Enalapril (Monograph)

Brand name: Vasotec
Drug class: Angiotensin-Converting Enzyme Inhibitors
- ACE Inhibitors
VA class: CV800
Chemical name: (S)-1-[N-[1-(Ethoxycarbonyl)-3-phenylpropyl]-l-alanyl]-l-proline(Z)-2-butenedioate (1:1)
Molecular formula: C₂₀H₂₈N₂O₅•C₄H₄O₄C₁₈H₂₄N₂O₅
CAS number: 75847-73-3

Enalaprilat/Enalapril Maleate is also contained as an ingredient in the following combinations:
Enalapril Maleate and Hydrochlorothiazide

Medically reviewed by Drugs.com on Oct 26, 2023. Written by ASHP.

Warning

May cause fetal and neonatal morbidity and mortality if used during pregnancy.¹ ²⁴⁵ ²⁵⁴ ²⁶³ ²⁷⁶ ²⁷⁷ ²⁹⁶ ²⁹⁷ ³⁰³ ³⁰⁵ ⁴⁵³ ⁴⁵⁴ See Fetal/Neonatal Morbidity and Mortality under Cautions.
If pregnancy is detected, discontinue as soon as possible.¹ ²⁵⁴ ²⁷⁷ ²⁹⁶ ⁴⁵⁴

Introduction

Nonsulfhydryl ACE inhibitor.¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ¹⁰ ²⁷⁷

Uses for Enalapril

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).¹ ² ⁴ ⁵ ⁹ ⁵⁴ ¹¹⁰ ¹¹⁶ ¹¹⁹ ¹²⁰ ¹²² ¹²³ ¹²⁴ ¹²⁷ ¹²⁸ ¹²⁹ ¹³⁰ ¹³¹ ¹⁴⁰ ¹⁴² ¹⁴³ ¹⁴⁴ ¹⁵⁵ ¹⁸⁶ ²⁰³ ²²⁰ ¹²⁰⁰ May use enalaprilat when oral therapy is not practical.²⁷⁷ ²⁸⁵ ²⁸⁶

ACE inhibitors are recommended as one of several preferred agents for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics.⁵⁰¹ ⁵⁰² ⁵⁰³ ⁵⁰⁴ ¹²⁰⁰ While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.⁵⁰¹ ⁵⁰² ⁵⁰⁴

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).⁵⁰¹ ⁵⁰² ⁵⁰³ ⁵⁰⁴ ⁵¹⁵ ¹²⁰⁰ ¹²⁰¹

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.¹²⁰⁰ (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

Table 1. ACC/AHA BP Classification in Adults1200
Category	SBP (mm Hg)		DBP (mm Hg)
Normal	<120	and	<80
Elevated	120–129	and	<80
Hypertension, Stage 1	130–139	or	80–89
Hypertension, Stage 2	≥140	or	≥90

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP.¹²⁰⁰ However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.⁵⁰¹ ⁵⁰³ ⁵⁰⁴ ⁵⁰⁵ ⁵⁰⁶ ⁵⁰⁷ ⁵⁰⁸ ⁵¹⁵ ⁵²³ ⁵²⁶ ⁵³⁰ ¹²⁰⁰ ¹²⁰¹ ¹²⁰⁷ ¹²⁰⁹ ¹²²² ¹²²³ ¹²²⁹

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) of <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.¹²⁰⁰ In addition, an SBP goal of <130 mm Hg generally is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg.¹²⁰⁰ These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.¹²⁰⁰ ¹²⁰² ¹²¹⁰

Other hypertension guidelines generally have based target BP goals on age and comorbidities.⁵⁰¹ ⁵⁰⁴ ⁵³⁶ Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients compared with⁵⁰¹ ⁵⁰⁴ ⁵³⁶ those recommended by the 2017 ACC/AHA hypertension guideline.¹²⁰⁰

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the current ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.¹²²² ¹²²³ ¹²²⁴ ¹²²⁹

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient’s BP treatment goal.¹²⁰⁰ ¹²²⁰

For decisions regarding when to initiate drug therapy (BP threshold), the current ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors.¹²⁰⁰ ¹²⁰⁷ ASCVD risk assessment recommended by ACC/AHA for all adults with hypertension.¹²⁰⁰

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥ 90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).¹²⁰⁰

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.¹²⁰⁰

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years of age are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg.¹²⁰⁰

Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.⁵⁰² ¹²⁰⁰

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP.¹²⁰⁰ Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in patients with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.¹²⁰⁰

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to ACE inhibitors.⁴¹⁹ ⁴²⁰ ⁴²² ⁵⁰¹ ⁵⁰⁴ ¹²⁰⁰ However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar BP lowering in black patients as in other racial groups.¹²⁰⁰

ACE inhibitors may be preferred in hypertensive patients with heart failure, ischemic heart disease, diabetes mellitus, CKD, or cerebrovascular disease or post-MI.⁵⁰¹ ⁵⁰² ⁵⁰⁴ ⁵²³ ⁵²⁴ ⁵²⁵ ⁵²⁶ ⁵²⁷ ⁵³⁴ ⁵³⁵ ⁵³⁶ ⁵⁴³ ¹²⁰⁰ ¹²¹⁴ ¹²¹⁵

