Product Monograph - Irbesartan/HCTZ

Recent Major Label Changes

7 Warnings and Precautions, Gastrointestinal 2026-01

Table of Contents

Recent Major Label Changes ................................................................................................... 2

Table of Contents .................................................................................................................... 2

Part 1: Healthcare 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 .................................................................................................. 6
4.5 Missed Dose...................................................................................................... 6
5. Overdosage................................................................................................................ 6
6. Dosage Forms, Strengths, and Composition ................................................................. 7
7.
Warnings and Precautions ........................................................................................... 7
Carcinogenesis and Genotoxicity................................................................................... 7
Cardiovascular.............................................................................................................. 8
Driving and Operating Machinery.................................................................................. 8
Endocrine and Metabolism ........................................................................................... 9
Gastrointestinal ............................................................................................................ 9
Hepatic/Biliary/Pancreatic ............................................................................................ 9
Immune ....................................................................................................................... 9
Ophthalmologic ..........................................................................................................10
Renal ........................................................................................................................10
Respiratory..................................................................................................................10
Skin ........................................................................................................................11 7.1 Special Populations ..........................................................................................11
7.1.1 Pregnancy ............................................................................................... 11
7.1.2 Breastfeeding .......................................................................................... 12
7.1.3 Pediatrics ................................................................................................ 12
7.1.4 Geriatrics................................................................................................. 12
8.
Adverse Reactions ......................................................................................................12
8.1 Adverse Reaction Overview ..............................................................................12
8.2 Clinical Trial Adverse Reactions.........................................................................12
8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ........................................................................................................17
8.5 Post-Market Adverse Reactions ........................................................................18
9.
Drug Interactions ........................................................................................................19
9.2 Drug Interactions Overview ..............................................................................19
9.3 Drug-Behaviour Interactions .............................................................................19
9.5 Drug-Drug Interactions .....................................................................................19
9.6 Drug-Food Interactions.....................................................................................25
9.7 Drug-Herb Interactions .....................................................................................25
10.
Clinical Pharmacology .................................................................................................25
10.1 Mechanism of Action........................................................................................25
10.2 Pharmacodynamics ..........................................................................................26
10.3 Pharmacokinetics .............................................................................................27
11. Storage, Stability and Disposal ....................................................................................29

Part 2: Scientific Information..................................................................................................30

13. Pharmaceutical Information .......................................................................................30
14.
Clinical Trials ...............................................................................................................30
14.1 Clinical Trials by Indication................................................................................30
14.2 Comparative Bioavailability Studies ..................................................................33
16. Non-Clinical Toxicology ...............................................................................................34
17. Supporting Product Monographs ................................................................................43

Patient Medication Information .............................................................................................44

Part 1: Healthcare Professional Information

1. Indications

IRBESARTAN/HCTZ (irbesartan/hydrochlorothiazide) is indicated:

for the treatment of essential hypertension in patients for whom combination therapy is appropriate (see 4 DOSAGE AND ADMINISTRATION).
as initial therapy 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 14 CLINICAL TRIALS and 4 DOSAGE AND ADMINISTRATION).

IRBESARTAN/HCTZ is not indicated as initial therapy in patients with mild to moderate essential hypertension.

1.1 Pediatrics

Pediatrics (< 18 years of age): The safety and efficacy of IRBESARTAN/HCTZ in patients <18 years of age have not been established. Therefore, Health Canada has not authorized an indication for pediatric use (see 7 WARNINGS AND PRECAUTIONS, 7.1 Special Populations).

1.2 Geriatrics

Geriatrics (> 65 years of age): In clinical studies, no overall differences in safety or efficacy were observed between patients > 65 years of age and younger patients (see 7 WARNINGS AND PRECAUTIONS, 7.1 Special Populations).

2. Contraindications

IRBESARTAN/HCTZ 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 who are hypersensitive to other sulphonamide-derived drugs, because of the hydrochlorothiazide component.
Patients with anuria.
Pregnant women (see 7 WARNINGS AND PRECAUTIONS, 7.1 Special Populations).
Nursing women (see 7 WARNINGS AND PRECAUTIONS, 7.1 Special Populations).
Combination 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) (7 see WARNINGS AND PRECAUTIONS, Renal, and 9 DRUG INTERACTIONS).
Combination with angiotensin converting enzyme (ACE) inhibitors in patients with diabetic nephropathy (see 7 WARNINGS AND PRECAUTIONS, Renal, and 9 DRUG INTERACTIONS).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption (due to lactose component of the IRBESARTAN/HCTZ tablets).

3. Serious Warnings and Precautions Box

When used in pregnancy, angiotensin receptor (AT₁) blockers (ARB) can cause injury and even death of the developing fetus. When pregnancy is detected, IRBESARTAN/HCTZ should be discontinued as soon as possible (see 7 WARNINGS AND PRECAUTIONS, 7.1 Special Populations).

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 IRBESARTAN/HCTZ (irbesartan/hydrochlorothiazide) should be determined by the titration of the individual components.
Use of IRBESARTAN/HCTZ in patients with liver impairment is not advisable.
Dosage adjustment may be required in hemodialysis patients (see 4.2 Recommended Dose and
Dosage Adjustment).

4.2 Recommended Dose and Dosage Adjustment

Once the patient has been stabilized on the individual components as described below, either one tablet of IRBESARTAN/HCTZ 150/12.5 mg, 300/12.5 mg or 300/25 mg once daily may be substituted if the doses on which the patient was stabilized are the same as those in the fixed combination.

Irbesartan Monotherapy

The recommended dose of irbesartan is 150 mg once daily. In patients whose blood pressure is not adequately controlled, the daily dose may be increased to 300 mg.

SEVERE HYPERTENSION (Sitting DBP ≥ 110 mmHg)

The starting dose of IRBESARTAN/HCTZ for initial treatment of severe hypertension is one tablet of IRBESARTAN/HCTZ 150/12.5 mg once daily (see 1 INDICATIONS and 14 CLINICAL TRIALS). The dosage may be increased after 2 - 4 weeks of therapy to a maximum of 300/25 mg once daily. IRBESARTAN/HCTZ is not recommended as initial therapy in patients with intravascular volume depletion (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular).

DOSE ADJUSTMENT IN SPECIAL POPULATION

Diuretic Treated Patients

In patients receiving diuretics, irbesartan 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 2 - 3 days prior to the administration of irbesartan to reduce the likelihood of hypotension (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular, and 9 DRUG INTERACTIONS). If this is not possible because of the patient’s condition, irbesartan should be administered with caution and the blood pressure monitored closely. The recommended starting dose of irbesartan is 75 mg once daily in hypovolemic patients (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular). Thereafter, the dosage should be adjusted according to the individual response of the patient.

Geriatric

No initial dosage adjustment in irbesartan 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 Special Populations).

Renal Insufficiency

No initial dosage adjustment in irbesartan is generally necessary in patients with renal impairment, although due to the apparent greater sensitivity of hemodialysis patients, an initial dose of 75 mg is recommended in this group of patients.

The usual regimens of therapy with IRBESARTAN/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 IRBESARTAN/HCTZ is not recommended.

Hepatic Insufficiency

No initial dosage adjustment in irbesartan is generally necessary in patients with mild to moderate hepatic impairment. Since thiazide diuretics may precipitate hepatic coma, the use of a fixed combination product such as IRBESARTAN/HCTZ is not advisable.

4.4 Administration

IRBESARTAN/HCTZ may be administered with or without food, however it should be taken consistently with respect to food intake.

4.5 Missed Dose

Patients should be instructed to take IRBESARTAN/HCTZ at the next scheduled dose and not take two doses at the same time if they miss a dose.

5. Overdosage

No specific information is available on the treatment of overdosage with IRBESARTAN/HCTZ (irbesartan/hydrochlorothiazide). The patient should be closely monitored, and the treatment should be symptomatic and supportive, including fluid and electrolyte replacement.

Irbesartan

No data or very little data available in regard to overdosage in humans.

