ENALAPRIL MALEATE
DESCRIPTION:
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, ENVAS should be discontinued as
soon as possible. See WARNINGS,
Fetal/Neonatal Morbidity and Mortality.
I.V. INJ - Does not induce sudden fall in blood pressure, has long duration of action ( 6 hrs ), no rebound phenomenon & can be titrated for controlled outcomes
ENVAS (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 C20H28N2O5.C4H4O4.
Enalapril maleate 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, 10mg, and 20 mg tablets for oral
administration. In addition to the active ingredient enalapril maleate, each
tablet contains the following inactive ingredients: lactose, magnesium stearate,
starch, and other ingredients. The 2.5 mg, 10 mg and 20 mg tablets also contain
iron oxides.
*Registered trademark of MERCK & CO., INC.
ACTIONS/CLINICAL PHARMACOLOGY:
Mechanism Of Action
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 ENVAS alone for up
to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were
observed. In patients treated with ENVAS 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 ENVAS remains to be elucidated.
While the mechanism through which ENVAS lowers blood pressure is believed to
be primarily suppression of the renin-angiotensin-aldosterone system, ENVAS is
antihypertensive even in patients with low-renin hypertension. Although ENVAS
was 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.
Pharmacokinetics And Metabolism
Following oral administration of ENVAS, 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 ENVAS 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 14C enalapril maleate.
Radioactivity was found to cross the placenta following administration of
labeled drug to pregnant hamsters.
Pharmacodynamics And Clinical Effects
Hypertension: Administration of ENVAS 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.)
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).
In some patients achievement of optimal blood pressure reduction may require
several weeks of therapy.
The antihypertensive effects of ENVAS have continued during long term therapy.
Abrupt withdrawal of ENVAS 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 ENVAS, 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 ENVAS are approximately additive.
In a clinical pharmacology study, indomethacin or sulindac was administered to
hypertensive patients receiving ENVAS. In this study there was no evidence of
a blunting of the antihypertensive action of ENVAS.
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 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.
Heart Failure, Mortality Trials: In a multicenter, placebo-controlled clinical
trial, 2569 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-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.
SURVIVAL (%)
Six Months One Year
ENVAS (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.
INDICATIONS AND USAGE:
Hypertension
ENVAS is indicated for the treatment of hypertension.
ENVAS is effective alone or in combination with other antihypertensive agents,
especially thiazide-type diuretics. The blood pressure lowering effects of
ENVAS and thiazides are approximately additive.
Heart Failure
ENVAS is indicated for the treatment of symptomatic congestive heart failure,
usually in combination with diuretics and digitalis. In these patients ENVAS
improves symptoms, increases survival, and decreases the frequency of
hospitalization (see ACTIONS/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 percent), ENVAS decreases the rate of development of
overt heart failure and decreases the incidence of hospitalization for heart
failure. (See ACTIONS/CLINICAL PHARMACOLOGY, Heart Failure, Mortality Trials for
details and limitations of survival trials.)
In using ENVAS 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 ENVAS does not have a
similar risk. (See WARNINGS.)
In considering use of ENVAS, 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.)
CONTRAINDICATIONS:
ENVAS is contraindicated in patients who are hypersensitive to this product
and in patients with a history of angioedema related to previous treatment with
an angiotensin converting enzyme inhibitor.
WARNINGS:
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, ENVAS should be discontinued as
soon as possible. See WARNINGS,
Fetal/Neonatal Morbidity and Mortality.
ANAPHYLACTOID AND POSSIBLY RELATED REACTIONS
Presumably because angiotensin-converting enzyme inhibitors affect the
metabolism of eicosanoids and polypeptides, including endogenous bradykinin,
patients receiving ACE inhibitors (including ENVAS) may be subject to a
variety of adverse reactions, some of them serious.
