When pregnancy is detected, discontinue enalapril as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
Acute coronary syndrome:
Non-ST elevation acute coronary syndrome (off-label use): Note: Patients should be hemodynamically stable before initiation. Use as a component of an appropriate medical regimen, which may also include antiplatelet agent(s), a beta-blocker, and a statin. Continue angiotensin-converting enzyme inhibitor therapy indefinitely for patients with concurrent diabetes, left ventricular ejection fraction ≤40%, hypertension, or stable chronic kidney disease (Ref). Dosing is based on expert opinion and general dosing range in manufacturer's labeling.
Oral: Initial: 2.5 to 5 mg in 1 or 2 divided doses (depending on initial blood pressure); titrate slowly based on tolerability and response up to 40 mg/day in 1 or 2 divided doses (Ref).
ST-elevation myocardial infarction (off-label use): Note: Patients should be hemodynamically stable before initiation. Use as a component of an appropriate medical regimen, which may also include antiplatelet agent(s), a beta-blocker, and a statin (Ref). Dosing is based on expert opinion and general dosing range in manufacturer's labeling.
Oral: Initial: 2.5 to 5 mg in 1 or 2 divided doses (depending on initial blood pressure); titrate slowly based on tolerability and response up to 40 mg/day in 1 or 2 divided doses (Ref).
Heart failure with reduced ejection fraction:
Note: If tolerated, an angiotensin II receptor-neprilysin inhibitor is generally preferred over an angiotensin-converting enzyme inhibitor (Ref).
Oral: Initial: 2.5 mg twice daily; increase dose (eg, double) as tolerated every ≥1 to 2 weeks to a target dose of 10 to 20 mg twice daily (Ref). In hospitalized patients, may titrate more rapidly as tolerated (Ref).
Hypertension, chronic:
Note: For patients who warrant combination therapy (BP >20/10 mm Hg above goal or suboptimal response to initial monotherapy), may use with another appropriate agent (eg, long-acting dihydropyridine calcium channel blocker or thiazide diuretic) (Ref).
Oral: Initial: 5 to 10 mg once daily; evaluate response after ~2 to 4 weeks and titrate dose (eg, increase the daily dose by doubling), as needed, up to 40 mg/day in 1 or 2 divided doses; if additional blood pressure control is needed, consider combination therapy. Patients with severe asymptomatic hypertension and no signs of acute end organ damage should be evaluated for medication titration within 1 week (Ref).
Posttransplant erythrocytosis, kidney transplant recipients (off-label use): Note: For patients with a hemoglobin concentration >17 g/dL (Ref).
Oral: Initial: 2.5 or 5 mg daily; if inadequate response seen within 4 weeks, may titrate up to 40 mg/day based on hemoglobin and blood pressure response; if hemoglobin remains >17 g/dL after an additional 4 weeks, consider additional therapy (eg, phlebotomy) (Ref).
Proteinuric chronic kidney disease, diabetic or nondiabetic (off-label use):
Oral: Initial: 2.5 to 5 mg in 1 or 2 divided doses depending on baseline BP; titrate gradually (eg, by doubling the dose every 2 to 4 weeks) up to the maximally tolerated dose, not to exceed 40 mg/day in 1 or 2 divided doses. If proteinuria target is not met despite optimized dosage, consider additional therapies (eg, sodium-glucose cotransporter-2 inhibitor) (Ref).
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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: (expert opinion derived from Elung-Jensen 2003; Hoyer 1993; Kelly 1986; MacFadyen 1993; Sica 1991; manufacturer’s labeling).
CrCl >30 mL/minute: No dosage adjustment necessary.
CrCl 10 to 30 mL/minute: Initial: 2.5 mg daily in 1 or 2 divided doses; titrate slowly based on tolerability and response. Maximum recommended dose: 20 mg/day.
CrCl <10 mL/minute: Consider alternative therapy; risk of adverse effects or complications (eg, hyperkalemia, kidney failure) are increased (Ref). Initial: 1.25 mg once daily (or 2.5 mg every other day); titrate slowly based on tolerability and response. Maximum recommended dose: 10 mg/day.
Hemodialysis, intermittent (thrice weekly): Dialyzable (~45% [enalaprilat]) (Ref): Note: Avoid use if an AN69 hemofilter is used (associated with anaphylactoid reaction) (Ref).
