Ava-Enalapril Product Monograph

SUMMARY PRODUCT INFORMATION

*the splitting of Ava-Enalapril is not recommended.

INDICATIONS AND CLINICAL USE

AVA-ENALAPRIL (enalapril maleate) is indicated for:

• essential or renovascular hypertension
• treatment of symptomatic congestive heart failure

Hypertension

AVA-ENALAPRIL is indicated in the treatment of essential or renovascular hypertension. It is usually administered in association with other drugs, particularly thiazide diuretics. In using AVA-ENALAPRIL consideration should be given to the risk of angioedema (see WARNINGS AND PRECAUTIONS).

Geriatrics (>65 years of age): See DOSAGE AND ADMINISTRATION.

Pediatrics (<16 years of age): AVA-ENALAPRIL may be used in children (see DOSAGE AND ADMINISTRATION).

Congestive Heart Failure

AVA-ENALAPRIL is indicated in the treatment of symptomatic congestive heart failure usually in combination with diuretics and/or digitalis. In these patients, AVA-ENALAPRIL improves symptoms, increases survival, and decreases the frequency of hospitalization (see CLINICAL TRIALS for details and limitations of survival trials). Treatment with AVA-ENALAPRIL should be initiated under close medical supervision.

In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction ≤ 35%), enalapril decreases the rate of development of overt heart failure and decreases the incidence of hospitalization for heart failure.

CONTRAINDICATIONS

AVA-ENALAPRIL is contraindicated in:

• Patients who are hypersensitive to these products or to any ingredient in their 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.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

• When used in pregnancy, angiotensin converting enzyme (ACE) inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected, AVA-ENALAPRIL should be discontinued as soon as possible.

General

Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with enalapril. 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 patent airway should be administered promptly when indicated.

If angioedema occurs, AVA-ENALAPRIL 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 sulfate 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 enalapril, 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.

Ear/Nose/Throat

Cough: A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of enalapril has been reported.

Such possibility should be considered as part of the differential diagnosis of the cough.

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. Several cases of agranulocytosis and neutropenia have been reported in which a causal relationship to enalapril cannot be excluded. Current experience with the drug shows the incidence to be rare. 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: Hepatitis, jaundice (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with enalapril in patients with or without pre-existing liver abnormalities (see ADVERSE REACTIONS). In most cases the changes were reversed on discontinuation of the drug.

Should the patient receiving AVA-ENALAPRIL experience any unexplained symptoms (see CONSUMER INFORMATION), particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigation be carried out. Discontinuation of AVA-ENALAPRIL should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. AVA-ENALAPRIL 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 enalapril (see DRUG INTERACTIONS).

Peri-Operative Considerations

Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril blocks angiotensin II formation, secondary to compensatory rennin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

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.

Use of AVA-ENALAPRIL should include appropriate assessment of renal function.

Hyperkalemia: Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately one percent of hypertensive patients in clinical trials with enalapril. In most cases these were isolated values, which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in 0.28% of hypertensive patients. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes. The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function should be given only for documented hypokalemia and with caution and frequent monitoring of serum potassium since they may lead to a significant increase in serum potassium. Hyperkalemia can cause serious, sometimes fatal, arrhythmias. If concomitant use of AVA-ENALAPRIL and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see DRUG INTERACTIONS, Agents Increasing Serum Potassium).

Special Populations

Pregnant Women: ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, AVA-ENALAPRIL 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.

Enalapril has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit and may, theoretically, be removed by exchange transfusion, although there is no experience with the latter procedure.

Animal Data

Maternal and fetal toxicity occurred in some rabbits given enalapril at doses of 1 mg/kg/day or more. Saline supplementation prevented the maternal and fetal toxicity seen at doses of 3 and 10 mg/kg/day, but not at 30 mg/kg/day (50 times the maximum human dose). Enalapril was not teratogenic in rabbits.

There was no fetotoxicity or teratogenicity in rats treated with enalapril at doses up to 200 mg/kg/day (333 times the maximum human dose). Fetotoxicity expressed as a decrease in average fetal weight, occurred in rats given 1200 mg/kg/day of enalapril, but did not occur when these animals were supplemented with saline. The drug crosses the placental barrier in rats and hamsters.

