Vasotec (Enalapril Maleate)

VASOTEC® VASOTEC® I.V.

Frosst

Enalapril Maleate

Enalaprilat

Angiotensin Converting Enzyme Inhibitor

Action And Clinical Pharmacology: Enalapril is an ACE inhibitor which is used in the treatment of hypertension and heart failure. Enalaprilat is an active metabolite of enalapril and is used in the treatment of hypertension.

Angiotensin converting enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to the pressor substance, angiotensin II. After absorption, enalapril, a pro-drug, is hydrolyzed to enalaprilat, its active metabolite, which inhibits ACE. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release) and decreased aldosterone secretion. Although the latter decrease is small, it results in a small increase in serum potassium. In patients treated with enalapril and a thiazide diuretic there was essentially no change in serum potassium (see Precautions).

ACE is identical to kininase II. Thus, both Vasotec and Vasotec I.V. may also block the degradation of bradykinin, a potent vasodepressor peptide. However, the role that this plays in the therapeutic effects of either drug is unknown.

While the mechanism through which Vasotec and Vasotec I.V. lowers blood pressure is believed to be primarily the suppression of the renin-angiotensin-aldosterone system, both Vasotec and Vasotec I.V. also lower blood pressure in patients with low-renin hypertension.

Administration of Vasotec or Vasotec I.V. to patients with hypertension results in a reduction of both supine and standing blood pressure. Abrupt withdrawal of Vasotec or Vasotec I.V. has not been associated with a rapid increase in blood pressure. Following administration of Vasotec I.V., the onset of action usually occurs within 15 minutes, with the maximum effect occurring within 1 to 4 hours. In most patients studied, after oral administration of an individual dose of enalapril, the onset of antihypertensive activity is seen at 1 hour with peak reduction of blood pressure achieved by 4 to 6 hours. At recommended doses, the antihypertensive effect has been shown to be maintained for a least 24 hours. In some patients the effect may diminish towards the end of the dosing interval (see Dosage). On occasion, achievement of optimal blood pressure reduction may require several weeks of therapy.

In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of Vasotec, there was an increase in renal blood flow; glomerular filtration rate was usually unchanged. The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black than in nonblack patients.

When Vasotec is given together with thiazide-type diuretics, its blood pressure lowering effect is approximately additive.

Administration of enalapril to patients with congestive heart failure reduces afterload and preload of the heart, resulting in an increase in cardiac output, without reflex tachycardia.

In a multi-centre, placebo-controlled, double-blind study (SOLVD), 2 569 patients with symptomatic heart failure (primarily New York Heart Association Class II and III and ejection fraction £35%), were randomized to placebo or enalapril given as an adjunct to conventional therapy. Diseases that excluded patients from enrolment in the study included severe stable angina, hemodynamically significant valvular or outflow tract obstruction, renal failure, cerebral vascular disease (e.g., significant carotid artery diseases), advanced pulmonary disease, malignancies, active myocarditis and constrictive pericarditis. The use of enalapril was associated with an 11% reduction in all-cause mortality (which corresponds to a 16% risk reduction in all-cause mortality) and a 30% reduction in hospitalization for heart failure (which corresponds to a 36% risk reduction in hospitalization for heart failure). The chief difference in mortality was in deaths due to progressive heart failure. There was no significant difference in the number of deaths classified as due to arrhythmia without worsening congestive heart failure.

A second multicenter trial used the SOLVD protocol for a study of asymptomatic or minimally symptomatic patients. SOLVD-Prevention patients, who had left ventricular ejection fraction £35% and no history of symptomatic heart failure, were randomized to placebo (n=2117) or enalapril (n=2111) and followed for up to 5 years. The majority of patients in the SOLVD-Prevention trial had a history of ischemic heart disease. A history of myocardial infarction was present in 80% of patients, current angina pectoris in 34%, and a history of hypertension in 37%. No statistically significant mortality effect was demonstrated in this population. Enalapril-treated subjects had 32% fewer first hospitalizations for heart failure, and 32% fewer total heart failure hospitalizations. Compared to placebo, 32% fever 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, 1 166 vs. 1 201 first hospitalizations, 2 649 vs. 2 840 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 multi-centre, placebo-controlled trial (CONSENSUS), 253 patients with severe congestive heart failure (New York Heart Association Class IV) were randomized to placebo or enalapril given as an adjunct to conventional therapy. The use of enalapril was associated with an improvement of symptoms and a reduction in mortality from the progression of heart failure. No difference was seen in the incidence of sudden cardiac death.

