Vasotec

Enalapril is used alone or together with other medicines to treat high blood pressure (hypertension). High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. Lowering blood pressure can reduce the risk of strokes and heart attacks.

Enalapril is an angiotensin converting enzyme (ACE) inhibitor. It works by blocking a substance in the body that causes the blood vessels to tighten. As a result, enalapril relaxes the blood vessels. This lowers blood pressure and increases the supply of blood and oxygen to the heart.

Enalapril is also used in combination with other medicines to treat congestive heart failure and cut down on the number of hospital visits for heart problems.

This medicine is available only with your doctor's prescription. .

This product is available in the following dosage forms:

• Powder for Solution
• Tablet
• Solution

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 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 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 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

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 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 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 (see DRUG INTERACTIONS).

In trials in patients treated with digitalis and diuretics, treatment with enalapril resulted in decreased systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure and heart size, and increased cardiac output and exercise tolerance. Heart rate was unchanged or slightly reduced, and mean ejection fraction was unchanged or increased. There was a beneficial effect on severity of heart failure as measured by the New York Heart Association (NYHA) classification and on symptoms of dyspnea and fatigue. Hemodynamic effects were observed after the first dose and appeared to be maintained in uncontrolled studies lasting as long as four months. Effects on exercise tolerance, heart size, and severity and symptoms of heart failure were observed in placebo-controlled studies lasting from eight weeks to over one year.

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), cerebrovascular disease (e.g., significant carotid artery disease), advanced pulmonary disease, malignancies, active myocarditis and constrictive pericarditis. The mortality benefit associated with enalapril does not appear to depend upon digitalis being present.

A second multicenter trial used the SOLVD protocol for study of asymptomatic or minimally symptomatic patients. 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 percent of patients, current angina pectoris in 34 percent, and a history of hypertension in 37 percent. No statistically significant mortality effect was demonstrated in this population. Enalapril-treated subjects had 32% fewer first hospitalizations for heart failure, and 32% fewer total heart failure hospitalizations. Compared to placebo, 32 percent fewer patients receiving enalapril developed symptoms of overt heart failure. Hospitalizations for cardiovascular reasons were also reduced. There was an insignificant reduction in hospitalizations for any cause in the enalapril treatment group (for enalapril vs. placebo, respectively, 1166 vs. 1201 first hospitalizations, 2649 vs. 2840 total hospitalizations), although the study was not powered to look for such an effect.

The SOLVD-Prevention trial was not designed to determine whether treatment of asymptomatic patients with low ejection fraction would be superior, with respect to preventing hospitalization, to closer follow-up and use of enalapril at the earliest sign of heart failure. However, under the conditions of follow-up in the SOLVD-Prevention trial (every 4 months at the study clinic; personal physician as needed), 68% of patients on placebo who were hospitalized for heart failure had no prior symptoms recorded which would have signaled initiation of treatment.

The SOLVD-Prevention trial was also not designed to show whether enalapril modified the progression of underlying heart disease.

In another multicenter, placebo-controlled trial (CONSENSUS) limited to patients with NYHA Class IV congestive heart failure and radiographic evidence of cardiomegaly, use of enalapril was associated with improved survival. The results are shown in the following table.

In both CONSENSUS and SOLVD-Treatment trials, patients were also usually receiving digitalis, diuretics or both.

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 <50 kg received either 0.625, 2.5 or 20 mg of enalapril daily and patients who weighed ≥ 50 kg received either 1.25, 5, or 40 mg of enalapril daily. Enalapril administered once daily lowered trough blood pressure in a dose-dependent manner. The dose-dependent antihypertensive efficacy of enalapril was consistent across all subgroups (age, Tanner stage, gender, race). However, the lowest doses studied, 0.625 mg and 1.25 mg, corresponding to an average of 0.02 mg/kg once daily, did not appear to offer consistent antihypertensive efficacy. In this study, VASOTEC was generally well tolerated.

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 DOSAGE AND ADMINISTRATION, Preparation Of Suspension).

• ACE Inhibitors
• Congestive Heart Failure (CHF) Symptoms, Stages, and Prognosis
• Diabetes (Type 1 and Type 2)
• Heart Attack
• High Blood Pressure (Hypertension) Medications
• Kidney Failure

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Store the Epaned® mixed oral liquid in the refrigerator or at room temperature for up to 60 days. Keep the Vasotec® mixed oral liquid in the refrigerator and store it for up to 30 days. Do not freeze.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Vasotec, there are no specific foods that you must exclude from your diet when receiving Vasotec.

Do not to use salt substitutes containing potassium without consulting your doctor.

Take Vasotec exactly as prescribed.

This medication comes in tablet form and is taken 1 to 2 times a day, with or without food.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Vasotec at the same time.

Take Vasotec exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

Your doctor will prescribe the appropriate dosage of Vasotec depending on the severity of your high blood pressure, your kidney function, what other medications you take, and your response to Vasotec .

The dosages range from 2.5 to 40 mg each day.  Your doctor will start you on a low dose of Vasotec, and slowly increase your dose depending on your response.

In the U.S.

