Enalapril Tablets 2.5, 5, 10 and 20 mg

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 tablets

Angiotensin Converting Enzyme Inhibitor ATC C09AA02

Taro Pharmaceuticals Inc. Date of Revision:

East Drive June 13, 2008

Brampton, Ontario L6T 1C1

www.taro.ca

Submission Control No: 121287

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 9 DRUG INTERACTIONS 14 DOSAGE AND ADMINISTRATION 15 OVERDOSAGE 17 ACTION AND CLINICAL PHARMACOLOGY 17 STORAGE AND STABILITY 19 DOSAGE FORMS, COMPOSITION AND PACKAGING 20

PART II: SCIENTIFIC INFORMATION 21

PHARMACEUTICAL INFORMATION 21 CLINICAL TRIALS 22 DETAILED PHARMACOLOGY 26 TOXICOLOGY 28 BIBLIOGRAPHY 33

PART III: CONSUMER INFORMATION. 35

PrTARO-ENALAPRIL

Enalapril Tablets

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

TARO-ENALAPRIL 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.

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, TARO-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, TARO-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 dialyzed 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

Hypoglycermia:

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 TARO-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 TARO-ENALAPRIL should be considered when appropriate. There are no adequate studies in patients with cirrhosis and/or liver dysfunction. TARO- 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 TARO-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 may 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 TARO-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, TARO-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 (TARO-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).

TARO-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 or enalaprilat 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 TARO-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 VARNINGS AND PRECAUTIONS).

Drug-Food Interactions

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

DOSAGE AND ADMINISTRATION

Dosing Considerations

The absorption of TARO-ENALAPRIL is not affected by food. Dosage must be individualized. Special attention for dialysis patients.

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 TARO-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 TARO- 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 TARO-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. TARO-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). TARO-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 TARO-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:

Renal Status Creatinine Clearance mL/min (mL/s) Initial Dose mg/day

Normal Renal Function Mild Impairment

Moderate to Severe Impairment Dialysis Patients

>80 mL/min (> 1.33 mL/s)

<= 80 > 30 mL/min (<= 1.33 > 0.50 mL/s)

<= 30 mL/min (<= 0.50 mL/s)

--

5 mg

5 mg

2.5 mg

2.5 mg on dialysis days *

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

Congestive Heart Failure:

TARO-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 TARO-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 multicenter 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

TARO-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 WARNING 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 either drug 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

*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 tablets 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 at controlled room temperature (15degC-30degC). Keep container tightly closed. Protect from excessive heat, moisture and direct light.

Note: 1000 tablet bottle: discard remaining tablets six months after opening bottle.

DOSAGE FORMS, COMPOSITION AND PACKAGING

TARO-ENALAPRIL tablets are supplied as follows:

2.5 mg tablets:

Physical Description:

White, oval-shaped tablets, plain on one side, with the other side scored and engraved with "T" and "2.5".

Packaging:

Available in bottles of 100, 500 and 1000, and in blisters of 30 tablets (10x3 blister packs/carton).

5 mg tablets:

Physical Description:

White, rounded triangle-shaped tablets, scored on one side and engraved

TARO 5

on the other side.

Packaging:

Available in bottles of 100, 500 and 1000, and in blisters of 30 tablets (10x3 blister packs/carton).

10 mg tablets:

Physical Description:

Pink, rounded triangle-shaped tablets, scored on one side and engraved

TARO 10

on the other side.

Packaging:

Available in bottles of 100, 500 and 1000, and in blisters of 30 tablets (10x3 blister packs/carton).

20 mg tablets:

Physical Description:

Peach, rounded triangle-shaped tablets, scored on one side and engraved

TARO 20

on the other side.

Packaging:

Available in bottles of 100, 500 and 1000, and in blisters of 30 tablets (10x3 blister packs/carton).

