VASOTEC®
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.
DESCRIPTION
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 48In 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 cerebrovascular 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 Cough:
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.)
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. Pregnancy 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 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. 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. 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: 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. Hypertension Dosage Adjustment in Hypertensive Patients with Renal
Impairment 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). Dosage Adjustment in Patients with Heart Failure and Renal Impairment or
Hyponatremia 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:
Storage * Registered trademark of MERCK & CO., Inc.
Issued July 1995
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 Categories C (first trimester) and D
(second and third trimesters). See WARNINGS, Fetal/Neonatal Morbidity and
Mortality.
Safety and effectiveness in children have not been
established.
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.
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 1.6 (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 or der of decreasing severity.
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.
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).
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.
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.
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.
NDC 0006-0014-94 unit of use bottles of 90 (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
0006-0014-68 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).NDC 0006-0712-94 unit of use bottles of 90 (with desiccant)
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
0006-0712-68 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).NDC 0006-0713-94 unit of use bottles of 90 (with desiccant)
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
0006-0713-68 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).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).
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.
COPYRIGHT © MERCK &
CO. Inc., 1988,1989, 1992, 1993
All rights reserved.
**Based on patient
weight of 50 kg
Printed in USA