Teva-Losartan/HCTZ Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

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

RECENT MAJOR LABEL CHANGES ............................................................................................ 2

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

PART I: HEALTH PROFESSIONAL INFORMATION .................................................................... 5

1 INDICATIONS .............................................................................................................. 5

1.1 Pediatrics .................................................................................................................... 5

1.2 Geriatrics .................................................................................................................... 5

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

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................. 6

4 DOSAGE AND ADMINISTRATION ................................................................................. 6

4.1 Dosing Considerations ................................................................................................ 6

4.2 Recommended Dose and Dosage Adjustment .......................................................... 6

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

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 ...................................................................................................... 14

7.1.3 Pediatrics .............................................................................................................. 14

7.1.4 Geriatrics ............................................................................................................... 14

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

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

8.2 Clinical Trial Adverse Reactions ................................................................................ 15

8.3 Less Common Clinical Trial Adverse Reactions ........................................................ 16

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................... 16

8.5 Post-Market Adverse Reactions ............................................................................... 17

9 DRUG INTERACTIONS ................................................................................................. 19

9.1 Serious Drug Interactions ......................................................................................... 19

9.4 Drug-Drug Interactions ............................................................................................. 19

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

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

9.7 Drug-Laboratory Test Interactions ........................................................................... 26

10 CLINICAL PHARMACOLOGY ........................................................................................ 26

10.1 Mechanism of Action ............................................................................................ 26

10.2 Pharmacodynamics............................................................................................... 27

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

11 STORAGE STABILITY AND DISPOSAL ........................................................................... 29

12 SPECIAL HANDLING INSTRUCTIONS ............................................................................ 30

PART II: SCIENTIFIC INFORMATION ........................................................................................ 31

13 PHARMACEUTICAL INFORMATION ............................................................................. 31

14 CLINICAL TRIALS......................................................................................................... 32

14.1 Clinical Trials by Indication ................................................................................... 32

14.2 Comparative Bioavailability Studies ..................................................................... 33

15 MICROBIOLOGY ......................................................................................................... 36

16 NON-CLINICAL TOXICOLOGY ...................................................................................... 36

17 SUPPORTING PRODUCT MONOGRAPHS ..................................................................... 45

PATIENT MEDICATION INFORMATION ................................................................................... 46

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Hypertension:

TEVA-LOSARTAN/HCTZ (losartan potassium and hydrochlorothiazide) is indicated for:

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

TEVA-LOSARTAN/HCTZ is not indicated as the initial therapy for essential hypertension, except in patients with severe essential hypertension (Sitting DBP ≥110 mmHg) for whom the benefit of a prompt blood pressure reduction exceeds the risk of initiating combination therapy in these patients (see 4 DOSAGE AND ADMINISTRATION and 14 CLINICAL TRIALS).

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.

1.2 Geriatrics

Geriatrics (>65 years of age): No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see 4 DOSAGE AND ADMINISTRATION).

2 CONTRAINDICATIONS

• Patients who are hypersensitive to this drug or to any ingredient in the formulation. For a complete listing, see the 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• Because of the hydrochlorothiazide component, TEVA-LOSARTAN/HCTZ is also contraindicated in patients with anuria, and in patients who are hypersensitive to other sulfonamide-derived drugs.
• Concomitant use of angiotensin receptor antagonists (ARBs) –including TEVA-LOSARTAN/ HCTZ- or of angiotensin-converting-enzyme inhibitors (ACEIs) with aliskiren-containing drugs in patients with diabetes mellitus (type 1 or type 2) or moderate to severe renal impairment (GFR < 60 ml/min/1.73m²) is contraindicated (see 7 WARNINGS AND PRECAUTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) and Renal, and 9 DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin-System (RAS) with ACEIs, ARBs or aliskiren-containing drugs).

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• Dosage must be individualized.
• The fixed combination is not for initial therapy, except for severe hypertension.
• The dose of TEVA-LOSARTAN/HCTZ should be determined by the titration of the individual components.

4.2 Recommended Dose and Dosage Adjustment

Hypertension: Once the patient has been stabilized on the individual components as described below, either one tablet TEVA-LOSARTAN/HCTZ 50 mg / 12.5 mg or 100 mg / 12.5 mg, or one tablet 100 mg / 25 mg once daily may be substituted if the doses on which the patient was stabilized are the same as those in the fixed combination. The maximum dose is one tablet TEVA-LOSARTAN/HCTZ 100 mg / 25 mg once daily.

