Sandoz Lisinopril Product Monograph

ACTIONS AND CLINICAL PHARMACOLOGY

Sandoz Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor which is used in the treatment of hypertension, congestive heart failure and following myocardial infarction in hemodynamically stable patients.

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 potassium. In patients treated with lisinopril and a thiazide diuretic there was essentially no change in serum potassium (see PRECAUTIONS).

ACE is identical to kininase II. Thus, 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 lisinopril lowers blood pressure is believed to be primarily the suppression of the renin-angiotensin-aldosterone system (RAAS), lisinopril also lowers blood pressure in patients with low-renin hypertension.

Pharmacodynamics

Hypertension

Adults: Administration of lisinopril to patients with hypertension results in a reduction of both supine and standing blood pressure. Abrupt withdrawal of 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 6 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 than with lower doses. However, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was 6 hours after dosing. On occasion, achievement of optimal blood pressure reduction may require 2 to 4 weeks of therapy.

Pediatrics (6-16 years of age): In a clinical study involving 115 hypertensive pediatric patients 6 to 16 years of age, patients who weighed <50 kg received either 0.625, 2.5, or 20 mg of lisinopril daily and patients who weighed ≥ 50 kg received either 1.25, 5, or 40 mg of lisinopril daily. At the end of 2 weeks, lisinopril administered once daily lowered trough blood pressure in a dose-dependent manner with consistent antihypertensive efficacy demonstrated at doses >1.25 mg (0.02 mg/kg). This effect was confirmed in a withdrawal phase, where the diastolic pressure rose by about 9 mmHg more in patients randomized to placebo than it did in patients who were randomized to remain on the middle and high doses of lisinopril. The dose-dependent antihypertensive effect of lisinopril was consistent across several demographic subgroups: age, Tanner stage, gender, race. In this study, lisinopril was generally well-tolerated.

Adults: 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 9 hypertensive patients, following administration of 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 lisinopril on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.

When lisinopril is given together with thiazide-type diuretics, its blood pressure lowering effect is approximately additive.

Congestive heart failure

Administration of 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 lisinopril ≤35 mg once daily reduced the risk of the combined outcome of mortality and hospitalization in patients with chronic congestive heart failure (CHF). 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 lisinopril on mortality and morbidity in patients with chronic CHF. A total of 1596 patients were randomized into the low dose and 1568 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 6 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 lisinopril was associated with an 11.6% (p=0.002) risk reduction over low dose (2.5 and 5 mg). High dose 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).

Pharmacokinetics

After oral administration of 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.

Adults: In a study in elderly healthy subjects (≥65 years of age), a single dose of lisinopril 20 mg produced higher serum concentrations and higher values for the area under the plasma curve (AUC) 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 CHF. 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 CHF. Renal clearance of lisinopril was decreased in the elderly, particularly in the presence of CHF.

The elimination of lisinopril in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate (GFR) is <30 mL/min. With renal function ≤30 mL/min, peak and through lisinopril levels increase, time to peak concentration increases and time to steady state is prolonged (see PRECAUTIONS, Renal Impairment, and DOSAGE AND ADMINISTRATION).

Lisinopril can be removed by dialysis.

Pediatrics (6-16 years of age): The pharmacokinetics of lisinopril were studied in 29 pediatric hypertensive patients between 6 and 16 years of age with GFR >30 mL/min/1.73 m². After doses of 0.1 to 0.2 mg/kg, steady state peak plasma concentrations of lisinopril occurred within 6 hours and the extent of absorption based on urinary recovery was about 28%. These values are similar to those obtained previously in adults. The typical value of lisinopril oral clearance (systemic clearance/absolute bioavailability) in a child weighing 30 kg is 10 L/h, which increases in proportion to renal function.

Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly.

INDICATIONS AND CLINICAL USE

Hypertension

Sandoz Lisinopril is indicated in the treatment of essential hypertension and in renovascular hypertension. It may be used alone or concomitantly with thiazide diuretics. A great majority of patients (>80%) with severe hypertension required combination therapy. Sandoz Lisinopril has been used concomitantly with beta blockers and calcium antagonists, but the data on such use are limited.

Heart Failure

Sandoz Lisinopril is indicated in the management of symptomatic congestive heart failure as adjunctive treatment with diuretics and, where appropriate, digitalis. Treatment with Sandoz Lisinopril should be initiated under close medical supervision, usually in a hospital.

Treatment Following Acute Myocardial Infarction

Sandoz Lisinopril is indicated in the treatment of hemodynamically stable patients as early as within 24 hours following acute myocardial infarction, to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, ASA and beta-blocker(s).

Therapy with Sandoz Lisinopril should be reassessed after 6 weeks. If there is no evidence of symptomatic or asymptomatic left ventricular dysfunction, treatment with Sandoz Lisinopril can be stopped.

Sandoz Lisinopril should not be used if systolic blood pressure is <100 mmHg, if clinically relevant renal failure is present, or if there is a history of bilateral stenosis of the renal arteries (see PRECAUTIONS, Hypotension Following Acute Myocardial Infarction, Renal Impairment).

In using Sandoz Lisinopril, attention should be given to the risk of angioedema (see WARNINGS, Angioedema).