Initial: 2.5 mg 3 times weekly administered post dialysis on dialysis days; titrate slowly based on tolerability and response (Ref). Maximum recommended dose: 10 mg once daily (Ref).
Peritoneal dialysis: Dialyzable (manufacturer’s labeling): Dose as in CrCl <10 mL/minute (Ref).
CRRT: Dose as in CrCl 10 to 30 mL/minute (expert opinion). Avoid use if an AN69 hemofilter is used (associated with anaphylactoid reaction) (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Dose as in CrCl 10 to 30 mL/minute (expert opinion). Avoid use if an AN69 hemofilter is used (associated with anaphylactoid reaction) (Ref).
Conversion from IV enalaprilat to oral enalapril therapy:
CrCl >30 mL/minute: May initiate enalapril 5 mg once daily.
CrCl 10 to 30 mL/minute: May initiate enalapril 2.5 mg once daily.
CrCl <10 mL/minute: May initiate enalapril 1.25 mg once daily.
The liver dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Matt Harris, PharmD, MHS, BCPS, FAST, Jeong Park, PharmD, MS, BCTXP, FCCP, FAST, Arun Jesudian, MD, Sasan Sakiani, MD
Note: Use of angiotensin-converting enzyme inhibitors in patients with cirrhosis and ascites should be avoided, as use can further diminish renal blood flow and precipitate hepatorenal syndrome (Ref). Bioavailability of enalapril is decreased in patients with cirrhosis because conversion of enalapril to enalaprilat (active form) is diminished; however, this does not appear to impact its clinical effects (Ref).
Liver impairment prior to treatment initiation:
Initial or dose adjustment in patients with preexisting liver cirrhosis:
Child-Turcotte-Pugh class A to C: No dosage adjustment necessary; avoid use in patients with ascites (Ref).
Refer to adult dosing.
(For additional information see "Enalapril: Pediatric drug information")
Heart failure: Limited data available: Infants, Children and Adolescents: Oral: Initial: 0.1 mg/kg/day in 1 to 2 divided doses; increase as tolerated and based on clinical response over 2 weeks to maximum daily dose of 0.5 mg/kg/day; one pediatric study (n=63, age range: 9 days to 17.2 years, dosage range: 0.04 to 0.94 mg/kg/day) reported improvement in 39 patients at a mean dose of 0.36 ± 0.24 mg/kg/day (Ref).
Hypertension: Infants, Children and Adolescents: Oral: Initial: 0.08 mg/kg/day in divided doses once or twice daily, maximum initial daily dose: 5 mg/day; adjust dose based on blood pressure response; maximum daily dose: 0.6 mg/kg/day not to exceed 40 mg/day (Ref).
Proteinuria, nephrotic syndrome: Limited data available: Oral:
Fixed dosing: Children ≥7 years and Adolescents: 2.5 to 5 mg/day was reported in a retrospective study in normotensive pediatric patients as either monotherapy (n=17; mean age: 13.7 years; range: 8 to 17 years) or with prednisone (n=11; mean age: 12.6 years; range: 7 to 16 years); significant decrease in proteinuria (with or without nephrotic syndrome) occurred; no significant change in blood pressure was observed (Ref); a case series of three adolescents with sickle anemia nephropathy reported an initial dose of 5 mg/day; one patient required an increase to 7.5 mg/day (Ref).
Weight-directed dosing: Children and Adolescents: Initial: 0.2 mg/kg/day; titrate to response at 4- to 12-week intervals; range: 0.2 to 0.6 mg/kg/day; maximum daily dose: 20 mg/day; a crossover dose comparison trial showed effects on proteinuria were dose-dependent (Ref); if combined with other angiotensin blockade (ARB), lower doses have been reported (0.1 to 0.16 mg/kg/day) (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Infants, Children, and Adolescents:
Manufacturer's labeling: Use in infants, children, and adolescents ≤16 years of age with GFR <30 mL/minute/1.73 m2 is not recommended; dosing data not available in this population.
Alternate recommendations (Ref):
GFR >50 mL/minute/1.73 m2: No dosage adjustment necessary.
GFR 10 to 50 mL/minute/1.73 m2: Administer 75% of usual dose.
GFR <10 mL/minute/1.73 m2: Administer 50% of usual dose.