Severe Hypertension (Sitting DBP ≥110 mmHg): The starting dose of LOSARTAN/HCTZ for initial treatment of severe hypertension is one tablet of LOSARTAN/HCTZ 50 mg / 12.5 mg once daily. For patients who do not respond adequately to LOSARTAN/HCTZ 50 mg / 12.5 mg after 2 to 4 weeks of therapy, the dosage may be increased to one tablet of TEVA-LOSARTAN/HCTZ 100 mg / 25 mg once daily. The maximum dose is one tablet of TEVA-LOSARTAN/HCTZ 100 mg / 25 mg once daily.

Losartan Monotherapy: The usual starting dose of losartan monotherapy is 50 mg once daily.

Dosage should be adjusted according to blood pressure response. The maximal antihypertensive effect is attained 3-6 weeks after initiation of therapy.

The usual dose range for losartan is 50 to 100 mg once daily. A dose of 100 mg daily should not be exceeded, as no additional antihypertensive effect is obtained with higher doses.

In most patients taking losartan 50 mg once daily, the antihypertensive effect is maintained. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. This can be evaluated by measuring the blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, either twice daily administration with the same total daily dosage, or an increase in the dose should be considered. If blood pressure is not adequately controlled with losartan alone, a non-potassium-sparing diuretic may be administered concomitantly.

For patients with volume-depletion, a starting dose of 25 mg once daily should be considered (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular - Hypotension and 9 DRUG INTERACTIONS).

Diuretic Treated Patients: In patients receiving diuretics, losartan therapy should be initiated with caution, since these patients may be volume-depleted and thus more likely to experience hypotension following initiation of additional antihypertensive therapy. Whenever possible, all diuretics should be discontinued two to three days prior to the administration of losartan, to reduce the likelihood of hypotension (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular -Hypotension and 9 DRUG INTERACTIONS, Diuretics). If this is not possible because of the patient's condition, losartan should be administered with caution and the blood pressure monitored closely. Thereafter, the dosage should be adjusted according to the individual response of the patient.

Dosage Adjustment in Renal Impairment: No initial dosage adjustment in losartan is usually necessary for patients with renal impairment, including those requiring hemodialysis. However, appropriate monitoring of these patients is recommended.

The usual regimens of therapy with TEVA-LOSARTAN/HCTZ may be followed as long as the patient's creatinine clearance is >30 mL / min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so TEVA-LOSARTAN/HCTZ is not recommended.

Patients with Liver Impairment: Since dosage adjustment of losartan is required in patients with liver impairment, and thiazide diuretics may precipitate hepatic coma, a fixed combination product such as TEVA-LOSARTAN/HCTZ is not advisable (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic -Patients with Liver Impairment).

Geriatrics (>65 years of age): No initial dosage adjustment is necessary for most elderly patients. Appropriate caution should nevertheless be used when prescribing to the elderly, as increased vulnerability to drug effect is possible in this patient population (see 7 WARNINGS AND PRECAUTIONS, 7.1.4 Geriatrics).

4.4 Administration

TEVA-LOSARTAN/HCTZ tablet is for oral administration.

TEVA-LOSARTAN/HCTZ may be administered with or without food, however it should be taken consistently with respect to food intake at about the same time every day.

4.5 Missed Dose

If a dose is missed, an extra dose should not be taken. The usual schedule must be resumed.

5 OVERDOSAGE

No specific information is available on the treatment of overdosage with losartan potassium and hydrochlorothiazide. Treatment is symptomatic and supportive.

Losartan: Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia.

If symptomatic hypotension should occur, supportive treatment should be instituted.

Neither losartan nor its active metabolite can be removed by hemodialysis.

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.

The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Description

TEVA-LOSARTAN/HCTZ 50 mg / 12.5 mg tablets are yellow, tear drop shaped, film-coated tablets, with “rph” on one side and “L92” on the other. Each tablet contains 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide, as the active ingredients. Available in bottles of 30 tablets.

TEVA-LOSARTAN/HCTZ Tablets 100 mg / 12.5 mg are white biconvex, oval shaped, film-coated tablets, debossed “LH” on one side and plain on the other side. Each tablet contains 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide, as the active ingredients. Available in blister packages of 30 tablets.

TEVA-LOSARTAN/HCTZ Tablets 100 mg / 25 mg are yellow, biconvex, oval shaped, film-coated tablets, debossed “100” on one side and plain on the other side. Each tablet contains 100 mg of losartan potassium and 25 mg of hydrochlorothiazide, as the active ingredients. Available in blister packages of 30 tablets.

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 ADVERSE REACTIONS, 8.5 Post Market Adverse Reactions). The photosensitizing action of hydrochlorothiazide may be a possible mechanism for NMSC (see 16 NON-CLINICALTOXICOLOGY, Carcinogenicity – 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 ADVERSE REACTIONS, 8.5 Post Market Adverse Reactions)

Cardiovascular

Hypotension: Occasionally, symptomatic hypotension has occurred after administration of losartan, in some cases after the first dose. It is more likely to occur in patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In these patients, because of the potential fall in blood pressure, therapy should be started under close medical supervision. Similar considerations apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident.

