|
This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or
standards of non-Merck sources.
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(e NAL a pril)
Generic Available (U.S.)
Yes
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of hypertension; treatment of symptomatic heart failure; treatment of asymptomatic left ventricular dysfunction
Use: Unlabeled/Investigational
Unlabeled: To delay the progression of nephropathy and reduce risks of cardiovascular events in hypertensive patients with type 1 or 2 diabetes mellitus; hypertensive crisis, diabetic nephropathy, hypertension secondary to scleroderma renal crisis, diagnosis of aldosteronism, idiopathic edema, Bartter's syndrome, postmyocardial infarction for prevention of ventricular failure
Investigational: Severe congestive heart failure in infants, neonatal hypertension, acute cardiogenic pulmonary edema (enalaprilat)
Pregnancy Risk Factor
C (1st trimester); D (2nd and 3rd trimesters)
Pregnancy Considerations
Due to adverse events observed in some animal studies, enalapril is considered pregnancy category C during the first trimester. Based on human data, enalapril is considered pregnancy category D if used during the second and third trimesters (per the manufacturer; however, one study suggests that fetal injury may occur at anytime during pregnancy). Enalaprilat, the active metabolite of enalapril, crosses the placenta. First trimester exposure to ACE inhibitors may cause major congenital malformations. An increased risk of cardiovascular and/or central nervous system malformations was observed in one study; however, an increased risk of teratogenic events was not observed in other studies. Second and third trimester use of an ACE inhibitor is associated with oligohydramnios. Oligohydramnios due to decreased fetal renal function may lead to fetal limb contractures, craniofacial deformation, and hypoplastic lung development. The use of ACE inhibitors during the second and third trimesters is also associated with anuria, hypotension, renal failure (reversible or irreversible), skull hypoplasia, and death in the fetus/neonate. Chronic maternal hypertension itself is also associated with adverse events in the fetus/infant. ACE inhibitors are not recommended during pregnancy to treat maternal hypertension or heart failure. Those who are planning a pregnancy should be considered for other medication options if an ACE inhibitor is currently prescribed or the ACE inhibitor should be discontinued as soon as possible once pregnancy is detected. The exposed fetus should be monitored for fetal growth, amniotic fluid volume, and organ formation. Infants exposed to an ACE inhibitor in utero, especially during the second and third trimester, should be monitored for hyperkalemia, hypotension, and oliguria.[U.S. Boxed Warning]: Based on human data, ACE inhibitors can cause injury and death to the developing fetus when used in the second and third trimesters. ACE inhibitors should be discontinued as soon as possible once pregnancy is detected.
Lactation
Enters breast milk/not recommended (AAP rates “compatible”; AAP 2001 update pending)
Breast-Feeding Considerations
Enalapril and enalaprilat are excreted in breast milk. Breast-feeding is not recommended by the manufacturer.
Contraindications
Hypersensitivity to enalapril or enalaprilat; angioedema related to previous treatment with an ACE inhibitor; patients with idiopathic or hereditary angioedema
Warnings/Precautions
Boxed warnings:
• Pregnancy: See “Special populations” below.
Concerns related to adverse effects:
• Angioedema: At any time during treatment (especially following first dose) angioedema may occur rarely with ACE inhibitors; it may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). African-Americans may be at an increased risk. Prolonged frequent monitoring may be required especially if tongue, glottis, or larynx are involved as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early and appropriate management is critical. Use in patients with idiopathic or hereditary angioedema or previous angioedema associated with ACE inhibitor therapy is contraindicated.
• Cholestatic jaundice: A rare toxicity associated with ACE inhibitors includes cholestatic jaundice, which may progress to fulminant hepatic necrosis; discontinue if marked elevation of hepatic transaminases or jaundice occurs.
• Cough: An ACE inhibitor cough is a dry, hacking, nonproductive one that usually occurs within the first few months of treatment and should generally resolve within 1-4 weeks after discontinuation of the ACE inhibitor. Other causes of cough should be considered (eg, pulmonary congestion in patients with heart failure) and excluded prior to discontinuation.
• Hyperkalemia: May occur with ACE inhibitors; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.
• Hypersensitivity reactions: Anaphylactic/anaphylactoid reactions can occur with ACE inhibitors. Severe anaphylactoid reactions may be seen during hemodialysis (eg, CVVHD) with high-flux dialysis membranes (eg, AN69), and rarely, during low density lipoprotein apheresis with dextran sulfate cellulose. Rare cases of anaphylactoid reactions have been reported in patients undergoing sensitization treatment with hymenoptera (bee, wasp) venom while receiving ACE inhibitors.
