Cardene SR (Page 2 of 4)

Electrophysiologic Effects

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

Nicardipine 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* and the functional and effective refractory periods of the atrium were not prolonged by nicardipine and the relative and effective refractory periods of the His-Purkinje system were slightly shortened after intravenous nicardipine.

Renal Function

There is a transient increase in electrolyte excretion, including sodium. CARDENE does not cause generalized fluid retention, as measured by weight changes.

*PA=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.

Effects in Hypertension

CARDENE SR produced decreases in both systolic and diastolic blood pressure throughout the dosing interval in clinical trials. The antihypertensive efficacy of CARDENE SR administered twice daily has been demonstrated using in-clinic blood pressure measures in placebo-controlled trials involving patients with mild to moderate hypertension and in trials using 12 or 24 hour ambulatory blood pressure monitoring.

INDICATIONS AND USAGE

CARDENE SR is indicated for the treatment of hypertension. CARDENE SR may be used alone or in combination with other anti-hypertensive drugs.

CONTRAINDICATIONS

CARDENE is contraindicated in patients with hypersensitivity to the drug.

Because part of the effect of CARDENE is secondary to reduced afterload, the drug is also contraindicated in patients with advanced aortic stenosis. Reduction of diastolic pressure by any means in these patients may worsen rather than improve myocardial oxygen balance.

WARNINGS

Increased Angina in Patients With Angina

In short-term, placebo-controlled angina trials with CARDENE (an immediate release oral dosage form of nicardipine), about 7% of patients on CARDENE (compared with 4% of patients on placebo) have developed increased frequency, duration or severity of angina. 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 CARDENE 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

CARDENE 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 to 10 days.

PRECAUTIONS

General

Because CARDENE decreases peripheral resistance, careful monitoring of blood pressure during the initial administration and titration of CARDENE is suggested. CARDENE, 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. Blood Pressure:

Since the liver is the major site of biotransformation and since CARDENE is subject to first-pass metabolism, CARDENE 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 CARDENE. Use in Patients With Impaired Hepatic Function:

When 45-mg CARDENE SR bid was given to hypertensive patients with moderate renal impairment, mean AUC and C values were approximately 2-fold to 3-fold higher than in patients with mild renal impairment. Doses in these patients must be adjusted. Mean AUC and C values were similar in patients with mildly impaired renal function and normal volunteers (see and ). Use in Patients With Impaired Renal Function: max max CLINICAL PHARMACOLOGYDOSAGE AND ADMINISTRATION

Drug Interactions

In controlled clinical studies, adrenergic beta-receptor blockers have been frequently administered concomitantly with CARDENE. The combination is well tolerated. Beta-Blockers:

Cimetidine increases CARDENE plasma levels. Patients receiving the two drugs concomitantly should be carefully monitored. Cimetidine:

Some calcium blockers may increase the concentration of digitalis preparations in the blood. CARDENE usually does not alter the plasma levels of digoxin; however, serum digoxin levels should be evaluated after concomitant therapy with CARDENE is initiated. Digoxin:

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 CARDENE, an increased volume of circulating fluids might be required if such an interaction were to occur. Fentanyl Anesthesia:

Concomitant administration of nicardipine and cyclosporine results in elevated plasma cyclosporine levels. Plasma concentrations of cyclosporine should therefore be closely monitored, and its dosage reduced accordingly, in patients treated with nicardipine. Cyclosporine:

When therapeutic concentrations of furosemide, propranolol, dipyridamole, warfarin, quinidine or naproxen were added to human plasma (in vitro), the plasma protein binding of CARDENE was not altered.

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 maximum recommended daily dose in man, assuming a patient weight of 60 kg).

Pregnancy

Pregnancy Category C. 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 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. CARDENE SR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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