Pharmacokinetics: Enalapril is rapidly absorbed with peak serum concentrations occurring within 1 hour. Based on urinary recovery the extent of absorption is approximately 60%.

Following absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent angiotensin-converting enzyme inhibitor (which itself is poorly absorbed). Peak serum concentrations of enalaprilat occur 3 to 4 hours after an oral dose of enalapril maleate. Excretion of enalapril is primarily renal. Approximately 94% 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% of the dose, and intact enalapril. Except for conversion to enalaprilat, there is no evidence of significant metabolism of enalapril. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to ACE. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours. The absorption of enalapril is not influenced by the presence of food in the gastrointestinal tract.

Pharmacodynamics: 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 0.50 mL/s (30 mL/min) or less. With renal function £0.50 mL/s (£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 is prolonged at this level of renal insufficiency (see Dosage). Enalaprilat is dialyzable at the rate of 1.03 mL/s (62 mL/min).

When used in hypertensive, normolipidemic patients, enalapril had no effect on plasma lipoprotein fractions.

Studies in dogs indicate that enalapril crosses the blood brain barrier poorly, if at all; enalaprilat does not enter the brain.

Indications And Clinical Uses: Vasotec: In the treatment of essential or renovascular hypertension. It is usually administered in association with other drugs, particularly thiazide diuretics.

In using enalapril consideration should be given to the risk of angioedema (see Warnings).

Enalapril should normally be used in those patients in whom treatment with a diuretic or beta-blocker was found ineffective or has been associated with unacceptable adverse effects.

Enalapril can also be tried as an initial agent in those patients in whom use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.

Enalapril is indicated in the treatment of symptomatic congestive heart failure usually in combination with diuretics and/or digitalis. In these patients, enalapril improves symptoms, increases survival, and decreases the frequency of hospitalization (see Pharmacology for details and limitations of survival trials). Treatment with enalapril should be initiated under close medical supervision.

In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction 35%), enalapril decreases the rate of development of overt heart failure and decreases the incidence of hospitalization for heart failure (see Pharmacology for details and limitations of survival trials).

Pregnancy: When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected enalapril should be discontinued as soon as possible (see Warnings, Pregnancy and Information for the Patient).

Vasotec I.V.: For the treatment of hypertension when oral therapy is not practical.

Enalaprilat has been studied with only one other antihypertensive agent, furosemide, which showed approximately additive effects on blood pressure.

Due to insufficient experience with enalaprilat in the treatment of accelerated or malignant hypertension, this drug is not recommended in such situations (see Dosage).

Contra-Indications: Patients who are hypersensitive to these products or any of their components and in patients with a history of angioneurotic edema relating to previous treatment with an angiotensin-converting enzyme inhibitor.

Manufacturers’ Warnings In Clinical States: Angioedema: Angioedema has been reported in patients treated with Vasotec and Vasotec I.V. This may occur at any time during treatment. Angioedema associated with laryngeal edema and/or shock may be fatal. If angioedema occurs, Vasotec or Vasotec I.V. should be discontinued and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Where swelling is confined to the face, lips and mouth the condition will usually resolve without further treatment, although antihistamines may be useful in relieving symptoms. These patients should be followed carefully until the swelling has resolved. However, where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy such as s.c. epinephrine (0.5 mL 1:1 000) should be administered promptly when indicated.

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in nonblack patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see Contraindications).

Hypotension: Symptomatic hypotension has occurred after administration of both Vasotec and Vasotec I.V., usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision, usually in a hospital. Such patients should be followed closely for the first 2 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 (see Adverse Effects).

If hypotension occurs, the patient should be placed in supine position and, if necessary, receive an i.v. infusion of normal saline. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion.

Neutropenia/Agranulocytosis: Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Several cases of agranulocytosis and neutropenia have been reported in which a causal relationship to enalapril cannot be excluded. Current experience with the drug shows the incidence to be rare. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and renal disease.

Pregnancy: ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, enalapril should be discontinued as soon as possible.