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

Dual blockade of the Renin-Angiotensin System (RAS) : There is evidence that co-administration of angiotensin receptor antagonists (ARBs), such as losartan potassium and hydrochlorothiazide, or of angiotensin-converting-enzyme inhibitors (ACEIs) 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 TEVA-LOSARTAN/ HCTZ in combination with aliskiren-containing drugs is contraindicated in these patients. Co-administration of ARBs, including TEVA-LOSARTAN/ HCTZ , with other agents blocking the RAS, such as ACEIs or aliskiren-containing drugs, is not recommended in any patients, as adverse outcomes cannot be excluded.

Endocrine and Metabolism

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

Thiazides may decrease serum PBI levels without signs of thyroid disturbance.

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

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

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

Hepatic/Biliary/Pancreatic

Patients with Liver Impairment: Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan and its active metabolite in cirrhotic patients after administration of losartan potassium tablets, a lower dose should be considered for patients with hepatic impairment, or a history of hepatic impairment (see 4 DOSAGE AND ADMINISTRATION and 10 CLINICAL PHARMACOLOGY).

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

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

Anaphylactic reactions, angioedema (involving swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, and/or tongue and pharynx, requiring intubation/tracheotomy in some cases) have been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with ACE inhibitors. Vasculitis, including Henoch-Schoenlein purpura, has been reported rarely.

Ophthalmologic

Choroidal Effusion, Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulphonamide, can cause an idiosyncratic reaction, resulting in choroidal effusion, acute transient myopia and 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 hydrochlorothiazide 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 sulphonamide or penicillin allergy.

Renal

Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal functions have been reported 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.

Increases in Serum Potassium: Concomitant use of other drugs that may increase serum potassium may lead to hyperkalemia (see 9 DRUG INTERACTIONS).

The use of ARBs – including TEVA-LOSARTAN/HCTZ – or of ACEIs 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 DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACEIs, or aliskiren-containing drugs).

Use of losartan should include appropriate assessment of renal function.

Thiazides should be used with caution.

Because of the hydrochlorothiazide component, TEVA-LOSARTAN/HCTZ is not recommended in patients with severe renal impairment (creatinine clearance ≤ 30 mL / min).

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 distress: Very rare severe cases of acute respiratory distress including pneumonitis and pulmonary edema have been reported after taking hydrochlorothiazide. In such cases, pulmonary edema typically develops within minutes to hours after hydrochlorothiazide intake. At onset, symptoms can include dyspnea, fever, pulmonary deterioration and hypotension. TEVA-LOSARTAN/HCTZ should be discontinued, and appropriate treatment should be given if the patient presents with acute respiratory distress. TEVA-LOSARTAN/HCTZ should not be administered to patients who previously experienced acute respiratory distress 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

Drugs that act directly on the renin-angiotensin-aldosterone-system (RAAS) can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, TEVA-LOSARTAN/HCTZ should be discontinued as soon as possible.

The use of ARB is not recommended during pregnancy. Epidemiological evidence regarding the risk of teratogenicity following exposure to angiotensin converting enzyme inhibitors (another class of therapeutic products interfering with the RAAS) during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Given the current evidence available on the risk with ARB, similar risks may exist for this class of drugs. Patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

The use of ARBs during the second and third trimesters is known to induce human fetotoxicity (decreased renal function; oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

Infants with a history of in utero exposure to ARBs 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 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. Neither losartan nor the active metabolite can be removed by hemodialysis.

Thiazides cross the placental barrier and appear in cord blood. The routine use of diuretics in otherwise healthy pregnant women is not recommended and exposes mother and fetus to unnecessary hazard including fetal or neonatal jaundice, thrombocytopenia and possibly other adverse experiences which have occurred in the adult. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia.

Animal data

Losartan potassium has been shown to produce adverse effects in rat fetuses and neonates, which include decreased body weight, mortality and/or renal toxicity. Significant levels of losartan and its active metabolite were shown to be present in rat milk. Based on pharmacokinetic assessments, these findings are attributed to drug exposure in late gestation and during lactation.

7.1.2 Breast-feeding

It is not known whether losartan or its active metabolite are excreted in human milk, but significant levels of both of these compounds have been found in the milk of lactating rats. Thiazides appear in human milk. Because many drugs are excreted in human milk and because of their potential for affecting the nursing infant adversely, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

7.1.3 Pediatrics

Pediatrics (<18 years of age): Losartan potassium and hydrochlorothiazide has not been studied in children, therefore use in this age group is not recommended.