Each tablet of Taro-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 and the following nonmedicinal ingredients: lactose, magnesium stearate, pregelatinized corn starch, sodium bicarbonate, red and/or yellow iron oxides.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Enalapril Maleate Enalapril Sodium Chemical Name: L-Proline, 1-[N-[1-ethoxycarbonyl)-3- phenylpropyl]-L-alanyl]-, (S)-, (Z)-2- butenedioate (1:1) Molecular L-Proline, 1-[N-[1- ethoxycarbonyl)-3- phenylpropyl]-L-alanyl]-, (S)-, Sodium (1:1) Formula: C20H28N2O5 *C4H4O4 C20H27N2NaO5 Molecular Mass: 492.53 398.43 Structural Formula: Physicochemical Properties: Enalapril maleate is a white to off-white crystalline powder which melts at [?] 143degC to 144degC. 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

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 multicenter, 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

Table 7 - Results of SOLVD-Prevention Study

A second multicenter 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 SOLVD- Prevention 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 multicenter, 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.

Comparative Bioavailability

A single-dose, two-way crossover study in 22 normal healthy male subjects, under fasting conditions, established the bioequivalence of TARO-ENALAPRIL (enalapril tablets) 20 mg, manufactured by Taro Pharmaceuticals Inc., to the product Vasotec(r) 20 mg tablets, manufactured by Merck Frosst Canada Ltd.

Table 10 -Summary Table of Comparative Bioavailability Data (Enalapril Tablets, 20 mg)

*Expressed as arithmetic means (CV%) only.

HVasotec(r) 20 mg Tablets (Merck Frosst Canada Ltd.) were purchased in Canada. A single-dose, two-way crossover study in 22 normal healthy male and female subjects, under fasting conditions, established the bioequivalence of TARO-EANALAPRIL (enalapril tablets) 2.5 mg, manufactured by Taro Pharmaceuticals Inc., to the product Vasotec(r) 2.5 mg tablets, manufactured by Merck Frosst Canada Ltd. Results are summarized in the following table.

Table 11 -Summary Table of Comparative Bioavailability Data (Enalapril Tablets, 2.5 mg)

Canada Ltd.)

*Based on least squares means.

* *Expressed as arithmetic means (CV%) only.

HVasotec(r) 2.5 mg Tablets (Merck Frosst Canada Ltd.) were purchased in Canada.

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) 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.

BIBLIOGRAPHY

1. Biollaz J, Burnier M, Turini GA, Brunner DB, Porchet M, Gomez HJ, Jones KH. Three new long-acting converting-enzyme inhibitors: Relationship between plasma converting-enzyme activity and response to angiotensin I. Clin Pharmacol Ther 1981; 29:665-70.

2. Biollaz J, Schelling JL, Jacot des Combes B, Brunner DB, Desponds G, Brunner HR. Enalapril maleate and a lysine analogue (MK-521) in normal volunteers; relationship between plasma drug levels and the renin angiotensin system. Br J Clin Pharmacol 1982; 14:363-8.

3. Biollaz J, Brunner HR, Gavras I, Waeber B, Gavras H. Antihypertensive therapy with MK- 421: Angiotensin II - Renin relationships to evaluate efficacy of converting enzyme blockade. J Cardiovasc Pharmacol 1982; 4:966-72.

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.

5. Cleary JP, Taylor JW. Enalapril: A new angiotensin converting enzyme inhibitor. Drug Intell Clin Pharm 1986; 20(3):177-86.

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.

7. Cody RJ, Covit AB, Schaer GL, Laragh JH. Evaluation of a long-acting converting enzyme inhibitor (enalapril) for the treatment of chronic congestive heart failure. J Am CoIl Cardiol 1983; 1(4):1154-9.

8. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Cintron G, Shabetai R, Haakenson C. A comparison of enalapril with hydralazineisosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325:303- 10.

9. Gavras H, Biollaz J, Waeber B, Brunner HR, Gavras I, Davies RO. Antihypertensive effect of the new oral angiotensin converting enzyme inhibitor "MK-421". Lancet 1981; ii:543-7.