The most likely manifestations of overdosage would be hypotension and/or tachycardia; bradycardia might also occur in this setting. Irbesartan is not 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, and Composition

Table 1 - Dosage Forms, Strengths, Composition and Packaging

Route of

Dosage Form/

Non-medicinal Ingredients

Administration

Strength/Composition

Oral

Tablet, 150/12.5 mg, 300/12.5 mg and 300/25 mg

Croscarmellose sodium, hydroxypropylcellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, silica colloidal anhydrous, polyethylene glycol, titanium dioxide, and talc.

IRBESARTAN/HCTZ 150/12.5 mg and 300/12.5 mg also contain ferric oxide red and ferric oxide yellow.

IRBESARTAN/HCTZ 300 mg/25 mg also contains ferric oxide red and ferric oxide black.

IRBESARTAN/HCTZ (irbesartan/hydrochlorothiazide) 150 mg/12.5 mg: apricot, oval biconvex film-coated tablets, debossed with 150H on one side.

IRBESARTAN/HCTZ (irbesartan/hydrochlorothiazide) 300 mg/12.5 mg: apricot, oval biconvex film-coated tablets, debossed with 300H on one side.

IRBESARTAN/HCTZ (irbesartan/hydrochlorothiazide) 300 mg/25 mg: dark pink, oval biconvex film-coated tablets, debossed with 300 on one side and 25H on other side.

IRBESARTAN/HCTZ 150/12.5 mg, 300/25 mg and 300/12.5 mg tablets are available in bottles of 100 and 500 tablets.

7. Warnings and Precautions

Carcinogenesis and Genotoxicity

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-CLINICAL TOXICOLOGY, Carcinogenicity).

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

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 irbesartan, 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 (see 4 DOSAGE AND ADMINISTRATION). 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 the irbesartan component of IRBESARTAN/HCTZ or of angiotensin converting enzyme (ACE) inhibitors 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 IRBESARTAN/HCTZ in combination with aliskiren-containing drugs is contraindicated in these patients (see 2 CONTRAINDICATIONS).

The use of IRBESARTAN/HCTZ in combination with an ACE inhibitor is contraindicated in patients with diabetic nephropathy (see 2 CONTRAINDICATIONS).

Further, co-administration of ARBs, including the irbesartan component of IRBESARTAN/HCTZ, with other agents blocking the RAS, such as ACE inhibitors or aliskiren-containing drugs, is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia.

Driving and Operating Machinery

The effect of irbesartan on the ability to drive and use machinery has not been studied, but based on its pharmacodynamic properties, irbesartan is unlikely to affect this ability. When driving vehicles or operating machinery, it should be taken into account that occasionally dizziness or weariness may occur during treatment of hypertension.

Endocrine and Metabolism

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalemia, hyponatremia and hypochloremic alkalosis). Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Calcium excretion is decreased by thiazides which may cause intermittent and slight elevation of serum calcium. If calcium or a calcium sparing drug (e.g., vitamin D therapy) is prescribed, serum calcium levels should be monitored, and calcium dosage adjusted accordingly. Marked hypercalcemia suggests the possibility of hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesemia.

Hyperuricemia may occur, and an acute attack of gout may be precipitated in certain patients receiving thiazide therapy.

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

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

IRBESARTAN/HCTZ may induce hypoglycemia, particularly in patients treated for diabetes. Therefore, dose adjustment of antidiabetic treatment such as repaglinide or insulin may be required (see 8 ADVERSE REACTIONS).

Insulin requirements in diabetic patients may be altered and latent diabetes mellitus may become manifest during thiazide diuretic therapy.

Gastrointestinal

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, including Irbesartan/hydrochlorothiazide. These patients presented with abdominal pain, (with or without nausea, vomiting and diarrhoea). Symptoms resolved after discontinuation of angiotensin II receptor antagonists. Intestinal angioedema should be included in the differential diagnosis of patients treated with angiotensin II receptor antagonists presenting with abdominal pain. If intestinal angioedema is diagnosed, IRBESARTAN/HCTZ should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

Hepatic/Biliary/Pancreatic

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

Immune

Hypersensitivity Reaction

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

Systemic Lupus Erythematosus

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

Ophthalmologic

Choroidal effusion, Secondary Acute Angle-Closure Glaucoma and/or Acute Myopia

Hydrochlorothiazide is a sulfonamide. Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction, which may result in choroidal effusion, secondary acute angle-closure glaucoma and/or acute transient myopia (see 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse Reactions). 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 sulfonamide or penicillin allergy.

Renal

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 impairment the diuretic should be discontinued.

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 ARBs including the irbesartan component of IRBESARTAN/HCTZ or of the ACE inhibitors 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).

The use of ARBs including the irbesartan component of IRBESARTAN/HCTZ in combination with an ACE inhibitor is contraindicated in patients with diabetic nephropathy due to risk of hyperkalemia, hypotension and renal impairment (see 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS).

Use of irbesartan should include appropriate assessment of renal function.

Thiazides should be used with caution.

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

Respiratory

Acute Respiratory Distress

Severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms can include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, IRBESARTAN/HCTZ should be withdrawn and appropriate treatment should be given. IRBESARTAN/HCTZ must not be administered to patients who previously experienced ARDS following intake of hydrochlorothiazide or another thiazide diuretic.

Skin

Photosensitivity

Photosensitivity reactions have been reported with the use of thiazide diuretics. If the photosensitivity reactions occur during treatment with hydrochlorothiazide drugs, treatment should be stopped.

Psoriasis

The use of IRBESARTAN/HCTZ in patients with psoriasis or a history of psoriasis should be carefully weighed as it may exacerbate psoriasis.

7.1 Special Populations

7.1.1 Pregnancy

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

The use of ARB is contraindicated during pregnancy. Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE 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 ARBs 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, hyperkalaemia).

Infants with histories of in utero exposure to an ARB 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 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. Irbesartan is not 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 reactions that have occurred in adults. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia. 7.1.2 Breastfeeding

It is not known whether irbesartan is excreted in human milk, but significant levels of radioactivity have been found in the milk of lactating rats. Thiazides appear in human milk. Thiazides in high doses causing intense diuresis can inhibit the milk production.

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): 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): Of the 2650 hypertensive patients receiving

irbesartan/hydrochlorothiazide in clinical studies, 618 patients were ≥ 65 years of age. No overall age-related differences were seen in the adverse effect profile but greater sensitivity in some older individuals cannot be ruled out.

8. Adverse Reactions

8.1 Adverse Reaction Overview

Irbesartan/hydrochlorothiazide was evaluated for safety in 2746 patients with essential hypertension including 968 patients for ≥ 1 year.

The most commonly reported adverse events (AEs) (occurring in ≥10% of patients treated with irbesartan/hydrochlorothiazide) was headache (11.0%), which occurred at a significantly higher incidence in the placebo group (16.1%).

The AEs most frequently resulting in clinical intervention (discontinuation of

irbesartan/hydrochlorothiazide) were due to dizziness (0.7%) and headache (0.7%). The AE of hypotension is more likely to occur in volume depleted patients (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular).

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

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.

Hypertension

In placebo-controlled clinical trials, therapy was discontinued due to a clinical or laboratory AE in 3.6 % of patients treated with irbesartan/hydrochlorothiazide, versus 6.8 % of patients given placebo.