Enalaprilat has been used effectively to control BP in adults with severe hypertension or hypertensive emergencies^{† [off-label]}.²⁸⁷ ²⁸⁸ ²⁸⁹ ²⁹⁰ ¹²⁰⁰ However, for treatment of hypertensive emergencies, some clinicians prefer short-acting antihypertensive agents administered by continuous IV infusion for greater ease in titrating dosage to promptly but gradually reduce BP.⁵⁰² ⁵⁴² ¹²⁰⁰

Heart Failure

Management of heart failure, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-adrenergic blocking agents (β-blockers).¹ ⁴ ⁴² ⁴⁴ ⁵⁷ ⁶¹ ⁶³ ⁶⁴ ¹⁴⁶ ¹⁴⁷ ¹⁴⁸ ¹⁵⁰ ¹⁵¹ ¹⁵² ¹⁵³ ¹⁵⁸ ¹⁵⁹ ²²⁵ ²⁴⁵ ²⁶⁰ ⁵²⁴ ⁷⁰⁰

Some evidence indicates that therapy with an ACE inhibitor may be less effective than angiotensin receptor-neprilysin inhibitor (ARNI) therapy (e.g., sacubitril/valsartan) in reducing cardiovascular death and heart failure-related hospitalization.⁷⁰⁰ ⁷⁰²

ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend that patients with chronic symptomatic heart failure and reduced left ventricular ejection fraction (LVEF) (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.⁷⁰⁰

Asymptomatic Left Ventricular Dysfunction

Treatment of clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction ≤35%) to improve survival and to reduce the incidence of overt heart failure and subsequent hospitalizations for heart failure.¹ ²⁹⁵ ²⁹⁸ ³⁶⁰ ⁵²⁴ ⁷⁰⁴ ⁷⁰⁵

Left Ventricular Dysfunction After Acute MI

ACE inhibitors, including enalapril and enalaprilat, have been used to reduce mortality and prevent the development of left ventricular dilatation and dysfunction following acute MI^{† [off-label]}.²⁹⁹ ³⁰⁰ ³⁰⁷ ³⁰⁸ ³⁰⁹ ³¹⁰ ³¹¹ ⁵²⁴

Expert guidelines recommend initiation of an oral ACE inhibitor within the first 24 hours of acute MI in patients with an anterior infarct, heart failure, or ejection fraction ≤40% who do not have any contraindications (e.g., hypotension, shock, renal dysfunction).⁵²⁷ Use with caution (and with gradual upward titration) during initial postinfarction period because of the possibility of hypotension or renal dysfunction.⁵²⁷ ¹¹⁰⁰

Continue therapy indefinitely in patients with left ventricular dysfunction or other compelling indications (e.g., hypertension, diabetes mellitus, CKD).⁵²⁵ ¹¹⁰⁰

Diabetic Nephropathy

A recommended agent in the management of patients with diabetes mellitus and persistent albuminuria^{† [off-label]} who have modestly elevated (30–300 mg/24 hours) or higher (>300 mg/24 hours) levels of urinary albumin excretion; slows rate of progression of renal disease in such patients.²⁵ ⁵³ ⁵⁴ ⁵⁵ ⁵⁶ ⁵⁷ ⁵³⁵ ⁵³⁶ ¹²³²

Enalapril Dosage and Administration

General

BP Monitoring and Treatment Goals

Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.¹²⁰⁰
If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.¹²¹⁶
If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., calcium-channel blocker, thiazide diuretic).¹²⁰⁰ ¹²¹⁶ Many patients will require at least 2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved, add a third drug.¹²⁰⁰ ¹²¹⁶ ¹²²⁰

Administration

Administer enalapril orally once or twice daily; administer enalaprilat every 6 hours by slow IV infusion.¹ ²⁷⁷ Do not administer enalaprilat by other parenteral routes.²⁷⁷

Oral Administration

Administer enalapril orally without regard to meals.¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ¹⁰ ⁹¹ ³⁵⁰ ³⁷¹ Administer enalapril as extemporaneously prepared oral suspension in patients unable to swallow tablets.¹

Reconstitution

Preparation of extemporaneous suspension containing enalapril maleate 1 mg/mL: Add 50 mL of sodium citrate dihydrate (Bicitra) to a polyethylene terephthalate (PET) bottle containing ten 20-mg tablets of enalapril maleate; shake contents for ≥2 minutes.¹ Allow concentrated suspension to stand for 60 minutes following reconstitution, then shake for an additional minute.¹ Dilute concentrated suspension with 150 mL of syrup (Ora-Sweet SF); shake container to disperse ingredients.¹ ⁴⁰⁸ Shake suspension before dispensing each dose.¹

IV Administration

Administer enalaprilat by slow IV infusion as undiluted or diluted solution.²⁷⁷

Dilution

Can dilute enalaprilat injection with up to 50 mL of compatible IV infusion solution.²⁷⁷

For solution and drug compatibility information, see Compatibility under Stability.

