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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

Warning(s)

  • 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

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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 weeks360 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 Clcr >30 mL/minute: Manufacturer states that no adjustment of enalapril maleate dosage is required.1

Adults with Clcr ≤30 mL/minute or Scr ≥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 Clcr <30 mL/minute per 1.73 m2.1

Some clinicians recommend dosage of 75–100% of usual enalapril dosage in patients with Clcr of 10–50 mL/minute and dosage of 50% of usual enalapril dosage in those with Clcr <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 Clcr >30 mL/minute: No adjustment of enalaprilat dosage required.277

Adults with Clcr ≤30 mL/minute or Scr ≥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 Clcr >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 Scr >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 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.1 379 407

General Precautions

Renal Effects

Transient increases in BUN and Scr possible, especially in patients with preexisting renal impairment or those receiving concomitant diuretic therapy.1 4 234 254 262 Possible increases in BUN and Scr 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 Clcr <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 (Clcr ≤30 mL/minute or Scr >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 Clcr <30 mL/minute but not in those with Clcr 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 CHF, 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/felodipine fixed-combination preparation: Tightly closed container at 25°C (may be exposed to 15–30°C).372 Protect from light and moisture.372

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

For information on systemic interactions resulting from concomitant use, see Interactions.

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.

* 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

Vasotec I.V.

Biovail

* 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)

Biovail

5 mg*

Vasotec (scored)

Biovail

10 mg*

Vasotec

Biovail

20 mg*

Vasotec

Biovail

* 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

Biovail

Other Enalapril Maleate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release core (felodipine only), film-coated

5 mg with Felodipine 5 mg

Lexxel

AstraZeneca

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Enalapril Maleate 10MG Tablets (MYLAN): 30/$11.99 or 90/$16.97

Enalapril Maleate 2.5MG Tablets (MYLAN): 30/$13.99 or 60/$15.98

Enalapril Maleate 20MG Tablets (MYLAN): 30/$11.99 or 60/$13.98

Enalapril Maleate 5MG Tablets (MYLAN): 30/$11.99 or 90/$16.99

Enalapril-Hydrochlorothiazide 10-25MG Tablets (TARO): 30/$27.99 or 90/$72.97

Enalapril-Hydrochlorothiazide 5-12.5MG Tablets (APOTEX): 30/$23.99 or 90/$64.99

Vaseretic 10-25MG Tablets (VALEANT): 30/$110.23 or 90/$297.41

Vaseretic 5-12.5MG Tablets (BTA PHARMACEUTICALS): 30/$41.99 or 90/$125.97

Vasotec 10MG Tablets (VALEANT): 30/$95.99 or 90/$281.96

Vasotec 2.5MG Tablets (VALEANT): 60/$162.24 or 180/$447.19

Vasotec 20MG Tablets (VALEANT): 30/$132.99 or 90/$375.96

Vasotec 5MG Tablets (VALEANT): 30/$87.99 or 90/$245.42

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 8, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

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103. Ajayi AA, Hockings N, Reid JL. Age and the pharmacodynamics of angiotensin converting enzyme inhibitors enalapril and enalaprilat. Br J Clin Pharmacol. 1986; 21:349-57. [IDIS 215133] [PubMed 3011047]

104. Millar JA, Derkx FHM, McLean K et al. Pharmacodynamics of converting enzyme inhibition: the cardiovascular, endocrine and autonomic effects of MK421 (enalapril) and MK521. Br J Clin Pharmacol. 1982; 14:347-55. [IDIS 158813] [PubMed 6289857]

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109. Sassano P, Chatellier G, Alhenc-Gelas F et al. Antihypertensive effect of enalapril as first-step treatment of mild and moderate uncomplicated essential hypertension: evaluation by two methods of blood pressure measurement. Am J Med. 1984; 77(Suppl 2A):18-22. [IDIS 190603] [PubMed 6089555]

110. Brunner HR, Waeber B, Nussberger J et al. Long-term clinical experience with enalapril in essential hypertension. J Hypertens. 1983; 1(Suppl 1):103-7. [PubMed 6681024]

111. Bauer JH. Role of angiotensin converting enzyme inhibitors in essential and renal hypertension. Am J Med. 1984; 77(Suppl 2A):43-51. [IDIS 190606] [PubMed 6206722]

112. Jones RI, Hornung RS, Cashman PMM et al. Effect of enalapril at rest, during tilt, static and dynamic exercise in systemic hypertension. Am J Cardiol. 1985; 55:1534-8. [IDIS 201344] [PubMed 2988326]

113. Izzo JL Jr, Larrabee PS, Kamm DE. Physiologic adaptation to chronic angiotensin converting enzyme inhibition (ACEI). Clin Pharmacol Ther. 1984; 35:248.

114. Cooper WD, Doyle G, Donohoe J et al. Enalapril in the treatment of hypertension associated with impaired renal function. Br J Clin Pharmacol. 1985; 20:280-1P.

115. Smith CD, Smith RD, Korn JH. Hypertensive crisis in systemic sclerosis: treatment with the new oral angiotensin converting enzyme inhibitor MK 421 (enalapril) in captopril-intolerant patients. Arthritis Rheum. 1984; 27:826-8. [IDIS 188191] [PubMed 6331462]

116. Hodsman GP, Brown JJ, Cumming AMM et al. Enalapril in treatment of hypertension with renal artery stenosis: changes in blood pressure, renin, angiotensin I and II, renal function, and body composition. Am J Med. 1984; 77:52-60.

117. Webster J, Newnham DM, Petrie JC. Initial dose of enalapril in hypertension. BMJ. 1985; 290:1623-4. [IDIS 201073] [PubMed 2988687]

118. Jones RI, Hornung RS, Cashman PMM et al. Duration and diurnal variation of the hypotensive effect of enalapril in patients with essential hypertension. J Am Coll Cardiol. 1984; 3:616.

119. O’Keefe CL, Prior N, Yaffe J et al. Individualized antihypertensive therapy with enalapril/hydrochlorothiazide: use of 24 hour ambulatory blood pressure monitoring. Circulation. 1983; 68:III-37.

120. Nelson EB, Pool JL, Taylor AA et al. Long term efficacy of enalapril plus hydrochlorothiazide in the treatment of essential hypertension. Clin Pharmacol Ther. 1983; 33:230.

121. Chrysant SG, Brown RD, Kem DC et al. Antihypertensive and metabolic effects of a new converting enzyme inhibitor, enalapril. Clin Pharmacol Ther. 1983; 33:741-6. [IDIS 171769] [PubMed 6303673]

122. Vlasses PH, Rotmensch HH, Swanson BN et al. Comparative antihypertensive effects of enalapril maleate and hydrochlorothiazide, alone and in combination. J Clin Pharmacol. 1983; 23:227-33. [IDIS 172100] [PubMed 6308068]

123. Bauer JH, Jones LB. Comparative studies: enalapril versus hydrochlorothiazide as first-step therapy for the treatment of primary hypertension. Am J Kidney Dis. 1984; 4:55-64. [PubMed 6331157]

124. Bauer JH, Reams GP. Hemodynamic and renal function in essential hypertension during treatment with enalapril. Am J Med. 1985; 79(Suppl 3C):10-3. [IDIS 208147] [PubMed 2996341]

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