Enalaprilat (2 brand names, 1 dosage form, 1 route)
Available dosage forms: INJECTABLE.
Routes of administration: INJECTION.
Brand Names
- ENALAPRILAT
- VASOTEC
Boxed Warning
USE IN PREGNANCY When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, enalaprilat injection should be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality .
Indications and Usage
Enalaprilat injection is indicated for the treatment of hypertension when oral therapy is not practical. Enalaprilat injection has been studied with only one other antihypertensive agent, furosemide, which showed approximately additive effects on blood pressure. Enalapril, the pro-drug of enalaprilat, has been used extensively with a variety of other antihypertensive agents, without apparent difficulty except for occasional hypotension. In using enalaprilat injection, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that enalaprilat injection does not have a similar risk (see WARNINGS). In considering use of enalaprilat, it should be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, it should be noted that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks (see WARNINGS, Angioedema ).
Dosage and Administration
FOR INTRAVENOUS ADMINISTRATION ONLY The dose in hypertension is 1.25 mg every six hours administered intravenously over a five minute period. A clinical response is usually seen within 15 minutes. Peak effects after the first dose may not occur for up to four hours after dosing. The peak effects of the second and subsequent doses may exceed those of the first. No dosage regimen for enalaprilat injection has been clearly demonstrated to be more effective in treating hypertension than 1.25 mg every six hours. However, in controlled clinical studies in hypertension, doses as high as 5 mg every six hours were well tolerated for up to 36 hours. There has been inadequate experience with doses greater than 20 mg per day. In studies of patients with hypertension, enalaprilat has not been administered for periods longer than 48 hours. In other studies, patients have received enalaprilat for as long as seven days. The dose for patients being converted to enalaprilat injection from oral therapy for hypertension with enalapril maleate is 1.25 mg every six hours. For conversion from intravenous to oral therapy, the recommended initial dose of oral enalapril maleate, is 5 mg once a day with subsequent dosage adjustments as necessary.
Contraindications
Enalaprilat injection is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioedema related to previous treatment with an angiotensin-converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema.
Adverse Reactions
Enalaprilat has been found to be generally well tolerated in controlled clinical trials involving 349 patients (168 with hypertension, 153 with congestive heart failure and 28 with coronary artery disease). The most frequent clinically significant adverse experience was hypotension (3.4 percent), occurring in eight patients (5.2 percent) with congestive heart failure, three (1.8 percent) with hypertension and one with coronary artery disease. Other adverse experiences occurring in greater than one percent of patients were: headache (2.9 percent) and nausea (1.1 percent). Adverse experiences occurring in 0.5 to 1 percent of patients in controlled clinical trials included: myocardial infarction, fatigue, dizziness, fever, rash and constipation. Angioedema: Angioedema has been reported in patients receiving enalaprilat, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalaprilat should be discontinued and appropriate therapy instituted immediately (see WARNINGS). Cough: See PRECAUTIONS, Cough. Enalapril Maleate Since enalapril is converted to enalaprilat, those adverse experiences associated with enalapril might also be expected to occur with enalaprilat injection. The following adverse experiences have been reported with enalapril and, within each category, are listed in order of decreasing severity. Body as a Whole: Syncope, orthostatic effects, anaphylactoid reactions (see WARNINGS, Anaphylactoid reactions during membrane exposure), chest pain, abdominal pain, asthenia. Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see WARNINGS,Hypotension); pulmonary embolism and infarction; pulmonary edema; rhythm disturbances including atrial tachycardia and bradycardia; atrial fibrillation; orthostatic hypoten
Drug Interactions
Hypotension-Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalaprilat. The possibility of hypotensive effects with enalaprilat can be minimized by administration of an intravenous infusion of normal saline, discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalaprilat. If it is necessary to continue the diuretic, provide close medical supervision for at least one hour after the initial dose of enalaprilat (see WARNINGS). Agents Causing Renin Release: The antihypertensive effect of enalaprilat injection appears to be augmented by antihypertensive agents that cause renin release (e.g., diuretics). Non-Steroidal Anti-Inflammatory Agents: In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the coadministration of enalapril may result in a further deterioration of renal function. These effects are usually reversible. In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Other Cardiovascular Agents: Enalaprilat injection has been used concomitantly with digitalis, beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine and prazosin without evidence of clinically significant adverse interactions. Agents Increasing Serum Potassium: Enalaprilat injection attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or a
Mechanism of Action
Intravenous enalaprilat, or oral enalapril, after hydrolysis to enalaprilat, inhibits 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. 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 alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with enalapril 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 enalaprilat remains to be elucidated. While the mechanism through which enalaprilat lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, enalaprilat has anti-hypertensive activity even in patients with low-renin hypertension. In clinical studies, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalaprilat monotherapy than non-black patients.
Overdosage
In clinical studies, some hypertensive patients received a maximum dose of 80 mg of enalaprilat intravenously over a fifteen minute period. At this high dose, no adverse effects beyond those as associated with the recommended dosages were observed. A single intravenous dose of ≤4,167 mg/kg of enalaprilat was associated with lethality in female mice. No lethality occurred after an intravenous dose of 3,472 mg/kg. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Enalaprilat may be removed from general circulation by hemodialysis and has been removed from neonatal circulation by peritoneal dialysis (see WARNINGS, Anaphylactoid reactions during membrane exposure).