PRODUCT MONOGRAPH

Inhibace(r) (Cilazapril) Tablets 1.0, 2.5, 5.0 mg

ACTIONS AND CLINICAL PHARMACOLOGY

INHIBACE (cilazapril) is an angiotensin converting enzyme (ACE) inhibitor, which is used in the treatment of hypertension and congestive heart failure. INHIBACE 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 INHIBACE, 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 INHIBACE 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, INHIBACE may interfere with the degradation of the vasodepressor peptide bradykinin. The role that this plays in the therapeutic effects of INHIBACE is unknown.

Hypertension

The antihypertensive effect of INHIBACE 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 INHIBACE 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 INHIBACE is maintained during long-term therapy. No rapid increase in blood pressure has been observed after abrupt withdrawal of INHIBACE. The antihypertensive effect of angiotensin converting enzyme inhibitors, including INHIBACE 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 INHIBACE.

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, INHIBACE 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 INHIBACE 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 INHIBACE 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

Elderly Patients:

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.

Renal Impairment:

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.

Hepatic Impairment:

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.

Congestive Heart Failure:

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.

CONTRAINDICATIONS

INHIBACE (cilazapril) is contraindicated in patients who are hypersensitive to cilazapril, its components or other ACE inhibitors. INHIBACE 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. INHIBACE, like other ACE inhibitors is contraindicated during pregnancy and lactation (see WARNINGS: Pregnant Women and Nursing Women).

WARNINGS

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, INHIBACE (cilazapril) should be discontinued as soon as possible.

General

INHIBACE tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Angioedema

Angioedema has been reported in patients treated with angiotensin-converting enzyme inhibitors including INHIBACE. Angioedema associated with laryngeal edema and/or shock may be fatal. If angioedema occurs, INHIBACE should be promptly discontinued and appropriate therapy instituted without delay. 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 INHIBACE 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 INHIBACE 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 INHIBACE, 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 INHIBACE. Once the blood pressure has increased after volume expansion, INHIBACE 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

mg of INHIBACE.

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 ACE Inhibitors. However, in no patient could a causal relationship to cilazapril be established. Periodic monitoring of white blood cell counts should be considered in patients with collagen vascular disease and renal disease such as systemic lupus erythematosus and scleroderma, or in patients receiving immunosuppressive therapy, especially when they also have impaired renal function.

Pregnant Women

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, INHIBACE 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, intrauterine growth restriction, anuria, renal tubular dysplasia, 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.

PRECAUTIONS

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-aldersterone system, rarely, acute renal failure have been reported 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 and produce increases in blood urea nitrogen and/or serum creatinine. Although these alterations are usually reversible upon discontinuation of Inhibace and/or diuretic therapy, cases of severe renal dysfunction and, rarely, acute renal failure have been reported. In susceptible patients, concomitant diuretic use may further increase risk. Use of INHIBACE (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.

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 development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia (see Drug Interactions and ADVERSE REACTIONS).

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.

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.

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 INHIBACE (see ADVERSE REACTIONS). Jaundice was also spontaneously reported in one patient worldwide. Should the patient receiving INHIBACE 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 INHIBACE should be considered when appropriate. There are no adequate studies in patients with cirrhosis and/or liver dysfunction. INHIBACE 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.

Cough

A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of INHIBACE, has been reported. Such possibility should be considered as part of the differential diagnosis of the cough. Pediatric Use The safety and effectiveness of the use of INHIBACE 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 INHIBACE 0.5 mg must be strictly followed (see WARNINGS, 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 INHIBACE can be minimized by either discontinuing the diuretic, or increasing the salt intake prior to initiation of treatment with INHIBACE. If it is not possible to discontinue the diuretic, the starting dose of INHIBACE 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 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 INHIBACE 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 INHIBACE 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 non- steroidal anti-inflammatory drug (NSAID) may reduce the antihypertensive effect of INHIBACE. 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 INHIBACE 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

: Lithium should generally not be given with ACE inhibitors. ACE inhibitors reduce the renal clearance of lithium and add a risk of lithium toxicity.

