DESCRIPTION Enalapril maleate and hydrochlorothiazide combines an angiotensin converting enzyme inhibitor, enalapril maleate, and a diuretic, hydrochlorothiazide. 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 C 20 H 28 N 2 O 5 ∙C 4 H 4 O 4 , 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. Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7 H 8 ClN 3 O 4 S 2 and its structural formula is: It is a white, or practically white, crystalline powder with a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium hydroxide solution. Enalapril maleate and hydrochlorothiazide is available in two tablet combinations of enalapril maleate with hydrochlorothiazide: enalapril maleate and hydrochlorothiazide 5/12.5 mg, containing 5 mg enalapril maleate and 12.5 mg hydrochlorothiazide and contain the following inactive ingredients: ferric oxide black, ferric oxide yellow, lactose monohydrate, magnesium stearate, pregelatinized starch, purified water, and sodium bicarbonate. Enalapril maleate and hydrochlorothiazide 10/25 mg, containing 10 mg enalapril maleate and 25 mg hydrochlorothiazide and contain the following inactive ingredients: ferrix oxide yellow, ferric oxide red, lactose monohydrate, magnesium stearate, pregelatinized starch, purified water, and sodium bicarbonate.

Chemical Structure Chemical

Structure

AND USAGE Enalapril maleate oral solution is an angiotensin-converting enzyme inhibitor indicated for: treatment of hypertension in adults and children older than one month, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1.1) . treatment of symptomatic heart failure (1.2) . treatment of asymptomatic left ventricular dysfunction, to decrease the rate of development of overt heart failure and reduce hospitalization for heart failure (1.3) .

1.1 Hypertension Enalapril maleate oral solution is indicated for the treatment of hypertension, to lower blood pressure in adults and children older than one month <span class="opacity-50 text-xs">[see Pediatric Use (8.4) and Clinical Studies (14) ]</span> . Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in Black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Enalapril maleate oral solution is effective alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of enalapril maleate oral solution and thiazides are approximately additive.

1.2 Heart Failure Enalapril maleate oral solution is indicated for the treatment of symptomatic heart failure, usually in combination with diuretics and digitalis. In these patients, enalapril maleate oral solution increases survival and decreases the frequency of hospitalization.

1.3 Asymptomatic Left Ventricular Dysfunction In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction ≤35 percent), enalapril maleate oral solution decreases the rate of development of overt heart failure and decreases the incidence of hospitalization for heart failure.

DOSAGE AND ADMINISTRATION Hypertension In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of enalapril maleate tablets. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with enalapril maleate tablets to reduce the likelihood of hypotension (see WARNINGS, Hypotension). If the patient's blood pressure is not controlled with Enalapril Maleate Tablets 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, Hypotension 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 tablets alone, a diuretic may be added. Concomitant administration of enalapril maleate tablets 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 Impairment The usual dose of enalapril is recommended for patients with a creatinine clearance more than 30 mL/min (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance less than or equal to 30 mL/min (serum creatinine more than or equal to 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.

Renal Status

Creatinine- Clearance ml/min Initial Dose mg/day Normal Renal Function >80 mL/min 5 mg Mild Impairment ≤80 >30 mL/min 5 mg Moderate to Severe Impairment ≤30 mL/min 2.5 mg Dialysis Patients* - 2.5 mg on dialysis days † *See WARNINGS, Anaphylactoid Reactions During Membrane Exposure 2 Dosage on nondialysis days should be adjusted depending on the blood pressure response.

Heart Failure

Enalapril maleate tablets are 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 enalapril maleate tablets, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and PRECAUTIONS, Drug Interactions). If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of enalapril maleate tablets 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 enalapril maleate tablets, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and PRECAUTIONS, Drug Interactions). If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of enalapril maleate tablets 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 DOSAGE AND ADMINISTRATION, Heart Failure, WARNINGS and PRECAUTIONS, Drug Interactions). The dose may be increased to 2.5 mg b.i.d., then 5 mg b.i.d. and higher as needed, usually at intervals of four days or more if at the time of 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 CLINICAL PHARMACOLOGY, Clinical Pharmacology in Pediatric Patients). Enalapril maleate is not recommended in neonates and in pediatric patients with glomerular filtration rate less than 30 mL/min/1.73 m 2 , as no data are available. Preparation of Suspension (for 200 mL of a 1.0 mg/mL suspension)

Add

50 mL of sodium citrate and citric acid oral solution, USP to a polyethylene terephthalate (PET) bottle containing ten 20 mg tablets of enalapril maleate 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° to 8°C (36° to 46°F) and can be stored for up to 30 days. Shake the suspension before each use.

