Vasotec Information
Vasotec ()
Vasotec () Use In Pregnancy
Vasotec () 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-[-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline, ()-2-butenedioate salt (1:1). Its empirical formula is CHNO•CHO, 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, sodium bicarbonate, and starch. The 10 mg and 20 mg tablets also contain iron oxides.
Vasotec () Clinical Pharmacology
Mechanism of Action
Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of enalapril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with 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 ). 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 () lowers 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 ). 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 C-enalapril maleate. Radioactivity was found to cross the placenta following administration of labeled drug to pregnant hamsters.
Pharmacodynamics and Clinical Effects
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
In the above pediatric studies, enalapril maleate was given as tablets of Vasotec () 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 under ).
Vasotec () Indications And Usage
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 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 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 are insufficient to show that Vasotec () does not have a similar risk (see ).
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 inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks (see ).
Vasotec () Contraindications
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 and in patients with hereditary or idiopathic angioedema.
Vasotec () Warnings
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.
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 ). 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 Vasotec () in patients at risk for excessive hypotension who are able to tolerate such adjustments (see and ). 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 Vasotec () , which usually 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 cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.
Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
Fetal/Neonatal Morbidity and Mortality
ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.
In a published restrospective 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 trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study have 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 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 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 exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.
No teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. On a body surface area basis, the doses used were 57 times and 12 times, respectively, the maximum recommended human daily dose (MRHDD).
Vasotec () Precautions
General
Information for Patients
Drug Interactions
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 , sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an 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
Nursing Mothers
Enalapril and enalaprilat have been detected in human breast milk. Because of the potential for serious adverse reactions in nursing infants from enalapril, a decision should be made whether to discontinue nursing or to discontinue Vasotec () , taking into account the importance of the drug to the mother.
Pediatric Use
Antihypertensive effects of Vasotec () have been established in hypertensive pediatric patients age 1 month to 16 years. Use of Vasotec () in these age groups is supported by evidence from adequate and well-controlled studies of Vasotec () in pediatric and adult patients as well as by published literature in pediatric patients (see and ).
Vasotec () is not recommended in neonates and in pediatric patients with glomerular filtration rate
Vasotec () Adverse Reactions
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 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 Vasotec () reporting adverse experiences was comparable to placebo.
Vasotec () 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 ).
Vasotec () Dosage And Administration
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 ). 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 and ).
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 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 ).
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.
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. 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 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 and ). 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.
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 and ). 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 , and ). 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 ).
Vasotec () is not recommended in neonates and in pediatric patients with glomerular filtration rate
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 Vasotec () 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™ 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.
Vasotec () How Supplied
Vasotec () Tablets, 2.5 mg, are white, oval shaped tablet with "VASO 2.5" and scored on one side and scored on the other.They are supplied as follows:NDC 64455-140-30 bottles of 30 (with desiccant)NDC 64455-140-90 unit of use bottles of 90 (with desiccant)
Vasotec () Tablets, 5 mg, are white, rounded triangle shaped tablet with "VASO 5" on one side and scored on the other.They are supplied as follows:NDC 64455-141-30 bottles of 30 (with desiccant)NDC 64455-141-90 unit of use bottles of 90 (with desiccant)NDC 64455-141-10 bottles of 1,000 (with desiccant)
Vasotec () Tablets, 10 mg, are rust red, rounded triangle shaped tablet with "VASO 10" on one side and scored on the other. They are supplied as follows:NDC 64455-142-30 bottles of 30 (with desiccant)NDC 64455-142-90 unit of use bottles of 90 (with desiccant)NDC 64455-142-10 bottles of 1,000 (with desiccant)
Vasotec () Tablets, 20 mg, are peach, rounded triangle shaped tablet with "VASO 20" on one side and scored on the other.They are supplied as follows:NDC 64455-143-30 bottles of 30 (with desiccant)NDC 64455-143-90 unit of use bottles of 90 (with desiccant)NDC 64455-143-10 bottles of 1,000 (with desiccant)
Vasotec ()
Vasotec () Principal Display Panel - . Mg Tablet Label
Vasotec () Principal Display Panel - Mg Tablet Label
Vasotec () Principal Display Panel - Mg Tablet Label
Vasotec () Principal Display Panel - Mg Tablet Label
