VASOTEC (Brand for ENALAPRIL MALEATE)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-May administer without regard to meals.
Oral Liquid Formulations
-Use a calibrated device to measure the appropriate oral dosage of enalapril.

Ready-to-use Oral Solution
-Solution contains enalapril 1 mg/mL.
-Storage: Store refrigerated (2 to 8 degrees C or 36 to 46 degrees F) in a tightly closed container. Patients may store at room temperature (20 to 25 degrees C or 68 to 77 degrees F) for up to 60 days.
Powder for Oral Solution
-Final concentration after reconstitution is 1 mg/mL.
-Prior to reconstitution, tap the bottle of enalapril powder 5 times to loosen the powder.
-Add approximately one-half (75 mL) of the provided diluent (Ora-Sweet SF) to the bottle of enalapril powder, and shake vigorously for 30 seconds.
-Add the remainder of the provided diluent and shake vigorously for an additional 30 seconds.
-Storage: The reconstituted solution is stable for 60 days at room temperature (25 degrees C or 77 degrees F).

Extemporaneous Compounding-Oral
Extemporaneous Oral Suspension Formulations
NOTE: An FDA-approved oral solution is commercially available; commercially available products are preferred over compounded products when available.

An oral suspension yielding 1 mg/mL may be prepared using the following procedure:
-Add 10 mL of Bicitra to a PET bottle containing two 20 mg enalapril tablets.
-Shake bottle manually for at least 5 minutes.
-Allow to stand at room temperature for 20 minutes.
-Add 30 mL of Ora-Sweet SF and shake manually for roughly 2 minutes.
-Storage: According to the authors, data on file indicate stability of this suspension for 4 weeks at 5 degrees C with ambient relative humidity.
-While other extemporaneous formulations have been reported , this formulation appears to have greater stability and achieves a concentration for ease of use and dosage titration.

The manufacturer of Vasotec tablets recommends the following procedure to prepare a greater quantity (200 mL) of a 1 mg/mL suspension:
-Add 50 mL of Bicitra to a PET bottle containing ten (10) Vasotec 20 mg tablets and shake for at least 2 minutes.
-Let concentrate stand for 60 minutes; after standing, shake the concentrate for an additional minute.
-Add 150 mL of Ora-Sweet SF and shake the suspension to disperse the ingredients.
-Storage: The resultant suspension is stable for 30 days when refrigerated at 2 to 8 degrees C (36 to 46 degrees F).



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-May be administered undiluted or in up to 50 mL of a compatible IV infusion solution.
-Administer by slow, direct IV infusion over a period of at least 5 minutes.

Preparation and Stability of Enalaprilat Dilutions for Parenteral Administration
-Prepare in a sterile environment, using aseptic technique.
-Each dose should be diluted with no more than 50 mL of compatible solution for intravenous administration.
-Enalaprilat injection may be diluted with the following solutions for intravenous administration: 5% Dextrose Injection, 0.9% Sodium Chloride Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and Lactated Ringer's Injection.
-Dilutions made with these solutions maintain full activity for at least 24 hours at room temperature.
-For a 25 mcg/mL dilution often used in neonatal or small pediatric patients: combine 1 mL of enalaprilat 1.25 mg/mL and 49 mL of compatible solution for intravenous administration.

Specific incidences of adverse reactions in pediatric patients are not available from the manufacturer; however, the manufacturer states that the adverse reaction profile of enalapril in pediatric patients appears to be similar to that seen in adults.

Blood dyscrasias have rarely been associated with enalapril. Rare cases of neutropenia, thrombocytopenia, and bone marrow suppression have been reported with enalapril use. Agranulocytosis has also been associated with ACE-inhibitor use, including enalapril. Patients with renal impairment or collagen vascular disease appear to be at highest risk. Hemolytic anemia, including cases of hemolysis in patients with G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded. Small decreases in hemoglobin and hematocrit occur frequently but are rarely clinically significant unless another cause of anemia is also present. Monitor complete blood counts regularly during the first several months of therapy and as needed thereafter.