AEs regardless of drug relationship, occurring in ≥1% of the irbesartan/ hydrochlorothiazide patients in placebo-controlled clinical trials include the following:

Table 2: Adverse events regardless of drug relationship, occurring in ≥1% of the irbesartan/ hydrochlorothiazide patients in placebo-controlled clinical trials

	Irbesartan/ HCTZ n = 898 (%)	Irbesartan n = 400 (%)	HCTZ n = 380 (%)	Placebo n = 236 (%)
Cardiovascular
Edema	3.1	1.5	1.6	2.5
Tachycardia	1.2	0.5	0.5	0.4
Dermatologic
Rash	1.2	1.8	3.2	1.7
Gastrointestinal
Nausea/vomiting	3.2	1.5	2.4	0.4
Dyspepsia	2.1	0.3	1.6	0.8
Diarrhea	2.1	2.8	1.1	3.4
Abdominal Pain	1.7	1.5	1.6	0.8
General
Fatigue	6.5	4.0	3.2	3.0
Influenza	2.8	2.0	1.8	1.3
Chest Pain	1.8	1.5	1.6	1.3

	Irbesartan/ HCTZ n = 898 (%)	Irbesartan n = 400 (%)	HCTZ n = 380 (%)	Placebo n = 236 (%)
Immunology
Allergy	1.1	0.5	0.5	0
Musculoskeletal
Musculoskeletal Pain	6.5	6.0	9.7	4.7
Muscle Cramp	1.0	0.8	2.1	1.3
Nervous System
Headache	11.0	9.3	11.6	16.1
Dizziness	7.6	5.5	4.7	4.2
Orthostatic Dizziness	1.1	1.0	0.8	0.4
Anxiety / Nervousness	1.0	1.0	0.5	1.7
Renal/Genitourinary
Urination abnormal	1.9	0.5	2.1	0.8
Urinary Tract Infection	1.6	1.5	2.4	2.5
Respiratory
URTI	5.6	8.3	7.1	5.5
Sinus disorder	2.9	4.5	3.2	4.7
Cough	2.2	2.3	2.6	3.0

Irbesartan/

HCTZ

n = 898

(%)

Irbesartan

n = 400

(%)

HCTZ

n = 380

(%)

Placebo n = 236

(%)

Pharyngitis

2.1

2.3

2.9

1.7

Rhinitis

1.9

2.0

1.6

2.5

Severe Hypertension

In a clinical study in patients with severe hypertension (SeDBP ≥110 mmHg), the overall pattern of AEs reported through seven weeks of follow-up was similar in patients treated with irbesartan/hydrochlorothiazide as initial therapy and in patients treated with irbesartan as initial therapy.

Table 3: Most common adverse events regardless of drug relationship, occurring in ≥1% of the irbesartan/ hydrochlorothiazide patients with Severe Hypertension in controlled clinical trial

	Number (%) of Subjects Irbesartan/HCTZ N = 468	Number (%) of Subjects Irbesartan N = 227
Headache	19 (4.1)	15 (6.6)
Dizziness	16 (3.4)	9 (4.0)
Nasopharyngitis	8 (1.7)	10 (4.4)
Bronchitis	6 (1.3)	6 (2.6)
Fatigue	6 (1.3)	1 (0.4)
Upper Respiratory Tract Infection	6 (1.3)	4 (1.8)
Erectile Dysfunction	5 (1.1)	0
Nausea	5 (1.1)	5 (2.2)
Diarrhea	4 (0.9)	3 (1.3)
Sinusitis	4 (0.9)	3 (1.3)
Cough	3 (0.6)	4 (1.8)
Muscle Spasms	2 (0.4)	3 (1.3)

The incidence of the pre-specified AEs was: 0% reported cases of syncope in either treatment group; 0.6% and 0% cases of hypotension, 3.6% and 4.0% cases of dizziness, 4.3% and 6.6% cases of headache, 0.2% and 0% cases of hyperkalemia, and 0.6% and 0.4% cases of hypokalemia reported in the group treated with irbesartan/hydrochlorothiazide and the group treated with irbesartan, respectively.

The rate of discontinuation due to AEs was 1.9% and 2.2% in the group treated with irbesartan/hydrochlorothiazide and the group treated with irbesartan, respectively.

Irbesartan Alone

In addition, the following potentially important events occurred in < 1% of patients receiving irbesartan, regardless of drug relationship:

Body as a Whole: chills, facial edema, fever, upper extremity edema;

Cardiovascular: angina pectoris, arrhythmic/conduction disorder, cardiac murmur, cardio-respiratory arrest, flushing, heart failure, hypertension, hypertensive crisis, myocardial infarction, syncope;

Dermatologic: dermatitis, ecchymosis, erythema, erythema face, photosensitivity, pruritus, urticaria;

Endocrine: gout, libido disorder, sexual dysfunction;

Gastrointestinal: abdominal distention, constipation, flatulence, gastroenteritis, hepatitis;

Hematologic: anemia, lymphocytopenia, thrombocytopenia;

Investigations: increased creatine phosphokinase (CPK);

Musculoskeletal: arthritis, bursitis, extremity swelling, joint stiffness, muscle cramp, muscular weakness, musculoskeletal chest pain, musculoskeletal trauma, myalgia;

Nervous System: cerebrovascular accident, depression, emotional disturbances, numbness, paraesthesia, sleep disturbance, somnolence, transient ischemic attack, tremor, vertigo;

Renal/Genitourinary: abnormal urination, prostate disorder;

Respiratory: congestion, dyspnea, epistaxis, pulmonary congestion, tracheobronchitis, wheezing;

Special Senses: conjunctivitis, ear infection, ear pain, hearing impaired, taste disturbance, visual disturbance.

Hydrochlorothiazide alone

Other adverse events that have been reported with hydrochlorothiazide, without regard to causality, are listed below:

Body as a Whole: weakness;

Digestive: cramping, gastric irritation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, sialadenitis;

Hematologic: agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, thrombocytopenia; Hypersensitivity: anaphylactic reactions, fever, necrotizing angiitis (vasculitis and cutaneous vasculitis), photosensitivity, purpura, respiratory distress including pneumonitis and pulmonary edema, urticaria;

Metabolic: glycosuria, hyperglycemia, hyperuricemia;

Musculoskeletal: muscle spasm;

Nervous System/Psychiatric: restlessness;

Renal: interstitial nephritis, renal dysfunction, renal failure;

Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis;

Special Senses: transient blurred vision, xanthopsia.

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

Data

Clinical Trial Findings

IRBESARTAN/HYDROCHLOROTHIAZIDE

Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in 2.3% of patients. No patient was discontinued due to increased BUN. One patient was discontinued due to a minor increase in serum creatinine.

Liver Function Tests: Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated with irbesartan/hydrochlorothiazide alone, one patient was discontinued due to elevated liver enzymes.

IRBESARTAN

Creatine Phosphokinase: In an open-label extension study, significant increases in plasma creatine phosphokinase (CPK) were commonly observed (1.6%) in irbesartan treated subjects.

Creatinine, Blood Urea Nitrogen: Minor increases in BUN or serum creatinine were observed in less than 0.7% of patients with essential hypertension treated with irbesartan alone versus 0.9% on placebo.

Hemoglobin: Mean decreases in hemoglobin of 0.16g/dL were observed in patients receiving irbesartan. No patients were discontinued due to anemia.

Hyperkalemia: In placebo-controlled trials, greater than a 10% increase in serum potassium was observed in 0.4% of irbesartan treated patients compared to 0.5% of patients receiving placebo.

Liver Function Tests: In placebo-controlled trials, elevations of aspartate aminotransferase (AST) and alanine transaminase (ALT) ≥3X upper limit of normal (ULN) occurred in 0.1% and 0.2%, respectively, of irbesartan treated patients compared to 0.3% and 0.3%, respectively, of patients receiving placebo. In patients treated with irbesartan for a mean duration of > 1 year, the cumulative incidence of AST and/or ALT elevations ≥3X ULN was 0.4%.

Neutropenia: Neutropenia (<1000 cells/mm³) was observed in 0.3% of irbesartan treated patients compared to 0.5% of patients receiving placebo.

8.5 Post-Market Adverse Reactions

The following adverse reactions were reported in post-marketing use:

General: asthenia, syncope;

Hepatic/Biliary/Pancreatic: hepatobiliary disorders (acute hepatitis, cholestatic or cytolytic hepatitis); elevated liver function tests; jaundice;

Immune: anaphylactic reactions, anaphylactic shock; angioedema (involving swelling of the face, lips, and/or tongue) has been reported rarely;

Musculoskeletal: myalgia;

Gastrointestinal: intestinal angioedema;

Renal: impaired renal function including cases of renal failure in patients at risk (see

7 WARNINGS AND PRECAUTIONS, Renal);

Endocrine and Metabolism: hypoglycemia (see 7 WARNINGS AND PRECAUTIONS);

Hematologic: anemia (cases of positive dechallenge and rechallenge have been reported post-market), thrombocytopenia (including thrombocytopenic purpura);

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

Ear/Nose/Throat: tinnitus;

Gastrointestinal: anorexia, gastric irritation, sialadenitis;

Hematologic: agranulocytosis, bone marrow depression, leucopenia, thrombocytopenia;

Hepatic/Biliary/Pancreatic: pancreatitis;

Immune: necrotizing angiitis (vasculitis, cutaneous vasculitis), photosensitivity;

Ophthalmologic: eye disorders (secondary acute angle-closure glaucoma, acute myopia and choroidal effusion; frequency unknown), xanthopsia;

Renal: interstitial nephritis;

Respiratory: respiratory distress (including pneumonitis and pulmonary oedema), Acute respiratory distress syndrome (ARDS) (see 7 WARNINGS AND PRECAUTIONS);

Skin: psoriasis (and psoriasis exacerbation), toxic epidermal necrolysis;

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, with important uncertainty, that 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

9.2 Drug Interactions Overview

Irbesartan does not substantially induce or inhibit the following isoenzymes: CYP 1A1, 1A2, 2A6, 2B6, 2D6, 2E1. There was no induction or inhibition of CYP 3A4.