• Hypotension/syncope: Symptomatic hypotension with or without syncope can occur with ACE inhibitors (usually with the first several doses); effects are most often observed in volume-depleted patients; correct volume depletion prior to initiation; close monitoring of patient is required especially with initial dosing and dosing increases; blood pressure must be lowered at a rate appropriate for the patient's clinical condition. Although dose reduction may be necessary, hypotension is not a reason for discontinuation of future ACE inhibitor use especially in patients with heart failure where a reduction in systolic blood pressure is a desirable observation.
• Neutropenia/agranulocytosis: Another ACE inhibitor, captopril, has been associated with rare cases of agranulocytosis, neutropenia, or leukopenia with myeloid hypoplasia. Patients with renal impairment are at high risk of developing neutropenia. Patients with both renal impairment and collagen vascular disease (eg, systemic lupus erythematosus) are at an even higher risk of developing neutropenia. Periodically monitor CBC with differential in these patients.
• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.
Disease-related concerns:
• Aortic stenosis: Use with caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.
• Cardiovascular disease: Initiation of therapy in patients with ischemic heart disease or cerebrovascular disease warrants close observation due to the potential consequences posed by falling blood pressure (eg, MI, stroke). Fluid replacement, if needed, may restore blood pressure; therapy may then be resumed. Discontinue therapy in patients whose hypotension recurs.
• Collagen vascular disease: Use with caution in patients with collagen vascular disease especially with concomitant renal impairment; may be at increased risk for hematologic toxicity.
• Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Use with caution in patients with HCM and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition.
• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.
• Renal impairment: Use with caution in pre-existing renal insufficiency; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment.
Concurrent drug therapy issues:
• Angiotensin receptor blockers: Concurrent use of angiotensin receptor blockers may increase the risk of clinically-significant adverse events (eg, renal dysfunction, hyperkalemia).
Special populations:
• Pregnancy: [U.S. Boxed Warning]: Based on human data, ACEIs can cause injury and death to the developing fetus when used in the second and third trimesters. ACEIs should be discontinued as soon as possible once pregnancy is detected.
Dosage form specific issues:
• Benzyl alcohol: Injection contains benzyl alcohol which has been associated with “gasping syndrome” in neonates.
Other warnings/precautions:
• Surgery: Use with caution before, during, or immediately after major surgery. Cardiopulmonary bypass, intraoperative blood loss or vasodilating anesthesia increases endogenous renin release. Use of ACE inhibitors perioperatively will blunt angiotensin II formation and may result in hypotension.
Adverse Reactions
Note: Frequency ranges include data from hypertension and heart failure trials. Higher rates of adverse reactions have generally been noted in patients with CHF. However, the frequency of adverse effects associated with placebo is also increased in this population.
1% to 10%:
Cardiovascular: Hypotension (0.9% to 7%), chest pain (2%), syncope (0.5% to 2%), orthostasis (2%), orthostatic hypotension (2%)
Central nervous system: Headache (2% to 5%), dizziness (4% to 8%), fatigue (2% to 3%)
Dermatologic: Rash (2%)
Gastrointestinal: Abnormal taste, abdominal pain, vomiting, nausea, diarrhea, anorexia, constipation
Neuromuscular & skeletal: Weakness
Renal: Serum creatinine increased (0.2% to 20%), worsening of renal function (in patients with bilateral renal artery stenosis or hypovolemia)
Respiratory (1% to 2%): Bronchitis, cough, dyspnea
<1% (Limited to important or life-threatening): Agranulocytosis, alopecia, anaphylactoid reaction, angina pectoris, angioedema, ataxia, atrial fibrillation, atrial tachycardia, bone marrow suppression, bradycardia, bronchospasm, cardiac arrest, cerebral vascular accident, cholestatic jaundice, depression, eosinophilic pneumonitis, erythema multiforme, exfoliative dermatitis, flushing, giant cell arteritis, gynecomastia, hallucinations, hemolysis with G6PD, Henoch-Schönlein purpura, hepatitis, ileus, impotence, jaundice, lichen-form reaction, melena, MI, neutropenia, ototoxicity, pancreatitis, paresthesia, pemphigus, pemphigus foliaceus, peripheral neuropathy, photosensitivity, psychosis, pulmonary edema, pulmonary embolism, pulmonary infiltrates, Raynaud's phenomenon, sicca syndrome, somnolence, Stevens-Johnson syndrome, systemic lupus erythematosus, thrombocytopenia, toxic epidermal necrolysis, toxic pustuloderma, vertigo.
A syndrome which may include arthralgia, elevated ESR, eosinophilia and positive ANA, fever, interstitial nephritis, myalgia, rash, and vasculitis has been reported for enalapril and other ACE inhibitors.
