PRODUCT MONOGRAPH

PrNOVO-ENALAPRIL (Enalapril Tablets) 2.5 mg, 5 mg, 10 mg and 20 mg Professed Standard Each tablet is made with 2.5, 5, 10 or 20 mg of enalapril maleate that appears as 2, 4, 8 or 16 mg of enalapril sodium in the tablet Angiotensin Converting Enzyme Inhibitor Novopharm Limited Toronto, Canada Control Number: 114355 Date of Preparation: September 1, 1998 Date of Revision: October 16, 2007

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 8 DRUG INTERACTIONS 14 DOSAGE AND ADMINISTRATION 15 OVERDOSAGE 17 ACTION AND CLINICAL PHARMACOLOGY 17 STORAGE AND STABILITY 20 DOSAGE FORMS, COMPOSITION AND PACKAGING 20

PART II: SCIENTIFIC INFORMATION 21

PHARMACEUTICAL INFORMATION 21 CLINICAL TRIALS 22 CLINICAL TRIALS 24 DETAILED PHARMACOLOGY 27 TOXICOLOGY 29 BIBLIOGRAPHY 36

PART III: CONSUMER INFORMATION 39

PrNOVO-ENALAPRIL

Enalapril Tablets

Each tablet is made with 2.5, 5, 10 or 20 mg of enalapril maleate that appears as 2, 4, 8 or 16 mg of enalapril sodium in the tablet Professed Standard

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

*For a complete listing see Dosage Forms, Composition and Packaging section. The splitting of Novo-Enalapril

tablets is not advised.

CONTRAINDICATIONS

NOVO-ENALAPRIL is contraindicated in: Patients who are hypersensitive to these products or any of their components. 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, NOVO- ENALAPRIL (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, NOVO-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 impairments (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 NOVO-ENALAPRIL (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 NOVO-ENALAPRIL (enalapril) should be considered when appropriate. There are no adequate studies in patients with cirrhosis and/or liver dysfunction. 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 renin 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 NOVO-ENALAPRIL (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 the 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, arrthythmias. If concomitant use of NOVO-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, Agent 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, NOVO-ENALAPRIL (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 (NOVO-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).

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

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 and enalaprilat decrease 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. (see WARNINGS AND PRECAUTIONS, Hyperkalemia).

Agents Causing Renin Release:

The antihypertensive effect of NOVO-ENALAPRIL (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. Beta- adrenergic 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

NOVO-ENALAPRIL for Oral Administration Only Dosing Consideration

The absorption of NOVO-ENALAPRIL (enalapril) is not affected by food. Dosage must be individualized. Special attention for dialysis patients. The splitting of NOVO-ENALAPRIL tablet 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 NOVO-ENALAPRIL (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 NOVO- ENALAPRIL (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 NOVO-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 in the treatment of accelerated or malignant hypertension. NOVO-ENALAPRIL (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). NOVO-ENALAPRIL (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 NOVO-ENALAPRIL (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:

NOVO-ENALAPRIL (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 NOVO-ENALAPRIL (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).

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

NOVO-ENALAPRIL (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 and a thiazide diuretic there was essentially no change in serum potassium (see WARNINGS AND PRECAUTIONS). ACE is identical to kininase II. Thus, NOVO-ENALAPRIL (enalapril) 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 NOVO-ENALAPRIL (enalapril) lowers blood pressure is believed to be primarily the suppression of the renin-angiotensin-aldosterone system, NOVO- ENALAPRIL (enalapril) also lowers blood pressure in patients with low-renin hypertension.

Pharmacodynamics

Administration of NOVO-ENALAPRIL (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. Following administration of enalapril, the onset of action usually occurs within 15 minutes, with the maximum effect occurring within one to four hours. 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

* Effective half-life of accumulation.

Absorption:

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. 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 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 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 between 15degC - 30degC. Keep container tightly closed. Protect from moisture and high humidity.

DOSAGE FORMS, COMPOSITION AND PACKAGING

NOVO-ENALAPRIL is supplied in a tablet dosage form of oral administration. Each tablet of Novo-Enalapril is made with 2.5, 5, 10 or 20 mg of enalapril maleate that appears as 2, 4, 8 or 16 mg of enalapril sodium, respectively in the tablets. NOVO-ENALAPRIL 2.5 mg: White to off-white, oval-shaped, scored, biconvex compressed tablets, engraved N scoreline N on one the scored side and 2.5 on the other side. Available in bottles of 100. Unit dose of 30. NOVO-ENALAPRIL 5 mg: White to off-white, barrel-shaped, biconvex tablets, engraved N | N on one side and 5 on the other side. Available in bottles of 100, 500 and 1000. Unit dose of 30. NOVO-ENALAPRIL 10 mg: Rust-red, barrel-shaped, biconvex tablets, engraved N on one side and 1 | 0 on the other side. Available in bottles of 100, 500 and 1000. Unit dose of 30. NOVO-ENALAPRIL 20 mg: Peach coloured, barrel-shaped, biconvex tablets, engraved N on one side and 2 | 0 on the other side. Available in bottles of 100, 500 and 1000. Unit dose of 30. In addition to the active ingredient, enalapril maleate, each tablet contains as non-medicinal ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, sodium bicarbonate and talc. Both 10 mg and 20 mg tablets also contain: D & C red #30 aluminum Lake, FD & C blue #1 aluminum Lake HT and FD & C yellow #6 aluminum Lake HT.