Lisinopril/HCTZ (Type Z) Product Monograph

RECENT MAJOR LABEL CHANGES

7 Warnings and Precautions – Respiratory 11/2024

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed. RECENT MAJOR LABEL CHANGES ............................................................................................ 2

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

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

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

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

2 CONTRAINDICATIONS ......................................................................................................... 4

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

4.4 Administration .................................................................................................................. 7

4.5 Missed Dose ..................................................................................................................... 7

5 OVERDOSAGE ..................................................................................................................... 7

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

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

7.1 Special Populations .......................................................................................................... 15

7.1.1 Pregnant Women .......................................................................................................... 15

7.1.2 Breast-feeding .............................................................................................................. 16

7.1.3 Pediatrics ...................................................................................................................... 16

7.1.4 Geriatrics ...................................................................................................................... 16

8 ADVERSE REACTIONS ......................................................................................................... 16

8.1 Adverse Drug Reaction Overview ...................................................................................... 16

8.2 Clinical Trial Adverse Reactions ......................................................................................... 17

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

............................................................................................................................................. 19

8.5 Post-Market Adverse Reactions ........................................................................................ 20

9 DRUG INTERACTIONS ......................................................................................................... 23

9.1 Serious Drug Interactions ................................................................................................. 23

9.2 Drug Interactions Overview .............................................................................................. 23

9.4 Drug-Drug Interactions ..................................................................................................... 23

9.5 Drug-Food Interactions .................................................................................................... 33

9.6 Drug-Herb Interactions .................................................................................................... 33

9.7 Drug-Laboratory Test Interactions .................................................................................... 33

10 CLINICAL PHARMACOLOGY............................................................................................... 34

10.1 Mechanism of Action ..................................................................................................... 34

10.2 Pharmacodynamics ........................................................................................................ 35

10.3 Pharmacokinetics ........................................................................................................... 35

11 STORAGE, STABILITY AND DISPOSAL ................................................................................. 37

12 SPECIAL HANDLING INSTRUCTIONS .................................................................................. 37

PART II : SCIENTIFIC INFORMATION ....................................................................................... 38

13 PHARMACEUTICAL INFORMATION ................................................................................... 38

14 CLINICAL TRIALS ............................................................................................................... 39

14.1 Clinical Trials by Indication ............................................................................................. 39

14.3 Comparative Bioavailability Studies ................................................................................ 39

15 MICROBIOLOGY ............................................................................................................... 42

16 NON-CLINICAL TOXICOLOGY ............................................................................................. 42

17 SUPPORTING PRODUCT MONOGRAPHS ........................................................................... 53

PATIENT MEDICATION INFORMATION ................................................................................... 54

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

LISINOPRIL/HCTZ (TYPE Z) (lisinopril and hydrochlorothiazide tablets) is indicated for:

• The treatment of essential hypertension in patients for whom combination therapy is appropriate.

LISINOPRIL/HCTZ (TYPE Z) is not indicated for initial therapy (see 4

DOSAGE AND ADMINISTRATION). Patients in whom lisinopril and diuretic are initiated simultaneously can develop symptomatic hypotension (see 9 DRUG INTERACTIONS).

LISINOPRIL/HCTZ (TYPE Z) is not indicated for the treatment of renovascular hypertension (see 7 WARNINGS AND PRECAUTIONS, Hypotension).

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use (see 7.1.3 Pediatrics).

1.2 Geriatrics

Geriatrics (> 65 years of age): In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of lisinopril (see 7.1.4 Geriatrics).

2 CONTRAINDICATIONS

LISINOPRIL/HCTZ (TYPE Z) is contraindicated in:

• Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING;
• Patients with a known allergy to angiotensin converting enzyme (ACE) inhibitors;
• Patients with a history of hereditary/idiopathic angioedema or angioedema related to previous treatment with an ACE inhibitor (see 7 WARNINGS AND PRECAUTIONS, Immune, Angioedema);
• Women who are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraception (see 7.1.1 Pregnant Women and 8 ADVERSE REACTIONS);
• Nursing women (see 7.1.2 Breast-feeding);
• Patients who have anuria because of the hydrochlorothiazide component;
• Patients who are hypersensitive to other sulfonamide-derived drugs;
• Combination with sacubitril/valsartan due to an increased risk of angioedema;

• Combination with aliskiren-containing drugs in patients with:

  o diabetes mellitus (type 1 or type 2),

  o moderate to severe renal impairment (GFR < 60 ml/min/1.73m²),

  o hyperkalemia (>5mMol/L) or,

  o congestive heart failure who are hypotensive (see 7 WARNINGS AND PRECAUTIONS,

  Dual blockade of the Renin-Angiotensin System (RAS) and Renal, 9.4 Drug-Drug Interactions)

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

  o diabetes mellitus (type 1 or type 2) with end organ damage,

  o moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73m²),

  o hyperkalemia (> 5mMol/L) or

  o congestive heart failure and are hypotensive (see 9.4 Drug-Drug Interactions)

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

• When used in pregnancy, ACE inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected, LISINOPRIL/HCTZ (TYPE Z) should be discontinued as soon as possible (see 7.1.1 Pregnant Women).

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• Dosage must be individualized. The fixed combination is not for initial therapy. The dose of

  LISINOPRIL/HCTZ (TYPE Z) should be determined by the titration of the individual components.

• Patients usually do not require doses in excess of 50 mg of hydrochlorothiazide daily, particularly when combined with antihypertensive agents.

4.2 Recommended Dose and Dosage Adjustment

Patients should be titrated on the individual drugs. If the fixed combination represents the dosage determined by this titration, the use of LISINOPRIL/HCTZ (TYPE Z) may be more convenient in the management of patients. If during maintenance therapy dosage adjustment is necessary, it is advisable to use individual drugs.

