Metabolism and Excretion: Moexipril is relatively rapidly converted to its active metabolite moexiprilat, but persists longer than some other ACE inhibitor prodrugs, such that its t_½ is over one hour and it has a significant AUC. Both moexipril and moexiprilat are converted to diketopiperazine derivatives and unidentified metabolites. After I.V. administration of moexipril, about 40% of the dose appears in urine as moexiprilat, about 26% as moexipril, with small amounts of the metabolites; about 20% of the I.V. dose appears in feces, principally as moexiprilat. After oral administration, only about 7% of the dose appears in urine as moexiprilat, about 1% as moexipril, with about 5% as other metabolites. Fifty-two percent of the dose is recovered in feces as moexiprilat and 1% as moexipril.

Special Populations

Decreased Renal Function: The effective elimination t_½ and AUC of both moexipril and moexiprilat are increased with decreasing renal function. There is insufficient information available to characterize this relationship fully, but at creatinine clearances in the range of 10 to 40 mL/min, the t_½ of moexiprilat is increased by a factor of 3 to 4.

Decreased Hepatic Function: In patients with mild to moderate cirrhosis given single 15 mg doses of moexipril, the Cmax of moexipril was increased by about 50% and the AUC increased by about 120%, while the Cmax for moexiprilat was decreased by about 50% and the AUC increased by almost 300%.

Elderly Patients: In elderly male subjects (65-80 years old) with clinically normal renal and hepatic function, the AUC and Cmax of moexiprilat is about 30% greater than those of younger subjects (19-42 years old).

Pharmacokinetic Interactions With Other Drugs: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine.

Pharmacodynamics and Clinical Effect

Single and multiple doses of 15 mg or more of UNIVASC gives sustained inhibition of plasma ACE activity of 80-90%, beginning within 2 hours and lasting 24 hours (80%).

In controlled trials, the peak effects of orally administered moexipril increased with the dose administered over a dose range of 7.5 to 60 mg, given once a day. Antihypertensive effects were first detectable about 1 hour after dosing, with a peak effect between 3 and 6 hours after dosing. Just before dosing (i.e., at trough), the antihypertensive effects were less prominently related to dose and the antihypertensive effect tended to diminish during the 24-hour dosing interval when the drug was administered once a day.

In multiple dose studies in the dose range of 7.5 to 30 mg once daily, UNIVASC lowered sitting diastolic and systolic blood pressure effects at trough by 3 to 6 mmHg and 4 to 11 mmHg, more than placebo, respectively. There was a tendency toward increased response with higher doses over this range. These effects are typical of ACE inhibitors but, to date, there are no trials of adequate size comparing moexipril with other antihypertensive agents.

The trough diastolic blood pressure effects of moexipril were approximately 3 to 6 mmHg in various studies. Generally, higher doses of moexipril leave a greater fraction of the peak blood pressure effect still present at trough. During dose titration, any decision as to the adequacy of a dosing regimen should be based on trough blood pressure measurements. If diastolic blood pressure control is not adequate at the end of the dosing interval, the dose can be increased or given as a divided (BID) regimen.

During chronic therapy, the antihypertensive effect of any dose of UNIVASC is generally evident within 2 weeks of treatment, with maximal reduction after 4 weeks. The antihypertensive effects of UNIVASC have been proven to continue during therapy for up to 24 months.

UNIVASC, like other ACE inhibitors, is less effective in decreasing trough blood pressures in blacks than in non-blacks. Placebo-corrected trough group mean diastolic blood pressure effects in blacks in the proposed dose range varied between +1 to -3 mmHg compared with responses in non-blacks of -4 to -6 mmHg.

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