Product Information
ENALAPRIL MALEATE TABLETS,
USP
Rx only
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, enalapril maleate
should be discontinued as soon as possible. See WARNINGS, Fetal / Neonatal Morbidity and Mortality.
DESCRIPTION
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
L-Proline,1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]- , (S)-,
(Z)-2-butenedioate (1:1). Its molecular formula is, C20H28N2O5·C4H4O4, and its structural formula is:
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,10 mg and 20 mg
tablets for oral administration. In addition, each tablet contains the following
inactive ingredients: hypromellose, anhydrous lactose, corn starch, stearic acid
and talc. The 10 mg and 20 mg tablets also contain iron oxides.
CLINICAL PHARMACOLOGY
Mechanism of ActionEnalapril, 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 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 enalapril remains to be
elucidated.
While the mechanism through which enalapril lowers blood
pressure is believed to be primarily suppression of the renin-angiotensin-
aldosterone system, enalapril is antihypertensive even in patients with
low-renin hypertension. Although enalapril 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 MetabolismFollowing oral
administration of enalapril maleate, 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 enalapril 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 enalapril 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 enalapril have continued during long term therapy.
Abrupt withdrawal of enalapril 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 enalapril, 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 enalapril are approximately additive.
In a
clinical pharmacology study, indomethacin or sulindac was administered to
hypertensive patients receiving enalapril. In this study there was no evidence
of a blunting of the antihypertensive action of enalapril. (see PRECAUTIONS,
Drug Interactions.)
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, 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-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. SOLVDPrevention 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 |
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 63-76%. 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 less than 50 kg received
either 0.625, 2.5 or 20 mg of enalapril daily and patients who weighed greater than or equal to 50 kg
received either 1.25, 5, 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 maleate was generally well tolerated.
In the above pediatric
studies, enalapril maleate was given as tablets 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
Preparation of Suspension under DOSAGE AND
ADMINISTRATION).
INDICATIONS AND USAGE
HypertensionEnalapril maleate is indicated for
the treatment of hypertension.
Enalapril maleate is effective alone or
in combination with other antihypertensive agents, especially thiazide-type
diuretics. The blood pressure lowering effects of enalapril maleate and
thiazides are approximately additive.
Heart FailureEnalapril maleate is indicated for
the treatment of symptomatic congestive heart failure, usually in combination
with diuretics and digitalis. In these patients enalapril maleate improves
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 DysfunctionIn
clinically stable asymptomatic patients with left ventricular dysfunction
(ejection fraction ≤35 percent), enalapril maleate decreases the rate of
development of overt heart failure and decreases 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, 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 does not have a similar risk. (See
WARNINGS.)
In considering use of enalapril maleate, 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.)
CONTRAINDICATIONS
Enalapril maleate 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 and in patients with
hereditary or idiopathic angioedema.
WARNINGS
Anaphylactoid and Possibly Related
ReactionsPresumably because angiotensin-converting enzyme inhibitors affect
the metabolism of eicosanoids and polypeptides, including endogenous bradykinin,
patients receiving ACE inhibitors (including enalapril maleate) may be subject
to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema:
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has
been reported in patients treated with angiotensin converting enzyme inhibitors,
including enalapril maleate. This may occur at any time during treatment. In
such cases enalapril maleate 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.)
Intestinal Angioedema: Intestinal angioedema has been
reported in patients treated with ACE inhibitors. These patients presented with
abdominal pain (with or without nausea or vomiting); in some cases there was no
prior history of facial angioedema and C-1 esterase levels were normal. The
angioedema was diagnosed by procedures including abdominal CT scan or
ultrasound, or at surgery, and symptoms resolved
after stopping the ACE
inhibitor. Intestinal angioedema should be included in the differential
diagnosis of patients on ACE inhibitors presenting with abdominal pain.
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.
HypotensionExcessive hypotension is rare in
uncomplicated hypertensive patients treated with enalapril maleate alone.
Patients with heart failure given enalapril maleate 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
enalapril maleate 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 enalapril
maleate, which usually can be given without difficulty once the blood pressure
has stabilized. If symptomatic hypotension develops, a dose reduction or
discontinuation of enalapril maleate or concomitant diuretic may be
necessary.
Neutropenia/AgranulocytosisAnother 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 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 FailureRarely, 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 MortalityACE
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.