In rare cases (probably less than once in every 1 000) in which no alternative to ACE inhibitor therapy will be found, the mothers should be apprised of the potential hazards to their fetuses. Serial ultrasound examinations should be performed to assess fetal development and well-being and the volume of amniotic fluid.

If oligohydramnios is observed, enalapril should be discontinued unless it is considered life-saving for the mother. A non-stress test (NST), and/or a biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. If concerns regarding fetal well-being still persist, a contraction stress testing (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with a history 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 a means of reversing hypotension and/or substituting for impaired renal function; however, experience with those procedures has been limited.

Enalapril has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit and may, theoretically, be removed by exchange transfusion, although there is no experience with the latter procedure.

Human Data: It is not known whether exposure limited to the first trimester of pregnancy can adversely affect fetal outcome. 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 and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure.

Animal Data: No reproductive or teratogenicity studies have been performed with enalaprilat.

Maternal and fetal toxicity occurred in some rabbits given enalapril at doses of 1 mg/kg/day or more. Saline supplementation prevented the maternal and fetal toxicity seen at doses of 3 and 10 mg/kg/day, but not at 30 mg/kg/day (50 times the maximum human dose). Enalapril was not teratogenic in rabbits.

There was no fetotoxicity or teratogenicity in rats treated with enalapril at doses up to 200 mg/kg/day (333 times the maximum human dose). Fetotoxicity expressed as a decrease in average fetal weight, occurred in rats given 1 200 mg/kg/day of enalapril, but did not occur when these animals were supplemented with saline. The drug crosses the placental barrier in rats and hamsters.

Precautions: Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

Use of enalapril should include appropriate assessment of renal function.

Hyperkalemia: Elevated serum potassium (>5.7 mEq/L) was observed in approximately 1% of hypertensive patients in clinical trials with enalapril. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in 0.28% of hypertensive patients. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia (see Drug Interactions, Agents Increasing Serum Potassium).

Valvular Stenosis: There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril blocks 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.

Patients with Impaired Liver Function: Hepatitis, jaundice (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with Vasotec in patients with or without pre-existing liver abnormalities (see Adverse Effects). In most cases the changes were reversed on discontinuation of the drug.

Should the patient receiving Vasotec experience any unexplained symptoms (see Information for the Patient), particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigation be carried out. Discontinuation of Vasotec should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. Both Vasotec and Vasotec I.V. should be used with particular caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

Cough: A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of Vasotec has been reported.

Such possibility should be considered as part of the differential diagnosis of the cough.

Lactation: Enalapril and enalaprilat are secreted in human milk in trace amounts. In general, nursing should be interrupted if Vasotec is given to a nursing mother.

Children: Neither enalapril nor enalaprilat have been studied in children and, therefore, use in this age group is not recommended.

Anaphylactoid Reactions during Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g., polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Anaphylactoid Reactions during Desensitization: There have been isolated reports of patients experiencing sustained life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasp) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.

Anaphylactoid Reactions during LDL Apheresis: Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

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 or enalaprilat. The possibility of hypotensive effects with enalapril or enalaprilat can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril or enalaprilat (see Warnings and Dosage). If the diuretic cannot be discontinued, patients should be placed under close medical supervision for at least 1 hour after the initial dose of Vasotec I.V. (see Warnings).

Agents Increasing Serum Potassium: Since enalapril and enalaprilat decreases aldosterone production, elevation of serum potassium may occur. Potassium sparing diuretics such as spironolactone, triamterene or amiloride, or potassium supplements should be given only for documented hypokalemia and with caution and frequent monitoring of serum potassium since they may lead to a significant increase in serum potassium. Salt substitutes which contain potassium should also be used with caution.

Agents Causing Renin Release: The antihypertensive effect of both Vasotec and Vasotec I.V. is augmented by antihypertensive agents that cause renin release (e.g., diuretics).

Agents Affecting Sympathetic Activity: Agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) may be used with caution. Beta-adrenergic blocking drugs add some further antihypertensive effect to enalapril.

Lithium Salts: As with other drugs which eliminate sodium, lithium clearance may be reduced. Therefore, the serum lithium levels should be monitored carefully if lithium salts are to be administered.

Information for the Patient: Angioedema: Angioedema, including laryngeal edema, may occur especially following the first dose of enalapril or enalaprilat. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.

Hypotension: Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with 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.