Intermittent hemodialysis: Administer 50% of usual dose.
Peritoneal dialysis: Administer 50% of usual dose.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution. 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 (Ref).
Use may be associated with increased blood urea nitrogen and increased serum creatinine, resulting in oliguria and acute kidney injury (AKI) in all ages. Increases in serum creatinine are expected and usually stabilize within 20% to 30% of baseline; higher increases may indicate high efferent tone (such as with hypovolemia, congestive heart failure, or renal artery stenosis) (Ref).
Mechanism: Related to pharmacologic action; inhibits efferent arteriolar vasoconstriction, lowering glomerular filtration pressure (and inhibiting renal autoregulation), which can lead to a reduction in the glomerular filtration rate (GFR). Kidney hypoperfusion from systemic hypotension may also occur (Ref).
Onset: Intermediate; increases in serum creatinine generally occur within 2 weeks of initiation and stabilize within 2 to 4 weeks (Ref). However, more immediate increases may occur in patients with other risk factors for AKI (Ref).
Risk factors:
• Patients with low renal blood flow whose GFR is dependent on efferent arteriolar vasoconstriction by angiotensin II, including (Ref):
- Low effective circulating volume (sodium or volume depletion)
- Congestive heart failure
- Hypotension or shock
- Renal artery stenosis
• High dose at initiation (Ref)
• Age:
- Neonates; risk may be higher in preterm neonates (Ref)
- Older adults (Ref)
• Preexisting kidney impairment (Ref)
• Concurrent diuretic and/or nonsteroidal anti-inflammatory drug use (Ref)
Angioedema may occur rarely; edema may manifest in the head and neck (potentially compromising the airway) or the intestine (presenting as abdominal pain). Use is contraindicated in patients with idiopathic or hereditary angioedema or previous angioedema associated with any angiotensin-converting enzyme inhibitors or neprilysin inhibitors (Ref).
Mechanism: Related to pharmacologic action (ie, increased bradykinin and substance P, vascular permeability, vasodilation) (Ref).
Onset: Varied; may occur at any time during treatment. Most cases occur within the first week of therapy but may also occur years after therapy (Ref).
Risk factors:
• Black patients (estimated 4- to 5-fold higher risk); the mechanism for this is not completely understood but may be related to genetic variants (Ref)
• Females (Ref)
• Smoking history (Ref)
• Previous history of angioedema (Ref)
• Age >65 years (Ref)
• Seasonal allergies (Ref)
• Concurrent use of mechanistic target of rapamycin (mTOR) inhibitors (eg, everolimus) (Ref)
• Concurrent use of neprilysin inhibitor (contraindicated)
A dry, hacking, nonproductive cough that is typically associated with tickling or scratching in the throat may occur with angiotensin converting enzyme inhibitors (ACEI) in adult and pediatric patients (Ref). Recurrence is likely with rechallenge (Ref). Resolution of cough typically occurs 1 to 4 weeks after ACEI discontinuation but may persist for up to 3 months (Ref).
Mechanism: Various proposed mechanisms. May be related to pharmacologic action (ie, increased bradykinin and substance P, resulting in accumulation in the lungs and bronchoconstriction) (Ref).
Onset: Varied; within hours to 4 weeks after initiation but can be delayed for up to 6 months (Ref).
Risk factors:
• Females (Ref)
• Possibly certain genetic variants (some of which may be independent of the bradykinin pathway) (Ref).
Hyperkalemia (elevated serum potassium) may occur with angiotensin-converting enzyme inhibitors (ACEI), including enalapril (Ref).
Mechanism: Related to pharmacologic action; inhibits formation of circulating angiotensin II, which leads to efferent arteriole vasodilation and subsequent lowering of glomerular filtration rate, which lowers potassium elimination. Additionally, ACEI interfere with the generation and release of aldosterone from the adrenal cortex, leading to an impairment of potassium excretion from the kidney (Ref).
