Following oral administration of single doses of 10-40 mg, MONOPRIL lowered blood pressure within one hour, with peak reductions achieved 2-6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. Following four weeks of monotherapy in placebo-controlled trials in patients with mild-to-moderate hypertension, once-daily doses of 20-80 mg lowered supine or seated systolic and diastolic blood pressures 24 hours after dosing by an average of 8-9/6-7 mmHg more than placebo. The trough effect was about 50-60% of the peak diastolic response and about 80% of the peak systolic response.

In most trials, the antihypertensive effect of MONOPRIL increased during the first several weeks of repeated measurements. The antihypertensive effect of MONOPRIL has been shown to continue during long-term therapy for at least 2 years. Abrupt withdrawal of MONOPRIL has not resulted in a rapid increase in blood pressure.

Limited experience in controlled and uncontrolled trials combining fosinopril with a calcium channel blocker or a loop diuretic has indicated no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system.

ACE inhibitors are generally less effective in blacks than in non-blacks. The effectiveness of MONOPRIL was not influenced by age, sex, or weight.

In hemodynamic studies in hypertensive patients, after three months of therapy, responses (changes in B P, heart rate, cardiac index, and PVR) to various stimuli (e.g., isometric exercise, 45° head-up tilt, and mental challenge) were unchanged compared to baseline, suggesting that MONOPRIL does not affect the activity of the sympathetic nervous system. Reduction in systemic blood pressure appears to have been mediated by a decrease in peripheral vascular resistance without reflex cardiac effects. Similarly, renal, splanchnic, cerebral, and skeletal muscle blood flow were unchanged compared to baseline, as was glomerular filtration rate.

Pediatric

Reduction of blood pressure with low (0.1 mg/kg), medium (0.3 mg/kg) and high (0.6 mg/kg) target doses of once-daily fosinopril was evaluated in a randomized, double-blind study of 252 pediatric patients 6 to 16 years of age with hypertension or high-normal blood pressure. Fosinopril doses in the medium and high dose groups were titrated to target doses after one week and the total duration of treatment was four weeks. The maximum dose studied was 40 mg once daily. At the end of four weeks ot treatment, the mean reductions from baseline in trough systolic blood pressure were similar in all three dose groups. Withdrawal of fosinopril treatment resulted in an increase in blood pressure towards baseline over a two week period. Fosinopril was generally well tolerated.

Heart Failure

In a randomized, double-blind, placebo-controlled trial, 179 patients with heart failure, all receiving diuretics and some receiving digoxin, were administered single doses of 1, 20, or 40 mg of MONOPRIL or placebo. Doses of 20 and 40 mg of MONOPRIL resulted in acute decreases in pulmonary capillary wedge pressure (pre- load) and mean arterial blood pressure and systemic vascular resistance (afterload). One hundred fifty-five of these patients were re-randomized to once-daily therapy with MONOPRIL (1, 20, or 40 mg) for an additional 10 weeks. Hemodynamic measurements made 24 hours after dosing showed (relative to baseline) continued reduction in pulmonary capillary wedge pressure, mean arterial blood pressure, right atrial pressure and an increase in cardiac index and stroke volume for the 20 and 40 mg dose groups. No tachyphylaxis was seen.

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