Impaired Liver Function: Patients should be advised to return to the physician if he/she experiences any symptoms possibly related to liver dysfunction. This would include “viral-like symptoms” in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.

Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.

Pregnancy: Patients should be advised to report promptly to their physician if they become pregnant, since the use of Vasotec during pregnancy can cause injury and even death of the developing fetus.

Note: As with many other drugs, certain advice to patients being treated with Vasotec is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Adverse Reactions: Vasotec: In controlled clinical trials involving 2 314 hypertensive patients and 363 patients with congestive heart failure, the most severe adverse reactions were: angioedema (0.2%), hypotension (2.3%) and renal failure (5 cases).

In hypertensive patients, hypotension occurred in 0.9% and syncope in 0.5%, with a discontinuation rate of 0.1%.

In congestive heart failure patients, hypotension occurred in 4.4% and syncope 0.8%, with a discontinuation rate of 2.5%.

The most frequent clinical adverse reactions in controlled clinical trials were: headache (4.8%), dizziness (4.6%) and fatigue (2.8%). Discontinuation of therapy was required in 6% of the 2 677 patients.

Laboratory Test Findings: Hyperkalemia: (see Precautions).

Creatinine, BUN: Increases in serum creatinine and BUN were reported in about 20% of patients with renovascular hypertension and in about 0.2% of patients with essential hypertension treated with enalapril alone.

In patients with congestive heart failure, who were also receiving diuretics and/or digitalis, increases in BUN and serum creatinine, usually reversible upon discontinuation of Vasotec and/or concomitant therapy, were observed in about 9.7% of patients.

Hemoglobin and Hematocrit: Decreases in hemoglobin and hematocrit (mean approximately 0.34 g% and 1 vol% respectively) occurred frequently in either hypertensive or congestive heart failure patients treated with Vasotec, but were rarely of clinical importance. In clinical trials, less than 0.1% of patients discontinued therapy due to anemia.

Hepatic: Elevations of liver enzymes and/or serum bilirubin have occurred (see Precautions).

Adverse reactions reported in uncontrolled trials and/or marketing experience: The following occurred in an incidence of 0.5 to 1%: insomnia, impotence, renal dysfunction, renal failure and oliguria.

The following occurred at an incidence of

  • Cardiovascular: myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see Warnings). Cardiac arrest, pulmonary embolism, rhythm disturbances, angina pectoris;
  • Dermatologic: pemphigus, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrosis, urticaria, photosensitivity, alopecia;
  • Gastrointestinal: anorexia, ileus, pancreatitis, dyspepsia, constipation, stomatits;
  • Hematologic: hemolytic anemia, neutropenia, thrombocytopenia, bone marrow depression;
  • Hepatic: liver function abnormalities, hepatitis, jaundice, hepatic failure;
  • Nervous System/Psychiatric: vertigo, depression, confusion, ataxia;
  • Respiratory: bronchospasm/asthma, rhinorrhea, pulmonary infiltrates;
  • Other: flushing, tinnitus, hearing impairment, glossitis, blurred vision.

A symptom complex has been reported which may include fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated erythrocyte sedimentation rate, eosinophilia and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may occur. These symptoms have disappeared after discontinuation of therapy.

Laboratory Test Findings: hyponatremia.

Vasotec I.V.: Since enalapril is converted to enalaprilat, those adverse reactions associated with Vasotec tablets might also be expected to occur with Vasotec I.V.

The incidence of symptomatic hypotension is 3.4% with Vasotec I.V. Other adverse experiences occurring in greater than 1% of patients were headache (2.9%) and nausea (1.1%).

Adverse reactions occurring in 0.5 to 1% of patients in controlled clinical trials include myocardial infarct, fatigue, dizziness, fever, rash and constipation.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Limited data are available for overdosage in humans. The most prominent features of overdosage reported to date are marked hypotension, beginning some 6 hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system, and stupor. Serum enalaprilat levels 100- and 200-fold higher than usually seen after therapeutic doses have been reported after ingestion of 300 mg and 440 mg of enalapril, respectively.

The recommended treatment of overdosage is i.v. infusion of normal saline solution. If ingestion is recent, induce emesis. Enalaprilat may be removed from the general circulation by hemodialysis.

Dosage And Administration: Vasotec: For oral administration only.

The absorption of enalapril is not affected by food.

Dosage must be individualized.