Once the patient has been successfully titrated with the individual components as described below, either one LISINOPRIL/HCTZ (TYPE Z) 10/12.5 mg or one or two 20/12.5 mg or 20/25 mg tablets once daily may be substituted if the titrated doses are the same as those in the fixed combination (see 1 INDICATIONS and 7 WARNINGS AND PRECAUTIONS).

Lisinopril monotherapy

For lisinopril monotherapy the recommended initial dose in patients not on diuretics is 10 mg of lisinopril once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range of lisinopril is 10 to 40 mg administered in a single daily dose. 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 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 lisinopril.

Diuretic Treated Patients

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of lisinopril. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with lisinopril to reduce the likelihood of hypotension (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular). The dosage of lisinopril should be adjusted according to blood pressure response.

If the patient's blood pressure is not controlled with lisinopril alone, diuretic therapy may be resumed as described above.

If the diuretic cannot be discontinued, an initial dose of 5 mg of lisinopril alone should be administered and the patient remain 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, Cardiovascular and 9 DRUG INTERACTIONS).

As a rule, concomitant diuretic therapy is not necessary when LISINOPRIL/HCTZ (TYPE Z) is used.

Dosage Adjustment in the Presence of Pathologies

Renal Impairment: In patients with creatinine clearance greater than 30 mL/min the usual dose titration of the individual components is required.

Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g.: polyacrylonitrile [PAN] and during low density lipoproteins (LDL) apheresis with dextran sulphate and treated concomitantly with an ACE inhibitor (see 7 WARNINGS AND PRECAUTIONS, Immune).

For patients with creatinine clearance between 10 and 30 mL/min the starting dose of lisinopril is 2.5 - 5.0 mg/day. The dosage may then be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.

When concomitant diuretic therapy is required in patients with severe renal impairment (creatinine clearance < 10 mL/min), a loop diuretic, rather than a thiazide diuretic is preferred for use with lisinopril. Therefore, for patients with severe renal dysfunction the lisinopril-hydrochlorothiazide combination tablet is not recommended.

Dosage Adjustments in Special Populations

Pediatrics (< 18 years of age): Health Canada has not authorized an indication for pediatric use (see 7.1.3 Pediatrics).

Geriatrics (> 65 years of age): In clinical studies the efficacy and tolerability of lisinopril and hydrochlorothiazide, administered concomitantly, were similar in both elderly and younger hypertensive patients. Based on pharmacokinetic studies, additional dosage adjustments may need to be considered (see 7.1.4 Geriatrics, 10.3 Pharmacokinetics).

4.4 Administration

The tablet should be swallowed whole with water. The tablet should not be crushed, split or chewed.

LISINOPRIL/HCTZ (TYPE Z) should be taken at the same time each day.

4.5 Missed Dose

If the patient misses a dose, they should be advised not to take an extra dose to make up for the missed dose and just resume their usual schedule.

5 OVERDOSAGE

No specific information is available on the treatment of overdosage with lisinopril and hydrochlorothiazide tablets. Treatment is symptomatic and supportive. Therapy with LISINOPRIL/HCTZ (TYPE Z) should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, if ingestion is recent, and correction of dehydration, electrolyte imbalance and hypotension by established procedures.

Lisinopril

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. 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 7 WARNINGS AND PRECAUTIONS, Immune). Serum electrolytes and creatinine should be monitored frequently.

Hydrochlorothiazide

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

For management of a suspected drug overdose, contact your regional poison control centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1: Dosage Forms, Strengths, Composition and Packaging

LISINOPRIL/HCTZ (TYPE Z) 10 mg / 12.5 mg are peach, round, biconvex tablets, engraved with N on one side and 10/12.5 on the other side. Each tablet contains 10 mg of lisinopril (as lisinopril dihydrate) and 12.5 mg of hydrochlorothiazide. Available in bottles of 100 and blister pack boxes of 30.

LISINOPRIL/HCTZ (TYPE Z) 20 mg / 12.5 mg are white to off-white, round, biconvex tablets, engraved with N on one side and 20/12.5 on the other side. Each tablet contains 20 mg of lisinopril (as lisinopril dihydrate) and 12.5 mg of hydrochlorothiazide. Available in bottles of 100 and blister pack boxes of 30.

LISINOPRIL/HCTZ (TYPE Z) 20 mg / 25 mg are peach, round, biconvex tablets, engraved with N on one side and 20/25 on the other side. Each tablet contains 20 mg of lisinopril (as lisinopril dihydrate) and 25 mg of hydrochlorothiazide. Available in bottles of 100 and blister pack boxes of 30.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Carcinogenesis and Mutagenesis

Non-melanoma skin cancer: An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin] after hydrochlorothiazide therapy was reported in some epidemiological studies. The risk may be higher with increasing cumulative use (see 8.5 Post-Market Adverse Reactions). The photosensitizing action of hydrochlorothiazide may be a possible mechanism for NMSC (see 16 NON-CLINICAL TOXICOLOGY, Hydrochlorothiazide).

Patients taking hydrochlorothiazide should be informed of the potential risk of NMSC. They should be advised to regularly check their skin for new lesions as well as changes to existing ones, and to promptly report any suspicious skin lesions. Patients should also be advised to limit exposure to sunlight, to avoid the use of indoor tanning equipment, and to use adequate protection (e.g. a broad spectrum sunscreen with a SPF of 30 or higher, clothing, and a hat) when exposed to sunlight or UV light to minimize the risk of skin cancer.