ANGIOEDEMA: Angioedema of the face, extremities, lips, tongue, glottis and/or
larynx has been reported in patients treated with angiotensin converting enzyme
inhibitors, including ENVAS. This may occur at any time during treatment. In
such cases ENVAS should be promptly discontinued and appropriate therapy and
monitoring should be provided until complete and sustained resolution of signs
and symptoms has occurred. In instances where swelling has been confined to the
face and lips the condition has generally resolved without treatment, although
antihistamines have been useful in relieving symptoms. Angioedema associated
with laryngeal edema may be fatal. WHERE THERE IS INVOLVEMENT OF THE TONGUE,
GLOTTIS OR LARYNX, LIKELY TO CAUSE AIRWAY OBSTRUCTION, APPROPRIATE THERAPY,
E.G., SUBCUTANEOUS EPINEPHRINE SOLUTION 1:1000 (0.3 ML TO 0.5 ML) AND/OR
MEASURES NECESSARY TO ENSURE A PATENT AIRWAY, SHOULD BE PROMPTLY PROVIDED. (See
ADVERSE REACTIONS.)
PATIENTS WITH A HISTORY OF ANGIOEDEMA UNRELATED TO ACE INHIBITOR THERAPY MAY BE
AT INCREASED RISK OF ANGIOEDEMA WHILE RECEIVING AN ACE INHIBITOR (See also
INDICATIONS AND USAGE and CONTRAINDICATIONS).
Anaphylactoid Reactions During Desensitization: Two patients undergoing
desensitizing treatment with hymenoptera venom while receiving ACE inhibitors
sustained life-threatening anaphylactoid reactions. In the same patients, these
reactions were avoided when ACE inhibitors were temporarily withheld, but they
reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have
been reported in patients dialyzed with high-flux membranes and treated
concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been
reported in patients undergoing low-density lipoprotein apheresis with dextran
sulfate absorption.
Hypotension
Excessive hypotension is rare in uncomplicated hypertensive patients treated
with ENVAS alone. Patients with heart failure given ENVAS commonly have some
reduction in blood pressure, especially with the first dose, but discontinuation
of therapy for continuing symptomatic hypotension usually is not necessary when
dosing instructions are followed; caution should be observed when initiating
therapy. (See DOSAGE AND ADMINISTRATION.) Patients at risk for excessive
hypotension, sometimes associated with oliguria and/or progressive azotemia, and
rarely with acute renal failure and/or death, include those with the following
conditions or characteristics: heart failure, hyponatremia, high dose diuretic
therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis,
or severe volume and/or salt depletion of any etiology. It may be advisable to
eliminate the diuretic (except in patients with heart failure), reduce the
diuretic dose or increase salt intake cautiously before initiating therapy with
ENVAS in patients at risk for excessive hypotension who are able to tolerate
such adjustments. (See PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS.) In
patients at risk for excessive hypotension, therapy should be started under very
close medical supervision and such patients should be followed closely for the
first two weeks of treatment and whenever the dose of enalapril and/or diuretic
is increased. Similar considerations may apply to patients with ischemic heart
or cerebrovascular disease, in whom an excessive fall in blood pressure could
result in a myocardial infarction or cerebrovascular accident.
If excessive hypotension occurs, the patient should be placed in the supine
position and, if necessary, receive an intravenous infusion of normal saline. A
transient hypotensive response is not a contraindication to further doses of
ENVAS, which usually can be given without difficulty once the blood pressure
has stabilized. If symptomatic hypotension develops, a dose reduction or
discontinuation of ENVAS or concomitant diuretic may be necessary.
Neutropenia/Agranulocytosis
Another angiotensin converting enzyme inhibitor, captopril, has been shown to
cause agranulocytosis and bone marrow depression, rarely in uncomplicated
patients but more frequently in patients with renal impairment especially if
they also have a collagen vascular disease. Available data from clinical trials
of enalapril are insufficient to show that enalapril does not cause
agranulocytosis at similar rates. Marketing experience has revealed several
cases of neutropenia or agranulocytosis in which a causal relationship to
enalapril cannot be excluded. Periodic monitoring of white blood cell counts in
patients with collagen vascular disease and renal disease should be considered.
Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice and progresses to fulminant hepatic necrosis, and
(sometimes) death. The mechanism of this syndrome is not understood. Patients
receiving ACE inhibitors who develop jaundice or marked elevations of hepatic
enzymes should discontinue the ACE inhibitor and receive appropriate medical
follow-up.