Rate of Administration

Infuse dose over ≥5 minutes.²⁷⁷ In patients at risk of excessive hypotension, infusion of dose over up to 1 hour is preferred.^d

Dosage

Available as enalapril maleate (oral tablets); dosage expressed in terms of the salt.¹ Also available as enalaprilat (IV injection); dosage expressed in terms of the base.^d

Dosage of enalapril and enalaprilat are not identical; caution when converting from oral to IV therapy or vice versa.²⁷⁷

May minimize risk of hypotension in patients currently receiving diuretic therapy by discontinuing the diuretic, reducing diuretic dosage, or cautiously increasing salt intake prior to initiating enalapril maleate or enalaprilat.⁶⁰⁰ ⁶⁰¹ (See Hypotension under Cautions.) For information on initiation of oral enalapril maleate or IV enalaprilat when diuretic therapy is not withheld, see the individual dosage sections in Dosage and Administration.

Pediatric Patients

Hypertension

Oral

Children 1 month to 16 years of age: Initially, enalapril maleate 0.08 mg/kg (up to 5 mg) once daily.¹ ¹¹⁵⁰ Some experts state dose may be administered as a single dose or in 2 divided doses daily.¹¹⁵⁰

Initiate drug at the low end of the dosage range per some experts; may increase dosage every 2–4 weeks until BP controlled, maximum dosage (0.58 mg/kg, up to 40 mg daily)¹ reached, or adverse effects occur.¹¹⁵⁰

Adults

Hypertension

Enalapril Therapy

Oral

Manufacturer recommends initial dosage of 5 mg daily in patients not currently receiving a diuretic.⁶⁰⁰ Adjust dosage at 2- to 4-week intervals to achieve BP control.¹¹ ²³¹

In patients currently receiving diuretic therapy, discontinue diuretic, if possible, 2–3 days before initiating enalapril.¹ ⁶ ²³⁶ ²³⁹ May cautiously resume diuretic therapy if BP not controlled adequately with enalapril alone.¹ ² ¹¹⁰ ¹¹⁶ ¹¹⁹ ¹²⁰ ¹²² ¹²³ ¹²⁴ ¹²⁷ ¹²⁸ ¹²⁹ ¹³⁰ ¹⁴⁰ ¹⁴² ¹⁴³ ²⁰³ ²²⁰ If diuretic cannot be discontinued, give initial enalapril maleate dose of 2.5 mg under close medical supervision (observe patient for ≥2 hours and until BP has stabilized for at least an additional hour).⁶⁰⁰

When switching from IV enalaprilat to oral enalapril, initiate enalapril maleate at 5 mg once daily as monotherapy.²⁷⁷ If used with a diuretic, initiate enalapril maleate at 2.5 mg once daily (in patients who responded to enalaprilat 0.625 mg every 6 hours).²⁷⁷ Adjust dosage as necessary.²⁷⁷

Usual maintenance dosage: Manufacturer states 10–40 mg daily, given in 1 dose or 2 divided doses.¹ Some experts state 5–40 mg daily, given in 1 dose or 2 divided doses.¹²⁰⁰

If effectiveness diminishes toward end of dosing interval in patients treated once daily, consider increasing dosage or administering drug in 2 divided doses.¹ ¹³

Enalapril/Hydrochlorothiazide Fixed-combination Therapy

Oral

Manufacturer states fixed-combination preparation should not be used for initial antihypertensive therapy.²⁵⁴ ³⁴⁸

If BP is not adequately controlled by monotherapy with either enalapril or hydrochlorothiazide, or if stable dosages of these drugs have been achieved,²⁵⁴ ³⁴⁸ can switch to the fixed-combination preparation containing enalapril maleate 5 mg and hydrochlorothiazide 12.5 mg or, alternatively, enalapril maleate 10 mg and hydrochlorothiazide 25 mg.²⁵⁴

Adjust dosage of either or both drugs according to patient’s response.²⁵⁴ ³⁴⁸

Enalaprilat Therapy

Initially, enalaprilat 1.25 mg every 6 hours in patients not receiving a diuretic or in those converting from enalapril monotherapy.²⁷⁷

In patients receiving a diuretic, enalaprilat 0.625 mg initially.²⁷⁷ If BP response after 1 hour is inadequate, administer another dose of 0.625 mg.²⁷⁷ May administer additional doses of 1.25 mg at 6-hour intervals.²⁷⁷

In patients at risk of marked hypotension (see Hypotension under Cautions), ≤0.625 mg of enalaprilat initially, given by slow IV infusion (over ≥5 minutes, preferably up to 1 hour) under very close medical supervision.^d

Hypertensive Emergency† [off-label]

IV

Enalaprilat: 1.25–5 mg, repeated every 6 hours as necessary, has been recommended.¹²⁰⁰

Without compelling condition: Initial goal is to reduce SBP by no more than 25% within 1 hour, followed by further reduction if stable toward 160/100 to 110 mm Hg within the next 2–6 hours, avoiding excessive declines in BP that could precipitate renal, cerebral, or coronary ischemia.¹²⁰⁰ If patient is stable, can further reduce BP toward normal in the next 24–48 hours.¹²⁰⁰

Heart Failure

Oral

Usual initial enalapril maleate dosage: 2.5 mg twice daily in patients with normal renal function and serum sodium concentration.¹ ⁵²⁴

Usual maintenance dosage: 5–40 mg daily, given in 2 divided doses.⁴² ⁴⁴ ⁵⁷ ⁶¹ ⁶³ ⁶⁴ ¹⁴⁶ ¹⁴⁷ ¹⁴⁸ ¹⁵⁰ ¹⁵¹ ¹⁵² ¹⁵³ ¹⁵⁴ ²⁴⁵ ⁵²⁴

