Enalapril

What it is used for

Hypertension Enalapril maleate is indicated for the treatment of hypertension. Enalapril maleate is effective alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of enalapril maleate and thiazides are approximately additive. Heart Failure Enalapril maleate is indicated for the treatment of symptomatic congestive heart failure, usually in combination with diuretics and digitalis.

In these patients enalapril maleate improves symptoms, increases survival, and decreases the frequency of hospitalization (see CLINICAL PHARMACOLOGY, Heart Failure, Mortality Trials for details and limitations of survival trials). Asymptomatic Left Ventricular Dysfunction In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction ≤35 percent), enalapril maleate decreases the rate of development of overt heart failure and decreases the incidence of hospitalization for heart failure (see CLINICAL PHARMACOLOGY, Heart Failure, Mortality Trials for details and limitations of survival trials).

In using enalapril maleate consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that enalapril maleate does not have a similar risk (see WARNINGS, Neutropenia/Agranulocytosis ).

In considering use of enalapril maleate, it should be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, it should be noted that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks (see WARNINGS, Head and Neck Angioedema ).

Side effects, and when to stop

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

Hypertension

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

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.

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 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 Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Who should not take it

Enalapril maleate is contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an angiotensin-converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema.

Do not coadminister aliskiren with enalapril maleate in patients with diabetes (see PRECAUTIONS, Drug Interactions ).

Enalapril maleate is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer enalapril maleate within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNINGS, Head and Neck Angioedema ).

Other medicines and 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. 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 tablets and other agents that affect the RAS.

Do not coadminister 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).

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.

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 ( see 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.