Hypertension In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of enalapril maleate tablets. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with enalapril maleate tablets to reduce the likelihood of hypotension (see WARNINGS, Hypotension). If the patient's blood pressure is not controlled with Enalapril Maleate Tablets 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, Hypotension 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 tablets alone, a diuretic may be added. Concomitant administration of enalapril maleate tablets 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 Impairment The usual dose of enalapril is recommended for patients with a creatinine clearance more than 30 mL/min (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance less than or equal to 30 mL/min (serum creatinine more than or equal to 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.

Renal Status

Creatinine- Clearance ml/min Initial Dose mg/day Normal Renal Function >80 mL/min 5 mg Mild Impairment ≤80 >30 mL/min 5 mg Moderate to Severe Impairment ≤30 mL/min 2.5 mg Dialysis Patients* - 2.5 mg on dialysis days † *See WARNINGS, Anaphylactoid Reactions During Membrane Exposure 2 Dosage on nondialysis days should be adjusted depending on the blood pressure response.

Heart Failure

Enalapril maleate tablets are 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 enalapril maleate tablets, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and PRECAUTIONS, Drug Interactions). If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of enalapril maleate tablets 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 enalapril maleate tablets, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and PRECAUTIONS, Drug Interactions). If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of enalapril maleate tablets 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 DOSAGE AND ADMINISTRATION, Heart Failure, WARNINGS and PRECAUTIONS, Drug Interactions). The dose may be increased to 2.5 mg b.i.d., then 5 mg b.i.d. and higher as needed, usually at intervals of four days or more if at the time of 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 CLINICAL PHARMACOLOGY, Clinical Pharmacology in Pediatric Patients). Enalapril maleate is not recommended in neonates and in pediatric patients with glomerular filtration rate less than 30 mL/min/1.73 m 2 , as no data are available. Preparation of Suspension (for 200 mL of a 1.0 mg/mL suspension)

Add

50 mL of sodium citrate and citric acid oral solution, USP to a polyethylene terephthalate (PET) bottle containing ten 20 mg tablets of enalapril maleate 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° to 8°C (36° to 46°F) and can be stored for up to 30 days. Shake the suspension before each use.

Enalapril maleate oral solution is contraindicated in patients with:

a history of angioedema or hypersensitivity related to previous treatment with an angiotensin converting enzyme (ACE) inhibitor. [see Warnings and Precautions ( 5.2 )]
hereditary or idiopathic angioedema. [see Warnings and Precautions ( 5.2 )] Do not co-administer aliskiren with enalapril maleate oral solution in patients with diabetes [see Drug Interactions ( 7.2 )]. Enalapril maleate oral solution is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer enalapril maleate oral solution within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor [see Warnings and Precautions ( 5.2 )].
Hypersensitivity related to previous treatment with an ACEI. ( 4 )
Hereditary or idiopathic angioedema. ( 4 )
Do not co-administer aliskiren in patients with diabetes. ( 4 )
In combination with a neprilysin inhibitor. ( 4 )

ADVERSE REACTIONS 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 conrolled 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

Maleate (n=2314) Incidence (discontinuation) Placebo (n=230)

Incidence

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

Maleate (n=673) Incidence (discontinuation) Placebo (n=339)

Incidence

Body As A Whole Orthostatic Effects 2.2 (0.1)