9.3 Drug-Behaviour Interactions

Alcohol, barbiturates and narcotics should be avoided (especially with initiation of therapy) due to an interaction with the hydrochlorothiazide component of IRBESARTAN/HCTZ (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 4: Established or Potential Drug-Drug Interactions

Proper/Common

name

Source

Evidence

Effect

Clinical comment

Alcohol, barbiturates, or narcotics

Potentiation of orthostatic hypotension may occur.

Avoid alcohol, barbiturates or narcotics, especially with initiation of therapy.

Agents increasing Serum Potassium

RCS

Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of irbesartan with potassium-sparing diuretics, potassium

supplements, salt substitutes containing potassium or other

Proper/Common name	Source of Evidence	Effect	Clinical comment
		potassium-raising medicinal products may lead to increases in serum potassium, sometimes severe. Such co-administration requires close monitoring of serum potassium. Concomitant thiazide diuretic use may attenuate any effect that irbesartan may have on serum potassium.
Amphotericin B	T	Amphotericin B increases the risk of hypokalemia induced by thiazide diuretics	Monitor serum potassium level.
Antidiabetic agents (e.g. insulin and oral antihyperglycemic agents) (e.g. repaglinide)	CT	Thiazide-induced hyperglycemia may compromise blood sugar control. Depletion of serum potassium augments glucose intolerance. May induce hypoglycemia. Irbesartan has the potential to inhibit OATP1B1. In a clinical study, co- administration of irbesartan and repaglinide, 300 mg irbesartan once daily for 4 days then followed by a single dose of 2 mg repaglinide, 1 hour after irbesartan (with consideration of the Tmax difference between the two drugs), increased the Cmax and AUC of repaglinide (substrate of OATP1B1) by 1.8-fold and 1.3-fold, respectively.	Monitor glycemic control, supplement potassium if necessary, to maintain appropriate serum potassium levels. Dose adjustment of antidiabetic treatment such as repaglinide may be required (see 7 WARNINGS AND PRECAUTIONS).
Antihypertensive drugs See also: Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACE	CT	Hydrochlorothiazide may potentiate the action of other antihypertensive drugs (e.g. guanethidine, methyldopa, beta- blockers, vasodilators, calcium channel blockers,	Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalemia, hyponatremia and hypochloremic alkalosis). Periodic determination of

Proper/Common name	Source of Evidence	Effect	Clinical comment
inhibitors or aliskiren-containing drugs		diuretics, ACE inhibitors, ARB, and direct renin inhibitors).	serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
Antineoplastic drugs, including cyclophosphamide and methotrexate	C	Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.	Hematological status should be closely monitored in patients receiving this combination. Dose adjustment of cytotoxic agents may be required.
Beta-blockers	C	The hyperglycemic effect of beta-blockers may be enhanced by thiazides.
Bile acid sequestrants, e.g., cholestyramine	CT	Bile acid sequestrants bind thiazide diuretics in the gut and impair gastrointestinal absorption by 43-85%. Administration of thiazide 4 hours after a bile acid sequestrant reduced absorption of hydrochlorothaizide by 30-35%.	Give thiazide 2-4 hours before or 6 hours after the bile acid sequestrant. Maintain a consistent sequence of administration. Monitor blood pressure, and increase dose of thiazide, if necessary.
Calcium and vitamin D supplements	C	Thiazides decrease renal excretion of calcium and increase calcium release from bone.	Monitor serum calcium, especially with concomitant use of high doses of calcium supplements. Dose reduction or withdrawal of calcium and/or vitamin D supplements may be necessary.
Carbamazepine	C	Carbamazepine may cause clinically significant hyponatremia. Concomitant use with thiazide diuretics may potentiate hyponatremia.	Monitor serum sodium levels. Use with caution. If possible, another class of diuretics should be used.
Corticosteroids, and adrenocorticotropic hormone (ACTH)	T	Intensified electrolyte depletion, particularly hypokalemia, may occur.	Monitor serum potassium, and adjust medications, as required.

Proper/Common name	Source of Evidence	Effect	Clinical comment
Diazoxide	C	The hyperglycemic effect of diazoxide may be enhanced by thiazides.
Digoxin	CT	When irbesartan was administered as 150 mg once daily under steady-state conditions, no effect was seen on the pharmacokinetics of digoxin at steady-state. Thiazide-induced electrolyte disturbances, i.e. hypokalemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events.	Concomitant administration of hydrochlorothiazide and digoxin requires caution. Monitor electrolytes and digoxin levels closely. Supplement potassium or adjust doses of digoxin or thiazide, as required.
Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACE inhibitors or aliskiren-containing drugs	CT	Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACE inhibitors or aliskiren-containing drugs is contraindicated in patients with diabetes and/or moderate to severe renal impairment, and is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia. Dual Blockade of the Renin- Angiotensin-System (RAS) with ARBs and ACE inhibitors is contraindicated in patients with diabetic nephropathy and is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure and hyperkalemia.	See 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS, Dual Blockade of the Renin-Angiotensin-System (RAS).

Proper/Common name	Source of Evidence	Effect	Clinical comment
Drugs that alter GI motility, i.e., anti- cholinergic agents, such as atropine and prokinetic agents, such as metoclopramide, domperidone	CT, T	Bioavailability of thiazide diuretics may be increased by anticholinergic agents due to a decrease in gastrointestinal motility and gastric emptying. Conversely, prokinetic drugs may decrease the bioavailability of thiazide diuretics.	Dose adjustment of thiazide may be required.
Gout medications (allopurinol, uricosurics, xanthine oxidase inhibitors)	T, RCS	Thiazide-induced hyperuricemia may compromise control of gout by allopurinol and probenecid. The co-administration of hydrochlorothiazide and allopurinol may increase the incidence of hypersensitivity reactions to allopurinol.	Dosage adjustment of gout medications may be required.
Lithium	CT	Thiazide diuretics reduce the renal clearance of lithium and add a high risk of lithium toxicity. As with other drugs which eliminate sodium, lithium clearance may be reduced in the presence of irbesartan. Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of irbesartan and lithium.	Concomitant use of thiazide diuretics with lithium is generally not recommended. If such use is deemed necessary, reduce lithium dose by 50% and monitor lithium levels closely. Serum lithium levels should be monitored carefully if lithium salts are to be administered with irbesartan.
Nonsteroidal anti- inflammatory drugs (NSAID) (including selective COX-2 inhibitors)	CT	In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective	Monitor renal function periodically in patients receiving irbesartan and NSAID therapy.

Proper/Common name	Source of Evidence	Effect	Clinical comment
		COX-2 inhibitors, with ARBs, including irbesartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. The antihypertensive effect of ARBs, including irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors. In some patients, the administration of a NSAID can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics.	When IRBESARTAN/HCTZ and NSAID are used concomitantly, the patient should be observed closely to determine if the desired effect is obtained.
Pressor Amines (e.g., Norepinephrine)	CT	In the presence of diuretics, possible decreased response to pressor amines may be seen but not sufficient to preclude their use.
Selective serotonin reuptake inhibitors (SSRIs, e.g., citalopram, escitalopram, sertraline)	T, C	Concomitant use with thiazide diuretics may potentiate hyponatremia.	Monitor serum sodium levels. Use with caution.
Skeletal muscle relaxants of the curare family, e.g., tubocurare	C	Thiazide drugs may increase the responsiveness of some skeletal muscle relaxants, such as curare derivatives
Topiramate	CT	Additive hypokalemia. Possible thiazide-induced increase in topiramate serum concentrations.	Monitor serum potassium and topiramate levels. Use potassium supplements, or adjust topiramate dose as necessary.

