Fosinopril clinical studies

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Amr Marawan, M.D. [2], Ahmed Zaghw, M.D. [3]

Fosinopril

• Fosinopril sodium tablet

Fosinopril and Hydrochlorothiazide

• Fosinopril sodium and Hydrochlorothiazide tablet

Overview

Captopril tablet is an angiontensin converting enzyme inhibitor drug that is FDA approved for the treatment of hypertension, heart failure, left ventricular dysfunction after myocardial infarction, diabetic nephropathy. Adverse reactions include hypotension, rash, hyperkalemia, disorder of taste, cough. hypotension, rash, hyperkalemia, disorder of taste, cough.

Category

Antihypertensive Agents, Angiotensin Converting Enzyme Inhibitors. Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]; Associate Editor(s)-in-Chief: Amr Marawan, M.D. [5]

Clinical Studies and Clinical effect

Adult

Administration of fosinopril to patients with mild-to-moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt-and/or volume-depleted. Use of fosinopril in combination with thiazide diuretics gives a blood pressure-lowering effect greater than that seen with either agent alone.

Following oral administration of single doses of 10 to 40 mg, fosinopril sodium lowered blood pressure within one hour, with peak reductions achieved 2 to 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 to 80 mg lowered supine or seated systolic and diastolic blood pressures 24 hours after dosing by an average of 8 to 9/6 to 7 mmHg more than placebo. The trough effect was about 50 to 60% of the peak diastolic response and about 80% of the peak systolic response.

In most trials, the antihypertensive effect of fosinopril increased during the first several weeks of repeated measurements. The antihypertensive effect of fosinopril has been shown to continue during long-term therapy for at least 2 years. Abrupt withdrawal of fosinopril 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 fosinopril was not influenced by age, sex, or weight.

In hemodynamic studies in hypertensive patients, after three months of therapy, responses (changes in BP, 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 fosinopril 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 1 week and the total duration of treatment was 4 weeks. The maximum dose studied was 40 mg once daily. At the end of 4 weeks of 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 2-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 fosinopril sodium or placebo. Doses of 20 and 40 mg of fosinopril sodium resulted in acute decreases in pulmonary capillary wedge pressure (preload) 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 fosinopril sodium (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.

Fosinopril was studied in 3 double-blind, placebo-controlled, 12 to 24 week trials including a total of 734 patients with heart failure, with fosinopril sodium doses from 10 to 40 mg daily. Concomitant therapy in 2 of these 3 trials included diuretics and digitalis; in the third trial patients were receiving only diuretics. All 3 trials showed statistically significant benefits of fosinopril therapy, compared to placebo, in one or more of the following: exercise tolerance (one study), symptoms of dyspnea, orthopnea and paroxysmal nocturnal dyspnea (2 studies), NYHA classification (2 studies), hospitalization for heart failure (2 studies), study withdrawals for worsening heart failure (2 studies), and/or need for supplemental diuretics (2 studies). Favorable effects were maintained for up to two years. Effects of fosinopril on long-term mortality in heart failure have not been evaluated. The once-daily dosage for the treatment of congestive heart failure was the only dosage regimen used during clinical trial development and was determined by the measurement of hemodynamic responses.

References

Adapted from the FDA Package Insert.