PRODUCT MONOGRAPH

SANDOZ LISINOPRIL

(Lisinopril Tablets) 5, 10 and 20 mg USP

Angiotensin Converting Enzyme Inhibitor

Sandoz Canada Inc. Date of Revision: September 24, 2007 145 Jules-Leger Boucherville, QC, Canada J4B 7K8 Control No. : 099076, 114720

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 10 DRUG INTERACTIONS. 15 DOSAGE AND ADMINISTRATION 16 OVERDOSAGE 19 ACTION AND CLINICAL PHARMACOLOGY 19 STORAGE AND STABILITY 22 DOSAGE FORMS, COMPOSITION AND PACKAGING 22

PART II: SCIENTIFIC INFORMATION 23

PHARMACEUTICAL INFORMATION 23 CLINICAL TRIALS 23 DETAILED PHARMACOLOGY 25 TOXICOLOGY. 25 REFERENCES 32

PART III: CONSUMER INFORMATION 34

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Sandoz Lisinopril Lisinopril Tablets 5, 10 and 20 mg

Angiotensin Converting Enzyme Inhibitor PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Sandoz Lisinopril is contraindicated in patients who:

• are hypersensitive to any component of this product;

• have a history of angioneurotic edema relating to previous treatment with an angiotensin- converting enzyme inhibitor;

• have hereditary or idiopathic angioedema.

• have a known allergy to angiotensin-converting enzyme inhibitors

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

When used in pregnancy, ACE inhibitors can cause injury or even death to the developing fetus. When pregnancy is detected, Sandoz Lisinopril should be discontinued as soon as possible (WARNINGS AND PRECAUTIONS, Use in Pregnancy, CONSUMER INFORMATION).

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Angioedema

Angioedema has been reported in patients treated with Sandoz Lisinopril. This may occur at any time during treatment. Angioedema associated with laryngeal or tongue edema and/or shock may be fatal. If angioedema occurs, Sandoz Lisinopril should be promptly discontinued and the patient should be observed until the swelling subsides. Where swelling is confined only to the tongue, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. However, where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, emergency therapy should be administered promptly when indicated. This includes giving subcutaneous adrenaline (0.5 mL 1:1000), and/or maintaining a patent airway. The patient should be under close medical supervision until complete and sustained symptom resolution has occurred. 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).

Hypotension

Symptomatic hypotension has occurred after administration of Sandoz Lisinopril, 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, vomiting, or possibly in patients with renin dependent renovascular hypertension (see DOSAGE AND ADMINISTRATION). 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 blood pressure could potentially fall, patients at risk for hypotension should start therapy 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 lisinopril and/or diuretic is increased. Similar considerations 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 may not be a contraindication to further doses. These can usually be given to hypertensive patients without difficulty once the blood pressure has increased after volume expansion. However, lower doses of Sandoz Lisinopril and/or reduced concomitant diuretic therapy should be considered. If hypotension occurs during treatment following acute myocardial infarction, consideration should be given to Sandoz Lisinopril discontinuation (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION, Treatment Following Acute Myocardial Infarction). In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with Sandoz Lisinopril. If hypotension occurs, a reduction of dose or discontinuation of therapy should be considered.

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 lisinopril 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.

Use in Pregnancy

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, Sandoz Lisinopril should be discontinued as soon as possible. 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, experience with those procedures has been limited and has not been associated with significant clinical benefit. Lisinopril 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. Human Data: It is not known whether exposure limited to the first trimester of pregnancy can adversely affect fetal outcome. 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; oligohydramnios in this setting has been 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.

Animal Data:

Lisinopril was not teratogenic in mice treated on days 6-15 of gestation with up to 1 000 mg/kg/day (625 times the maximum recommended human dose). There was an increase in fetal resorptions at doses down to 100 mg/kg; at doses of 1 000 mg/kg this was prevented by saline supplementation. There was no fetotoxicity or teratogenicity in rats treated with up to

300 mg/kg/day (188 times the maximum recommended dose) of lisinopril at days 6-17 of gestation. In rats receiving lisinopril from day 15 of gestation through day 21 postpartum, there was an increased incidence in pup deaths on days 2-7 postpartum and a lower average body weight of pups on day 21 postpartum. The increase in pup deaths and decrease in pup weight did not occur with maternal saline supplementation. Lisinopril, at doses up to 1 mg/kg/day, was not teratogenic when given throughout the organogenic period in saline supplemented rabbits. Saline supplementation (physiologic saline in place of tap water) was used to eliminate maternotoxic effects and enable evaluation of the teratogenic potential at the highest possible dosage level. The rabbit has been shown to be extremely sensitive to angiotensin converting enzyme inhibitors (captopril and enalapril) with maternal and fetotoxic effects apparent at or below the recommended therapeutic dosage levels in man. Fetotoxicity was demonstrated in rabbits by an increased incidence of fetal resorptions at an oral dose of lisinopril of 1 mg/kg/day and by an increased incidence of incomplete ossification at the lowest dose tested (0.1 mg/kg/day). A single intravenous dose of 15 mg/kg of lisinopril administered to pregnant rabbits on gestation days 16, 21 or 26 resulted in 88% to 100% fetal death. By whole body autoradiography, radioactivity was found in the placenta following administration of labelled lisinopril to pregnant rats, but none was found in the fetuses.