Metabolism/Transport Effects
Substrate of CYP3A4 (minor)
Drug Interactions
Allopurinol: ACE Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Risk D: Consider therapy modification
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Antacids: May decrease the serum concentration of ACE Inhibitors. Management: Separate fosinopril administration from antacids by at least 2 hours. US and Canadian recommendations for use of other ACE- inhibitors with antacids may vary. Consult appropriate labeling. Monitor for decreased therapeutic effects of ACE-inhibitors. Risk D: Consider therapy modification
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Aprotinin: May diminish the antihypertensive effect of ACE Inhibitors. Risk C: Monitor therapy
AzaTHIOprine: ACE Inhibitors may enhance the neutropenic effect of AzaTHIOprine. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Management: Upon completion/discontinuation of conivaptan, allow at least 7 days before initiating therapy with drugs that are CYP3A4 substrates. Risk D: Consider therapy modification
CycloSPORINE: ACE Inhibitors may enhance the nephrotoxic effect of CycloSPORINE. Risk D: Consider therapy modification
CycloSPORINE (Systemic): ACE Inhibitors may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
DPP-IV Inhibitors: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Eplerenone: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Everolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Ferric Gluconate: ACE Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Risk C: Monitor therapy
Gold Sodium Thiomalate: ACE Inhibitors may enhance the adverse/toxic effect of Gold Sodium Thiomalate. An increased risk of nitritoid reactions has been appreciated. Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Iron Dextran Complex: ACE Inhibitors may enhance the adverse/toxic effect of Iron Dextran Complex. Specifically, patients receiving an ACE inhibitor may be at an increased risk for anaphylactic-type reactions. Management: Follow iron dextran recommendations closely regarding both having resuscitation equipment and trained personnel on-hand prior to iron dextran administration and the use of a test dose prior to the first therapeutic dose. Risk D: Consider therapy modification
Lanthanum: May decrease the serum concentration of ACE Inhibitors. Management: Administer angiotensin-converting enzyme inhibitors at least two hours before or after lanthanum. Risk D: Consider therapy modification
Lithium: ACE Inhibitors may increase the serum concentration of Lithium. Risk D: Consider therapy modification
Loop Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Loop Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: ACE Inhibitors may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of ACE Inhibitors. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Potassium Salts: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Salicylates: May diminish the antihypertensive effect of ACE Inhibitors. They may also diminish other beneficial pharmacodynamic effects desired for the treatment of CHF. The effects are likely dose-related. 100 mg doses aspirin appear to cause no problems, whereas 300 mg doses appear to significantly affect ACE Inhibitor efficacy. Risk C: Monitor therapy
Sirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Sodium Phosphates: ACE Inhibitors may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ACEIs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Risk D: Consider therapy modification
Temsirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Thiazide Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Thiazide Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
TiZANidine: May enhance the hypotensive effect of ACE Inhibitors. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Tolvaptan: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Trimethoprim: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: Avoid bayberry, blue cohosh, cayenne, ephedra, ginger, ginseng (American), kola, licorice (may worsen hypertension). Avoid black cohosh, california poppy, coleus, golden seal, hawthorn, mistletoe, periwinkle, quinine, shepherd's purse (may have increased antihypertensive effect).
Storage
Enalaprilat: Clear, colorless solution which should be stored at <30°C. I.V. is stable for 24 hours at room temperature in D5W or NS.
Compatibility
Stable in dextran 40 10% in dextrose, D5LR, D5NS, D5W, hetastarch 6%, NS.
Y-site administration: Compatible: Allopurinol, amifostine, amikacin, aminophylline, ampicillin, ampicillin/sulbactam, aztreonam, butorphanol, calcium gluconate, cefazolin, cefoperazone, ceftazidime, ceftizoxime, chloramphenicol, cimetidine, cisatracurium, cladribine, clindamycin, dextran 40, dobutamine, docetaxel, dopamine, doxorubicin liposome, erythromycin lactobionate, esmolol, etoposide, famotidine, fentanyl, filgrastim, ganciclovir, gatifloxacin, gemcitabine, gentamicin, granisetron, heparin, hetastarch, hydrocortisone sodium succinate, labetalol, lidocaine, linezolid, magnesium sulfate, melphalan, meropenem, methylprednisolone sodium succinate, metronidazole, morphine, nafcillin, nicardipine, penicillin G potassium, phenobarbital, piperacillin, piperacillin/tazobactam, potassium chloride, potassium phosphates, propofol, ranitidine, remifentanil, sodium acetate, sodium nitroprusside, teniposide, thiotepa, tobramycin, trimethoprim/sulfamethoxazole, vancomycin, vinorelbine. Incompatible: Amphotericin B, amphotericin B cholesteryl sulfate complex, cefepime, phenytoin.
Compatibility when admixed: Compatible: Dobutamine, dopamine, heparin, meropenem, nitroglycerin, potassium chloride, sodium nitroprusside.