In a published retrospective epidemiological study, infants
whose mothers had taken an ACE inhibitor during their first trimester of
pregnancy appeared to have an increased risk of major congenital malformations
compared with infants whose mothers had not undergone first timester exposure to
ACE inhibitor drugs. The number of cases of birth defects is small and the
findings of this study are not yet been repeated.
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 enalapril maleate 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, enalapril maleate 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 towards 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 57 times and 12 times, respectively, the maximum recommended human
daily dose (MRHDD).
PRECAUTIONS
General
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 heart failure
whose renal function may depend on the activity of the
renin-angiotensin-aldosterone system, treatment with angiotensin converting
enzyme inhibitors, including enalapril maleate, 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 maleate 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 enalapril maleate
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 enalapril
maleate. (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 light-headedness, 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 exposure to ACE inhibitors. 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 enalapril maleate is 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 nonsteroidal
anti-inflammatory drugs, the co-administration 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: Enalapril maleate 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: Enalapril maleate 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 enalapril maleate.
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 enalapril maleate 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.
Gold: Nitritoid reactions (symptoms
include facial flushing, nausea, vomiting and hypotension) have been reported
rarely in patients on therapy with injectable gold (sodium aurothiomalate) and
concomitant ACE inhibitor therapy including Enalapril.
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 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).
Pregnancy
Pregnancy
Categories C (first trimester)
and D (second
and third trimesters). See WARNINGS,
Fetal/Neonatal
Morbidity and Mortality.Nursing MothersEnalapril 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 enalapril maleate, taking into account
the importance of the drug to the mother.
Pediatric UseAntihypertensive effects of
enalapril maleate have been established in hypertensive pediatric patients age 1
month to 16 years. Use of enalapril maleate in these age groups is supported by
evidence from adequate and well-controlled studies of enalapril maleate in
pediatric and adult patients as well as by published literature in pediatric
patients. (See CLINICAL PHARMACOLOGY,
Clinical Pharmacology
in Pediatric Patients and DOSAGE AND ADMINISTRATION.)
Enalapril
maleate is not recommended in neonates and in pediatric patients with glomerular
filtration rate less than 30 mL/min/1.73 m
2, as no data are
available.
ADVERSE REACTIONS
ADVERSE REACTIONSEnalapril maleate has been
evaluated for safety in more than 10,000 patients, including over 1000 patients
treated for one year or more. Enalapril maleate has been found to be generally
well tolerated in conrolled 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 enalapril maleate
reporting adverse experiences was comparable to placebo.
HYPERTENSION
Adverse experiences occurring in
greater than one percent of patients with hypertension treated with enalapril
maleate in controlled clinical trials are shown below. In patients treated with
enalapril maleate, the maximum duration of therapy was three years; in placebo
treated patients the maximum duration of therapy was 12 weeks.
| Enalapril Maleate (n=2314) Incidence (discontinuation)
| Placebo (n=230) Incidence
|
Body As A Whole |
|
|
Fatigue
| 3.0 (less than 0.1)
| 2.6
|
Orthostatic Effets
| 1.2 (less than 0.1) | 0.0
|
Asthenia
| 1.1 (0.1) | 0.9
|
Digestive |
|
|
Diarrhea
| 1.4 (less than 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 FAILUREAdverse experiences occurring in
greater than one percent of patients with heart failure treated with enalapril
maleate 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 enalapril maleate and
placebo, respectively.
| Enalapril Maleate (n=673) Incidence (discontinuation)
| Placebo (n=339) Incidence |
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 Hypotension | 1.6 (0.1)
| 0.3
|
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 Infection | 1.3 (0.0) | 2.4
|
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, eosinophilic pneumonitis.
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 enalapril maleate 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 enalapril maleate 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 occured 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.
Pediatric
Patients
The adverse experience profile for pediatric patients
appears to be similar to that seen in adult patients.
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 enalapril
maleate 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 enalapril maleate 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 enalapril maleate 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. (See WARNINGS, Anaphylactoid reactions during membrane exposure.)
DOSAGE AND ADMINISTRATION
HypertensionIn patients who are currently being
treated with a diuretic, symptomatic hypotension occasionally may occur
following the initial dose of Enalapril Maleate Tablets. The diuretic should, if
possible, be discontinued for two to three days before beginning therapy with
Enalapril Maleate Tablets to reduce the likelihood of hypotension. (See
WARNINGS.) If the patient's blood pressure is not controlled with Enalapril
Maleate Tablets 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
Enalapril Maleate Tablets alone, a diuretic may be added.
