Prinivil (Merck Canada, 10 mg, 20 mg) Product Monograph

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TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

TABLE OF CONTENTS .............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................... 4

1 INDICATIONS .............................................................................................................. 4

1.1 Pediatrics .......................................................................................................... 4

1.2 Geriatrics........................................................................................................... 4

2 CONTRAINDICATIONS ................................................................................................. 5

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................ 5

4 DOSAGE AND ADMINISTRATION................................................................................. 5

4.1 Dosing Considerations ....................................................................................... 5

4.2 Recommended Dose and Dosage Adjustment..................................................... 5

4.5 Missed Dose ...................................................................................................... 8

5 OVERDOSAGE ............................................................................................................. 8

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 8

7 WARNINGS AND PRECAUTIONS .................................................................................. 9

7.1 Special Populations .......................................................................................... 13

7.1.1 Pregnant Women ....................................................................................... 13

7.1.2 Breast-feeding............................................................................................ 13

7.1.3 Pediatrics ................................................................................................... 13

7.1.4 Geriatrics ................................................................................................... 13

8 ADVERSE REACTIONS ................................................................................................ 14

8.1 Adverse Reaction Overview.............................................................................. 14

8.2 Clinical Trial Adverse Reactions ........................................................................ 14

8.2.1 Clinical Trial Adverse Reactions – Pediatrics ................................................ 17

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other

Quantitative Data ...................................................................................................... 17

8.5 Post-Market Adverse Reactions........................................................................ 18

9 DRUG INTERACTIONS................................................................................................ 20

9.1 Serious Drug Interactions ................................................................................. 20

9.2 Drug Interactions Overview.............................................................................. 20

9.3 Drug-Behavioural Interactions.......................................................................... 20

9.4 Drug-Drug Interactions .................................................................................... 20

9.5 Drug-Food Interactions .................................................................................... 25

9.6 Drug-Herb Interactions .................................................................................... 25

9.7 Drug-Laboratory Test Interactions .................................................................... 25

10 CLINICAL PHARMACOLOGY ....................................................................................... 25

10.1 Mechanism of Action.................................................................................. 25

10.2 Pharmacodynamics .................................................................................... 26

10.3 Pharmacokinetics ....................................................................................... 27

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 28

PART II: SCIENTIFIC INFORMATION ...................................................................................... 29

13 PHARMACEUTICAL INFORMATION............................................................................ 29

14 CLINICAL TRIALS........................................................................................................ 30

15 MICROBIOLOGY ........................................................................................................ 30

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 30

PATIENT MEDICATION INFORMATION ................................................................................. 41

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

PRINIVIL® (lisinopril tablets) is indicated for:

• Hypertension

PRINIVIL® 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. PRINIVIL® has been used concomitantly with beta-blockers and calcium antagonists, but the data on such use are limited.

• Heart Failure

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

• Treatment Following Acute Myocardial Infarction

PRINIVIL® 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 PRINIVIL® should be reassessed after six weeks. If there is no evidence of symptomatic or asymptomatic left ventricular dysfunction, treatment with PRINIVIL® can be stopped.

PRINIVIL® should not be used if systolic blood pressure is less than 100 mmHg, if clinically relevant renal failure is present, if there is a history of bilateral stenosis of the renal arteries (see 7 WARNINGS and PRECAUTIONS).

In using PRINIVIL®, attention should be given to the risk of angioedema (see 7 WARNINGS and PRECAUTIONS).

1.1 Pediatrics

• Pediatrics (<6 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use in children under the age of 6. See 4 DOSAGE AND ADMINISTRATION.
• Pediatrics (6-16 years): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of PRINIVIL® in pediatric patients has been established. Therefore, Health Canada has authorized an indication for pediatric use. See 4 DOSAGE AND ADMINISTRATION.

1.2 Geriatrics

• Evidence from clinical studies and experience suggests that use in the geriatric population is associated with similar safety and effectiveness (see 4 DOSAGE AND ADMINISTRATION).