Fetal/Neonatal Morbidity And Mortality
ACE inhibitors can cause fetal and neonatal morbidity and death when
administered to pregnant women. Several dozen cases have been reported in the
world literature. When pregnancy is detected, ACE inhibitors should be
discontinued as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy
has been associated with fetal and neonatal injury, including hypotension,
neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and
death. Oligohydramnios has also been reported, presumably resulting from
decreased fetal renal function: oligohydramnios in this setting has been
associated with fetal limb contractures, craniofacial deformation, and
hypoplastic lung development. Prematurity intrauterine growth retardation, and
patent ductus arteriosus have also been reported, although it is not clear
whether these occurrences were due to the ACE- inhibitor exposure.
These adverse effects do not appear to have resulted from intrauterine ACE-
inhibitor exposure that has been limited to the first trimester. Mothers whose
embryos and fetuses are exposed to ACE inhibitors only during the first
trimester should be so informed. Nonetheless, when patients become pregnant,
physicians should make every effort to discontinue the use of ENVAS as soon as
possible.
Rarely, (probably less often than once in every thousand pregnancies), no
alternative to ACE inhibitors will be found. In these rare cases, the mothers
should be apprised of the potential hazards to their fetuses, and serial
ultrasound examinations should be performed to assess the intraamniotic
environment.
If oligohydramnios is observed, ENVAS should be discontinued unless it is
considered lifesaving for the mother. Contraction stress testing (CST), a non-
stress test (NST), or biophysical profiling (BPP) may be appropriate, depending
upon the week of pregnancy. Patients and physicians should be aware, however,
that oligohydramnios may not appear until after the fetus has sustained
irreversible injury.
Infants with histories of In Utero exposure to ACE inhibitors should be closely
observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs,
attention should be directed toward support of blood pressure and renal
perfusion. Exchange transfusion or dialysis may be required as means of
reversing hypotension and/or substituting for disordered renal function.
Enalapril, which crosses the placenta, has been removed from neonatal
circulation by peritoneal dialysis with some clinical benefit, and theoretically
may be removed by exchange transfusion, although there is no experience with the
latter procedure.
No teratogenic effects of enalapril were seen in studies of pregnant rats and
rabbits. On a body surface area basis, the doses used were up to 57 times, and
12 times, respectively, the maximum recommended human dose (MRHDD).
PRECAUTIONS:
General
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 heart failure whose renal function may
depend on the activity of the renin- angiotensin-aldosterone system, treatment
with angiotensin converting enzyme inhibitors, including ENVAS, 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 ENVAS has been given
concomitantly with a diuretic. This is more likely to occur in patients with
pre-existing renal impairment. Dosage reduction and/or discontinuation of the
diuretic and/or ENVAS may be required.
EVALUATION OF PATIENTS WITH HYPERTENSION OR HEART FAILURE SHOULD ALWAYS INCLUDE
ASSESSMENT OF RENAL FUNCTION. (See DOSAGE AND ADMINISTRATION.)
Hyperkalemia: Elevated serum potassium (greater than 5.7 mEq/L) was observed in
approximately one percent of hypertensive patients in clinical trials. In most
cases these were isolated values which resolved despite continued therapy.
Hyperkalemia was a cause of discontinuation of therapy in 0.28 percent of
hypertensive patients. In clinical trials in heart failure, hyperkalemia was
observed in 3.8 percent of patients but was not a cause for discontinuation.
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 ENVAS. (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.
Information For Patients
Angioedema: Angioedema, including laryngeal edema, may occur at any time during
treatment with angiotensin converting enzyme inhibitors, including enalapril.
Patients should be so advised and told to report immediately any signs or
symptoms suggesting angioedema (swelling of face, extremities, eyes, lips,
tongue, difficulty in swallowing or breathing) and to take no more drug until
they have consulted with the prescribing physician.
Hypotension: Patients should be cautioned to report lightheadedness, especially
during the first few days of therapy. If actual syncope occurs, the patients
should be told to discontinue the drug until they have consulted with the
prescribing physician.
All patients should be cautioned that excessive perspiration and dehydration may
lead to an excessive fall in blood pressure because of reduction in fluid
volume. Other causes of volume depletion such as vomiting or diarrhea may also
lead to a fall in blood pressure; patients should be advised to consult with the
physician.