Concomitant
administration of Enalapril Maleate Tablets 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.
Renal Status
| Creatinine- Clearance ml/min
| Initial Dose mg/day |
Normal Renal Function
| >80 mL/min
| 5 mg
|
Mild Impairment
| ≤80> 30 mL/min | 5 mg
|
Moderate to Severe Impairment
| ≤30 mL/min | 2.5 mg
|
Dialysis Patients***
| - -
| 2.5 mg on dialysis days†
|
***See WARNINGS, Anaphylactoid reactions during
membrane exposure.
†Dosage on nondialysis days should
be adjusted depending on the blood pressure response.
Heart Failure
Enalapril Maleate Tablets are 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 Enalapril Maleate Tablets, 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 Enalapril Maleate Tablets 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 Enalapril Maleate Tablets, 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 Enalapril Maleate Tablets 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.
Pediatric Hypertensive Patients
The usual recommended
starting dose is 0.08 mg/kg (up to 5 mg) once daily. Dosage should be adjusted
according to blood pressure response. Doses above 0.58 mg/kg (or in excess of 40
mg) have not been studied in pediatric patients.
(See CLINICAL
PHARMACOLOGY,
Clinical Pharmacology in Pediatric
Patients.)
Enalapril maleate is not recommended in neonates and in
pediatric patients with glomerular filtration rate less than 30 mL/ min/1.73 m
2, as no data are available.
Preparation of Suspension (for 200 mL of a 1.0 mg/mL suspension)
Add 50 mL of Bicitra
®** to a polyethylene
terephthalate (PET) bottle containing ten 20 mg tablets of Enalapril maleate and
shake for at least 2 minutes. Let concentrate stand for 60 minutes. Following
the 60-minute hold time, shake the concentrate for an additional minute. Add 150
mL of Ora-Sweet SF
TM*** to the concentrate in the PET
bottle and shake the suspension to disperse the ingredients.
The
suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to
30 days. Shake the suspension before each use.
HOW SUPPLIED
Enalapril Maleate Tablets, USP
Quantity
| NDC Number
| Strength
| Description
|
Bottles of 30 Bottles of 60 Bottles of 100 | NDC 54868-4332-1 NDC 54868-4332-0 NDC 54868-4332-2 | 2.5 mg
| White, rount flat-faced beveled edged, compressed tablets with W on one side
and breakline on the other
side. |
Bottles of 30 Bottles of 60 Bottles of 90 Bottles of 100 | NDC 54868-4357-0 NDC 54868-4357-1 NDC 54868-4357-3 NDC 54868-4357-2 | 5 mg
| White, rount flat-faced beveled edged, compressed tablets with W on one side
and breakline on the other
side.
|
Bottles of 30 Bottles of 60 Bottles of 90 Bottles of 100 | NDC 54868-4358-0 NDC 54868-4358-1 NDC 54868-4358-3 NDC 54868-4358-2 | 10 mg
| Light Salmon, round flat-faced beveled edged, compressed tablets with W on
one side plain on the other
side. |
Bottles of 30 Bottles of 60 Bottles of 90 Bottles of 100 | NDC 54868-4331-1 NDC 54868-4331-2 NDC 54868-4331-3 NDC 54868-4331-0 | 20 mg
| Light Beige, rount flat-faced beveled edged, compressed tablets with W on
one side plain on the other side. |
Storage
Store below 30°C
(86°F) and avoid transient temperatures above 50°C (122°F). Keep container
tightly closed. Protect from moisture.
Dispense in a tight container as
per USP, if product package is
subdivided.
___________________________________________________________________________________________________________________________________
** Registered trademark of Alza Corporation.
*** Trademark of Paddock Laboratories, Inc.
Manufactured
by:
Wockhardt Limited,
Mumbai,
India.
Distributed by:
Wockhardt USA LLC.
20 Waterview Blvd.
Parsippany, NJ 07054
USA.
Rev.221209
Relabeling and Repackaging by:
Physicians Total Care, Inc.
Tulsa, OK 74146
PRINCIPAL DISPLAY PANEL
Enalapril Maleate Tablets
2.5 mg
5 mg
10 mg
20 mg
Physicians Total Care, Inc.