PRODUCT MONOGRAPH

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Gen-Cilazapril

(Cilazapril as cilazapril monohydrate) 1 mg, 2.5 mg, 5 mg Tablets Angiotensin Converting Enzyme Inhibitor Genpharm Inc. 85 Advance Road Etobicoke, Ontario M8Z 2S6 Control No. : 111022 Date of Preparation: January 24, 2008

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 12 DOSAGE AND ADMINISTRATION 13 SYMPTOMS AND TREATMENT OF OVERDOSAGE 15 ACTION AND CLINICAL PHARMACOLOGY 16 STABILITY AND STORAGE RECOMENDATIONS 19 DOSAGE FORMS, COMPOSITION AND PACKAGING 19

PART II: SCIENTIFIC INFORMATION 20

PHARMACEUTICAL INFORMATION 20 CLINICAL TRIALS 21 PHARMACOLOGY 22 TOXICOLOGY 25 REFERENCES 37

PART III: CONSUMER INFORMATION. 40

Gen-Cilazapril

(Cilazapril as cilazapril monohydrate)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Gen-Cilazapril (cilazapril) is contraindicated in patients who are hypersensitive to cilazapril or any ACE inhibitors. Gen-Cilazapril is also contraindicated in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with ascites.

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, Gen-Cilazapril (cilazapril) should be discontinued as soon as possible.

Angioedema

Angioedema has been reported in patients treated with cilazapril. Angioedema associated with laryngeal edema and/or shock may be fatal. If angioedema occurs, Gen-Cilazapril should be promptly discontinued and appropriate therapy instituted without delay. The patient should be followed carefully until the swelling has resolved. Swelling confined to the face, lips and mouth usually resolves without treatment, although antihistamines may provide symptomatic relief. Swelling of the tongue, glottis or larynx, may cause airway obstruction, therefore, subcutaneous adrenaline (0.5 mL 1:1000) should be administered promptly when indicated. 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 an increased risk of angioedema while receiving an ACE inhibitor (see CONTRAINDICATIONS).

Hypotension

Occasionally, symptomatic hypotension has occurred after administration of cilazapril usually after the first dose or when the dose had been increased. It is more likely to occur in patients with sodium or volume depletion in connection with diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Patients with congestive heart failure, especially those vigorously treated with loop diuretics, may experience excessive hypotension in response to ACE inhibitors. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of Gen-Cilazapril 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). In patients with severe heart failure, whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including Gen-Cilazapril, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death. 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 does not necessitate discontinuation of Gen-Cilazapril. Once the blood pressure has increased after volume expansion, Gen-Cilazapril therapy may be continued. If symptoms persist, the dosage should be reduced or the drug discontinued.

Two elderly male patients, with a history of previous myocardial infarctions, on high diuretic dosage (240 mg and 120 mg of furosemide daily, respectively) for congestive heart failure NYHA Class III died within 8 hours after the addition of a single dose of 2.5 mg of cilazapril.

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.

Cough

A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of cilazapril, has been reported. Such possibility should be considered as part of the differential diagnosis of the cough.

Hyperkalemia

In clinical trials, elevated serum potassium (greater than 5.5 mEq/L) was observed in approximately 0.7% of hypertensive patients and 0.8% of congestive heart failure patients receiving cilazapril. In most cases these were isolated values which resolved despite continued therapy, however in one case the patient discontinued treatment. Risk factors for the developmental hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia (see DRUG INTERACTIONS and ADVERSE REACTIONS). Patients should be advised not to use potassium supplements or salt substitutes containing potassium without consulting their physician.

Neutropenia/Agranulocytosis

Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Cases of leucopenia and neutropenia have rarely been reported in patients treated with cilazapril. However, in no patient could a causal relationship to cilazapril be established. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and renal disease.

Patients With Impaired Liver Function

Hepatitis (hepatocellular and/or cholestatic), jaundice, elevations of liver enzymes and/or serum bilirubin have occurred during therapy with cilazapril in patients with or without pre-existing liver abnormalities. In most cases the changes were reversed on discontinuation of the drug. Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fluminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Elevations of liver enzymes and/or serum bilirubin have been reported for cilazapril (see ADVERSE REACTIONS). Jaundice was also spontaneously reported in one patient worldwide. Should the patient receiving Gen-Cilazapril experience any symptoms of jaundice 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 Gen-Cilazapril should be considered when appropriate. There are no adequate studies in patients with cirrhosis and/or liver dysfunction. Gen-Cilazapril 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.

Surgery/Anesthesia

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, cilazapril blocks angiotensin II formation, secondary to compensatory renin release. This may result in arterial hypotension which can be corrected by volume expansion.