Hyperkalemia: Patients should be told not to use salt substitutes containing
potassium without consulting their physician.
Neutropenia: Patients should be told to report promptly any indication of
infection (e.g., sore throat, fever) which may be a sign of neutropenia.
Pregnancy: Female patients of childbearing age should be told about the
consequences of second- and third-trimester exposure to ACE inhibitors, and they
should also be told that these consequences do not appear to have resulted from
intrauterine ACE-inhibitor exposure that has been limited to the first
trimester. These patients should be asked to report pregnancies to their
physicians as soon as possible.
NOTE: As with many other drugs, certain advice to patients being treated with
enalapril is warranted. This information is intended to aid in the safe and
effective use of this medication. It is not a disclosure of all possible adverse
or intended effects.
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 enalapril. The possibility of hypotensive effects with enalapril can be
minimized by either discontinuing the diuretic or increasing the salt intake
prior to initiation of treatment with enalapril. If it is necessary to continue
the diuretic, provide close medical supervision after the initial dose for at
least two hours and until blood pressure has stabilized for at least an
additional hour. (See WARNINGS and DOSAGE AND ADMINISTRATION.)
Agents Causing Renin Release: The antihypertensive effect of ENVAS is
augmented by antihypertensive agents that cause renin release (e.g., diuretics).
Other Cardiovascular Agents: ENVAS has been used concomitantly with beta
adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents,
hydralazine, prazosin and digoxin without evidence of clinically significant
adverse interactions.
Agents Increasing Serum Potassium: ENVAS attenuates potassium loss caused by
thiazide-type diuretics. Potassium-sparing diuretics (e.g., spironolactone,
triamterene, or amiloride), potassium supplements, or potassium-containing salt
substitutes may lead to significant increases in serum potassium. Therefore, if
concomitant use of these agents is indicated because of demonstrated
hypokalemia, they should be used with caution and with frequent monitoring of
serum potassium. Potassium sparing agents should generally not be used in
patients with heart failure receiving ENVAS.
Lithium: Lithium toxicity has been reported in patients receiving lithium
concomitantly with drugs which cause elimination of sodium, including ACE
inhibitors. A few cases of lithium toxicity have been reported in patients
receiving concomitant ENVAS and lithium and were reversible upon
discontinuation of both drugs. It is recommended that serum lithium levels be
monitored frequently if enalapril is administered concomitantly with lithium.
Carcinogenesis, Mutagenesis, 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: 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 in male and female
rats treated up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared
on a body surface area basis).
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters).
See WARNINGS, Fetal/Neonatal Morbidity And Mortality.
Nursing Mothers
Enalapril and enalaprilat have been detected in human breast milk. Because of
the potential for serious adverse reactions in nursing infants from enalapril, a
decision should be made whether to discontinue nursing or to discontinue
ENVAS, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
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 enalapril. The possibility of hypotensive effects with enalapril can be
minimized by either discontinuing the diuretic or increasing the salt intake
prior to initiation of treatment with enalapril. If it is necessary to continue
the diuretic, provide close medical supervision after the initial dose for at
least two hours and until blood pressure has stabilized for at least an
additional hour. (See WARNINGS and DOSAGE AND ADMINISTRATION.)
Agents Causing Renin Release: The antihypertensive effect of ENVAS is
augmented by antihypertensive agents that cause renin release (e.g., diuretics).
Other Cardiovascular Agents: ENVAS has been used concomitantly with beta
adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents,
hydralazine, prazosin and digoxin without evidence of clinically significant
adverse interactions.
Agents Increasing Serum Potassium: ENVAS attenuates potassium loss caused by
thiazide-type diuretics. Potassium-sparing diuretics (e.g., spironolactone,
triamterene, or amiloride), potassium supplements, or potassium-containing salt
substitutes may lead to significant increases in serum potassium. Therefore, if
concomitant use of these agents is indicated because of demonstrated
hypokalemia, they should be used with caution and with frequent monitoring of
serum potassium. Potassium sparing agents should generally not be used in
patients with heart failure receiving ENVAS.