Mechanism of Action
Competitive inhibitor of angiotensin-converting enzyme (ACE); prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor; results in lower levels of angiotensin II which causes an increase in plasma renin activity and a reduction in aldosterone secretion
Pharmacodynamics/Kinetics
Onset of action: Oral: ~1 hour; I.V.: ≤15 minutes
Peak effect: Oral: 4-6 hours; I.V.: 1-4 hours
Duration: Oral: 12-24 hours; I.V.: ~ 6 hours
Absorption: Oral: 55% to 75%
Protein binding: 50% to 60%
Metabolism: Prodrug, undergoes hepatic biotransformation to enalaprilat
Half-life elimination:
Enalapril: Adults: Healthy: 2 hours; Congestive heart failure: 3.4-5.8 hours
Enalaprilat: Infants 6 weeks to 8 months of age: 6-10 hours; Adults: 35-38 hours
Time to peak, serum: Oral: Enalapril: 0.5-1.5 hours; Enalaprilat (active): 3-4.5 hours
Excretion: Urine (60% to 80%); some feces
Dosage
Use lower listed initial dose in patients with hyponatremia, hypovolemia, severe congestive heart failure, decreased renal function, or in those receiving diuretics.
Oral: Enalapril: Children 1 month to 17 years: Hypertension: Initial: 0.08 mg/kg/day (up to 5 mg) in 1-2 divided doses; adjust dosage based on patient response; doses >0.58 mg/kg (40 mg) have not been evaluated in pediatric patients
Investigational: Congestive heart failure: Initial oral doses of enalapril: 0.1 mg/kg/day increasing as needed over 2 weeks to 0.5 mg/kg/day have been used in infants
Investigational: Neonatal hypertension: I.V. doses of enalaprilat: 5-10 mcg/kg/dose administered every 8-24 hours have been used; monitor patients carefully; select patients may require higher doses
Adults:
Oral: Enalapril:
Asymptomatic left ventricular dysfunction: 2.5 mg twice daily, titrated as tolerated to 20 mg/day
Heart failure: Initial: 2.5 mg once or twice daily (usual range: 5-40 mg/day in 2 divided doses); titrate slowly at 1- to 2-week intervals. Target dose: 10-20 mg twice daily (ACC/AHA 2009 Heart Failure Guidelines)
Hypertension: 2.5-5 mg/day then increase as required, usually at 1- to 2-week intervals; usual dose range (JNC 7): 2.5-40 mg/day in 1-2 divided doses. Note: Initiate with 2.5 mg if patient is taking a diuretic which cannot be discontinued. May add a diuretic if blood pressure cannot be controlled with enalapril alone.
I.V.: Enalaprilat:
Heart failure: Avoid I.V. administration in patients with unstable heart failure or those suffering acute myocardial infarction.
Hypertension: 1.25 mg/dose, given over 5 minutes every 6 hours; doses as high as 5 mg/dose every 6 hours have been tolerated for up to 36 hours. Note: If patients are concomitantly receiving diuretic therapy, begin with 0.625 mg I.V. over 5 minutes; if the effect is not adequate after 1 hour, repeat the dose and administer 1.25 mg at 6-hour intervals thereafter; if adequate, administer 0.625 mg I.V. every 6 hours.
Conversion from I.V. to oral therapy if not concurrently on diuretics: 5 mg once daily; subsequent titration as needed; if concurrently receiving diuretics and responding to 0.625 mg I.V. every 6 hours, initiate with 2.5 mg/day.
Dosing adjustment in renal impairment:
Oral: Enalapril:
Clcr 30-80 mL/minute: Administer 5 mg/day titrated upwards to maximum of 40 mg.
Clcr <30 mL/minute: Administer 2.5 mg day; titrated upward until blood pressure is controlled.
For heart failure patients with sodium <130 mEq/L or serum creatinine >1.6 mg/dL, initiate dosage with 2.5 mg/day, increasing to twice daily as needed. Increase further in increments of 2.5 mg/dose at >4-day intervals to a maximum daily dose of 40 mg.
I.V.: Enalaprilat:
Clcr >30 mL/minute: Initiate with 1.25 mg every 6 hours and increase dose based on response.
Clcr <30 mL/minute: Initiate with 0.625 mg every 6 hours and increase dose based on response.
Hemodialysis: Moderately dialyzable (20% to 50%); administer dose postdialysis (eg, 0.625 mg I.V. every 6 hours) or administer 20% to 25% supplemental dose following dialysis; Clearance: 62 mL/minute.
Peritoneal dialysis: Supplemental dose is not necessary, although some removal of drug occurs.
Dosing adjustment in hepatic impairment: Hydrolysis of enalapril to enalaprilat may be delayed and/or impaired in patients with severe hepatic impairment, but the pharmacodynamic effects of the drug do not appear to be significantly altered; no dosage adjustment.
Administration: I.V.
