(e NAL a pril)
- Enalapril Maleate
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution Reconstituted, Oral, as maleate:
Epaned: 1 mg/mL (150 mL) [contains methylparaben, propylparaben, saccharin sodium; berry-citrus flavor]
Tablet, Oral, as maleate:
Vasotec: 2.5 mg [scored]
Vasotec: 5 mg [DSC]
Vasotec: 5 mg [scored]
Vasotec: 10 mg [DSC]
Vasotec: 10 mg [scored]
Vasotec: 20 mg [DSC]
Vasotec: 20 mg [scored]
Generic: 2.5 mg, 5 mg, 10 mg, 20 mg
Brand Names: U.S.
- Angiotensin-Converting Enzyme (ACE) Inhibitor
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
55% to 75%
Prodrug, undergoes hepatic biotransformation to enalaprilat
Urine (61%; 18% of which was enalapril, 43% was enalaprilat); feces (33%; 6% of which was enalapril, 27% was enalaprilat) (Ulm, 1982)
Onset of Action
~1 hour; Peak effect: 4 to 6 hours
Time to Peak
Serum: Oral: Enalapril: 0.5 to 1.5 hours; Enalaprilat (active metabolite): 3 to 4.5 hours
Duration of Action
12 to 24 hours
Enalapril: CHF: Neonates (n=3, PNA: 10-19 days): 10.3 hours (range: 4.2-13.4 hours) (Nakamura, 1994); CHF: Infants and Children ≤6.5 years of age (n=11): 2.7 hours (range: 1.3-6.3 hours) (Nakamura, 1994); Adults: Healthy: 2 hours; Congestive heart failure: 3.4 to 5.8 hours
Enalaprilat: CHF: Neonates (n=3, PNA: 10-19 days): 11.9 hours (range: 5.9-15.6 hours) (Nakamura, 1994); CHF: Infants and Children ≤6.5 years of age (n=11): 11.1 hours (range: 5.1-20.8 hours) (Nakamura, 1994); Infants 6 weeks to 8 months of age: 6 to 10 hours (Lloyd, 1989); Adults: ~35 hours (Till, 1984; Ulm, 1982)
~50% (Davies, 1984)
Special Populations: Renal Function Impairment
In those with glomerular filtration rate (GFR) 30 mL/minute or less, the peak and trough enalaprilat levels increase, Tmax increases, and time to steady state may be delayed.
Use: Labeled Indications
Asymptomatic left ventricular dysfunction: Treatment of asymptomatic left ventricular dysfunction
Heart failure: Treatment of symptomatic heart failure (HF)
Hypertension: Treatment of hypertension
Hypertension: The 2014 guideline for the management of high blood pressure in adults (Eighth Joint National Committee [JNC 8]) recommends initiation of pharmacologic treatment to lower blood pressure for the following patients:
• Patients ≥60 years of age with systolic blood pressure (SBP) ≥150 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg. Goal of therapy is SBP <150 mm Hg and DBP <90 mm Hg.
• Patients <60 years of age with SBP ≥140 mm Hg or DBP is ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.
• Patients ≥18 years of age with diabetes and SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.
• Patients ≥18 years of age with chronic kidney disease (CKD) and SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.
Chronic kidney disease (CKD) and hypertension: Regardless of race or diabetes status, the use of an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) as initial therapy is recommended to improve kidney outcomes. In the general nonblack population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic, calcium channel blocker, ACEI, or ARB. In the general black population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic or a calcium channel blocker instead of an ACEI or ARB.
Coronary artery disease (CAD) and hypertension: The American Heart Association, American College of Cardiology and American Society of Hypertension (AHA/ACC/ASH) 2015 scientific statement for the treatment of hypertension in patients with CAD recommends the use of an ACE inhibitor (or an ARB) as part of a regimen in patients with hypertension and chronic stable angina if there is prior MI, LV systolic dysfunction, diabetes mellitus, or CKD. A BP target of <140/90 mm Hg is reasonable for the secondary prevention of cardiovascular events. A lower target BP (<130/80 mm Hg) may be appropriate in some individuals with CAD, previous MI, stroke or transient ischemic attack, or CAD risk equivalents (AHA/ACC/ASH [Rosendorff 2015]).