Lithium: Lithium toxicity has been reported in patients receiving lithium
concomitantly with drugs which cause elimination of sodium, including ACE
inhibitors. A few cases of lithium toxicity have been reported in patients
receiving concomitant ENVAS and lithium and were reversible upon
discontinuation of both drugs. It is recommended that serum lithium levels be
monitored frequently if enalapril is administered concomitantly with lithium.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
ENVAS has been evaluated for safety in more than 10,000 patients, including
over 1000 patients treated for one year or more. ENVAS has been found to be
generally well tolerated in controlled clinical trials involving 2987 patients.
For the most part, adverse experiences were mild and transient in nature. In
clinical trials, discontinuation of therapy due to clinical adverse experiences
was required in 3.3 percent of patients with hypertension and in 5.7 percent of
patients with heart failure. The frequency of adverse experiences was not
related to total daily dosage within the usual dosage ranges. In patients with
hypertension the overall percentage of patients treated with ENVAS reporting
adverse experiences was comparable to placebo.
HYPERTENSION
Adverse experiences occurring in greater than one percent of patients with
hypertension treated with ENVAS in controlled clinical trials are shown below.
In patients treated with ENVAS, the maximum duration of therapy was three
years; in placebo treated patients the maximum duration of therapy was 12 weeks.
ENVAS
Placebo D B Placebo D B Placebo
Incidence (n = 230)
(discontinuation) Incidence
-------------------------------------------------------------------------------------------------------------------
Body As A Whole
Fatigue 3.0 (<0.1) 2.6
Orthostatic Effects 1.2 (<0.1) 0.0
Asthenia 1.1 (0.1) 0.9
Digestive
Diarrhea 1.4 (<0.1) 1.7
Nausea 1.4 (0.2) 1.7
Nervous/Psychiatric
Headache 5.2 (0.3) 9.1
Dizziness 4.3 (0.4) 4.3
Respiratory
Cough 1.3 (0.1) 0.9
Skin
Rash 1.4 (0.4) 0.4
HEART FAILURE
Adverse experiences occurring in greater than one percent of patients with heart
failure treated with ENVAS are shown below. The incidences represent the
experiences from both controlled and uncontrolled clinical trials (maximum
duration of therapy was approximately one year). In the placebo treated
patients, the incidences reported are from the controlled trials (maximum
duration of therapy is 12 weeks). The percentage of patients with severe heart
failure (NYHA Class IV) was 29 percent and 43 percent for patients treated with
ENVAS and placebo, respectively.
ENVAS Placebo
(n = 673) (n = 339)
Incidence Incidence
(discontinuation)
----------------------------------------------------------------------------------------------------------
Body As A Whole
Orthostatic Effects 2.2 (0.1) 0.3
Syncope 2.2 (0.1) 0.9
Chest Pain 2.1 (0.0) 2.1
Fatigue 1.8 (0.0) 1.8
Abdominal Pain 1.6 (0.4) 2.1
Asthenia 1.6 (0.1) 0.3
Cardiovascular
Hypotension 6.7 (1.9) 0.6
Orthostatic 1.6 (0.1) 0.3
Hypotension
Angina Pectoris 1.5 (0.1) 1.8
Myocardial Infarction 1.2 (0.3) 1.8
Digestive
Diarrhea 2.1 (0.1) 1.2
Nausea 1.3 (0.1) 0.6
Vomiting 1.3 (0.0) 0.9
Nervous/Psychiatric
Dizziness 7.9 (0.6) 0.6
Headache 1.8 (0.1) 0.9
Vertigo 1.6 (0.1) 1.2
Respiratory
Cough 2.2 (0.0) 0.6
Bronchitis 1.3 (0.0) 0.9
Dyspnea 1.3 (0.1) 0.4
Pneumonia 1.0 (0.0) 2.4
Skin
Rash 1.3 (0.0) 2.4
Urogenital
Urinary Tract 1.3 (0.0) 2.4
Infection
Other serious clinical adverse experiences occurring since the drug was marketed
or adverse experiences occurring in 0.5 to 1.0 percent of patients with
hypertension or heart failure in clinical trials are listed below and, within
each category, are in order of decreasing severity.
Body As A Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid And
Possibly Related Reactions).
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; palpitation, Raynaud's phenomenon.