INFORMATION FOR PATIENTS

Pregnancy:

Since the use of ACE inhibitors during pregnancy can cause injury and even death of the developing fetus, patients should be advised to stop the medication and report promptly to their physician if they become pregnant.

Angioedema:

Angioedema, including laryngeal edema, may occur especially following the first dose of cilazapril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician. Should the tongue and/or larynx be involved, the physician should be consulted immediately.

Hypotension:

Patients should be cautioned to report light-headedness, especially during the first few days of INHIBACE therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.

Neutropenia:

Patients should be advised to report promptly any indication of infection (e.g., sore throat, fever) since this may be an early sign of neutropenia.

Impaired Liver Function:

Patients should be advised to return to the physician if he/she experiences any symptoms possibly related to liver dysfunction. This would include "viral-like symptoms" in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.

Hyperkalemia:

Patients should be advised not to use potassium supplements or salt substitutes containing potassium without consulting their physician.

Surgery:

Patients planning to undergo surgery and/or anesthesia should be told to inform their physician that they are taking an ACE inhibitor.

Nursing Mothers:

Patients should be advised not to breast feed if they are taking INHIBACE.

Ability to Drive and Use Machines:

As with other ACE-inhibitors, impairment of performance in activities requiring complete mental alertness (e.g. driving a motor vehicle) is not to be expected with INHIBACE. However, it should be noted that dizziness may occasionally occur (see ADVERSE REACTIONS).

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Limited data are available with regard to overdosage in humans. The most likely manifestations are hypotension, which may be severe, hyperkalaemia, hyponatraemia and renal impairment with metabolic acidosis. Treatment should be mainly symptomatic and supportive. Hemodialysis removes cilazapril and cilazaprilat from the general circulation to a limited extent. Specific therapy with angiotensinamide may be considered if conventional therapy is ineffective.

DOSAGE AND ADMINISTRATION

Dosage of INHIBACE (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 INHIBACE 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 INHIBACE 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 INHIBACE 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 INHIBACE 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 INHIBACE 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 INHIBACE.

Concomitant Diuretic Therapy:

In patients receiving diuretics, INHIBACE 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 INHIBACE to reduce the likelihood of hypotension (see WARNINGS). If this is not possible because of the patient's condition, INHIBACE 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)

INHIBACE 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 INHIBACE must be adjusted according to individual tolerability, response, and clinical status.

Dosage Adjustment in Renal Impairment

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

Hemodialysis patients: INHIBACE 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 INHIBACE, treatment should be initiated with caution at a dose of 0.5 mg once daily or less as significant hypotension may occur (see PRECAUTIONS).

Congestive Heart Failure

INHIBACE 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 INHIBACE because severe hypotention 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 hypotention. Serum potassium should also be monitored (see WARNINGS and PRECAUTIONS, Drug Interactions). Therapy with INHIBACE should be initiated with a recommended starting dose of 0.5 mg once daily under close medical surpervision. In elderly patients with congestive heart failure on high diuretic dosage the recommended starting dose of INHIBACE 0.5 mg must be strictly followed (see WARNINGS). 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:

PHARMACEUTICAL INFORMATION

Drug Substance:

Proper Name:

cilazapril monohydrate

Chemical Name:

9(s)-[1(s)-(ethoxycarbonyl)-3-

phenylpropylamino]-octahydro-10-oxo-6H-pyridazo [1,2-a] [1,2] diazepine-1(s)-carboxylic acid monohydrate

Structural Formula:

Molecular Formula: C22H31N3O5 *H2O

Molecular Weight:

435.52

Physical Form:

White to off-white crystalline powder

Solubility:

Water (25 oC) 0.5 g/100 mL

pka1, pka2: 3.3, 6.4

pH (1% suspension):

4.9

Partition Coefficient: 0.8 (octanol-pH 7.4 buffer 22 oC) Melting Point: 98 oC with decomposition

Composition

INHIBACE 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. Non-medicinal ingredients: the tablets also contain lactose, cornstarch, hydroxypropyl methylcellulose, talc, sodium stearyl fumarate and titanium dioxide. Iron oxide is present as the colouring agent in the 1 mg, 2.5 mg and 5 mg tablets.

Stability and Storage Recommendations

Store 15-30 oC. Keep container tightly closed.