Risk factors:
• Disease states associated with hyperkalemia (congestive heart failure, diabetes mellitus, chronic kidney disease) (Ref)
• Concurrent use of medications which cause hyperkalemia (ACEI, angiotensin receptor blockers, spironolactone, nonsteroidal anti-inflammatory drugs, beta blockers, heparin, tacrolimus, cyclosporine) (Ref)
• Acute kidney injury (elevated BUN and/or serum creatinine) (Ref)
• High dietary intake of potassium or concomitant use of potassium supplements (including potassium-containing salt substitutes) (Ref)
• Baseline elevated potassium level (≥5 mmol/L) (Ref)
• Age >70 years (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency ranges include data from hypertension and heart failure trials. Higher rates of adverse reactions have generally been noted in patients with heart failure. However, the frequency of adverse effects associated with placebo is also increased in this population.
1% to 10%:
Cardiovascular: Hypotension (≤7%), orthostatic hypotension (2%), syncope (≤2%)
Dermatologic: Skin rash (1%)
Gastrointestinal: Diarrhea (2%), nausea (1%), vomiting (1%)
Nervous system: Dizziness (8%), headache (2%), orthostatic dizziness (1% to 2%), vertigo (2%)
Neuromuscular & skeletal: Asthenia (1% to 2%)
Respiratory: Bronchitis (1%), cough (1% to 2%) (table 1) , dyspnea (1%)
Drug (Enalapril) |
Placebo |
Indication |
Number of Patients (Enalapril) |
Number of Patients (Placebo) |
---|---|---|---|---|
2% |
0.6% |
Cardiac failure |
673 |
339 |
1% |
0.9% |
Hypertension |
2,314 |
230 |
<1%: Renal: Increased blood urea nitrogen, increased serum creatinine
Frequency not defined:
Cardiovascular: Acute myocardial infarction, atrial fibrillation, atrial tachycardia, bradycardia, cardiac arrhythmia, cerebrovascular accident, flushing, palpitations, pulmonary embolism, Raynaud's disease
Dermatologic: Alopecia, diaphoresis, erythema multiforme, exfoliative dermatitis, pemphigus, pruritus, skin photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Gastrointestinal: Anorexia, constipation, dysgeusia, dyspepsia, glossitis, intestinal obstruction, melena, sore throat, stomatitis, xerostomia
Genitourinary: Impotence, oliguria
Hematologic & oncologic: Bone marrow depression, neutropenia
Infection: Herpes zoster infection
Nervous system: Abnormal dreams, anosmia, ataxia, confusion, depression, drowsiness, dysesthesia, flank pain, insomnia, nervousness, paresthesia
Neuromuscular & skeletal: Muscle cramps
Ophthalmic: Blurred vision, conjunctivitis, dry eye syndrome, lacrimation
Otic: Tinnitus
Respiratory: Asthma, bronchospasm, eosinophilic pneumonitis, hoarseness, pulmonary edema, pulmonary infarct, pulmonary infiltrates, rhinorrhea, upper respiratory tract infection
Postmarketing:
Cardiovascular: Vasculitis
Dermatologic: Psoriasis (Song 2021)
Endocrine & metabolic: Gynecomastia (Llop 1994), hyperkalemia (Albareda 1998), hyponatremia (Gonzalez-Martinez 1993)
Gastrointestinal: Pancreatitis (Carnovale 2003, Maringhini 1997)
Hematologic: Agranulocytosis (Elis 1991), decreased hematocrit (Graafland 1992, Ozbek 1997), decreased hemoglobin (Graafland 1992, Ozbek 1997), eosinophilia (Barnes 1983), hemolysis (with G6PD), hemolytic anemia, increased erythrocyte sedimentation rate, leukocytosis, positive ANA titer, thrombocytopenia (Ackroyd 1989)
Hepatic: Cholestatic jaundice (Todd 1990), hepatic failure (Jeserich 2000), hepatitis (Macias 2003), increased liver enzymes (Macias 2003), increased serum bilirubin (Macias 2003)
Hypersensitivity: Angioedema (Sato 2021), nonimmune anaphylaxis (Tunon-de-Lara 1992)
Nervous system: Peripheral neuropathy (Hormigo 1992), visual hallucination (Doane 2013)
Neuromuscular & skeletal: Arthralgia (Peppers 1995), arthritis, myalgia (Peppers 1995), myositis, serositis
Renal: Acute kidney injury (Hennesy 1992), renal insufficiency (Albareda 1998)
Miscellaneous: Fever
Hypersensitivity to enalapril or any component of the formulation; angioedema related to previous treatment with an ACE inhibitor; idiopathic or hereditary angioedema; concomitant use with aliskiren in patients with diabetes mellitus; coadministration with or within 36 hours of switching to or from a neprilysin inhibitor (eg, sacubitril).