Digestive: Ileus, pancreatitis, hepatic failure, hepatitis (hepatocellular
(proven on rechallenge) or cholestatic jaundice), (see WARNINGS, Hepatic
Failure), melena, anorexia, dyspepsia, constipation, glossitis, stomatitis, dry
mouth.
Hematologic: Rare cases of neutropenia, thrombocytopenia and bone marrow
depression.
Musculoskeletal: Muscle cramps.
Nervous/Psychiatric: Depression, confusion, ataxia, somnolence, insomnia,
nervousness, peripheral neuropathy (e.g., paresthesia, dysesthesia), dream
abnormality.
Respiratory: Bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, upper
respiratory infection, pulmonary infiltrates.
Skin: Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson
syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus,
alopecia, flushing, diaphoresis, photosensitivity.
Special Senses: Blurred vision, taste alteration, anosmia, tinnitus,
conjunctivitis, dry eyes, tearing.
Urogenital: Renal failure, oliguria, renal dysfunction (see PRECAUTIONS and
DOSAGE AND ADMINISTRATION), flank pain, gynecomastia, impotence.
Miscellaneous: A symptom complex has been reported which may include some or all
of the following: a positive ANA, an elevated erythrocyte sedimentation rate,
arthralgia/arthritis, myalgia, myositis, fever, serositis, vasculitis,
leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic
manifestations.
Angioedema: Angioedema has been reported in patients receiving ENVAS, 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 ENVAS should be
discontinued and appropriate therapy instituted immediately. (See WARNINGS.)
Hypotension: In the hypertensive patients, hypotension occurred in 0.9 percent
and syncope occurred in 0.5 percent of patients following the initial dose or
during extended therapy. Hypotension or syncope was a cause for discontinuation
of therapy in 0.1 percent of hypertensive patients. In heart failure patients,
hypotension occurred in 6.7 percent and syncope occurred in 2.2 percent of
patients. Hypotension or syncope was a cause for discontinuation of therapy in
1.9 percent of patients with heart failure. (See WARNINGS.)
Fetal/Neonatal Morbidity And Mortality: (See WARNINGS, Fetal/Neonatal Morbidity
And Mortality).
Cough: See PRECAUTIONS, Cough
Clinical Laboratory Test Findings
Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia.
Creatinine, Blood Urea Nitrogen: In controlled clinical trials minor increases
in blood urea nitrogen and serum creatinine, reversible upon discontinuation of
therapy, were observed in about 0.2 percent of patients with essential
hypertension treated with ENVAS alone. Increases are more likely to occur in
patients receiving concomitant diuretics or in patients with renal artery
stenosis. (See PRECAUTIONS.) In patients with heart failure who were also
receiving diuretics with or without digitalis increases in blood urea nitrogen
or serum creatinine, usually reversible upon discontinuation of ENVAS and/or
other concomitant diuretic therapy, were observed in about 11 percent of
patients. Increases in blood urea nitrogen or creatinine were a cause for
discontinuation in 1.2 percent of patients.
Hematology: Small decreases in hemoglobin and hematocrit (mean decreases of
approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently
in either hypertension or congestive heart failure patients treated with ENVAS
but are rarely of clinical importance unless another cause of anemia coexists.
In clinical trials, less than 0.1 percent of patients discontinued therapy due
to anemia. Hemolytic anemia, including cases of hemolysis in patients with G- 6-
PD deficiency, has been reported; a causal relationship to enalapril cannot be
excluded.
Liver Function Tests: Elevations of liver enzymes and/or serum bilirubin have
occurred (see WARNINGS, Hepatic Failure).
OVERDOSAGE:
Limited data are available in regard to overdosage in humans.
Single oral doses of enalapril above 1,000 mg/kg and >/=1,775 mg/kg were
associated with lethality in mice and rats, respectively.
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.
DOSAGE AND ADMINISTRATION:
Hypertension
In patients who are currently being treated with a diuretic, symptomatic
hypotension occasionally may occur following the initial dose of ENVAS. The
diuretic should, if possible, be discontinued for two to three days before
beginning therapy with ENVAS to reduce the likelihood of hypotension. (See
WARNINGS.) If the patient's blood pressure is not controlled with ENVAS alone,
diuretic therapy may be resumed.
