Irbesartan (Sivem Pharmaceuticals) Product Monograph

Recent Major Label Changes

Table of Contents

Recent Major Label Changes…….……………………………………………………………………………………….…...............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 ....................................................................... 4

4 Dosage and Administration......................................................................................... 5

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

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

4.4 Administration .......................................................................................................... 5

4.5 Missed Dose .............................................................................................................. 6

5 Overdose .................................................................................................................... 6

6 Dosage Forms, Strengths, Composition and Packaging ................................................ 6

7 Warnings and Precautions .......................................................................................... 7

7.1 Special Populations ................................................................................................... 9

7.1.1 Pregnancy ................................................................................................................................ 9

7.1.2 Breastfeeding .......................................................................................................................... 9

7.1.3 Pediatrics ................................................................................................................................. 9

7.1.4 Geriatrics ............................................................................................................................... 10

8 Adverse Reactions .................................................................................................... 10

8.2 Clinical Trial Adverse Reactions .............................................................................. 10

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data .............................................................................................................. 12

8.5 Post-Market Adverse Reactions .............................................................................. 13

9 Drug Interactions ...................................................................................................... 13

9.2 Drug Interactions Overview .................................................................................... 13

9.3. Drug-Behaviour Interactions ................................................................................... 13

9.4 Drug-Drug Interactions ........................................................................................... 13

9.5. Drug-Food Interactions ........................................................................................... 17

9.6. Drug-Herb Interactions ........................................................................................... 17

10 Clinical Pharmacology ............................................................................................... 17

10.1 Mechanism of Action .............................................................................................. 17

10.2 Pharmacodynamics ................................................................................................. 17

10.3 Pharmacokinetics .................................................................................................... 18

11 Storage, Stability, and Disposal ................................................................................. 19

Part 2: Scientific Information ............................................................................................... 20

13 Pharmaceutical Information ..................................................................................... 20

14 Clinical Trials ............................................................................................................ 21

14.1 Clinical Trials by Indication ..................................................................................... 21

14.3 Comparative Bioavailability Studies ....................................................................... 25

15 Microbiology ........................................................................................................... 25

16 Non-Clinical Toxicology ............................................................................................. 26

17 Supporting Product Monographs .............................................................................. 31

Patient Medication Information .......................................................................................... 32

Part 1: Healthcare Professional Information

1 Indications

IRBESARTAN is indicated for the treatment of:

• essential hypertension. IRBESARTAN may be used alone or concomitantly with thiazide diuretics.
• hypertensive patients with type 2 diabetes mellitus and renal disease to reduce the rate of progression of nephropathy as measured by the reduction of microalbuminuria, and the occurrence of doubling of serum creatinine. (see 14 Clinical Trials).

1.1 Pediatrics

Pediatrics (< 18 years of age): The safety and efficacy of irbesartan 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 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 the 6 Dosage Forms, Strengths, Composition and Packaging.
• 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) (see 7 Warnings and Precautions, Cardiovascular and Renal, and 9 Drug Interactions).
• Combination with Angiotensin-Converting Enzyme Inhibitors (ACEIs) in patients with diabetic nephropathy (see 7 Warnings and Precautions, Cardiovascular and Renal and 9 Drug Interactions).
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption (due to the lactose component of IRBESARTAN tablets).
• Pregnant women (see 7 Warnings and Precautions, 7.1 Special Populations).
• Nursing women (see 7 Warnings and Precautions, 7.1 Special Populations).

3 Serious Warnings and Precautions Box

4 Dosage and Administration

4.1 Dosing Considerations

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure (BP) elevation, salt restriction, and other pertinent clinical factors. The dosage of other antihypertensive agents used with IRBESARTAN may need to be adjusted.

4.2 Recommended Dose and Dosage Adjustment

Essential Hypertension

The recommended initial dose of IRBESARTAN is 150 mg once daily. In patients whose BP is not adequately controlled, the daily dose may be increased to 300 mg.

Essential Hypertension with Type 2 Diabetic Renal Disease

The recommended initial dose of IRBESARTAN is 150 mg once daily. In patients whose BP is not adequately controlled, the daily dose may be increased to 300 mg once daily, the preferred maintenance dose.

Geriatric

No initial dosage adjustment is required in the elderly (see 10 Clinical Pharmacology, 10.3 Pharmacokinetics, Special Population and Conditions and 7 Warnings and Precautions).