Heart failure: The ACCF/AHA 2013 heart failure guidelines recommend the use of ACE inhibitors, along with other guideline directed medical therapies, to prevent heart failure in patients with a reduced ejection fraction who have a history of MI (Stage B HF), to prevent heart failure in any patient with a reduced ejection fraction (Stage B HF), or to treat those with heart failure and reduced ejection fraction (Stage C HFrEF) (ACCF/AHA [Yancy 2013]).
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
Hypersensitivity to enalapril or any component of the formulation; angioedema related to previous treatment with an ACE inhibitor; patients with idiopathic or hereditary angioedema; concomitant use with aliskiren in patients with diabetes mellitus
Documentation of allergenic cross-reactivity for ACE inhibitors is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Canadian labeling: Additional contraindications (not in U.S. labeling): Concomitant use with aliskiren-containing drugs in patients with moderate-to-severe renal impairment (GFR <60 mL/minute/1.73 m2)
Use lower listed initial dose in patients with hyponatremia, hypovolemia, severe congestive heart failure, decreased renal function, or in those receiving diuretics.
Asymptomatic left ventricular dysfunction: Oral: 2.5 mg twice daily, titrated as tolerated to 20 mg daily
Heart failure with reduced ejection fraction (HFrEF): Oral: Initial: 2.5 mg twice daily (usual range: 5 to 40 mg daily in 2 divided doses); titrate slowly at 1- to 2-week intervals. Target dose: 10 to 20 mg twice daily (ACCF/AHA [Yancy, 2013])
Hypertension: Oral: 2.5 to 5 mg daily then increase as required, usually at 1- to 2-week intervals; usual dose range (ASH/ISH [Weber, 2014]): 10 to 40 mg daily. Target dose (JNC 8 [James, 2013]): 20 mg daily in 1 or 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.
Conversion from IV enalaprilat to oral enalapril therapy: If not concurrently receiving diuretics, initiate enalapril 5 mg once daily; if concurrently receiving diuretics and responding to enalaprilat 0.625 mg IV every 6 hours, initiate with enalapril 2.5 mg once daily; subsequent titration as needed.
Refer to adult dosing.
Hypertension: Infants, Children, and Adolescents: Oral: Initial: 0.08 mg/kg (up to 5 mg) once daily; adjust dosage based on patient response; doses >0.58 mg/kg (40 mg) have not been evaluated in pediatric patients
Heart failure (off-label dosing): Infants, Children, and Adolescents: Oral: Initial: 0.1 mg/kg/day in 1 to 2 divided doses; increase as required over 2 weeks to maximum of 0.5 mg/kg/day. Note: Mean dose required for CHF improvement in 39 children (9 days to 17 years) was 0.36 mg/kg/day; select individuals have been treated with doses up to 0.94 mg/kg/day (Leversha 1994; Momma 2006).
Dosing: Renal Impairment
Note: Use in infants and children ≤16 years of age with GFR <30 mL/minute/1.73 m2 is not recommended (no dosing data exists).
CrCl >30 mL/minute: No dosage adjustment necessary
CrCl ≤30 mL/minute: Administer 2.5 mg day; titrated upward until blood pressure is controlled.
Heart failure patients with sodium <130 mEq/L or serum creatinine >1.6 mg/dL: Initiate dosage with 2.5 mg daily, 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.
Intermittent hemodialysis (IHD): Moderately dialyzable (20% to 50%): Initial: 2.5 mg on dialysis days; adjust dose on nondialysis days depending on blood pressure response.
Conversion from IV enalaprilat to oral enalapril therapy:
CrCl >30 mL/minute: May initiate enalapril 5 mg once daily.
CrCl ≤30 mL/minute: May initiate enalapril 2.5 mg once daily.
Alternate recommendations (Aronoff 2007):
CrCl >50 mL/minute: No dosage adjustment necessary
CrCl 10 to 50 mL/minute: Administer 75% to 100% of usual dose
CrCl <10 mL/minute: Administer 50% of usual dose
Peritoneal dialysis: Supplemental dose is not necessary, although some removal of drug occurs.
Dosing: Hepatic Impairment
No dosage adjustment is necessary. 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.
Epaned: Solution kit (for 150 mL, enalapril solution 1 mg/mL): Kit contains 1 bottle of enalapril powder and 1 bottle of Ora-Sweet SF dilution to be added to the enalapril powder prior to dispensing. Firmly tap the enalapril powder for oral solution bottle on a hard surface 5 times. Add approximately one-half (75 mL) of the Ora-Sweet SF diluent to the enalapril 150 mL oral solution bottle and shake well for 30 seconds. Add the remainder of the Ora-Sweet SF diluent and shake well for an additional 30 seconds. May be used for 60 days after reconstitution.