Renal dysfunction may occur during enalapril treatment, but this effect is usually reversible if therapy is discontinued. Renal failure (unspecified), azotemia, oliguria, and flank pain have been reported during enalapril use. Patients with severe heart failure whose renal function may depend on the renin-angiotensin-aldosterone system are at risk for renal impairment with ACE-inhibitor use. Some patients with hypertension or heart failure and no prior evidence of renal impairment may experience elevations in serum creatinine and blood urea nitrogen; these elevations are usual mild and transient. Renal insufficiency may be related to hypovolemia, low serum sodium concentrations, or preexisting renal artery stenosis. In patients who are either hypovolemic or have a low serum sodium, correction of these abnormalities may correct the renal dysfunction. Although rare, serious renal effects include ischemic renal tubular necrosis and glomerulonephritis.

Hypotension occurred in 0.9% of patients in clinical trials of enalapril for hypertension and in 6.7% of patients receiving the drug for congestive heart failure. Hypotension occurred in 3.4% of patients who received IV enalaprilat in clinical trials. Syncope was reported in 0.5-2.2% of patients receiving enalapril for hypertension or heart failure. Chest pain (unspecified) was reported in 2.1% of enalapril-treated patients in clinical trials of patients with heart failure; this is the same incidence as those who received placebo. Orthostatic hypotension (1.6%) and orthostatic effects (1.2-2.2%), angina pectoris (1.5%, heart failure only), and myocardial infarction (0.5-1.2%) were reported in patients during controlled clinical trials. Of note, angina and myocardial infarction occurred at a lower rate in the enalapril group than in the placebo group during trials of oral enalapril. Other cardiovascular-related adverse reactions occurring in 0.5-1% of patients or during post-marketing use include: cardiac arrest, cerebrovascular accident (stroke), pulmonary embolism and infarction, pulmonary edema, arrhythmias (including atrial tachycardia, bradycardia, and atrial fibrillation), palpitations, and Raynaud's phenomenon.

Cough was reported in 1.3%-2.2% of enalapril-treated patients in clinical trials. ACE inhibition can result in the accumulation of kinins in the respiratory tract, sometimes causing a persistent, nonproductive cough. However, accumulation of kinins does not adequately explain the mechanism of ACE inhibitor-induced cough. Kinins have a very short plasma half-life, therapeutic doses of ACE inhibitors are usually not high enough to cause accumulation of circulating bradykinin, and there is a female preponderance of cases. Rather, evidence is growing that ACE inhibitor-induced cough may be related to substance P stimulation of C-fiber receptors in the respiratory tract. This cough may occur more frequently in patients with chronic obstructive pulmonary disease and is often overlooked as a potential adverse effect of enalapril therapy. Dyspnea (1.3%), bronchitis (1.3%), and pneumonia (1%, which was less than placebo) have also have been reported during enalapril clinical trials. Other respiratory-related adverse events occurring in 0.5%-1% or during post-marketing use of enalapril include: eosinophilic pneumonia, pulmonary infiltrates, bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, and upper respiratory infection.

In clinical trials of enalapril for hypertension, approximately 1% of enalapril-treated patients developed elevated serum potassium (> 5.7 mEq/L); 0.28% of these patients discontinued therapy due to hyperkalemia. In heart failure patients, hyperkalemia was observed in 3.8% of patients but was not a cause for discontinuation. Patients with renal impairment, diabetes, heart failure, and those receiving other medications that may increase potassium concentrations are at the highest risk of developing hyperkalemia. Although less common, hyponatremia has also been reported with enalapril use.

Enalapril therapy has been associated with rash (unspecified) in approximately 0.5%-1.4% of enalapril/enalaprilat-treated patients in clinical trials. Enalapril has also been associated with acute generalized exanthematous pustulosis (AGEP). The nonfollicular, pustular, erythematous rash starts suddenly and is associated with a temperature above 38 degrees C. Drugs are the main cause of AGEP. A period of 2-3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP. Unintentional reexposure may cause a second episode within 2 days. Other dermatologic adverse reactions that have been reported in association with enalapril use include: exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, and photosensitivity.