CONTRAINDICATIONS

Lisinopril is contraindicated in patients who:

• Are hypersensitive to the drug or to any ingredient in the formulation. For a complete listing, see the PHARMACEUTICAL INFORMATION section of the product monograph;
• Have a known allergy to angiotensin-converting enzyme (ACE) inhibitors.
• Have a history of hereditary/idiopathic angioedema, or angioedema related to previous treatment with an ACE inhibitor (see WARNINGS, Angioedema);
• Are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraception (see WARNINGS, Special Populations, Pregnant Women and ADVERSE REACTIONS);
• Are nursing (see WARNINGS, Special Populations, Nursing Women);
• Are taking sacubitril/valsartan due to an increased risk of angioedema;

• Are taking aliskiren-containing drugs and have

  • diabetes mellitus (type 1 or type 2)
  • moderate to severe renal impairment (GFR < 60 ml/min/1.73 m²)
  • hyperkalemia (> 5mMol/L) or
  • congestive heart failure who are hypotensive (see WARNINGS, Dual Blockade of the Renin-Angiotensin System (RAS), PRECAUTIONS, Renal Impairment, and DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) with ACE inhibitors, ARBs or aliskiren-containing drugs);

• Are taking angiotensin receptor blockers (ARBs) or other ACE inhibitors in patients with:

  • diabetes with end organ damage,
  • moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73m2),
  • hyperkalemia (> 5mMol/L) or

  • congestive heart failure who are hypotensive (see DRUG INTERACTIONS,

    Angiotensin receptor blockers (ARBs) or other ACE inhibitors);

• Are less than 6 years of age;
• Are 6 to 16 years of age with severe kidney insufficiency (GFR < 60 mL/min/1.73m²).

Sandoz Lisinopril is contraindicated in combination with a neprilysin inhibitor (e.g. sacubitril). Do not administer Sandoz Lisinopril within 36 hours of switching to or from sacubitril/valsartan, a product containing a neprilysin inhibitor (See WARNINGS and DRUG INTERACTIONS).

WARNINGS

Serious Warnings and Precautions

Angioedema

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).

Patients receiving coadministration of ACE inhibitor with a mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus), a neutral endopeptidase (NEP) inhibitor, or tissue plasminogen activator may be at increased risk for angioedema. Caution should be used when either initiating ACE inhibitor therapy in patients already taking a mTOR inhibitor, or a NEP inhibitor or vice versa. Monitor patients for potential development of angioedema after initiation of tissue plasminogen activator infusion (see DRUG INTERACTIONS).

Patients receiving concomitant ACE inhibitor and neprilysin inhibitor therapy may be at increased risk for angioedema (see CONTRAINDICATIONS and DRUG INTERACTIONS).

Dual Blockade of the Renin-Angiotensin System (RAS)

There is evidence that co-administration of angiotensin converting enzyme inhibitors (ACEIs), such as lisinopril, or of angiotensin receptor antagonists (ARBs) with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe renal impairment (GFR < 60 ml/min/1.73 m²). Therefore, the use of lisinopril in combination with aliskiren-containing drugs is contraindicated in these patients (see CONTRAINDICATIONS).

Further, co-administration of ACEIs, including lisinopril, with other agents blocking the RAS, such as ARBs or aliskiren-containing drugs, is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, decreased renal function (including acute renal failure), and hyperkalemia.

Avoid the concomitant use of ACE inhibitors and ARBs in patients with diabetic nephropathy.

If dual blockade therapy is considered necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

Hypotension

Symptomatic hypotension has occurred after administration of 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 CHF, 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 2 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 lisinopril and/or reduced concomitant diuretic therapy should be considered.

If hypotension occurs during treatment following acute myocardial infarction, consideration should be given to lisinopril discontinuation (see ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION, Treatment Following Acute Myocardial Infarction).

In some patients with CHF who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with 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 ACE 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 are contraindicated during pregnancy because these agents can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, Sandoz Lisinopril 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 towards 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.

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.

Animal Data: Lisinopril was not teratogenic in mice treated on days 6-15 of gestation with ≤1000 mg/kg/day (625× the maximum recommended human dose). There was an increase in fetal resorptions at doses ≥100 mg/kg; at doses of 1000 mg/kg, this was prevented by saline supplementation. There was no fetotoxicity or teratogenicity in rats treated with ≤300 mg/kg/day (188× 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 ≤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.

contraindicated during breast-feeding.

PRECAUTIONS

Renal Impairment

As a consequence of inhibiting the RAAS, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the RAAS, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe CHF, 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.

The use of ACEIs - including lisinopril - or ARBs with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment

(GFR < 60 ml/min/1.73 m²). (See CONTRAINDICATIONS and DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) with ACEIs, ARBs or aliskiren-containing drugs).

In acute myocardial infarction, treatment with lisinopril should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration >177 mcmol/L and/or proteinuria >500 mg/24 hour. If renal dysfunction develops during treatment with Sandoz Lisinopril (serum creatinine concentration >265 mcmol/L or a doubling from the pre-treatment 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 those in cardiogenic shock.

During the first 3 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 lisinopril had a higher (9.0% vs. 3.7%) incidence of persistent hypotension (systolic blood pressure <90 mmHg for more than 1 hour) than placebo.

Hypoglycemia

Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycemia, especially during the first month of combined use. In addition, hypoglycemia appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment (See PRECAUTIONS, Drug Interactions).

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 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.

Nitritoid Reactions – Gold

Nitritoid reactions (symptoms of vasodilatation including flushing, nausea, dizziness and hypotension, which can be very severe) following injectable gold (for example, sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitor therapy (see PRECAUTIONS, Drug Interactions).

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 CHF. 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 (≤35 mg) versus low dose (≤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 (e.g., spironolactone, triamterene, or amiloride), potassium supplements, other drugs that may increase potassium levels (e.g., heparin, co-trimoxazole) and/or potassium-containing salt substitutes or other drugs that may increase serum potassium (e.g. trimethoprim-containing products) (see PRECAUTIONS, Drug Interactions).

The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes or other drugs that may increase serum potassium, particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalemia can cause serious, sometimes fatal, arrhythmias.

If concomitant use of lisinopril and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

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.

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), marked elevations of liver enzymes and/or serum bilirubin have occurred during therapy with lisinopril in patients with or without pre-existing liver abnormalities (see ADVERSE REACTIONS). In most cases the changes were reversed on discontinuation of the drug.

