Enalapril Maleate

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue enalapril maleate as soon as possible [see Warnings and Precautions (5.1) ]. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1) ]. WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue enalapril maleate as soon as possible. ( 5.1 ) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Angioedema and Anaphylactoid Reactions. ( 5.2 ) Impaired Renal Function: Assess renal function. ( 5.5 ) Hyperkalemia. ( 5.6 ) 5.1 Fetal Toxicity 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 as soon as possible [see Use in Specific Populations (8.1) ] . 5.2 Angioedema and Anaphylactoid Reactions Angioedema Head and Neck Angioedema Angioedema of the face, extremities, lips, tongue, glottis and/or larynx, including some fatal reactions, have occurred in patients treated with angiotensin converting enzyme inhibitors, including enalapril maleate, at any time during treatment. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Enalapril maleate should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms of angioedema has occurred. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor [see Contraindications (4) ] . ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients. Patients receiving co-administration 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 Drug Interactions (7.6 , 7.7) ]. Intestinal Angioedema Intestinal angioedema has occurred 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. In some cases, the angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Anaphylactoid Reactions Anaphylactoid Reactions during Desensitization Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. Anaphylactoid Reactions during Dialysis Sudden and potentially life-threatening anaphylactoid reactions have occurred in some patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions must be initiated. Symptoms have not been relieved by antihistamines in these situations. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. 5.3 Hypotension Enalapril maleate can cause symptomatic hypotension, sometimes complicated by oliguria, progressive azotemia, acute renal failure or death. Patients at risk of excessive hypotension include those with the following conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg, ischemic heart disease, cerebrovascular disease, hyponatremia, high dose diuretic therapy, renal dialysis, or severe volume and/or salt depletion of any etiology. In these patients, enalapril maleate 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 maleate and/or diuretic is increased. Symptomatic hypotension is also possible in patients with severe aortic stenosis or hypertrophic cardiomyopathy. Surgery/Anesthesia In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril maleate may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be through this mechanism, it can be corrected by volume expansion. 5.4 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. 5.5 Impaired Renal Function Monitor renal function in patients treated with enalapril maleate. Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, post-myocardial infarction or volume depletion) may be at particular risk of developing acute renal failure on enalapril maleate. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on enalapril maleate [see Adverse Reactions (6.2) , Drug Interactions (7.2 , 7.3) ] . 5.6 Hyperkalemia Serum potassium should be monitored in patients receiving enalapril maleate. Drugs that inhibit the renin angiotensin system can cause hyperkalemia. 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 [see Drug Interactions (7.3) ].

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere: Angioedema [see Warnings and Precautions (5.2) ] Hypotension [see Warnings and Precautions (5.3) ] Hepatic failure [see Warnings and Precautions (5.4) ] Renal impairment [see Warnings and Precautions (5.5) ] Hyperkalemia [see Warnings and Precautions (5.6) ] The most common adverse reaction for patients treated for hypertension (≥3%) was fatigue. ( 6.1 ) The most common adverse reactions for patients treated for heart failure (>6%) were hypotension and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Enalapril has been evaluated for safety in more than 10,000 patients, including over 1,000 patients treated for one year or more. In clinical trials, discontinuation of therapy for clinical adverse experiences was required in 3.3% of patients with hypertension and in 5.7% of patients with heart failure. Hypertension Adverse reactions (where rate on enalapril exceeds the rate on placebo by at least 0.2%) occurring in greater than 1% of patients with hypertension treated with enalapril in controlled clinical trials are shown below. In patients treated with enalapril, the maximum duration of therapy was three years; in placebo treated patients, the maximum duration of therapy was 12 weeks. Adverse Reactions Occurring in Greater Than 1% of Patients With Hypertension Enalapril Maleate Tablets (n = 2,314) Incidence (discontinuation) Placebo (n = 230) Incidence Body As A Whole Fatigue 3 (<0.1) 2.6 Orthostatic Effects 1.2 (<0.1) 0 Asthenia 1.1 (0.1) 0.9 Respiratory Cough 1.3 (0.1) 0.9 Skin Rash 1.4 (0.4) 0.4 Heart Failure Adverse reactions seen in clinical trials of heart failure were similar to those seen in clinical trials for hypertension. In patients treated for heart failure, there was an increased incidence of hypotension 6.7 percent versus 0.6 percent in placebo and dizziness 7.9 percent versus 0.6 percent in placebo. 6.2 Other Adverse Reactions from Clinical Studies or Postmarketing Experience The following adverse reactions have been reported in clinical studies or postmarketing experience with enalapril. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Other serious clinical adverse experiences occurring since the drug was marketed or adverse experiences occurring in 0.5% to 1% of patients with hypertension or heart failure in clinical trials are listed below and, within each category, are in order of decreasing severity. Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients [see Warnings and Precautions (5.3) ] ; pulmonary embolism and infarction; pulmonary edema; rhythm disturbances, including atrial tachycardia and bradycardia; atrial fibrillation; palpitation; Raynaud's phenomenon. Digestive: Ileus, pancreatitis, 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: 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, dermatologic manifestations.

<table cellspacing="0" cellpadding="0" border="0"><col width="459.9pt"/><col/><col/><tbody><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Adverse Reactions Occurring in Greater Than 1% of Patients With Hypertension</content></paragraph></td></tr><tr><td/><td><paragraph><content styleCode="bold">Enalapril Maleate Tablets (n = 2,314) Incidence (discontinuation)</content></paragraph></td><td><paragraph><content styleCode="bold">Placebo (n = 230) Incidence</content></paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="italics">Body As A Whole </content></paragraph></td></tr><tr><td><paragraph>Fatigue </paragraph></td><td><paragraph>3 (&lt;0.1)</paragraph></td><td><paragraph>2.6</paragraph></td></tr><tr><td><paragraph>Orthostatic Effects </paragraph></td><td><paragraph>1.2 (&lt;0.1)</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Asthenia </paragraph></td><td><paragraph>1.1 (0.1)</paragraph></td><td><paragraph>0.9</paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="italics">Respiratory </content></paragraph></td></tr><tr><td><paragraph>Cough </paragraph></td><td><paragraph>1.3 (0.1)</paragraph></td><td><paragraph>0.9</paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="italics">Skin </content></paragraph></td></tr><tr><td><paragraph>Rash </paragraph></td><td><paragraph>1.4 (0.4)</paragraph></td><td><paragraph>0.4</paragraph></td></tr></tbody></table>