Injection solution: Administer direct IVP over at least 5 minutes or dilute up to 50 mL and infuse.
Monitoring Parameters
Blood pressure; serum creatinine and potassium; if patient has collagen vascular disease and/or renal impairment, periodically monitor CBC with differential
Test Interactions
Positive Coombs' [direct]; may cause false-positive results in urine acetone determinations using sodium nitroprusside reagent
Dietary Considerations
Limit salt substitutes or potassium-rich diet.
Patient Education
Do not use potassium supplement or salt substitutes without consulting prescriber. Take first dose at bedtime. This drug does not eliminate need for diet or exercise regimen as recommended by prescriber. May cause dizziness, fainting, lightheadedness, postural hypotension, nausea, vomiting, abdominal pain, dry mouth, or transient loss of appetite. Report persistent nausea and vomiting; chest pain or palpitations; mouth sores; fever or chills; swelling of extremities, face, mouth, or tongue; skin rash; numbness, tingling, or pain in muscles; or respiratory difficulty or unusual cough.
Geriatric Considerations
Due to frequent decreases in glomerular filtration (also creatinine clearance) with aging, elderly patients may have exaggerated responses to ACE inhibitors; differences in clinical response due to hepatic changes are not observed. ACE inhibitors may be preferred agents in elderly patients with congestive heart failure and diabetes mellitus. Diabetic proteinuria is reduced and insulin sensitivity is enhanced. In general, the side effect profile is favorable in the elderly and causes little or no CNS confusion; use lowest dose recommendations initially; adjust dose for renal function in the elderly. Many elderly may be volume depleted due to diuretic use and/or blunted thirst reflex resulting in inadequate fluid intake.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: In patients on chronic ACE inhibitor therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; however, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent. Episodes of intraoperative hypotension may be managed by fluid administration and/or modest doses of alpha-adrenergic agents. Severe hypotension may occur in patients who are sodium- and/or volume-depleted, initiate lower doses and monitor closely when starting therapy in these patients. ACE inhibitor therapy may elicit an increase in potassium and creatinine, especially when used in patients with bilateral renal artery stenosis. In those patients experiencing cough on an ACE inhibitor, the ACE inhibitor may be discontinued and, if necessary, angiotensin-receptor blocker therapy instituted. Concomitant NSAID therapy may attenuate blood pressure control; use of NSAIDs should be avoided or limited, with monitoring of blood pressure control. In the setting of heart failure, NSAID use may be associated with an increased risk for fluid accumulation and edema. Because of the potent teratogenic effects of ACE inhibitors, these drugs should be avoided, if possible, when treating women of childbearing potential not on effective birth control measures. Aging patients with a decrease in glomerular filtration (also creatinine clearance), severe heart failure, and renal failure may experience an exaggerated response with administration of ACE inhibitors. Diabetic proteinuria is reduced and insulin sensitivity is enhanced.
Evidence-Based Information: ACE inhibitors decrease morbidity and mortality in patients with asymptomatic and symptomatic left ventricular dysfunction. In this situation, they decrease hospitalizations for, and retard progression to, decompensated heart failure. ACE inhibitors are also indicated in patients postmyocardial infarction in whom left ventricular ejection fraction is <40%. When used in patients with heart failure, the target dose or maximum tolerated dose should be achieved, if possible. Lower daily doses of ACE inhibitors have not demonstrated the same cardioprotective effects. ACE inhibitors have renal protective effects in patients with diabetic proteinuria. The HOPE trial examined the use of ramipril at a dose of between 2.5-10 mg daily in patients without heart failure at high risk for cardiovascular events and documented a significant improvement in cardiovascular outcome compared to placebo.
Cardiovascular Considerations
Heart Failure: The ACC/AHA 2009 Heart Failure Guidelines recommend that ACE inhibitors be used in patients with a reduced EF (with or without heart failure symptoms) unless contraindicated. ACE inhibitors decrease morbidity and mortality in patients with asymptomatic and symptomatic left ventricular dysfunction. In this situation, they decrease hospitalizations for, and retard progression to, congestive heart failure. When used in patients with heart failure, the target dose should be achieved, if possible. Lower daily doses of ACE inhibitors have demonstrated the same mortality effects as high doses, but have not decreased hospitalizations to the extent that high-dose ACE inhibitors have, as demonstrated in the ATLAS study (Packer M, 1999).
Hypertension: The ALLHAT study (ALLHAT Collaborative Group, 2002) compared CV outcomes of lisinopril, amlodipine, or chlorthalidone in hypertensive patients having at least one other risk factor for coronary heart disease. Investigators found no difference between the groups on the primary outcome of fatal coronary disease or nonfatal MI. The ACC/AHA 2009 Heart Failure Guidelines suggest that ACE inhibitors or angiotensin receptor blockers (ARBs) can be beneficial in patients with hypertension and LVH without symptoms of heart failure. JNC 7 suggests that patients can benefit from treatment with an ACE inhibitor if they have hypertension and heart failure, acute myocardial infarction, high coronary disease risk, diabetes, chronic kidney disease, or history of stroke.