Very rarely, it has been reported that in some patients the undesirable development of hepatitis has progressed to hepatic failure. Patients receiving lisinopril who develop jaundice or marketed elevation of hepatic enzymes should discontinue lisinopril and receive appropriate medical follow-up (See PRECAUTIONS, Patients with Impaired Liver Function). Should the patient receiving Sandoz Lisinopril experience any unexplained symptoms (see INFORMATION FOR PATIENTS), 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 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 lisinopril, has been reported.

Such a possibility should be considered as part of the differential diagnosis of the cough.

Use in Children (6-16 years of age)

Antihypertensive effects of lisinopril have been established in hypertensive pediatric patients aged 6 to 16 years. There are no data of the effects of lisinopril in hypertensive patients <6 years of age or in patients with GFR <30 mL/min/1.73 m² (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, Pharmacokinetics, DOSAGE AND ADMINISTRATION, Pediatric Patients).

Use in the Elderly

In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of 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).

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.

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, 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.

Dual Blockade of the Renin-Angiotensin System (RAS) with ACE inhibitors, ARBs or aliskiren-containing drugs

Dual Blockade of the Renin-Angiotensin System (RAS) with ACE inhibitors, ARBs or aliskiren-containing drugs is contraindicated in patients with diabetes and/or renal impairment (see CONTRAINDICATIONS). Co-administration of ARBs, ACE inhibitors or aliskiren-containing drugs is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, decreased renal function (including acute renal failure), and hyperkalemia when compared to the use of a single RAS-acting agent. See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) and PRECAUTIONS, Renal Impairment).

Potassium Supplements, potassium-sparing agents or potassium-containing salt substitutes and other drugs that may increase serum potassium levels

Since lisinopril decreases aldosterone production, elevation of serum potassium may occur. Potassium sparing diuretics such as spironolactone, triamterene or amiloride, potassium supplements and other drugs that may increase potassium levels (e.g., heparin, co-trimoxazole) should be given only for documented hypokalemia and with caution and with frequent monitoring of serum potassium since they may lead to a significant increase in serum potassium. Potassium-containing salt substitutes or other drugs that may increase serum potassium (e.g., trimethoprim-containing products) should also be used with caution (see also PRECAUTIONS, Hyperkalemia).

Agents Causing Renin Release

The antihypertensive effect of 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.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of ACE inhibitors or angiotensin II receptor antagonists may be attenuated by NSAIDs including selective COX-2 inhibitors.

In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted including those on diuretic therapy) who are being treated with NSAIDS including selective COX-2 inhibitors, the co-administration of ACE inhibitors or angiotensin II receptor antagonists may result in further deterioration of renal function. Cases of acute renal failure, usually reversible, have been reported. This combination should therefore be administered with caution in this patient population.

Indomethacin may diminish the antihypertensive efficacy of concomitantly administered lisinopril.

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.

Gold

Nitritoid reactions (symptoms of vasodilatation including facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (for example, sodium aurothiomalate) and concomitant ACE inhibitor therapy including lisinopril.

Antidiabetics

Tissue Plasminogen Activators

Concomitant treatment with tissue plasminogen activators may increase the risk of angioedema. Monitor patients for potential development of angioedema after initiation of tissue plasminogen activator infusion.

Drugs that may increase the risk of angioedema

Concomitant treatment of ACE inhibitors with mammalian target of rapamycin (mTOR) Inhibitors (e.g., temsirolimus, sirolimus, everolimus), or neutral endopeptidase (NEP) inhibitors, or tissue plasminogen activator may increase the risk of angioedema. Caution should be used when these drugs are used concomitantly (see WARNINGS, Angioedema).

Neprilysin Inhibitors

Patients taking a concomitant neprilysin inhibitor (e.g. sacubitril) may be at increased risk for angioedema (see CONTRAINDICATIONS and WARNINGS).

ADVERSE REACTIONS

In controlled clinical trials involving 3269 patients, 2633 patients with hypertension and 636 patients with CHF, excluding the ATLAS CHF study patients (see ACTION AND CLINICAL PHARMACOLOGY), the most frequent clinical adverse reactions were: dizziness (4.4%), headache (5.6%), asthenia/fatigue (2.7%), diarrhea (1.8%) and cough (3.0%), all of which were more frequent than in placebo-treated patients. Discontinuation of therapy was required in 5.9% of patients.

For adverse reactions which occurred in hypertensive patients and patients with CHF treated with lisinopril in controlled clinical trials, comparative incidence data are listed in the table below.

Incidence of Adverse Reactions Occurring in Patients Treated with Lisinopril in Controlled Clinical Trials

Hypertension

(2633 Patients)

%

Congestive Heart Failure

(636 Patients)

%

Cardiovascular

Hypotension

Orthostatic effects

Chest pain

Angina

Edema

Palpitation

Rhythm disturbances

0.8

0.9

1.1

0.3

0.6

0.8

0.5

5.2

1.3

7.4

3.8

2.5

1.9

0.6

Hypertension

(2633 Patients)

%

Congestive Heart Failure

(636 Patients)

%

Gastrointestinal

Diarrhea

Nausea

Vomiting

Dyspepsia

Anorexia

Constipation

Flatulence

1.8 1.9 1.1 0.5 0.4 0.2 0.3

6.1 4.9 2.4 1.9 1.4 0.8 0.5

Nervous System

Dizziness

Headache

Paresthesia

Depression

Somnolence

Insomnia

Vertigo

4.4 5.6 0.5 0.7 0.8 0.3 0.2

14.2 4.6 2.8 1.1 0.6 2.4 0.2

Respiratory

Cough

Dyspnea

Orthopnea

3.0 0.4 0.1

6.4 7.4 0.9

Dermatologic

Rash

Pruritus

1.0 0.5

5.0 1.4

Musculoskeletal

Muscle cramps

Back pain

Leg pain

Shoulder pain

0.5 0.5 0.1 0.2

2.2 1.7 1.3 0.8

Other

Asthenia/Fatigue

Blurred vision

Fever

Flushing

Gout

Decreased libido

Malaise

2.7 0.3 0.3 0.3 0.2 0.2 0.3

7.1 1.1 1.1 0.3 1.7 0.2 1.1

Angioedema

Angioedema has been reported in patients receiving lisinopril (0.1%). Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with Sandoz Lisinopril should be discontinued and appropriate therapy instituted immediately (see WARNINGS, Angioedema).