Alternatives to hydrochlorothiazide may be considered for patients who are at a particularly high risk for NMSC (e.g., light coloured skin, known personal or family history of skin cancer, ongoing immunosuppressive therapy, etc.) (see 8.5 Post-Market Adverse Reactions).

Cardiovascular

Dual blockade of the Renin-Angiotensin System (RAS): There is evidence that co-administration of angiotensin converting enzyme (ACE) inhibitors, such as the Lisinopril component in lisinopril and hydrochlorothiazide tablets, 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/1.73m²). Therefore, the use of LISINOPRIL/HCTZ (TYPE Z) in combination with aliskiren-containing drugs is contraindicated in these patients (see 2 CONTRAINDICATIONS).

Further, co-administration of ACE inhibitors, including the Lisinopril component of LISINOPRIL/HCTZ (TYPE Z), 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, or vomiting. Therefore, LISINOPRIL/HCTZ (TYPE Z) should not be used to start therapy or when a dose change is needed. Severe hypotension is also a risk in renin-dependant renovascular hypertension; LISINOPRIL/HCTZ (TYPE Z) is not indicated for this condition (see 1 INDICATIONS). In patients with ischemic heart or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (see 8 ADVERSE REACTIONS). Because blood pressure could potentially fall, patients at risk for hypotension should start lisinopril 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 hydrochlorothiazide is increased. 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.

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. Re-institution of therapy at reduced dosages, or re-institution with either component alone, should be considered.

Valvular Stenosis, Hypertrophic Cardiomyopathy: There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much after load reduction.

LISINOPRIL/HCTZ (TYPE Z) should be given with caution to patients with aortic or hypertrophic cardiomyopathy.

Driving and Operating Machinery

Dizziness or tiredness may occur during treatment with LISINOPRIL/HCTZ (TYPE Z). Exercise caution when driving or operating a vehicle or potentially dangerous machinery.

Ear/Nose/Throat

Cough: A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of lisinopril and hydrochlorothiazide tablets has been reported.

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

Endocrine and Metabolism

Metabolism: Thiazide therapy may impair glucose tolerance. Dosage adjustment of hypoglycemic agents may be required (see 9 DRUG INTERACTIONS).

Increases in cholesterol, triglyceride and glucose levels may be associated with thiazide diuretic therapy.

Hyperuricemia: Hyperuricemia may occur, or acute gout may be precipitated, in certain patients receiving thiazide therapy.

Serum protein-bound iodine (PBI) levels: Thiazides may decrease serum PBI levels without signs of thyroid disturbance.

Thiazides should be discontinued before carrying out tests for parathyroid function.

Hypomagnesemia: Thiazides have been shown to increase excretion of magnesium; this may result in hypomagnesemia.

Hypercalcemia: Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism.

Hyperkalemia: In clinical trials hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1.4% of hypertensive patients. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was not a cause of discontinuation of therapy. 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 (see 9.4 Drug-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 (with very rare progression to hepatic failure), 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. In most cases the changes were reversed on discontinuation of the drug, and appropriate medical follow up.

Should the patient receiving LISINOPRIL/HCTZ (TYPE Z) experience any unexplained symptoms, 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 LISINOPRIL/HCTZ (TYPE Z) should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. LISINOPRIL/HCTZ (TYPE Z) 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 (see 4.1 Dosing Considerations).

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Immune

Hypersensitivity Reactions: Sensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma.

Systemic lupus erythematosus: The possibility of exacerbation or activation of systemic lupus erythematosus has been reported in patients treated with hydrochlorothiazide.

Angioedema: Angioedema has been uncommonly reported in patients treated with lisinopril and hydrochlorothiazide tablets and may occur at any time during therapy. Angioedema associated with laryngeal or tongue edema and/or shock may be fatal. If angioedema occurs, LISINOPRIL/HCTZ (TYPE Z) should be promptly discontinued and the patient should be treated, and observed until the swelling subsides. Where swelling is confined only to the tongue, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.

However, where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, and especially in cases where there has been a history of airway surgery, emergency therapy should be administered promptly when indicated. This includes giving subcutaneous adrenaline/epinephrine (0.5 mL 1:1000) and/or maintaining a patent airway. The

patient should be under close medical supervision until the complete and sustained symptom resolution has occurred.

Patients co-administered ACE inhibitor and dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g. alogliptin, linagliptin, saxagliptin, and sitagliptin) may be at increased risk for angioedema (see 9 DRUG INTERACTIONS).

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 with a mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus), 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 9 DRUG INTERACTIONS).

Anaphylactoid Reactions during membrane exposure: Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., polyacrylonitrile [PAN] and during low density lipoproteins (LDL) apheresis with dextran sulphate) 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 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 9 DRUG INTERACTIONS).

Ophthalmologic

Choroidal Effusion, Acute Myopia and Secondary Angle-Closure Glaucoma related to Hydrochlorothiazide: Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in choroidal effusion, acute transient myopia and/or acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity, blurred vision or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss.

The primary treatment is to discontinue LISINOPRIL/HCTZ (TYPE Z) as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

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 (see 9 DRUG INTERACTIONS).

Thiazides may increase the responsiveness to tubocurarine (see 9.4 Drug-Drug Interactions).

Renal

Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system (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 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 ACE inhibitors, including the lisinopril component of LISINOPRIL/HCTZ (TYPE Z) or ARBs with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment (GFR < 60 mL/min/1.73m²) (see 2 CONTRAINDICATIONS and 9.4 Drug-Drug Interactions).

Use of LISINOPRIL/HCTZ (TYPE Z) should include appropriate assessment of renal function.

Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 mL/min or below i.e., moderate or severe renal insufficiency (see 4.1 Dosing Considerations).

Azotemia: Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, the diuretic should be discontinued.

