Enalapril
FDA Drug Information • Also known as: Enalapril Maleate
- Brand Names
- Enalapril Maleate
- Route
- ORAL
- Dosage Form
- SOLUTION
- Product Type
- HUMAN PRESCRIPTION DRUG
⚠ Boxed Warning (Black Box)
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 )
Description
11 DESCRIPTION Enalapril maleate (enalapril maleate) oral solution is the maleate salt of enalapril, the ethyl ester prodrug 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
What Is Enalapril Used For?
1 INDICATIONS 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 [see Pediatric Use (8.4) and Clinical Studies (14) ] . 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...
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Hypertension Adult: recommended initial dose is 5 mg once daily. Maximum dose is 40 mg daily. ( 2.1 ) Pediatrics: recommended starting dose is 0.08 mg/kg (up to 5 mg) once daily. ( 2.1 ) Heart Failure: Initiate at 2.5 mg twice daily. Titrate up to 20 mg twice daily as tolerated. ( 2.2 ) Asymptomatic Left Ventricular Dysfunction: Initiate at 2.5 mg twice daily. Titrate up to 10 mg twice daily. ( 2.3 ) Enalapril maleate oral solution is a ready-to-use solution intended for oral use only. 2.1 Hypertension Adults : The recommended initial dose in adults is 5 mg taken orally once a day. Titrate upward to maximum of 40 mg daily as needed to help achieve blood pressure goals. The dose may be divided and administered twice daily if the antihypertensive effect diminishes at the end of the dosing interval. Use with diuretics: If additional blood pressure reduction is needed, enalapril maleate oral solution may be administered with a low dose of diuretic. The recommended initial dose in patients taking diuretics is 2.5 mg daily. Dosage Adjustment for Renal Impairment: See table below. The dosage may be titrated upward as needed to a maximum of 40 mg daily. Renal Status Creatinine-Clearance mL/min Initial Dose mg/day Normal or Mild Impairment of Renal Function >30 mL/min 5 mg Moderate to Severe Impairment ≤30 mL/min 2.5 mg Dialysis Patients*† – 2.5 mg * = [See Warnings and Precautions (5.2) ]. † = Should be taken after hemodialysis on dialysis days [see Clinical Pharmacology (12.3) ] . Calculated using ideal body weight. Children greater than 1 month of age: The usual recommended starting dose is 0.08 mg/kg (up to 5 mg) once daily. Adjust dose based on 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 (12.3) ] . Enalapril maleate oral solution is not recommended in neonates (i.e., infants 1 month of age or less), preterm infants who have not reached a corrected post-conceptual age of 44 weeks, and in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m 2 . 2.2 Heart Failure The recommended initial dose is 2.5 mg twice a day titrated up to a maximum of 20 mg twice a day, as tolerated. Doses are usually given in combination with diuretics and digitalis. In patients with hyponatremia (serum sodium less than 130 mEq/L) or serum creatinine greater than 1.6 mg/dL, the recommended initial dose is 2.5 mg once daily. Diuretic dose may need to be adjusted to minimize hypovolemia and hypotension. The appearance of hypotension after the initial dose of enalapril maleate oral solution does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. 2.3 Asymptomatic Left Ventricular Dysfunction The recommended initial dose is 2.5 mg twice a day titrated up to a maximum of 10 mg twice a day, as tolerated. Diuretic dose may need to be adjusted [see Dosage and Administration (2.1) ] .
Side Effects (Adverse Reactions)
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,...
Drug Interactions
7 DRUG INTERACTIONS In patients who are elderly, volume-depleted (as on diuretic therapy), or with compromised renal function, use with NSAIDs, including selective COX-2 inhibitors, may result in deterioration of renal function, including renal failure. Monitor renal function periodically. ( 7.1 ) Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension and hyperkalemia. ( 7.2 ) Avoid potassium sparing agents in patients with heart failure. ( 7.3 ) Monitor serum lithium levels frequently. ( 7.4 ) 7.1 Non-Steroidal Anti-Inflammatory Agents (NSAIDs) 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, co-administration 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. 7.2 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. In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on enalapril maleate 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). 7.3 Agents 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. 7.4 Lithium Lithium toxicity has been reported in patients receiving enalapril and lithium concomitantly which was generally reversible. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium. 7.5 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...
Contraindications
4 CONTRAINDICATIONS Enalapril maleate 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 in patients with diabetes [see Drug Interactions (7.2) ] . 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 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 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Enalapril maleate can cause fetal harm when administered to a pregnant woman. 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. 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. When pregnancy is detected, discontinue enalapril maleate as soon as possible. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the general U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Adverse reactions in the fetus or in neonates with a history of in utero exposure to enalapril maleate Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, oligohydramnios, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. 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...
Overdosage
10 OVERDOSAGE Limited data are available in regard to overdosage in humans. Single oral doses of enalapril above 1,000 mg/kg and ≥1,775 mg/kg were associated with lethality in mice and rats, respectively. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Enalaprilat may be removed from general circulation by hemodialysis and has been removed from neonatal circulation by peritoneal dialysis.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Enalapril maleate oral solution, 1 mg/mL is available as a ready-to-use solution that contains 1 mg/mL of enalapril maleate. It is a clear, colorless raspberry flavored oral solution, packaged in a 150 mL, white, round, high-density polyethylene bottle with a child-resistant cap and tamper-evident seal. Each bottle contains 150 mL. It is supplied as follows: One 150 mL bottle with child-resistant closure: NDC 69238-1729-7 Store refrigerated (2° to 8°C (36° to 46°F). Patients may store enalapril maleate oral solution at room temperature (20° to 25°C/68° to 77°F). If stored at room temperature, discard after 60 days. Avoid freezing and excessive heat. Keep container tightly closed.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.