Enalaprilat Injection USP Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Enalaprilat Injection USP is indicated for:

• Treatment of hypertension when oral therapy is not practical.

Enalaprilat injection has been studied with only one other antihypertensive agent, furosemide, which showed approximately additive effects on blood pressure.

Due to insufficient experience with Enalaprilat injection in the treatment of accelerated or malignant hypertension, this drug is not recommended in such situations (see DOSAGE AND ADMINISTRATION).

The product should be administered under the supervision of a qualified health professional who is experienced in the use of antihypertension IV agents and in the management of patients with severe hypotension or heart failure. Appropriate management of therapy and complications is only possible when adequate diagnostic and treatment facilities are readily available.

Pediatrics (<16 years of age):

Enalaprilat Injection USP has not been studied in children and, therefore, use in this group is not recommended.

CONTRAINDICATIONS

Enalaprilat Injection USP is contraindicated in:

• Patients who are hypersensitive to this product or to any ingredient in its formulation. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.
• Patients with a history of angioneurotic edema relating to previous treatment with an angiotensin converting enzyme inhibitor.
• Patients with hereditary or idiopathic angioedema.

Concomitant use of angiotensin converting enzyme (ACE) inhibitors – including Enalaprilat Injection USP, with aliskiren-containing drugs in patients with diabetes mellitus (type 1 or type 2) or moderate to severe renal impairment (GFR < 60 mL/min/1.73m²) is contraindicated (see WARNINGS and PRECAUTIONS, Dual blockade of the Renin-Angiotensin System (RAS) and Renal and DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) with ACE inhibitors, ARBs, or aliskiren-containing drugs).

WARNINGS AND PRECAUTIONS

GENERAL

Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with Enalaprilat injection. This may occur at any time during treatment and may be life-threatening.

Very rarely, fatalities have been reported due to angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. However, where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy which may include subcutaneous adrenaline solution 1:1000 (0.3 mL to 0.5 mL) and/or measures to ensure a patient airway should be administered promptly when indicated.

If angioedema occurs, Enalaprilat Injection USP should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since this may be life-threatening and treatment with antihistamines and corticosteroids may not be sufficient.

In patients who experience angioedema, future administration is contraindicated (see

CONTRAINDICATIONS).

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in non-black patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see CONTRAINDICATIONS).

Anaphylactoid Reactions during Membrane Exposure: Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g. polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Anaphylactoid Reactions during Desensitization: There have been isolated reports of patients experiencing sustained life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasp) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least

24 hours, but they have reappeared upon inadvertent rechallenge.

Anaphylactoid Reactions during LDL Apheresis: Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL)-apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

CARDIOVASCULAR

Hypotension: Symptomatic hypotension has occurred after administration of Enalaprilat injection, usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision, usually in a hospital. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (see ADVERSE REACTIONS).

If hypotension occurs, the patient should be placed in supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion.

Valvular Stenosis: There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

ENDOCRINE AND METABOLISM

Hypoglycemia: Rare cases of hypoglycemia in diabetic patients on oral antidiabetic agents or insulin have been reported. Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycemia, especially during the first month of combined use. In addition, hypoglycemia appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment (see

ADVERSE REACTIONS).

HEMATOLOGIC

Neutropenia/Agranulocytosis: Agranulocytosis and bone marrow depression have been caused by angiotensin converting enzyme inhibitors. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and renal disease.

HEPATIC/BILIARY/PANCREATIC

Patients with Impaired Liver Function: There are no adequate studies in patients with cirrhosis and/or liver dysfunction. Enalaprilat Injection USP should be used with particular caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

Nitritoid Reactions - Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and symptomatic hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including

Enalaprilat injection (see DRUG INTERACTIONS).