Respiratory

Acute Respiratory Toxicity: Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) have been reported after taking hydrochlorothiazide. Pulmonary edema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, LISINOPRIL/HCTZ (TYPE Z) should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

Skin

Photosensitivity: Photosensitivity reactions have been reported with the use of thiazide diuretics.

If photosensitivity reactions occur during treatment with hydrochlorothiazide-containing drugs, treatment should be stopped.

7.1 Special Populations

7.1.1 Pregnant Women

ACE inhibitors must be avoided during pregnancy because these agents can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, LISINOPRIL/HCTZ (TYPE Z) should be discontinued as soon as possible. The use of LISINOPRIL/HCTZ (TYPE Z) is contraindicated during pregnancy (see 2 CONTRAINDICATIONS).

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.

7.1.2 Breast-feeding

The presence of concentrations of ACE inhibitor have been reported in human milk. Thiazides also appear in human milk. The use of LISINOPRIL/HCTZ (TYPE Z) is contraindicated during breast-feeding (see 2 CONTRAINDICATIONS).

7.1.3 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Geriatrics (> 65 years of age): 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.

Ethnic Origin

ACE inhibitors cause a higher rate of angioedema in black patients than in non black patients.

The antihypertensive effect of ACE inhibitors is generally lower in black patients (usually a low-renin hypertensive population) than in non-black patients.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The most common adverse reaction observed was dizziness (7.5%), but also headache (5.2%), cough (3.9%), fatigue (3.7%) and hypotension, including orthostatic hypotension (3.2%). The most severe adverse reactions were syncope (0.8%), and hypotension (1.9%) (see 8.2 Clinical Trial Adverse Reactions, Table 2).

Marketing experience also informs on the safety profile of lisinopril and hydrochlorothiazide tablets (see 8.5 Post-Market Adverse Reactions). Symptomatic hypotension may occur (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension). In patients at increased risk of

symptomatic hypotension, initiation of therapy and dose adjustment should be monitored under close medical supervision.

Particular consideration should be given when therapy is administered to patients with ischaemic heart or cerebrovascular disease because an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

Hepato-biliary disorder (hepatis, jaundice, hepatic failure) have very rarely been observed. However, as thiazide drugs may cause electrolyte imbalance, additional cautious should be taken with patients with hepatic impairments (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been uncommonly reported in patients treated with ACE inhibitors, including lisinopril and hydrochlorothiazide tablets. This may occur at any time during therapy. In such cases, LISINOPRIL/HCTZ (TYPE Z) should be discontinued promptly and appropriate treatment and monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with anti-histamines and corticosteroids may not be sufficient (see 7 WARNINGS AND PRECAUTIONS, Immune, Angioedema).

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.

In clinical trials involving 930 patients, including 100 patients treated for 50 weeks or more, the most severe clinical adverse reactions were syncope (0.8%), and hypotension (1.9%). The most frequent clinical adverse reactions were: dizziness (7.5%), headache (5.2%), cough (3.9%), fatigue (3.7%) and orthostatic effects (3.2%).

Discontinuation of treatment due to adverse reactions occurred in 4.4% of patients, mainly because of dizziness, cough, fatigue or muscle cramps.

Adverse reactions that have occurred in clinical trials or in marketing experience are those which have been previously reported with lisinopril and hydrochlorothiazide when used separately for the treatment of hypertension.

Adverse reactions occurring in hypertensive patients treated with lisinopril and hydrochlorothiazide in controlled trials are shown in Table 2.

Table 2: Incidence of Adverse Reactions Occurring in Patients Treated with Lisinopril and

Hydrochlorothiazide in Controlled Clinical Trials

*See lisinopril and hydrochlorothiazide (Marketing Experience Only)

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

Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) (3.8%) and serum creatinine (4.2%) were observed in patients with essential hypertension treated with lisinopril and hydrochlorothiazide tablets. More marked increases have also been reported and were more likely to occur in patients with bilateral renal artery stenosis (see 7 WARNINGS AND PRECAUTIONS, Renal).

Increases in 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.

Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.5 g percent and 1.5 vol percent, respectively) occurred frequently in hypertensive patients treated with lisinopril and hydrochlorothiazide tablets but were rarely of clinical importance unless another cause of anemia coexisted. In clinical trials, 0.4% of patients discontinued therapy due to anemia. Rarely, hemolytic anemia has been reported.

Agranulocytosis and bone marrow depression, manifested as anemia, cytopenia or leukopenia, 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 7 WARNINGS AND PRECAUTIONS, Hematologic).

Hypokalemia, Hyperkalemia: (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, and 9 DRUG INTERACTIONS).

Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides and Calcium: (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism).

8.5 Post-Market Adverse Reactions

The following undesirable effects have been observed and reported during treatment with lisinopril and hydrochlorothiazide tablets 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

Rare: anemia.

Very rare: agranulocytosis, bone marrow depression, hemolytic anemia, leucopenia, thrombocytopenia (see Hematologic).

Cardiac and vascular disorders

Common: orthostatic effects (including hypotension), syncope.

Uncommon: palpitations.

Endocrine disorders

Rare: inappropriate antidiuretic hormone secretion.

Gastrointestinal disorders

Common: diarrhea, nausea, vomiting.

Uncommon: dry mouth.

Rare: pancreatitis.

Very rare: intestinal angioedema.

General disorders and administration site conditions

Common: asthenia, fatigue.

Uncommon: chest discomfort.

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/HCTZ (TYPE Z) who develop jaundice or marked elevation of hepatic enzymes should discontinue lisinopril and hydrochlorothiazide tablets and receive appropriate medical follow up (see 7 WARNINGS AND PRECAUTIONS,

Hepatic/Biliary/Pancreatic).