2 CONTRAINDICATIONS

PRINIVIL® (lisinopril tablets) 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
• Concomitant use of angiotensin-converting enzyme inhibitors (ACEIs) – including PRINIVIL® – with aliskiren-containing drugs in patients with diabetes mellitus (type 1 or type 2) or moderate to severe renal impairment (GFR <60 ml/min/1.73 m²) is contraindicated (see 7 WARNINGS AND PRECAUTIONS, and 9 DRUG INTERACTIONS).
• PRINIVIL® is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer PRINIVIL® within 36 hours of switching to or from sacubitril/valsartan, a product containing a neprilysin inhibitor. (See 7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS.)

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• Since absorption of PRINIVIL® tablets (lisinopril tablets) is not affected by food, the tablets

  may be administered before, during or after meals.

• PRINIVIL® should be administered in a single daily dose.

• PRINIVIL® should be taken at the same time each day. The splitting of PRINIVIL® tablets is

  not advised.

• Dosage adjustments should be based on the clinical response of each individual patient.

4.2 Recommended Dose and Dosage Adjustment

• 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 PRINIVIL® 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 PRINIVIL®.

Diuretic Treated Patients: In hypertensive patients who are currently being treated with a diuretic, symptomatic hypotension may occur occasionally following the initial dose of PRINIVIL®. The diuretic should be discontinued, if possible, for two to three days before beginning therapy with PRINIVIL® to reduce the likelihood of hypotension (see 7 WARNINGS AND PRECAUTIONS). The dosage of PRINIVIL® should be adjusted according to blood pressure response. If the patient’s blood pressure is not controlled with PRINIVIL® 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 7 WARNINGS AND PRECAUTIONS, 9 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:

* 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 7 WARNINGS AND PRECAUTIONS).

Dosage in the Elderly: In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of PRINIVIL®. 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 PRINIVIL®. Therefore, a lower starting dose of 2.5 or 5 mg is recommended. Thereafter, the dosage may be adjusted according to the blood pressure response.

Congestive Heart Failure

PRINIVIL® 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 PRINIVIL®, because severe hypotension and, more rarely, consequent renal failure have been reported (see 7 WARNINGS AND PRECAUTIONS).

Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt-/volume-depletion. If possible, the dose of diuretic should be reduced before beginning treatment.

The recommended initial dose is 2.5 mg per day. If required, the dose should be increased gradually, depending on the patient 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 (see 1 INDICATIONS).

The first dose of 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 PRINIVIL® must not be initiated in patients who are at risk of serious hemodynamic deterioration (see 7 WARNINGS and PRECAUTIONS). 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), PRINIVIL® should be withdrawn.

Renal function should be assessed before and during therapy with PRINIVIL® (see 7 WARNINGS AND PRECAUTIONS).

Dosing should normally continue for six weeks. At that time, patients with signs or symptoms of heart failure should continue with PRINIVIL® (see 4 DOSAGE AND ADMINISTRATION).

PRINIVIL® is compatible with intravenous or transdermal glyceryl trinitrate.

Pediatric Patients

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. PRINIVIL® 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 10 CLINICAL PHARMACOLOGY, 10.2 Pharmacodynamics, and 10.3 Pharmacokinetics).

PRINIVIL® is not recommended in pediatric patients <6 years or with glomerular filtration rate <30 mL/min/1.73 m² (see 10 CLINICAL PHARMACOLOGY, 10.2 Pharmacodynamics, and 10.3 Pharmacokinetics).

4.5 Missed Dose

Patients should be instructed that if they miss a dose of Prinivil, they should take the next dose as soon as possible. If no more than six hours have elapsed since the missed dose, the patient can take that day’s dose of medication and then return to the regularly scheduled time. The Patient should not double the dose.

5 OVERDOSAGE

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.

Lisinopril may be removed from the general circulation by hemodialysis (see 7 WARNINGS and PRECAUTIONS, Anaphylactoid Reactions during Membrane Exposure).

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Tablets PRINIVIL®, 10 mg, are light yellow, oval-shaped compressed tablets, engraved MSD 106 on one side and scored on the other. Available in blister packages of 28 tablets.