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Canadian labeling: Additional contraindications (not in US labeling): Concomitant use with aliskiren-containing drugs in patients with moderate to severe kidney impairment (GFR <60 mL/minute/1.73 m2).
Concerns related to adverse effects:
• Hypersensitivity reactions: Anaphylactic reactions/nonimmune anaphylaxis can occur with ACE inhibitors. Severe nonimmune anaphylaxis 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 nonimmune anaphylaxis 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 HF where a reduction in systolic blood pressure is a desirable observation.
Disease-related concerns:
• Aortic stenosis: Use with caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.
• Ascites: Generally, avoid use in patients with ascites due to cirrhosis or refractory ascites; if use cannot be avoided in patients with ascites due to cirrhosis, monitor BP and kidney function carefully to avoid rapid development of kidney failure (AASLD [Runyon 2013]).
• 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. In a retrospective cohort study of elderly patients (≥65 years of age) with myocardial infarction and impaired left ventricular function, administration of an ACE inhibitor was associated with a survival benefit, including patients with serum creatinine concentrations >3 mg/dL (265 micromol/L) (Frances 2000).
• Collagen vascular disease: Use with caution in patients with collagen vascular disease especially with concomitant kidney impairment; may be at increased risk for hematologic toxicity.
• Hypertrophic cardiomyopathy with left ventricular outflow tract obstruction: Use with caution in patients with hypertrophic cardiomyopathy and left ventricular outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition (AHA/ACC [Ommen 2020]).
• Kidney impairment: Use with caution in preexisting kidney insufficiency; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further kidney impairment.
Special populations:
• Race/Ethnicity: In Black patients, the BP-lowering effects of ACE inhibitors may be less pronounced. The exact mechanism is not known; differences in the renin-angiotensin-aldosterone system, low renin levels, and salt sensitivity more commonly found in Black patients may contribute (Brewster 2013; Helmer 2018).
• Surgical patients: 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). Based on current research and clinical guidelines in patients undergoing non-cardiac surgery, continuing ACE inhibitors is reasonable in the perioperative period. If ACE inhibitors are held before surgery, it is reasonable to restart postoperatively as soon as clinically feasible (ACC/AHA [Fleisher 2014]).
Dosage forms specific issues:
• Benzyl alcohol and derivatives: Oral solution: May contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol. Large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP 1997; CDC 1982). Some data suggest that benzoate displaces bilirubin from protein-binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral, as maleate:
Epaned: 1 mg/mL (150 mL) [contains sodium benzoate]
Generic: 1 mg/mL (150 mL)
Tablet, Oral, as maleate:
Vasotec: 2.5 mg, 5 mg, 10 mg, 20 mg [scored]
Generic: 2.5 mg, 5 mg, 10 mg, 20 mg
Yes
Solution (Enalapril Maleate Oral)
1 mg/mL (per mL): $4.08
Solution (Epaned Oral)
1 mg/mL (per mL): $4.98
Tablets (Enalapril Maleate Oral)
2.5 mg (per each): $0.52 - $1.46
5 mg (per each): $0.67 - $1.85
10 mg (per each): $0.26 - $1.94
20 mg (per each): $1.00 - $2.77
Tablets (Vasotec Oral)
2.5 mg (per each): $21.11
5 mg (per each): $24.49
10 mg (per each): $26.93
20 mg (per each): $38.32
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as maleate:
Vasotec: 5 mg, 10 mg, 20 mg [contains corn starch]
Generic: 2.5 mg, 5 mg, 10 mg, 20 mg
Oral: Administer without regard to meals.
Oral: May administer without regard to food.
Heart failure with reduced ejection fraction: Treatment of symptomatic heart failure with reduced ejection fraction (HFrEF) to improve symptoms, increase survival, and decrease hospitalizations. In patients with stable asymptomatic HFrEF, enalapril decreases the risk of developing overt heart failure and the incidence of heart failure hospitalizations.
Hypertension, chronic: Management of hypertension, alone or in combination with other antihypertensive agents.