Immune system disorders

Not known: anaphylactic/anaphylactoid reaction.

Investigations

Common: decreases in hemoglobin, increases in blood urea, increases in liver enzymes (see

7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic), increases in serum creatinine (see Renal).

Uncommon: decreases in hematocrit.

Rare: increases in serum bilirubin (see 7 WARNINGS AND PRECAUTIONS,

Hepatic/Biliary/Pancreatic).

Metabolism and nutrition disorders

Uncommon: gout.

Rare: hyperkalemia (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism), hyperglycemia (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism), hyperuricemia, hypokalemia.

Musculoskeletal, connective tissue and bone disorders

Common: muscle cramps.

Rare: muscle weakness.

Nervous system and psychiatric disorders

Common: dizziness, headache, paresthesia.

Uncommon: depressive symptoms.

Rare: olfactory disturbance.

Reproductive system and breast disorders

Common: impotence.

Respiratory, thoracic and mediastinal disorders

Common: cough (see 7 WARNINGS AND PRECAUTIONS, Ear/Nose/Throat). Very rare: Acute respiratory distress syndrome (ARDS) (see 7 WARNINGS AND PRECAUTIONS, Respiratory).

Skin and subcutaneous tissue disorders

Common: rash.

Uncommon: hypersensitivity/angioedema: angioedema of the face, extremities, lips, tongue, glottis and/or larynx (see 7 WARNINGS AND PRECAUTIONS, Immune). Very rare: cutaneous pseudolymphoma.

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 leucocytosis, rash, photosensitivity or other dermatological manifestation may occur.

Other side effects reported with the individual components alone, and which may be potential side effects with lisinopril and hydrochlorothiazide tablets are:

Lisinopril

Blood and lymphatic system disorders: rarely, hemolytic anemia has been reported. Cardiac disorders: Myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high risk patients; tachycardia.

Gastrointestinal disorders: abdominal pain and indigestion; pancreatitis. General disorders and administration site conditions: diaphoresis.

Infections and infestations: sinusitis.

Metabolism and nutrition disorders: hyponatremia.

Psychiatric disorders: mood alterations; mental confusion and vertigo have occurred; as with other ACE inhibitors, taste disturbance, sleep disturbance and hallucinations have been reported.

Renal and urinary disorders: acute renal failure; oliguria/anuria; renal dysfunction; uremia. Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome (ARDS), bronchospasm; rhinitis.

Skin and subcutaneous tissue disorders: alopecia; pruritis; psoriasis and severe skin disorders (including pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome and erythema multiforme) have been reported; urticaria.

Hydrochlorothiazide

Blood and lymphatic system disorders: agranulocytosis; aplastic anemia; hemolytic anemia; leucopenia; thrombocytopenia.

Ear and labyrinth disorders: vertigo.

Eye disorders: acute angle-closure glaucoma; acute myopia; choroidal effusion; transient blurred vision; xanthopsia.

Gastrointestinal disorders: constipation; gastric irritation; pancreatitis; sialadenitis. General disorders and administration site conditions: fever.

Hepatobiliary disorders: jaundice (intrahepatic cholestatic jaundice). Immune system disorders: anaphylactic reactions.

Metabolism and nutrition disorders: anorexia; electrolyte imbalance including hyponatremia; glycosuria; hyperglycemia; hyperuricemia.

Musculoskeletal and connective tissue disorders: muscle spasm; systemic lupus erythematosus.

Psychiatric disorders: restlessness.

Respiratory, thoracic and mediastinal disorders: respiratory distress (including pneumonitis and pulmonary edema).

Renal and urinary disorders: renal dysfunction and interstitial nephritis; renal failure. Skin and subcutaneous tissue disorders: cutaneous lupus erythematosus; photosensitivity; purpura; urticaria.

Vascular disorders: necrotizing angiitis (vasculitis) (cutaneous vasculitis).

Non-melanoma skin cancer: Some pharmacoepidemiological studies have suggested a higher risk of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) of the skin with increasing use of hydrochlorothiazide. A systematic review and meta-analysis undertaken by Health Canada suggested that, with important uncertainty, the use of hydrochlorothiazide for several years (>3 years) could lead to:

• 122 additional cases (95% CI, from 112 to 133 additional cases) of SCC per 1000 treated patients compared with non-use of hydrochlorothiazide (meta-analysis of 3 observational studies);
• 31 additional cases (95% CI, from 24 to 37 additional cases) of BCC per 1000 treated patients compared with non-use of hydrochlorothiazide (meta-analysis of 2 observational studies).

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

Serious Drug Interactions

• Combination with sacubitril/valsartan; see 2 CONTRAINDICATIONS;

• Combination with aliskiren-containing drugs; see 2 CONTRAINDICATIONS, 7

  WARNINGS AND PRECAUTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) and Renal, and 9.4 Drug-Drug Interactions;

• Combination with angiotensin receptor blockers (ARBs) or other ACE inhibitors; see

  2 CONTRAINDICATIONS and 9.4 Drug-Drug Interactions.

9.2 Drug Interactions Overview

Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney.

Use of LISINOPRIL/HCTZ (TYPE Z) and alcohol may increase the risk of orthostatic hypotension (see 9.4 Drug-Drug Interactions).

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 expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 3: Established or Potential Drug-Drug Interactions

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

9.5 Drug-Food Interactions

Lisinopril absorption is not influenced by the presence of food in the gastrointestinal tract.

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

Lisinopril and hydrochlorothiazide tablets combines the action of an angiotensin converting enzyme inhibitor, lisinopril, and a diuretic, hydrochlorothiazide.

