Enalapril Maleate (Page 4 of 6)

ADVERSE REACTIONS

Enalapril Maleate Tablets have been evaluated for safety in more than 10,000 patients, including over 1000 patients treated for one year or more. Enalapril Maleate Tablets have been found to be generally well tolerated in controlled clinical trials involving 2987 patients. For the most part, adverse experiences were mild and transient in nature. In clinical trials, discontinuation of therapy due to clinical adverse experiences was required in 3.3 percent of patients with hypertension and in 5.7 percent of patients with heart failure. The frequency of adverse experiences was not related to total daily dosage within the usual dosage ranges. In patients with hypertension the overall percentage of patients treated with Enalapril Maleate Tablets reporting adverse experiences was comparable to placebo.

Hypertension

Adverse experiences occurring in greater than one percent of patients with hypertension treated with Enalapril Maleate Tablets in controlled clinical trials are shown below. In patients treated with Enalapril Maleate Tablets, the maximum duration of therapy was three years; in placebo-treated patients the maximum duration of therapy was 12 weeks.

	Enalapril Maleate Tablets (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 Tablets 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 Tablets and placebo, respectively.

	Enalapril Maleate Tablets (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 Tablets, 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 Tablets 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 Tablets 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 Tablets 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 Tablets 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 G6PD 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 Oceanside Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.