General
Enalapril Maleate
Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators,
enalapril should be given with caution to patients with obstruction in the outflow
tract of the left ventricle.
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals.
In patients with severe congestive heart failure whose renal function may depend
on the activity of the renin-angiotensin-aldersterone system, treatment with
angiotensin converting enzyme inhibitors, including enalapril, may be associated
with oliguria and/or progressive azotemia and rarely with acute renal failure
and/or death.
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20 percent of patients. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when enalapril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of enalapril and/or discontinuation of the diuretic may be required.
Evaluation of the hypertensive patient should always include assessment
of renal function.
Hyperkalemia: Elevated serum potassium (greater than 5.7 mEq/L)
was observed in approximately one percent of hypertensive patients in clinical
trials treated with enalapril alone. In most cases these were isolated values
which resolved despite continued therapy, although hyperkalemia was a cause
of discontinuation of therapy in 0.28 percent of hypertensive patients. Hyperkalemia
was less frequent (approximately 0.1 percent) in patients treated with enalapril
plus hydrochlorothiazide. Risk factors for the development of hyperkalemia include
renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing
diuretics, potassium supplements and/or potassium-containing salt substitutes,
which should be used cautiously, if at all, with enalapril (see DRUG INTERACTIONS).
Cough: Presumably due to the inhibition of the degradation of
endogenous bradykinin, persistent nonproductive cough has been reported with
all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced
cough should be considered in the differential diagnosis of cough.
Surgery/Anesthesia: In patients undergoing major surgery or during
anesthesia with agents that produce hypotension, enalapril may block angiotensin
II formation secondary to compensatory renin release. If hypotension occurs
and is considered to be due to this mechanism, it can be corrected by volume
expansion.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis
is present, or after prolonged therapy. Interference with adequate oral electrolyte
intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia
and may also sensitize or exaggerate the response of the heart to the toxic
effects of digitalis (e.g., increased ventricular irritability). Because enalapril
reduces the production of aldosterone, concomitant therapy with enalapril attenuates
the diuretic-induced potassium loss (see DRUG INTERACTIONS,
Agents Increasing Serum Potassium).
Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents
may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent
diabetes mellitus may become manifest during thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy.
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Enalapril in combination with hydrochlorothiazide was not mutagenic in the
Ames microbial mutagen test with or without metabolic activation. Enalapril-hydrochlorothiazide
did not produce DNA single strand breaks in an in vitro alkaline elution
assay in rat hepatocytes or chromosomal aberrations in an in vivo mouse
bone marrow assay.
Enalapril Maleate
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: rec-assay, 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).
Hydrochlorothiazide
Two year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice at doses up to approximately 600 mg/kg/day (53 times the MRHDD when compared on a body surface area basis) or in male and female rats at doses up to approximately 100 mg/ kg/day (18 times the MRHDD when compared on a body surface area basis). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity
assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537,
and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations,
or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster
bone marrow chromosomes, and the Drosophila sex-linked recessive lethal
trait gene. Positive test results were obtained only in the in vitro CHO
Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity)
assays, using concentrations of hydrochlorothiazide from 43 to 1300 µg/mL, and
in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation. In mice and rats these doses are 9 times and 0.7 times, respectively, the MRHDD when compared on a body surface area basis.
Pregnancy
Pregnancy Categories C (first trimester) and D
(second and third trimesters) (see WARNINGS,
Pregnancy, Enalapril Maleate, Fetal/Neonatal Morbidity and Mortality).
Nursing Mothers
Enalapril, enalaprilat, and hydrochlorothiazide have been detected in human breast milk. Because of the potential for serious reactions in nursing infants from either drug, a decision should be made whether to discontinue nursing or to discontinue VASERETIC, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of VASERETIC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk
of toxic reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal function,
care should be taken in dose selection. Evaluation of the hypertensive patient
should always include assessment of renal function (see DOSAGE AND ADMINISTRATION).
Last updated on RxList: 12/23/2008