Anaphylactoid reactions and angioedema are uncommon but serious adverse reactions known to be related to enalapril therapy. This is likely due to the inhibitory effect of ACE inhibitors on eicosanoid and polypeptide metabolism, including bradykinin metabolism. Angioedema, or angioneurotic edema, of the face, edema of the extremities, mucous membranes, tongue, lips, larynx (laryngeal edema), and glottis has occurred rarely during ACE inhibitor therapy but is reversible following discontinuance of the drug. Involvement of the upper respiratory tract can induce acute respiratory distress. The onset usually occurs within hours or at most 1 week after starting ACE inhibitor therapy, but may occur at any time during therapy. The mechanism is unknown but may involve drug-induced auto-antibodies, bradykinin accumulation, dysregulation of the complement system, or histamine. Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-Black patients. If angioedema occurs during therapy with enalapril, discontinue the drug immediately. Provide appropriate monitoring and therapy until signs and symptoms have resolved completely. Angioedema associated with laryngeal edema or tongue edema may be fatal. If there is involvement of the tongue, glottis or larynx, provide appropriate therapy (e.g., subcutaneous epinephrine 1:1000) and/or measures to ensure a patent airway. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Rarely, intestinal angioedema has been reported during post-marketing experience with ACE inhibitors. Patients with intestinal angioedema may present with abdominal discomfort. In some cases there is no prior history of facial angioedema and C-1 esterase levels are normal. Intestinal angioedema can be diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery. Symptoms resolve after stopping the ACE inhibitor. Include intestinal angioedema in the differential diagnosis of patients receiving ACE inhibitors who present with abdominal discomfort.

Gastrointestinal-related adverse events reported in enalapril-treated patients in clinical trials include: abdominal pain (1.6%), diarrhea (1.4%-2.1%), nausea (1.3%-1.4%), and vomiting (1.3%). Other less common gastrointestinal-related adverse events reported in enalapril-treated patients include: ileus, pancreatitis, melena, anorexia, dyspepsia, constipation (0.5%-1% for IV, incidence unknown for oral formulation), glossitis, stomatitis, and xerostomia. In addition, abdominal pain (with or without nausea and vomiting) is a presenting symptom of intestinal angioedema; consider intestinal angioedema in the differential diagnosis of patients presenting with abdominal pain.

Rarely, hepatitis and hepatic failure have been reported in patients receiving ACE inhibitors such as enalapril. Although not completely understood, hepatotoxicity has included cholestasis with jaundice, fulminant hepatic necrosis, and death. Discontinue enalapril in patients who develop jaundice, hyperbilirubinemia, or significantly elevated hepatic enzymes and institute appropriate follow-up and treatment.

Nervous system/psychiatric-related adverse events occurring in enalapril-treated patients during clinical trials include: fatigue (0.5%-3%), dizziness (0.5%-7.9%), headache (1.8%-5.2%) and vertigo (1.6%). Other less common nervous system/psychiatric-related adverse events include: depression, confusion, ataxia, drowsiness, insomnia, nervousness, peripheral neuropathy (e.g., paresthesias, dysesthesia), and abnormal dreams (e.g., nightmares). Fever has been reported in 0.5%-1% of patients who received IV enalaprilat during clinical trials. Fever may also be a symptom of a more serious condition such as neutropenia or as part of a symptom complex associated with enalapril use that includes a variety of symptoms; carefully evaluate patients who present with fever.

Asthenia (1.1%-1.6%) and muscle cramps (incidence unknown) have been reported in enalapril-treated patients.

Blurred vision, dysgeusia, anosmia, tinnitus, conjunctivitis, xerophthalmia, and tearing have been reported in enalapril-treated patients (incidence unknown).

Urinary tract infection was reported in 1.3% of patients in clinical trials of enalapril for heart failure. Gynecomastia has been reported in enalapril-treated patients (incidence unknown).

A symptom complex has been reported in enalapril-treated patients which may include some or all of the following: a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations.