Lisinopril

Angiotensin converting enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to the pressor substance, angiotensin II. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release) and decreased aldosterone secretion. Although the latter decrease is small, it results in a small increase in serum potassium. In patients treated with lisinopril plus a thiazide diuretic, there was essentially no change in serum potassium (see 7 WARNINGS AND 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 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, lisinopril also lowers blood pressure in patients with low-renin hypertension. However, black hypertensive patients (usually a low-renin hypertensive population) have a smaller average response to lisinopril monotherapy than non-black patients.

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

Hydrochlorothiazide

Hydrochlorothiazide is a diuretic and antihypertensive which interferes with the renal tubular mechanism of electrolyte reabsorption. It increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. While this compound is predominantly a saluretic agent, in vitro studies have shown that it has a carbonic anhydrase inhibitory action which seems to be relatively specific for the renal tubular mechanism. It does not appear to be concentrated in erythrocytes or the brain in sufficient amounts to influence the activity of carbonic anhydrase in those tissues.

Hydrochlorothiazide is useful in the treatment of hypertension. It may be used alone or as an adjunct to other antihypertensive drugs. Hydrochlorothiazide does not affect normal blood pressure. The mechanism of its antihypertensive action is not known. Lowering of the sodium content of arteriolar smooth muscle cells and diminished response to norepinephrine have been postulated.

10.2 Pharmacodynamics

Lisinopril

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 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 6 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 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.

Hydrochlorothiazide

Hydrochlorothiazide increases the excretion of sodium and chloride in approximately equivalent amounts and causes a simultaneous, usually minimal loss of bicarbonate. The excretion of ammonia is reduced slightly by hydrochlorothiazide and the blood ammonia concentration may be increased. The excretion of potassium is increased slightly. Calcium excretion is decreased by hydrochlorothiazide and magnesium excretion is increased.

Hydrochlorothiazide is eliminated rapidly by the kidney. Its rate of elimination is decreased somewhat by the coadministration of probenecid without, however, an accompanying reduction in diuresis.

10.3 Pharmacokinetics

Lisinopril

Absorption: Following oral administration of lisinopril, peak serum concentrations occur within about 7 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.

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.

Distribution: Lisinopril does not bind to plasma proteins other than ACE.

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

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

Elimination: Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.

Lisinopril can be removed by dialysis.

Hydrochlorothiazide

Absorption: Onset of the diuretic action following oral administration occurs in 2 hours and the peak action in about 4 hours. Diuretic activity lasts about 6 to 12 hours.

Metabolism: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney.

Elimination: The plasma half-life is 5.6 - 14.8 hours when the plasma levels can be followed for at least 24 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours.

Lisinopril - Hydrochlorothiazide

Distribution: Concomitant administration of lisinopril and hydrochlorothiazide has little, or no effect on the bioavailability of either drug. The combination tablet is bioequivalent to concomitant administration of the separate entities.

Special Populations and Conditions

• Geriatrics: In a study in elderly healthy subjects (65 years and above), a single dose of lisinopril 20 mg produced higher serum concentrations and higher values for the area under the plasma curve than those seen in young healthy adults given a similar dose. In another study, single daily doses of lisinopril 5 mg were given for 7 consecutive days to young and elderly healthy volunteers. Maximum serum concentrations of lisinopril on Day 7 were higher in the elderly volunteers than in the young.
• Pregnancy and Breast-feeding: Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Renal Insufficiency: Impaired renal function decreases elimination of lisinopril. This decrease becomes clinically important when the glomerular filtration rate is below 30 mL/min (see 7 WARNINGS AND PRECAUTIONS, Renal, and 4 DOSAGE AND ADMINISTRATION).

11 STORAGE, STABILITY AND DISPOSAL

Store between 15°C - 30°C. Protect from light and moisture.

12 SPECIAL HANDLING INSTRUCTIONS

Not applicable.

PART II : SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance: Lisinopril

Proper name: Lisinopril

Chemical Name: 1-[N²-[(S)-1-Carboxy-3-phenylpropyl]-L-lysyl]-L-proline dihydrate

Structural Formula:

NH

HH

HO₂C

H₂N

N

CO₂H

HO

2 H₂O

Molecular Formula: C₂₁H₃₁N₃O_5• 2H₂O

Molecular Weight: 441.52

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

Drug Substance: Hydrochlorothiazide

Proper name: Hydrochlorothiazide

Chemical name: 1. 2H-1,2,4-Benzothiadiazine-7-sulfonamide,6-chloro-3,4-dihydro-,1,1-dioxide

1. 2. 6-Chloro-3,4 dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide

Structural Formula:

Molecular Formula: C₇H₈ClN₃O₄S₂

Molecular Weight: 297.74

Description: Hydrochlorothiazide is a white to off-white, crystalline powder. It practically insoluble in water, but freely soluble in sodium hydroxide solution.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Essential Hypertension

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

14.3 Comparative Bioavailability Studies

A blinded, single dose, randomized, three-period, six-sequence, three-treatment, crossover study between LISINOPRIL/HCTZ (TYPE Z) 20 mg / 12.5 mg Tablets (Sanis Health Inc., Canada) and ZESTORETIC^® 20 mg / 12.5 mg Tablets (AstraZeneca Canada Inc.) and PRINZIDE® 20 mg / 12.5 mg Tablets (Merck Frosst Canada Ltd.) in 35 healthy subjects (male and female) under fasting conditions. A summary of the bioavailability data comparing LISINOPRIL/HCTZ (TYPE Z) 20 mg / 12.5 mg Tablets (Sanis Health Inc., Canada) and ZESTORETIC® 20 mg / 12.5 mg Tablets (AstraZeneca Canada Inc.) is presented in the following table:

¹ Due to the design of the study, meaningful AUC_I and T_½ parameters could not be calculated. ² LISINOPRIL/HCTZ (TYPE Z) (lisinopril and hydrochlorothiazide) 20 mg / 12.5 mg Tablets (Sanis Health Inc., Canada)

³ ZESTORETIC® (lisinopril and hydrochlorothiazide) 20 mg/ 12.5 mg Tablets (AstraZeneca Canada Inc.)