Following initial dose, monitor closely for ≥2 hours and until BP has stabilized for at least an additional hour.²⁴⁵ To minimize risk of hypotension, reduce diuretic dosage, if possible, prior to initiating therapy.¹ Adjust dosage gradually as tolerated to prespecified target (≥20 mg of enalapril maleate daily) or maximum tolerated dosage.⁵²⁴

In patients with hyponatremia (serum sodium concentration <130 mEq/L), manufacturer recommends initial enalapril maleate dosage of 2.5 mg daily under close monitoring.¹ Increase dosage at intervals of ≥4 days, to 2.5 mg twice daily, then 5 mg twice daily, and then higher, provided excessive hypotension or deterioration of renal function is not present at the time of intended dosage adjustment; dosage should not exceed 40 mg daily.¹

Asymptomatic Left Ventricular Dysfunction

Oral

Initially, enalapril maleate 2.5 mg twice daily.¹ Titrate upward as tolerated to target dosage of 20 mg daily, given in divided doses.¹ Following initial dose, monitor closely for ≥2 hours and until BP has stabilized for at least an additional hour.¹ To minimize risk of hypotension, reduce diuretic dosage, if possible, prior to initiating therapy.¹

Prescribing Limits

Pediatric Patients

Hypertension

Oral

Maximum 0.58 mg/kg or 40 mg of enalapril maleate daily.¹

Adults

Hypertension

Oral

Dosage of enalapril/hydrochlorothiazide fixed combination generally should not exceed enalapril maleate 20 mg and hydrochlorothiazide 50 mg daily.²⁵⁴ ³²³ ³⁴⁸

IV

Enalaprilat dosages up to 5 mg every 6 hours were well tolerated for up to 36 hours in controlled clinical studies.²⁷⁷ Insufficient experience with dosages >20 mg daily.²⁷⁷

Enalaprilat usually is not administered for >48 hours, but has been administered for as long as 7 days.²⁷⁷

Heart Failure

Oral

Maximum 40 mg of enalapril maleate daily, given in 2 divided doses.¹ ²⁴⁵ ⁵²⁴

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.¹

Renal Impairment

Hypertension

Enalapril Therapy

Oral

Patients with Cl_cr >30 mL/minute: Manufacturer states that no adjustment of enalapril maleate dosage is required.¹

Adults with Cl_cr ≤30 mL/minute or S_cr ≥3 mg/dL: Manufacturer recommends initial enalapril maleate dosage of 2.5 mg once daily; titrate until BP is controlled or to maximum of 40 mg daily.¹ When switching from IV enalaprilat, initiate oral therapy at 2.5 mg once daily;²⁷⁷ adjust dosage according to patient’s BP response.²⁷⁷

Manufacturer does not recommend use of enalapril in pediatric patients with Cl_cr <30 mL/minute per 1.73 m².¹

Some clinicians recommend dosage of 75–100% of usual enalapril dosage in patients with Cl_cr of 10–50 mL/minute and dosage of 50% of usual enalapril dosage in those with Cl_cr <10 mL/minute.²⁶⁴

Hemodialysis patients: Enalapril maleate 2.5 mg on dialysis days; on days between dialysis, adjust dosage according to BP response.¹

Enalapril/Hydrochlorothiazide Fixed-combination Therapy

Oral

Not recommended in patients with severe renal impairment.²⁵⁴ No dosage adjustment required if Cl_cr >30 mL/minute.⁴⁵⁵

Enalaprilat Therapy

Adults with Cl_cr >30 mL/minute: No adjustment of enalaprilat dosage required.²⁷⁷

Adults with Cl_cr ≤30 mL/minute or S_cr ≥3 mg/dL: Enalaprilat 0.625 mg initially.²⁷⁷ If BP response after 1 hour is inadequate, administer another dose of 0.625 mg.²⁷⁷ May administer additional doses of 1.25 mg at 6-hour intervals.²⁷⁷

Hemodialysis patients: Enalaprilat 0.625 mg every 6 hours.²⁷⁷

Heart Failure

Oral

Patients with S_cr >1.6 mg/dL: Enalapril maleate 2.5 mg daily initially under close monitoring.¹ Increase dosage at intervals of ≥4 days, to 2.5 mg twice daily, then 5 mg twice daily, and then higher, provided excessive hypotension or deterioration of renal function is not present at the time of intended dosage adjustment; do not exceed 40 mg daily.¹

Geriatric Patients

Hypertension

Initiate therapy with enalapril/hydrochlorothiazide fixed combination at lower end of usual range.²⁵⁴ ³⁴⁸

Cautions for Enalapril

Contraindications

Known hypersensitivity (e.g. history of angioedema) to enalapril, enalaprilat, or another ACE inhibitor or any ingredient in the formulation.¹ ^d
History of hereditary or idiopathic angioedema.¹ ^d

