloride 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.