Vasotec

Generic Name: Enalaprilat/Enalapril Maleate
Class: Angiotensin-Converting Enzyme 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

• 
  

  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 Vasotec

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).^{1 2 4 5 9 54 110 116 119 120 122 123 124 127 128 129 130 131 140 142 143 144 155 186 203 220 312 351} May use enalaprilat when oral therapy is not practical.^{277 285 286}

One of several preferred initial therapies in hypertensive patients with heart failure, postmyocardial infarction, high coronary disease risk, diabetes mellitus, chronic renal failure, and/or cerebrovascular disease.⁴²¹

Can be used as monotherapy for initial management of uncomplicated hypertension;^{1 2 9 54 73 107 108 109 110 123 125 186 200 201 206 231 247 267 312 351 352 353} however, thiazide diuretics are preferred by JNC 7.⁴²¹

Enalaprilat has been used effectively to control BP in adults with severe hypertension or hypertensive emergencies†.^{287 288 289 290 351}

Enalaprilat has been used for rapid reduction of BP in pediatric patients 1–17 years of age† with hypertensive urgencies or emergencies.⁴⁴⁹

CHF

Management of symptomatic CHF, usually in conjunction with cardiac glycosides, diuretics, and β-adrenergic blocking agents.^{1 4 42 44 57 61 63 64 146 147 148 150 151 152 153 158 159 225 245 260 360 416}

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 CHF.^{1 418}

Diabetic Nephropathy

A first-line agent in the treatment of diabetic nephropathy† in hypertensive patients with type 2 diabetes mellitus.^{396 411}

Vasotec Dosage and Administration

General

Hypertension

• 
  

  Enalapril/felodipine and enalapril/hydrochlorothiazide fixed combinations should not be used for initial treatment of hypertension.^{254 348 372}

  
  

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

Administer enalapril/felodipine fixed combination (Lexxel) either without food or with a light meal (administration with substantial meal increases peak plasma felodipine concentrations).³⁷² Swallow tablets whole; do not crush, chew, or divide.³⁷²

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

Pediatric Patients

Hypertension

Oral

Children 1 month to 16 years of age: Enalapril maleate 0.08 mg/kg (up to 5 mg) once daily.^{1 449}

Adjust dosage until the desired BP goal is achieved (up to maximum dosage of 0.58 mg/kg or 40 mg).^{1 449}

Hypertensive Urgencies or Emergencies†

Rapid Reduction of BP†

IV

Children and adolescents 1–17 years of age: Enalaprilat 0.05–0.1 mg/kg per dose (up to 1.25 mg per dose) given by direct IV injection†.⁴⁴⁹

Adults

Hypertension

Oral

Initially, enalapril maleate 2.5–5 mg daily as monotherapy.^{1 312 351 421} 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).^{1 13}

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

Usual dosage: Enalapril maleate 10–40 mg daily, given in 1 dose or 2 divided doses.^{1 11 107 123 312 351 421}

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}

IV

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

Enalapril/Hydrochlorothiazide Combination Therapy

Oral

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}

Enalapril/Felodipine Combination Therapy

Oral

If BP is not adequately controlled by monotherapy with either enalapril (or another ACE inhibitor) or felodipine (or another dihydropyridine-derivative calcium-channel blocking agent), can switch to the fixed-combination preparation containing enalapril maleate 5 mg and felodipine 5 mg daily.³⁷² If BP is not adequately controlled after 1 or 2 weeks, increase dosage to enalapril maleate 10 mg and felodipine 10 mg once daily.³⁷²

If control of BP is still inadequate, consider adding a thiazide diuretic.³⁷²

CHF

Oral

Manufacturer recommends initial enalapril maleate dosage of 2.5 mg twice daily.¹ Usual maintenance dosage: 2.5–20 mg twice daily.¹

Some clinicians recommend initial enalapril maleate dosage of 2.5 mg once or twice daily in patients with normal renal function and serum sodium concentration.^{245 360 379 416} Usual maintenance dosage: 2.5–20 mg daily, given in 2 divided doses.^{42 44 57 61 63 64 146 147 148 150 151 152 153 154 245 360}