Use in Nursing Mothers

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

Race

Angiotensin converting inhibitors cause a higher rate of angioedema in black patients than in non- black patients. The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black patients (usually a low-renin hypertensive population) than in non-black patients.

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. In acute myocardial infarction, treatment with lisinopril should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 177 mmol/L and/or proteinuria exceeding 500 mg/24 hour. If renal dysfunction develops during treatment with Sandoz Lisinopril (serum creatinine concentration exceeding 265 mmol/L or a doubling from the pretreatment value), then the physician should consider withdrawal of Sandoz Lisinopril. Use of Sandoz Lisinopril should include appropriate assessment of renal function.

Hypotension Following Acute Myocardial Infarction

Lisinopril treatment following acute myocardial infarction must not be initiated in patients at risk of further serious hemodynamic deterioration after vasodilator treatment. These include patients with systolic blood pressure of 100 mmHg or lower or those in cardiogenic shock. During the first three days following the infarction, dosage reduction should occur if systolic blood pressure is between 100 and 120 mmHg (see DOSAGE AND ADMINISTRATION, Treatment Following Acute Myocardial Infarction). Patients with myocardial infarction in the GISSI-3 study treated with Sandoz Lisinopril had a higher (9.0% vs 3.7%) incidence of persistent hypotension (systolic blood pressure less than 90 mmHg for more than 1 hour) than patients treated with placebo.

Hyperkalemia

In clinical trials with daily doses of 2.5 to 20 mg, hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 2.2% of hypertensive patients and 4.0% of patients with congestive heart failure. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in approximately 0.1% of hypertensive patients. As shown in the ATLAS trial (see ACTION AND CLINICAL PHARMACOLOGY), high dose (up to 35 mg) versus low dose (up to 5 mg) treatment may predispose CHF patients to hyperkalemia (6.4% versus 3.5%). This event was manageable and rarely led to treatment withdrawal. Therapy discontinuation rates due to hyperkalemia for high versus low dose were 0.4% versus 0.1%, respectively. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes (see DRUG INTERACTIONS).

Valvular Stenosis, Hypertrophic Cardiomyopathy

There is concern on theoretical grounds that patients with aortic stenosis or hypertrophic cardiomyopathy might be at particular risk of decreased coronary perfusion when treated with vasodilators. Sandoz Lisinopril should be given with caution to these patients.

Surgery/Anesthesia

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, lisinopril 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.

Patients with Impaired Liver Function

Hepatitis, jaundice (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with lisinopril in patients with or without preexisting liver abnormalities (see ADVERSE REACTIONS). In most cases the changes were reversed on discontinuation of the drug. Should the patient receiving Sandoz Lisinopril 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 Sandoz Lisinopril should be considered when appropriate. There are no adequate studies in patients with cirrhosis and/or liver dysfunction. Sandoz Lisinopril should be used with particular caution in patients with preexisting 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 Sandoz Lisinopril has been reported. Such a possibility should be considered as part of the differential diagnosis of the cough.

Geriatrics

In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of Sandoz Lisinopril. Pharmacokinetic studies, however, indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients so that dosage adjustments should be made with particular caution (see DOSAGE AND ADMINISTRATION).

Pediatrics

Safety and effectiveness in children have not been established.

Diabetic Patients

In diabetic patients treated with oral antidiabetic agents or insulin, glycemic control should be closely monitored during the first month of treatment with lisinopril.

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 Hymenoptera 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.

Occupation Hazards

Ability to drive and use machines; dizziness or tiredness may occur during treatment with lisinopril.

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 lisinopril. The possibility of symptomatic hypotension with lisinopril can be minimized by discontinuing the diuretic prior to initiation of treatment with lisinopril and/or lowering the initial dose of lisinopril (see WARNINGS AND PRECAUTIONS, Hypotension and DOSAGE AND ADMINISTRATION).

Hypotension - Patients on Antihypertensive Therapy

When lisinopril is given to patients already treated with other antihypertensive agents, further falls in blood pressure may also occur.

