Univasc Information
Univasc (Moexipril hcl)
Univasc (Moexipril hcl) Description
Univasc (Moexipril hcl) (moexipril hydrochloride), the hydrochloride salt of moexipril, has the empirical formula CHNO•HCl and a molecular weight of 535.04. It is chemically described as [3S-[2[R*(R*)],3R*]]-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, monohydrochloride. It is a non-sulfhydryl containing precursor of the active angiotensin-converting enzyme (ACE) inhibitor moexiprilat and its structural formula is:
Moexipril hydrochloride is a fine white to off-white powder. It is soluble (about 10% weight-to-volume) in distilled water at room temperature.
Univasc (Moexipril hcl) is supplied as scored, coated tablets containing 7.5 mg and 15 mg of moexipril hydrochloride for oral administration. In addition to the active ingredient, moexipril hydrochloride, the tablet core contains the following inactive ingredients: lactose, magnesium oxide, crospovidone, magnesium stearate and gelatin. The film coating contains hydroxypropyl cellulose, hypromellose, polyethylene glycol 6000, magnesium stearate, titanium dioxide, and ferric oxide.
Univasc (Moexipril hcl) Clinical Pharmacology
Moexipril hydrochloride is a prodrug for moexiprilat, which inhibits ACE in humans and animals. The mechanism through which moexiprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes the conversion of the inactive decapeptide angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor that also stimulates aldosterone secretion by the adrenal cortex and provides negative feedback on renin secretion. ACE is identical to kininase II, an enzyme that degrades bradykinin, an endothelium-dependent vasodilator. Moexiprilat is about 1000 times as potent as moexipril in inhibiting ACE and kininase II. Inhibition of ACE results in decreased angiotensin II formation, leading to decreased vasoconstriction, increased plasma renin activity, and decreased aldosterone secretion. The latter results in diuresis and natriuresis and a small increase in serum potassium concentration (mean increases of about 0.25 mEq/L were seen when moexipril was used alone, see ).
Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of moexipril remains to be elucidated. Although the principal mechanism of moexipril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect on blood pressure even in apparent low-renin hypertension. As is the case with other ACE inhibitors, however, the antihypertensive effect of moexipril is considerably smaller in black patients, a predominantly low-renin population, than in non-black hypertensive patients.
Single and multiple doses of 15 mg or more of Univasc (Moexipril hcl) 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 (Moexipril hcl) 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 (Moexipril hcl) is generally evident within 2 weeks of treatment, with maximal reduction after 4 weeks. The antihypertensive effects of Univasc (Moexipril hcl) have been proven to continue during therapy for up to 24 months.
Univasc (Moexipril hcl) , 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.
The effectiveness of Univasc (Moexipril hcl) was not significantly influenced by patient age, gender, or weight. Univasc (Moexipril hcl) has been shown to have antihypertensive activity in both pre- and postmenopausal women who have participated in placebo-controlled clinical trials.
Formal interaction studies with moexipril have not been carried out with antihypertensive agents other than thiazide diuretics. In these studies, the added effect of moexipril was similar to its effect as monotherapy. In general, ACE inhibitors have less than additive effects with beta-adrenergic blockers, presumably because both work by inhibiting the renin-angiotensin system.
Univasc (Moexipril hcl) Indications And Usage
Univasc (Moexipril hcl) is indicated for treatment of patients with hypertension. It may be used alone or in combination with thiazide diuretics.
In using Univasc (Moexipril hcl) , consideration should be given to the fact that another ACE inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that Univasc (Moexipril hcl) does not have a similar risk (see ).
In considering use of Univasc (Moexipril hcl) , it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see , Angioedema).
Univasc (Moexipril hcl) Contraindications
Univasc (Moexipril hcl) is contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an ACE inhibitor.
Univasc (Moexipril hcl) Warnings
Univasc (Moexipril hcl) can cause symptomatic hypotension, although, as with other ACE inhibitors, this is unusual in uncomplicated hypertensive patients treated with Univasc (Moexipril hcl) alone. Symptomatic hypotension was seen in 0.5% of patients given moexipril and led to discontinuation of therapy in about 0.25%. Symptomatic hypotension is most likely to occur in patients who have been salt- and volume-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume- and salt-depletion should be corrected and, in general, diuretics stopped, before initiating therapy with Univasc (Moexipril hcl) (see , and ).
In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or progressive azotemia, and rarely, with acute renal failure and death. In these patients, Univasc (Moexipril hcl) therapy should be started under close medical supervision, and patients should be followed closely for the first two weeks of treatment and whenever the dose of moexipril or an accompanying diuretic is increased. Care in avoiding hypotension should also be taken in patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease, in whom an excessive decrease in blood pressure could result in a myocardial infarction or a cerebrovascular accident.
If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with an intravenous infusion of normal saline. Univasc (Moexipril hcl) treatment usually can be continued following restoration of blood pressure and volume.
ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these were caused by the ACE inhibitor exposure.
Fetal and neonatal morbidity do not appear to have resulted from intrauterine ACE inhibitor exposure limited to the first trimester. Mothers who have used ACE inhibitors only during the first trimester should be informed of this. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of moexipril as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.
If oligohydramnios is observed, moexipril should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not be detected until after the fetus has sustained irreversible injury.