Proper/Common

name

Source

Evidence

Effect

Clinical comment

Warfarin

When irbesartan was

administered as 300 mg once daily under steady-state conditions, no

pharmacodynamic effect on PT was demonstrated in subjects stabilized on warfarin.

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

9.5 Drug-Food Interactions

No statistically significant effects of food were observed on the C_max, AUC_(inf)or T_1/2of irbesartan or on the AUC_(inf)or T_1/2of hydrochlorothiazide. In the fasted and fed states, T_maxincreased from 1 to 2 hours for irbesartan and from 1.5 to 3.5 hours for hydrochlorothiazide. The C_maxfor hydrochlorothiazide decreased 21% in the fed state relative to the fasted state. None of these changes were considered to be clinically significant.

9.6 Drug-Herb Interactions

There have been no clinical studies to assess the possible interaction of any herbal products and irbesartan/hydrochlorothiazide.

10. Clinical Pharmacology

10.1 Mechanism of Action

Irbesartan/hydrochlorothiazide combines the actions of irbesartan, an angiotensin II AT₁receptor blocker (ARB), and that of a thiazide diuretic, hydrochlorothiazide.

Irbesartan

Irbesartan antagonizes angiotensin II by blocking AT₁receptors.

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

Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking in a non-competitive manner the binding of angiotensin II to the AT₁receptor found in many tissues. Irbesartan has no agonist activity at the AT₁receptor. AT₂receptors have been found in many tissues, but to date they have not been associated with cardiovascular homeostasis. Irbesartan has essentially no affinity for the AT₂receptors.

Irbesartan does not inhibit ACE, also known as kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin, nor does it affect renin or other hormone receptors or ion channels involved in cardiovascular regulation of blood pressure and sodium homeostasis. Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an ARB tends to reverse the potassium loss associated with these diuretics.

The mechanism of the antihypertensive effect of thiazides is not fully understood.

10.2 Pharmacodynamics

Irbesartan

In healthy subjects, single oral doses of irbesartan ≤ 300 mg produced dose-dependent inhibition of the pressor effect of angiotensin II infusions. The inhibition was complete (100%) 4 hours following oral doses of 150 mg or 300 mg. Partial inhibition of 40% and 60% was still present 24 hours post-dose with 150 mg and 300 mg irbesartan respectively.

In hypertensive patients, angiotensin II receptor inhibition following chronic administration of irbesartan caused a 1.5-2 fold rise in angiotensin II plasma concentration and a 2-3 fold increase in plasma renin levels. Aldosterone plasma concentrations generally declined following irbesartan administration, however serum potassium levels were not significantly affected at recommended doses.

During clinical trials, minimal incremental blood pressure response was observed at doses > 300 mg.

The blood pressure lowering effect of irbesartan was apparent after the first dose and substantially present within 1-2 weeks, with the maximal effect occurring by 4-6 weeks. In long-term studies, the effect of irbesartan appeared to be maintained for more than one year. There was essentially no change in average heart rate in patients treated with irbesartan in controlled trials.

There was no rebound effect after withdrawal of irbesartan.

Black hypertensive patients had a smaller blood pressure response to irbesartan monotherapy than Caucasians.

There was no significant difference in blood pressure response based on age and gender.

Hydrochlorothiazide

Onset of the diuretic action following oral administration occurred in 2 hours and the peak action in about 4 hours. Diuretic activity lasts about 6 - 12 hours.

Irbesartan/Hydrochlorothiazide

The components of irbesartan/hydrochlorothiazide were shown to have an additive effect on blood pressure reduction, reducing blood pressure to a greater degree than either component alone.

The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide was apparent after the first dose and substantially present within 1-2 weeks, with the maximal effect occurring by 6-8 weeks. In long-term follow-up studies, the effect of irbesartan/hydrochlorothiazide was maintained for >1 year.

10.3 Pharmacokinetics

Table 5: Pharmacokinetic Parameters for Irbesartan

Irbesartan

T_max(h)

t_½(h)

Clearance

(mL/minute)

Volume of distribution

(L)

Single dose mean

1.5-2

11-15

Plasma 157 -176

Renal 3.0 - 3.5

53-93

Table 6: Pharmacokinetic Parameters for Hydrochlorothiazide

Hydrochlorothiazide

T_max(h)

t_½(h)

Clearance

(mL/minute)

Volume of distribution

(L/kg)

Single dose mean

1.5-2

5-15

Plasma 192-343

Predominantly Renal

(unchanged)

1.5-4.2

Irbesartan

Following either oral or intravenous administration of ¹⁴C-labeled irbesartan, > 80% of the circulating plasma radioactivity was attributable to unchanged irbesartan. The primary circulating metabolite was the inactive irbesartan glucuronide (approximately 6%). The remaining oxidative metabolites did not add appreciably to the pharmacologic activity.

In vitro studies of irbesartan indicated that the oxidation of irbesartan was primarily by cytochrome P-450 isoenzyme CYP 2C9. Metabolism of irbesartan by CYP 3A4 was negligible. Irbesartan was neither metabolized, nor does it substantially induce or inhibit the following isoenzymes: CYP 1A1, 1A2, 2A6, 2B6, 2D6, 2E1. There was no induction or inhibition of CYP 3A4.

Absorption

Irbesartan is an orally active agent. The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60% - 80%. Following oral administration, peak plasma concentrations are attained at 1.5-2 hours after dosing. Steady-state concentrations are achieved within 3 days.

Distribution

The average volume of distribution of irbesartan is 53-93 litres.

Irbesartan is approximately 96% protein-bound in the plasma, primarily to albumin and α₁-acid glycoprotein.

Metabolism

Irbesartan is metabolized via glucuronide conjugation, and oxidation by the cytochrome P-450 system.

Elimination

Irbesartan and its metabolites are excreted by both biliary and renal routes. Following either oral or intravenous administration of ¹⁴C-labeled irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces. Less than 2% of the dose is excreted in urine as unchanged irbesartan. Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range with an average terminal elimination half-life of 11-15 hours.

Total plasma and renal clearances are in the range of 157 - 176 and 3.0 - 3.5 mL/minute, respectively.

Hydrochlorothiazide

Hydrochlorothiazide was not metabolized but is eliminated rapidly by the kidney. The plasma half-life was observed to vary between 5.6 and 14.8 hours when the plasma levels could be followed for at least 24 hours. At least 61 percent of the oral dose was eliminated unchanged within 24 hours.

Absorption

Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract. The bioavailability is approximately 65 - 70%.

Distribution

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

Metabolism

Hydrochlorothiazide is not metabolized.

Elimination

Hydrochlorothiazide is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours. The plasma half-life has been observed to vary from 5.6 and 14.8 hours.

Special Populations and Conditions

Geriatrics
In subjects > 65 years old, irbesartan elimination half-life was not significantly altered, but AUC and C_maxvalues were about 20 - 50% greater than those of young subjects.
Hepatic Insufficiency
The pharmacokinetics of irbesartan following repeated oral administration were not significantly affected in patients with mild to moderate cirrhosis of the liver. No data is available in patients with severe liver disease.
Renal Insufficiency
The mean AUC and C_maxof irbesartan were not altered in patients with any degree of renal impairment, including patients on hemodialysis. However, a wide variance was seen in patients with severe renal impairment.

11. Storage, Stability and Disposal

IRBESARTAN/HCTZ (irbesartan/hydrochlorothiazide) tablets can be stored between 15 and 30°C. Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substances: irbesartan/hydrochlorothiazide

	Irbesartan	Hydrochlorothiazide
Chemical Name	2-butyl-3-[(2¹-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,3- diazaspiro [4,4] non-1-en-4-one.	6-chloro-3,4-dihydro-2H-1,2,4-benzo-thiadiazine-7-sulfonamide 1,1-dioxide
Molecular Formula and molecular mass	C25 H28 N6O 428.5 g/mol	C₇H₈ClN₃O₄S₂ 297.7 g/mol
Structural Formula
Physicochemical Properties	Irbesartan is a white to off-white crystalline powder. It is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at a pH of 7.4. Irbesartan is slightly soluble in alcohol and methylene chloride and practically insoluble in water.	Hydrochlorothiazide is a white, or practically white, crystalline powder. Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution.