Nursing Women: Enalapril and enalaprilat are secreted in human milk in trace amounts. Use of ACE inhibitors (Ava-Enalapril) is not recommended during breast-feeding.

Pediatrics (<16 years of age): The safety and antihypertensive effect have been studied short-term (one month) in patients aged 6 to 16 years (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

AVA-ENALAPRIL is not recommended in neonates and in children with glomerular filtration rate <30 mL/min/1.73 m², as no data are available.

ADVERSE REACTIONS

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 maleate in controlled clinical trials are shown below. In patients treated with enalapril maleate, the maximum duration of therapy was three years; in placebo treated patients the maximum duration of therapy was 12 weeks.

Table 1 – Hypertension

Enalapril Maleate

n=2314

Placebo n=230 Body As A Whole

Fatigue 3.0 2.6 Orthostatic Effects 1.2 0.0 Asthenia 1.1 0.9 Digestive

Diarrhea 1.4 1.7 Nausea 1.4 1.7 Nervous/Psychiatric

Headache 5.2 9.1 Dizziness 4.3 4.3 Respiratory

Cough 1.3 0.9 Skin

Rash 1.4 0.4

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 maleate 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 maleate and placebo, respectively.

Table 2 - Congestive Heart Failure

Enalapril Maleate

n=673

Placebo n=339 Body As A Whole

Orthostatic Effects 2.2 0.3 Syncope 2.2 0.9 Chest Pain 2.1 2.1 Fatigue 1.8 1.8 Abdominal Pain 1.6 2.1 Asthenia 1.6 0.3 Cardiovascular

Hypotension 6.7 0.6 Orthostatic Hypotension 1.6 0.3 Angina Pectoris 1.5 1.8 Myocardial Infarction 1.2 1.8 Digestive

Diarrhea 2.1 1.2 Nausea 1.3 0.6 Vomiting 1.3 0.9 Nervous/Psychiatric

Dizziness 7.9 0.6 Headache 1.8 0.9 Vertigo 1.6 1.2 Respiratory

Cough 2.2 0.6 Bronchitis 1.3 0.9 Dyspnea 1.3 0.4 Pneumonia 1.0 2.4 Skin

Rash 1.3 2.4 Urogenital

Urinary Tract Infection 1.3 2.4

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 maleate 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 maleate 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 maleate, 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.

Post-Market 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

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 enalapril.. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Agents Increasing Serum Potassium: Since enalapril 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 since they may lead to a significant increase in serum potassium. Salt substitutes, which contain potassium, should also be used with caution (see WARNINGS AND PRECAUTIONS, Hyperkalemia).

Agents Causing Renin Release: The antihypertensive effect of enalapril 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. Betaadrenergic blocking drugs add some further antihypertensive effect to enalapril.

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.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors: The antihypertensive effect of enalapril may be diminished with concomitant non-steroidal anti-inflammatory drug use including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors). In some patients with compromised renal function who are being treated with non-steroidal 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 enalapril (see WARNINGS AND PRECAUTIONS).

Drug-Food Interactions

The absorption of enalapril is not influenced by the presence of food in the gastrointestinal tract.

DOSAGE AND ADMINISTRATION

AVA-ENALAPRIL for Oral Administration Only

Dosing Considerations

• The absorption of AVA-ENALAPRIL is not affected by food.
• Dosage must be individualized.
• Special attention for dialysis patients.
• The splitting of AVA-ENALAPRIL tablets is not advised.

Recommended Dose and Dosage Adjustment

Hypertension: Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation and salt restriction; the dosage of other antihypertensive agents being used with AVA-ENALAPRIL may need to be adjusted. The recommended initial dose in patients not on diuretics is 5 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 10 to 40 mg per day administered in a single dose or two divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, an increase in dosage or twice-daily administration should be considered. If blood pressure is not controlled, a diuretic may be added.

The maximum daily dose is 40 mg. Raising the dose above that level is not recommended because of the possibility of increased adverse reactions.

Symptomatic hypotension occasionally may occur following the initial dose of AVA-ENALAPRIL and is more likely in patients who are currently being treated with a diuretic. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with AVA-ENALAPRIL to reduce the likelihood of hypotension (see WARNINGS AND PRECAUTIONS).

If the diuretic cannot be discontinued, an initial dose of 2.5 mg should be used to determine whether excessive hypotension occurs.

