Label: NICARDIPINE HYDROCHLORIDE capsule

Mechanism of Action

Nicardipine hydrochloride capsules are a calcium entry blocker (slow channel blocker or calcium ion antagonist) that inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle without changing serum calcium concentrations. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. The effects of nicardipine hydrochloride capsules are more selective to vascular smooth muscle than cardiac muscle. In animal models, Nicardipine hydrochloride capsules produce relaxation of coronary vascular smooth muscle at drug levels that cause little or no negative inotropic effect.

Pharmacokinetics and Metabolism

Nicardipine hydrochloride capsules are 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 capsules are 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 capsules were administered 1 or 3 hours after a high-fat meal, the mean C max and mean AUC were lower (20% to 30%) than when nicardipine hydrochloride capsules were 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 capsules 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 capsules 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-, 30-, and 40-mg doses every 8 hours averaged 36, 88, and 133 ng/mL, respectively. Hence, increasing the dose from 20 to 30 mg every 8 hours more than doubled C max and increasing the dose from 20 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 capsules are also non-linear, although there is a reproducible terminal plasma half-life that averaged 8.6 hours following 30- 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 to 4 hours. Steady-state plasma levels are achieved after 2 to 3 days of tid dosing (every 8 hours) and are twofold higher than after a single dose.

Nicardipine hydrochloride capsules are highly protein bound (>95%) in human plasma over a wide concentration range.

Nicardipine hydrochloride capsules are 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 capsules do 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 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 capsules are 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 capsules 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.

Geriatric Pharmacokinetics

The steady-state pharmacokinetics of nicardipine hydrochloride capsules in elderly hypertensive patients (≥65 years) are similar to those obtained in young normal adults. After 1 week of nicardipine hydrochloride capsules dosing at 20 mg three times a day, the C max, T max, AUC, terminal plasma half-life and the extent of protein binding of nicardipine hydrochloride capsules observed in healthy elderly hypertensive patients did not differ significantly from those observed in young normal volunteers

Hemodynamics

In man, nicardipine hydrochloride capsules produce a significant decrease in systemic vascular resistance. The degree of vasodilation and the resultant hypotensive effects are more prominent in hypertensive patients. In hypertensive patients, nicardipine reduces the blood pressure at rest and during isometric and dynamic exercise. In normotensive patients, a small decrease of about 9 mm Hg in systolic and 7 mm Hg in diastolic blood pressure may accompany this fall in peripheral resistance. An increase in heart rate may occur in response to the vasodilation and decrease in blood pressure, and in a few patients this heart rate increase may be pronounced. In clinical studies mean heart rate at time of peak plasma levels was usually increased by 5 to 10 beats per minute compared to placebo, with the greater increases at higher doses, while there was no difference from placebo at the end of the dosing interval. Hemodynamic studies following intravenous dosing in patients with coronary artery disease and normal or moderately abnormal left ventricular function have shown significant increases in ejection fraction and cardiac output with no significant change, or a small decrease, in left ventricular end-diastolic pressure (LVEDP). Although there is evidence that nicardipine hydrochloride capsules increase coronary blood flow, there is no evidence that this property plays any role in its effectiveness in stable angina. In patients with coronary artery disease, intracoronary administration of nicardipine caused no direct myocardial depression. Nicardipine hydrochloride capsules do, however, have a negative inotropic effect in some patients with severe left ventricular dysfunction and could, in patients with very impaired function, lead to worsened failure.

“Coronary Steal”, the detrimental redistribution of coronary blood flow in patients with coronary artery disease (diversion of blood from underperfused areas toward better perfused areas), has not been observed during nicardipine treatment. On the contrary, nicardipine has been shown to improve systolic shortening in normal and hypokinetic segments of myocardial muscle, and radio-nuclide angiography has confirmed that wall motion remained improved during an increase in oxygen demand. Nonetheless, occasional patients have developed increased angina upon receiving nicardipine. Whether this represents steal in those patients, or is the result of increased heart rate and decreased diastolic pressure, is not clear.

In patients with coronary artery disease nicardipine improves L.V. diastolic distensibility during the early filling phase, probably due to a faster rate of myocardial relaxation in previously underperfused areas. There is little or no effect on normal myocardium, suggesting the improvement is mainly by indirect mechanisms such as afterload reduction, and reduced ischemia. Nicardipine has no negative effect on myocardial relaxation at therapeutic doses. The clinical consequences of these properties are as yet undemonstrated.

Electrophysiologic Effects

In general, no detrimental effects on the cardiac conduction system were seen with the use of nicardipine hydrochloride capsules.

Nicardipine hydrochloride increased the heart rate when given intravenously during acute electrophysiologic studies and prolonged the corrected QT interval to a minor degree. The sinus node recovery times and SA conduction times were not affected by the drug. The PA, AH, and HV intervals 1 and the functional and effective refractory periods of the atrium were not prolonged by nicardipine hydrochloride capsules and the relative and effective refractory periods of the His-Purkinje system were slightly shortened after intravenous nicardipine hydrochloride.

1PA = conduction time from high to low right atrium, AH = conduction time from low right atrium to His bundle deflection or AV nodal conduction time, HV = conduction time through the His bundle and the bundle branch-Purkinje system.

Renal Function

There is a transient increase in electrolyte excretion, including sodium. Nicardipine hydrochloride capsules do not cause generalized fluid retention, as measured by weight changes, although 7% to 8% of the patients experience pedal edema.