10. Gomez HJ, Cirillo VJ. Angiotensin converting enzyme inhibitors: The clinical pharmacology of captopril and enalapril maleate. Clinical pharmacology and therapeutics (International Congress Series No. 604), Velasco, M. ed., Excerpta Medica, Amsterdam. 1983; 52-7.

11. Hodsman GP, Brown JJ, Davies DL, Fraser R, Lever AF, Morton JJ, Murray GD, Robertson JIS. Converting-enzyme inhibitor enalapril (MK-421) in treatment of hypertension with renal artery stenosis. Br Med J 1982; 285:1697-9.

12. Hodsman GP, Brown JJ, Cumming AMM, Davies DL, East BW, Lever AF, Morton JJ, Murray GD, Robertson JIS. Enalapril (MK-421) in the treatment of hypertension with renal artery stenosis, (Symposium: On the renin-angiotensin-aldosterone system: Treatment of hypertension and heart failure, Milan, Italy, 28 May 1983). J Hypertens 1 1983 (Suppl 1);

109-17. Ibsen H, Egan B, Osterziel K, Vander A, Julius S. Reflex-hemodynamic adjustments and baroreflex sensitivity during converting enzyme inhibition with MK-421 in normal humans. Hypertension 1983; 5 (Suppl I):184-91. Larochelle P, Carruthers SG, Krip G. Comparison of monotherapy with enalapril and atenolol in mild to moderate hypertension. Can Med Assoc J 1987; (37):803-8. McNabb WR, Brooks BA, Noormohamed F, Lant AF. The effect of enalapril on serum prolactin. Br J Clin Pharmacol 1983; 15:752-4. Millar JA, Derx FHM, McLean K, Reid JL. Pharmacodynamics of converting enzyme inhibition: The cardiovascular, endocrine and autonomic effects of MK-421 (enalapril) and MK-521. Br J Clin Pharmacol 1982; 14:347-55. Oberman A, Cutter GR, Rogers WJ, Mantle JA. Clinical Endpoints. 1982; 341-55 in Congestive Heart Failure; ed. Braunwald E, Mock M, Watson J. Grune & Stratton. Packer M, Hung Lee W, Yushak M, Medina N. Comparison of captopril and enalapril in patients with severe chronic heart failure. N Engl J Med 1986; 315:847-53. Packer M, Hung Lee W, Medina N, Yushak M, Kessler PD. Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure. Ann Intern Med 1987; 106 (3):346-54. Packer M, ed. Do vasodilators prolong life in heart failure? N Engl J Med 1987; 316:1471- 73. Turini GA, Waeber B, Brunner HR. The reninangiotensin system in refractory heart failure: Clinical, hemodynamic and hormonal effects of captopril and enalapril. Eur Heart J 1983; 4:189-97. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316:1429- 35. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325:293-302. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327:685-91. Wilkins LH, Dustan HP, Walker JF, Oparil S. Enalapril in low-renin essential hypertension. Clin Pharmacol Ther 1983; 34(3):297-302. Product Monograph for Vasotec(r), Merck Frosst Canada Ltd., Date of revision: October 10, 2007, Control number 116570 . IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

Pr

TARO-ENALAPRIL tablets

(enalapril tablets)

This leaflet is part III of a three-part "Product Monograph" published when TARO-ENALAPRIL was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about TARO-ENALAPRIL. Contact your physician or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

TARO-ENALAPRIL is available only on prescription from your physician.

What the medication is used for:

• reducing high blood pressure

When blood pressure is high, the workload of the heart and arteries increases so that over time, these organs may not function as they should. In turn, this could lead to damage of the "vital organs": brain - heart - kidneys, and result in stroke, heart failure, heart attack, blood vessel disease or kidney disease.

treating patients with heart failure

TARO-ENALAPRIL may also be used to treat patients with heart failure. This is a condition where the heart cannot pump adequate amounts of blood to satisfy the needs of the body.

If your physician has recommended a particular diet, for instance - less salt - follow the diet carefully. This could help your medicine better control your blood pressure. Your physician may also recommend weight loss. Do follow these suggestions.

pressure very easily, and check how the medicine is controlling it.