Enalapril is contraindicated in patients with a history of angiotensin-converting enzyme inhibitors (ACE inhibitors) hypersensitivity. Angiotensin-converting enzyme inhibitors (ACE inhibitors) hypersensitivity usually manifests as a result of alterations in kinin generation in sensitive individuals; there is no evidence of a specific immune-mediated reaction. However, such reactions can be potentially life-threatening, even if they are not true 'allergic' reactions. Enalapril is contraindicated in patients with a history of ACE-inhibitor induced angioedema, hereditary angioedema, or idiopathic angioedema. If angioedema occurs, discontinue ACE inhibitor therapy and initiate appropriate treatment. The incidence of ACE inhibitor-induced angioedema is higher in Black patients than non-Black patients. In addition, ACE inhibitors are less effective in lowering blood pressure in Black patients.

Treatment with ACE inhibitors, such as enalapril, may increase the risk of anaphylactoid reactions in patients undergoing hymenoptera venom (insect sting) allergy desensitization. Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. However, a retrospective analysis of 79 patients who underwent hymenoptera venom (insect sting) allergy desensitization did not show an association between ACE inhibitor therapy and increased frequency of systemic reactions to venom immunotherapy. Of 17 patients taking an ACE inhibitor while undergoing desensitization, none experienced a systemic reaction to venom immunotherapy; whereas, 13 of 62 patients not taking an ACE inhibitor experienced a systemic reaction during venom immunotherapy. Anaphylactoid reactions have been reported in patients taking ACE inhibitors who were receiving dialysis with high-flux membranes; the mechanism is unknown. When anaphylactoid symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath, or low blood pressure are recognized, stop the dialysis and initiate aggressive treatment for the hypersensitivity reaction. Anaphylactoid reactions have also occurred in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption (a procedure dependent upon devices not approved in the United States). Although a causal relationship to ACE inhibitor therapy has not been firmly established, treatment with enalapril may increase the risk for anaphylactoid reactions during membrane exposure. ACE inhibitors may also precipitate low blood pressure in dialysis patients who are volume-depleted.

Use enalapril with caution in patients who exhibit hypotension. Hypotension can occur if enalapril is administered to patients with hypovolemia or hyponatremia, or to patients receiving dialysis, diuretics or other antihypertensives. Use enalapril cautiously in patients with congestive heart failure (initial doses should be lower than in the treatment of hypertension) because of a greater risk of developing hypotension. Hypotension may aggravate ischemia in patients with coronary artery disease or cerebrovascular disease precipitating a myocardial infarction or cerebrovascular accident. Use enalapril with caution in patients with aortic stenosis or hypertrophic cardiomyopathy. As with all vasodilators, give ACE inhibitors with caution to patients with obstruction in the outflow tract of the left ventricle.

Enalapril is a prodrug and its conversion to its active metabolite, enalaprilat, may be delayed in patients with hepatic disease. The delay is not expected to be clinically significant in patients with stable, modest hepatic impairment; however, patients with severe hepatic impairment (e.g., cirrhosis) may not be able to adequately convert enalapril to enalaprilat. In these patients, it may be prudent to choose an ACE inhibitor that does not require hepatic activation (e.g., captopril, lisinopril).

In patients undergoing major surgery or during anesthesia with agents that lower blood pressure, enalapril may block angiotensin II formation secondary to compensatory renin release. Therefore, use enalapril with caution prior to surgery. If hypotension occurs during surgery and/or anesthesia and is considered to be due to blockade of angiotensin II formation, it can be corrected by volume expansion.

Correct electrolyte imbalances in patients with pre-existing hyperkalemia or hypokalemia before enalapril is initiated. ACE inhibitors can elevate serum potassium concentrations and could worsen the pre-existing condition. Hyperkalemia may be associated with serious cardiac arrhythmias. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes. Monitor patients with these risk factors closely for hyperkalemia.