Effects in Angina Pectoris

In controlled clinical trials of up to 12 weeks’ duration in patients with chronic stable angina, nicardipine hydrochloride capsules increased exercise tolerance and reduced nitroglycerin consumption and the frequency of anginal attacks. The antianginal efficacy of nicardipine hydrochloride capsules (20 to 40 mg) have been demonstrated in four placebo-controlled studies involving 258 patients with chronic stable angina. In exercise tolerance testing, nicardipine hydrochloride capsules significantly increased time to angina, total exercise duration and time to 1 mm ST segment depression. Included among these four studies was a dose-definition study in which dose-related improvements in exercise tolerance at 1 and 4 hours postdosing and reduced frequency of anginal attacks were seen at doses of 10, 20 and 30 mg tid. Effectiveness at 10 mg tid was, however, marginal. In a fifth placebo-controlled study, the antianginal efficacy of nicardipine hydrochloride capsules were demonstrated at 8 hours postdose (trough). The sustained efficacy of nicardipine hydrochloride capsules have been demonstrated over long-term dosing. Blood pressure fell in patients with angina by about 10/8 mm Hg at peak blood levels and was little different from placebo at trough blood levels.

Effects in Hypertension

Nicardipine hydrochloride capsules produced dose-related decreases in both systolic and diastolic blood pressure in clinical trials. The antihypertensive efficacy of nicardipine hydrochloride capsules administered three times daily has been demonstrated in three placebo-controlled studies involving 517 patients with mild to moderate hypertension. The blood pressure responses in the three studies were statistically significant from placebo at peak (1 hour postdosing) and trough (8 hours postdosing) although it is apparent that well over half of the antihypertensive effect is lost by the end of the dosing interval. The results from placebo controlled studies of nicardipine hydrochloride capsules given three times daily are shown in the following table:

The responses are shown as differences from the concurrent placebo control group. The large changes between peak and trough effects were not accompanied by observed side effects at peak response times. In a study using 24-hour intra-arterial blood pressure monitoring, the circadian variation in blood pressure remained unaltered, but the systolic and diastolic blood pressures were reduced throughout the whole 24 hours.

When added to beta-blocker therapy, nicardipine hydrochloride capsules further lower both systolic and diastolic blood pressure.

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 hydrochloride it is important to be aware of the relatively large peak to trough differences in blood pressure effect (See DOSAGE AND ADMINISTRATION).

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 capsules 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 (see ADVERSE REACTIONS).

Use in Patients With Congestive Heart Failure

Although preliminary hemodynamic studies in patients with congestive heart failure have shown that nicardipine hydrochloride capsules 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 capsules are 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 to 10 days.

General

Blood Pressure

Because nicardipine hydrochloride capsules decrease peripheral resistance, careful monitoring of blood pressure during the initial administration and titration of nicardipine hydrochloride capsules are suggested. Nicardipine hydrochloride capsules like other calcium channel blockers, may occasionally produce symptomatic hypotension. Caution is advised to avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage. Because of prominent effects at the time of peak blood levels, initial titration should be performed with measurements of blood pressure at peak effect (1 to 2 hours after dosing) and just before the next dose.

Use in Patients With Impaired Hepatic Function: Since the liver is the major site of biotransformation and since nicardipine hydrochloride capsules are subject to first pass metabolism, the drug should be used with caution in patients having impaired liver function or reduced hepatic blood flow. Patients with severe liver disease developed elevated blood levels (fourfold increase in AUC) and prolonged half-life (19 hours) of nicardipine (see DOSAGE AND ADMINISTRATION).

Use in Patients With Impaired Renal Function: When nicardipine hydrochloride capsules 20 mg or 30 mg tid was given to hypertensive patients with mild renal impairment, mean plasma concentrations, AUC and C max were approximately twofold higher in renally impaired patients than in healthy controls. Doses in these patients must be adjusted (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Drug Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Rats treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of 5, 15 or 45 mg/kg/day) for 2 years showed a dose-dependent increase in thyroid hyperplasia and neoplasia (follicular adenoma/carcinoma). One- and 3 month studies in the rat have suggested that these results are linked to a nicardipine-induced reduction in plasma thyroxine (T4) levels with a consequent increase in plasma levels of thyroid stimulating hormone (TSH). Chronic elevation of TSH is known to cause hyperstimulation of the thyroid. In rats on an iodine deficient diet, nicardipine administration for 1 month was associated with thyroid hyperplasia that was prevented by T4 supplementation. Mice treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of up to 100 mg/kg/day) for up to 18 months showed no evidence of neoplasia of any tissue and no evidence of thyroid changes. There was no evidence of thyroid pathology in dogs treated with up to 25 mg nicardipine/kg/day for 1 year and no evidence of effects of nicardipine on thyroid function (plasma T4 and TSH) in man.

There was no evidence of a mutagenic potential of nicardipine in a battery of genotoxicity tests conducted on microbial indicator organisms, in micronucleus tests in mice and hamsters, or in a sister chromatid exchange study in hamsters.

No impairment of fertility was seen in male or female rats administered nicardipine at oral doses as high as 100 mg/kg/day (50 times the 40 mg tid maximum recommended antianginal or antihypertensive dose in man, assuming a patient weight of 60 kg).

Pregnancy

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.

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.

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

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

• 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 coadministered with short- and long-acting nitrates.
• 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, 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 safety coadministered with thiazide diuretics.

2. Beta-blockers: nicardipine hydrochloride capsules may be safely coadministered with beta-blocker (see PRECAUTIONS, Drug Interactions).

Special Patient Population