Warnings/Precautions

Warnings

Hypotension

Risk of marked hypotension, sometimes associated with oliguria, azotemia, and, rarely, death, in volume- and/or salt-depleted patients (e.g., those with heart failure with or without associated renal insufficiency, hyponatremia, high-dose or recent intensive diuretic therapy or recent increase in diuretic dose, dialysis).¹ ⁶ ⁵⁷ ¹²² ¹⁵² ¹⁶³ ¹⁶⁴ ¹⁶⁵ ²³⁹ ²⁴⁵ ²⁶⁰ ⁶⁰⁰ Severe hypotension reported in such patients following IV enalaprilat doses as low as 0.2 mg.^d Severe hypotension may result in MI or stroke in patients with ischemic cardiovascular or cerebrovascular disease.¹

Hypotension may occur in patients undergoing surgery or during anesthesia with agents that produce hypotension; recommended treatment is fluid volume expansion.¹

To minimize potential for hypotension, consider recent antihypertensive therapy, extent of BP elevation, sodium intake, fluid status, and other clinical conditions.¹ ⁵ ⁶ ²³⁹ May minimize potential for hypotension in patients at risk for excessive hypotension by withholding diuretic therapy (except in patients with heart failure), reducing diuretic dosage, and/or cautiously increasing sodium intake prior to initiation of enalapril.⁶ ²³⁶ ²³⁹ ⁶⁰⁰ (See Dosage under Dosage and Administration.)

Initiate therapy in patients at risk for excessive hypotension under close medical supervision; monitor closely for first 2 weeks following initiation of enalapril or any increase in enalapril or diuretic dosage.²⁴⁵ ²⁶⁰ ⁶⁰⁰ ^b

If excessive hypotension occurs, immediately place patient in supine position and, if necessary, administer IV infusion of 0.9% sodium chloride.¹ ⁴ ⁵ ¹⁸³ ²⁴⁵ ²⁵⁴ Enalapril therapy usually can be continued following restoration of volume and BP.¹ ²⁴⁵ If symptomatic hypotension develops, dosage reduction or discontinuance of enalapril or diuretic may be necessary.¹ ²⁴⁵

Hematologic Effects

Neutropenia and agranulocytosis reported with captopril;¹ ²⁰⁸ ²⁰⁹ ²¹⁰ risk of neutropenia appears to depend principally on presence of renal impairment and presence of collagen vascular disease (e.g., systemic lupus erythematosus, scleroderma).¹ ²²³ ²²⁶ Several cases of neutropenia or agranulocytosis reported with enalapril; causal relationship could not be excluded.¹ ⁶ ¹⁷⁵

Consider monitoring leukocytes in patients with collagen vascular disease, especially if renal impairment exists.¹

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when ACE inhibitors used during pregnancy.¹ ⁴⁵³ ⁴⁵⁴ (See Boxed Warning.) Such potential risks occur throughout pregnancy, especially during the second and third trimesters.⁴⁵⁴

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.⁴⁵³ ⁴⁵⁴

Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.⁴⁵⁴ Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.²⁹⁷

Hepatic Effects

Clinical syndrome that usually is manifested initially by cholestatic jaundice and may progress to fulminant hepatic necrosis (occasionally fatal) reported rarely with ACE inhibitors.¹

If jaundice or marked elevation of liver enzymes occurs, discontinue drug and monitor patient.¹

Sensitivity Reactions

Anaphylactoid reactions and/or angioedema possible; if associated with laryngeal edema, may be fatal.¹ ²⁴⁵ ²⁵⁴ Immediate medical intervention (e.g., epinephrine) for involvement of tongue, glottis, or larynx.¹ ²⁴⁵ ²⁵⁴ Intestinal angioedema possible; consider in differential diagnosis of patients who develop abdominal pain.⁴⁵²

Anaphylactoid reactions reported in patients receiving ACE inhibitors while undergoing LDL apheresis with dextran sulfate absorption¹ ²⁵⁴ ²⁷⁷ ³¹⁹ ³²⁰ ³²¹ or following initiation of hemodialysis that utilized high-flux membrane.¹ ²⁵⁴ ²⁷⁷ ³⁰² ³⁰⁴ ³⁰⁶

Life-threatening anaphylactoid reactions reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom.¹ ²⁵⁴ ²⁷⁷

Contraindicated in patients with a history of angioedema associated with ACE inhibitors and in patients with hereditary or idiopathic angioedema.¹ ⁴⁰⁷

General Precautions

Renal Effects

Transient increases in BUN and S_cr possible, especially in patients with preexisting renal impairment or those receiving concomitant diuretic therapy.¹ ⁴ ²³⁴ ²⁵⁴ ²⁶² Possible increases in BUN and S_cr in patients with unilateral or bilateral renal-artery stenosis;¹ ⁶ ⁵⁰ ¹¹⁶ ¹⁶¹ ¹⁶⁷ ¹⁶⁹ ²³¹ ²³⁴ ³⁷⁹ generally reversible following discontinuance of ACE inhibitor and/or diuretic.¹ ¹⁶¹ ¹⁶⁷ ²³⁴ ³⁷⁹

Possible oliguria, progressive azotemia, and, rarely, acute renal failure and/or death in patients with severe heart failure.¹ ¹⁵² ²⁴⁵ ²⁵⁴ ²⁶²

Closely monitor renal function following initiation of therapy in patients with heart failure or unilateral or bilateral renal-artery stenosis.¹ ²⁴⁵ Some patients may require dosage reduction or discontinuance of ACE inhibitor or diuretic and/or adequate sodium repletion.¹ ⁴² ¹⁵² ¹⁶⁶ ²³⁶ ²³⁹ ²⁶⁰ ²⁶²

Hyperkalemia

Possible hyperkalemia, especially in patients with renal impairment or diabetes mellitus and those receiving drugs that can increase serum potassium concentrations (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes).¹ ⁶⁴ ¹⁵² ¹⁷² ¹⁷⁴ ²³⁵ ²³⁹ ²⁴⁵ ²⁵⁴ (See Specific Drugs under Interactions.)

