Nicardipine

Description

DESCRIPTION Nicardipine hydrochloride capsules for oral administration each contain 20 mg or 30 mg of nicardipine hydrochloride, USP. Nicardipine hydrochloride is a calcium ion influx inhibitor (slow channel blocker or calcium channel blocker). Nicardipine hydrochloride is a dihydropyridine structure with the IUPAC (International Union of Pure and Applied Chemistry) chemical name 2-(benzyl-methyl amino)ethyl methyl 1,4‑dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate monohydrochloride, and it has the following structure: The molecular formula of nicardipine hydrochloride, USP is C 26 H 29 N 3 O 6 . HCl. Nicardipine hydrochloride, USP is a pale greenish yellow, odorless, crystalline powder that melts at about 167°C to 171°C. It is soluble in methanol, sparingly soluble in ethanol, and slightly soluble in acetone, chloroform and water. It has a molecular weight of 515.99 g/mol. Nicardipine hydrochloride capsules are available in hard gelatin capsules containing 20 mg or 30 mg nicardipine hydrochloride, USP with colloidal silicon dioxide, magnesium stearate, and pregelatinized maize starch as the inactive ingredients. The 20 mg strength is provided in blue opaque capsules, while the 30 mg capsules have light blue opaque cap and white opaque body. The capsule shell contains FD&C blue no. 1, FD&C red no. 3, D&C yellow no. 10, gelatin, and titanium dioxide. The capsules are printed with black ink composed of ammonia solution, black iron oxide, potassium hydroxide, propylene glycol, and shellac. chem structure

What Is Nicardipine Used For?

INDICATIONS AND USAGE 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 ).

Dosage and Administration

DOSAGE AND ADMINISTRATION Angina The dose should be individually titrated for each patient beginning with 20 mg three times daily. Doses in the range of 20 mg to 40 mg three times a day have been shown to be effective. At least 3 days should be allowed before increasing the nicardipine hydrochloride capsules dose to ensure achievement of steady-state plasma drug concentrations. Concomitant Use with Other Antianginal Agents Sublingual NTG may be taken as required to abort acute anginal attacks during nicardipine hydrochloride capsules therapy. Prophylactic Nitrate Therapy: Nicardipine hydrochloride capsules may be safely co‑administered with short- and long-acting nitrates. Beta-blockers: Nicardipine hydrochloride capsules may be safely co-administered with beta-blockers (see Drug Interactions ). Hypertension The dose of nicardipine hydrochloride capsules should be individually adjusted according to the blood pressure response beginning with 20 mg three times daily. The effective doses in clinical trials have ranged from 20 mg to 40 mg three times daily. The maximum blood pressure lowering effect occurs approximately 1 hour to 2 hours after dosing. To assess the adequacy of blood pressure response, the blood pressure should be measured at trough (8 hours after dosing). Because of the prominent peak effects of nicardipine, blood pressure should be measured 1 hour to 2 hours after dosing, particularly during initiation of therapy (see PRECAUTIONS: Blood Pressure , INDICATIONS and CLINICAL PHARMACOLOGY: Effects in Hypertension ). At least 3 days should be allowed before increasing the nicardipine hydrochloride capsules dose to ensure achievement of steady-state plasma drug concentrations. Concomitant Use with Other Antihypertensive Agents Diuretics: Nicardipine hydrochloride capsules may be safely co‑administered with thiazide diuretics. Beta-blockers: Nicardipine hydrochloride capsules may be safely co-administered with beta-blockers (see Drug Interactions ). Special Patient Populations Renal Insufficiency Although there is no evidence that nicardipine hydrochloride capsules impairs renal function, careful dose titration beginning with 20 mg tid is advised (see PRECAUTIONS ). Hepatic Insufficiency Nicardipine hydrochloride capsules should be administered cautiously in patients with severely impaired hepatic function. A suggested starting dose of 20 mg twice a day is advised with individual titration based on clinical findings maintaining the twice a day schedule (see PRECAUTIONS ). Congestive Heart Failure Caution is advised when titrating nicardipine hydrochloride capsules dosage in patients with congestive heart failure (see WARNINGS ).

Side Effects (Adverse Reactions)

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)...

Drug Interactions

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.

Contraindications

CONTRAINDICATIONS 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.

Pregnancy and Breastfeeding

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.

Overdosage

OVERDOSAGE Overdosage with a 600-mg single dose (15 times to 30 times normal clinical dose) has been reported. Marked hypotension (blood pressure unobtainable) and bradycardia (heart rate 20 bpm in normal sinus rhythm) occurred, along with drowsiness, confusion and slurred speech. Supportive treatment with a vasopressor resulted in gradual improvement with normal vital signs approximately 9 hours posttreatment. Based on results obtained in laboratory animals, overdosage may cause systemic hypotension, bradycardia (following initial tachycardia) and progressive atrioventricular conduction block. Reversible hepatic function abnormalities and sporadic focal hepatic necrosis were noted in some animal species receiving very large doses of nicardipine. For treatment of overdose standard measures (for example, evacuation of gastric contents, elevation of extremities, attention to circulating fluid volume, and urine output) including monitoring of cardiac and respiratory functions should be implemented. The patient should be positioned so as to avoid cerebral anoxia. Frequent blood pressure determinations are essential. Vasopressors are clinically indicated for patients exhibiting profound hypotension. Intravenous calcium gluconate may help reverse the effects of calcium entry blockade.

How Supplied

HOW SUPPLIED Nicardipine hydrochloride capsules,20 mg are available in blue opaque cap imprinted with “ NP ” over “20mg” in black lettering and blue opaque body imprinted with “ NP ” over “20mg” in black lettering, size “ 3 ” hard gelatin capsules filled with pale greenish yellow powder. These are supplied in bottles of 90 (NDC 69238-2691-1). Nicardipine hydrochloridecapsules, 30 mg are available in light blue opaque cap imprinted with “ NP ” over “30mg” in black lettering and white opaque body imprinted with “ NP ” over “30mg” in black lettering, size “ 2 ” hard gelatin capsules filled with pale greenish yellow powder. These are supplied in bottles of 90 (NDC 69238-2692-1) Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Dispense in light-resistant containers. 2. Maalox is a registered trademark of Novartis. Manufactured by: Ritsa Pharma Private Limited Hyderabad, Telangana 500078, India (IND) Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 08-2024-00