In very rare cases, intestinal angioedema has been reported with angiotensin-converting enzyme inhibitors, including lisinopril.

Hypotension

In hypertensive patients, hypotension occurred in 0.8% and syncope occurred in 0.2% of patients. Hypotension or syncope was a cause for discontinuation of therapy in 0.3% of hypertensive patients (see WARNINGS, Hypotension).

In patients with CHF, hypotension occurred in 5.2% and syncope occurred in 1.7% of patients. Hypotension and dizziness were causes for discontinuation of therapy in 1.7% of these patients.

As shown in the ATLAS trial (see ACTION AND CLINICAL PHARMACOLOGY), high dose (≤35 mg) versus low dose (≤5 mg) treatment may predispose patients to hypotension-related symptoms such as: dizziness (18.9% versus 12.1%), syncope (7.0% versus 5.1%), and hypotension (10.8% versus 6.7%). These events were manageable and rarely led to treatment withdrawal. Therapy discontinuation rates for high versus low dose were: dizziness 0.3 and 0%, hypotension 0.8% and 0.6%, and for syncope 0.3% and 0.3%, respectively.

Treatment Following Acute Myocardial Infarction

In a controlled, open trial, involving 19,394 acute myocardial infarction patients (GISSI-3, see INDICATIONS AND CLINICAL USE, Treatment Following Acute Myocardial Infarction), comparing lisinopril alone, transdermal glycerol trinitrate, lisinopril and transdermal glycerol trinitrate, or control (no treatment), the most frequent in-hospital adverse events at 6 weeks were as follows:

Event

Control

n=4729

%

Lisinopril

n=4713

%

Lisinopril + GTN n=4722

%

GTN alone n=4731

%

Persistent hypotension

Shock

Renal dysfunction

Stroke

Re-infarction

Hemorrhagic events

Postinfarction angina

Ventricular fibrillation

Sustained ventricular tachycardia

Atrial flutter or fibrillation

Complete atrioventricular block

Asystole

Intraventricular septal rupture

Papillary muscle rupture

Late CHF (>4 days)

3.6

2.5

1.1

0.6

2.2

1.2

13.2

3.1

2.5

6.4

2.4

1.2

0.3

0.3

4.5

8.8

2.8

2.4

0.6

2.2

1.3

13.9

2.5

2.1

6.3

2.9

1.2

0.4

0.4

4.5

9.3

2.2

2.4

0.9

2.2

1.1

12.3

2.4

1.8

5.3

2.5

1.3

0.2

0.5

4.2

3.9

1.9

1.1

0.8

1.9

0.9

11.8 2.2

2.3

5.7

2.1

1.2

0.2

0.4

4.2

Pediatric Patients (6-16 years of age)

The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients.

Laboratory Test Findings

Serum Electrolytes

Hyperkalemia and hyponatremia have occurred (see PRECAUTIONS, Hyperkalemia).

Creatinine, Blood Urea Nitrogen

Increases in blood urea nitrogen (BUN) and serum creatinine, usually reversible upon discontinuation of therapy, were observed in 1.1% and 1.6% of patients, respectively with essential hypertension treated with lisinopril alone. Increases were more common in patients receiving concomitant diuretics and in patients with renal artery stenosis (see PRECAUTIONS, Renal Impairment). Reversible increases in BUN (14.5%) and serum creatinine (11.2%) were observed in approximately 12.0% of patients with CHF on 2.5 to 20 mg lisinopril and on concomitant diuretic therapy. Frequently, these abnormalities resolved when the dosage of the diuretic was decreased.

As shown in the ATLAS trial (see ACTION AND CLINICAL PHARMACOLOGY), high dose (≤35 mg) versus low dose (≤5 mg) treatment may predispose patients to increased serum creatinine (9.9% versus 7.0%). This event was manageable and rarely led to treatment withdrawal. Therapy discontinuation rates due to increased serum creatinine for high versus low dose were 0.3% versus 0.4%, respectively.

Hematology

Decreases in hemoglobin and hematocrit (mean decreases of approximately 0.9 g % and 0.6 vol %, respectively) occurred frequently in patients treated with lisinopril but were rarely of clinical importance in patients without some other cause of anemia.

Rarely, hemolytic anemia has been reported.

Agranulocytosis and bone marrow depression, manifested as anemia, thrombocytopenia or leucopenia, have been caused by ACE inhibitors, including lisinopril. Several cases of agranulocytosis and neutropenia have been reported in which a causal relationship to lisinopril cannot be excluded (see WARNINGS, Neutropenia/Agranulocytosis).

Hepatic

Elevations of liver enzymes and/or serum bilirubin have occurred (see PRECAUTIONS, Patients with Impaired Liver Function).

Discontinuations

Overall, 1.0% of patients discontinued therapy due to laboratory adverse experiences, principally elevations in BUN (0.8%), serum creatinine (0.1%) and serum potassium (0.1%).

Post-Marketing Experience

The following undesirable effects have been observed and reported during treatment with lisinopril with the following frequencies: Very common (≥ 10%), common (≥ 1%, < 10%), uncommon (≥ 0.1%, < 1%), rare (≥ 0.01%, < 0.1%), very rare (< 0.01%) including isolated reports.

