TABLETS
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
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, VASOTEC should be discontinued as soon as possible. See WARNINGS, Fetal/Neonat
al Morbidity and Mortality.
VASOTEC* (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·C4H404, 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 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.
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-aidosterone 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 VASOTEC alone for up to
48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated
with VASOTEC 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 VASOTEC remains to be elucidated.
While the mechanism through which VASOTEC lower blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, VASOTEC is antihypertensive even in patients with low-renin
hypertension. Although VASOTEC 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 VASOTEC, 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 VASOTEC 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 VASOTEC 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 VASOTEC have continued during long term therapy. Abrupt withdrawal of VASOTEC 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 reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of VASOTEC, 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 VASOTEC are
approximately additive.
In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving VASOTEC. In this study there was no evidence of a blunting of the antihypertensive action of VASOTEC.
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. Effect
s 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. Th
e 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 election fraction <=35% and no history of symptomatic heart failure, were randomized to pl
acebo (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. 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 f
ollowing table.
SURVIVAL (%) Six Months One Year VASOTEC (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.
Hypertension
VASOTEC is indicated for the treatment of hypertension.
VASOTEC is effective alone or in combination with other antihypertensive agents, especially thiazide-type
diuretics. The blood pressure lowering effects of VASOTEC and thiazides are approximately additive.
Heart Failure
VASOTEC is indicated for the treatment of symptomatic congestive heart failure, usually in combination with
diuretics and digitalis. In these patients VASOTEC 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 Dysfunction
In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction =<35 percent), VASOTEC 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 VASOTEC 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 ar
e insufficient to show that VASOTEC does not have a similar risk. (See WARNINGS.)
In considering use of VASOTEC, 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 inhibitor monotherapy have been reported to have a higher incidence of angioedema
compared to non-blacks. (See WARNINGS, Angioedema.)
VASOTEC 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.
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 VASOTEC)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 VASOTEC. This may occur at any
time during treatment. In such cases VASOTEC 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 confi
ned 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 (a procedure dependent upon device
s not approved in the United States).
Hypotension
Excessive hypotension is rare in uncomplicated hypertensive patients treated with VASOTEC alone. Patients with heart failure given VASOTEC 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 o
liguria 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 diuret
ic 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 VASOTEC 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 clos
ely 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 cerebrovasormar disease, in whom an excessive fall in blood pressure could resul
t 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 VASOTEC, which usuall
y can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of VASOTEC 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 wh
o 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.<
BR>
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 VASOTEC 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, VASOTEC 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 pre
gnancy. 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 dialys
is 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 mg/kg basis, the
doses used were up to 333 times (in rats), and 50 times (in rabbits) the maximum recommended human dose.
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 heartfailure whose renal
function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin
converting enzyme inhibitors, including VASOTEC, 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 VASOTEC
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 VASOTEC 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 VASOTEC. (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 sugg
esting 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 bl
ood 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 effect
s.
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 VASOTEC is augmented by antihypertensive
agents that cause renin release (e.g., diuretics).
Other Cardiovascular Agents: VASOTEC has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine, prazosin and digoxin without evidence of clinically significant adverse interaction
s.
Agents Increasing Serum Potassium: VASOTEC 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 ag
ents should generally not be
used in patients with heart failure receiving VASOTEC.
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
VASOTEC 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 rats at doses up to 90 mg/kg/day (150 times** the maximum daily human dose). Enalapril has also been administered for 94 weeks to male and female mic
e at doses up to 90 and 180 mg/kg/day, respectively, (150 and 300 times** the maximum daily dose for humans) and showed no evidence of carcinogenicity.
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 with 10 to 90 mg/kg/day of enalapril.
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS,
Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
Enalapril and enalaprilat are detected in human milk in trace amounts. Caution should be exercised when VASOTEC is given to a nursing mother.
Pediatric Use
Safety and effectiveness in children have not been established.
VASOTEC has been evaluated for safety in more than 10,000 patients, including over 1000 patients treated for one year or more VASOTEC 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 hea
rt 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 VASOTEC reporting adverse experiences was comparable to
placebo.
HYPERTENSION
Adverse experiences occurring in greater than one percent of patients with hypertension treated with VASOTEC in controlled clinical trials are shown below. In patients treated with VASOTEC, the maximum duration of therapy
was three years; In placebo treated patients the maximum duration of therapy was 12 weeks.
VASOTEC Placebo (n = 2314) (n = 230) Incidence Incidence (discontinuation) ________________________________________________________________ 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
VASOTEC 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
VASOTEC and placebo, respectively.
VASOTEC 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 1.6tien4) 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 or
der 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.
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, dysosthesia).
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 a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, r
ash and other dermatologic manifestations.
Angioedema: Angioedema has been reported in patients receiving VASOTEC, 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 VASOTEC 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 thera
py 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 o 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 tre
ated with VASOTEC 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 digital
is, increases in blood urea nitrogen or serum creatinine, usually reversible upon discontinuation of VASOTEC and/or other concomitant diuretic therapy, were observed in about 11 percent of patients. Increases in blood urea nitrogen or creatinine were a c
ause for discontinuation in 1.2 percent of patients.
