Renal Dysfunction: Because renal elimination is not an important pathway, bioavailability and pharmacokinetics of SULAR were not significantly different in patients with various degrees of renal impairment. Dosing adjustments in patients with mild to moderate renal impairment are not necessary.

Geriatric: Elderly patients have been found to have 2 to 3 fold higher plasma concentrations (Cmax and AUC) than young subjects. This should be reflected in more cautious dosing (See DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency: In patients with liver cirrhosis given 10 mg SULAR, plasma concentrations of the parent compound were 4 to 5 times higher than those in healthy young subjects. Lower starting and maintenance doses should be used in cirrhotic patients (See DOSAGE AND ADMINISTRATION).

Gender and Race: The effect of gender or race on the pharmacokinetics of nisoldipine has not been investigated.

Disease States: Hypertension does not significantly alter the pharmacokinetics of nisoldipine.

Pharmacodynamics

Hemodynamic Effects

Administration of a single dose of nisoldipine leads to decreased systemic vascular resistance and blood pressure with a transient increase in heart rate. The change in heart rate is greater with immediate release nisoldipine preparations. The effect on blood pressure is directly related to the initial degree of elevation above normal. Chronic administration of nisoldipine results in a sustained decrease in vascular resistance and small increases in stroke index and left ventricular ejection fraction. A study of the immediate release formulation showed no effect of nisoldipine on the renin-angiotensin-aldosterone system or on plasma norepinephrine concentration in normals. Changes in blood pressure in hypertensive patients given SULAR were dose related over the range of 10 - 60 mg/day. Nisoldipine does not appear to have significant negative inotropic activity in intact animals or humans, and did not lead to worsening of clinical heart failure in three small studies of patients with asymptomatic and symptomatic left ventricular dysfunction. There is little information, however, in patients with severe congestive heart failure, and all calcium channel blockers should be used with caution in any patient with heart failure.

Electrophysiologic Effects

Nisoldipine has no clinically important chronotropic effects. Except for mild shortening of sinus cycle, SA conduc- tion time and AH intervals, single oral doses up to 20 mg of immediate release nisoldipine did not significantly change other conduction parameters. Similar electrophysiologic effects were seen with single iv doses, which could be blunted in patients pre-treated with beta-blockers. Dose and plasma level related flattening or inversion of T-waves have been observed in a few small studies. Such reports were concentrated in patients receiving rapidly increased high doses in one study; the phenomenon has not been a cause of safety concern in large clinical trials.

Clinical Studies in Hypertension

The antihypertensive efficacy of SULAR was studied in 5 double-blind, placebo-controlled, randomized studies, in which over 600 patients were treated with SULAR as monotherapy and about 300 with placebo; 4 of the five studies compared 2 or 3 fixed doses while the fifth allowed titration from 10 - 40 mg. Once daily administration of SULAR produced sustained reductions in systolic and diastolic blood pressures over the 24 hour dosing interval in both supine and standing positions. The mean placebo-subtracted reductions in supine systolic and diastolic blood pressure at trough, 24 hours post-dose, in these studies, are shown below. Changes in standing blood pressure were similar:

MEAN SUPINE TROUGH SYSTOLIC AND DIASTOLIC BLOOD PRESSURE CHANGES (mm Hg)

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