Dual blockade of the Renin-Angiotensin System (RAS)

There is evidence that the co-administration of angiotensin converting enzyme (ACE) inhibitors, such as Enalaprilat Injection USP, or of angiotensin receptor antagonists (ARBs) with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe renal impairment (GFR < 60 mL/min/1.73m²). Therefore, the use of Enalaprilat Injection USP, in combination with aliskiren-containing drugs is contraindicated in these patients (see CONTRAINDICATIONS). Further, co-administration of ACE inhibitors, including Enalaprilat Injection USP, with other agents blocking the RAS, such as ARBs or aliskiren-containing drugs, is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure and hyperkalemia.

RENAL

Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

The use of ACE inhibitors – including Enalaprilat Injection USP – or ARBs with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment (GFR < 60 mL/min/1.73m²). (See CONTRAINDICATIONS and DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) with ARBs, ACE inhibitors, or aliskiren-containing drugs).

SPECIAL POPULATIONS

Pregnant Women: ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, Enalaprilat Injection USP should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations, have also been reported following exposure in the first trimester of pregnancy.

Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.

Animal Data

No reproductive or teratogenicity studies have been performed with Enalaprilat injection.

Pediatrics (<16 years of age): Enalaprilat Injection USP has not been studied in children and, therefore, use in this age group is not recommended.

ADVERSE REACTIONS

ENALAPRIL TABLET:

ADVERSE DRUG REACTION OVERVIEW

In controlled clinical trials involving 2314 hypertensive patients and 363 patients with congestive heart failure, the most severe adverse reactions were: angioedema (0.2%), hypotension (2.3%)

and renal failure (5 cases).

In hypertensive patients, hypotension occurred in 0.9% and syncope in 0.5%, with a discontinuation rate of 0.1%.

In congestive heart failure patients, hypotension occurred in 4.4% and syncope in 0.8%, with a discontinuation rate of 2.5%.

The most frequent clinical adverse reactions in controlled clinical trials were: headache (4.8%), dizziness (4.6%) and fatigue (2.8%). Discontinuation of therapy was required in 6.0% of the

2677 patients.

CLINICAL TRIAL ADVERSE DRUG REACTIONS - HYPERTENSION

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adverse experiences occurring in greater than one percent of patients with hypertension treated with enalapril tablets in controlled clinical trials are shown below. In patients treated with enalapril tablets, the maximum duration of therapy was three years; in placebo-treated patients the maximum duration of therapy was 12 weeks.

LESS COMMON CLINICAL TRIAL ADVERSE DRUG REACTIONS (<1%) - HYPERTENSION

Cardiovascular: Hypotension, chest pain, palpitations, acute myocardial infarction.

Digestive: Vomiting, dysphagia, abdominal pain.

Hematologic: Anemia, leukopenia.

Hypersensitivity: Angioedema.

Musculoskeletal: Muscle cramps.

Nervous System/Psychiatric: Insomnia, nervousness, somnolence, paresthesia.

Respiratory: Dyspnea.

Skin: Pruritus, hyperhidrosis.

Special Senses: Taste disturbance.

Urogenital: Renal failure, proteinuria, oliguria, impotence.

CLINICAL TRIAL ADVERSE DRUG REACTIONS – HEART FAILURE

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adverse experiences occurring in greater than one percent of patients with heart failure treated with enalapril tablets are shown below. The incidences represent the experiences from both controlled and uncontrolled clinical trials (maximum duration of therapy was approximately one year). In the placebo-treated patients, the incidences reported are from the controlled trials

(maximum duration of therapy is 12 weeks). The percentage of patients with severe heart failure

[New York Heart Association (NYHA) Class IV] was 29 percent and 43 percent for patients treated with enalapril tablets and placebo, respectively.

LESS COMMON CLINICAL TRIAL ADVERSE DRUG REACTIONS (<1%) – HEART FAILURE

Cardiovascular: Palpitations.

Musculoskeletal: Muscle cramps.

Nervous System/Psychiatric: Insomnia.

Skin: Pruritus.