Agents Increasing Serum Potassium

Since lisinopril 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, with caution and frequent monitoring of serum potassium, since they may lead to a significant increase in serum potassium. Potassium-containing salt substitutes should also be used with caution.

Agents Causing Renin Release

The antihypertensive effect of Sandoz Lisinopril 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 lisinopril.

NSAIDs

The antihypertensive effect of lisinopril may be diminished with concomitant nonsteroidal anti- inflammatory drug use. In some patients with compromised renal function who are being treated with nonsteroidal anti-inflammatory drugs, the coadministration of ACE inhibitors may result in further deterioration of renal function. Indomethacin may diminish the antihypertensive efficacy of concomitantly-administered Sandoz Lisinopril.

Lithium Salts

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

Antidiabetics

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycemic agents) may cause an increased blood glucose lowering effect with risk of hypoglycemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.

DOSAGE AND ADMINISTRATION

Since absorption of Sandoz Lisinopril tablets is not affected by food, the tablets may be administered before, during or after meals. Sandoz Lisinopril should be administered in a single daily dose. Sandoz Lisinopril should be taken at the same time each day. Dosage must be individualized.

Essential Hypertension

In patients with essential hypertension, not on diuretic therapy, the usual recommended starting dose is 10 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 daily dose. In some patients, acheivement of optimal blood pressure reduction may require two to four weeks of therapy. The antihypertensive effect may diminish toward the end of the dosing interval regardless of the administered dose, but most commonly with a dose of 10 mg daily. 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, an increase in dose should be considered. The maximum dose used in long-term controlled clinical trials was 80 mg/day. If blood pressure is not controlled with Sandoz Lisinopril alone, a low dose of a diuretic may be added. Hydrochlorothiazide 12.5 mg has been shown to provide an additive effect. After the addition of a diuretic, it may be possible to reduce the dose of Sandoz Lisinopril.

Diuretic Treated Patients: WARNINGS AND PRECAUTIONS

In hypertensive patients who are currently being treated with a diuretic, symptomatic hypotension may occur occasionally following the initial dose of Sandoz Lisinopril. The diuretic should be discontinued, if possible, for two to three days before beginning therapy with Sandoz Lisinopril to reduce the likelihood of hypotension (see

). The dosage of Sandoz Lisinopril should be adjusted according to blood pressure response. If the patient's blood pressure is not controlled with Sandoz Lisinopril alone, diuretic therapy may be resumed as described above.

If the diuretic cannot be discontinued, an initial dose of 5 mg should be used under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS AND PRECAUTIONS, Hypotension and DRUG INTERACTIONS). A lower starting dose is required in the presence of renal impairment, in patients in whom diuretic therapy cannot be discontinued, patients who are volume- and/or salt-depleted for any reason, and in patients with renovascular hypertension.

Dosage Adjustment in Renal Impairment:

Dosage in patients with renal impairment should be based on creatinine clearance as outlined in the table below:

Creatinine Clearance Starting Dose

<=70 >30 mL/min (<=1.17 >=0.5 mL/s)

<=30 >=10 mL/min (<=0.5 >=0.17 mL/s)

<10 mL/min (<0.17 mL/s) (including patients on dialysis)

5.0-10.0 mg/day

2.5-5.0 mg/day

2.5 mg/dayx

x

Dosage and/or frequency of administration should be adjusted depending on the blood pressure response.

The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily. Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g. polyacrylonitrile [PAN] and treated concomitantly with an ACE inhibitor) (see WARNINGS AND PRECAUTIONS, Anaphylactoid Reactions During Membrane Exposure).

Dosage in the Elderly:

In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of Sandoz Lisinopril. Pharmacokinetic studies, however, indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients so that dosage adjustments should be made with particular caution.

Renovascular Hypertension

Some patients with renovascular hypertension, especially those with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, may develop an exaggerated response to the first dose of Sandoz Lisinopril. Therefore, a lower starting dose of 2.5 or 5 mg is recommended, under close medical supervision. Thereafter, the dosage may be adjusted according to the blood pressure response. Doses should be carefully titrated.

Congestive Heart Failure

Sandoz Lisinopril is to be used in conjunction with a diuretic and, where appropriate, digitalis. Therapy must be initiated under close medical supervision, usually in a hospital. Blood pressure and renal function should be monitored, both before and during treatment with Sandoz Lisinopril, because severe hypotension and, more rarely, consequent renal failure have been reported (see WARNINGS AND PRECAUTIONS, Hypotension and Renal Impairment). 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. The recommended initial dose is 2.5 mg per day. If required, the dose should be increased gradually, depending on the patient response by increments of no greater than 10 mg and at intervals of no less than 2 weeks, up to a maximum of 35 mg once daily. Dose adjustment should be based on the individual patient's tolerance and clinical response. The usual effective dosage range is 5-20 mg per day administered in a single daily dose. Dose titration may be performed over a 2-4 week period, or more rapidly if indicated by the presence of residual signs and symptoms of heart failure.