0.3 Syncope 2.2 (0.1)

0.9 Chest Pain 2.1 (0.0)

2.1 Fatigue 1.8 (0.0)

1.8 Abdominal Pain 1.6 (0.4)

2.1 Asthenia 1.6 (0.1)

0.3 Cardiovascular Hypotension 6.7 (1.9)

0.6 Orthostatic Hypotension 1.6 (0.1)

0.3 Angina Pectoris 1.5 (0.1)

1.8 Myocardial Infarction 1.2 (0.3)

1.8 Digestive Diarrhea 2.1 (0.1)

1.2 Nausea 1.3 (0.1)

0.6 Vomiting 1.3 (0.0)

0.9 Nervous/Psychiatric Dizziness 7.9 (0.6)

0.6 Headache 1.8 (0.1)

0.9 Vertigo 1.6 (0.1)

1.2 Respiratory Cough 2.2 (0.0)

0.6 Bronchitis 1.3 (0.0)

0.9 Dyspnea 1.3 (0.1)

0.4 Pneumonia 1.0 (0.0)

2.4 Skin Rash 1.3 (0.0)

2.4 Urogenital Urinary Tract Infection 1.3 (0.0)

2.4 Other serious clinical adverse experiences occurring since the drug was marketed or adverse experiences occurring in 0.5 to 1.0 percent of patients with hypertension or heart failure in clinical trials are listed below and, within each category, are in 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, Head and Neck Angioedema). 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, Hypotension). 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, Hyperkalemia), 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, Impaired Renal Function). 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 1.0 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 cannot be excluded.

Liver Function Tests

Elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS, Hepatic Failure). To report SUSPECTED ADVERSE REACTIONS, contact Wockhardt USA LLC at 1-800-346- 6854 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

Maleate (n=2314) Incidence (discontinuation) Placebo (n=230)

Incidence

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

Maleate (n=673) Incidence (discontinuation) Placebo (n=339)

Incidence

Body As A Whole Orthostatic Effects 2.2 (0.1)

0.3 Syncope 2.2 (0.1)

0.9 Chest Pain 2.1 (0.0)

2.1 Fatigue 1.8 (0.0)

1.8 Abdominal Pain 1.6 (0.4)

2.1 Asthenia 1.6 (0.1)

0.3 Cardiovascular Hypotension 6.7 (1.9)

0.6 Orthostatic Hypotension 1.6 (0.1)

0.3 Angina Pectoris 1.5 (0.1)

1.8 Myocardial Infarction 1.2 (0.3)

1.8 Digestive Diarrhea 2.1 (0.1)

1.2 Nausea 1.3 (0.1)

0.6 Vomiting 1.3 (0.0)

0.9 Nervous/Psychiatric Dizziness 7.9 (0.6)

0.6 Headache 1.8 (0.1)

0.9 Vertigo 1.6 (0.1)

1.2 Respiratory Cough 2.2 (0.0)

0.6 Bronchitis 1.3 (0.0)

0.9 Dyspnea 1.3 (0.1)

0.4 Pneumonia 1.0 (0.0)

2.4 Skin Rash 1.3 (0.0)

2.4 Urogenital Urinary Tract Infection 1.3 (0.0)

2.4 Other serious clinical adverse experiences occurring since the drug was marketed or adverse experiences occurring in 0.5 to 1.0 percent of patients with hypertension or heart failure in clinical trials are listed below and, within each category, are in 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, Head and Neck Angioedema). 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, Hypotension). 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, Hyperkalemia), 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, Impaired Renal Function). 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 1.0 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 cannot be excluded.

Liver Function Tests

Elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS, Hepatic Failure). To report SUSPECTED ADVERSE REACTIONS, contact Wockhardt USA LLC at 1-800-346- 6854 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 enalapril maleate) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors, including enalapril maleate. This may occur at any time during treatment. In such cases enalapril maleate should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided (see ADVERSE REACTIONS). Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema (see PRECAUTIONS ).

Intestinal

Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS). Anaphylactoid reactions during desensitization Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid reactions during membrane exposure Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

Hypotension

Excessive hypotension is rare in uncomplicated hypertensive patients treated with enalapril maleate alone. Patients with heart failure given enalapril maleate commonly have some reduction in blood pressure, especially with the first dose, but discontinuation of therapy for continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy (see DOSAGE AND ADMINISTRATION). Patients at risk for excessive hypotension, sometimes associated with 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 enalapril maleate in patients at risk for excessive hypotension who are able to tolerate such adjustments (see PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS). In patients at risk for excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed 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 enalapril maleate, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of enalapril maleate 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 toxicity Pregnancy category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue enalapril maleate tablets as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue enalapril maleate tablets, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to enalapril maleate tablets for hypotension, oliguria, and hyperkalemia [see PRECAUTIONS, Pediatric Use ]. 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).

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 enalapril maleate) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors, including enalapril maleate. This may occur at any time during treatment. In such cases enalapril maleate should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided (see ADVERSE REACTIONS). Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema (see PRECAUTIONS ).