• Epaned
• Vasotec

Available Dosage Forms:

• Powder for Solution
• Tablet
• Solution

Therapeutic Class: Antihypertensive

Pharmacologic Class: Enalapril

Enalapril is used alone or together with other medicines to treat high blood pressure (hypertension). High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. Lowering blood pressure can reduce the risk of strokes and heart attacks.

Enalapril is an angiotensin converting enzyme (ACE) inhibitor. It works by blocking a substance in the body that causes the blood vessels to tighten. As a result, enalapril relaxes the blood vessels. This lowers blood pressure and increases the supply of blood and oxygen to the heart.

Enalapril is also used in combination with other medicines to treat congestive heart failure and cut down on the number of hospital visits for heart problems.

This medicine is available only with your doctor's prescription. .

• Tell all of your health care providers that you take Vasotec. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
• To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
• Have your blood pressure checked often. Talk with your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• If you are taking a salt substitute that has potassium, potassium-sparing diuretics, or potassium, talk with your doctor.
• If you are on a low-salt or salt-free diet, talk with your doctor.
• If you are taking lithium, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with Vasotec.
• Low white blood cell counts have happened with captopril, a drug like this one. This may lead to more chance of getting an infection. Most of the time, this has happened in people with kidney problems, mainly if they have certain other health problems. Call your doctor right away if you have signs of infection like fever, chills, or sore throat. Talk with your doctor.
• If you are taking this medicine and have high blood pressure, talk with your doctor before using OTC products that may raise blood pressure. These include cough or cold drugs, diet pills, stimulants, ibuprofen or like products, and some natural products or aids.
• Talk with your doctor before you drink alcohol.
• Be careful in hot weather or while being active. Drink lots of fluids to stop fluid loss.
• Tell your doctor if you have too much sweat, fluid loss, throwing up, or loose stools. This may lead to low blood pressure.
• This medicine may not work as well in black patients. Talk with the doctor.
• A very bad reaction called angioedema has happened with Vasotec. Sometimes, this has been deadly. The chance of angioedema may be higher in black patients. Talk with the doctor.

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•C4H4O4, and its structural formula is:

Enalapril maleate is a white to off-white, crystalline powder with a molecular weight of 492.53. It is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol.

Enalapril is a pro-drug; following oral administration, it is bioactivated by hydrolysis of the ethyl ester to enalaprilat, which is the active angiotensin converting enzyme inhibitor.

Enalapril maleate is supplied as 2.5 mg, 5 mg, 10 mg, and 20 mg tablets for oral administration. In addition 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.

NDC 0187-0143-30

Vasotec®
(Enalapril Maleate)

20 mg

30 Tablets

Rx ONLY

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Usual Adult Dose for Hypertension:

Initial dose (oral tablets or solution): 5 mg orally once a day
Maintenance dose (oral tablets or solution): 10 to 40 mg orally per day as a single dose or in 2 divided doses
Maximum dose: 40 mg orally daily as a single dose or in 2 divided doses

In combination with diuretics:
Initial dose: 2.5 mg orally once a day
If feasible, the diuretic should be discontinued 2 to 3 days prior to initiation of therapy with enalapril. If required, diuretic therapy may be gradually resumed.

Parenteral: 1.25 to 5 mg IV over a 5 minute period every 6 hours

Comments:
-Clinical response is usually seen within 15 minutes after IV administration.
-If required, diuretic therapy may be gradually resumed.

Usual Adult Dose for Congestive Heart Failure:

Initial dose: 2.5 mg orally once a day
Maintenance dose: 2.5 to 20 mg daily in 2 divided doses
Maximum dose: 40 mg orally per day in 2 divided doses

Comments:
-Treatment is usually combined with diuretics and digitalis.
-Doses should be titrated upward, as tolerated, over a period of a few days or weeks.

Usual Adult Dose for Left Ventricular Dysfunction:

Initial dose: 2.5 mg orally twice a day
Maintenance dose: 20 mg orally per day in 2 divided doses

Comments:
-After the initial dose, the patient should be observed for at least 2 hours and until blood pressure has stabilized for at least an additional hour.
-If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension.

Usual Pediatric Dose for Hypertension:

Oral tablets or solution:
Children 1 month to 17 years:
Initial dose: 0.08 mg/kg/day (up to 5 mg) in 1 to 2 divided doses. Adjust dosage based on patient response.
Maximum dose: Doses greater than 0.58 mg/kg (40 mg) have not been evaluated in pediatric patients.

Comment:
-Not recommended in neonates and in pediatric patients with glomerular filtration rate less than 30 mL/min, as no data are available.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with Vasotec, especially:

• lithium;

• a diuretic or "water pill";

• gold injections to treat arthritis; or

• >b>NSAIDs (nonsteroidal anti-inflammatory drugs) - aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

This list is not complete. Other drugs may interact with enalapril, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Do not use if you are pregnant. If you become pregnant, stop taking this medicine and tell your doctor right away.

You should not use enalapril if you have ever had angioedema. Do not take enalapril within 36 hours before or after taking medicine that contains sacubatril (such as Entresto).

If you have diabetes, do not use enalapril together with any medication that contains aliskiren (such as Tekturna or Tekamlo).