Nisoldipine

SULAR is indicated for the treatment of hypertension. It may be used alone or in combination with other anti-hypertensive agents.

Nisoldipine is a member of the dihydropyridine class of calcium channel antagonists (calcium ion antagonists or slow channel blockers) that inhibit the transmembrane influx of calcium into vascular smooth muscle and cardiac muscle. It reversibly competes with other dihydropyridines for binding to the calcium channel. Because the contractile process of vascular smooth muscle is dependent upon the movement of extracellular calcium into the muscle through specific ion channels, inhibition of the calcium channel results in dilation of the arterioles. In vitro studies show that the effects of nisoldipine on contractile processes are selective, with greater potency on vascular smooth muscle than on cardiac muscle.

The dosage of SULAR must be adjusted to each patient's needs. Therapy usually should be initiated with 17 mg orally once daily, then increased by 8.5 mg per week or longer intervals, to attain adequate control of blood pressure. Usual maintenance dosage is 17 to 34 mg once daily. Blood pressure response increases over the 8.5 - 34 mg daily dose range but adverse event rates also increase. Doses beyond 34 mg once daily are not recommended. SULAR has been used safely with diuretics, ACE inhibitors, and beta-blocking agents. Patients over age 65, or patients with impaired liver function, are expected to develop higher plasma concentrations of nisoldipine. Their blood pressure should be monitored closely during any dosage adjustment. A starting dose not exceeding 8.5 mg daily is recommended in these patient groups. SULAR tablets should be administered orally once daily.

SULAR is contraindicated in patients with known hypersensitivity to dihydropyridine calcium channel blockers.

Increased angina and/or myocardial infarction in patients with coronary artery disease: Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed increased frequency, duration and/or severity of angina, or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been established. In controlled studies of SULAR in patients with angina this was seen about 1.5% of the time in patients given nisoldipine, compared with 0.9% in patients given placebo.

ADVERSE EXPERIENCES More than 6000 patients world-wide have received nisoldipine in clinical trials for the treatment of hypertension, either as the immediate release or the SULAR extended release formulation. Of about 1,500 patients who received SULAR in hypertension studies, about 55% were exposed for at least 2 months and about one third were exposed for over 6 months, the great majority at doses equivalent to 17 mg and above. SULAR is generally well-tolerated. In the U.S. clinical trials of SULAR in hypertension, 10.9% of the 921 SULAR patients discontinued treatment due to adverse events compared with 2.9% of 280 placebo patients. The frequency of discontinuations due to adverse experiences was related to dose, with a 5.4% and 10.9% discontinuation rate at the lowest and highest daily dose, respectively.

A 30 to 45% increase in AUC and C max of nisoldipine was observed with concomitant administration of cimetidine 400 mg twice daily. Ranitidine 150 mg twice daily did not interact significantly with nisoldipine (AUC was decreased by 15 - 20%). No pharmacodynamic effects of either histamine H 2 receptor antagonist were observed. CYP3A4 inhibitors and inducers: SULAR is substrate of CYP3A4 and coadministration of SULAR with any known inducer or inhibitor of CYP3A4 should be avoided in general. Coadministration of phenytoin with a dose bioequivalent to 34 mg SULAR tablets in epileptic patients lowered the nisoldipine plasma concentrations to undetectable levels. Coadministration of SULAR with phenytoin should be avoided and alternative antihypertensive therapy should be considered.

Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F).