Diabetes

Administration of ACE inhibitors in patients with diabetes may potentiate the blood glucose lowering effect of oral hypoglycemic agents or insulin.

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 sytem 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 Gen-Cilazapril (cilazapril) should include appropriate assessment of renal function. Reduced dosages may be required for patients with renal impairment depending on their creatinine clearance (see DOSAGE AND ADMINISTRATION, Dosage Adjustment in Patients with Renal Impairment.

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 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.

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, wasps) 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. Cilazapril use must therefore be interrupted before the start of desensitization therapy. In this situation, cilazapril must not be replaced by a beta-blocker.

Pregnant Women

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, Gen-Cilazapril 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. Dialysis clearance was estimated to be 2.4 L/h for cilazapril and 2.2-2.8 L/h for cilazaprilat.

Animal Data:

In fertility and general reproduction performance testing in rats, dosing with 50 mg/kg/day of cilazapril resulted in greater implantation losses, less viable fetuses, smaller pups, and dilatation of the renal pelvis in the pups. No teratogenic effects and no adverse effects on postnatal pup development were observed in rats and cynomolgus monkeys during embryotoxicity testing. In the rats, however, at a dose of 400 mg/kg/day, renal cavitation was observed in the pups. In peri- and post-natal toxicity testing in rats, dosing with 50 mg/kg/day resulted in greater pup mortality, smaller pups, and delayed unfolding of the pinna. On

administration of 14C-cilazapril to pregnant mice, rats and monkeys, radioactivity was measured in the fetuses.

Nursing Women

The presence of concentrations of ACE inhibitor have been reported in human milk. Use of ACE inhibitors is not recommended during breast-feeding.

Pediatric Use

The safety and effectiveness of the use of cilazapril in children have not been established. Therefore, use in this age group is not recommended.

Use in Elderly

Although clinical experience has not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. In elderly patients with congestive heart failure on high diuretic dosage, the recommended starting dose of Gen-Cilazapril 0.5 mg must be strictly followed (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension, and DOSAGE AND ADMINISTRATION).

DRUG INTERACTIONS

Diuretic Therapy

: Patients concomitantly taking ACE inhibitors and diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy. The possibility of hypotensive effects after the first dose of Gen-Cilazapril can be minimized by either discontinuing the diuretic, or increasing the salt intake prior to initiation of treatment with Gen-Cilazapril. If it is not possible to discontinue the diuretic, the starting dose of Gen-Cilazapril should be reduced and the patient should be closely observed for several hours following initial dose and until blood pressure has stabilized (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Agents Increasing Serum Potassium

: Since cilazapril decreases aldosterone production, elevation of serum potassium may occur. Potassium sparing diuretics such as spironolactone, triamterene or amiloride, or potassium supplements should be given only for documented hypokalemia and with caution since they may lead to a significant increase in serum potassium particularly in patients with renal impairment. Therefore, if concomitant use for such agents is indicated, their dosage should be reduced when Gen-Cilazapril is initiated and serum potassium and renal function should be monitored carefully. Salt substitutes containing potassium should also be used with caution.

Agents Causing Renin Release

: The antihypertensive effect of Gen-Cilazapril 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) should be used with caution. Beta- adrenergic blocking drugs may add some further antihypertensive effect to cilazapril.

Inhibitors of Endogenous Prostaglandin Synthesis

: Concomitant administration of a nonsteroidal anti-inflammatory drug (NSAID) may reduce the antihypertensive effect of Gen-Cilazapril. The introduction of therapy with cilazapril (2.5 mg once daily) in hypertensive patients receiving indomethacin (50 mg twice daily) did not result in a reduction in blood pressure. However, the introduction of therapy with indomethacin (50 mg twice daily) in hypertensive patients receiving cilazapril (2.5 mg once daily) did not attenuate the blood pressure lowering effects of cilazapril. The interaction does not appear to occur in patients treated with cilazapril prior to the administration of a NSAID. There was no evidence of a pharmacokinetic interaction between cilazapril and indomethacin.

Digoxin

: No pharmacodynamic or pharmacokinetic interactions (and no increase in plasma digoxin concentrations) were observed when cilazapril therapy (5 mg once daily) was administered to healthy volunteers receiving digoxin (0.25 mg twice daily).

Lithium Salts

: As with other drugs which eliminate sodium, lithium elimination may be reduced. Therefore, the serum lithium levels should be monitored carefully if lithium salts are to be administered.

DOSAGE AND ADMINISTRATION

Dosage of Gen-Cilazapril (cilazapril) must be individualized. Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other pertinent clinical factors. The dosage of other antihypertensive agents being used with Gen-Cilazapril may need to be adjusted. The dose should always be taken at about the same time each day.

