Nicardipine

ADVERSE REACTIONS 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.

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.