Monitor serum potassium concentration carefully in these patients.¹ ²³⁵ ²⁴⁵

Cough

Persistent and nonproductive cough;¹ ²⁷⁷ resolves after drug discontinuance.¹ ¹⁷³ ²⁴¹ ²⁵² ²⁵⁶ ²⁵⁸ ²⁷⁷

Valvular Stenosis

Use with caution in patients with obstruction in the outflow tract of the left ventricle (e.g., aortic stenosis, hypertrophic cardiomyopathy).¹

Use of Fixed Combinations

When used in fixed combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with hydrochlorothiazide.^e

Specific Populations

Pregnancy

Enalapril/enalaprilat: Category C (1st trimester); Category D (2nd and 3rd trimesters).¹ ^d (See Boxed Warning.)

Lactation

Distributed into milk; discontinue nursing or the drug.¹ ²⁵⁴

Pediatric Use

Antihypertensive effects of oral enalapril established in hypertensive pediatric patients 1 month to 16 years of age;¹ adverse effect profile of enalapril similar to that in adults.¹ Enalapril is not recommended for neonates or for pediatric patients with Cl_cr <30 mL/minute per 1.73 m².¹

Safety and efficacy of IV enalaprilat or of oral enalapril in fixed combination with felodipine or hydrochlorothiazide not established in children.²⁴⁵ ²⁵⁴ ^e

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently to enalapril in fixed combination with hydrochlorothiazide than younger adults; select dosage with caution.⁴⁵⁵ (See Geriatric Patients under Dosage and Administration.)

Renal Impairment

Systemic exposure to enalaprilat may be increased.¹ ⁸⁹ ⁹³ ⁹⁴ ⁹⁶ ²⁸¹ (See Absorption: Special Populations, under Pharmacokinetics.) Initial dosage adjustment may be necessary depending on degree of renal impairment.¹ ²⁶⁴ ²⁷⁷ (See Renal Impairment under Dosage and Administration.)

Deterioration of renal function may occur.¹ (See Renal Effects under Cautions.)

Enalapril/hydrochlorothiazide fixed combinations are not recommended in patients with severe renal impairment (Cl_cr ≤30 mL/minute or S_cr >3 mg/dL).^e

Black Patients

BP reduction achieved with ACE inhibitor may be smaller in black patients compared with nonblack patients.¹ ² ⁹ ⁷⁸ ¹²¹ ²⁶⁹ ²⁷⁰ ²⁷¹ ⁴¹⁹ ⁴²⁰ ⁴⁵⁰ ⁴⁵¹ (See Hypertension under Uses.)

Higher incidence of angioedema reported with ACE inhibitors in black patients compared with other races.¹ ³⁴⁸ ³⁴⁹ ⁴²⁰

Common Adverse Effects

Enalapril in patients with hypertension: Headache, fatigue, dizziness.¹

Enalapril in patients with heart failure: Orthostatic effects, syncope, chest pain, hypotension, diarrhea, dizziness, cough.¹

Enalaprilat: Hypotension.^d

Drug Interactions

Specific Drugs

Drug	Interaction	Comments
Antidiabetic agents	Possible hypoglycemia in diabetic patients¹⁷⁶	Consider risk of hypoglycemia if used concomitantly¹⁷⁶
Diuretics	Increased hypotensive effect¹ ⁴ ¹²⁰ ¹²² ¹²⁸ ¹²⁹ ¹³¹ ²⁵⁴	If possible, discontinue diuretic before initiating enalapril or enalaprilat¹ ⁶ ²³⁶ ²³⁹ (see Dosage under Dosage and Administration)
Diuretics, potassium-sparing (amiloride, spironolactone, triamterene)	Enhanced hyperkalemic effect¹ ²⁴⁵	Use with caution; monitor serum potassium concentrations frequently¹ ²⁴⁵
Hypotensive agents (e.g., nitrates, certain anesthetics)	Increased hypotensive effect¹ ⁵
Lithium	Increased serum lithium concentrations; possible toxicity¹ ⁷⁸ ¹⁸⁰	Use with caution; monitor serum lithium concentrations frequently¹
NSAIAs	Possible reduced BP response to enalapril;³²² ³²³ ³²⁴ ³²⁵ ³²⁶ ³²⁷ ³²⁸ ³²⁹ ³⁷⁰ ⁴⁰⁴ ⁷⁰⁶ potential for acute reduction of renal function;³²⁴ ³³⁰ possible attenuation of hemodynamic effects in patients with heart failure³⁷⁹ ⁴⁰⁴	Monitor BP carefully and be alert for evidence of impaired renal function³²⁴
Potassium supplements or potassium-containing salt substitutes	Enhanced hyperkalemic effect¹ ²⁴⁵	Use with caution; monitor serum potassium concentrations frequently¹ ²⁴⁵