Intestinal

Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS). Anaphylactoid reactions during desensitization Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid reactions during membrane exposure Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

Hypotension

Excessive hypotension is rare in uncomplicated hypertensive patients treated with enalapril maleate alone. Patients with heart failure given enalapril maleate commonly have some reduction in blood pressure, especially with the first dose, but discontinuation of therapy for continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy (see DOSAGE AND ADMINISTRATION). Patients at risk for excessive hypotension, sometimes associated with 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 enalapril maleate in patients at risk for excessive hypotension who are able to tolerate such adjustments (see PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS). In patients at risk for excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed 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 enalapril maleate, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of enalapril maleate 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 toxicity Pregnancy category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue enalapril maleate tablets as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue enalapril maleate tablets, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to enalapril maleate tablets for hypotension, oliguria, and hyperkalemia [see PRECAUTIONS, Pediatric Use ]. 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).

PRECAUTIONS General Aortic Stenosis/Hypertrophic Cardiomyopathy As with all vasodilators, enalapril should be given with caution to patients with obstruction in the outflow tract of the left ventricle.

Impaired Renal

Function As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including enalapril maleate, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death [see PRECAUTIONS, Drug Interaction]. In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20 percent of patients. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when enalapril maleate has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or enalapril maleate may be required. Evaluation of patients with hypertension or heart failure should always include assessment of renal function (s ee DOSAGE AND ADMINISTRATION).

Hyperkalemia

Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately one percent of hypertensive patients in clinical trials. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in 0.28 percent of hypertensive patients. In clinical trials in heart failure, hyperkalemia was observed in 3.8 percent of patients but was not a cause for discontinuation. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with enalapril maleate (see Drug Interactions).

Cough

Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. Information for Patients Angioedema Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin-converting enzyme inhibitors, including enalapril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician.

Hypotension

Patients should be cautioned to report lightheadedness, especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician. All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician.

Hyperkalemia

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

Neutropenia

Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia.

Pregnancy

Female patients of childbearing age should be told about the consequences of exposure to enalapril maleate tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. NOTE: As with many other drugs, certain advice to patients being treated with enalapril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Drug Interactions Neprilysin Inhibitors

Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema (see WARNINGS ).

Dual

Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on enalapril maleate tablets and other agents that affect the RAS. Do not co-administer aliskiren with enalapril maleate in patients with diabetes. Avoid use of aliskiren with enalapril maleate in patients with renal impairment (GFR <60 ml/min). Hypotension - Patients on Diuretic Therapy Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide close medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS, Hypotension and DOSAGE AND ADMINISTRATION).

Agents Causing Renin Release

The antihypertensive effect of enalapril maleate is augmented by antihypertensive agents that cause renin release (e.g., diuretics). Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDS, including selective COX-2 inhibitors, with ACE inhibitors, including enalapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving enalapril and NSAID therapy. 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 maleate. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.

Other Cardiovascular Agents

Enalapril maleate has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine, prazosin and digoxin without evidence of clinically significant adverse interactions. A gents Increasing Serum Potassium Enalapril maleate attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (e.g., Spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. Potassium-sparing agents should generally not be used in patients with heart failure receiving enalapril maleate.

Lithium

Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant enalapril maleate and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium.

Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalapril maleate. mTOR (Mammalian Target of Rapamycin)

Inhibitors

Patients receiving coadministration of ACE inhibitor and mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see WARNINGS, Head and Neck Angioedema ). 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 E.coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow. There were no adverse effects on reproductive performance 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 enalapril maleate, taking into account the importance of the drug to the mother.

Pediatric Use

Neonates with a history of in utero exposure to enalapril Maleate If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a 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. Antihypertensive effects of enalapril maleate have been established in hypertensive pediatric patients age 1 month to 16 years. Use of enalapril maleate in these age groups is supported by evidence from adequate and well-controlled studies of enalapril maleate in pediatric and adult patients as well as by published literature in pediatric patients (see CLINICAL PHARMACOLOGY, Clinical Pharmacology in Pediatric Patients and DOSAGE AND ADMINISTRATION). Enalapril maleate is not recommended in neonates and in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m 2 , as no data are available.

General Aortic Stenosis/Hypertrophic

Cardiomyopathy As with all vasodilators, enalapril should be given with caution to patients with obstruction in the outflow tract of the left ventricle.

Impaired Renal

Function As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including enalapril maleate, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death [see PRECAUTIONS, Drug Interaction]. In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20 percent of patients. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when enalapril maleate has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or enalapril maleate may be required. Evaluation of patients with hypertension or heart failure should always include assessment of renal function (s ee DOSAGE AND ADMINISTRATION).

