Enalapril Maleate (Page 2 of 8)

Heart Failure

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 4 months. Effects on exercise tolerance, heart size, and severity and symptoms of heart failure were observed in placebo-controlled studies lasting from 8 weeks to over 1 year.

Heart Failure, Mortality Trials

In a multicenter, placebo-controlled clinical trial, 2,569 patients with all degrees of symptomatic heart failure and ejection fraction ≤ 35% were randomized to placebo or enalapril and followed for up to 55 months (SOLVD-Treatment). Use of enalapril was associated with an 11% reduction in all-cause mortality and a 30% reduction in hospitalization for heart failure. Diseases that excluded patients from enrollment in the study included severe stable angina (> 2 attacks/day), hemodynamically significant valvular or outflow tract obstruction, renal failure (creatinine > 2.5 mg/dL), cerebral vascular disease (e.g., significant carotid artery disease), advanced pulmonary disease, malignancies, active myocarditis and constrictive pericarditis. The mortality benefit associated with enalapril does not appear to depend upon digitalis being present.

A second multicenter trial used the SOLVD protocol for study of asymptomatic or minimally symptomatic patients. SOLVD-Prevention patients, who had left ventricular ejection fraction ≤ 35% and no history of symptomatic heart failure, were randomized to placebo (n = 2,117) or enalapril (n = 2,111) and followed for up to 5 years. The majority of patients in the SOLVD-Prevention trial had a history of ischemic heart disease. A history of myocardial infarction was present in 80% of patients, current angina pectoris in 34%, and a history of hypertension in 37%. No statistically significant mortality effect was demonstrated in this population. Enalapril-treated subjects had 32% fewer first hospitalizations for heart failure, and 32% fewer total heart failure hospitalizations. Compared to placebo, 32% fewer patients receiving enalapril developed symptoms of overt heart failure. Hospitalizations for cardiovascular reasons were also reduced. There was an insignificant reduction in hospitalizations for any cause in the enalapril treatment group (for enalapril vs. placebo, respectively, 1,166 vs. 1,201 first hospitalizations, 2,649 vs. 2,840 total hospitalizations), although the study was not powered to look for such an effect.

The SOLVD-Prevention trial was not designed to determine whether treatment of asymptomatic patients with low ejection fraction would be superior, with respect to preventing hospitalization, to closer follow-up and use of enalapril at the earliest sign of heart failure. However, under the conditions of follow-up in the SOLVD-Prevention trial (every 4 months at the study clinic; personal physician as needed), 68% of patients on placebo who were hospitalized for heart failure had no prior symptoms recorded which would have signaled initiation of treatment.

The SOLVD-Prevention trial was also not designed to show whether enalapril modified the progression of underlying heart disease.

In another multicenter, placebo-controlled trial (CONSENSUS) limited to patients with NYHA Class IV congestive heart failure and radiographic evidence of cardiomegaly, use of enalapril was associated with improved survival. The results are shown in the following table.

SURVIVAL (%)

Six Months

One Year

Enalapril Maleate (n = 127)

74

64

Placebo (n = 126)

56

48

In both CONSENSUS and SOLVD-Treatment trials, patients were also usually receiving digitalis, diuretics or both.

Clinical Pharmacology in Pediatric Patients

A multiple dose pharmacokinetic study was conducted in 40 hypertensive male and female pediatric patients aged 2 months to ≤ 16 years following daily oral administration of 0.07 to 0.14 mg/kg enalapril maleate. At steady state, the mean effective half-life for accumulation of enalaprilat was 14 hours and the mean urinary recovery of total enalapril and enalaprilat in 24 hours was 68% of the administered dose. Conversion of enalapril to enalaprilat was in the range of 63% to 76%. The overall results of this study indicate that the pharmacokinetics of enalapril in hypertensive children aged 2 months to ≤ 16 years are consistent across the studied age groups and consistent with pharmacokinetic historic data in healthy adults.

In a clinical study involving 110 hypertensive pediatric patients 6 to 16 years of age, patients who weighed < 50 kg received either 0.625 mg, 2.5 mg or 20 mg of enalapril daily and patients who weighed ≥ 50 kg received either 1.25 mg, 5 mg or 40 mg of enalapril daily. Enalapril administration once daily lowered trough blood pressure in a dose-dependent manner. The dose-dependent antihypertensive efficacy of enalapril was consistent across all subgroups (age, Tanner stage, gender, race). However, the lowest doses studied, 0.625 mg and 1.25 mg, corresponding to an average of 0.02 mg/kg once daily, did not appear to offer consistent antihypertensive efficacy. In this study, enalapril was generally well tolerated.

In the above pediatric studies, enalapril was given as tablets of enalapril maleate and for those children and infants who were unable to swallow tablets or who required a lower dose than is available in tablet form, enalapril was administered in a suspension formulation (see DOSAGE AND ADMINISTRATION: Pediatric Hypertensive Patients: Preparation of Suspension).

INDICATIONS AND USAGE

Hypertension

Enalapril maleate tablets, USP are indicated for the treatment of hypertension.

Enalapril maleate tablets are effective alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of enalapril maleate tablets and thiazides are approximately additive.

Heart Failure

Enalapril maleate tablets are indicated for the treatment of symptomatic congestive heart failure, usually in combination with diuretics and digitalis. In these patients enalapril maleate tablets improve symptoms, increases survival, and decreases the frequency of hospitalization (see CLINICAL PHARMACOLOGY: Heart Failure, Mortality Trials for details and limitations of survival trials).

Asymptomatic Left Ventricular Dysfunction

In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction ≤ 35%), enalapril maleate tablets decrease the rate of development of overt heart failure and decrease the incidence of hospitalization for heart failure (see CLINICAL PHARMACOLOGY: Heart Failure, Mortality Trials for details and limitations of survival trials).

In using enalapril maleate tablets 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 enalapril maleate tablets do not have a similar risk. (See WARNINGS.)

In considering use of enalapril maleate tablets, 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: Head and Neck Angioedema.)

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