Special Senses: Taste disturbance.

Urogenital: Renal failure, impotence.

ABNORMAL HEMATOLOGIC AND CLINICAL CHEMISTRY FINDINGS

Hyperkalemia: (See WARNINGS AND PRECAUTIONS, RENAL)

Creatinine, Blood Urea Nitrogen (BUN): Increases in serum creatinine and BUN were reported in about 20% of patients with renovascular hypertension and in about 0.2% of patients with essential hypertension treated with enalapril tablets alone.

In patients with congestive heart failure, who were also receiving diuretics and/or digitalis, increases in BUN and serum creatinine, usually reversible upon discontinuation of enalapril tablets and/or concomitant therapy, were observed in about 9.7% of patients.

Hemoglobin and Hematocrit: Decreases in hemoglobin and hematocrit (mean approximately

0.34 g% and 1.0 vol%, respectively) occurred frequently in either hypertensive or congestive heart failure patients treated with enalapril tablets, but were rarely of clinical importance. In clinical trials, less than 0.1% of patients discontinued therapy due to anemia.

Hepatic: Elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS

AND PRECAUTIONS).

Pediatric Patients: In a four-week placebo-controlled clinical trial, 110 hypertensive pediatric patients (6-16 years of age) received medication for 14 days including 51 patients for a four-week period. The adverse experience profile was no different from that seen in adult patients.

POSTMARKET ADVERSE DRUG REACTIONS

Adverse Reactions Reported in Uncontrolled Trials and/or Marketing Experience

Other serious clinical adverse experiences occurring since the drug was marketed or adverse experiences occurring in 0.5 to 1.0 percent of patients with hypertension or heart failure in clinical trials are listed below and, within each category, are in order of decreasing severity.

Body as a Whole

Anaphylactoid reactions (see WARNINGS AND PRECAUTIONS).

Cardiovascular

Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high-risk patients (see WARNINGS AND PRECAUTIONS);

pulmonary embolism and infarction; pulmonary edema; angina pectoris; arrhythmia including atrial tachycardia and bradycardia; atrial fibrillation; palpitation, Raynaud’s phenomenon.

Digestive

Ileus, pancreatitis, hepatic failure, hepatitis (hepatocellular or cholestatic jaundice), liver function abnormalities (see WARNINGS AND PRECAUTIONS), melena, anorexia, dyspepsia, constipation, glossitis, stomatitis, dry mouth.

Hematologic

Rare cases of neutropenia, thrombocytopenia, hemolytic anemia and bone marrow depression.

Metabolic

Rare cases of hypoglycemia in diabetic patients on oral antidiabetic agents or insulin have been reported (see WARNINGS AND PRECAUTIONS).

Musculoskeletal

Muscle cramps.

Nervous System/Psychiatric

Vertigo, depression, confusion, ataxia, somnolence, insomnia, nervousness, peripheral neuropathy (e.g. paresthesia, dysesthesia), dream abnormality.

Respiratory

Bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, upper respiratory infection, pulmonary infiltrates, eosinophilic pneumonitis.

Skin

Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, photosensitivity.

Special Senses

Blurred vision, taste alteration, anosmia, tinnitus, conjunctivitis, dry eyes, tearing, hearing impairment.

Urogenital

Renal failure, oliguria, renal dysfunction (see WARNINGS AND PRECAUTIONS and

DOSAGE AND ADMINISTRATION), flank pain, gynecomastia, impotence.

A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive antinuclear antibody (ANA), elevated erythrocyte sedimentation rate, eosinophilia and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may occur. These symptoms may be reversible upon discontinuation of therapy.

In very rare cases, intestinal angioedema has been reported with angiotensin converting enzyme inhibitors including enalapril.

Laboratory Test Findings: Hyponatremia

ENALAPRILAT INJECTION

ADVERSE DRUG REACTION OVERVIEW

Since enalapril is converted to enalaprilat, those adverse reactions associated with enalapril tablets might also be expected to occur with Enalaprilat Injection USP.