Tablets PRINIVIL®, 20 mg, are peach, oval-shaped compressed tablets, engraved MSD 207 on one side and scored on the other. Available in blister packages of 28 tablets.

The splitting of PRINIVIL® tablets is not advised.

COMPOSITION

PRINIVIL® is supplied as 10 mg and 20 mg tablets for oral administration. In addition to the active ingredient lisinopril, each tablet contains the following non-medicinal ingredients: calcium phosphate, corn starch, iron oxide, magnesium stearate, mannitol, and pregelatinized starch. The splitting of PRINIVIL® tablets is not advised.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

Angioedema

Angioedema has been reported in patients treated with PRINIVIL® (lisinopril tablets). This may occur at any time during treatment. Angioedema associated with shock may be fatal. If angioedema occurs, PRINIVIL® should be promptly discontinued and the patient should be observed until the swelling subsides. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. When there is 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 2 CONTRAINDICATIONS).

Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema. Caution should be used when these drugs are used concomitantly.

Patients receiving concomitant ACE inhibitor and neprilysin inhibitor therapy may be at increased risk for angioedema (see 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS).

Patients receiving concomitant ACE inhibitor and dipeptidyl peptidase IV (DPP-IV) inhibitors such as alogliptin, linagliptin, saxagliptin, and sitagliptin may be at increased risk for angioedema (see 9 DRUG INTERACTIONS). Caution should be used when these drugs are used concomitantly.

Carcinogenesis and Mutagenesis

See 16 NON-CLINICAL TOXICOLOGY.

Cardiovascular

Dual Blockade of the Renin-Angiotensin System (RAS)

There is evidence that co-administration of angiotensin-converting enzyme inhibitors (ACEIs), such as PRINIVIL®, 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 PRINIVIL® in combination with aliskiren-containing drugs is contraindicated in these patients (see 2 CONTRAINDICATIONS). Further, co-administration of ACEIs, including PRINIVIL®, 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, renal failure, and hyperkalemia.

Hypotension: Symptomatic hypotension has occurred after administration of PRINIVIL®, 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 4 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 8 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 PRINIVIL® and/or reduced concomitant diuretic therapy should be considered.

If hypotension occurs during treatment following acute myocardial infarction, consideration should be given to PRINIVIL® discontinuation (see 8 ADVERSE REACTIONS, and 4 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 PRINIVIL®. If hypotension occurs, a reduction of dose or discontinuation of therapy should be considered.

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 4 DOSAGE AND ADMINISTRATION).

Patients with myocardial infarction in the GISSI-3 study treated with PRINIVIL® 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.

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.

PRINIVIL® should be given with caution to these patients.

Ear/Nose/Throat

A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of PRINIVIL® has been reported.

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

Endocrine and Metabolism

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 9 DRUG INTERACTIONS).

Hematologic

Neutropenia/Agranulocytosis: Agranulocytosis and bone marrow depression have been caused by angiotensin-converting enzyme inhibitors. Several cases of agranulocytosis and neutropenia have been reported in which a causal relationship to 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.

Hepatic/Biliary/Pancreatic

Patients with Impaired Liver Function: Hepatitis, jaundice (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with lisinopril in patients with or without pre-existing liver abnormalities (see 8 ADVERSE REACTIONS). In most cases the changes were reversed on discontinuation of the drug.

Should the patient receiving PRINIVIL® experience any unexplained symptoms (see

PATIENT MEDICATION 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 PRINIVIL® should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. PRINIVIL® 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.

Immune

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, wasp) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.

Peri-Operative Considerations

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.

Renal

Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

The use of ACEIs – including PRINIVIL® – or ARBs with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment (GFR <60 ml/min/1.73 m²) (see 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS).

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 µmol/L and/or proteinuria exceeding 500 mg/24 hour. If renal dysfunction develops during treatment with PRINIVIL® (lisinopril tablets) (serum creatinine concentration exceeding 265 µmol/L or a doubling from the pre-treatment value), then the physician should consider withdrawal of PRINIVIL®.

Use of PRINIVIL® should include appropriate assessment of renal function.