According to the manufacturer, enalapril is not recommended for use in pediatric patients with GFR < 30 ml/min/1.73m2 since data are unavailable. Dosage adjustment of enalapril is recommended in adult patients with moderate to severe renal impairment or renal failure (i.e., CrCl <= 30 mL/min). Treatment with ACE inhibitors has demonstrated favorable effects on the progression of renal disease in diabetic and nondiabetic patients; however, minor increases in BUN and serum creatinine may occur. These effects, more commonly reported in patients with renal artery stenosis or those receiving concomitant diuretic therapy, are usually reversible and are not considered a reason to withhold therapy unless accompanied by hyperkalemia. If enalapril is initiated in patients with renal artery stenosis, monitor renal function during the first few weeks of therapy. Neutropenia and/or agranulocytosis have been reported during therapy with ACE inhibitors. This effect rarely occurs in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen-vascular disease (e.g., systemic lupus erythematosus (SLE) or scleroderma) or are receiving concomitant immunosuppression. Data from clinical trials of enalapril are insufficient to show that the drug does not cause agranulocytosis. Therefore, establish complete blood counts prior to and during enalapril therapy whenever the drug is administered to patients with pre-existing renal disease or autoimmune disease. Use enalapril with caution in patients with pre-existing bone marrow suppression.

Use of enalapril is not recommended in neonates and premature neonates who have not reached a corrected post-conceptual age of 44 weeks. It is unknown whether postnatal use of ACE inhibitors before maturation of renal function is complete has long-term deleterious effects on the kidney. Nephrogenesis is thought to be complete around birth; however, maturation of kidney function (e.g., glomerular filtration, tubular function) may continue until approximately 2 years of age. In addition, for unknown reasons, neonates and infants have an increased sensitivity to ACE inhibitors which makes them susceptible to prolonged or excessive decreases in blood pressure. It has been theorized this may be due to higher renin concentrations in the first few months of life and an increased dependence on the renin-angiotensin system and/or decreased drug clearance due to immature elimination systems.

Closely observe neonates with in utero exposure to enalapril for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occur, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required to reverse hypotension and/or support renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.

Description: Enalapril is an oral and parenteral angiotensin-converting enzyme (ACE) inhibitor used in the treatment of hypertension. Enalapril is longer-acting than captopril but shorter-acting than other ACE inhibitors and is usually dosed twice daily when given orally. In some patients, once-daily dosing may be acceptable. Neither enalapril nor enalaprilat contains a sulfhydryl group, which has implications regarding the drug's adverse reaction profile. In children with hypertension and chronic kidney disease, proteinuria, or diabetes mellitus, an ACE inhibitor (or angiotension receptor blocker) is recommended as the initial antihypertensive agent unless there is an absolute contraindication. In general, ACE inhibitors appear to have a lesser effect on blood pressure in Black patients (low renin population) than in non-Black patients; a higher initial dose or alternative initial therapy (e.g., thiazide diuretic, long-acting calcium channel blocker) may be considered in this population. Oral enalapril is FDA-approved for pediatric patients as young as 1 month of age; enalaprilat injection is not FDA-approved in pediatric patients.

For the treatment of hypertension:
Oral dosage:
Infants, Children, and Adolescents 16 years and younger: 0.08 mg/kg PO once daily (Max: 5 mg) initially; adjust dosage based on clinical response. Max: 0.6 mg/kg/day, up to 40 mg/day, given in 1 to 2 divided doses. In patients with hyponatremia, hypovolemia, moderate-severe congestive heart failure, renal dysfunction, or in those receiving diuretics, a lower initial maximum dose of 2.5 mg is recommended. In patients at risk for hypotension or deterioration of renal function, dosage increases are generally recommended at intervals of 4 days or more.
Adolescents 17 years: 5 mg PO once daily initially. The usual dosage range is 10 to 40 mg/day PO, given in 1 to 2 divided doses. In patients with hyponatremia, hypovolemia, moderate-severe congestive heart failure, renal dysfunction (i.e., Scr greater than 1.6 mg/dL), or in those receiving diuretics, an initial dose of 2.5 mg is recommended. In patients at risk for hypotension or deterioration of renal function, dosage increases are generally recommended at intervals of 4 days or more. If blood pressure is not controlled with monotherapy, a diuretic may be added.
Intravenous dosage* (enalaprilat):
Neonates, Infants, Children, and Adolescents: 5 to 10 mcg/kg/dose IV every 8 to 24 hours (determined by blood pressure readings) (Max: 1.25 mg/dose). Monitor blood pressure and urine output carefully due to the risk of prolonged hypotension and acute renal failure, especially in neonates; select patients may require higher doses.