Blood and lymphatic system disorders

Very rare: agranulocytosis, anemia, bone marrow depression, hemolytic anemia (see

WARNINGS, Neutropenia/Agranulocytosis) leucopenia, thrombocytopenia,

Immune system disorders

Incidence not known: anaphylactic/anaphylactoid reactions

Endocrine disorders

Rare: inappropriate antidiuretic hormone secretion

Metabolism and nutrition disorders

Uncommon: hyperkalemia (see PRECAUTIONS, Hyperkalemia).

Rare: hyponatremia.

Very rare: hypoglycemia (see PRECAUTIONS, Diabetic Patients).

Nervous system and psychiatric disorders

Common: dizziness, headache.

Uncommon: hallucinations, mood alterations (including depressive symptoms), paresthesia, sleep disturbances, taste disturbance, vertigo.

Rare: mental confusions, olfactory disturbance.

Cardiac and vascular disorders

Common: orthostatic effects (including hypotension) (see WARNINGS, Hypotension), syncope (frequency refers to congestive heart failure patient population, frequency in hypertensive patient population is “uncommon”). Uncommon: myocardial infarction or cerebrovascular accident (both possibly secondary to excessive hypotension in high risk patients, see PRECAUTIONS, Hypotension Following Acute Myocardial Infarction), palpitations, tachycardia.

Respiratory, thoracic and mediastinal disorders

Common: cough.

Uncommon: rhinitis.

Very rare: bronchospasm, sinusitis.

Gastrointestinal disorders

Common: diarrhea, vomiting.

Uncommon: abdominal pain, indigestion, nausea.

Rare: dry mouth.

Very rare: intestinal angioedema (see WARNINGS, Angioedema and ADVERSE EVENTS,

Angioedema), pancreatitis.

Hepato-biliary disorders

Very rare: hepatitis – either hepatocellular or cholestatic, jaundice, hepatic failure. Very rarely it has been reported that in some patients the undesirable development of hepatitis has progressed to hepatic failure. Patients receiving lisinopril who develop jaundice or marketed elevation of hepatic enzymes should discontinue lisinopril and receive appropriate medical follow-up (see PRECAUTIONS, Patients with Impaired Liver Function).

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritis, hypersensitivity/angioedema: angioedema of the face, extremities, lips, tongue, glottis, and/or larynx (see WARNINGS, Angioedema). Rare: alopecia, psoriasis, urticaria.

Very rare: cutaneous pseudolymphoma, diaphoresis, erythema multiforme, pemphigus,

Stevens-Johnson Syndrome, toxic epidermal necrolysis.

A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, a positive antinuclear antibodies (ANA), elevated red blood cell sedimentation rate (ESR), eosinophilia and leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur.

Renal and urinary disorders

Common: renal dysfunction.

Rare: acute renal failure, uremia.

Very rare: oliguria/anuria (see PRECAUTIONS – Renal Impairment).

Reproductive system and breast disorders

Uncommon: impotence.

General disorders and administration site conditions

Uncommon: asthenia, fatigue.

Investigations

Uncommon: increases in blood urea, increases in serum creatinine (see PRECAUTIONS,

Renal Impairment), increases in liver enzymes (see PRECAUTIONS, Patients with Impaired Liver Function).

Rare: decreases in hemoglobin, decreases in hematocrit, increases in serum bilirubin

(see PRECAUTIONS, Patients with Impaired Liver Function).

SYMPTOMS AND TREATMENT OF OVERDOSAGE

For management of suspected drug overdose, contact your regional Poison Control Centre immediately.

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 PRECAUTIONS, Anaphylactoid Reactions during Membrane Exposure). Serum electrolytes and creatinine should be monitored frequently.

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 and should be adjusted according to blood pressure response.

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, achievement 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

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 2-3 days before beginning therapy with Sandoz Lisinopril to reduce the likelihood of hypotension (see WARNINGS). 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 ≥2 hours and until blood pressure has stabilized for ≥1 additional hour (see WARNINGS AND PRECAUTIONS, Hypotension, 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

* 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 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 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 increased risk of severe hypotension and renal insufficiency to the first dose of lisinopril. In these patients, treatment should be started at low doses (2.5 or 5 mg), 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 diuretics, 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, Hypotension and PRECAUTIONS, 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. The Sandoz Lisinopril dose should be increased:

• by increments of ≤10 mg,
• at intervals of ≥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.

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 3 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 PRECAUTIONS, Hypotension Following Acute Myocardial Infarction). After 3 days, if hypotension occurs (systolic blood pressure ≤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 <90 mmHg for >1 hour), Sandoz Lisinopril should be withdrawn.

Renal function should be assessed before and during therapy with Sandoz Lisinopril (see PRECAUTIONS, Renal Impairment).

Dosing should normally continue for 6 weeks. At that time, patients with signs or symptoms of heart failure should continue with Sandoz Lisinopril (see DOSAGE AND ADMINISTRATION, Congestive Heart Failure).

Lisinopril is compatible with intravenous or transdermal glyceryl trinitrate.

Pediatric Patients (6-16 years of age)

For patients who can swallow tablets, the dose should be individualized according to patient profile and blood pressure response. The recommended initial dose is 2.5 mg in patients 20 to <50 kg and 5 mg in patients ≥50 kg. Sandoz Lisinopril is given once daily. The dosage should be adjusted according to the needs of the patient to a maximum of 20 mg daily in patients 20 to <50 kg and 40 mg in patients ≥50 kg (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, Pharmacokinetics).

Sandoz Lisinopril is not recommended in pediatric patients <6 years of age or with GFR <30 mL/min/1.73 m² (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, Pharmacokinetics).

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Lisinopril dihydrate

Chemical Name: (S)-1-[N 2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate.