7.1.4 Geriatrics

Geriatrics (>65 years of age): No overall differences in safety were observed between elderly patients and younger patients, but appropriate caution should nevertheless be used when prescribing to the elderly, as increased vulnerability to drug effect is possible in this patient population (see 8 ADVERSE REACTIONS).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Losartan potassium and hydrochlorothiazide has been evaluated for safety in 2498 patients treated for essential hypertension. Of these, 1088 were treated with losartan potassium and hydrochlorothiazide monotherapy in controlled clinical trials. In open studies, 926 patients were treated with losartan potassium and hydrochlorothiazide for a year or more.

The following potentially serious adverse reactions have been reported rarely with losartan potassium and hydrochlorothiazide in controlled clinical trials: syncope, hypotension.

In controlled clinical trials, discontinuations of therapy due to clinical adverse experiences occurred in 2.4% and 2.1% of patients treated with losartan potassium and hydrochlorothiazide and placebo, respectively.

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 these double-blind controlled clinical trials, the following adverse reactions reported with losartan potassium and hydrochlorothiazide in ≥ 1% of patients, regardless of drug relationship:

Table 2 - Adverse Reactions Reported with Losartan Potassium-Hydrochlorothiazide Occurring in ≥1% of Patients

In these controlled clinical trials for essential hypertension, dizziness was the only adverse experience, occurring in more than 1% of cases, that was reported as drug-related, and that occurred at a greater incidence in losartan potassium - hydrochlorothiazide-treated (3.3%) than placebo-treated (2.1%) patients.

Severe Hypertension (SiDBP ≥110 mmHg): The adverse experience profile for patients with severe hypertension (SiDBP ≥110 mmHg) treated with losartan/hydrochlorothiazide as initial therapy was similar to the adverse experience profile in patients treated with losartan monotherapy at the time of first dose, at 4 weeks of therapy, and at 6 weeks of therapy. Additionally, the adverse experience rates for hypotension, syncope, dizziness, and increased serum creatinine (all of which are signs and symptoms of hypoperfusion) did not differ between the treatment groups.

Hypertensive patients with a history of cough: In an 8-week controlled study of the incidence of cough in hypertensive patients with a history of cough during ACE inhibitor therapy, the incidence of cough reported by patients receiving losartan potassium or hydrochlorothiazide was similar and was significantly less than in patients rechallenged with an ACE inhibitor. In addition, an overall analysis of double-blind clinical trials in 4131 patients revealed that the incidence of spontaneously reported cough in patients treated with losartan potassium monotherapy (n=2085; 3.1%) or losartan potassium and hydrochlorothiazide (n=858; 2.6%) was similar to that of patients treated with placebo (n=535; 2.6%) or hydrochlorothiazide alone (n=271; 4.1%), whereas the incidence with ACE inhibitors (n=239) was 8.8%.

8.3 Less Common Clinical Trial Adverse Reactions

In double-blind, controlled clinical trials with losartan potassium alone, the following adverse experiences were reported at an occurrence rate of less than 1%, regardless of drug relationship:

Cardiovascular: orthostatic effects

Ear/Nose/Throat: epistaxis, tinnitus

Gastrointestinal: constipation

General: malaise

Neurologic: somnolence, vertigo

Skin: rash

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

Clinical Trial Findings

Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred.

Hyperkalemia: In controlled hypertensive trials with losartan monotherapy and losartan potassium and hydrochlorothiazide, a serum potassium >5.5 mEq / L occurred in 1.5% and 0.7% of patients, respectively. However, no patient discontinued losartan or losartan potassium and hydrochlorothiazide therapy due to hyperkalemia.

Serum Creatinine, Blood Urea Nitrogen (BUN): Minor increases in blood urea nitrogen (1.0%) and serum creatinine (1.0%) were observed in patients with essential hypertension treated with losartan potassium and hydrochlorothiazide. 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).

Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.1 percent of patients with essential hypertension treated with losartan potassium alone. In clinical studies, no patient discontinued taking losartan potassium alone due to increased BUN or serum creatinine.

No other adverse experiences have been reported with losartan potassium and hydrochlorothiazide which have not been reported with losartan or hydrochlorothiazide individually.

8.5 Post-Market Adverse Reactions

The following additional adverse reactions have been reported in post-marketing experience with losartan potassium and hydrochlorothiazide and/or in clinical trials or post-marketing use with the individual components:

Blood and Lymphatic System Disorders: Thrombocytopenia, anemia, aplastic anemia, hemolytic anemia, leukopenia, and agranulocytosis.

Cardiac Disorders: Palpitation, tachycardia.