Vascular Disease: The ACC/AHA 2009 Heart Failure Guidelines suggest that ACE inhibitors can be useful in preventing heart failure in patients who have a history of atherosclerotic vascular disease, diabetes, or hypertension with associated cardiovascular risk factors. The HOPE trial (Heart Outcomes Prevention Evaluation Study Investigators, 2000) investigated the value of an ACE inhibitor (ramipril 5-10 mg daily) versus placebo in patients who had evidence of vascular disease or diabetes (one other cardiovascular risk factor) and were at least 55 years of age. Patients were excluded if they had a low ejection fraction, heart failure, or were on an ACE inhibitor. The primary outcome was a composite of death from cardiovascular cause, myocardial infarction, or stroke; 9297 patients were enrolled and randomized. Ramipril significantly reduced the risk of death from CV causes, MI, or stroke over placebo. New cases of diabetes were also reduced in the ramipril group. In the EUROPA trial, patients with stable coronary artery disease (at low risk for cardiovascular events) received perindopril or placebo and were evaluated for incidence of cardiovascular events after four years of treatment. In this randomized, placebo-controlled, prospective study, 12,218 patients received either perindopril (8 mg/day, n=6110) or placebo (n=6108) and were assessed for the primary endpoint of a cardiovascular event, defined as cardiovascular death, myocardial infarction, or cardiac arrest. The study population was well balanced with respect to baseline demographics and concomitant medication use (including beta-blockers, platelet inhibitors, antihyperlipidemics, calcium channel blockers, nitrates, and diuretics). Intent-to-treat analysis revealed that 603 (10%) of placebo patients experienced the primary endpoint of a cardiovascular event compared to 488 (8%) of perindopril-receiving patients, for a 20% relative risk reduction (p=0.0003). This result was not influenced by presence of other comorbidities (eg, diabetes, hypertension) or concomitant beta-blocker, calcium channel blocker, or lipid-lowering therapies. Withdrawal from the study (postrandomization) due to adverse reactions was similar between treatment groups. Number needed to treat analysis suggests that treatment of 50 patients over a 4-year period will prevent one major cardiovascular event.
Acute Coronary Syndromes: In the treatment of unstable angina/non-ST-segment elevation MI, ACE inhibitors are recommended when hypertension persists despite treatment with nitroglycerin and a beta-blocker in patients with LV systolic dysfunction or CHF and in ischemic patients with diabetes (Class I). ACE inhibitors are also recommended for all post-ACS individuals (Class IIa). According to 2004 ACC/AHA STEMI guidelines, an ACE inhibitor should be administered orally within the first 24 hours of STEMI to patients with anterior infarction, pulmonary congestion, or LVEF <0.4, in the absence of hypotension or known contraindications to this class of medicines. In the emergency management of complicated STEMI, a short-acting ACEI (eg, captopril 1-6.25 mg) may be added once the patient's systolic blood pressure is >100 mm Hg and not <30 mm Hg below baseline. The VALIANT trial evaluated the effects of valsartan (target dose: 160 mg twice daily), captopril (target dose: 50 mg twice daily), and the combination (target doses: valsartan 80 mg twice daily and captopril 150 mg once daily) in a randomized, double-blind trial of patients with acute MI (0.5-10 days post-MI) complicated by left ventricular systolic dysfunction, heart failure, or both. Enrollment in the study numbered 14,703 patients and followed for a median of 24.7 months. There was no difference in the primary endpoint (all cause mortality) among the 3 groups. There was no difference in incidence of CV death, recurrent MI, or hospitalization for heart failure either. Hypotension and renal dysfunction occurred significantly more often in the valsartan group than captopril alone. Cough, rash, and taste disturbances occurred more often in the captopril group. The authors (Pfeffer MA, 2003) concluded that valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after MI. Combining valsartan with captopril increased the rate of adverse events without improving survival.
Potential Adverse Events: ACE inhibitor therapy may elicit rapid increases in potassium and creatinine, especially when used in patients with bilateral renal artery stenosis. When ACE inhibition is introduced in patients with pre-existing diuretic therapy who are hypovolemic, the ACE inhibitor may induce acute hypotension. In those patients experiencing cough on an ACE inhibitor, the ACE inhibitor may be discontinued and, if necessary, ARB therapy instituted. Because of the potent teratogenic effects of ACE inhibitors, these drugs should be avoided, if possible, when treating women of childbearing potential not on effective birth control measures.