For the treatment of hypertensive emergency* or hypertensive urgency*:
Intravenous dosage (enalaprilat):
Neonates: 5 to 10 mcg/kg/dose (Max: 1.25 mg) IV every 8 to 24 hours (determined by blood pressure readings). Monitor blood pressure and urine output carefully due to the risk of prolonged hypotension and acute renal failure, especially in neonates; select patients may require higher doses.
Infants, Children, and Adolescents: 5 to 10 mcg/kg/dose (Max: 1.25 mg) IV every 8 to 24 hours (determined by blood pressure readings). Monitor blood pressure and urine output carefully due to the risk of prolonged hypotension and acute renal failure; select patients may require higher doses.
Oral dosage (hypertensive urgency only):
Infants, Children, and Adolescents: 0.08 mg/kg/dose PO (Max: 5 mg) once daily initially; adjust dosage based on clinical response. Max: 0.6 mg/kg/day, up to 40 mg/day, given in 1 to 2 divided doses.

For the treatment of congestive heart failure (CHF)*:
Oral dosage:
Neonates: The manufacturer recommends against use in neonates due to the lack of data. Very limited data describe the use of 0.01 to 0.27 mg/kg/day PO in neonates and infants; however, there are concerns about the risk for adverse effects. Cases of acute hypotension and acute renal failure have been reported after doses of 0.1 mg/kg/day PO in hypertensive infants; therefore, conservative initial dosages and careful monitoring of blood pressure and renal function are recommended. As part of a small pediatric study (total n = 63 patients), 15 infants ages 9 days to 9 months with left-to-right shunts received enalapril; all but 1 patient in this group was younger than 4 months old (neonatal-specific data was not reported separately). Four patients improved while receiving enalapril (mean dosage = 0.19 mg/kg/day PO), 6 patients experienced no change in clinical status (mean dosage = 0.27 mg/kg/day PO), and 5 patients discontinued enalapril due to adverse events (mean dosage = 0.11 mg/kg/day PO). Eight patients in the entire cohort developed renal failure within 14 days of initiating enalapril (7 of the 8 developed renal failure within 5 days); 3 of these patients were 4 weeks or younger and all 3 died. In another case series, doses of 0.1 to 0.16 mg/kg/day PO were used in 3 neonatal patients with CHF without adverse events.
Infants, Children, and Adolescents: In 39 children, after a test dose, enalapril was titrated to a dose of 0.16 mg/kg/day PO by the end of the first week. Subsequently, the mean dose required for improvement in CHF was 0.36 mg/kg/day PO. In select cases, dosages up to 0.94 mg/kg/day PO have been used. A maximum dose for this indication has not been determined; however, the maximum for pediatric patients with hypertension is 40 mg/day PO.