Hematology: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3g percent and 1.0 vol percent, respectively) occur frequently in either hypertension or congestive heart failure patients treated with VASOTEC but are ra
rely 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 re
ported; 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).
Limited data are available in regard to overdosage in humans.
The oral LD50 of enalapril is 2000 mg/kg in mice and rats. 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.
Hypertension
In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur
following the initial dose of VASOTEC. The diuretic should, if possible, be discontinued for two to three days
before beginning therapy with VASOTEC to reduce the likelihood of hypotension. (See WARNINGS.) If the
patient’s blood pressure is not controlled with VASOTEC 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 pati
ents 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 VASOTEC alone,
a diuretic may be added.
Concomitant administration of VASOTEC 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 on
ce 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 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
VASOTEC 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. Dose should be titrated upward, as tolerated, over a period of a few days or weeks. The maximum daily dose administered in clinical trails was 40 mg
in divided doses.
After the initial dose of VASOTEC, the patient should b observed under medical supervision for at least two hours an until blood pressure has stabilized for at least an additional hour. (See WARNINGS and PRECAUTIONS, Drug Interactions.) If possib
le, 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 VASOTEC does not preclude subsequent careful dose titration with the drug, following effec
tive 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 VASOTEC, 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 VASOTEC 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 d
osage adjustment there is not excessive, hypotension or
significant deterioration of renal function. The maximum daily dose is 40 mg.
No. 3411 – Tablets VASOTEC, 2.5 mg, are yellow, biconvex barrel shaped, scored, compressed tablets with
code MSD 14 on one side and VASOTEC on the other. They are supplied as follows:
-
NDC 0006-0014-94 unit of use bottles of 90 (with desiccant)
NDC 0006-0014-68 bottles of 100 (with desiccant)
(6505-01-351-3157, 2.5 mg 100’s)
NDC 0006-0014-28 unit dose packages of 100
NDC 0006-0014-98 unit of use bottles of 180 (with desiccant)
NDC 0006-0014-82 bottles of 1,000 (with desiccant)
NDC 0006-0014-87 bottles of 10,000 (with desiccant).
No. 3412 – Tablets VASOTEC, 5 mg, are white, barrel shaped, scored, compressed tablets, with code MSD 712 on one side and VASOTEC on the other. They are supplied as follows:
-
NDC 0006-0712-94 unit of use bottles of 90 (with desiccant)
NDC 0006-0712-68 bottles of 100 (with desiccant)
(6505-01-236-8880,5 mg 100’s)
NDC 0006-0712-28 unit dose packages of 100
(6505-01-244-4811, 5 mg individually sealed 100’s)
NDC 0006-0712-98 unit of use bottles of 180 (with desiccant)
NDC 0006-0712-82 bottles of 1,000 (with desiccant)
NDC 0006-0712-81 bottles of 4,000 (with desiccant)
(6505-01-319-9526, 5 mg 4,000’s)
NDC 0006-0712-87 bottles of 10,000 (with desiccant)
(6505-01-379-5575, 5 mg 10,000’s).
No. 3413 – Tablets VASOTEC, 10 mg, are salmon, barrel shaped, Compressed tablets, with code MSD 713 on one side and VASOTEC on the other. They are supplied as follows:
-
NDC 0006-0713-94 unit of use bottles of 90 (with desiccant)
NDC 0006-0713-68 bottles of 100 (with desiccant) (6505-01-236-8881, 10 mg 100’s)
NDC 0006-0713-28 unit dose packages of 100 (6505-01-314-6028, 10 mg individually sealed 100’s)
NDC 0006-0713-98 unit of use bottles of 180 (with desiccant)
NDC 0006-0713-82 bottles of 1,000 (with desiccant)
NDC 0006-0713-81 bottles of 4,000 (with desiccant)
(6505-01-320-4728, 10 mg 4,000’s)
NDC 0006-0713-87 bottles of 10,000 (with desiccant)
(6505-01-378-8022, 10 mg 10,000’s).
No. 3414 – Tablets VASOTEC, 20 mg, are peach, barrel shaped, compressed tablets, with code MSD 714 on
one side and VASOTEC on the other. They are supplied as follows:
-
NDC 0006-0714-94 unit of use bottles of 90 (with desiccant)
NDC 0006-0714-68 bottles of 1 00 (with desiccant)
(6505-01-237-0545,20 mg 100’s)
NDC 0006-0714-28 unit dose packages of 100
(6505-01-318-0465, 20 mg individually sealed 100’s)
NDC 0006-0714-82 bottles of 1,000 (with desiccant)
NDC 0006-0714-87 bottles of 10,000 (with desiccant)
(6505-01-378-8780, 20 mg 10,000’s).
Storage
Store below 30ºC (86ºF) and avoid transient temperatures above 50ºC (122ºF). Keep container tightly closed. Protect from moisture.
Dispense in a tight container, if product package is subdivided.
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © MERCK & CO. Inc., 1988,1989, 1992, 1993
All rights reserved.
**Based on patient weight of 50 kg
Issued July 1995
Printed in USA