Hypertension:

Monotherapy: The recommended initial dose of Gen-Cilazapril is 2.5 mg once daily. Dosage should be adjusted according to blood pressure response, generally, at intervals of at least two weeks. The usual dose range for Gen-Cilazapril is 2.5 to 5 mg once daily. Minimal additional blood pressure lowering effects were achieved with a dose of 10 mg once daily. A dose of 10 mg should not be exceeded. In most patients, the antihypertensive effect of Gen-Cilazapril is maintained with a once a day dosing regimen. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, either twice daily administration with the same total daily dose, or an increase in dose should be considered. If blood pressure is not adequately controlled with Gen-Cilazapril alone a non- potassium-sparing diuretic may be administered concomitantly. After the addition of a diuretic, it may be possible to reduce the dose of Gen-Cilazapril.

Concomitant Diuretic Therapy: In patients receiving diuretics, Gen-Cilazapril therapy should be initiated with caution, since they are usually volume depleted and more likely to experience hypotension following ACE inhibition. Whenever possible, all diuretics should be discontinued two to three days prior to the administration of Gen-Cilazapril to reduce the likelihood of hypotension (see WARNINGS AND PRECAUTIONS). If this is not possible because of the patient's condition, Gen-Cilazapril should be started at 0.5 mg once daily and the blood pressure closely monitored after the first dose until stabilized. Thereafter, the dose should be adjusted according to individual response.

Dosage in Elderly Patients (Over 65 Years) Gen-Cilazapril treatment should be initiated with 1.25 mg (half of a 2.5 mg tablet) once daily or less, depending on the patient's volume status and general condition. Thereafter, the dose of Gen-Cilazapril must be adjusted according to individual tolerability, response, and clinical status.

Dosage Adjustment in Renal Impairment

(see WARNINGS AND PRECAUTIONS, Anaphylactoid Reactions during Membrane Exposure) The following dose schedules are recommended in patients with hypertension:

Hemodialysis patients: Gen-Cilazapril should be administered on days when dialysis is not performed and the dosage should be adjusted according to blood pressure response.

Dosage Adjustment in Hepatic Impairment

Should patients with liver cirrhosis require treatment with Gen-Cilazapril, treatment should be initiated with caution at a dose of 0.5 mg once daily or less as significant hypotension may occur (see WARNINGS AND PRECAUTIONS).

Congestive Heart Failure

Gen-Cilazapril can be used as adjunctive therapy with digitalis and/or diuretics in patients with congestive heart failure. Therapy should be initiated under close medical supervision. Blood pressure and renal function should be monitored both before and during treatment with Gen- Cilazapril because severe hypotension and more rarely, 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 should also be monitored (see DRUG INTERACTIONS). Therapy with Gen-Cilazapril should be initiated with a recommended starting dose of 0.5 mg once daily under close medical supervision. In elderly patients with congestive heart failure on high diuretic dosage the recommended starting dose of Gen-Cilazapril 0.5 mg must be strictly followed (see WARNINGS AND PRECAUTIONS). The dose should be increased to the lowest maintenance dose of 1 mg daily, usually within a 5 day period, according to tolerability and clinical status. Further titration within the usual maintenance dose of 1 mg to 2.5 mg daily should be carried out based on patients response, clinical status and tolerability. The usual maximum dose is 2.5 mg once daily. A few patients have been titrated to 5 mg once daily with some additional benefits being achieved. However only limited data is available in congestive heart failure patients treated with 5 mg once daily.

Dosage Adjustment in Patients with Congestive Heart Failure and Renal Impairment or Hyponatremia: Reduced dosage may be required for patients with congestive heart failure and renal impairment or hyponatremia depending on the creatinine clearance. The following dosing is recommended:

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Limited data are available with regard to overdosage in humans. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should be normally treated by intravenous volume expansion with normal saline. Hemodialysis removes cilazapril and cilazaprilat from the general circulation to a limited extent.