Note: Commercial oral solution kit is available (1 mg/mL).
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, 2011).
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):1915-20.9784772Boulton 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):1155-7.9626379Vasotec® prescribing information, Valeant Pharmaceuticals North America LLC, Bridgewater, NJ; 2011.
Limit salt substitutes or potassium-rich diet.
Solution kit: Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Do not freeze. Protect from moisture. Once reconstituted, the solution should be stored at 15°C to 30°C (59°F to 86°F) and may be stored for up to 60 days.
Tablet: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture.
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Aliskiren: May enhance the hyperkalemic effect of ACE Inhibitors. Aliskiren may enhance the hypotensive effect of ACE Inhibitors. Aliskiren may enhance the nephrotoxic effect of ACE Inhibitors. Management: Aliskiren use with ACEIs or ARBs in patients with diabetes is contraindicated. Combined use in other patients should be avoided, particularly when CrCl is less than 60 mL/min. If combined, monitor potassium, creatinine, and blood pressure closely. Consider therapy modification
Allopurinol: ACE Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Consider therapy modification
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy
Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of ACE Inhibitors. Angiotensin II Receptor Blockers may increase the serum concentration of ACE Inhibitors. Management: In US labeling, use of telmisartan and ramipril is not recommended. It is not clear if any other combination of an ACE inhibitor and an ARB would be any safer. Consider alternatives to the combination when possible. Consider therapy modification
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy
Aprotinin: May diminish the antihypertensive effect of ACE Inhibitors. Monitor therapy
AzaTHIOprine: ACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Canagliflozin: May enhance the hyperkalemic effect of ACE Inhibitors. Canagliflozin may enhance the hypotensive effect of ACE Inhibitors. Monitor therapy
Ciprofloxacin (Systemic): ACE Inhibitors may enhance the arrhythmogenic effect of Ciprofloxacin (Systemic). Monitor therapy
Dapoxetine: May enhance the orthostatic hypotensive effect of ACE Inhibitors. Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
DPP-IV Inhibitors: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy
Drospirenone: ACE Inhibitors may enhance the hyperkalemic effect of Drospirenone. Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy
Eplerenone: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy
Everolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy
Ferric Gluconate: ACE Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Monitor therapy
Ferric Hydroxide Polymaltose Complex: ACE Inhibitors may enhance the adverse/toxic effect of Ferric Hydroxide Polymaltose Complex. Specifically, the risk for angioedema or allergic reactions may be increased. 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. Monitor therapy
Grass Pollen Allergen Extract (5 Grass Extract): ACE Inhibitors may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). Specifically, ACE inhibitors may increase the risk of severe allergic reaction to Grass Pollen Allergen Extract (5 Grass Extract). Consider therapy modification
Heparin: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy
Heparin (Low Molecular Weight): May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy
Icatibant: May diminish the antihypertensive effect of ACE Inhibitors. 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. 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. Consider therapy modification
Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy
Lithium: ACE Inhibitors may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an ACE inhibitor. Monitor patient response to lithium closely following addition or discontinuation of concurrent ACE inhibitor treatment. Consider therapy modification
Loop Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Loop Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nicorandil: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. 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. Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Potassium Salts: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy
Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy
Pregabalin: ACE Inhibitors may enhance the adverse/toxic effect of Pregabalin. Specifically, the risk of angioedema may be increased. Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Sacubitril: ACE Inhibitors may enhance the adverse/toxic effect of Sacubitril. Specifically, the risk of angioedema may be increased with this combination. Avoid combination
Salicylates: May enhance the nephrotoxic effect of ACE Inhibitors. Salicylates may diminish the therapeutic effect of ACE Inhibitors. Monitor therapy
Sirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. 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. Consider therapy modification
Temsirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Monitor therapy
Thiazide and Thiazide-Like Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Monitor therapy
TiZANidine: May enhance the hypotensive effect of ACE Inhibitors. Monitor therapy
Tolvaptan: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy
Trimethoprim: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy
Positive Coombs' [direct]; may cause false-positive results in urine acetone determinations using sodium nitroprusside reagent
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.
