NICARDIPINE HYDROCHLORIDE

Nicardipine hydrochloride capsules for oral administration each contain 20 mg or 30 mg of nicardipine hydrochloride USP. Nicardipine hydrochloride capsules are 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: Nicardipine hydrochloride USP is a greenish-yellow, odorless, crystalline powder that melts at about 169°C. It is freely soluble in chloroform, methanol and glacial acetic acid, sparingly soluble in anhydrous ethanol, slightly soluble in n-butanol, water, 0.01 M potassium dihydrogen phosphate, acetone and dioxane, very slightly soluble in ethyl acetate, and practically insoluble in benzene, ether and hexane. It has a molecular weight of 515.99. Nicardipine hydrochloride capsules are available in hard gelatin capsules containing 20 mg or 30 mg nicardipine hydrochloride USP with magnesium stearate and pregelatinized starch as the inactive ingredients. The 20 mg strength is provided in opaque, light green capsules while the 30 mg strength is provided in capsules with an opaque green cap and opaque light green body. The capsule shells contain gelatin, titanium dioxide, D&C Yellow #10, and FD&C Green #3; the 30 mg capsule shells also contain FD&C Blue #1. The black imprinting ink contains shellac, propylene glycol, ammonia, black iron oxide and potassium hydroxide. Structure

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 ).

Angina The dose should be individually titrated for each patient beginning with 20 mg three times daily. Doses in the range of 20 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 1. Sublingual NTG may be taken as required to abort acute anginal attacks during nicardipine hydrochloride capsules therapy. 2. Prophylactic Nitrate Therapy: Nicardipine hydrochloride capsules may be safely coadministered with short- and long-acting nitrates. 3. Beta-blockers: Nicardipine hydrochloride capsules may be safely coadministered 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 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 to 2 hours after dosing, particularly during initiation of therapy (see PRECAUTIONS: Blood Pressure , INDICATIONS AND USAGE 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 1. Diuretics: Nicardipine hydrochloride capsules may be safely coadministered with thiazide diuretics. 2. Beta-blockers: Nicardipine hydrochloride capsules may be safely coadministered with beta-blockers (see Drug Interactions ). Special Patient Populations Renal Insufficiency Although there is no evidence that nicardipine hydrochloride capsules impair 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 ).

Nicardipine hydrochloride capsules are contraindicated in patients with hypersensitivity to the drug. Because part of the effect of nicardipine hydrochloride capsules is 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.

In multiple-dose US and foreign controlled short-term (up to 3 months) studies 1910 patients received nicardipine hydrochloride capsules 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 capsules. 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 capsules (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 capsules 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 CAPSULES (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 capsules 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 capsules (n=1390) 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 capsules 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 CAPSULES (n=1390) 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 ANI Pharmaceuticals, Inc. at 1-855-204-1431 or 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 capsules. 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 capsules usually do not alter the plasma levels of digoxin; however, serum digoxin levels should be evaluated after concomitant therapy with nicardipine hydrochloride capsules is 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 was not altered.