ACTION AND CLINICAL PHARMACOLOGY

Gen-Cilazapril (cilazapril) is an angiotensin converting enzyme (ACE) inhibitor, which is used in the treatment of hypertension and congestive heart failure. Gen-Cilazapril suppresses the renin-angiotensin-aldosterone system and thereby reduces both supine and standing systolic and diastolic blood pressures. Renin is an enzyme that is released by the kidneys into the circulation to stimulate the production of angiotensin I, an inactive decapeptide. Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II, a potent vasoconstrictor. Angiotensin II also stimulates aldosterone secretion, leading to sodium and fluid retention. After absorption, cilazapril, a pro-drug, is hydrolysed to cilazaprilat, the active metabolite, which prevents the conversion of angiotensin I to angiotensin II by inhibition of ACE. Following the administration of Gen-Cilazapril, plasma ACE activity is inhibited more than 90% within two hours at therapeutic doses. Plasma renin activity (PRA) and angiotensin I concentrations are increased and angiotensin II concentrations and aldosterone secretion are decreased. The increase in PRA comes as a result of the loss of negative feedback on renin release caused by the reduction in angiotensin II. The decreased aldosterone secretion may lead to small increases in serum potassium along with sodium and fluid loss. In patients with normal renal function, serum potassium usually remains within the normal range during Gen-Cilazapril treatment. Mean serum potassium values increased by 0.02 mEq/L in patients with a normal baseline serum creatinine and by 0.11 mEq/L in patients with a raised serum creatinine. In patients concomitantly taking potassium-sparing diuretics, potassium levels may rise. ACE is identical to kininase II. Therefore, Gen-Cilazapril may interfere with the degradation of the vasodepressor peptide bradykinin. The role that this plays in the therapeutic effects of Gen- Cilazapril is unknown.

Hypertension:

The antihypertensive effect of Gen-Cilazapril is usually apparent within the first hour after administration, with maximum effect observed between three and seven hours after dosing. Supine and standing heart rates remain unchanged. Reflex tachycardia has not been observed. Small, clinically insignificant alterations of heart rate may occur. At recommended doses, the effect of Gen-Cilazapril in hypertensive patients and in patients with congestive heart failure is maintained for up to 24 hours. In some patients, blood pressure reduction may diminish toward the end of the dosage interval. Blood pressure should be assessed after two to four weeks of therapy, and dosage adjusted if required. The antihypertensive effect of Gen-Cilazapril is maintained during long-term therapy. No rapid increase in blood pressure has been observed after abrupt withdrawal of Gen-Cilazapril. The antihypertensive effect of angiotensin converting enzyme inhibitors, including Gen- Cilazapril is generally lower in black patients than in non-blacks. Racial differences in response are no longer evident when cilazapril is administered in combination with hydrochlorothiazide. In hypertensive patients with moderate to severe renal impairment, the glomerular filtration rate and renal blood flow remained in general unchanged with Gen-Cilazapril.

Congestive Heart Failure

In patients with congestive heart failure the renin-angiotensin-aldosterone and the sympathetic nervous systems are generally activated leading to enhanced systemic vasoconstriction and to the promotion of sodium and water retention. By suppressing the renin-angiotensin-aldosterone system, Gen-Cilazapril improves loading conditions in the failing heart by reducing systemic vascular resistance (afterload) and pulmonary capillary wedge pressure (preload) in patients on diuretics and/or digitalis. The onset of action of Gen-Cilazapril occurs within 1-2 hours, reaching its maximum effect within 2-4 hours after the first dose. The exercise tolerance of these patients was increased and was associated with an improvement of clinical symptomatology. Patients studied belonged primarily to New York Heart Association Class II and III. The effect of Gen- Cilazapril on survival in patients with heart failure has not been evaluated.

Pharmacokinetics

Cilazapril is well absorbed and rapidly converted to the active form, cilazaprilat. Peak plasma concentrations, and times to peak plasma concentrations for cilazapril and cilazaprilat following the oral administration of 0.5 to 5 mg cilazapril are given below:

Maximum plasma concentrations of cilazaprilat are reached within two hours after administration of cilazapril. Maximum ACE inhibition is greater than 90% after 1 to 5 mg cilazapril. Maximum ACE inhibition is 70 to 80% after 0.5 mg cilazapril. Dose proportionality is observed following the administration of 1 to 5 mg cilazapril. Apparent non-proportionality is observed at 0.5 mg reflective of the binding to ACE. The higher doses of cilazapril are associated with longer duration of maximum ACE inhibition. The absolute bioavailability of cilazaprilat after oral administration of cilazapril is 57% based on urinary recovery data. (The absolute bioavailability of cilazaprilat after oral administration of cilazaprilat is 19%.) Ingestion of food immediately before the administration of cilazapril reduces the average peak plasma concentration of cilazaprilat by 29%, delays the peak by one hour and reduces the bioavailability of cilazaprilat by 14%. These pharmacokinetic changes have little influence on plasma ACE inhibition. Cilazaprilat is eliminated unchanged by the kidneys. The total urinary recovery of cilazaprilat after intravenous administration of 2.5 mg is 91%. Total clearance is 12.3 L/h and renal clearance is 10.8 L/h. The total urinary recovery of cilazaprilat following the oral administration of 2.5 mg cilazapril is 52.6%. Half-lives for the periods 1 to 4 hours and 1 to 7 days after the intravenous administration of 2.5 mg cilazaprilat are 0.90 and 46.2 hours respectively. These data suggest the saturable binding of cilazaprilat to ACE. The early elimination phase corresponds to the clearance of free drug. During the terminal elimination phase, almost all of the drug is bound to enzyme. Following the oral administration of 0.5, 1, 2.5 and 5 mg cilazapril, terminal elimination phase half-lives for cilazaprilat are 48.9, 39.8, 38.5 and 35.8 h respectively. After multiple dose, daily administration of 2.5 mg cilazapril for 8 days, pharmacokinetic parameter values for intact cilazapril after the last dose are similar to the first dose. For cilazaprilat, peak plasma concentrations are achieved at the same time but are 30% higher after the last dose. Trough plasma concentrations and areas under the curve are 20% higher. The terminal elimination phase half-life after the last dose is 53.8 h. The effective half-life of accumulation for cilazaprilat is 8.9 h.