Non-ST-elevation acute coronary syndrome; Posttransplant erythrocytosis, kidney transplant recipients; Proteinuric chronic kidney disease, diabetic or nondiabetic; ST-elevation myocardial infarction
Enalapril may be confused with Anafranil, Elavil, Eldepryl, ramipril
Significant differences exist between oral and IV dosing. Use caution when converting from one route of administration to another.
Acepril [Hungary, Switzerland] may be confused with Accupril which is a brand name for quinapril [US, Canada, multiple international markets]
Acepril: Brand name for enalapril [Hungary, Switzerland], but also brand name for captopril [Great Britain]; lisinopril [Malaysia]
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Aliskiren: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Aliskiren may enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Aliskiren may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme 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. Risk D: Consider therapy modification
Allopurinol: Angiotensin-Converting Enzyme Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Risk C: Monitor therapy
Alteplase: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Alteplase. Specifically, the risk for angioedema may be increased. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Angiotensin II: Angiotensin-Converting Enzyme Inhibitors may enhance the therapeutic effect of Angiotensin II. Risk C: Monitor therapy
Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Angiotensin II Receptor Blockers may increase the serum concentration of Angiotensin-Converting Enzyme Inhibitors. Management: 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 when possible. Monitor blood pressure, renal function, and potassium if combined. Risk D: Consider therapy modification
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Aprotinin: May diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Arginine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
AzaTHIOprine: Angiotensin-Converting Enzyme Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine. Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
Dapoxetine: May enhance the orthostatic hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Dipeptidyl Peptidase-IV Inhibitors: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Drospirenone-Containing Products: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Eplerenone: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Everolimus: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Ferric Gluconate: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Risk C: Monitor therapy
Ferric Hydroxide Polymaltose Complex: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Ferric Hydroxide Polymaltose Complex. Specifically, the risk for angioedema or allergic reactions may be increased. Risk C: Monitor therapy
Finerenone: Angiotensin-Converting Enzyme Inhibitors may enhance the hyperkalemic effect of Finerenone. Risk C: Monitor therapy
Flunarizine: May enhance the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Gelatin (Succinylated): Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Gelatin (Succinylated). Specifically, the risk of a paradoxical hypotensive reaction may be increased. Risk C: Monitor therapy
Grass Pollen Allergen Extract (5 Grass Extract): Angiotensin-Converting Enzyme 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). Risk X: Avoid combination
Heparin: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Heparins (Low Molecular Weight): May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Herbal Products with Blood Pressure Increasing Effects: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Icatibant: May diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Iloperidone: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Indoramin: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Iron Dextran Complex: Angiotensin-Converting Enzyme 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. Risk C: Monitor therapy
Isocarboxazid: May enhance the antihypertensive effect of Antihypertensive Agents. Risk X: Avoid combination
Lanthanum: May decrease the serum concentration of Angiotensin-Converting Enzyme Inhibitors. Management: Administer angiotensin-converting enzyme (ACE) inhibitors at least two hours before or after lanthanum. Risk D: Consider therapy modification
Levodopa-Foslevodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Foslevodopa. Risk C: Monitor therapy
Lithium: Angiotensin-Converting Enzyme Inhibitors may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an ACE inhibitor. Monitor for increased concentrations/toxic effects of lithium if an ACE inhibitor is initiated/dose increased, or if switching between ACE inhibitors. Risk D: Consider therapy modification
Loop Diuretics: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Loop Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: Angiotensin-Converting Enzyme 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 Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May diminish the therapeutic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: 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. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Polyethylene Glycol-Electrolyte Solution: Angiotensin-Converting Enzyme Inhibitors may enhance the nephrotoxic effect of Polyethylene Glycol-Electrolyte Solution. Risk C: Monitor therapy
Potassium Salts: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Prazosin: Antihypertensive Agents may enhance the hypotensive effect of Prazosin. Risk C: Monitor therapy
Pregabalin: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Pregabalin. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Racecadotril: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk for angioedema may be increased with this combination. Risk C: Monitor therapy
Ranolazine: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Sacubitril: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Sacubitril. Specifically, the risk of angioedema may be increased with this combination. Risk X: Avoid combination
Salicylates: May enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Salicylates may diminish the therapeutic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Silodosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Sirolimus Products: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk for angioedema may be increased. Risk C: Monitor therapy
Sodium Phosphates: Angiotensin-Converting Enzyme Inhibitors may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Risk C: Monitor therapy
Sparsentan: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk X: Avoid combination
Tacrolimus (Systemic): Angiotensin-Converting Enzyme Inhibitors may enhance the hyperkalemic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Temsirolimus: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Tenapanor: May decrease serum concentrations of the active metabolite(s) of Enalapril. Tenapanor may decrease the serum concentration of Enalapril. Risk C: Monitor therapy
Terazosin: Antihypertensive Agents may enhance the hypotensive effect of Terazosin. Risk C: Monitor therapy
Thiazide and Thiazide-Like Diuretics: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Tolvaptan: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Trimethoprim: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Urapidil: May interact via an unknown mechanism with Angiotensin-Converting Enzyme Inhibitors. Management: Avoid concomitant use of urapidil and angiotensin-converting enzyme (ACE) inhibitors. Risk D: Consider therapy modification
Urokinase: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Vasopressin: Drugs Suspected of Causing SIADH may enhance the therapeutic effect of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor therapy
Avoid use of angiotensin-converting enzyme (ACE) inhibitor therapy in patients who may become pregnant and who are not using effective contraception (ADA 2021).