To date there is insufficient experience with enalapril maleate in the treatment of accelerated or malignant hypertension. Ava-Enalapril, therefore, is not recommended in such situations.

Pediatrics (<16 years of age): The usual recommended starting dose is 0.08 mg/kg (up to 5 mg) once daily. Dosage should be adjusted according to blood pressure response. Doses above 0.58 mg/kg (or in excess of 40 mg) have not been studied in pediatric patients (see ACTION AND CLINICAL PHARMACOLOGY). AVA-ENALAPRIL is not recommended in neonates and in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m², as no data are available.

Geriatrics (>65 years of age): The starting dose should be 2.5 mg. Some elderly patients may be more responsive to AVA-ENALAPRIL than younger patients.

Dosing Adjustment in Renal Impairment: (See WARNINGS AND PRECAUTIONS, Anaphylactoid Reactions during Membrane Exposure)

The doses should be reduced in patients with hypertension according to the following guidelines:

^x Enalaprilat is dialyzable. Dosage on nondialysis days should be adjusted depending on the blood pressure response.

Congestive Heart Failure: Enalapril is generally used in conjunction with a diuretic and/or digitalis. Blood pressure and renal function should be monitored, both before and during treatment with AVA-ENALAPRIL , because severe hypotension and, more rarely, consequent renal failure have been reported (see WARNINGS AND PRECAUTIONS).

Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. If possible, the dose of diuretic should be reduced before beginning treatment to reduce the likelihood of hypotension. Serum potassium also should be monitored (see DRUG INTERACTIONS, Drug-Drug Interactions).

The recommended initial dose in patients with symptomatic heart failure or asymptomatic left ventricular dysfunction (ejection fraction ≤35%) is 2.5 mg once a day, to be administered under close medical supervision to determine the initial effect on blood pressure. After the initial dose, the patient should be observed for at least two hours or until the pressure has stabilized for at least another additional hour (see WARNINGS AND PRECAUTIONS, Hypotension).

In the absence of, or after effective management of symptomatic hypotension following initiation of therapy, the dose should be increased gradually depending on the patient's response. The usual therapeutic dosing range is 5 to 20 mg daily, given as a single dose or two divided doses.

This dose titration may be performed over a 2 to 4 week period, or more rapidly if indicated by the presence of residual signs and symptoms of heart failure. The dosage regimen, in patients with symptomatic heart failure, which was effective in reducing mortality and the need for hospitalization in multicentre studies ranged between 16.4 and 18.8 mg/day. The majority of patient experience in clinical studies has been with twice-daily dosage.

The maximum daily dose is 40 mg.

Dosage Adjustment in Patients with Congestive Heart Failure and Renal Impairment or Hyponatremia: In patients with heart failure who have hyponatremia (serum sodium less than 130 mEq/L) or with serum creatinine greater than 1.6 mg/dL, therapy should be initiated at 2.5 mg daily under close medical supervision (see DOSAGE AND ADMINISTRATION, Congestive Heart Failure and DRUG INTERACTIONS, Drug-Drug Interactions).

The dose may be increased to 2.5 mg b.i.d. then 5 mg b.i.d. and higher as needed, usually at intervals of four days or more if at the time of dosage adjustment there is not excessive hypotension or significant deterioration of renal function.

The maximum daily dose is 40 mg.

OVERDOSAGE

Limited data are available for overdosage in humans. The most prominent features of overdosage reported to date are marked hypotension, beginning some six hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system, and stupor. Serum enalaprilat levels 100- and 200-fold higher than usually seen after therapeutic doses have been reported after ingestion of 300 mg and 440 mg of enalapril, respectively.

The recommended treatment of overdosage is intravenous infusion of normal saline solution. If ingestion is recent, induce emesis. Enalaprilat may be removed from the general circulation by hemodialysis (see WARNINGS AND PRECAUTIONS, Anaphylactoid Reactions during Membrane Exposure).

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

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

AVA-ENALAPRIL is an ACE inhibitor, which is used in the treatment of hypertension and heart failure.

Angiotensin converting enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to the pressor substance, angiotensin II. After absorption, enalapril, a pro-drug, is hydrolyzed to enalaprilat, its active metabolite, which inhibits ACE. 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. In patients treated with enalapril maleate and a thiazide diuretic there was essentially no change in serum potassium (see WARNINGS AND PRECAUTIONS).