Hypertension: Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation and salt restriction; the dosage of other antihypertensive agents being used with enalapril may need to be adjusted.

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/day administered in a single dose or 2 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, a diuretic may be added.

The maximum daily dose is 40 mg. Raising the dose above that level is not recommended because of the possibility of increased adverse reactions.

Symptomatic hypotension occasionally may occur following the initial dose of enalapril and is more likely in patients who are currently being treated with a diuretic. The diuretic should, if possible, be discontinued for 2 to 3 days before beginning therapy with enalapril to reduce the likelihood of hypotension (see Warnings).

If the diuretic cannot be discontinued, an initial dose of 2.5 mg should be used to determine whether excessive hypotension occurs.

To date there is insufficient experience with enalapril in the treatment of accelerated or malignant hypertension. Enalapril, therefore, is not recommended in such situations.

Geriatrics (over 65 years): The starting dose should be 2.5 mg. Some elderly patients may be more responsive to enalapril than younger patients.

Congestive Heart Failure: Enalapril is generally used in conjunction with a diuretic and/or digitalis. Blood pressure and renal function should be monitored, both before and during treatment with enalapril, because severe hypotension and, more rarely, consequent renal failure have been reported (see Warnings and Precautions).

Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. If possible, the dose of diuretic should be reduced before beginning treatment to reduce the likelihood of hypotension. Serum potassium also should be monitored (see Precautions, Drug Interactions).

The recommended initial dose in patients with symptomatic heart failure or asymptomatic left ventricular dysfunction (ejection fraction £35%) is 2.5 mg once a day, to be administered under close medical supervision to determine the initial effect on blood pressure. After the initial dose, the patient should be observed for at least 2 hours or until the pressure has stabilized for at least another additional hour (see Warnings, Hypotension).

In the absence of, or after effective management of symptomatic hypotension following initiation of therapy, the dose should be increased gradually depending on the patient’s response. The usual therapeutic dosing range is 5 to 20 mg daily, given as a single dose or 2 divided doses.

This dose titration may be performed over a 2 to 4 week period, or more rapidly if indicated by the presence of residual signs and symptoms of heart failure. The dosage regimen, in patients with symptomatic heart failure, which was effective in reducing mortality and the need for hospitalization in multi-centre studies ranged between 16.4 and 18.8 mg/day. The majority of patient experience in clinical studies has been with twice daily dosage.

The maximum daily dose is 40 mg.

Dosage Adjustment in Patients with Congestive 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, Congestive 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 4 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.

Vasotec I.V.: For i.v. administration only.

Enalaprilat vials should be inspected visually and should not be used if particulate matter or discoloration is observed.

Enalaprilat may be administered i.v. as supplied, or mixed with up to 50 mL of 1 of the following diluents: 5% Dextrose Injection, 0.9% Sodium Chloride Injection, 0.9% Sodium Chloride Injection in 5% Dextrose, 5% Dextrose in Lactated Ringer’s Injection.

Diluted solutions should be used within 24 hours.

The dose is 1.25 mg every 6 hours administered i.v. over at least 5 minutes. A clinical response is usually seen within 15 minutes. Peak effects after the first dose may not occur for up to 4 hours after dosing. The peak effects of the second and subsequent doses may exceed those of the first.

No dosage regimen for enalaprilat has been clearly demonstrated to be more effective in treating hypertension than 1.25 mg every 6 hours. However, in controlled clinical studies in hypertension, doses as high as 5 mg every 6 hours were well tolerated for up to 36 hours. There has been inadequate experience with doses greater than 20 mg/day.

In studies of patients with hypertension, enalaprilat has not been administered for periods longer than 48 hours. In other studies, patients have received enalaprilat for as long as 7 days.

The dose for patients being converted to enalaprilat from oral therapy for hypertension with enalapril is 1.25 mg every 6 hours administered i.v. over at least 5 minutes. For conversion from i.v. to oral therapy, the recommended initial dose of enalapril tablets is 5 mg once a day with subsequent dosage adjustments as necessary.

Patients on Diuretic Therapy: For patients on diuretic therapy the recommended starting dose for hypertension is 0.625 mg administered i.v. over at least 5 minutes. A clinical response is usually seen within 15 minutes. Peak effects after the first dose may not occur for up to 4 hours after dosing, although most of the effect is usually apparent within the first hour. If after 1 hour there is an inadequate clinical response, the 0.625 mg dose may be repeated. Additional doses of 1.25 mg may be administered at 6-hour intervals.