The incidence of symptomatic hypotension is 3.4% with Enalaprilat injection. Other adverse experiences occurring in greater than one percent of patients were headache (2.9%) and nausea (1.1%).

Adverse reactions occurring in 0.5 to 1.0% of patients in controlled clinical trials include myocardial infarct, fatigue, dizziness, fever, rash and constipation.

DRUG INTERACTIONS

DRUG-DRUG INTERACTIONS

Hypotension – Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalaprilat. The possibility of hypotensive effects with enalaprilat can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalaprilat (see WARNINGS AND

PRECAUTIONS and DOSAGE AND ADMINISTRATION). If the diuretic cannot be discontinued, patients should be placed under close medical supervision for at least one hour after the initial dose of Enalaprilat Injection USP (see WARNINGS AND PRECAUTIONS).

Agents Increasing Serum Potassium: Since enalaprilat decreases aldosterone production, elevation of serum potassium may occur. Potassium-sparing diuretics such as spironolactone, eplerenone, triamterene or amiloride, or potassium supplements should be given only for documented hypokalemia and with caution and frequent monitoring of serum potassium particularly in patients with impaired renal function since they may lead to a significant increase in serum potassium. Salt substitutes which contain potassium should also be used with caution.

Agents Causing Renin Release: The antihypertensive effect of Enalaprilat injection is augmented by antihypertensive agents that cause renin release (e.g. diuretics).

Agents Affecting Sympathetic Activity: Agents affecting sympathetic activity (e.g. ganglionic blocking agents or adrenergic neuron blocking agents) may be used with caution.

Lithium Salts: As with other drugs which eliminate sodium, lithium clearance may be reduced.

Therefore, the serum lithium levels should be monitored carefully if lithium salts are to be administered.

NonSteroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2

Inhibitors: In some patients with compromised renal function who are being treated with nonsteroidal anti-inflammatory drugs including selective cyclooxygenase-2 inhibitors, the coadministration of ACE inhibitors may result in further deterioration of renal function.

Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and symptomatic hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalaprilat (Enalaprilat injection) (see WARNINGS AND PRECAUTIONS).

Dual Blockade of the Renin-Angiotensin System (RAS) with ACE inhibitors, ARBs or aliskiren-containing drugs

Dual blockade of the Renin-Angiotensin System with ACE inhibitors, ARBs or aliskiren-containing drugs is contraindicated in patients with diabetes and/or renal impairment, and is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia. See CONTRAINDICATIONS and WARNINGS AND PRECAUIONS, Dual Blockade of the Renin-Angiotensin System (RAS).

DOSAGE AND ADMINISTRATION

Enalaprilat Injection USP is for Intravenous Administration Only

DOSING CONSIDERATIONS

• Special attention for dialysis patients.

RECOMMENDED DOSE AND DOSAGE ADJUSTMENT

The dose is 1.25 mg every six hours administered intravenously over at least five minutes. A clinical response is usually seen within 15 minutes. Peak effects after the first dose may not occur for up to four hours after dosing. The peak effects of the second and subsequent doses may exceed those of the first.

No dosage regimen for Enalaprilat injection has been clearly demonstrated to be more effective in treating hypertension than 1.25 mg every six hours. However, in controlled clinical studies in hypertension, doses as high as 5 mg every six hours were well tolerated for up to 36 hours. There has been inadequate experience with doses greater than 20 mg per day.

In studies of patients with hypertension, Enalaprilat injection has not been administered for periods longer than 48 hours. In other studies, patients have received Enalaprilat injection for as long as seven days. The dose for patients being converted to Enalaprilat injection from oral therapy for hypertension with enalapril is 1.25 mg every six hours administered intravenously over at least five minutes. For conversion from intravenous to oral therapy, the recommended initial dose of enalapril tablets is 5 mg once a day with subsequent dosage adjustments as necessary.