For the treatment of proteinuria* in pediatric patients:
Oral dosage (weight-based dosing):
Children and Adolescents: 0.07 to 0.7 mg/kg/day PO given in 1 to 2 divided doses. Begin with a low dose and titrate every 4 to 12 weeks based on clinical response and patient tolerance. Max: 20 to 40 mg/day.
Oral dosage (fixed dosing):
Children and Adolescents 7 to 17 years: 2.5 to 5 mg/day PO decreased proteinuria with no significant effects on blood pressure in a retrospective study in normotensive patients when used with (n = 11) or without (n = 17) prednisone. In a small case study of adolescents with sickle nephropathy (n = 3), initial treatment was 5 mg/day; 1 patient required a dosage increase to 7.5 mg/day due to weight gain during puberty.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, doses up to 0.27 mg/kg/day PO and 10 mcg/kg/dose IV have been used off-label.
-Infants
0.6 mg/kg/day PO for hypertension; however, doses as high as 0.94 mg/kg/day PO have been used off-label for congestive heart failure; safety and efficacy of IV enalaprilat has not been established; however doses up to 10 mcg/kg/dose IV have been used off-label.
-Children
0.6 mg/kg/day PO (Max: 40 mg/day PO) for hypertension; doses of up to 0.94 mg/kg/day PO have been used off-label for congestive heart failure; safety and efficacy of IV enalaprilat has not been established; however, doses up to 10 mcg/kg/dose IV (Max: 1.25 mg/dose IV) have been used off-label.
-Adolescents
13 to 16 years: 0.6 mg/kg/day PO (Max: 40 mg/day PO) for hypertension; doses of up to 0.94 mg/kg/day PO have been used off-label for congestive heart failure; safety and efficacy of IV enalaprilat has not been established; however, doses up to 10 mcg/kg/dose IV (Max: 1.25 mg/dose IV) have been used off-label.
17 years: 40 mg/day PO for hypertension; safety and efficacy of IV enalaprilat has not been established; however, doses up to 10 mcg/kg/dose IV (Max: 1.25 mg/dose IV) have been used off-label.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Use is not recommended in pediatric patients with a GFR less than 30 mL/minute/1.73 m2, as no data is available per FDA-approved labeling. Alternatively, the following has been recommended:
GFR more than 50 mL/minute/1.73 m2: No adjustment necessary.
GFR 10 to 50 mL/minute/1.73 m2: Administer 75% of usual dose.
GFR less than 10 mL/minute/1.73 m2: Administer 50% of usual dose.

Intermittent hemodialysis (IHD)

Administer 50% of usual dose.

Peritoneal dialysis (PD)
Administer 50% of usual dose.

Continuous renal replacement therapy (CRRT)
Administer 75% of usual dose.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Enalapril competes with the natural substrate, angiotensin I, thereby inhibiting its conversion to angiotensin II. Angiotensin II is a potent vasoconstrictor and a negative feedback mediator for renin activity. Thus, when enalapril lowers angiotensin II plasma levels, blood pressure decreases and plasma renin activity increases. In addition, baroreceptor reflex mechanisms are stimulated in response to the fall in blood pressure. Kininase II, identical to ACE, is an enzyme that degrades bradykinin, a potent vasodilator, to inactive peptides. Whether increased bradykinin levels play a part in the therapeutic effects of ACE inhibitors is presently unclear. Bradykinin-induced vasodilation is thought to be of secondary importance in the blood-pressure lowering effect of ACE inhibitors. A bradykinin mechanism may, however, contribute to ACE-inhibitor-induced angioneurotic edema.

ACE-inhibiting drugs can act locally to reduce vascular tone by decreasing local angiotensin II-induced sympathetic and/or vasoconstrictive activity. ACE inhibitors also can inhibit presynaptic norepinephrine release and postsynaptic adrenergic receptor activity, decreasing vascular sensitivity to vasopressor activity; however, this action may not be clinically evident at usual doses. Decreases in plasma angiotensin II levels also reduce aldosterone secretion, with a subsequent decrease in sodium and water retention. As antihypertensives, ACE inhibitors reduce LVH and do not worsen insulin resistance or hyperlipidemia.

Enalapril causes arterial dilation, thereby lowering total peripheral vascular resistance. In hypertensive patients, blood pressure is decreased with little or no change in heart rate, stroke volume, or cardiac output. However, in patients with heart failure, enalapril increases cardiac output, cardiac index, stroke volume, and exercise tolerance. The drug also decreases pulmonary wedge pressure, pulmonary vascular resistance, and mean arterial and right atrial pressures in these patients.