Enalapril Pharmacokinetics

Absorption

Bioavailability

Approximately 55–75% of an oral dose of enalapril is rapidly absorbed;¹ ² ⁸³ ⁸⁴ enalaprilat is poorly absorbed from GI tract.¹ ¹² ¹⁷ ⁸⁵ ⁹⁷ ¹⁸⁷

Enalapril undergoes first-pass metabolism to enalaprilat (the active moiety).¹ ² ¹⁰ ⁴⁶ ⁸³ ⁹⁵ ⁹⁷ ⁹⁹ ¹⁹⁰ Peak serum concentrations of enalapril and enalaprilat are achieved within 0.5–1.5 and 3–4.5 hours, respectively, following oral administration.¹ ² ⁴ ⁵ ¹⁰ ⁴⁶ ⁸³ ⁸⁴ ⁸⁶ ⁸⁸ ⁹¹ ²⁴⁴ ²⁸³ ²⁸⁴

Concomitant oral administration of enalapril and hydrochlorothiazide has little, if any, effect on the bioavailability of either drug in the combination.^e

Onset

Following a single oral dose of enalapril, antihypertensive effects are observed in 1 hour, with peak BP reduction at 4–8 hours.¹ ⁴³ ⁴⁶ ⁹⁰

Following IV dose of enalaprilat, hypotensive effect usually is apparent within 5–15 minutes, with maximal effect within 1–4 hours;²⁷⁷ ²⁸⁶ ²⁸⁷ ²⁸⁸ ²⁸⁹ effects of second and third doses may exceed those of first dose.²⁷⁷

Duration

Following oral administration of enalapril, hypotensive effect generally persists for 12–24 hours.¹ ⁴¹ ⁴³ ⁴⁴ ⁴⁵ ⁴⁶ ⁴⁸ ⁵⁰ ⁵⁸ ²³¹ Several weeks of therapy may be required before full effect is achieved.¹ ⁴⁶ ⁵¹ ⁶² ⁷⁹

Following IV administration of recommended doses of enalaprilat, hypotensive effect persists for approximately 6 hours.²⁷⁷ ²⁸⁶

Food

Food does not affect absorption of enalapril.¹ ⁸⁸ ⁹¹

Special Populations

In patients with impaired renal function, enalaprilat concentrations and AUCs may be increased; time to peak and steady-state serum concentration may be delayed.¹ ⁸⁹ ⁹³ ⁹⁴ ⁹⁶ ²⁸¹ Effective half-life for accumulation of enalaprilat is prolonged in patients with Cl_cr <30 mL/minute but not in those with Cl_cr of 30–60 mL/minute.¹ ⁹³ ⁹⁴

Distribution

Extent

Enalapril appears to cross the blood-brain barrier poorly, if at all; enalaprilat does not appear to distribute into the CNS.¹ ²

Enalaprilat crosses the placenta.²⁶³

Enalapril and enalaprilat are distributed into milk in trace amounts.¹ ²⁷⁷

Plasma Protein Binding

Enalaprilat: Approximately 50–60%.² ⁴ ¹⁰

Elimination

Metabolism

Metabolized in the liver, principally to an active metabolite, enalaprilat.¹ ² ¹⁰ ⁴⁶ ⁹⁵ ⁹⁷ ⁹⁹

Elimination Route

Enalapril is eliminated in urine (60–78% within 24–48 hours) as unchanged drug and enalaprilat¹ ⁴ ⁸⁴ ⁸⁷ ²⁴⁴ and also in feces (approximately 33% within 24–48 hours).¹ ² ⁴ ⁸⁴

Enalaprilat is eliminated in urine as unchanged drug.^d

Enalaprilat is removed by hemodialysis¹ ² ⁸⁹ ⁹⁴ ²⁸² and peritoneal dialysis.²⁴⁵ ²⁵⁴ ²⁶³

Half-life

Enalapril: <2 hours.⁸⁶ ¹⁰⁰ ¹⁰¹ ²⁸³ ²⁸⁴

Enalaprilat: 11 hours.¹ ² ⁸⁷

Special Populations

In patients with hepatic impairment, elimination of enalaprilat may be prolonged.²⁸³ ²⁸⁴ Hydrolysis of enalapril to enalaprilat may be delayed⁸⁸ ⁹⁵ ²⁸³ and/or impaired²⁸³ in patients with severe hepatic impairment.⁸⁸ ⁹⁵ ²⁸³

In patients with GFR ≤30 mL/minute, half-life of enalaprilat is prolonged.^d

In patients with heart failure, enalapril half-life may be increased and enalaprilat elimination prolonged.¹⁰⁰

Stability

Storage

Oral

Extemporaneous Suspension

1-mg/mL preparation of enalapril maleate tablets in syrup (Ora-Sweet SF) and sodium citrate dihydrate (Bicitra) (see Oral Administration under Dosage and Administration): Up to 30 days at 2–8°C.¹ ⁴⁰⁸

Tablets

Enalapril: Tight container at 25°C (may be exposed to 15–30°C); protect from moisture.¹

Enalapril/hydrochlorothiazide fixed-combination preparations: Tightly closed container at 25°C (may be exposed to 15–30°C). ⁴⁵⁵ Protect from moisture.⁴⁵⁵