Treatment Following Acute Myocardial Infarction

Treatment of hemodynamically stable patients may be started as early as within 24 hours following the onset of symptoms of myocardial infarction. Patients should receive, as appropriate, standard recommended treatments such as thrombolytics, ASA and beta-blocker(s) (see INDICATIONS AND CLINICAL USE, Treatment Following Acute Myocardial Infarction). The first dose of Sandoz Lisinopril is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily thereafter. Patients with a low systolic blood pressure (between 100 and 120 mmHg) when treatment is started or during the first three days after the infarct should be given a lower dose, 2.5 mg orally. Treatment with Sandoz Lisinopril must not be initiated in patients who are at risk of serious hemodynamic deterioration (see WARNINGS AND PRECAUTIONS, Hypotension Following Acute Myocardial Infarction). After three days if hypotension occurs (systolic blood pressure less than or equal to 100 mmHg), a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than one hour), Sandoz Lisinopril should be withdrawn. Renal function should be assessed before and during therapy with Sandoz Lisinopril (see WARNINGS AND PRECAUTIONS, Renal Impairment). Dosing should normally continue for six weeks. At that time, patients with signs or symptoms of heart failure should continue with Sandoz Lisinopril (see DOSAGE AND ADMINISTRATION, Congestive Heart Failure). Sandoz Lisinopril is compatible with intravenous or transdermal glyceryl trinitrate.

OVERDOSAGE

Overdose symptoms include severe hypotension, electrolyte disturbances, and renal failure. Overdosed patients should be kept under very close observation. Therapeutic measures depend on the nature and severity of symptoms. Measures to prevent absorption and methods to speed elimination should be employed. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. If available, angiotensin II may be beneficial. If severe hypotension occurs, place the patient in the shock position and infuse intravenous normal saline immediately. Vasopressors including angiotensin II may be considered if fluid replacement is inadequate or contraindicated. Circulating lisinopril may be removed by hemodialysis. Avoid high-flux polyacrylonitrile dialysis membranes (see WARNINGS AND PRECAUTIONS, Anaphylactoid Reactions During Membrane Exposure). Serum electrolytes and creatinine should be monitored frequently.

ACTION AND CLINICAL PHARMACOLOGY

Sandoz Lisinopril is an ACE inhibitor which is used in the treatment of hypertension, congestive heart failure and following myocardial infarction in hemodynamically stable patients. Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to the pressor substance, angiotensin II. 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 K+. In patients treated with Sandoz Lisinopril and a thiazide diuretic there was essentially no change in serum potassium (see WARNINGS AND PRECAUTIONS). ACE is identical to kininase II. Thus, Sandoz Lisinopril may also block the degradation of bradykinin, a potent vasodilator peptide. However, the role that this plays in the therapeutic effects of Sandoz Lisinopril is unknown. While the mechanism through which Sandoz Lisinopril lowers blood pressure is believed to be primarily the suppression of the renin-angiotensin-aldosterone system, Sandoz Lisinopril also lowers blood pressure in patients with low-renin hypertension.