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

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

Pharmacodynamics

Administration of enalapril to patients with hypertension results in a reduction of both supine and standing blood pressure. Abrupt withdrawal of enalapril has not been associated with a rapid increase in blood pressure. In most patients studied, after oral administration of an individual dose of enalapril, the onset of antihypertensive activity is seen at one hour with peak reduction of blood pressure achieved by 4-6 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. Following administration of enalapril, there was an increase in renal blood flow; glomerular filtration rate was usually unchanged.

When enalapril is given together with thiazide-type diuretics, its blood pressure lowering effect is approximately additive.

Administration of enalapril to patients with congestive heart failure reduces afterload and preload of the heart, resulting in an increase in cardiac output, without reflex tachycardia.

When used in hypertensive, normolipidemic patients, enalapril had no effect on plasma lipoprotein fractions.

Studies in dogs indicate that enalapril crosses the blood brain barrier poorly, if at all; enalaprilat does not enter the brain.

Pharmacokinetics

Table 3 - Summary of Enalaprilat’s Pharmacokinetic Parameters in Healthy Volunteers Further to a 10 mg Oral Dose of Enalapril Maleate

* Effective half-life of accumulation.

Absorption:

AVA-ENALAPRIL is rapidly absorbed with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery the extent of absorption of enalapril from enalapril maleate is approximately 60%. The absorption of enalapril is not influenced by the presence of food in the gastrointestinal tract.

Metabolism:

Following absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent angiotensin converting enzyme inhibitor (which itself is poorly absorbed). Peak serum

concentrations of enalaprilat occur 3 to 4 hours after an oral dose of enalapril maleate. Except for conversion to enalaprilat, there is no evidence of significant metabolism of enalapril.

Excretion:

Excretion of enalapril is primarily renal. Approximately 94% of the 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 serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to ACE. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours.

In hypertensive children aged 2 months to 15 years the kinetics of enalapril were approximately similar to adults (see DOSAGE AND ADMINISTRATION).

Special Populations and Conditions

Pediatrics: In pediatric patients the antihypertensive effect of enalapril has been studied in hypertensive children aged 6 - 16 years (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

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

Renal Insufficiency: 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 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. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency (see DOSAGE AND ADMINISTRATION). Enalaprilat is dialyzable at the rate of 62 mL/min (1.03 mL/s).

STORAGE AND STABILITY

Store at controlled room temperature (15°C - 30°C). Keep container tightly closed. Protect from moisture.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Ava-Enalapril 2.5, 5, 10 and 20 mg tablets.

AVA-ENALAPRIL 2.5 mg Tablets are white, oval, flat, beveled edged tablets engraved “EN” score “2.5” on one side and “APO” on the other side. Available in bottles of 100.

AVA-ENALAPRIL 5 mg Tablets are white, rounded triangle shaped, biconvex tablets, scored on one side and engraved “APO” over “EN5” on the other side. Available in bottles of 100.

AVA-ENALAPRIL 10 mg Tablets are reddish-pink, rounded triangle shaped, biconvex tablets, scored on one side and engraved “APO” over “EN10” on the other side. Available in bottles of 100.

AVA-ENALAPRIL 20 mg Tablets are peach coloured, rounded triangle shaped, biconvex tablets, scored on one side and engraved “APO” over “EN20” on the other side. Available in bottles of 100.

In addition to the active ingredient, enalapril maleate, each tablet also contains the non-medicinal ingredients lactose and zinc stearate. Each 10 mg tablet also contains orange ferric oxide and each 20 mg tablet also contains yellow ferric oxide and orange ferric oxide.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Enalapril maleate

Chemical Name: L-Proline, 1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-, (S)-, (Z)-2-butenedioate (1:1).

Molecular formula C₂₀H₂₈N₂O₅•C₄H₄O₄

Molecular weight: 492.53

Structural Formula:

Physicochemical properties: Enalapril maleate is a white to off-white crystalline powder which melts at ≈143°C to 144°C. It is sparingly soluble in water (pH 3.4), soluble in ethanol, and freely soluble in methanol and dimethylformamide. The pKa¹ and pKa² of the base moiety are 3.0 and 5.4 respectively.

