FDA label 4d3a9fbe-9f84-e1a0-e063-6294a90a7857

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).

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.