AVAILABILITY OF DOSAGE FORMS

INHIBACE (cilazapril) is available in film-coated tablets containing:

• 1 mg cilazapril - yellow, oval shaped, single scored biconvex tablets, imprinted CIL 1.

Available in bottles of 100 tablets. 2.5 mg cilazapril - pinkish-brown, oval shaped, single scored biconvex tablets, imprinted CIL 2,5. Available in bottles of 100 tablets. 5 mg cilazapril - reddish-brown, oval shaped, single scored biconvex tablets, imprinted CIL 5. Available in bottles of 100 tablets.

PHARMACOLOGY

In in vitro studies, using hippurylhistidylleucine as substrate, cilazaprilat, the active metabolite of cilazapril, inhibited the activity of ACE from rabbit lung (IC50 0.97-1.93 nM), hog lung (IC50 2.83 nM), human lung (IC50 1.39 nM), and human plasma (IC50 0.61 nM). Cilazaprilat (20 uM) did not have any effect on a number of other porcine, bovine, or human enzymes except E. coli dipeptidyl carboxypeptidase. In ex vivo studies, oral administration of 0.1 and 0.25 mg/kg cilazapril to rats inhibited plasma ACE activity by 76% and 96% respectively and 0.3-3 mg/kg significantly inhibited tissue ACE activity in a number of arteries and veins.

In vivo

, the dose of cilazapril and/or cilazaprilat required to reduce the angiotensin pressor response by 50% are summarized below:

In the anesthetised SHAD rats 0.06 umol/kg i.v. cilazaprilat potentiated the bradykinin induced vasodepressor response. The antihypertensive activity of cilazapril was assessed in a number of experimental animal models. In spontaneously hypertensive rats (SHR), single oral doses of 10 and 30 mg/kg cilazapril reduced systolic blood pressure for longer than six hours. Repeated daily dosing with oral doses of 10 and 30 mg/kg cilazapril demonstrated 24-hour activity and at the higher dose, antihypertensive effect became maximum after one week. When administered twice daily, the lowest oral dose of cilazapril that reduced systolic blood pressure was 1 mg/kg. Dose dependent decreases in systolic blood pressure were observed between oral doses of 1 and 10 mg/kg twice daily. No further increase in effect was observed with an oral dose of 30 mg/kg twice daily. Intravenous administration of up to 10 mg/kg of either cilazapril or cilazaprilat to conscious SHR evoked only small reductions in blood pressure. The reason for this disparity with the oral dosing data in the same animal model is unclear. Following the oral administration of 10 mg/kg cilazapril, the maximum decrease in systolic arterial pressure observed in conscious renal hypertensive hypovolemic dogs was approximately double that observed in normovolemic dogs. In the hypovolemic dogs, the systolic blood pressure fell significantly within 30 minutes of the first dose. The effect persisted for 6 hours. Maximum decrease in systolic arterial pressure in conscious normotensive hypovolemic dogs was similar to that observed in renal hypotensive normovolemic dogs. Heart rate changes accompanying the antihypertensive action of cilazapril in the rat and the dog were minimal. Total peripheral resistance and regional vascular resistance were reduced in all vascular beds except in the heart in SHR administered multiple, oral, daily doses of 10 mg/kg cilazapril. Regional blood flow to the kidneys, intestine and skin increased. Regional blood flow to the heart decreased. No changes were observed in cardiac output, cardiac index, stroke volume or heart rate. Hemodynamic and blood flow changes were similar after acute or repeated (twice daily for two weeks) administration of 1 mg/kg cilazapril. Additional increases in blood flow to the lungs, stomach, small intestine, pancreas and thymus were observed however. In conscious dogs, cilazapril had no effect on left ventricular pressure and on force of cardiac contraction at 3 mg/kg p.o. and marginal effects at 10 mg/kg p.o. At these doses, slight decreases were noted in abdominal aortic blood flow and heart rate. In anesthetized dogs, intravenous cilazapril doses of 0.03-1 mg/kg evoked dose dependent decreases in blood pressure and left ventricular pressure. At 1 mg/kg, left ventricular end diastolic pressure was decreased 15%, myocardial contractile force was reduced and heart rate was unchanged. At 0.3 mg/kg, cardiac output, coronary blood flow, left ventricular minute work, left ventricular stroke work, and cardiac index were decreased 15%, 12%, 31%, 40%, and 12% respectively. In the anesthetized dog with ischemic heart failure, intravenous doses of cilazaprilat (0.1-1 mg/kg) reduced total peripheral resistance, left ventricular end diastolic pressure, dp/dt, and mean aortic blood pressure. Cardiac output, heart rate, pulmonary arterial pressure and right arterial pressure remained unchanged. Oral administration of 3 mg/kg cilazapril did not have an effect on the increase in blood pressure and heart rate accompanying exercise in conscious cats. In anesthetized cats, cilazapril (10 mg/kg i.v.) increased right ventricular force of contraction (28%) and cardiac output (19%). Heart rate changes were minor. The pharmacokinetics of cilazapril and cilazaprilat have been examined in mice, rats, dogs, monkeys, marmosets and baboons. The oral absorption of cilazapril is rapid and peak plasma concentrations of cilazapril occur in less than 1 hour. Absorption is 70-89%. Cilazapril plasma concentrations decline rapidly with a half life of 0.7-2.7 hours. Plasma concentrations are less than dose proportional in baboons, and in rats and marmoset levels are too low for reliable quantitation. Cilazaprilat is produced rapidly in all species and peak concentrations occur in less than 1.5 hours. Bioavailability from oral cilazapril is 70-89%. Cilazaprilat plasma concentrations decline in a biphasic manner with half lives of 0.5-3.5 hours and 12-68 hours. Plasma concentrations are less than dose proportional, and show a low order of dose dependence during the terminal phase. This is consistent with saturable binding to ACE. The distribution of drug related material is largely confined to excretory organs, but all major tissues are exposed, including the fetus of pregnant animals. There is no evidence of tissue retention, and more than 95% of the dose is recovered within three days. Repeat administration leads to some accumulation, but only in a limited number of tissues, notably the liver and kidney. Excretion is rapid in all species. More than 90% of the total recovery in urine is achieved within 24 hours. Excretion is predominantly hepatic in rats and baboons, and renal in marmosets.