Read the following information carefully. If you need any explanations, or further information, ask your physician or pharmacist.

When it should not be used:

Do not take TARO-ENALAPRIL if you:

are allergic to enalapril or enalaprilat or any other component of TARO-ENALAPRIL (see What the important non-medicinal ingredients are).

have a history of swelling of the face, lips, tongue, throat, or sudden difficulty breathing or swallowing.

have been diagnosed with swelling of the face, lips, tongue, throat, or sudden difficulty breathing or swallowing due to genetic factors or unknown reasons (please refer to Side Effects and What to do About Them).

What the medicinal ingredient is:

Each tablet is made with enalapril maleate that appears as enalapril sodium in the tablet.

What the important nonmedicinal ingredients are:

Lactose, magnesium stearate, pregelatinized corn starch, sodium bicarbonate. Tablets 10 mg and 20 mg contain red and /or yellow oxides.

What dosage forms it comes in:

TARO-ENALAPRIL tablets come in four different strengths:

2.5 mg (white): Each tablet is made with 2.5 mg of enalapril maleate that appears as 2 mg of enalapril sodium in the tablet. 5 mg (white): Each tablet is made with 5 mg of enalapril maleate that appears as 4 mg of enalapril sodium in the tablet. 10 mg (pink): Each tablet is made with 10 mg of enalapril maleate that appears as 8 mg of enalapril sodium in the tablet. 20 mg (peach): Each tablet is made with 20 mg of enalapril maleate that appears as 16 mg of enalapril sodium in the tablet.

TARO-ENALAPRIL is one of a class of medicines known as angiotensin converting enzyme (ACE) inhibitors. They lower blood pressure by specifically blocking a naturally occurring substance called angiotensin II. Angiotensin II normally tightens your blood vessels. TARO-ENALAPRIL allows them to relax and therefore help lower high blood pressure.

This medicine does not cure high blood pressure, but does help control it. So, it is important to continue taking the tablets regularly to keep your blood pressure down. You may have to take blood pressure medicine for life.

Keep your regular appointments with your physician, even if you feel well. High blood pressure may not be easily recognized by you, because you may not "feel any symptoms"; but your physician can measure your blood

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

TARO-ENALAPRIL should not be used during pregnancy. If you discover that you are pregnant while taking TARO- ENALAPRIL, stop the medication and please contact your physician as soon as possible.

This medicine may not be suitable for certain people. So, tell your physician or pharmacist if you think any of the following applies to you:

You have previously taken TARO-ENALAPRIL or other medication of the same type - Angiotensin Converting Enzyme (ACE) inhibitors such as enalapril, lisinopril, captopril, and you were allergic or reacted badly to it, particularly if you experienced swelling of the face, lips,

tongue, or throat, or had sudden difficulty breathing or swallowing. (These are symptoms of conditions called hereditary angioedema or idiopathic angioedema.)

You should not take this medicine if you have been diagnosed with hereditary angioedema or idiopathic angioedema (angioedema of unknown cause).

Dizziness or drowsiness may occasionally occur when taking medication to lower blood pressure. Therefore, before you perform tasks which may require special attention (driving a car or operating dangerous machinery), wait until you know how you respond to your medicine.

You should be aware that black patients are at increased risk of these types of reactions to ACE inhibitors.

You are pregnant, breast-feeding or thinking of becoming pregnant. Taking TARO-ENALAPRIL during pregnancy can cause injury and even death to your developing baby. This medicine should not be used during pregnancy. If you become pregnant while taking TARO-ENALAPRIL, stop the medication and report to your physician as soon as possible. It is possible that TARO-ENALAPRIL passes into breast milk. You should not breast-feed while taking TARO-ENALAPRIL.

You suffer from low blood pressure (you may notice this

You are undergoing dialysis.

You have any of these conditions:

• diabetes

• heart or blood vessel disease

• liver disease

• kidney disease

You are receiving gold (sodium aurothiomalate) injections.

You are taking "water pills" or potassium supplements.

You use potassium containing salt substitutes with your food.