Medications considered acceptable for the treatment of chronic hypertension during pregnancy may generally be used in patients trying to conceive. Angiotensin-converting enzyme (ACE) inhibitors are fetotoxic. Transition patients prior to conception to an agent preferred for use during pregnancy unless treatment with an ACE inhibitor is absolutely necessary (ACC/AHA [Whelton 2018]; ACOG 2019; NICE 2019). Closely monitor pregnant patients on ACE inhibitors with serial ultrasounds.
When ACE inhibitors are used for the treatment of proteinuric chronic kidney disease in patients who could become pregnant, discontinue use at the first positive pregnancy test (ADA 2021; Fakhouri 2022).
ACE inhibitors are not recommended for the treatment of heart failure in patients planning to become pregnant (AHA/ACC/HFSA [Heidenreich 2022]).
Enalapril crosses the placenta; the active metabolite enalaprilat can be detected in the newborn (Schubiger 1988).
Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Exposure to an angiotensin-converting enzyme (ACE) inhibitor during the first trimester of pregnancy may be associated with an increased risk of fetal malformations (ACOG 2019; ESC [Regitz-Zagrosek 2018]). Following exposure during the second or third trimesters, 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. Oligohydramnios may not appear until after an irreversible fetal injury has occurred. ACE inhibitor use during pregnancy is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. Monitor infants exposed to an ACE inhibitor in utero for hyperkalemia, hypotension, and oliguria. Exchange transfusions or dialysis may be required to reverse hypotension or improve renal function.
Chronic maternal hypertension is also associated with adverse events in the fetus/infant. Chronic maternal hypertension may increase the risk of birth defects, low birth weight, premature delivery, stillbirth, and neonatal death. Actual fetal/neonatal risks may be related to duration and severity of maternal hypertension. Untreated chronic hypertension may also increase the risks of adverse maternal outcomes, including gestational diabetes, preeclampsia, delivery complications, stroke, and myocardial infarction (ACOG 2019).
Discontinue ACE inhibitors as soon as possible once pregnancy is detected. Agents other than ACE inhibitors are recommended for the treatment of chronic hypertension during pregnancy (ACOG 2019; ESC [Cífková 2020]; SOGC [Magee 2022]). Consider the use of ACE inhibitors only for pregnant patients with hypertension refractory to other medications (ACOG 2019). Closely monitor pregnant patients on ACE inhibitors with serial ultrasounds.
ACE inhibitors are not recommended for the treatment of heart failure or proteinuric chronic kidney disease during pregnancy (AHA/ACC/HFSA [Heidenreich 2022]; ESC [Regitz-Zagrosek 2018]; Fakhouri 2022).
Enalapril and enalaprilat are present in breast milk.
Data related to the presence of enalapril and enalaprilat in breast milk are available from multiple reports.
• Enalapril and enalaprilat breast milk concentrations were evaluated in one patient who was 12 months' postpartum following administration of enalapril 10 mg/day for 11 months. The highest level of enalapril was 2.05 ng/mL at 4 hours after the dose. The highest level of enalaprilat was 0.75 ng/mL at 8.75 hours after the dose (Rush 1991).
