Enalapril Maleate
Tablets USP
Revised: November 2007
Rx only

/Enalapril Maleate
Tablets USP
Revised: November 2007
Rx only
Enalapril Maleate
Tablets USP
Revised: November 2007
Rx only
2018-09-06T09:12:40+00:00

Prescription Drug Name:

Enalapril Maleate
Tablets USP
Revised: November 2007
Rx only

ID:

B11DE2CB-8782-DDF2-2101-BAFFA641C8A0

Code:

34391-3

USE IN PREGNANCY


id: 97F19224-B0A8-9E9B-0F7B-D69A17B1F13D
displayName: BOXED WARNING SECTION
FDA Article Code: 34066-1

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, enalapril should be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

DESCRIPTION


id: AB0167C0-6F4F-2B11-8ABA-2C09331ED377
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

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 chemical formula is C20H28N2O5•C4H4O4, and its structural formula is:Enalapril maleate is a white to off-white, crystalline powder with a molecular weight of 492.52. 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. Each tablet for oral administration, contains 2.5 mg, 5 mg, 10 mg or 20 mg of enalapril maleate. In addition, each tablet contains the following inactive ingredients: anhydrous lactose, crospovidone, iron oxide red 30 (in 10 mg and 20 mg only), iron oxide yellow 10 (in 20 mg only), magnesium stearate, microcrystalline cellulose and potassium bicarbonate.

CLINICAL PHARMACOLOGY


id: 92C6B6DC-1CDC-E25B-46C7-9BBAD78C3FD0
displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1

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 stimu-lates 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 enalapril alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with enalapril 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 enalapril remains to be elucidated.While the mechanism through which enalapril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, enalapril is antihypertensive even in patients with low-renin hypertension. Although enalapril 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 enalapril maleate, 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 enalapril 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 enalapril maleate 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 maleate, 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 enalapril have continued during long term therapy. Abrupt withdrawal of enalapril 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 enalapril maleate, 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 enalapril are approximately additive.In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril. (See PRECAUTIONS,Drug Interactions.)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. 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.

INDICATIONS AND USAGE


id: D0A3A447-8018-341C-05C2-41E18C38110B
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

Hypertension
Enalapril maleate is indicated for the treatment of hypertension.
Enalapril maleate is effective alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of enalapril maleate and thiazides are approximately additive.
Heart Failure
Enalapril maleate is indicated for the treatment of symptomatic congestive heart failure, usually in combination with diuretics and digitalis. In these patients enalapril maleate 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), enalapril maleate 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 enalapril maleate 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 enalapril maleate does not have a similar risk. (See WARNINGS.)In considering use of enalapril maleate, 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 WARNINGS,Angioedema.)

CONTRAINDICATIONS


id: 7757C9E1-958A-6D91-0457-C6E3D3E2378A
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Enalapril maleate 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.

ADVERSE REACTIONS


id: F00C583B-21F2-2818-36E5-B07652041D50
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

Enalapril maleate has been evaluated for safety in more than 10,000 patients, including over 1000 patients treated for one year or more. Enalapril maleate 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 enalapril maleate reporting adverse experiences was comparable to placebo.HYPERTENSION Adverse experiences occurring in greater than one percent of patients with hypertension treated with enalapril maleate in controlled clinical trials are shown below. In patients treated with enalapril maleate, the maximum duration of therapy was three years; in placebo treated patients the maximum duration of therapy was 12 weeks.