>10%: Renal: Increased serum creatinine (≤20%)
1% to 10%:
Cardiovascular: Hypotension (1% to 7%), chest pain (2%), orthostatic effect (1% to 2%), orthostatic hypotension (2%), syncope (≤2%)
Central nervous system: Dizziness (4% to 8%), headache (2% to 5%), fatigue (2% to 3%)
Dermatologic: Skin rash (1% to 2%)
Gastrointestinal: Abdominal pain, anorexia, constipation, diarrhea, dysgeusia, nausea, vomiting
Neuromuscular & skeletal: Weakness
Renal: Renal insufficiency (in patients with bilateral renal artery stenosis or hypovolemia)
Respiratory: Bronchitis (1% to 2%), cough (1% to 2%), dyspnea (1% to 2%)
<1%, postmarketing, and/or case reports: Acute generalized exanthematous pustulosis, agranulocytosis, alopecia, anaphylactoid reaction, angina pectoris, angioedema, anosmia, arthritis, asthma, ataxia, atrial fibrillation, atrial tachycardia, bone marrow depression, bradycardia, cardiac arrest, cardiac arrhythmia, cerebrovascular accident, cholestatic jaundice, confusion, conjunctivitis, depression, eosinophilia, eosinophilic pneumonitis, erythema multiforme, exfoliative dermatitis, giant-cell arteritis, gynecomastia, hallucination, hemolysis (with G6PD), herpes zoster, IgA vasculitis, increased erythrocyte sedimentation rate, intestinal obstruction, insomnia, interstitial nephritis, leukocytosis, lichenoid eruption, melena, myocardial infarction, myositis, neutropenia, ototoxicity, pancreatitis, pemphigus, pemphigus foliaceus, peripheral neuropathy, positive ANA titer, psychosis, pulmonary edema, pulmonary embolism, pulmonary infarct, pulmonary infiltrates, Raynaud's phenomenon, serositis, Sjogren's syndrome, skin photosensitivity, Stevens-Johnson syndrome, stomatitis, systemic lupus erythematosus, thrombocytopenia, toxic epidermal necrolysis, upper respiratory tract infection, vasculitis, visual hallucination (Doane, 2013)
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. Risk may also be increased with concomitant use of mTOR inhibitor (eg, everolimus) therapy. 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.
• 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 preexisting renal insufficiency; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Pregnancy: [U.S. Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.
• Surgery: In patients on chronic ACE inhibitor therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; 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. However, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis, 2011).
Blood pressure; serum creatinine and potassium; if patient has collagen vascular disease and/or renal impairment, periodically monitor CBC with differential
2013 ACCF/AHA Heart Failure guideline recommendations: Within 1-2 weeks after initiation and periodically thereafter, reassess renal function and serum potassium especially in patients with preexisting hypotension, hyponatremia, diabetes mellitus, azotemia, or those taking potassium supplements (ACCF/AHA [Yancy 2013]).
Pregnancy Risk Factor
[U.S. Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected. Enalapril crosses the placenta; the active metabolite enalaprilat can be detected in the newborn (Schubiger 1988).
Drugs that act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. The use of these drugs in pregnancy is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. Teratogenic effects may occur following maternal use of an ACE inhibitor during the first trimester, although this finding may be confounded by maternal disease. Because adverse fetal events are well documented with exposure later in pregnancy, ACE inhibitor use in pregnant women is not recommended (Seely 2014; Weber 2014). Infants exposed to an ACE inhibitor in utero should be monitored for hyperkalemia, hypotension, and oliguria. Oligohydramnios may not appear until after irreversible fetal injury has occurred. Exchange transfusions or dialysis may be required to reverse hypotension or improve renal function, although data related to the effectiveness in neonates is limited.
Chronic maternal hypertension itself is also associated with adverse events in the fetus/infant and mother. ACE inhibitors are not recommended for the treatment of uncomplicated hypertension in pregnancy (ACOG 2013) and they are specifically contraindicated for the treatment of hypertension and chronic heart failure during pregnancy by some guidelines (Regitz-Zagrosek 2011). In addition, ACE inhibitors should generally be avoided in women of reproductive age (ACOG 2013). If treatment for hypertension or chronic heart failure in pregnancy is needed, other agents should be used (ACOG 2013; Regitz-Zagrosek 2011).
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Have patient report immediately to prescriber signs of infection, signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weak, shortness of breath, numbness or tingling feeling), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), severe dizziness, passing out, cough that will not go away, angina, severe abdominal pain, severe nausea, or vomiting (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.
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