Pharmacokinetics: Enalapril is administered orally and enalaprilat is administered parenterally. Enalapril maleate is a prodrug; it is converted by hydrolysis of the ethyl ester to enalaprilat, the active drug. Animal studies indicate that enalapril crosses the blood-brain barrier poorly, if at all. Enalaprilat does not enter the brain. Excretion of enalapril and enalaprilat is primarily renal. Approximately 94% of a dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat (accounting for about 40% of the dose) and intact enalapril. The half-life of enalaprilat after multiple doses of enalapril is about 11 hours.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
After oral administration, peak serum concentrations are achieved within about 1 hour. The extent of absorption is approximately 60%. Peak serum concentrations of enalaprilat occur 3 to 4 hours after an oral dose of enalapril maleate. In most patients, the onset of antihypertensive activity after a single dose of enalapril occurs about 1 hour after administration, with peak reductions in blood pressure achieved by 4 to 6 hours. At recommended doses, the antihypertensive effect of enalapril monotherapy is maintained for at least 24 hours in many patients. However, in some patients, the effect diminishes towards the end of the 24-hour dosing interval. The pharmacokinetics of enalapril oral solution are similar to that of the tablets.

Intravenous Route
The onset of antihypertensive activity usually occurs within 15 minutes of administration, with peak reductions in blood pressure achieved within 1 to 4 hours. At recommended doses, the antihypertensive effect of enalaprilat is maintained for approximately 6 hours.


-Special Populations
Pediatrics
Neonates
The mean half-lives of enalapril and enalaprilat in 3 term neonates less than 20 days old with congestive heart failure receiving oral enalapril 0.1 to 0.14 mg/kg/day were 10.3 +/- 5.2 hours and 11.9 +/- 5.3 hours, respectively. The mean AUC per dose normalized for body surface area for enalapril and enalaprilat was 197.6 +/- 123.2 ng x hour/mL per 1 mg/m2 and 497.8 +/- 196.4 ng x hour/mL per 1 mg/m2, respectively. Peak serum concentrations of enalapril and enalaprilat occurred at 12 hours in 2 patients and 8 hours in 1 patient.

Infants, Children, and Adolescents
The mean half-lives of enalapril and enalaprilat in 11 infants and children 1 month to 6.5 years with congestive heart failure receiving oral enalapril 0.05 to 0.3 mg/kg/day were 2.7 +/- 1.4 hours and 11.1 +/- 4.3 hours, respectively; this was significantly different than the values seen in healthy adult volunteers for enalapril (1.4 +/- 1 hours) and enalaprilat (5.3 +/- 1.6 hours). The mean AUC per dose normalized for body surface area for enalapril and enalaprilat were 51.1 +/- 30 ng x hour/mL per 1 mg/m2 and 83.1 +/- 47 ng x hour/mL per 1 mg/m2, respectively; this was significantly different than the values seen in healthy adult volunteers for enalapril (21.7 +/- 8.6 ng x hour/mL per 1 mg/m2, p < 0.05) but not for enalaprilat (64.6 +/- 17.8 ng x hour/mL per 1 mg/m2). In a multiple dose pharmacokinetic study in 40 pediatric patients (2 months to 15 years) with hypertension receiving oral enalapril, the median half-life for accumulation was 14.6 to 16.3 hours. Peak serum concentrations of enalapril and enalaprilat were observed at approximately 1 hour and 3 to 4 hours, respectively. Infants and children 2 months to 6 years required slightly higher weight-based doses (0.13 mg/kg and 0.11 mg/kg) compared to the older age group (0.11 mg/kg and 0.07 mg/kg) to achieved a similar AUC at steady state.

Renal Impairment
Renal insufficiency prolongs the elimination of enalaprilat. The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is reduced <= 30 mL/minute. With glomerular filtration rate <= 30 mL/minute, peak and trough enalaprilat levels increase, time to peak concentration increases, the time to steady state may be delayed, and the effective elimination half-life of enalaprilat is prolonged. Enalaprilat is hemodialyzable at a rate of 62 mL/minute. Administering enalapril 1 hour after hemodialysis reduces enalaprilat AUC by approximately 50% compared to off-dialysis days. Enalapril can been removed from neonatal circulation by peritoneal dialysis.