Parenteral

Injection

<30°C.²⁷⁷

Compatibility

Parenteral

Solution Compatibilityd HID

Compatible
Dextran 40 10% in dextrose 5%
Dextrose 5% in Ringer’s injection, lactated
Dextrose 5% in sodium chloride 0.9%^d
Dextrose 5% in water
Hetastarch 6% in sodium chloride 0.9%
Normosol R
Sodium chloride 0.9%^d

Drug Compatibility

Admixture CompatibilityHID
Compatible
Dobutamine HCl
Dopamine HCl
Heparin sodium
Meropenem
Nitroglycerin
Potassium chloride
Sodium nitroprusside

Y-Site CompatibilityHID
Compatible
Allopurinol sodium
Amifostine
Amikacin sulfate
Aminophylline
Ampicillin sodium
Ampicillin sodium–sulbactam sodium
Aztreonam
Bivalirudin
Butorphanol tartrate
Calcium gluconate
Cefazolin sodium
Ceftaroline fosamil
Ceftazidime
Chloramphenicol sodium succinate
Cisatracurium besylate
Cladribine
Clindamycin phosphate
Co-trimoxazole
Dexmedetomidine HCl
Dextran 40
Dobutamine HCl
Docetaxel
Dopamine HCl
Doripenem
Doxorubicin HCl liposome injection
Erythromycin lactobionate
Esmolol HCl
Etoposide phosphate
Famotidine
Fenoldopam mesylate
Fentanyl citrate
Filgrastim
Ganciclovir sodium
Gemcitabine HCl
Gentamicin sulfate
Granisetron HCl
Heparin sodium
Hetastarch in lactated electrolyte injection (Hextend)
Hetastarch in sodium chloride 0.9%
Hydrocortisone sodium succinate
Labetalol HCl
Lidocaine HCl
Linezolid
Magnesium sulfate
Melphalan HCl
Meropenem
Methylprednisolone sodium succinate
Metronidazole
Morphine sulfate
Nafcillin sodium
Nicardipine HCl
Oxaliplatin
Pemetrexed disodium
Penicillin G potassium
Phenobarbital sodium
Piperacillin sodium–tazobactam sodium
Potassium chloride
Potassium phosphates
Propofol
Ranitidine HCl
Remifentanil HCl
Sodium acetate
Sodium nitroprusside
Teniposide
Thiotepa
Tobramycin sulfate
Vancomycin HCl
Vinorelbine tartrate
Incompatible
Amphotericin B
Amphotericin B cholesteryl sulfate complex
Nesiritide
Phenytoin sodium

Actions

Enalapril is a prodrug; has little pharmacologic activity until hydrolyzed to enalaprilat.¹ ² ⁴ ⁵ ⁶ ⁷ ⁸ ¹⁶ ¹⁷ ²⁰
Suppresses the renin-angiotensin-aldosterone system.¹ ² ⁴ ⁵ ¹⁰

Advice to Patients

Risk of angioedema, anaphylactoid reactions, or other sensitivity reactions.¹ Importance of reporting sensitivity reactions (e.g., edema of the face, eyes, lips, tongue, or extremities; hoarseness; swallowing or breathing with difficulty) immediately to clinician and of discontinuing the drug.¹
Importance of reporting signs of infection (e.g., sore throat, fever).¹
Risk of hypotension.¹ Importance of informing clinicians promptly if lightheadedness or fainting occurs.¹
Importance of adequate fluid intake; risk of volume depletion with excessive perspiration, dehydration, vomiting, or diarrhea.¹
Risks of use during pregnancy.¹ ⁴⁵³ ⁴⁵⁴ (See Boxed Warning.)
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (including salt substitutes containing potassium).¹
Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.¹
Importance of advising patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Enalaprilat
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV use only	equivalent to 1.25 mg of anhydrous enalaprilat per mL*	Enalaprilat Injection

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Enalapril Maleate
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	2.5 mg*	Vasotec (scored)	Valeant
		5 mg*	Vasotec (scored)	Valeant
		10 mg*	Vasotec (scored)	Valeant
		20 mg*	Vasotec (scored)	Valeant

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Enalapril Maleate and Hydrochlorothiazide
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	5 mg Enalapril Maleate and Hydrochlorothiazide 12.5 mg*	Enalapril Maleate and Hydrochlorothiazide Tablets
		10 mg Enalapril Maleate and Hydrochlorothiazide 25 mg*	Enalapril Maleate and Hydrochlorothiazide Tablets
			Vaseretic	Valeant

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

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Enalapril Therapy

Enalapril/Hydrochlorothiazide Fixed-combination Therapy

Enalaprilat Therapy

Heart Failure

Oral

Geriatric Patients

Hypertension

Cautions for Enalapril

Contraindications

Warnings/Precautions

Warnings

Hypotension

Hematologic Effects

Fetal/Neonatal Morbidity and Mortality

Hepatic Effects

Sensitivity Reactions

General Precautions

Renal Effects

Hyperkalemia

Cough

Valvular Stenosis

Use of Fixed Combinations

Specific Populations

Pregnancy

Lactation

Pediatric Use

Geriatric Use

Renal Impairment

Black Patients

Common Adverse Effects

Drug Interactions

Specific Drugs