Structural Formula:

Molecular Formula: C₂₁H₃₁N₃0₅·2H₂O

Molecular Mass: 441.53 g/mol

Description: Lisinopril is a white to off-white, crystalline powder. It is soluble in water and sparingly soluble in methanol and practically insoluble in ethanol.

STORAGE AND STABILITY

Store between 15°C and 30°C.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Sandoz Lisinopril is supplied as 5 mg, 10 mg and 20 mg tablets for oral administration. In addition to the medicinal ingredient lisinopril, each tablet contains the following nonmedicinal ingredients: calcium hydrogen phosphate dihydrate, croscarmellose sodium, ferric oxide red, magnesium stearate, maize starch, and, mannitol.

Sandoz Lisinopril Tablets 5 mg, are pink, round, convex, uncoated tablets, scored on one side, debossed “SZ 5” on the other side.

Sandoz Lisinopril Tablets 10 mg, are uniformly red, mottled, round, biconvex, uncoated tablets, scored on one side.

Sandoz Lisinopril Tablets 20 mg, are uniformly red, mottled, round, biconvex, uncoated tablets, debossed “SZ 20” on one side.

Sandoz Lisinopril Tablets are supplied in bottles of 100 tablets and in blister pack of 30 tablets. CLINICAL TRIALS

Comparative Bioavailability Study

* Expressed as the arithmetic mean (CV %) only

^‡Prinivil^® is manufactured by Merck, Canada, purchased in Canada ^†Zestril^® is manufactured by AstraZeneca, Canada, purchased in Canada ** Expressed as the arithmetic mean (range) only

DETAILED PHARMACOLOGY

Study Species/Strain No. of

Animals/Group

Route Dose Results

MECHANISM OF ACTION

In vitro ACE inhibitory activity* Hog plasma In vitro IC₅₀=1.7 ± 0.5 nM Augmentation of contractile response

to bradykinin

Guinea pig ileum 7 segments In vitro AC₅₀=1.6 nM

In vivo ACE inhibition in the rat** Male

Sprague/Dawley

8 IV ID₅₀=2.3

(1.7-3.1) mcg/kg

Duration of ACE inhibitory activity

of lisinopril in rats**

Male

Sprague/Dawley

4 IV 3 & 10 mcg/kg Duration approx. 110 mins.

In vivo ACE inhibitory activity of

lisinopril in conscious rats**

Sprague/Dawley 3-5 PO 0.03-3.0 mg/kg

(single dose)

Duration of at least 360 mins.

In vivo ACE inhibition in

anesthetized dogs**

Mongrel 6 IV 1-30 mcg/kg ID₅₀= 6.5 mcg/kg

In vivo ACE inhibitory activity of

lisinopril in conscious dogs**

Mongrel 3 PO 0.05-1.0 mg/kg

(single dose)

Duration of action between 6-24 hrs.

* Inhibition of enzymatic activity of hog plasma ACE using ¹⁴C labelled substrate. ** Blockage of functional (pressor) response to A1 challenge

EFFECTS ON BLOOD PRESSURE

Study Species/Strain No. of

Animals/Group

Route Dose Results

Antihypertensive activity in renal hypertensive dogs (single doses)

Mongrel 3 PO 0.3 mg/kg with

and without hydro-

chlorothiazide

After 2 hours: Lisinopril alone: 5% reduction in mean systolic pressure vs. pre-treatment. Lisinopril + HCTZ = 11% reduction in mean systolic pressure vs. pre-treatment. Antihypertensive activity in rats on a sodium-deficient diet (single doses)

Male

Sprague/Dawley

5 PO 0.03-3.0 mg/kg

daily for 4 days

After 2 hours: 11% reduction in mean systolic pressure vs. pre-treatment at 1 mg/kg. 22% reduction in mean systolic pressure vs. pre-treatment at 3 mg/kg. Consistent response over 4 days.

Antihypertensive activity in 2 kidney Grollman hypertensive rats (single doses)

Male

Sprague/Dawley

6-7 PO 1 & 3 mg/kg At 2 hours: approx. 6% reduction in mean systolic pressure vs. pre-treatment with the antihypertensive effect lasting up to 24 hours. Antihypertensive activity in

spontaneously hypertensive rats with and without hydrochlorothiazide

SH rats 3-6 PO 1.25 mg/kg

HCTZ= 50

mg/kg daily for 3 days

Enhancement of hypotensive activity over 3-5 days. 2 hours after drug administration, lisinopril alone reduced the average mean arterial pressure from 198 to 161 mmHg. In combination with HCTZ, the average mean arterial pressure was reduced from 202 to 132 mmHg.

Antihypertensive activity in

spontaneously hypertensive rats (single doses)

SH rats 3-9 PO & IV 0.1-20 mg/kg Slight fall in blood pressure at 0.312-5 mg/kg

PO. Pronounced fall at 20 mg/kg PO and 0.1 mg/kg IV with statistically significant reductions being observed for the majority of time points between ½ -18 hours.

TOXICOLOGY

A. Acute Toxicity of Lisinopril

LD₅₀ Values:

Species Sex Route LD₅₀ (g/kg) Mouse

Mouse

Rat

Rat

Dog

Dog

Mouse

Mouse

Rat

Rat

Male

Female Male

Female Male

Female Male

Female Male

Female

Oral

Oral

Oral

Oral

Oral

Oral

Intravenous Intravenous Intraperitoneal Intraperitoneal

>20 >20 >20 >20 >6

>6

>10 >10 >10 >10

Signs of Toxicity: Following oral administration to mice decreased activity and one male death (1/10) occurred. No signs of toxicity occurred in rats after oral administration. Dogs given 6 g/kg had transient diarrhea and increases in serum urea nitrogen. Intravenous administration to mice produced bradypnea, ataxia, clonic convulsions, exophthalmia, and tremors. After intraperitoneal administration in rats, ataxia and one female death (1/10) occurred. No signs of toxicity or death occurred in the males.