If the diuretic cannot be discontinued an initial dose of 2.5 mg should be used
under medical supervision for at least two hours and until blood pressure has
stabilized for at least an additional hour. (See WARNINGS and PRECAUTIONS, Drug
Interactions.)
The recommended initial dose in patients not on diuretics is 5 mg once a day.
Dosage should be adjusted according to blood pressure response. The usual dosage
range is 10 to 40 mg per day administered in a single dose or two divided doses.
In some patients treated once daily, the antihypertensive effect may diminish
toward the end of the dosing interval. In such patients, an increase in dosage
or twice daily administration should be considered. If blood pressure is not
controlled with ENVAS alone, a diuretic may be added.
Concomitant administration of ENVAS with potassium supplements, potassium salt
substitutes, or potassium-sparing diuretics may lead to increases of serum
potassium (see PRECAUTIONS).
Dosage Adjustment In Hypertensive Patients With Renal Impairment
The usual dose of enalapril is recommended for patients with a creatinine
clearance >30 mL/min (serum creatinine of up to approximately 3 mg/dL). For
patients with creatinine clearance =30 mL/min (serum creatinine >/=3 mg/dL),
the first dose is 2.5 mg once daily. The dosage may be titrated upward until
blood pressure is controlled or to a maximum of 40 mg daily.
Creatinine-
Clearance Initial Dose
Renal Status mL/min mg/day
---------------------------------------------------------------------------------------------------------------------
Normal Renal >80 mL/min 5 mg
Function
Mild Impairment =80 >30 mL/min 5 mg
Moderate to =30 mL/min 2.5 mg
Severe
Impairment
Dialysis -- 2.5 mg on
Patients* dialysis
days**
*See WARNINGS, Anaphylactoid Reactions During Membrane Exposure.
**Dosage on nondialysis days should be adjusted depending on the blood
pressure response.
Heart Failure
ENVAS is indicated for the treatment of symptomatic heart failure, usually in
combination with diuretics and digitalis. In the placebo- controlled studies
that demonstrated improved survival, patients were titrated as tolerated up to
40 mg, administered in two divided doses.
The recommended initial dose is 2.5 mg. The recommended dosing range is 2.5 to
20 mg given twice a day. Doses should be titrated upward, as tolerated, over a
period of a few days or weeks. The maximum daily dose administered in clinical
trials was 40 mg in divided doses.
After the initial dose of ENVAS, the patient should be observed under medical
supervision for at least two hours and until blood pressure has stabilized for
at least an additional hour. (See WARNINGS and PRECAUTIONS, Drug Interactions.)
If possible, the dose of any concomitant diuretic should be reduced which may
diminish the likelihood of hypotension. The appearance of hypotension after the
initial dose of ENVAS does not preclude subsequent careful dose titration with
the drug, following effective management of the hypotension.
Asymptomatic Left Ventricular Dysfunction
In the trial that demonstrated efficacy, patients were started on 2.5 mg twice
daily and were titrated as tolerated to the targeted daily dose of 20 mg (in
divided doses).
After the initial dose of ENVAS, the patient should be observed under medical
supervision for at least two hours and until blood pressure has stabilized for
at least an additional hour. (See WARNINGS and PRECAUTIONS, Drug Interactions.)
If possible, the dose of any concomitant diuretic should be reduced which may
diminish the likelihood of hypotension. The appearance of hypotension after the
initial dose of ENVAS does not preclude subsequent careful dose titration with
the drug, following effective management of the hypotension.
Dosage Adjustment In Patients With Heart Failure And Renal Impairment Or
Hyponatremia
In patients with heart failure who have hyponatremia (serum sodium less than 130
mEq/L) or with serum creatinine greater than 1.6 mg/dL, therapy should be
initiated at 2.5 mg daily under close medical supervision. (See DOSAGE AND
ADMINISTRATION, Heart Failure, WARNINGS and PRECAUTIONS, Drug Interactions.) The
dose may be increased to 2.5 mg b.i.d., then 5 mg b.i.d. and higher as needed,
usually at intervals of four days or more if at the time of dosage adjustment
there is not excessive hypotension or significant deterioration of renal
function. The maximum daily dose is 40 mg.
************************************************************************