Enalapril Placebo
Maleate
(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 enalapril maleate 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 enalapril maleate and placebo, respectively.
Enalapril Placebo
Maleate
(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 percent of patients with hypertension or heart failure in clinical trials are listed below and, within each category, are in order of decreasing severity.Body As A Whole: Anaphylactoid reactions (see WARNINGS,Anaphylactoid and Possibly Related Reactions).Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see WARNINGS,Hypotension); pulmonary embolism and infarction; pulmonary edema; rhythm disturbances including atrial tachycardia and bradycardia; atrial fibrillation; palpitation, Raynaud’s phenomenon.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, dysesthesia), dream abnormality.Respiratory: Bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, upper respiratory infection, pulmonary infiltrates, eosinophilic pneumonitis.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 some or all of the following: a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations.Angioedema: Angioedema has been reported in patients receiving enalapril maleate, 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 enalapril maleate 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 therapy 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 of patients with heart failure. (See WARNINGS.)Fetal/Neonatal Morbidity and Mortality: See WARNINGS,Fetal/Neonatal Morbidity and Mortality.Cough: See PRECAUTIONS,Cough.Pediatric Patients The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients.Clinical Laboratory Test Findings Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia.Creatinine, Blood Urea Nitrogen: In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.2 percent of patients with essential hypertension treated with enalapril maleate 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 digitalis, increases in blood urea nitrogen or serum creatinine, usually reversible upon discontinuation of enalapril maleate and/or other concomitant diuretic therapy, were observed in about 11 percent of patients. Increases in blood urea nitrogen or creatinine were a cause for discontinuation in 1.2 percent of patients.Hematology: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1 vol percent, respectively) occur frequently in either hypertension or congestive heart failure patients treated with enalapril maleate but are rarely 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 reported; a causal relationship to enalapril maleate cannot be excluded.Liver Function Tests: Elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS,Hepatic Failure).

OVERDOSAGE


id: BD54C4D8-2390-4E69-4841-1599F3E97ECD
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

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 WARNINGS,Anaphylactoid reactions during membrane exposure.)

DOSAGE AND ADMINISTRATION


id: E6595A15-F552-774D-6667-4B4BA3A16EFF
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

Hypertension In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of enalapril maleate. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with enalapril maleate to reduce the likelihood of hypotension. (See WARNINGS.) If the patient’s blood pressure is not controlled with enalapril maleate 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 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 enalapril maleate alone, a diuretic may be added.Concomitant administration of enalapril maleate with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics may lead to increases of serum potassium (see PRECAUTIONS).Dosage Adjustment in Hypertensive Patients with Renal ImpairmentThe usual dose of enalapril maleate 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.

Creatinine
Clearance Initial Dose
Renal Status mL/min mg/day
***See WARNINGS,Anaphylactoid reactions during membrane exposure.
†Dosage on nondialysis days should be adjusted depending on the blood pressure response.
Normal Renal
Function >80 mL/min 5 mg
Mild Impairment ≤80 >30 mL/min 5 mg
Moderate to Severe
Impairment ≤30 mL/mi 2.5 mg
Dialysis Patients*** 2.5 mg on
dialysis days†

HOW SUPPLIED


id: 569CCB7C-0678-D2C4-A0F2-BE3BB0E1352A
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Enalapril Maleate Tablets USP are supplied as follows:
2.5 mg tablet: White to off-white, round, biconvex tablet, debossed WATSON in a semi- circle over 668 on one side and a score on the other side, in bottles of 100 and 500.
5 mg tablet: White to off-white, round, biconvex tablet, debossed WATSON in a semi-circle over 669 with a score in the center on one side and plain on the other side, in bottles of 100 and 500.10 mg tablet: White-speckled pink, round, biconvex tablet, debossed WATSON in a semi-circle over 670 on one side and plain on the other side, in bottles of 100 and 500.20 mg tablet: White-speckled peach, round, biconvex tablet, debossed WATSON in a semi-circle over 671 on one side and plain on the other side, in bottles of 100 and 500.Store below 30°C (86°F) and avoid transient temperatures above 50°C (122°F). Keep container tightly closed. Protect from moisture.Dispense in a tight container.Manufactured for: Watson Laboratories, Inc.
Corona, CA 92880 USA
Manufactured by: Patheon Pharmaceuticals Inc.
Cincinnati, OH 45215 USA
Revised: November 2007