Eye Disorders: Xanthopsia, transient blurred vision.

Gastrointestinal Disorders: Dyspepsia, abdominal pain, gastric irritation, cramping, diarrhea, constipation, nausea, vomiting, pancreatitis, sialoadenitis.

General Disorders and Administration Site Conditions: Chest pain, edema/swelling, malaise, fever, weakness.

Hepatobiliary Disorders: Hepatitis, jaundice (intrahepatic cholestatic jaundice).

Immune System Disorders: Anaphylactic reactions, angioedema (including swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, and/or tongue and pharynx, requiring therapeutic intervention in some cases) has been reported rarely in patients treated with losartan. Some patients previously experienced angioedema with ACE inhibitors.

Investigations: Liver function abnormalities.

Metabolism and Nutrition Disorders: Anorexia, hyperglycemia, hyperuricemia, electrolyte imbalance including hyponatremia and hypokalemia.

Musculoskeletal and Connective Tissue Disorders: Back pain, muscle cramps, muscle spasm, myalgia, arthralgia.

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).

Nervous System Disorders: Dysgeusia, headache, migraine, paraesthesias.

Psychiatric Disorders: Insomnia, restlessness.

Renal and Urinary Disorders: Glycosuria, renal dysfunction, interstitial nephritis, renal failure.

Reproductive System and Breast Disorders: Erectile dysfunction/impotence.

Respiratory, Thoracic and Mediastinal Disorders: Cough, nasal congestion, pharyngitis, sinus disorder, upper respiratory infection, respiratory distress, including pneumonitis, pulmonary edema and Adult Respiratory Distress Syndrome have been reported rarely in post-marketing experience. Acute respiratory distress has been reported in very rare instances (see 7 WARNINGS AND PRECAUTIONS, Respiratory).

Skin and Subcutaneous Tissue Disorders: Rash, pruritus, purpura (including Henoch-

Schoenlein purpura), toxic epidermal necrolysis, urticaria, erythroderma, photosensitivity, cutaneous lupus erythematosus.

Vascular Disorders: Dose-related orthostatic effects, necrotizing angiitis (vasculitis)

(cutaneous vasculitis).

Cases of muscle pain, muscle weakness, myositis and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

9 DRUG INTERACTIONS

9.1 Serious 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; CT = Clinical Trial; T = Theoretical; RCS = Retrospective Cohort Study

9.5 Drug-Food Interactions

Grapefruit juice contains components that inhibit CYP 450 enzymes and may lower the concentration of the active metabolite of losartan which may reduce the therapeutic effect of TEVA-LOSARTAN/HCTZ. Consumption of grapefruit juice should be avoided while taking TEVA-LOSARTAN/HCTZ.

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

Losartan potassium and hydrochlorothiazide combines the actions of losartan potassium, an angiotensin II receptor antagonist, and that of a thiazide diuretic, hydrochlorothiazide.

Losartan: Losartan potassium antagonizes angiotensin II by blocking the angiotensin type one (AT₁) receptor.

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin system. Its effects include vasoconstriction and the stimulation of aldosterone secretion by the adrenal cortex.

Losartan, and its active metabolite, E-3174, block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to AT₁ receptors found in many tissues, including vascular smooth muscle. A second type of angiotensin II receptor has been identified as the AT₂ receptor, but it plays no known role in cardiovascular homeostasis to date. Both losartan and its active metabolite do not exhibit any agonist activity at the AT₁ receptor, and have much greater affinity, in the order of 1000-fold, for the AT₁ receptor than for the AT₂ receptor. In vitro binding studies indicate that losartan itself is a reversible, competitive antagonist at the AT₁ receptor, while the active metabolite is 10 to 40 times more potent than losartan, and is a reversible, non-competitive antagonist of the AT₁ receptor.

Neither losartan nor its active metabolite inhibits angiotensin converting enzyme (ACE), also known as kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin, nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

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.

10.2 Pharmacodynamics

Losartan: Losartan inhibits the pressor effect of angiotensin II. A dose of 100 mg inhibits this effect by about 85% at peak, with 25-40% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2-3 fold rise in plasma renin activity, and a consequent rise in angiotensin II plasma concentration, in hypertensive patients.

Maximum blood pressure lowering, following oral administration of a single dose of losartan, as seen in hypertensive patients, occurs at about 6 hours.

In losartan-treated patients during controlled trials, there was no meaningful change in heart rate.

There is no apparent rebound effect after abrupt withdrawal of losartan therapy.

Black hypertensive patients show a smaller average blood pressure response to losartan monotherapy than other hypertensive patients.

Hydrochlorothiazide: 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.