Infants with histories of to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or peritoneal dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.
Theoretically, the ACE inhibitor could be removed from the neonatal circulation by exchange transfusion, but no experience with this procedure has been reported.
No embryotoxic, fetotoxic, or teratogenic effects were seen in rats or in rabbits treated with up to 90.9 and 0.7 times, respectively, the Maximum Recommended Human Dose (MRHD) on a mg/m basis.
Univasc (Moexipril hcl) Precautions
No evidence of carcinogenicity was detected in long-term studies in mice and rats at doses up to 14 or 27.3 times the Maximum Recommended Human Dose (MRHD) on a mg/m basis.
No mutagenicity was detected in the Ames test and microbial reverse mutation assay, with and without metabolic activation, or in an nucleus anomaly test. However, increased chromosomal aberration frequency in Chinese hamster ovary cells was detected under metabolic activation conditions at a 20-hour harvest time.
Reproduction studies have been performed in rabbits at oral doses up to 0.7 times the MRHD on a mg/m basis, and in rats up to 90.9 times the MRHD on a mg/mbasis. No indication of impaired fertility, reproductive toxicity, or teratogenicity was observed.
Univasc (Moexipril hcl) Adverse Reactions
Univasc (Moexipril hcl) has been evaluated for safety in more than 2500 patients with hypertension; more than 250 of these patients were treated for approximately one year. The overall incidence of reported adverse events was only slightly greater in patients treated with Univasc (Moexipril hcl) than patients treated with placebo.
Reported adverse experiences were usually mild and transient, and there were no differences in adverse reaction rates related to gender, race, age, duration of therapy, or total daily dosage within the range of 3.75 mg to 60 mg. Discontinuation of therapy because of adverse experiences was required in 3.4% of patients treated with Univasc (Moexipril hcl) and in 1.8% of patients treated with placebo. The most common reasons for discontinuation in patients treated with Univasc (Moexipril hcl) were cough (0.7%) and dizziness (0.4%).
All adverse experiences considered at least possibly related to treatment that occurred at any dose in placebo-controlled trials of once-daily dosing in more than 1% of patients treated with Univasc (Moexipril hcl) alone and that were at least as frequent in the Univasc (Moexipril hcl) group as in the placebo group are shown in the following table:
Other adverse events occurring in more than 1% of patients on moexipril that were at least as frequent on placebo include: headache, upper respiratory infection, pain, rhinitis, dyspepsia, nausea, peripheral edema, sinusitis, chest pain, and urinary frequency. See and for discussion of anaphylactoid reactions, angioedema, hypotension, neutropenia/agranulocytosis, second and third trimester fetal/neonatal morbidity and mortality, hyperkalemia, and cough.
Other potentially important adverse experiences reported in controlled or uncontrolled clinical trials in less than 1% of moexipril patients or that have been attributed to other ACE inhibitors include the following:
Univasc (Moexipril hcl) Overdosage
Human overdoses of moexipril have not been reported. In case reports of overdoses with other ACE inhibitors, hypotension has been the principal adverse effect noted. Single oral doses of 2 g/kg moexipril were associated with significant lethality in mice. Rats, however, tolerated single oral doses of up to 3 g/kg.
No data are available to suggest that physiological maneuvers (e.g., maneuvers to change the pH of the urine) would accelerate elimination of moexipril and its metabolites. The dialyzability of moexipril is not known.
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of moexipril overdose, but angiotensin II is essentially unavailable outside of research facilities. Because the hypotensive effect of moexipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat moexipril overdose by infusion of normal saline solution. In addition, renal function and serum potassium should be monitored.
Univasc (Moexipril hcl) Dosage And Administration
The recommended initial dose of Univasc (Moexipril hcl) in patients not receiving diuretics is 7.5 mg, one hour prior to meals, once daily. Dosage should be adjusted according to blood pressure response. The antihypertensive effect of Univasc (Moexipril hcl) may diminish towards the end of the dosing interval. Blood pressure should, therefore, be measured just prior to dosing to determine whether satisfactory blood pressure control is obtained. If control is not adequate, increased dose or divided dosing can be tried. The recommended dose range is 7.5 to 30 mg daily, administered in one or two divided doses one hour before meals. Total daily doses above 60 mg a day have not been studied in hypertensive patients.
In patients who are currently being treated with a diuretic, symptomatic hypotension may occasionally occur following the initial dose of Univasc (Moexipril hcl) . The diuretic should, if possible, be discontinued for 2 to 3 days before therapy with Univasc (Moexipril hcl) is begun, to reduce the likelihood of hypotension (see ). If the patient's blood pressure is not controlled with Univasc (Moexipril hcl) alone, diuretic therapy may then be reinstituted. If diuretic therapy cannot be discontinued, an initial dose of 3.75 mg of Univasc (Moexipril hcl) should be used with medical supervision until blood pressure has stabilized (see and ).
Univasc (Moexipril hcl) How Supplied
Store, tightly closed, at controlled room temperature. Protect from excessive moisture.
If product package is subdivided, dispense in tight containers as described in USP-NF.
Univasc (Moexipril hcl)
Univasc (Moexipril hcl) Principal Display Panel - . Mg Tablet Bottle Label
Univasc (Moexipril hcl) Principal Display Panel - Mg Tablet Bottle Label
