ENALAPRIL MALEATE- enalapril maleate tablet
Preferred Pharmaceuticals Inc.
See full prescribing information for complete boxed warning.
- When pregnancy is detected, discontinue enalapril maleate tablets as soon as possible.
- Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (See Error! Hyperlink reference not valid..)
Enalapril maleate is the maleate salt of enalapril, the ethyl ester of a long-acting angiotensin-converting enzyme inhibitor, enalaprilat. Enalapril maleate is chemically described as (S)-1-[N -[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline, (Z) -2-butenedioate salt (1:1). Its empirical formula is C20 H28 N2 O5 •C4 H4 O4 , and its structural formula is:
Enalapril maleate, USP, is a white to off-white, crystalline powder with a molecular weight of 492.53. It is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol.
Enalapril is a pro-drug; following oral administration, it is bioactivated by hydrolysis of the ethyl ester to enalaprilat, which is the active angiotensin-converting enzyme inhibitor.
Enalapril maleate is supplied as 2.5 mg, 5 mg, 10 mg, and 20 mg tablets for oral administration. In addition to the active ingredient enalapril maleate, each tablet contains the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, pregelatinized starch and sodium bicarbonate. The 10 mg tablets also contain red ferric oxide, and 20 mg tablets also contain yellow ferric oxide.
Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of enalapril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with enalapril maleate tablets alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with enalapril maleate tablets plus a thiazide diuretic, there was essentially no change in serum potassium (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of enalapril maleate tablets remains to be elucidated.
While the mechanism through which enalapril maleate tablets lower blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, enalapril maleate tablets are antihypertensive even in patients with low-renin hypertension. Although enalapril maleate tablets were antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalapril monotherapy than non-black patients.
Following oral administration of enalapril maleate tablets, peak serum concentrations of enalapril occur within about one hour. Based on urinary recovery, the extent of absorption of enalapril is approximately 60 percent. Enalapril absorption is not influenced by the presence of food in the gastrointestinal tract. Following absorption, enalapril is hydrolyzed to enalaprilat, which is a more potent angiotensin-converting enzyme inhibitor than enalapril; enalaprilat is poorly absorbed when administered orally. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril maleate. Excretion of enalapril maleate tablets is primarily renal. Approximately 94 percent of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40 percent of the dose, and intact enalapril. There is no evidence of metabolites of enalapril, other than enalaprilat.
The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently representing a small fraction of the administered dose that has been bound to ACE. The amount bound does not increase with dose, indicating a saturable site of binding. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours. The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With glomerular filtration rate ≤30 mL/min, peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency (see DOSAGE AND ADMINISTRATION). Enalaprilat is dialyzable at the rate of 62 mL/min.
Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of enalapril maleate in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14 C-enalapril maleate. Radioactivity was found to cross the placenta following administration of labeled drug to pregnant hamsters.
Administration of enalapril maleate tablets to patients with hypertension of severity ranging from mild to severe results in a reduction of both supine and standing blood pressure usually with no orthostatic component. Symptomatic postural hypotension is therefore infrequent, although it might be anticipated in volume-depleted patients (see WARNINGS, Hypotension).
In most patients studied, after oral administration of a single dose of enalapril, onset of antihypertensive activity was seen at one hour with peak reduction of blood pressure achieved by four to six hours.
At recommended doses, antihypertensive effects have been maintained for at least 24 hours. In some patients the effects may diminish toward the end of the dosing interval (see DOSAGE AND ADMINISTRATION, Hypertension).
In some patients achievement of optimal blood pressure reduction may require several weeks of therapy.
The antihypertensive effects of enalapril maleate tablets have continued during long-term therapy. Abrupt withdrawal of enalapril maleate tablets has not been associated with a rapid increase in blood pressure.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalapril maleate tablets, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with renovascular hypertension.
When given together with thiazide-type diuretics, the blood pressure lowering effects of enalapril maleate tablets are approximately additive.
In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate tablets. In this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate tablets (see PRECAUTIONS, Drug Interactions).
In trials in patients treated with digitalis and diuretics, treatment with enalapril resulted in decreased systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure and heart size, and increased cardiac output and exercise tolerance. Heart rate was unchanged or slightly reduced, and mean ejection fraction was unchanged or increased. There was a beneficial effect on severity of heart failure as measured by the New York Heart Association (NYHA) classification and on symptoms of dyspnea and fatigue. Hemodynamic effects were observed after the first dose and appeared to be maintained in uncontrolled studies lasting as long as four months. Effects on exercise tolerance, heart size, and severity and symptoms of heart failure were observed in placebo-controlled studies lasting from eight weeks to over one year.
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