Nicardipine

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 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 ).

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.

Pharmacokinetics and Metabolism Nicardipine hydrochloride is completely absorbed following oral doses administered as capsules. Plasma levels are detectable as early as 20 minutes following an oral dose and maximal plasma levels are observed within 30 minutes to 2 hours (mean T max = 1 hour). While nicardipine hydrochloride is completely absorbed, it is subject to saturable first pass metabolism and the systemic bioavailability is about 35% following a 30 mg oral dose at steady‑state. When nicardipine hydrochloride was administered 1 hour or 3 hours after a high-fat meal, the mean C max and mean AUC were lower (20% to 30%) than when nicardipine hydrochloride was given to fasting subjects. These decreases in plasma levels observed following a meal may be significant, but the clinical trials establishing the efficacy and safety of nicardipine hydrochloride were done in patients without regard to the timing of meals. Thus, the results of these trials reflect the effects of meal-induced variability. The pharmacokinetics of nicardipine hydrochloride are nonlinear due to saturable hepatic first pass metabolism. Following oral administration, increasing doses result in a disproportionate increase in plasma levels. Steady-state C max values following 20 mg, 30 mg, and 40 mg doses every 8 hours averaged 36 ng/mL, 88 ng/mL, and 133 ng/mL, respectively. Hence, increasing the dose from 20 mg to 30 mg every 8 hours more than doubled C max and increasing the dose from 20 mg to 40 mg every 8 hours increased C max more than threefold. A similar disproportionate increase in AUC with dose was observed. Considerable inter-subject variability in plasma levels was also observed. Post-absorption kinetics of nicardipine hydrochloride are also non-linear, although there is a reproducible terminal plasma half-life that averaged 8.6 hours following 30 mg and 40 mg doses at steady‑state (tid). The terminal half-life represents the elimination of less than 5% of the absorbed drug (measured by plasma concentrations). Elimination over the first 8 hours after dosing is much faster with a half-life of 2 hours to 4 hours. Steady-state plasma levels are achieved after 2 days to 3 days of tid dosing (every 8 hours) and are twofold higher than after a single dose. Nicardipine hydrochloride is highly protein bound (> 95%) in human plasma over a wide concentration range. Nicardipine hydrochloride is metabolized extensively by the hepatic cytochrome P450 enzymes, CYP2C8, 2D6, and 3A4; less than 1% of intact drug is detected in the urine. Following a radioactive oral dose in solution, 60% of the radioactivity was recovered in the urine and 35% in feces. Most of the dose (over 90%) was recovered within 48 hours of dosing. Nicardipine hydrochloride does not induce its own metabolism, however, nicardipine causes inhibition of certain cytochrome P450 enzymes (including CYP3A4, CYP2D6, CYP2C8, and CYP2C19). Inhibition of these enzymes may result in increased plasma levels of certain drugs, including cyclosporine and tacrolimus (see Drug Interactions ). The altered pharmacokinetics may necessitate dosage adjustment of the affected drug or discontinuation of treatment. Nicardipine hydrochloride plasma levels were higher in patients with mild renal impairment (baseline serum creatinine concentration ranged from 1.2 mg/dL to 5.5 mg/dL) than in normal subjects. After 30 mg nicardipine hydrochloride tid at steady-state, C max and AUC were approximately twofold higher in these patients. Because nicardipine hydrochloride is extensively metabolized by the liver, the plasma levels of the drug are influenced by changes in hepatic function. Nicardipine hydrochloride plasma levels were higher in patients with severe liver disease (hepatic cirrhosis confirmed by liver biopsy or presence of endoscopically‑confirmed esophageal varices) than in normal subjects. After 20 mg nicardipine hydrochloride bid at steady-state, C max and AUC were 1.8 and fourfold higher, and the terminal half-life was prolonged to 19 hours in these patients.