Pharmacodynamics

Administration of Sandoz Lisinopril to patients with hypertension results in a reduction of both supine and standing blood pressure. Abrupt withdrawal of Sandoz Lisinopril has not been associated with a rapid increase in blood pressure. In most patients studied, after oral administration of an individual dose of lisinopril, the onset of antihypertensive activity is seen at one hour with peak reduction of blood pressure achieved by six hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses. However, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was six hours after dosing. On occasion, achievement of optimal blood pressure reduction may require 2 to 4 weeks of therapy. In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and in heart rate. In a study in nine hypertensive patients, following administration of Sandoz Lisinopril, there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of Sandoz Lisinopril on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large. When Sandoz Lisinopril is given together with thiazide-type diuretics, its blood pressure lowering effect is approximately additive. The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black (usually a low-renin hypertensive population) than in non-black patients. Administration of Sandoz Lisinopril to patients with congestive heart failure reduces afterload and preload of the heart, resulting in an increase in cardiac output, without reflex tachycardia. Exercise tolerance is improved. In the Assessment of Treatment with Lisinopril and Survival Study (ATLAS) higher doses of Sandoz Lisinopril up to 35 mg once daily reduced the risk of the combined outcome of mortality and hospitalization in patients with chronic congestive heart failure. The ATLAS study was an international, multicenter, double-blind, parallel group clinical trial which evaluated the effects of low doses, 2.5 mg-5.0 mg, versus high doses, 32.5 mg-35.0 mg Sandoz Lisinopril on mortality and morbidity in patients with chronic congestive heart failure. A total of 1 596 patients were randomized into the low-dose and 1 568 into the high-dose groups. Patients entered into the ATLAS study were NYHA Class II, III, or IV, were treated with diuretics for at least 60 days prior to entry into the study, and had a left ventricular ejection fraction (LVEF) <=30%. Class II patients were eligible only if they were hospitalized or received emergency room treatment in the previous six months. Prior treatment with ACE inhibitors and digoxin was permitted, and patients were permitted routine therapies, other than ACE inhibitors, for the duration of the study. The median follow-up period was 46 months. The protocol excluded patients with recent cardiac surgery, unstable coronary artery disease, unstable ventricular arrhythmias, unstable CHF, or a non-CHF disorder that may have limited survival during the course of the trial. Overall, 77% of patients were NYHA class III; 89% had previous ACE inhibitor treatment. For the principal secondary endpoint, all-cause mortality and all-cause hospitalization, high-dose Sandoz Lisinopril was associated with a 11.6% (p=0.002) risk reduction over low-dose (2.5 mg and 5 mg). High-dose Sandoz Lisinopril was also associated with an 8.4% risk reduction in all-cause mortality and cardiovascular hospitalizations (p=0.036). The total number of hospitalizations per patient for heart failure was reduced by 23.2% (p=0.002). In a double-blind, randomized, placebo-controlled, parallel group study carried out in normotensive patients with insulin-dependent diabetes mellitus of relatively short duration (mean 14-15 years), the effect on the development and progression of diabetic retinopathy was examined in a subgroup of 354 patients with evaluable retinal photographs treated with a daily dose of 10 and 20 mg Sandoz Lisinopril or placebo for up to 24 months. Preliminary data obtained in 103 patients with mild to moderate retinopathy and 72 patients with no retinopathy at baseline indicate that treatment with Sandoz Lisinopril results in a significant risk reduction in the progression of retinopathy compared to placebo. There was, however, no significant effect on the incidence of either the appearance of new cases or the regression of existing cases of retinopathy over a two- year observation period.

Pharmacokinetics

After oral administration of Sandoz Lisinopril, peak serum concentrations of lisinopril occur within approximately 7 hours, although patients with recent myocardial infarction have demonstrated an increase in time to peak serum concentration to about 8 to 10 hours. Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Lisinopril does not bind serum proteins other than ACE. Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the extent of absorption of lisinopril is approximately 25%, with large inter- subject variability (6-60%) at all doses tested (5-80 mg). Lisinopril absorption is not influenced by the presence of food in the gastrointestinal tract. Following multiple doses of lisinopril, the effective half-life of accumulation is 12 hours. In a study in elderly healthy subjects (65 years and above), a single dose of lisinopril 20 mg produced higher serum concentrations and higher values for the area under the curve than those seen in young healthy adults given a similar dose. In another study, single daily doses of lisinopril 5 mg were given for 7 consecutive days to young and elderly healthy volunteers and to elderly patients with congestive heart failure. Maximum serum concentrations of lisinopril on Day 7 were higher in the elderly volunteers than in the young, and still higher in the elderly patients with congestive heart failure. Renal clearance of lisinopril was decreased in the elderly, particularly in the presence of congestive heart failure. The elimination of lisinopril in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With renal function <=30 mL/min, peak and trough lisinopril levels increase, time to peak concentration increases and time to steady state is prolonged (see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS, Patients with Impaired Liver Function). Lisinopril can be removed by dialysis. Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly.

STORAGE AND STABILITY

Store between 15 and 30degC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms

Sandoz Lisinopril Tablets 5 mg, are pink, round convex uncoated tablets, scored on one side, plain on the other side. Sandoz Lisinopril Tablets 10 mg, are pink, round convex uncoated tablets, plain on either side. Sandoz Lisinopril Tablets 20 mg, are pink, round convex uncoated tablets, plain on either side. Composition Active ingredient: lisinopril (as dihydrate). Inactive ingredients: calcium hydrogen phosphate dihydrate, maize starch, croscarmellose sodium, magnesium stearate, mannitol, and ferric oxide.

Packaging

Sandoz Lisinopril 5 mg, 10 mg, and 20 mg tablets are available in blisters of 30 tablets (3x10) and in bottles of 100 tablets.