B. Subacute/Chronic Toxicology

Species Duration No. of

Animals/Group

Route Dose mg/kg/day Effects

Rat 2-Week 10 F +10 M Oral 3, 10, 30 At all doses, decreases of 2 to 16% in weight gain and

12 to 14% in heart weights were observed in female rats.

Rat 3-Month with

1-Month Interim

25 F + 25 M Oral 3, 10, 30 At all doses, increased serum urea nitrogen values (up to approximately 2-fold) and decreased heart weights (7 to 10%) were observed in female rats. At 10 and 30 mg, respectively, weight gain decreased 11 to 14% in males. An increased incidence of focal erosions of the gastric mucosa and focal renal tubular basophilia were also seen.

Rat 1-Year with

6-Month Interim

25 F + 25 M Oral 2,5, 10, 30, 90^a At all doses, a decrease in weight gain (up to 16%)

was observed; serum urea nitrogen increased up to 4-fold; serum sodium decreased (average down to 3 mEq/L) and serum potassium increased (average up to 0.5 mEq/L). At 2, 5, 10 and 30 mg, heart weight decreased; at 5, 10 and 30 mg, kidney weight increased; and at 5, 10, 30 and 90 mg, renal tubular basophilia increased. At 10, 30 and 90 mg, focal interstitial nephritis was observed.

Rat 3-Month with a 1-Month

Interim and a 1-Month Recovery

30 F + 30 M Oral 3, 30, 300, 3000 At all doses, weight gain decreased by 5 to 11%, and increases were observed in serum urea nitrogen (up to approximately 3-fold) and serum potassium (average up to 0.4 mEq/L). At 30, 300 and 3000 mg there was an increased incidence of focal renal tubular basophilia and focal necrosis of the glandular mucosa of the stomach. An increased incidence of focal tubular basophilia persisted in rats given 300 or 3000 mg/kg/day.

^a Dosing terminated Week 11, rats killed Week 27.

Species Duration No. of

Animals/Group

Route Dose mg/kg/day Effects

Rat 1-Month 15 F + 15 M Oral 30, 60

30, 60 (with saline)

Saline supplementation prevented decreased weight gain and elevations in serum urea nitrogen at 30 and 60 mg. Decreases in cardiac weight at 30 and 60 mg was suppressed by saline supplementation in males at 30 mg. At 30 and 60 mg, renal changes produced due to a low salt diet (renal tubular degeneration and renal tubular basophilia) were prevented by saline supplementation. Mild gastric erosions or necrotic changes were seen in 1 or 2 of 30 rats given 30 or 60 mg. These gastric changes were not seen in saline supplemented animals given these doses; however, the relationship of amelioration due to saline is uncertain because of the low incidence of this change, which is also occasionally seen in untreated animals. Rat 5-Day

6-Day Recovery

8 M Oral 5, 300 Consumption of 2% saline increased during treatment at 5 mg and on Days 2 to 4 post-treatment at 300 mg. Dog 2-Week 3 F + 3 M Oral 3, 10, 30 At 30 mg, slight mineralization of the papilla muscle of the heart was seen in 1 of 6 dogs.

Dog 3-Month with 1-Month

Interim

5 F + 5 M Oral 3, 10, 30 At 10 mg, hemoglobin concentration, hematocrit, and erythrocyte count decreased in 2 dogs. Marked increases in serum urea nitrogen and creatinine were observed in 2 of 10 dogs. One of these dogs had marked renal tubular degeneration and ulcers of the tongue, gums and gastric pyloric mucosa related to uremia. At 30 mg, there was an increase in serum urea nitrogen (average up to 2-fold) and a decrease in serum sodium (down to 4 mEq/L) and serum chloride (down to 3 mEq/L). At 10 and 30 mg, average cardiac weight was decreased (13 to 15%).

Dog 1-Year with 6-Month

Interim

5 F + 5 M Oral 3, 5, 15 At 15 mg, increases were observed in serum urea nitrogen (less than 2-fold). Decreases in serum sodium (average down to 2 mEq/L) and increases in serum potassium (average up to 0.5 mEq/L) occurred at all doses.

Dog 18-Day 3 F + 3 M Oral 60/ 90 with and

without saline

Saline supplementation prevented increases in serum urea nitrogen in dogs given 60 mg for 8 days followed by 90 mg for 8 or 9 days.

Species Duration No. of

Animals/Group

Route Dose mg/kg/day Effects

Dog 7-Day 4 F + 4 M IV 60, 90 Decreases in blood pressure and increases in serum urea nitrogen occurred in dogs given 60 or 90 mg/kg/day. Supplementation with physiologic saline (25 mL/kg one hour prior to dosing and 4 hours after dosing) prevented these changes. Increased serum potassium (average up to 0.6 mEq/L) and decreased serum chloride (average down to 0.4 mEq/L) values were seen in both supplemented and unsupplemented animals.

Dog 1-Month 2 F + 2 M Oral 3, 30, 300 and

1000

At 30 mg or greater, BUN increased and specific gravity of the urine decreased. Hyperplasia of renal epithelial cells was observed and deaths occurred. Dogs that died had dilation of distal renal tubules and fatty degeneration of renal tubular epithelium. No drug-related effects were observed at 3 mg. Dog 3-Month with 1-Month

Recovery (high dose)

Control

5 M + 5 F

3, 10,

30 mg/kg/day 3 M + 3 F

100 mg/kg/day 8 M + 8 F

Recovery Control 2 M + 2 F

100 mg/kg/day 5 M + 5 F

Oral 3, 10, 30 and 100 Eight of 16 dogs given 100 mg died or were killed because of poor physical condition. One of 6 dogs given 30 mg was killed because of poor physical condition. At 10 mg or greater increased BUN and dilation of renal tubules was seen. Fatty degeneration of renal tubular epithelium occurred at the 2 highest dosage levels. The changes are reversible as only slight dilation of renal tubules was present in some animals given 100 mg after 4 weeks of recovery.