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 over several weeks^{360 379} to prespecified target (≥20 mg of enalapril maleate daily) or maximum tolerated dosage.^{379 416}

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.^{1 360} 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.^{1 449}

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

CHF

Oral

Maximum 40 mg of enalapril maleate daily, given in 2 divided doses.^{1 245 416}

Special Populations

The following information addresses dosage of enalapril maleate or enalaprilat in special populations.³⁷² Dosages of drugs administered in fixed combination with enalapril maleate also may require adjustment in certain patient populations; the need for such dosage adjustments must be considered in the context of cautions, precautions, and contraindications specific to that population and drug.³⁷²

Hepatic Impairment

Hypertension

Enalapril/Felodipine Combination Therapy

Oral

May use the fixed combination if the optimum maintenance dosage of enalapril and felodipine administered separately corresponds to the amount of the drugs in the fixed combination.³⁷² Amount of felodipine in the fixed combination exceeds the recommended initial dosage for patients with hepatic impairment.³⁷²

Renal Impairment

Hypertension

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

IV

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

Enalapril/Hydrochlorothiazide Combination Therapy

Oral

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

Enalapril/Felodipine Combination Therapy

Oral

May use the fixed combination if the optimum maintenance dosage of enalapril and felodipine administered separately corresponds to the amount of the drugs in the fixed combination.³⁷² Amount of enalapril in the fixed combination exceeds the recommended initial dosage for patients with severe renal impairment.³⁷²

CHF

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

Enalapril/Hydrochlorothiazide Combination Therapy

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

Enalapril/Felodipine Combination Therapy

May use the enalapril/felodipine fixed combination if the optimum maintenance dosage of enalapril and felodipine administered separately corresponds to the amount of the drugs in the fixed combination.³⁷² Amount of felodipine in the fixed combination exceeds the recommended initial dosage for geriatric patients.³⁷²

Cautions for Vasotec

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 CHF with or without associated renal insufficiency, hyponatremia, intensive diuretic therapy or recent increase in diuretic dose, dialysis).^{1 6 57 122 152 163 164 165 239 245 260} 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 by withholding diuretic therapy and/or increasing sodium intake for 2–3 days prior to initiation of enalapril.^{1 6 236 239 372} (See Dosage under Dosage and Administration.)

Initiate therapy in patients with CHF (with or without associated renal insufficiency) under close medical supervision; monitor closely for first 2 weeks following initiation of enalapril or any increase in enalapril or diuretic dosage.^{1 245 260 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.^{1 372 453 454} (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.^{372 453 454}

Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.^{372 454} 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.^{1 245 254 379} 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 absorption^{1 254 277 319 320 321} 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.^{1 379 407}

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 CHF.^{1 152 245 254 262}

Closely monitor renal function following initiation of therapy in patients with CHF 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 64 152 172 174 235 239 245 254 379} (See Specific Drugs under Interactions.)

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

Cough

Persistent and nonproductive cough;^{1 277 379} 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 felodipine or hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with the concomitant agent.^{372 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.^{245 254 372 e}

Use with caution for rapid reduction of BP in pediatric patients 1–17 years of age†; may cause prolonged hypotension and acute renal failure, especially in neonates.⁴⁴⁹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently to enalapril in fixed combination with felodipine or hydrochlorothiazide than younger adults; select dosage with caution.^{372 455} (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

Blacks

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} however, no apparent population difference during combination therapy with ACE inhibitor and thiazide diuretic.^{1 244 351} Use in combination with a diuretic.^{1 244 351}

Higher incidence of angioedema reported with ACE inhibitors in blacks compared with other races.^{1 348 349 420}

Common Adverse Effects

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

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

Enalaprilat: Hypotension.^d

Interactions for Vasotec

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 potential for acute reduction of renal function;324 330 possible attenuation of hemodynamic effects in patients with CHF379 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

Vasotec 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 either hydrochlorothiazide or felodipine has little, if any, effect on the bioavailability of either drug in the combination.^{372 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 distr