⁴ Expressed as the arithmetic mean (CV%) only

¹ LISINOPRIL/HCTZ (TYPE Z) (lisinopril and hydrochlorothiazide) 20 mg / 12.5 mg Tablets (Sanis Health Inc., Canada)

² ZESTORETIC® (lisinopril and hydrochlorothiazide) 20 mg / 12.5 mg Tablets (AstraZeneca Canada Inc.)

³ Expressed as the arithmetic mean (CV%) only

A blinded, single dose, randomized, three-period, six-sequence, three-treatment, crossover study between LISINOPRIL/HCTZ (TYPE Z) 20 mg / 25 mg Tablets (Sanis Health Inc., Canada) and ZESTORETIC^® 20 mg / 25 mg Tablets (AstraZeneca Canada Inc.) and PRINZIDE® 20 mg / 25 mg Tablets (Merck Frosst Canada Ltd.) in 36 healthy subjects (male and female) under fasting conditions. A summary of the bioavailability data comparing LISINOPRIL/HCTZ (TYPE Z) 20 mg / 25 mg Tablets (Sanis Health Inc., Canada) and ZESTORETIC® 20 mg / 25 mg Tablets (AstraZeneca Canada Inc.) is presented in the following table.

¹ Due to the design of the study, meaningful AUC_I and T_½ parameters could not be calculated. ² LISINOPRIL/HCTZ (TYPE Z) (lisinopril and hydrochlorothiazide) 20 mg / 25 mg Tablets (Sanis Health Inc., Canada)

³ ZESTORETIC® (lisinopril and hydrochlorothiazide) 20 mg / 25 mg Tablets (AstraZeneca Canada Inc.)

⁴ Expressed as the arithmetic mean (CV%) only

¹ LISINOPRIL/HCTZ (TYPE Z) (lisinopril and hydrochlorothiazide) 20 mg / 25 mg Tablets (Sanis Health Inc., Canada)

² ZESTORETIC® (lisinopril and hydrochlorothiazide) 20 mg / 25 mg Tablets (AstraZeneca Canada Inc.)

³ Expressed as the arithmetic mean (CV%) only

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology

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 4: Subacute/Chronic Toxicology - Lisinopril

Species Duration No. of

Animals/Group

Route Dose

mg/kg/day

Results

Rat 1 Year with

6 Months

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.

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.

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

Hydrochlorothiazide: Hydrochlorothiazide was found to have relatively low toxicity in acute and chronic toxicity studies. In acute animal toxicity studies in mice the LD50 was >10,000 mg/kg suspension orally and was 884 mg/kg intravenously. In rats the acute LD50 was >10,000 mg/kg suspension orally and 3,130 mg/kg suspension intraperitoneally. In the rabbit the acute intravenous LD50 was 461 mg/kg and in the dog it was approximately 1000 mg/kg. Dogs tolerated ≥2000 mg/kg orally without signs of toxicity.

Subacute oral toxicity studies in the rat at 500, 1000 and 2000 mg/kg/day of suspension 5 days/week for 3 weeks displayed no sign of drug effect. Three of the rats given 2000 mg/kg/day hydrochlorothiazide sodium salt died after the 5^th day. These deaths were attributed to pneumonia. No sign of drug effect was observed among the other animals. In dogs given doses of 250, 500 and 1000 mg/kg 7 days/week for 8 weeks, no gross signs of drug effect were noted except for electrolyte imbalance.

Chronic oral toxicity studies in the rat using doses of ≤ 2000 mg/kg/day 5 days/week for 26 weeks showed no signs of drug effect and no drug related changes on post mortem examination. In dogs oral doses of 0, 125, 250 mg/kg/day 5 days/week for 26 weeks; 500 mg/kg/day for 7 weeks; 11 weeks without drug then 500 mg/kg/day 7 days/week for 8 weeks, were given. Slight depression of plasma potassium, small amounts of yellow crystalline precipitate in the bladder in 2/12 dogs were found on gross examination. Histomorphologic studies did not show drug related changes.

Table 5: Lisinopril and Hydrochlorothiazide:

Species Duration No. of

Animals/Group

Route Dose

mg/kg/day

Effects

Rat 27-weeks 15 M + 15 F Oral LISINOPRIL/HCTZ

(TYPE Z)*0/0, 3/10, 10/10, 30/10

mg/kg/day

All animals had average body weight gains approximately 5 to 25% below the controls throughout the study. Average serum nitrogen values were generally two to three times greater in drug-treated animals compared to controls. Other serum biochemical parameters changed very slightly. Decreases in erythrocyte parameters were seen at all dosage levels. Decreases in heart weight occurred at all dosage levels and increase in kidney weight occurred at the 2 highest dosage levels. Mineralization of the renal cortico-medullary junction occurred in 2 to 5 rats in each of the drug-treated groups. Very small or small necrotic foci of gastric mucosa occurred in 5 rats in the high dose group. Chronic nephritis and its early stage of renal tubular basophilia occurred among treated and control rats, but occurred at a greater incidence in treated rats.

*Hydrochlorothiazide

Carcinogenicity

Hydrochlorothiazide: According to the experimental data available, hydrochlorothiazide revealed inconsistent evidence of carcinogenic activity in rats and mice, with conflicting evidence of hepatic adenoma in male mice at the highest dose and adrenal pheocytochroma in one rat study but not in another. Current evidence is inadequate to draw a clear conclusion for a carcinogenic effect of hydrochlorothiazide in animals.