For conversion from i.v. to oral therapy, the recommended initial dose of Vasotec tablets for patients who have responded to 0.625 mg of enalaprilat every 6 hours is 2.5 mg once a day with subsequent dosage adjustment as necessary.

Dosage Adjustment in Renal Impairment: The usual dose of 1.25 mg of enalaprilat every 6 hours is recommended for patients with a creatinine clearance >0.50 mL/s [>30 mL/min] (serum creatinine of up to approximately 265.2 mol/L [3 mg/dL]). For patients with creatinine clearance 0.50 mL/s [30 mL/min] (serum creatinine 265.2 mol/L [3 mg/dL]), the initial dose is 0.625 mg (see Warnings).

If after 1 hour there is an inadequate clinical response, the 0.625 mg dose may be repeated. Additional doses of 1.25 mg may be administered at 6-hour intervals.

For dialysis patients the initial dose should be 0.625 mg every 6 hours (see Precautions, Anaphylactoid Reactions during Membrane Exposure).

For conversion from i.v. to oral therapy, the recommended initial dose of Vasotec is 5 mg once a day for patients with creatinine clearance >0.50 mL/s [>30 mL/min] and 2.5 mg once daily for patients with creatinine clearance 0.50 mL/s [30 mL/min]. Dosage should then be adjusted according to blood pressure response.

Diluted Solutions: Vasotec I.V. may be used as supplied, or may be diluted with the diluents listed below (up to 50 mL). The diluted solutions are stable for 24 hours at room temperature.

Diluents: 5% Dextrose Injection, 0.9% Sodium Chloride Injection, 0.9% Sodium Chloride Injection in 5% Dextrose, 5% Dextrose in Lactated Ringer’s Injection.

Parenteral Products: As with all parenteral drug products, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit.

Availability And Storage: Vasotec: 2.5 mg: Each yellow, barrel-shaped, biconvex, scored tablet, engraved 14 on one side and VASOTEC on the other, contains: enalapril maleate 2.5 mg. Nonmedicinal ingredients: cornstarch, lactose, magnesium stearate, pregelatinized starch, red and/or yellow iron oxides and sodium bicarbonate. Blisters of 30. Polyethylene bottles of 100 and 500.

5 mg: Each white, barrel-shaped, biconvex, scored tablet, engraved 712 on one side and VASOTEC on the other, contains: enalapril maleate 5 mg. Nonmedicinal ingredients: cornstarch, lactose, magnesium stearate, pregelatinized starch and sodium bicarbonate. Blisters of 30. Polyethylene bottles of 500.

10 mg: Each rust-red colored, barrel-shaped, biconvex tablet, engraved 713 on one side and VASOTEC on the other, contains: enalapril maleate 10 mg. Nonmedicinal ingredients: cornstarch, lactose, magnesium stearate, pregelatinized starch, red and/or yellow iron oxides and sodium bicarbonate. Blisters of 30. Polyethylene bottles of 500.

20 mg: Each peach-colored, barrel-shaped, biconvex tablet, engraved 714 on one side and VASOTEC on the other, contains: enalapril maleate 20 mg. Nonmedicinal ingredients: cornstarch, lactose, magnesium stearate, pregelatinized starch, red and/or yellow iron oxides and sodium bicarbonate. Blisters of 30. Polyethylene bottles of 100 and 500.

All strengths are gluten- and tartrazine-free. Store at controlled room temperature (15 to 30°C). Keep container tightly closed. Protect from moisture.

Note: Bottles of 500 mg tablets: Discard remaining tablets 6 months after opening bottle.

Vasotec I.V.: Each mL of clear, colorless solution contains: enalaprilat (anhydrous equivalent) 1.25 mg, sodium chloride 6.2 mg to adjust tonicity and sodium hydroxide to adjust pH (to approximately 7.0), water for injection, q.s.; with benzyl alcohol 9 mg as preservative. Vials of 2 mL.

Store at controlled room temperature (15 to 30°C). (Shown in Product Recognition Section)

VASOTEC® VASOTEC® I.V. Frosst Enalapril MaleateEnalaprilat Angiotensin Converting Enzyme Inhibitor

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