Losartan - Hydrochlorothiazide: The components of losartan potassium and hydrochlorothiazide have been shown to have an additive effect on blood pressure reduction, reducing blood pressure to a greater degree than either component alone.

The antihypertensive effect of losartan potassium and hydrochlorothiazide is sustained for a 24-hour period. In clinical studies of at least one year's duration, the antihypertensive effect was maintained with continued therapy. Despite the significant decrease in blood pressure, administration of losartan potassium and hydrochlorothiazide had no clinically significant effect on heart rate.

10.3 Pharmacokinetics

Absorption:

Losartan

Following oral administration, losartan is well absorbed, with systemic bioavailability of losartan approximately 33%. About 14% of an orally-administered dose of losartan is converted to the active metabolite, although about 1% of subjects did not convert losartan efficiently to the active metabolite.

Mean peak concentrations of losartan occur at about one hour, and that of its active metabolite at about 3-4 hours. Although maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times greater than that of losartan.

Hydrochlorothiazide

Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an oral bioavailability of about 65% to 75%. Peak concentrations of hydrochlorothiazide were reached approximately 2 hours after dosing.

Distribution:

Losartan

Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2% respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.

The volume of distribution of losartan is about 34 liters, and that of the active metabolite is about 12 liters.

Hydrochlorothiazide

Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Metabolism:

Losartan

Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite, E-3174, that is responsible for most of the angiotensin II receptor antagonism that follows oral losartan administration.

Various losartan metabolites have been identified in human plasma and urine. In addition to the active carboxylic acid metabolite, E-3174, several inactive metabolites are formed. In vitro studies indicate that the cytochrome P450 isoenzymes 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized.

Elimination:

Losartan

The terminal half-life of losartan itself is about 2 hours, and that of the active metabolite, about 6-9 hours. The pharmacokinetics of losartan and this metabolite are linear with oral losartan doses up to 200 mg and do not change over time. Neither losartan nor its metabolite accumulate in plasma upon repeated once-daily administration.

Total plasma clearance of losartan is about 600 mL / min, with about 75 mL / min accounted for by renal clearance. Total plasma clearance of the active metabolite is about 50 mL / min, with about 25 mL / min accounted for by renal clearance. Both biliary and urinary excretion contribute substantially to the elimination of losartan and its metabolites.

Following oral ¹⁴C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of ¹⁴C-labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces.

Hydrochlorothiazide

Hydrochlorothiazide is eliminated rapidly by the kidney. 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.

Special Populations and Conditions

• Patients with mild to moderate alcoholic cirrhosis

Following oral administration of losartan potassium to patients with mild to moderate alcoholic cirrhosis, AUC of losartan and its active metabolite, E-3174, were about 5-times and 1.7-times greater, respectively, than in young healthy male volunteers. Compared to these normal subjects, the total plasma clearance of losartan in patients with hepatic insufficiency was about 50% lower and the oral bioavailability was about 2-times higher.

11 STORAGE STABILITY AND DISPOSAL

TEVA-LOSARTAN/HCTZ Tablets 100 mg / 12.5 mg and 100 mg / 25 mg:

Store at room temperature (15°C - 25°C). Keep container tightly closed. Protect from light.

TEVA-LOSARTAN/HCTZ Tablets 50 mg / 12.5 mg:

For bottles: Store at room temperature (15°C - 30°C). Keep container tightly closed. Protect from light.

For blisters: Store at room temperature (15°C - 30°C). Protect from light.

12 SPECIAL HANDLING INSTRUCTIONS

There are no special requirements for use or handling of this product.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:	losartan potassium	hydrochlorothiazide
Chemical name:	2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol monopotassium salt.	6-chloro-3,4-dihydro-2H-1,2,4- benzothiadiazine-7-sulfonamide 1,1- dioxide.
Molecular formula:	C22H22ClKN6O	C7H8CIN3O4S2
Molecular mass:	461.01	297.74
Structural formula:
Physicochemical properties: (100 mg / 12.5 mg and 100 mg / 25 mg)	Losartan potassium is a white or almost white, crystalline powder. It’s solubility in water is 400 mg / ml.	Hydrochlorothiazide is a white, or practically white, crystalline powder. It is slightly soluble in water, but freely soluble in sodium hydroxide solution.
Physicochemical properties: (50 mg / 12.5 mg)	Losartan potassium is a white to off-white free-flowing crystalline powder. It is freely soluble in water, soluble in alcohol, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone. Oxidation of the 5- hydroxymethyl group on the	Hydrochlorothiazide is a white, or practically white, crystalline powder. It is slightly soluble in water, but freely soluble in sodium hydroxide solution.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Hypertension

Table 4 - Summary of Patient Demographics for Double-Blind Clinical Trial in Adult Patients with Severe Hypertension