The mutagenic potential was assessed in a series of in vitro and in vivo test systems. While some positive results were obtained in vitro, all in vivo studies provided negative results. Hydrochlorothiazide enhanced the UVA-induced formation of pyrimidine dimers in vitro and in the skin of repair deficient mice following oral treatment. It is therefore concluded that although there is no relevant mutagenic potential in vivo, hydrochlorothiazide could enhance the genotoxic effects of UVA light. This mechanism of photosensitization could be associated with a higher risk for non-melanoma skin cancer.

Table 6: Lisinopril:

Species Duration No. of

Animals/Group

Route Dose

mg/kg/day

Results

Mice

Cri:CD-1(ICR)BR

92 weeks 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 weeks 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 was seen at termination of the study (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.

Genotoxicity

Table 7: Lisinopril:

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 µg/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 Chinese Hamster Ovary ≤30 mM Negative for induction of chromosomal

with and without metabolic activation (13.25 mg/mL)

aberration

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

Lisinopril and Hydrochlorothiazide: The results of a battery of mutagenic and chromosomal aberration studies (Ames test, mammalian cell mutagenesis assay, an in vitro alkaline elution test for single strand DNA breaks, an in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse bone marrow chromosome aberration) failed to reveal a genotoxic potential for the combination of lisinopril and hydrochlorothiazide.

Reproductive and Developmental Toxicology

Lisinopril was not teratogenic in mice treated on days 6-15 of gestation with up to ≤1000 mg/kg/day (625x 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 (188x 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.

Fetotoxicity was demonstrated in rabbits by an increase 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 88-100% 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 8: Teratology Studies (Lisinopril)

Species Duration No. of

Animals/Group

Route Dose

mg/kg/day

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 weight gain decreased in all unsupplemented groups. The open field behavioral 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 (stemebrae, 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.

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

Species No of

Animals/Group

Route Dose

mg/kg/day

Duration of

Dosing

Results

Rat 24 F & 24 M Oral 30, 100, 300

300 with saline

Males were

dosed for 78

days prior to

mating and

females from

15 days prior

to mating

until sacrifice

on Day 20 of

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.

Species No of

Animals/Group

Route Dose

mg/kg/day

Duration of

Dosing

Results

gestation

Rat 20 F Oral 30, 100, 300

300 with saline

Day 15 of

gestation

through Day

21 post-

partum

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.

Hydrochlorothiazide: Hydrochlorothiazide has been administered to rats in a 2 litter study, to mice in a 2 generation study, and to rabbits in an established pregnancy test. None of these studies showed any evidence of teratogenic effects of hydrochlorothiazide. Offspring carried on to weaning or maturity did not show evidence of effects related to treatment.

Table 10: Teratology - lisinopril and hydrochlorothiazide:

Species Duration No. of

Animals/Group

Route Dose

mg/kg/day

Effects

Mouse 4-weeks 25 F Oral LISINOPRIL/HCTZ

(TYPE Z) 0/0, 10/10,

30/10, 90/10 mg/kg,

90/10 mg/kg + 0.9%

saline – Days 6 - 15

of gestation

There were no maternal deaths and no treatment-related abortions. In all drug-treated groups there were no treatment-related effects on mean live fetal weights and numbers of implants and live and dead fetuses. There was a dose-response increase in incidence of skeletal malformations. In addition, there was an increase in the incidence of lumbar ribs, a skeletal-variation, among drug treated groups. All of the skeletal malformations, with the exception of the fetus with the extra vertebra, were among mice not given saline supplementation and have occurred at comparable incidences in control groups of other studies, and some were observed in the control group of this study. A repeat of this study did not produce any evidence of treatment-related fetal skeletal malformations.

Rat 4-weeks 25 F Oral LISINOPRIL/HCTZ

(TYPE Z) 0/0, 10/10,

30/10, 90/10 mg/kg

+ 0.9% saline – Days

6 - 17 of gestation

In the lisinopril/hydrochlorothiazide 90/10 mg/kg/day group, there was a significant (P≤0.05) decrease in the number of live fetuses per pregnant female. Maternotoxicity was evident in all unsupplemented drug-treated groups. There were significant (P≤0.05) treatment-related decreases in live fetal weight in all drug-treated groups not supplemented with saline. Fetal weight in the 90/10 mg/kg/day group supplemented with saline was comparable to control. There was an increased incidence of fetuses with incompletely ossified sternebrae in the 30/10 and 90/10 mg/kg/day groups without saline supplementation which were considered to

Species Duration No. of

Animals/Group

Route Dose

mg/kg/day

Effects

represent an embryotoxic effect. Ossification was not delayed in the 10/10 mg/kg/day group or the 90/10 mg/kg/day group supplemented with saline.

Rat 4-weeks 20 or 22 F Oral LISINOPRIL/HCTZ

(TYPE Z) 0/0, 3/10, 30/10, 90/10 mg/kg + 0.9% saline – Days 6 - 17 of gestation

Fetotoxicity was apparent as treatment-related decreases in live fetal weight at all dosage levels without saline supplementation which were statistically significant (P≤0.05) in the 30/10 and 90/10 mg/kg/day groups. Results from this study confirmed those of the previous study. There was a delay in ossification, consistent with decreased live weights, at all dosage levels without saline supplementation. Maternotoxicity was evident in all unsupplemented drug-treated groups.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. ^PrZESTORETIC^® (Tablets, 10 mg / 12.5 mg, 20 mg / 12.5 mg and 20 mg / 25 mg), submission control # 274456, Product Monograph, Searchlight Pharma Inc. (November 10, 2023)