Rabbit 2-Week 6 F Oral 15 (1, 6 & 13

doses) with and without saline

Renal tubular basophilia and renal tubular dilation (considered sequela to necrosis) were seen after 6 and 13 doses in unsupplemented rabbits.

Two supplemented rabbits (6 doses) also had the same renal lesion. One rabbit drank very little saline and had increases in BUN, creatinine and potassium. Increases in these parameters were seen in unsupplemented animals after 1, 6, and 13 doses. C. Teratology Studies

Species

No. of Animals/Group

Dose mg/kg/day

Route

Duration of Dosing

Results

Mice 25 100, 300, 1000, 1000

with saline

Oral Day 6 through

Day 15 of gestation

No teratogenic effect was observed. There was an increased incidence of resorptions in all unsupplemented groups (no increase in serum urea nitrogen).

Rat 35 30, 100, 300, 300

with saline

Oral Day 6 through

Day 17 of gestation

No teratogenic effect was observed. Maternal effect was observed. Maternal weight gain decreased in all unsupplemented groups. The open field behavioural test (measure of spontaneous activity) showed increased activity in Week 5 postpartum F1 females at 300 mg with and without saline, but only in 300 mg with saline females in Week 6. When the open field test was repeated in males and females given 300 mg with and without saline in Week 11, no increase in activity was seen. Rabbit (New

Zealand)

18 0.1, 0.3, 1.0

all groups

with saline

Oral Day 6 through

Day 18 of gestation

No teratogenic effect was observed. At all doses there was an increased incidence of incomplete ossification (sternebrae, metacarpals, forefoot phalanges, pelvic bones, and tali and/or calcanea) which was considered to represent a fetotoxic effect. At 1 mg one rabbit had a high incidence of resorptions.

Rabbit (New

Zealand)

18 0.031, 0.125, 0.5 Oral Day 6 through

Day 18 of gestation

No fetotoxicity nor embryotoxicity was observed at maternotoxic doses. At 0.125 and 0.5 mg maternal deaths, decreased maternal weight gain and food consumption, as well as increases in BUN, creatinine and potassium were seen. In addition, doses of 0.5 mg produced decreases in serum sodium and chloride, diffuse distention of the renal distal tubules and degeneration of renal tubules. D. Fertility and Late Gestation and Lactation with Postnatal Evaluation Studies

Species

No. of Animals/Group Dose mg/kg/day

Route

Duration of Dosing

Results

Rat 24 F & 24 M 30, 100, 300

300 with saline

Oral Males were dosed

for 78 days prior to mating and females from 15 days prior to mating until sacrifice on Day 20 of gestation

Weight gain was reduced in unsupplemented males at all doses and during gestation in unsupplemented females. No effects on fertility and no signs of teratogenicity were observed. There was an increase in F1 pup deaths (3 to 8% vs. control 1%) Day 1 to 7 postpartum in 100 and 300 mg (saline and nonsaline) groups. Decreased mean F1 pup weight (3 to 7% less than controls) on Day 0 postpartum was seen in all unsupplemented groups.

Rat 20 F 30, 100, 300

300 with saline

Oral Day 15 of gestation

through Day 21 postpartum

On Days 2 to 7 postpartum, there was an increased number of dead pups (8 to 10% vs. control 0%). On Day 21 postpartum, a decrease in pup weights (8% less than controls) was observed in the unsupplemented 100 and 300 mg groups. There was no effect in the supplemented group. Pup development was not altered.

E. Genotoxicity Studies

Study Test System Dose Results Mutagenesis

Microbial mutagen with and

without metabolic activation

Salmonella typhimurium

TA1535, TA1537, TA98, TA100

Escherichia coli

WP2, WP2 uvrA

≤2000 mcg/plate

≤10 mg/plate

Negative for mutagenic potential

In vitro V-79 mammalian cell

mutagenesis with and without

metabolic activation

Chinese Hamster Lung Cell ≤10 mM

(4.42 mg/mL)

Negative for mutagenic potential

DNA Damage In vitro alkaline elution Rat Hepatocyte ≤30 mM

(13.25 mg/mL)

Negative for induction of DNA single strand breaks

Chromosomal Evaluation In vitro chromosomal aberration

assay with and without metabolic

activation

Chinese Hamster Ovary ≤30 mM

(13.25 mg/mL)

Negative for induction of chromosomal aberration

In vivo chromosomal aberration

assay

Bone Marrow Cells of Male Mice ≤5000 mg/kg Negative for increases in chromosomal aberrations

F. Carcinogenicity Studies

Species Duration No. of Animals/Group Route Dose mg/kg/day Results

Mice

Cri:CD-1(ICR)BR

92-Week 50 F & 50 M Oral 15, 45, 135

mg/kg/day

No evidence of carcinogenic effect was observed. Decreased weight gain (7 to 15%) was seen in females at 135 mg. A greater incidence and severity of chronic nephritis in females and males given 45 and 135 mg was also seen.

Rats

Cri:CD(SD)BR

105-Week 50 F & 50 M Oral 10, 30, 90

mg/kg/day

No evidence of carcinogenic effect was observed. Decreased weight gain (5 to 14%) in male drug-treated rats during the first 67 weeks of the study was observed. Focal sacculations of the retinal vessels was more prevalent in rats given 30 or 90 mg than in controls in Drug Week 100. An increased incidence of renal tubular hypertrophy in drug-treated males at termination of study was seen (1 mg was considered the no-effect dose for this change in males based on an additional 105-week study at 1, 3, and

10 mg/kg/day). An increased incidence of chronic nephritis in drug-treated females (10 mg is the no-effect dose based on an additional 105-week study at 1, 3, and 10 mg/kg/day) was observed.

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