Hyperkalemia

Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately one percent of hypertensive patients in clinical trials. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in 0.28 percent of hypertensive patients. In clinical trials in heart failure, hyperkalemia was observed in 3.8 percent of patients but was not a cause for discontinuation. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with enalapril maleate (see Drug Interactions).

Cough

Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Information for Patients Angioedema Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin-converting enzyme inhibitors, including enalapril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician.

Hypotension

Patients should be cautioned to report lightheadedness, especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician. All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician.

Hyperkalemia

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

Neutropenia

Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia.

Pregnancy

Female patients of childbearing age should be told about the consequences of exposure to enalapril maleate tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. NOTE: As with many other drugs, certain advice to patients being treated with enalapril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Drug Interactions Neprilysin Inhibitors

Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema (see WARNINGS ).

Dual

Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on enalapril maleate tablets and other agents that affect the RAS. Do not co-administer aliskiren with enalapril maleate in patients with diabetes. Avoid use of aliskiren with enalapril maleate in patients with renal impairment (GFR <60 ml/min). Hypotension - Patients on Diuretic Therapy Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide close medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS, Hypotension and DOSAGE AND ADMINISTRATION).

Agents Causing Renin Release

The antihypertensive effect of enalapril maleate is augmented by antihypertensive agents that cause renin release (e.g., diuretics). Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDS, including selective COX-2 inhibitors, with ACE inhibitors, including enalapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving enalapril and NSAID therapy. 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 maleate. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.

Other Cardiovascular Agents

Enalapril maleate has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine, prazosin and digoxin without evidence of clinically significant adverse interactions. A gents Increasing Serum Potassium Enalapril maleate attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (e.g., Spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. Potassium-sparing agents should generally not be used in patients with heart failure receiving enalapril maleate.

Lithium

Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant enalapril maleate and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium.

Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalapril maleate. mTOR (Mammalian Target of Rapamycin)

Inhibitors

Patients receiving coadministration of ACE inhibitor and mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see WARNINGS, Head and Neck Angioedema ).

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 E.coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow. There were no adverse effects on reproductive performance 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 enalapril maleate, taking into account the importance of the drug to the mother.

Pediatric Use

Neonates with a history of in utero exposure to enalapril Maleate If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a 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. Antihypertensive effects of enalapril maleate have been established in hypertensive pediatric patients age 1 month to 16 years. Use of enalapril maleate in these age groups is supported by evidence from adequate and well-controlled studies of enalapril maleate in pediatric and adult patients as well as by published literature in pediatric patients (see CLINICAL PHARMACOLOGY, Clinical Pharmacology in Pediatric Patients and DOSAGE AND ADMINISTRATION). Enalapril maleate is not recommended in neonates and in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m 2 , as no data are available.

Drug Interactions Neprilysin Inhibitors Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema (see WARNINGS ).

Enalapril Maleate Dual

Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on enalapril maleate and hydrochlorothiazide and other agents that affect the RAS. Do not coadminister aliskiren with enalapril maleate and hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with enalapril maleate and hydrochlorothiazide in patients with renal impairment (GFR <60 mL/min). Hypotension – Patients on Diuretic Therapy Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and DOSAGE AND ADMINISTRATION ).

Agents Causing Renin Release

The antihypertensive effect of enalapril is augmented by antihypertensive agents that cause renin release (e.g., diuretics). Non-steroidal Anti-inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including enalapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving enalapril and NSAID therapy. 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 maleate. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors.

Other Cardiovascular Agents

Enalapril has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine and prazosin without evidence of clinically significant adverse interactions.

Agents Increasing Serum Potassium

Enalapril attenuates diuretic-induced potassium loss. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia they should be used with caution and with frequent monitoring of serum potassium.

Lithium

Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant enalapril and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium.

Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalapril maleate and hydrochlorothiazide tablets. mTOR (mammalian target of rapamycin) inhibitors Patients receiving coadministration of ACE inhibitor and mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see WARNINGS ).

Hydrochlorothiazide

When administered concurrently the following drugs may interact with thiazide diuretics: Alcohol, Barbiturates, or Narcotics Potentiation of orthostatic hypotension may occur. Anti-diabetic drugs (oral agents and insulin) Dosage adjustment of the anti-diabetic drug may be required. Other antihypertensive drugs Additive effect or potentiation. Cholestyramine and colestipol resins Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively. Corticosteroids, ACTH Intensified electrolyte depletion, particularly hypokalemia. Pressor amines (e.g., norepinephrine) Possible decreased response to pressor amines but not sufficient to preclude their use. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) Possible increased responsiveness to the muscle relaxant.