Drug Interactions: Concomitant indomethacin therapy may blunt the reduction in sitting and 24-hour ambulatory diastolic blood pressure. Use of NSAIDs should be avoided or limited, with monitoring of blood pressure control in this setting. In patients with heart failure, NSAID use may be associated with an increased risk for fluid accumulation and edema.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Abnormal taste and orthostatic hypotension
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause drowsiness and dizziness; rarely may cause insomnia, confusion, depression
Mental Health: Effects on Psychiatric Treatment
May rarely cause agranulocytosis; use caution with clozapine and carbamazepine; may decrease lithium clearance resulting in an increase in serum lithium levels and potential lithium toxicity; monitor serum lithium levels
Nursing: Physical Assessment/Monitoring
Assess potential for interactions with other pharmacological agents or herbal products that may impact fluid balance or cardiac status. Blood pressure should be closely monitored with first dose or change in dose. Assess results of laboratory tests closely during first 3 months of therapy and regularly thereafter. Monitor for anaphylactic reaction, hypovolemia, angioedema, and postural hypotension.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution, as enalaprilat: 1.25 mg/mL (1 mL, 2 mL)
Tablet, oral, as maleate: 2.5 mg, 5 mg, 10 mg, 20 mg
Vasotec®: 2.5 mg, 5 mg, 10 mg, 20 mg [scored]
Pricing: U.S. (www.drugstore.com)
Tablets (Enalapril Maleate)
2.5 mg (30): $13.99
5 mg (30): $11.99
10 mg (30): $11.99
20 mg (30): $11.99
Tablets (Vasotec)
2.5 mg (60): $155.99
5 mg (30): $82.99
10 mg (30): $105.99
20 mg (30): $123.99
Extemporaneously Prepared
A 1 mg/mL oral suspension may be made with tablets, Bicitra® [discontinued] or equivalent, and Ora-Sweet® SF. Place ten 20 mg tablets in a 200 mL polyethylene terephthalate bottle; add 50 mL of Bicitra® [discontinued] or equivalent and shake well for at least 2 minutes. Let stand for 1 hour then shake for 1 additional minute; add 150 mL of Ora-Sweet® SF and shake well. Label “shake well” and "refrigerate". Stable for 30 days when stored in a polyethylene terephthalate bottle and refrigerated (Vasotec® prescribing information, 2001).
A 1 mg/mL oral suspension may be made with tablets and one of three different vehicles (cherry syrup, a 1:1 mixture of Ora-Sweet® and Ora-Plus®, or a 1:1 mixture of Ora-Sweet® SF and Ora-Plus®). Crush six 20 mg tablets in a mortar and reduce to a fine powder. Add 15 mL of the chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label “shake well” and “protect from light”. Stable for 60 days when stored in amber plastic prescription bottles in the dark at room temperature or refrigerated (Allen, 1998).
A 1 mg/mL oral suspension may be made with tablets and one of three different vehicles (deionized water, citrate buffer solution at pH 5.0, or a 1:1 mixture of Ora-Sweet® and Ora-Plus®). Crush twenty 10 mg tablets in a mortar and reduce to a fine powder. Add small portions of the chosen vehicle and mix to a uniform paste; mix while adding vehicle in incremental proportions to almost 200 mL; transfer to a graduated cylinder, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 200 mL. Label “shake well” and “protect from light”. Preparations made in citrate buffer solution at pH 5.0 and the 1:1 mixture of Ora-Sweet® and Ora-Plus® are stable for 91 days when stored in plastic prescription bottles in the dark at room temperature or refrigerated. Preparation made in deionized water is stable for 91 days refrigerated or 56 days at room temperature when stored in plastic prescription bottles in the dark. Note: To prepare the isotonic citrate buffer solution (pH 5.0), see reference (Nahata, 1998).
A more dilute, 0.1 mg/mL oral suspension may be made with tablets and an isotonic buffer solution at pH 5.0. Grind one 20 mg tablet in a glass mortar and reduce to a fine powder; mix with isotonic citrate buffer (pH 5.0) and filter; add quantity of buffer solution sufficient to make 200 mL. Label “shake well”, “protect from light”, and "refrigerate". Stable for 90 days (Boulton, 1994).
Allen LV Jr and Erickson MA 3rd, "Stability of Alprazolam, Chloroquine Phosphate, Cisapride, Enalapril Maleate, and Hydralazine Hydrochloride in Extemporaneously Compounded Oral Liquids," Am J Health Syst Pharm, 1998, 55(18):1915-20.
Boulton DW, Woods DJ, Fawcett JP, et al, “The Stability of an Enalapril Maleate Oral Solution Prepared From Tablets,” Aust J Hosp Pharm, 1994, 24(2):151-6.
Nahata MC, Morosco RS, and Hipple TF, "Stability of Enalapril Maleate in Three Extemporaneously Prepared Oral Liquids," Am J Health Syst Pharm, 1998, 55(11):1155-7.