You should also inform your physician or pharmacist if you have recently suffered from excessive vomiting or diarrhea.

If you have diabetes and are taking oral medicines to treat diabetes or insulin, you should closely monitor for low blood glucose levels, especially during the first month of treatment with TARO-ENALAPRIL.

If you have to undergo any dental or other surgery, inform the dentist or the physician in charge that you are taking this medicine.

Remember - This medicine is prescribed for the particular condition that you have. Do not give this medicine to other people, nor use it for any other condition.

Do not use outdated medicine.

INTERACTIONS WITH THIS MEDICATION

Do not take any other medicines

unless you have discussed the matter with your physician or pharmacist. Certain medications tend to increase your blood pressure, for example, non-prescription preparations for appetite control, asthma, colds, coughs, hay fever and sinus problems, or may also react badly with TARO-ENALAPRIL.

Your physician or pharmacist also needs to know if you are taking any other medication, whether on prescription or otherwise. It is particularly important to inform your physician if you are taking:

Diuretics or "water pills"; any other medicines to reduce blood pressure.

Diabetes medicine and/or insulin.

Potassium-containing medicines, potassium supplements.

Salt substitutes that contain potassium, as these may lead to increased levels of potassium in the blood which can be serious. In these cases, your physician may need to adjust the dosage of TARO-ENALAPRIL or monitor your blood level of potassium.

Lithium (a drug used to treat a certain kind of depression).

Certain pain and arthritis medicines, including gold therapy and non-steroidal anti-inflammatory drugs.

PROPER USE OF THIS MEDICATION

Usual Dose:

Take this medicine exactly as your physician ordered.

The absorption of this medicine is not affected by food; so it can be taken with or without a meal.

Try to take your medicine every day at the same time.

This way it becomes easy to remember your doses.

For patients with high blood pressure: Adults:

Your physician may adjust the dose according to your blood pressure response. The usual dose range is 10 mg to 40 mg per day given in a single dose or two divided doses. The maximum daily dose for TARO-ENALAPRIL is 40 mg.

Children (less than 16 years):

The usual starting dose is up to 5 mg once daily. Doses above 40 mg have not been studied.

For patients with congestive heart failure:

The initial dose is 2.5 mg taken once a day. Your physician will closely monitor you to determine the initial effect on

your blood pressure. The usual daily dose is 5 mg to 20 mg given in a single dose or two divided doses. The maximum daily dose is 40 mg.

Overdose:

In case of an overdose, contact your physician or pharmacist immediately so that medical attention may be given promptly. The most likely symptom would be a feeling of lightheadedness or dizziness due to a sudden or excessive drop in blood pressure.

IMPORTANT: PLEASE READ

Missed Dose:

If you miss a dose of this medicine, take it as soon as possible. However, if no more than six hours have elapsed since the missed dose, you may take that day's dose of medication and then go back to your regular dosing schedule.

Do not take a double dose.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Along with its intended action, any medication, including TARO-ENALAPRIL, may cause side effects. Most people do not experience any problem when taking this medicine; but if you notice any of the following, have other side effects or if the condition worsens, seek medical attention.

Dry cough, sore throat.

The initial dose may cause a greater fall in blood pressure than will occur following continued treatment. You may notice this as faintness or dizziness and it may help to lie down. If concerned, please consult your physician or pharmacist.

This is not a complete list of side effects. For any unexpected effects while taking TARO-ENALAPRIL, contact your physician or pharmacist.

HOW TO STORE IT

Store your tablets at 15degC-30degC, in a tightly closed container, away from heat and direct light, and out of damp places, such as the bathroom or kitchen.

Keep all medicines out of the reach of children.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 1-866-234-2345

toll-free fax 1-866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

or Taro Pharmaceuticals Inc. Brampton, Ontario L6T 1C1 1-800-268-1975

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at:

http://www.taro.ca

or by contacting the sponsor, Taro Pharmaceuticals Inc. at: 1-800-268-1975

This leaflet was prepared by Taro Pharmaceuticals Inc. Last revised: June 13, 2008