Hyperkalemia: In clinical trials 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. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, potassium-containing salt substitutes or other drugs that may increase serum potassium (e.g., trimethoprim-containing products) (see also 9 DRUG INTERACTIONS).

The use of potassium supplements, potassium-sparing diuretics, 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 PRINIVIL® and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

7.1 Special Populations

7.1.1 Pregnant Women

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, PRINIVIL® should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations, have also been reported following exposure in the first trimester of pregnancy.

Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.

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.

7.1.2 Breast-feeding

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

7.1.3 Pediatrics

Antihypertensive effects of lisinopril have been established in hypertensive pediatric patient aged 6 to 16 years. There are no data of the effects of lisinopril in hypertensive patients under the age of 6 or in patients with glomerular filtration rate <30 mL/min/1.73 m². (See 10 CLINICAL PHARMACOLOGY, and 4 DOSAGE AND ADMINISTRATION).

7.1.4 Geriatrics

In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of PRINIVIL®. 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 4 DOSAGE AND ADMINISTRATION).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

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.

For adverse reactions which occurred in hypertensive patients and patients with congestive heart failure treated with PRINIVIL® (lisinopril tablets) in controlled clinical trials, comparative incidence data are listed in the table below.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Table 2: INCIDENCE OF ADVERSE REACTIONS OCCURRING IN PATIENTS TREATED WITH PRINIVIL® IN CONTROLLED CLINICAL TRIALS

Angioedema

Angioedema has been reported in patients receiving PRINIVIL® (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 PRINIVIL® should be discontinued and appropriate therapy instituted immediately (see 7 WARNINGS and PRECAUTIONS).

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 7 WARNINGS and PRECAUTIONS).

In patients with congestive heart failure, 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.

Treatment Following Acute Myocardial Infarction

In a controlled, open trial, involving 19,394 acute myocardial infarction patients (GISSI-3, see 1 INDICATIONS), 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:

Table 3: Incidence of adverse reactions occurring in patients treated with lisinopril, transdermal glycerol trinitrate, lisinopril and transdermal glycerol trinitrate, or control

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

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

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Serum Electrolytes

Hyperkalemia and hyponatremia have occurred (see 7 WARNINGS and PRECAUTIONS).

Creatinine, Blood Urea Nitrogen

Increases in blood urea nitrogen 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 PRINIVIL® alone. Increases were more common in patients receiving concomitant diuretics and in patients with renal artery stenosis (see 7 WARNINGS and PRECAUTIONS). Reversible increases in blood urea nitrogen (14.5%) and serum creatinine (11.2%) were observed in approximately 12.0% of patients with congestive heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when the dosage of the diuretic was decreased.

Hematology

Decreases in hemoglobin and hematocrit (mean decreases of approximately 0.9 g percent and 0.6 vol percent, respectively) occurred frequently in patients treated with PRINIVIL® 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 angiotensin-converting enzyme inhibitors, including lisinopril. Several cases of agranulocytosis and neutropenia have been reported in which a causal relationship to lisinopril cannot be excluded (see 7 WARNINGS and PRECAUTIONS).

Hepatic

Elevations of liver enzymes and/or serum bilirubin have occurred (see 7 WARNINGS and PRECAUTIONS).

Discontinuations

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

8.5 Post-Market Adverse Reactions

Other Events in Controlled Clinical Trials or Post-Marketing Experience

Additional adverse reactions which were reported rarely, either during controlled clinical trials or after the drug was marketed, include:

Cardiovascular

• Myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high-risk patients (see 7 WARNINGS and PRECAUTIONS)
• Tachycardia

Dermatologic

• Alopecia
• Diaphoresis
• Pruritis
• Urticaria

Endocrine

• Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Gastrointestinal

• Abdominal pain and indigestion
• Dry mouth
• Pancreatitis
• Vomiting

Hematologic

• Hemolytic anemia

Hepatic

• Hepatitis
• Jaundice (hepatocellular and/or cholestatic)
• Liver function abnormalities
• Hepatic failure

Metabolic

Cases of hypoglycemia in diabetic patients on oral antidiabetic agents or insulin have been reported (see 9 DRUG INTERACTIONS).