CLINICAL TRIALS

Comparative Bioavailability Studies

Study demographics and trial design

Table 4 - Summary of patient demographics for clinical trials

Study results

Table 5 - Results of SOLVD-Treatment study

In a multicentre, placebo-controlled, double-blind study (SOLVD, see BIBLIOGRAPHY, no. 23), 2569 patients with symptomatic heart failure (primarily New York Heart Association Class II and III and ejection fraction ≤35%), were randomized to placebo or enalapril given as an adjunct to conventional therapy. Diseases that excluded patients from enrolment in the study included severe stable angina, hemodynamically significant valvular or outflow tract obstruction, renal failure, cerebral vascular disease (e.g., significant carotid artery diseases), advanced pulmonary disease, malignancies, active myocarditis and constrictive pericarditis. The use of enalapril was associated with an 11% reduction in all-cause mortality (which corresponds to a 16% risk reduction in all-cause mortality) and a 30% reduction in hospitalization for heart failure (which corresponds to a 36% risk reduction in hospitalization for heart failure). The chief difference in mortality was in deaths due to progressive heart failure. There was no significant difference in the number of deaths classified as due to arrhythmia without worsening congestive heart failure.

Study demographics and trial design

Table 6 - Summary of patient demographics for clinical trials

Study results

A second multicentre trial used the SOLVD protocol for a study of asymptomatic or minimally symptomatic patients. SOLVD-Prevention patients, who had left ventricular ejection fraction ≤35% and no history of symptomatic heart failure, were randomized to placebo (n=2117) or enalapril (n=2111) and followed for up to 5 years. The majority of patients in the SOLVDPrevention trial had a history of ischemic heart disease. A history of myocardial infarction was present in 80% of patients, current angina pectoris in 34%, and a history of hypertension in 37%.

No statistically significant mortality effect was demonstrated in this population. Enalapril treated subjects had 32% fewer first hospitalizations for heart failure, and 32% fewer total heart failure hospitalizations. Compared to placebo, 32% fewer patients receiving enalapril developed symptoms of overt heart failure.

Hospitalizations for cardiovascular reasons were also reduced. There was an insignificant reduction in hospitalizations for any cause in the enalapril treatment group (for enalapril vs. placebo, respectively, 1166 vs. 1201 first hospitalizations, 2649 vs. 2840 total hospitalizations), although the study was not powered to look for such an effect.

The SOLVD-Prevention trial was not designed to determine whether treatment of asymptomatic patients with low ejection fraction would be superior, with respect to preventing hospitalization, to closer follow-up and use of enalapril at the earliest sign of heart failure. However, under the conditions of follow-up in the SOLVD-Prevention trial (every four months at the study clinic; personal physician as needed), 68% of patients on placebo who were hospitalized for heart

failure had no prior symptoms recorded which would have signaled initiation of treatment. The SOLVD-Prevention trial was also not designed to show whether enalapril modified the progression of underlying heart disease.

Study demographics and trial design

Table 8 - Summary of patient demographics for clinical trials

Study results

Table 9 - Results of CONSENSUS study

In another multicentre, placebo-controlled trial (CONSENSUS, see BIBLIOGRAPHY, no. 22), 253 patients with severe congestive heart failure (New York Heart Association Class IV) were randomized to placebo or enalapril given as an adjunct to conventional therapy. The use of enalapril was associated with an improvement of symptoms and a reduction in mortality from the progression of heart failure. No difference was seen in the incidence of sudden cardiac death.

A comparative bioavailability study was performed using normal human volunteers. The rate and extent of absorption of enalapril and its active metabolite enalaprilat were measured and compared after a single 20 mg dose of AVA-ENALAPRIL (1 x 20 mg tablet or 4 x 5 mg tablets) and VASOTEC® (1 x 20 mg tablet). The results are summarized as follows:

Free Enalaprilat

Free Enalaprilat

* For the Tmax and T½ parameters, these are the arithmetic means (standard deviations).

DETAILED PHARMACOLOGY

Mechanism of Action

Effects on Blood Pressure

Other Effects

TOXICOLOGY

Acute Toxicity LD50 Values:

^a Merck Sharp and Dohme Research Laboratories, West Point, PA, USA ^b Nippon Merck-Banyu Co., Menuma, Japan

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

Sub-Acute and Chronic Toxicity

Teratology Studies

Fertility and Postnatal Evaluation Studies

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 = 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. 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.

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