TOXICOLOGY

ACUTE TOXICITY

The signs of toxicity include: ataxia, reduced motor activity, diarrhea, respiratory depression, tremors, piloerection, prostration, hunched appearance, salivation, emesis and facial fur-staining.

LONG-TERM TOXICITY (Cont'd)

TOXICOLOGY

Bone marrow nucleated cell count.

LONG-TERM TOXICITY (Cont'd)

LONG-TERM TOXICITY (Cont'd)

LONG-TERM TOXICITY (Cont'd)

TOXICOLOGY

REPRODUCTION AND TERATOLOGY (Cont'd)

REPRODUCTION AND TERATOLOGY (Cont'd)

CARCINOGENICITY

An eighty-eight week carcinogenicity study with cilazapril was conducted in mice initially dosed at 5, 25 or 100 mg/kg/day, subsequently reduced to 1, 7 or 50 mg/kg/day from week 11 onwards. Another carcinogenicity study was conducted in rats in which dose levels of 0.5, 4 or 40 mg/kg/day were administered for 104 weeks. Hypertrophy of renal afferent glomerular arterioles and interlobular arteries, and increased cortical nephropathy were the only recorded findings and occurred in the mid- and high-dose groups in both studies. Tri-PAs staining of kidney sections from the 104 week rat carcinogenicity study indicated no hyperplastic or neoplastic oxyphilic cell response and no enhancement of the development of oncocytomas.

MUTAGENICITY

No evidence of mutagenicity with cilazapril was found in the Ames test with or without metabolic activation (up to 2.0 mg/plate), "Treatment and Plate" test (up to 7,000 ucg/mL), unscheduled DNA synthesis assay (up to 200 ucg/mL), mutagenic assay with Chinese hamster V79 cells with or without metabolic activation (up to 4,800 ucg/mL), chromosomal abbreration test with or without metabolic activation (up to 3,500 ucg/mL), or in vivo micronucleus test in mice (2.0 g/kg).

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