13 NONCLINICAL TOXICOLOGY13.1 Carci

13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenes is , Mutagenes is , Impairment of Fertility
There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male
and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to
90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in
male mice) the maximum recommended human daily dose (MRHDD) when compared on a body surface
area basis.
Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with
or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: recassay,
reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and
the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow.
There were no adverse effects on reproductive performance of male and female rats treated with up to
90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body surface area basis).
14 CLINICAL STUDIES
14.1 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 percent were randomized to placebo or enalapril and followed for up
to 55 months (SOLVD-Treatment). Use of enalapril was associated with an 11 percent reduction in all-
14
cause mortality and a 30 percent 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=2117) or enalapril (n=2111) 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 percent of patients, current
angina pectoris in 34 percent, and a history of hypertension in 37 percent. 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 percent 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,
1166 vs. 1201 first hospitalizations, 2649 vs. 2840 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.