Patients on Diuretic Therapy: For patients on diuretic therapy the recommended starting dose for hypertension is 0.625 mg administered intravenously over at least five minutes. A clinical response is usually seen within 15 minutes. Peak effects after the first dose may not occur for up to four hours after dosing, although most of the effect is usually apparent within the first hour. If after one hour there is an inadequate clinical response, the 0.625 mg dose may be repeated.

Additional doses of 1.25 mg may be administered at six hour intervals.

For conversion from intravenous to oral therapy, the recommended initial dose of enalapril tablets for patients who have responded to 0.625 mg of enalaprilat every 6 hours is 2.5 mg once a day with subsequent dosage adjustments as necessary.

Dosage Adjustment in Renal Impairment: The usual dose of 1.25 mg of enalaprilat every six hours is recommended for patients with a creatinine clearance >30 mL/min [>0.50 mL/s] (serum creatinine of up to approximately 3 mg/dL [265.2 μmol/L]). For patients with creatinine clearance ≤30 mL/min [≤0.50 mL/s] (serum creatinine ≥3 mg/dL [≥265.2 μmol/L]), the initial dose is 0.625 mg (see WARNINGS AND PRECAUTIONS).

If after one hour there is an inadequate clinical response, the 0.625 mg dose may be repeated.

Additional doses of 1.25 mg may be administered at six hour intervals.

For dialysis patients, the initial dose should be 0.625 mg every six hours (see WARNINGS

AND PRECAUTIONS, Anaphylactoid Reactions during Membrane Exposure).

For conversion from intravenous to oral therapy, the recommended initial dose of enalapril tablets is 5 mg once a day for patients with creatinine clearance > 30 mL/min [> 0.50 mL/s] and 2.5 mg once daily for patients with creatinine clearance ≤ 30 mL/min [≤ 0.50 mL/s]. Dosage should then be adjusted according to blood pressure response.

ADMINISTRATION

Enalaprilat Injection USP may be administered intravenously as supplied, or mixed with up to 50 mL of one of the following diluents:

Dextrose Injection 5%

Sodium Chloride Injection 0.9%

Sodium Chloride Injection 0.9% in 5% Dextrose

Dextrose 5% in Lactated Ringer's Injection

Diluted solutions should be used within 24 hours.

Parenteral Products: As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitation, discolouration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

OVERDOSAGE

Limited data are available for overdosage in humans.

The recommended treatment of overdosage is intravenous infusion of normal saline solution.

Enalaprilat may be removed from the general circulation by hemodialysis (see WARNINGS

AND PRECAUTIONS, Anaphylactoid Reactions during Membrane Exposure).

ACTION AND CLINICAL PHARMACOLOGY

MECHANISM OF ACTION

Enalaprilat injection is an active metabolite of enalapril and is used in the treatment of hypertension.

Angiotensin converting enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to the pressor substance, angiotensin II. Enalaprilat is an ACE inhibitor.

Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release) and decreased aldosterone secretion. Although the latter decrease is small, it results in a small increase in serum potassium.

ACE is identical to kininase II. Thus, Enalaprilat injection may also block the degradation of bradykinin, a potent vasodepressor peptide. However, the role that this plays in the therapeutic effects of either drug is unknown.

While the mechanism through which Enalaprilat injection lowers blood pressure is believed to be primarily the suppression of the renin-angiotensin-aldosterone system, Enalaprilat injection also lowers blood pressure in patients with low-renin hypertension.

PHARMACODYNAMICS

Administration of Enalaprilat injection to patients with hypertension results in a reduction of both supine and standing blood pressure. Abrupt withdrawal of Enalaprilat injection has not been associated with a rapid increase in blood pressure. Following administration of Enalaprilat injection, the onset of action usually occurs within 15 minutes, with the maximum effect occurring within one to four hours. At recommended doses, the antihypertensive effect has been shown to be maintained for at least 24 hours. In some patients the effect may diminish towards the end of the dosing interval (see DOSAGE AND ADMINISTRATION). On occasion, achievement of optimal blood pressure reduction may require several weeks of therapy.