Renal Insufficiency

No initial dosage adjustment is required in patients with renal impairment (see 10 Clinical Pharmacology, 10.3 Pharmacokinetics, Special Population and Conditions). However, due to the apparent greater sensitivity of hemodialysis patients, an initial dose of 75 mg is recommended in this group of patients.

Hepatic Insufficiency

No initial dosage adjustment is required in patients with mild-to-moderate hepatic impairment (see 10 Clinical Pharmacology, 10.3 Pharmacokinetics, Special Population and Conditions).

Concomitant Diuretic Therapy

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.

4.4 Administration

IRBESARTAN may be administered with or without food.

The 300 mg and 150 mg Tablets may be split for ease of swallowing. Tablets should not be split to provide a lower dose. Both halves of a split tablet are to be taken at the same time.

4.5 Missed Dose

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

5 Overdose

Few cases of overdosage with irbesartan have been reported, with no complaints and no significant clinical sequelae. Reported overdoses ranged from 600 - 900 mg daily. Durations of overdosing ranged from 2 - 3 weeks up to 30 days and over. Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity.

The most likely manifestations of overdosage are hypotension and tachycardia; bradycardia might also occur.

No specific information is available on the treatment of overdosage with irbesartan. The patient should be closely monitored, and the treatment should be supportive and relieve symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdosage.

IRBESARTAN is not removed by hemodialysis.

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).

6 Dosage Forms, Strengths, Composition and Packaging

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Description

IRBESARTAN 75 mg tablets are white, oval, biconvex, film-coated tablets, debossed with 75 on one side.

IRBESARTAN 150 mg tablets are white, oval, biconvex, film-coated tablets, debossed with 150 on one side and score line on the other side.

IRBESARTAN 300 mg tablets are white, oval, biconvex, film-coated tablets, debossed with 300 on one side and score line on the other side.

IRBESARTAN 75 mg, 150 mg and 300 mg tablets are available in bottles of 100 tablets.

7 Warnings and Precautions

See 3 Serious Warnings and Precautions Box.

Cardiovascular

Hypotension – Volume-Depleted Patients:

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 BP, 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 BP could result in myocardial infarction or cerebrovascular accident.

Dual Blockade of the Renin-Angiotensin System (RAS)

There is evidence that co-administration of angiotensin receptor antagonists (ARBs), such as irbesartan, 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 in combination with aliskiren-containing drugs is contraindicated in these patients (see 2 Contraindications).

The use of IRBESARTAN in combination with of ACE inhibitors is contraindicated in patients with diabetic nephropathy (see 2 Contraindications).

Further, co-administration of ARBs, including IRBESARTAN, 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.

Lithium

Increases in serum lithium concentrations and lithium toxicity (including fatal outcome) have been reported with concomitant use of irbesartan and lithium (see 9 Drug Interactions). Therefore, this combination is not recommended. Serum lithium levels should be monitored carefully in patients receiving irbesartan and lithium if the combination is necessary.

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.

Driving and Operating Machinery

The effect of irbesartan on the ability to drive and use of 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

IRBESARTAN 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).

Gastrointestinal

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, including IRBESARTAN. These patients presented with abdominal pain, (with or without nausea, vomiting and diarrhea). 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 should be discontinued, and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

Renal

Renal Impairment:

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

The use of ARBs including IRBESARTAN, or of 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 IRBESARTAN in combination with an ACEI 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.

In hypertensive type 2 diabetic patients with proteinuria (≥900 mg/day), a population which has a high risk of renal artery stenosis, no patient treated with Irbesartan in IDNT had an early acute rise in serum creatinine attributable to renal artery disease. (see 10 Clinical Pharmacology).

Skin

The use of IRBESARTAN 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-aldosterone system (RAAS) can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, IRBESARTAN should be discontinued as soon as possible.

The use of ARBs 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 ARBs, 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 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 BP 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.

7.1.2 Breastfeeding

It is not known whether irbesartan is excreted in human milk, but significant levels have been found in the milk of lactating rats. 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): The safety and efficacy of irbesartan have not been established in children < 18 years of age. Therefore, IRBESARTAN is not indicated in this patient population.

