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 .

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 . 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 . 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 . 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 . 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 . Congestive Heart Failure Caution is advised when titrating nicardipine hydrochloride capsules dosage in patients with congestive heart failure .

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 . 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.

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 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.

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

0.3Dizziness

6.9

0.6Headache

6.4

2.6Asthenia

5.8

2.6Flushing

5.6

1.0Increased Angina

5.6

4.2Palpitations

3.3

0.0Nausea

1.9

0.3Dyspepsia

1.5

0.6Dry Mouth

1.4

0.3Somnolence

1.4

1.0Rash

1.2

0.3Tachycardia

1.2

0.6Myalgia

1.0

0.0Other Edema

1.0

0.0Paresthesia

1.0

0.3Sustained Tachycardia

0.8

0.0Syncope

0.8

0.0Constipation

0.6

0.6Dyspnea

0.6

0.0Abnormal

ECG 0.6

0.0Malaise

0.6

0.0Nervousness

0.6

0.3Tremor

0.6

0.0In

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

2.8Headache

8.2

4.7Pedal Edema

8.0

0.9Asthenia

4.2

0.5Palpitations

4.1

0.0Dizziness

4.0

0.0Tachycardia

3.4

0.5Nausea

2.2

0.9Somnolence

1.1

0.0Dyspepsia

0.8

0.5Insomnia

0.6

0.0Malaise

0.6

0.0Other Edema

0.6

1.4Abnormal Dreams

0.4

0.0Dry Mouth

0.4

0.0Nocturia

0.4

0.0Rash

0.4

0.0Vomiting

0.4

0.0Rare 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.