The safety and efficacy of losartan potassium and hydrochlorothiazide as initial therapy for severe hypertension (baseline mean SiDBP ≥ 110 mmHg confirmed on 2 separate occasions) was demonstrated in a six-week double-blind, randomized, multicenter study of 585 patients with severe hypertension. The primary endpoint was a comparison at 4 weeks of patients who achieved goal diastolic blood pressure (trough SiDBP <90 mmHg) on losartan/hydrochlorothiazide 50 mg / 12.5 mg versus patients on losartan 50 mg titrated to 100 mg as needed to reach goal diastolic blood pressure. The secondary endpoint was a comparison at 6 weeks of patients who achieved goal diastolic blood pressure on losartan/hydrochlorothiazide 50 mg / 12.5 mg titrated as needed to losartan/hydrochlorothiazide 100 mg / 25 mg versus patients on losartan 50 mg titrated to 100 mg and then to 150 mg. In a post-hoc analysis, patients who achieved goal systolic blood pressure (trough SiSBP <140 mmHg) were compared for the 2 treatment groups at 4 and 6 weeks.

Table 5 - Results of Losartan/Hydrochlorothiazide Efficacy Compared to Losartan in Double-Blind, Multicenter Study in Patients with Severe Hypertension

After 4 weeks of therapy, more patients who received losartan/hydrochlorothiazide 50 mg / 12.5 mg combination therapy reached target diastolic blood pressure than those who received losartan 50 or 100 mg monotherapy (17.6% versus 9.4%, respectively; p=0.007). Similarly, after 6 weeks of therapy, more patients who received the combination regimen reached target diastolic blood pressure than those who received the monotherapy regimen (29.8% versus 12.5%, respectively; p<0.001). Additionally, more patients achieved goal systolic blood pressure on combination therapy versus monotherapy at each time point (week 4: 24.5% versus 11.9%, respectively, p<0.001; week 6: 36.9% versus 14.1%, respectively, p<0.001). The safety and tolerability of losartan/hydrochlorothiazide for patients with severe hypertension were comparable to losartan monotherapy at the time of first dose, at 4 weeks of therapy, and at 6 weeks of therapy.

14.2 Comparative Bioavailability Studies

A blinded, single-dose, randomized, two-way, cross-over comparative bioavailability study of TEVA-LOSARTAN/HCTZ 100 mg / 25 mg tablets (Teva Canada Ltd.) and HYZAAR ® DS 100 mg / 25 mg tablets (Merck Frosst Canada Ltd.) was conducted under fasting conditions in 24 normal, healthy, non-smoking, adult subjects (23 males and 1 female). A summary of the bioavailability data is presented in the tables below.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ TEVA-LOSARTAN/HCTZ (losartan potassium and hydrochlorothiazide) 100 mg / 25 mg Tablets (Teva Canada Ltd.).

² HYZAAR® DS (losartan potassium and hydrochlorothiazide) 100 mg / 25 mg Tablets (Merck Frosst Canada Ltd.).

³ Expressed as the arithmetic mean (CV%) only

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ TEVA-LOSARTAN/HCTZ (losartan potassium and hydrochlorothiazide) 100 mg / 25 mg Tablets (Teva Canada Ltd.).

² HYZAAR® DS (losartan potassium and hydrochlorothiazide) 100 mg / 25 mg Tablets (Merck Frosst Canada Ltd.).

³ Expressed as the arithmetic mean (CV%) only

A randomized, two-way crossover bioequivalence study of TEVA-LOSARTAN/HCTZ 100 mg / 25 mg tablets (Teva Canada Ltd.) and HYZAAR® DS 100 mg / 25 mg tablets (Merck Frosst Canada Ltd.) administered as a single 1 x 100 mg/25 mg dose, was conducted in 24 healthy adult male subjects under fasting conditions. A summary of the bioavailability data is presented below.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ TEVA-LOSARTAN/HCTZ (losartan potassium and hydrochlorothiazide) 100 mg / 25 mg Tablets (Teva Canada Ltd.).

² HYZAAR® DS (losartan potassium and hydrochlorothiazide) 100 mg / 25 mg Tablets (Merck Frosst Canada Ltd.).

³ Expressed as the arithmetic mean (CV%) only.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ TEVA-LOSARTAN/HCTZ (losartan potassium and hydrochlorothiazide) 100 mg / 25 mg Tablets (Teva Canada Ltd.).

² HYZAAR® DS (losartan potassium and hydrochlorothiazide) 100 mg / 25 mg Tablets (Merck Frosst Canada Ltd.).