14. Clinical Trials

14.1 Clinical Trials by Indication

Irbesartan-Hydrochlorothiazide

The antihypertensive effects of irbesartan-hydrochlorothiazide tablets were examined in 4 placebo-controlled studies of 8-12 weeks in patients with mild-moderate hypertension. These trials included 1914 patients randomized to fixed doses of irbesartan (37.5 to 300 mg) and concomitant hydrochlorothiazide (6.25 - 25 mg). One factorial study compared all combinations of irbesartan (37.5, 100 and 300 mg or placebo) and hydrochlorothiazide (6.25, 12.5, and 25 mg or placebo). The irbesartan-hydrochlorothiazide combinations of 75/12.5 mg and 150/12.5 mg were compared to their individual components and placebo in a separate study. A third study investigated the ambulatory blood pressure responses to irbesartan -hydrochlorothiazide (75/12.5 mg and 150/12.5 mg) and placebo after 8 weeks of dosing. Another trial investigated the effects of the addition of irbesartan (75 mg) in patients not controlled on hydrochlorothiazide (25 mg) alone.

In controlled trials, the addition of irbesartan 150-300 mg to hydrochlorothiazide doses of 6.25, 12.5 or 25 mg produced further dose-related reductions in blood pressure of 8-10/3-6 mmHg, comparable to those achieved with the same monotherapy dose of irbesartan. The addition of hydrochlorothiazide to irbesartan produced further dose related reductions in blood pressure at trough (24 hours post-dose) of 5-6/2-3 mmHg (12.5 mg) and 7-11/4-5 mmHg (25 mg), also comparable to effects achieved with hydrochlorothiazide alone. Once-daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide, 300 mg irbesartan and 12.5 mg hydrochlorothiazide, or 300 mg irbesartan and 25 mg hydrochlorothiazide produced mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of about 13-15/7-9, 14/9-12, and 19-21/11-12 mmHg, respectively. Peak effects occurred at 3-6 hours, with the trough-to peak ratios >65%.

In another study, irbesartan (75-150 mg) or placebo was added on a background of 25 mg hydrochlorothiazide in patients not adequately controlled (SeDBP 93-120 mmHg) on hydrochlorothiazide (25 mg) alone. The addition of irbesartan (75-150 mg) gave an additive effect (systolic/diastolic) at trough (24 hours post-dosing) of 11/7 mmHg.

There was no difference in response for men and women or in patients over or under 65 years of age. Black patients had a larger response to hydrochlorothiazide than non-black patients and a smaller response to irbesartan. The overall response to the combination was similar for black and non-black patients.

Severe Hypertension

The efficacy of irbesartan/hydrochlorothiazide as initial therapy for severe hypertension (defined as a mean seated diastolic blood pressure (SeDBP) ≥110 mmHg confirmed on 2 separate occasions off all antihypertensive therapy) was studied in a 7-week, double-blind, randomized, multicenter study. Patients were randomized to either irbesartan and hydrochlorothiazide (150/12.5 mg) or to irbesartan (150 mg) once daily and followed for blood pressure response. These initial study regimens were increased at 1 week to irbesartan 300 mg/HCTZ 25 mg or to irbesartan 300 mg, respectively. The primary endpoint was a comparison at 5 weeks of the proportion of patients who achieved through SeDBP <90 mmHg. An additional supportive endpoint compared the proportion of subjects in each treatment group whose blood pressure was controlled, defined as simultaneous SeDBP <90 mmHg and SeSBP <140 mmHg.

Study demographics and trial design

The study randomized 697 patients, in a 2:1 ratio to receive either combination therapy (irbesartan plus HCTZ, N=468) or irbesartan monotherapy (N=229), and included 296 (42%) females, 101 (14%) blacks, and 92 (13%) ≥65 years of age. The mean age was 52 years. The mean blood pressure at baseline for the total population was 172/113 mmHg.

Table 7: Summary of patient demographics for clinical trial with irbesartan/hydrochlorothiazide in subjects with severe hypertension

Study #

Trial design

Dosage, route of administration and duration

Study subjects

(n=number)

Mean age in years

(Range)

Gender

CV131176

Multicenter, randomized, double-blind, active

controlled, 7-week, parallel group study.

Oral administration of irbesartan/HCTZ 150/12.5 mg or irbesartan 150 mg increased at 1 week to irbesartan/HCTZ 300/25 mg or to irbesartan 300 mg.

697

Irbesartan: 229

Irbesartan/HCTZ: 468

52.5

(23.0-83.0)

Male 57.5 %

Female 42.5 %

Study Results

The study results are summarized in table 8.

After 5 weeks of therapy, the mean SeDBP was 4.7 mmHg lower (p≤0.0001) and the mean SeSBP was 9.7 mmHg lower (p<0.0001) in the group treated with irbesartan/hydrochlorothiazide than in the group treated with irbesartan. Mean reductions from baseline for SeDBP and SeSBP at trough were 24.0 mmHg and 30.8 mmHg for irbesartan/hydrochlorothiazide-treated patients and 19.3 mmHg and 21.1 mmHg for irbesartan-treated patients, respectively. A greater proportion of patients on

irbesartan/hydrochlorothiazide achieved a diastolic blood pressure <90 mmHg (47.2% for irbesartan/hydrochlorothiazide, 33.2% for irbesartan; p=0.0005) and a greater proportion of the patients on irbesartan/hydrochlorothiazide achieved simultaneous control of SeSBP <140 mmHg and SeDBP <90 mmHg (34.6% versus 19.2%; p<0.0001). Similar results were seen when the patients were grouped according to gender, race or age (<65 years, ≥65 years). The proportions of subjects with controlled SeDBP, as well as with simultaneous SeDBP/SeSBP control, at each week of the double-blind period were consistently larger and statistically significantly greater for irbesartan/hydrochlorothiazide-treated patients than for irbesartan-treated patients.

Table 8: Results at week 5 of study with irbesartan/hydrochlorothiazide in subjects with severe hypertension

Endpoints

Irbesartan /HCTZ

150/12.5 mg force titrated to 300/25 mg

Irbesartan

150 mg force titrated to 300 mg

p value

Primary Endpoint: Proportion of subjects in each treatment group whose SeDBP was controlled (SeDBP <90 mmHg).

47.2 %

33.2 %

0.0005

Endpoints

Irbesartan /HCTZ

150/12.5 mg force titrated to 300/25 mg

Irbesartan

150 mg force titrated to 300 mg

p value

Other Endpoints:

Proportion of subjects whose BP
was controlled (simultaneous SeDBP < 90 mmHg and SeSBP <140 mmHg)
Mean changes from baseline in
trough
SeDBP
SeSBP

34.6 %

-24.0

-30.8

19.2%

-19.3

-21.1

<0.0001

14.2 Comparative Bioavailability Studies

A randomized, single dose, two-way crossover study of IRBESARTAN/HCTZ 300 mg/25 mg tablets (Sanis Health Inc.) and ^PrAVALIDE® 300 mg/25 mg tablets (sanofi-aventis Canada Inc.) was conducted in healthy, adult, male subjects under fasting conditions. Comparative bioavailability data from the 27 subjects that were included in the statistical analysis are presented in the following table:

Table 9: Summary Table of the Comparative Bioavailability Data

	Irbesartan (1 x 300 mg irbesartan/25 mg hydrochlorothiazide) Geometric Mean Arithmetic Mean (CV %)
Parameter		Test¹	Reference²		% Ratio of		90% Confidence Interval
					Geometric Means
AUC_T (ng·h/mL)		16458.3 17180.8 (30.9)	17739.2 18685.4 (33.9)	92.8		87.4 – 98.5
AUC_I (ng·h/mL)		19201.6 19784.0 (27.1)	20889.4 21546.7 (28.3)	91.9		86.1 – 98.2
CMAX (ng/mL)		3939.8 4151.6 (33.6)	3276.1 3454.6 (35.3)	120.3		108.6 – 133.1
TMAX3 (h)		1.0 (0.5 – 4.0)	1.0 (0.5 – 5.0)
T1/24 (h)		10.5 (26.5)	11.3 (31.8)