Nervous System

• Mental confusion
• Mood alterations
• Paresthesia
• Vertigo

Respiratory

• Bronchospasm
• Rhinitis
• Sinusitis

Severe Skin Disorders

• Erythema multiforme
• Pemphigus
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Cutaneous pseudolymphoma

Special Senses

• Taste disorders

Urogenital

• Acute renal failure
• Impotence
• Oliguria/anuria
• Renal dysfunction
• Uremia

A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leukocytosis. Rash, photosensitivity, or other dermatologic manifestations may also occur.

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

• Please see section 9.4 drug-drug interaction

9.2 Drug Interactions Overview

• Please see section 9.4 drug-drug interaction

9.3 Drug-Behavioural Interactions

• No information available

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the potential magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 4- Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

PRINIVIL® (lisinopril tablets) 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.

Angiotensin-converting enzyme 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 PRINIVIL® and a thiazide diuretic there was essentially no change in serum potassium (see 7 WARNINGS and PRECAUTIONS).

ACE is identical to kininase II. Thus, PRINIVIL® may also block the degradation of bradykinin, a potent vasodilator peptide. However, the role that this plays in the therapeutic effects of PRINIVIL® is unknown.

While the mechanism through which PRINIVIL® lowers blood pressure is believed to be primarily the suppression of the renin-angiotensin-aldosterone system, PRINIVIL® also lowers blood pressure in patients with low-renin hypertension.

10.2 Pharmacodynamics

Administration of PRINIVIL® to patients with hypertension results in a reduction of both supine and standing blood pressure. Abrupt withdrawal of PRINIVIL® 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 PRINIVIL®, 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 PRINIVIL® on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.

When PRINIVIL® 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 than in non-Black patients.

Administration of PRINIVIL® 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.

10.3 Pharmacokinetics

The pharmacokinetics of lisinopril were studied in 29 pediatric hypertensive patients between 6 years and 16 years with glomerular filtration rate >30 mL/min/1.73 m². After doses of 0.1 to 0.2 mg/kg, steady state peak plasma concentrations of lisinopril occured 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.

In a study in elderly healthy subjects (65 years and above), a single dose of lisinopril 20 mg produced higher serum concentrations 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.

Absorption

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.

Distribution:

After oral administration of PRINIVIL®, 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.

Metabolism:

Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine.

Elimination

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 4 DOSAGE AND ADMINISTRATION).

11 STORAGE, STABILITY AND DISPOSAL

Store at room temperature (15°C–30°C).

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Lisinopril

Chemical name: (S)-1-[N²-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate.

Molecular formula and molecular mass: C₂₁H₃₁N₃0₅•2H₂O; 441.53

Structural formula:

Physicochemical properties: Lisinopril is a white to off-white crystalline powder. Lisinopril contains three chiral centers and is optically active. The pKa values of Lisinopril determined by aqueous acidic/basic potentiometric titration at 25°C for pKa1 and pKa2 are 2.5 and 4.0 respectively.

Product Characteristics:

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

14 CLINICAL TRIALS

Pediatric Patients :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.

The clinical trial data on which the original indication was authorized is not available.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

Animal Data: Lisinopril was not teratogenic in mice treated on days 6–15 of gestation with up to 1000 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 1000 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.

Table 5 - Toxicology

* Inhibition of enzymatic activity of hog plasma ACE using ¹⁴C labeled substrate.

** Blockage of functional (pressor) response to AI challenge.

Table 6 – Acute Toxicity of Lisinopril

LD₅₀ Values:

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.

Table 7 - Subacute/Chronic Toxicology

Table 7 - Subacute/Chronic Toxicology (continued)

Table 7 - Subacute/Chronic Toxicology (continued)

Table 8 - Teratology Studies

Table 9 - Fertility and Late Gestation and Lactation with Postnatal Evaluation Studies

Table 10 - Genotoxicity Studies

Table 11 - Carcinogenicity Studies