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:

Acute Toxicity

The oral LD₅₀ of losartan potassium in male mice is 2248 mg / kg (6744 mg / m²). Significant lethality was observed in mice and rats after oral administration of 1000 mg / kg (3000 mg / m²) and 2000 mg/kg (11,800 mg / m²), respectively (see Table 6).

Table 6 - Acute Toxicity (Losartan)

Chronic Toxicity

The toxic potential of losartan potassium was evaluated in a series of repeated-dose oral toxicity studies of up to three months in monkeys and up to one year in rats and dogs. The toxic potential of losartan potassium and hydrochlorothiazide was evaluated in repeated-dose oral toxicity studies for up to six months in rats and dogs (see Table 7).

Table 7 - Chronic Toxicity

1. a) Oral Administration (Losartan)

1. b) Oral Administration (Losartan – Hydrochlorothiazide)

^† E-3174 (L-158,641): Primary pharmacologically active metabolite of losartan.

HCTZ = hydrochlorothiazide

1. c) I.V. Administration (Losartan)

^† E-3174 (L-158,641): Primary pharmacologically active metabolite of losartan.

Carcinogenicity:

Losartan: Losartan potassium was not carcinogenic when administered at maximum tolerated dosage levels to rats and mice for 105 weeks (maximum dose of 270 mg/kg/day) and 92 weeks (maximum dose of 200 mg/kg/day), respectively.

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.

Genotoxicity:

Losartan: Losartan potassium was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays. In addition, there was no evidence of direct genotoxicity in the in vitro alkaline elution and in vitro chromosomal aberration assays. Similarly, there was no induction of chromosomal aberrations in bone marrow cells of male or female mice after the administration of toxic oral doses of up to 1500 mg / kg (4500 mg / m²). In addition, the active metabolite E-3174 showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays.

Losartan - Hydrochlorothiazide: Losartan potassium and hydrochlorothiazide was negative in the Ames microbial mutagenesis assay and the V-79 Chinese hamster lung cell mutagenesis assay. In addition, there was no evidence of direct genotoxicity in the in vitro alkaline elution assay in rat hepatocytes and in vitro chromosomal aberration assay in Chinese hamster ovary cells at noncytotoxic concentrations.

Hydrochlorothiazide: 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 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.

Reproductive and Developmental Toxicology:

Losartan: Fertility and reproductive performance were not affected in studies with male and female rats given oral doses of losartan potassium up to approximately 150 and 300 mg/kg/day, respectively.

Losartan - Hydrochlorothiazide: Losartan potassium and hydrochlorothiazide administration had no effect on the reproductive performance or fertility in male rats at dosage levels of up to 135 mg/kg/day of losartan in combination with 33.75 mg/kg/day of hydrochlorothiazide. These dosage levels provided respective plasma concentrations (AUC) for losartan, the active metabolite E-3174, and hydrochlorothiazide that were approximately 260-, 120-, and 50-fold greater than those achieved in man with 50 mg of losartan potassium in combination with 12.5 mg hydrochlorothiazide. In female rats, however, the coadministration of losartan potassium and hydrochlorothiazide (10 mg / 2.5 mg/kg/day) induced a slight but statistically significant decrease in fecundity and fertility indices. Compared to plasma concentrations in man (see above) these dosage levels provided respective increases in plasma concentration (AUC) for losartan, the active metabolite E-3174, and hydrochlorothiazide of approximately 15-, 4-, and 5-fold.

Teratology

Losartan: Losartan potassium has been shown to produce adverse reactions in rat fetuses and neonates. The reactions include decreased body weight, mortality and/or renal toxicity. Pharmacokinetic evaluation of fetal plasma showed significant levels of losartan and its active metabolite, E-3174 (L-158,641), on Gestation Day 20 compared to negligible value on Gestation Day 15. In addition, significant levels of losartan and its active metabolite were shown to be present in rat milk. Based on these findings, the fetal and neonatal effects of losartan potassium in rats are attributed to drug exposure in late gestation and during lactation.

Losartan-Hydrochlorothiazide: There was no evidence of teratogenicity in rats or rabbits treated with losartan potassium and hydrochlorothiazide. Fetal toxicity in rats, as evidenced by a slight increase in supernumerary ribs in the F₁ generation, was observed when females were treated prior to and throughout gestation. As observed in studies with losartan alone, adverse fetal and neonatal effects, including decreased body weight and renal toxicity, also occurred when pregnant rats were treated with losartan potassium and hydrochlorothiazide during late gestation and/or lactation.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. ^PrHYZAAR^® and ^PrHYZAAR^® DS (Tablets, 50 mg / 12.5 mg, 100 mg / 12.5 mg, 100 mg / 25 mg), submission control #265018, Product Monograph, Organon Canada Inc. (NOV 02, 2022)