• The presence of enalaprilat in breast milk was evaluated in three patients, one treated with enalapril 5 mg for chronic glomerulonephritis and two treated with enalapril 10 mg for hypertension. Enalaprilat was not detected in breast milk (<0.2 ng/mL) of any patient 4 hours after the maternal dose. Serum concentrations of enalaprilat were significantly greater (179 ng/mL) in the first woman, who also had renal impairment, when compared to the two patients treated for hypertension (48 ng/mL, 23.9 ng/mL). Enalapril concentrations were not evaluated (Huttunen 1989).
• Breast milk concentrations of enalapril and enalaprilat were evaluated in five lactating patients treated for hypertension. Following a single dose of enalapril 20 mg, breast milk was sampled over 24 hours; serum samples were obtained at 2 and 4 hours. Breast milk concentrations of enalapril ranged from 0 to 5.9 mcg/mL with the highest concentration observed 6 hours after the dose (maximum maternal serum concentrations: 92 to 151 ng/mL). Enalapril was not detectable in the breast milk of one patient over the 24-hour dosing interval (maternal serum concentration: 151 ng/mL). Concentrations of enalaprilat ranged from 0 to 2.3 ng/mL (maximum maternal serum concentrations: 39 to 112 ng/mL). Peak breast milk concentrations of the metabolite occurred 6 hours after the dose in one patient and at 24 hours in two others; the metabolite was only measurable in a third patient at 24 hours. Mean peak breast milk concentrations for enalapril and enalaprilat were 1.74 ng/mL and 1.72 ng/mL, respectively (Redman 1990). Using the highest breast milk concentration of 5.9 ng/mL, the estimated exposure of enalapril to the breastfeeding infant would be 0.00089 mg/kg/day (relative infant dose: 1.1% based on a therapeutic infant dose of 0.08 mg/kg/day).
• In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer. When postpartum treatment with an ACE inhibitor is needed, available guidelines consider enalapril to be acceptable for use (AHA/ACC/HFSA [Heidenreich 2022], ESC [Cífková 2020]). Avoid breastfeeding if high maternal doses of an ACE inhibitor are needed (ACOG 2019).
Limit salt substitutes or potassium-rich diet.
BP; BUN; serum creatinine; electrolytes (eg, potassium [especially in patients on concomitant potassium-sparing diuretics, potassium supplements and/or potassium containing salts]); if patient has collagen vascular disease and/or kidney impairment, periodically monitor CBC with differential. If angioedema is suspected, assess risk of airway obstruction (eg, involvement of tongue, glottis, larynx, and/or history of airway surgery).
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
Onset of action: ~1 hour
Peak effect: 4 to 6 hours
Duration: 12 to 24 hours
Absorption: 55% to 75%
Protein binding: ~50% (Davies 1984)
Metabolism: Prodrug, undergoes hepatic biotransformation to enalaprilat
Half-life elimination:
Enalapril: CHF: Neonates (n=3, PNA: 10 to 19 days): 10.3 hours (range: 4.2 to 13.4 hours) (Nakamura 1994); CHF: Infants and Children ≤6.5 years of age (n=11): 2.7 hours (range: 1.3 to 6.3 hours) (Nakamura 1994); Adults: Healthy: 2 hours; CHF: 3.4 to 5.8 hours
Enalaprilat: CHF: Neonates (n=3, PNA: 10 to 19 days): 11.9 hours (range: 5.9 to 15.6 hours) (Nakamura 1994); CHF: Infants and Children ≤6.5 years of age (n=11): 11.1 hours (range: 5.1 to 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)
Time to peak, serum: Oral: Enalapril: 0.5 to 1.5 hours; Enalaprilat (active metabolite): 3 to 4.5 hours
Excretion: Urine (61%; 18% of which was enalapril, 43% was enalaprilat); feces (33%; 6% of which was enalapril, 27% was enalaprilat) (Ulm 1982)
Altered kidney function: 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.
Hepatic function impairment: Peak concentration and AUC of the parent drug, enalapril, was twice as high in patients with cirrhosis compared to healthy controls; however, peak concentration and AUC of the active drug, enalaprilat, was ~66% lower and ~50% lower, respectively, in cirrhosis. Time to peak concentration of enalaprilat was delayed in patients with cirrhosis (Ohnishi 1989).
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