In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Studies in dogs indicate that enalaprilat does not enter the brain.

SPECIAL POPULATIONS AND CONDITIONS

Pediatrics: Enalaprilat injection has not been studied in children and, therefore, use in this age group is not recommended.

Race: The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black than in non-black patients.

Renal Insufficiency: The disposition of enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min

(0.50 mL/s) or less. With renal function ≤30 mL/min (≤0.50 mL/s), peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed.

Enalaprilat is dialyzable at the rate of 62 mL/min (1.03 mL/s).

STORAGE AND STABILITY

Store between 15 and 30°C. Protect from light. Multi-dose vial: discard 28 days after initial puncture.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Enalaprilat Injection USP 1.25 mg per mL, is a clear, colourless solution and is supplied in vials containing 2 mL.

Each millilitre of Enalaprilat Injection USP contains enalaprilat 1.25 mg (anhydrous equivalent), sodium chloride 6.2 mg to adjust tonicity, sodium hydroxide to adjust pH, benzyl alcohol 9 mg, as a preservative and water for injection q.s..

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Proper name: Enalaprilat

Chemical name: L-Proline, 1-[N-(1-carboxy-3-phenylpropyl)-L-alanyl]-,dihydrate, (S)-.

Molecular formula: C₁₈H₂₄N₂O₅•2H₂O

Molecular mass: 384.43 g/mol

Structural formula:

Physicochemical properties: Enalaprilat is a white to off-white, hygroscopic crystalline powder.

It is sparingly soluble in methanol and in dimethylformamide; slightly soluble in water and in isopropyl alcohol; very slightly soluble in acetone, in alcohol, and in hexane; practically insoluble in acetonitrile and in chloroform.

DETAILED PHARMACOLOGY

MECHANISM OF ACTION

EFFECTS ON BLOOD PRESSURE

OTHER EFFECTS

TOXICOLOGY

LD50 VALUES

^aMerck Sharp and Dohme Research Laboratories, West Point, PA, USA

^bNippon Merck-Banyu Co., Menuma, Japan

Signs of Toxicity: ptosis, decreased activity, bradypnea, loss of righting, ataxia, dyspnea, and clonic convulsions.

SUBACUTE AND CHRONIC TOXICITY

MUTAGENICITY STUDIES

Enalapril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation, in the Rec-Assay, sister chromatid exchange with cultured Chinese hamster cells, (up to 20 mg/mL) and the micro-nucleus test with mice.

In vitro chromosomal aberration test showed enalapril was clastogenic at 10 and 20 mg/mL but not at 5 mg/mL.

CARCINOGENICITY STUDIES

There was no evidence of a carcinogenic effect when enalapril was administered for 106 weeks to rats (Charles River CD-1) at doses up to 90 mg/kg/day (150 times the maximum daily human dose).

Enalapril has also been administered for 94 weeks to male and female mice (Charles River

CD-1) at doses up to 90 and 180 mg/kg/day, respectively, (150 and 300 times the maximum daily dose for humans) and no evidence of carcinogenicity was noted.

REFERENCES

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4. 4. Brunner DB, Desponds G, Biollaz J, Keller I, Ferber F, Gavras H, Brunner HR, Schelling JL. Effect of a new angiotensin converting enzyme inhibitor MK-421 and its lysine analogue on the components of the renin system in healthy subjects. Br J Clin Pharmacol 1981;11:461-7.
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6. 6. Cleland JGF, Dargie HJ, McAlpine H, Ball SG, Morton JJ, Robertson JIS, Ford I. Severe hypotension after first dose of enalapril in heart failure. Br Med J 1985;291:1309-12.
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