Lithium

Should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with enalapril maleate and hydrochlorothiazide. Non-steroidal Anti-inflammatory Drugs In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when enalapril maleate and hydrochlorothiazide and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Side Effect	Reports	% of Total	Deaths	Hosp.
Acute kidney injury	916	11.9%	87	670
Drug ineffective	599	7.8%	20	214
Hypotension	556	7.2%	42	386
Dyspnoea	514	6.7%	22	281
Hypertension	451	5.8%	4	136
Hyperkalaemia	448	5.8%	35	317
Drug interaction	441	5.7%	26	264
Angioedema	412	5.3%	15	251
Off label use	347	4.5%	21	154
Diarrhoea	342	4.4%	34	183
Nausea	342	4.4%	8	183
Hyponatraemia	341	4.4%	12	269
Cough	323	4.2%	3	127
Dizziness	308	4.0%	11	179
Malaise	302	3.9%	9	155
Cardiac failure	295	3.8%	53	210
Drug hypersensitivity	280	3.6%	0	54
Headache	269	3.5%	2	89
Fatigue	236	3.1%	9	114
Toxicity to various agents	228	3.0%	80	156

Year	Reports	Deaths	Hosp.
2000	20	0	12
2001	6	0	2
2002	6	0	6
2003	5	1	4
2004	11	0	6
2005	10	0	4
2006	10	0	1
2007	18	4	5
2008	36	0	30
2009	24	2	12
2010	85	15	72
2011	136	26	111
2012	139	42	101
2013	172	18	128
2014	267	19	172
2015	353	38	224
2016	270	14	170
2017	478	41	283
2018	554	29	357
2019	509	41	230
2020	286	19	182
2021	316	20	179
2022	238	34	127
2023	182	16	96
2024	158	20	109
2025	45	1	17

Indication	Reports
Hypertension	2,892
Product used for unknown indication	2,486
Cardiac failure	451
Cardiac failure chronic	141
Essential hypertension	68
Cardiac failure congestive	66
Proteinuria	58
Blood pressure abnormal	48
Cardiac disorder	41
Blood pressure measurement	39

ENALAPRIL: 7,730 Adverse Event Reports & Safety Profile

What Are the Most Common ENALAPRIL Side Effects?

All ENALAPRIL Side Effects by Frequency

Who Reports ENALAPRIL Side Effects? Age & Gender Data

Is ENALAPRIL Getting Safer? Reports by Year

What Is ENALAPRIL Used For?

ENALAPRIL vs Alternatives: Which Is Safer?

Other Drugs in Same Class: Angiotensin Converting Enzyme Inhibitor [EPC]

Official FDA Label for ENALAPRIL

Drug Description

Chemical Structure Chemical

FDA Approved Uses (Indications)

1.2 Heart Failure Enalapril maleate oral solution is indicated for the treatment of symptomatic heart failure, usually in combination with diuretics and digitalis. In these patients, enalapril maleate oral solution increases survival and decreases the frequency of hospitalization.

Dosage & Administration

Dosage

Renal Status

Heart Failure

Asymptomatic Left Ventricular

Dosage

Pediatric Hypertensive Patients

Add

Add

Dosage

Renal Status

Heart Failure

Asymptomatic Left Ventricular

Dosage

Pediatric Hypertensive Patients

Add

Add

Contraindications

Known Adverse Reactions

Hypertension

Enalapril

Incidence

2.6 Orthostatic Effects 1.2 (&lt;0.1)

0.0 Asthenia 1.1 (0.1)

0.9 Digestive Diarrhea 1.4 (&lt;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)

Enalapril

Incidence

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)

Special

Pediatric Patients

Clinical Laboratory Test Findings Serum

Hematology

Liver Function Tests

Hypertension

Enalapril

Incidence

2.6 Orthostatic Effects 1.2 (&lt;0.1)

0.0 Asthenia 1.1 (0.1)

0.9 Digestive Diarrhea 1.4 (&lt;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)

2.6 Orthostatic Effects 1.2 (<0.1)

0.9 Digestive Diarrhea 1.4 (<0.1)

2.6 Orthostatic Effects 1.2 (<0.1)

0.9 Digestive Diarrhea 1.4 (<0.1)