Pharmacokinetics in Special Populations

Following the administration of 1 mg cilazapril to healthy elderly and young volunteers, the elderly group experienced greater peak plasma concentrations of cilazaprilat and areas under the curve (39% and 25%, respectively) and lower total clearance and renal clearance (20% and 28%, respectively) than the younger volunteers. In patients with renal impairment, peak plasma concentrations of cilazaprilat, times to peak plasma concentrations, early elimination phase half-lives, areas under the curve and 24 hour plasma concentrations all increase as creatinine clearance decreases. The changes in these parameters are small for patients with creatinine clearances of 40 mL/min or more. Cilazaprilat clearance (total and renal) decreases in parallel with creatinine clearance. Cilazaprilat is not eliminated in patients with complete renal failure. Hemodialysis reduces concentrations of both cilazapril and cilazaprilat to a limited extent. Following the administration of 1 mg cilazapril in patients with moderate to severe compensated liver cirrhosis, peak plasma concentrations of cilazapril and cilazaprilat are increased (57% and 28% respectively), attained 30 minutes and 45 minutes earlier, and total clearances are decreased (51% and 31% respectively), in comparison to healthy subjects. The renal clearance and early and terminal elimination phase half-lives of cilazaprilat are decreased 52%, 42% and 62% respectively. In patients with congestive heart failure the clearance of cilazaprilat is correlated with the creatinine clearance. Thus, dosage adjustments beyond those recommended for patients with impaired renal functions (see DOSAGE AND ADMINISTRATION under Congestive Heart Failure) should not be necessary.

STABILITY AND STORAGE RECOMENDATIONS

Store at controlled room temperature (15 to 30degC). Keep container tightly closed. Keep in a safe place out of the reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Gen-Cilazapril is available in film-coated tablets containing:

• 1 mg cilazapril - Yellow, oval-shaped, biconvex, film coated tablet, with "CI" scoreline "1" on one side and "G" on the other side. Available in HDPE (high density polyethylene) bottles of 100 and 500 tablets.

• 2.5 mg cilazapril - Pinkish brown, oval-shaped, biconvex, film coated tablet, with "CI" scoreline "2.5" on one side and "G" on the other side. Available in HDPE bottles of 100 and 500 tablets.

• 5 mg cilazapril - Reddish brown, oval-shaped, biconvex, film coated tablet, with "CI" scoreline "5" on one side and "G" on the other side. Available in HDPE bottles of 100 and 500 tablets.

Composition

Gen-Cilazapril 1 mg, 2.5 mg and 5 mg film-coated tablets contain 1 mg, 2.5 mg and 5 mg anhydrous cilazapril, as cilazapril monohydrate, respectively. The tablets contain the following non-medicinal ingredients: colloidal silicon dioxide, lactose, pregelatinized starch, sodium bicarbonate, sodium stearyl fumarate. In addition, the tablets contain the following ingredients as part of their colourant mixture: 1 mg: hydroxypropyl methylcellulose, polydextrose, polyethylene glycol, titanium dioxide, triacetin, yellow iron oxide. 2.5 mg: hydroxypropyl methylcellulose, polydextrose, polyethylene glycol, red iron oxide, titanium dioxide, triacetin, yellow iron oxide. 5 mg: D&C Yellow no. 10, FD&C Blue no. 2, FD&C Red no. 40, FD&C Yellow no. 6, polyethylene glycol, titanium dioxide. Product Monograph available upon request. Genpharm Inc. Etobicoke, Ontario M8Z 2S6