¹IRBESARTAN/HCTZ (irbesartan and hydrochlorothiazide) tablets, 300 mg/25 mg (Sanis Health Inc.) ^{2 Pr}AVALIDE® (irbesartan and hydrochlorothiazide) tablets, 300 mg/25 mg (sanofi-aventis Canada Inc.) ³Expressed as the median (range) only

⁴Expressed as the arithmetic mean (CV %) only

Table 10: Summary Table of the Comparative Bioavailability Data

	Hydrochlorothiazide
	(1 x 300 mg irbesartan/25 mg hydrochlorothiazide)
	Geometric Mean
	Arithmetic Mean (CV %)
Parameter		Test¹	Reference²		% Ratio of		90% Confidence
					Geometric Means		Interval
AUC_T (ng·h/mL)		966.66 979.84 (17.1)	949.48 970.94 (19.2)	101.8		94.6 – 109.6
AUC_I (ng·h/mL)		1009.67 1022.79 (16.6)	990.52 1010.89 (18.5)	101.9		95.1 – 109.3
CMAX (ng/mL)		168.46 173.57 (25.2)	166.31 172.97 (26.9)	101.3		90.7 – 113.1
TMAX3 (h)		1.75 (0.67 – 4.00)	1.50 (1.00 – 3.50)
T1/24 (h)		9.94 (16.5)	9.96 (19.1)

⁴Expressed as the arithmetic mean (CV %) only

16. Non-Clinical Toxicology

General Toxicology

Acute Toxicity

Irbesartan

Table 11: Acute Toxicity for Irbesartan

Species	Sex (N)	Route	LD₅₀(mg/kg)
Mouse	M (5) F (5)	PO	> 2000
Rat	M (5) F (5)	PO	> 2000
Mouse	M (5) F (5)	IV	> 50
Rat	M (5) F (5)	IV	> 50

Species

Sex (N)

Route

LD₅₀(mg/kg)

Mouse

M (5)

F (5)

200 - 2000

Rat

M (5)

F (5)

200 - 2000

After single administration, toxicity was slight and no target organ was identified. Very few toxic effects, characterized by pilo-erection and/or somnolence were noted at 2000 mg/kg by the oral route, 200 mg/kg by the intraperitoneal route and 50 mg/kg by the intravenous route. Acute oral toxicity studies with irbesartan in mice and rats indicated acute lethal doses were in excess of 2000 mg/kg, about 25 - 50 fold the maximum human dose (300 mg) on a mg/m²basis, respectively.

Irbesartan - hydrochlorothiazide

Table 12: Acute Toxicity for Irbesartan - hydrochlorothiazide

Species	Sex (N)	Route	LD₅₀(mg/kg)
Species	Sex (N)	Route	Irbesartan	HCTZ	Irbesartan/ HCTZ
Mouse	M (5) F (5)	PO	> 2000	> 4000	> 2000/4000
Rat	M (5)	PO	> 3000	> 500	> 3000/500

No mortality occurred following administration of the irbesartan/hydrochlorothiazide combination up to and including the highest dose of irbesartan: hydrochlorothiazide (2000/4000 mg/kg in mice or 3000/500 mg/kg in rats). No treatment-related clinical signs and body weight changes were observed. At necropsy, performed at the end of the 14-day observation period, pathologic examinations did not reveal any treatment-induced changes.

Subacute and Chronic Toxicity

Irbesartan

Table 13: Subacute and Chronic Toxicity Irbesartan

Species / Strain		Sex (N/Dose)	Dose (mg/kg/day)	Route	Time	Effects
	SUBACUTE TOXICITY
Rat		M (10) F (10)	0, 30, 70, 150	PO	4 weeks	Irbesartan only induced slight decrease in hemoglobin levels (at 150 mg/kg) and slight increase in glucose (≥30 mg/kg), urea (≥ 70 mg/kg), creatinine and K⁺levels (at 150 mg/kg), and slight decrease in Na⁺and Cl^-urinary concentrations and excretions (≥30 mg/kg).
Rat		M (10) F (10)	0, 0.8, 2, 5	IV	16 days	Very slight increase in Na⁺and Cl^-plasma levels (≥0.8 mg/kg/day in males). Very slight increase in K⁺plasma levels, in ASAT and slight decrease in kidney relative weight at 5 mg/kg/day in males.
Monkey		M (3) F (3)	0, 10, 30, 90	PO	4 weeks	Dose-related hyperplasia of the juxtaglomerular apparatus (from 30 mg/kg/day upwards).
Monkey		M (3) F (3)	0, 250, 500, 1000	PO	4 weeks	≥250 mg/kg/day: changes in the kidney (hyperplasia of the juxtaglomerular apparatus), heart (myocardial fibrosis) and erythrocytes parameters (slight anemia). At 500 mg/kg/day: increased platelet count, fibrogen and neutrophil levels and at 1000 mg/kg/day, health deterioration were also noted. One animal receiving 250 mg/kg/day presented the most severe heart lesions and marked electrocardiographic modifications on D1 and D29. However, pre-existing lesions could not be excluded.

Species / Strain		Sex (N/Dose)	Dose (mg/kg/day)	Route	Time	Effects
Monkey		M (3) F (3)	0, 0.8, 2, 5	IV	2 weeks	Irbesartan induced only a slight hyperplasia of the juxtaglomerular apparatus in 2/3 females receiving 5 mg/kg/day. One high-dose animal presented a marked heart hypertrophy with marked ECG changes on D1 and D10 suggesting that it was a preexisting lesion.
Rat		M (20) - F (20) [main study] M (10) - F (10) [reversibility study for control and high dose groups] M (5) - F (5) [toxicokinetics study]	0, 10, 30, 90	PO	26 weeks	Slight reduction of the body weight gain in males at 90 mg/kg/day (- 6 to - 8%). Other changes can be considered to be of pharmacological origin for some of them and have no clear toxicological significance for all of them. The no-observed adverse effect dose was considered to be 30 mg/kg/day.
	CHRONIC TOXICITY

Species / Strain

Sex (N/Dose)

Dose

(mg/kg/day)

Route

Time

Effects

Rat

M (20) - F (20) [main study]

M (10) - F (10) [reversibility study for control and high dose groups]

M (5) - F (5) [toxicokinetics

study]

0, 0, 250, 500, 1000

weeks

Slight reduction of body weight gain without any dose-relationship reversible.
Changes in hematology and blood biochemistry parameters demonstrating an effect on red blood cells and on the renal function, likely associated with the pharmacological activity of irbesartan and reversible.
Hyperplasia/hypertrophy of the juxtaglomerular apparatus in males (≥ 250 mg/kg/day) and in females (≥ 500 mg/kg/day) partially reversible.

Monkey

M (5) - F (5) [main study]

M (3) - F (3) [reversibility study for control and high dose groups)]

0, 10, 30, 90

months

Dose-related hyperplasia of juxtaglomerular apparatus in all treated animals partially reversible at the end of treatment.
Slight dose-related decrease in weight gain from the 30 mg/kg/day dose level upwards and slight anemia from 10 mg/kg/day upwards, both reversible on cessation of treatment.

Species / Strain

Sex (N/Dose)

Dose

(mg/kg/day)

Route

Time

Effects

Monkey

M (5)

F (5)

0, 20, 100,

500

weeks

Irbesartan was well tolerated and most of the changes observed were considered to be due to the pharmacological activity of the drug:
Dose-related decrease in blood pressure at doses ≥ 20 mg/kg/day associated with necrosis of the tip of the tail likely due to a decrease in blood flow at 500 mg/kg/day.
Dose-related hyperplasia / hypertrophy of the juxtaglomerular apparatus in all treated animals with degenerative kidney changes at 500 mg/kg/day.
Slight decrease in body weight gain and erythrocyte parameters at doses ≥100 mg/kg/day.