Vasotec® prescribing information, Merck & Co, Inc, West Point, PA, 2001.
References
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, “Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),” JAMA, 2002, 288(23):2981-97.
American Academy of Pediatrics Committee on Drugs, "Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics, 2001, 108(3):776-89.
American Diabetes Association, “Standards of Medical Care in Diabetes Mellitus -- 2011,” Diabetes Care, 2011, 34(Suppl 1):11-61.
Annane D, Bellissant E, Pussard E, et al, “Placebo-Controlled, Randomized, Double-Blind Study of Intravenous Enalaprilat Efficacy and Safety in Acute Cardiogenic Pulmonary Edema,” Circulation, 1996, 94(6):1316-24.
Anderson JL, Adams CD, Antman EM, et al, “ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration With the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine,” J Am Coll Cardiol, 2007, 50(7):e1-e157.
Antman EM, Anbe SC, Alpert JS, et al, “ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction),” Circulation, 2004, 110(5):588-636.
Antman EM, Hand M, Armstrong PW, et al, “2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines,” J Am Coll Cardiol, 2008, 51(2):210-49.
Chase MP, Fiarman GS, Scholz FJ, et al, “Angioedema of the Small Bowel Due to an Angiotensin-Converting Enzyme Inhibitor,” J Clin Gastroenterol, 2000, 31(3):254-7.
Chobanian AV, Bakris GL, Black HR, et al, “The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report,” JAMA, 2003, 289(19):2560-71.
Conlin P, Moore T, Swartz S, et al, “Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients,” Hypertension, 2000, 36(3):461-5.
Cooper WO, Hernandez-Diaz S, Arbogast PG, et al, “Major Congenital Malformations After First-Trimester Exposure to ACE Inhibitors,” N Engl J Med, 2006, 354(23):2443-51.
Erstad BL and Barletta JF, “Treatment of Hypertension in the Perioperative Patient,” Ann Pharmacother, 2000, 34(1):66-79.
Fox KM and EURopean Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease Investigators, “Efficacy of Perindopril in Reduction of Cardiovascular Events Among Patients With Stable Coronary Artery Disease: Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial (The EUROPA Study),” Lancet, 2003, 362(9386):782-8.
Hunt SA, Abraham WT, Chin MH, et al, “2009 Focused Update Incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation,” J Am Coll Cardiol, 2009, 53(15):e1-e90.
“K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Kidney Disease Outcome Quality Initiative,” Am J Kidney Dis, 2002, 39(2 Suppl 2):1-246. Available at http://www.kidney.org/professionals/KDOQI/guidelines_ckd/toc.htm
Lindenfeld J, Albert NM, Boehmer JP, et al, “HFSA 2010 Comprehensive Heart Failure Practice Guideline,” J Card Fail, 2010, 16(6):e1-194.
Mastrobattista JM, “Angiotensin Converting Enzyme Inhibitors in Pregnancy,” Semin Perinatol, 1997, 21(2):124-34.
Miller DR, Oliveria SA, Berlowitz DR, et al, “Angioedema Incidence in US Veterens Initiating Angiotensin-Converting Enzyme Inhibitors,” Hypertension, 2008, 51(6):1-7.
National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents, “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents,” Pediatrics, 2004, 114 (2 Suppl):555-76.
Packer M, Poole-Wilson PA, Armstrong PW, et al, “Comparative Effects of Low and High Doses of the Angiotensin-Converting Enzyme Inhibitor, Lisinopril, on Morbidity and Mortality in Chronic Heart Failure,” Circulation, 1999, 100(23):2312-8.
Pfeffer MA, Greaves SC, Arnold JM, et al, “Early Versus Delayed Angiotensin-Converting Enzyme Inhibition Therapy in Acute Myocardial Infarction. The Healing and Early Afterload Reducing Therapy Trial,” Circulation, 1997, 95(12):2643-51.
Pfeffer MA, McMurray JJ, Velazquez EJ, et al, “Valsartan, Captopril, or Both in Myocardial Infarction Complicated by Heart Failure, Left Ventricular Dysfunction, or Both,” N Engl J Med, 2003, 349(20):1893-906.
Quan A , “Fetopathy Associated With Exposure to Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Antagonists,” Early Hum Dev, 2006, 82(1):23-8.
Smoger SH and Sayed MA, “Simultaneous Mucosal and Small Bowel Angioedema Due to Captopril,” South Med J, 1998, 91(11):1060-3.
Yusuf S, Sleight P, Pogue J, et al, “Effects of an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Cardiovascular Events in High-Risk Patients. The Heart Outcomes Prevention Evaluation Study Investigators,” N Engl J Med, 2000, 342(3):145-53.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
|