After repeated oral administrations at dose levels up to 1000 mg/kg per day, most of the treatment-related effects noted in all species are linked to the pharmacological activity of irbesartan. The kidney can be considered as the primary target organ: hyperplasia/hypertrophy of the juxtaglomerular apparatus which was observed in all species, is a direct consequence of the interaction with the renin-angiotensin system. Irbesartan also induced some hematology (slight decrease in erythrocyte parameters) and blood biochemistry variations (slight increase in urea, creatinine, phosphorus, potassium and calcium levels) likely due to a disturbance in the renal blood flow, and a slight decrease in heart weight which could result from a decrease in cardiac work load due to decreased peripheral vascular resistance. At high doses (> 500 mg/kg per day), degenerative changes of the kidney were noted which could be secondary to prolonged hypotensive effects.

Subacute and Chronic Toxicity (Cont’d)

Irbesartan/hydrochlorothiazide

Table 14: Subacute and Chronic Toxicity Irbesartan/Hydrochlorothiazide

Species / Strain

Sex

(N/Dose)

Dose

(mg/kg/day)

Route

Time

Effects

Rat

M (20)

F (20)

0*/0**, 10/10, 90/90

90/0, 0/90

months

Exposure to HCTZ was greater when administered in combination with irbesartan, than when given alone.
Body weight gains in the high dose group (90/90 mg/kg) were slightly decreased in females and moderately decreased in males.
Hemoglobin, hematocrit, and erythrocyte counts were slightly decreased in females given the high dose combination (90/90).
In the high dose combination, serum urea nitrogen and alkaline phosphatase (males)
were slightly elevated; serum potassium and calcium (Week 12) were slightly decreased in males; serum cholesterol and triglycerides were slightly to moderately decreased.
In the low dose combination, serum cholesterol, triglycerides and potassium were slightly decreased.
Slight increases in urine pH; urine protein concentrations markedly lower in high dose combination group.
Decreased heart weights in males and females at 10/10, 99/90 and 90/0.
Decreased liver weights in males.
Juxtaglomerular-cell hypertrophy/hyperplasia.
Increased urine output.
Increased kidney weights in females.
At necropsy, discoloration of the glandular stomach correlated with focal coagulative necrosis or ulceration of the mucosa were noted in all treated groups with an incidence slightly greater in rats given the high-dose combination.

Species / Strain

Sex

(N/Dose)

Dose

(mg/kg/day)

Route

Time

Effects

Monkey

M (20)

F (20)

0*/0**, 10/10, 90/90

0/90, 90/0

months

Exposure to HCTZ was approximately 60% greater when administered in combination with irbesartan than when administered alone.
Body weights of males in the high dose combination group (90/90) were mildly decreased.
Mean hemoglobin, hematocrit and erythrocyte values were mildly to moderately decreased at the high dose combination (90/90).
Moderate increases in BUN; mild to moderate increases in creatinine values; mean sodium, potassium, and chloride values were mildly to moderately decreased.
Mild to moderate juxtaglomerular apparatus, hypertrophy/hyperplasia [all treated with irbesartan either alone or in combination]

* Irbesartan

** Hydrochlorothiazide Genotoxicity

Irbesartan

Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian cell forward gene mutation assay). Irbesartan was negative in several tests for induction of chromosomal aberrations (in vitro - human lymphocyte assay; in vivo - mouse micronucleus study).

Irbesartan/Hydrochlorothiazide

Irbesartan/hydrochlorothiazide was not mutagenic in standard in vitro tests (Ames microbial test and Chinese hamster mammalian-cell forward gene-mutation assay).

Irbesartan/hydrochlorothiazide was negative in tests for induction of chromosomal aberrations (in vitro - human lymphocyte assay; in vivo - mouse micronucleus study).

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.

Carcinogenicity

Irbesartan

No evidence of carcinogenicity was observed when irbesartan was administered at doses of up to 500/1000 mg/kg/day (males/females, respectively) in rats and 1000 mg/kg/day in mice for 2 years. These doses provided systemic exposures of 3.6 - 24.9 times (rats) and 3.8 - 6.2 times (mice) the exposures in humans receiving 300 mg daily.

Irbesartan/Hydrochlorothiazide

No carcinogenicity studies have been conducted with the irbesartan/hydrochlorothiazide combination.

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.

Reproductive and developmental toxicology

Irbesartan

Fertility and reproductive performance were not affected in studies of male and female rats even at oral doses of irbesartan causing pronounced toxicity (up to 650 mg/kg/day). No significant effects on the number of corpora lutea, implants, or live fetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring except for a slight decrease of body weight gain during lactation which was reversible after weaning.

In a study of rats receiving maternally toxic doses of irbesartan (650 mg/kg/day), transient effects were observed in fetuses. These effects included increased incidences of renal pelvic cavitation at doses ≥50 mg/kg/day and subcutaneous edema at doses ≥180 mg/kg/day. Slight decreases in body weight gain were noted (prior to weaning) in offspring of females receiving irbesartan at doses ≥ 50 mg/kg/day. In rabbits, maternally toxic doses of irbesartan (30 mg/kg/day) were associated with maternal mortality and abortion. Surviving females receiving this dose had a slight increase in early resorption. However, no teratogenic effect was observed. Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral doses of radiolabeled irbesartan. These findings are attributed to drug exposure in late gestation and during lactation.

Irbesartan/hydrochlorothiazide

In a Segment II teratology study carried out in rats, a dose of the combination irbesartan/hydrochlorothiazide up to 150/150mg/day/kg did not show any teratogenic potential. There was decreased foetal body weight in the litters of dams given 150/150 mg/kg/day.

17. Supporting Product Monographs

^PrAVALIDE^®, irbesartan and hydrochlorothiazide tablets, 150/12.5 mg and 300/12.5 mg, control 295055, product monograph, sanofi-aventis Canada Inc. (2025-07-25)

Irbesartan/HCTZ Product Monograph

Product Monograph - Irbesartan/HCTZ

Recent Major Label Changes

1. Indications

1.1 Pediatrics

1.2 Geriatrics

2. Contraindications

3. Serious Warnings and Precautions Box

4. Dosage and Administration

4.1 Dosing Considerations

4.2 Recommended Dose and Dosage Adjustment

Irbesartan Monotherapy

Diuretic Treated Patients

Geriatric

Renal Insufficiency

Hepatic Insufficiency

4.4 Administration

4.5 Missed Dose

5. Overdosage

Irbesartan

Hydrochlorothiazide

Table 1 - Dosage Forms, Strengths, Composition and Packaging

7. Warnings and Precautions

Carcinogenesis and Genotoxicity

Cardiovascular

Driving and Operating Machinery

Endocrine and Metabolism

Gastrointestinal

Hepatic/Biliary/Pancreatic

Immune

Ophthalmologic

Renal

Respiratory

Skin

7.1 Special Populations

7.1.1 Pregnancy

7.1.3 Pediatrics

7.1.4 Geriatrics

8. Adverse Reactions

8.1 Adverse Reaction Overview

8.2 Clinical Trial Adverse Reactions

Hypertension

Severe Hypertension

Irbesartan Alone

Hydrochlorothiazide alone

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

Data

Clinical Trial Findings

8.5 Post-Market Adverse Reactions

Related to Irbesartan + Hydrochlorothiazide

Related to Irbesartan

Related to Hydrochlorothiazide

9. Drug Interactions

9.2 Drug Interactions Overview

9.3 Drug-Behaviour Interactions

9.4 Drug-Drug Interactions

Table 4: Established or Potential Drug-Drug Interactions

9.5 Drug-Food Interactions

9.6 Drug-Herb Interactions

10. Clinical Pharmacology

10.1 Mechanism of Action

10.2 Pharmacodynamics

10.3 Pharmacokinetics

Table 5: Pharmacokinetic Parameters for Irbesartan

Table 6: Pharmacokinetic Parameters for Hydrochlorothiazide

Absorption

Distribution

Metabolism

Elimination

Absorption

Distribution

Metabolism

Elimination

Special Populations and Conditions

11. Storage, Stability and Disposal

13. Pharmaceutical Information

Drug Substance

14. Clinical Trials

14.1 Clinical Trials by Indication

Irbesartan-Hydrochlorothiazide