7.1.4 Geriatrics

Geriatrics (>65 years of age): Of the 4140 hypertensive patients receiving irbesartan in clinical studies, 793 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

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials 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 is useful for identifying drug and approximating rates of adverse drug reactions in real-world use.

Irbesartan was evaluated for safety in > 4100 patients with essential hypertension including approximately 1300 patients treated for > 6 months and 400 patients for ≥1 year.

In placebo-controlled clinical trials, therapy was discontinued due to a clinical adverse event (AE) in 3.3 % of patients treated with irbesartan, versus 4.5% of patients given placebo.

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

AEs occurring in ≥1% of the 2606 hypertensive patients in placebo-controlled clinical trials include the following (see Table 2):

Table 2: Adverse events occurring in ≥1% of the 2606 hypertensive patients in placebo-controlled clinical trials

AEs of hypotension or orthostatic hypotension, unrelated to dosage, occurred in 0.4% of irbesartan treated patients, and in 0.2% of patients receiving placebo.

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

Body as a whole: fever;

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

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

Endocrine: gout, libido change, sexual dysfunction;

Gastrointestinal: constipation, distension abdomen, flatulence, gastroenteritis, hepatitis;

Hematologic: anemia, lymphocytopenia, thrombocytopenia;

Investigations: increased creatine phosphokinase (CPK);

Musculoskeletal: arthritis, muscle cramp, muscle weakness, myalgia;

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

Renal/Genitourinary: abnormal urination;

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

Special Senses: conjunctivitis, hearing abnormality, taste disturbance, visual disturbance.

Clinical Studies in Hypertension and Type 2 Diabetic Renal Disease

In clinical studies in patients with hypertension and type 2 diabetic renal disease, the adverse drug experiences were similar to those seen in clinical trials of hypertensive patients with the exception of orthostatic symptoms (dizziness, orthostatic dizziness, and orthostatic hypotension) observed in IDNT (The Irbesartan Diabetic Nephropathy Trial) (proteinuria ≥900 mg/day, and serum creatinine from 1.0-3.0 mg/dL). In IDNT orthostatic symptoms occurred more frequently in the irbesartan group (dizziness 10.2%, orthostatic dizziness 5.4%, orthostatic hypotension 5.4%) than in the placebo group (dizziness 6.0%, orthostatic dizziness 2.7%, orthostatic hypotension 3.2%). The rates of discontinuations due to orthostatic symptoms for irbesartan versus placebo were: dizziness 0.3% vs. 0.5%; orthostatic dizziness 0.2% vs. 0.0%; and orthostatic hypotension, 0.0% vs. 0.0%.

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

In controlled clinical trials of hypertension, clinically important differences in laboratory tests were rarely associated with irbesartan.

Creatine Phosphokinase: Significant increases in plasma creatine phosphokinase (CPK) were commonly observed (1.6%) in irbesartan treated subjects.

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

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

Hyperkalemia: The laboratory test parameter profile was similar in clinical trials conducted in patients with hypertension, type 2 diabetes and renal disease compared to that of patients with hypertension only, with the exception of hyperkalemia. In a placebo-controlled trial in 590 patients with hypertension, type 2 diabetes, microalbuminuria, and normal renal function (IRMA 2), hyperkalemia ≥ 5.5 mEq/L occurred in 29.4% of the patients in the irbesartan 300 mg group compared to 22% of the patients in the placebo group. Discontinuation for hyperkalemia occurred in 0.5% of the patients in the irbesartan group.

In another placebo-controlled trial in 1 715 patients with hypertension, type 2 diabetes, proteinuria ≥ 900 mg/day, and serum creatinine ranging from 1.0-3.0 mg/dl (IDNT), hyperkalemia ≥ 5.5 mEq/L occurred in 46.3% of the patients in the irbesartan group compared to 26.3% of the patients in the placebo group. Discontinuation for hyperkalemia occurred in 2.1% and 0.4% of the patients in the irbesartan and placebo groups, respectively.

Liver Function Tests: In placebo-controlled trials, elevations of AST and 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 over 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

General: asthenia, syncope.

Ear/Nose/Throat: tinnitus.

Endocrine and Metabolism: hypoglycemia (see 7 Warnings and Precautions).

Gastrointestinal: intestinal angioedema

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

Hepatic/Biliary/Pancreatic: elevated liver function tests, jaundice.

Immune: anaphylactic shock, angioedema (involving swelling of the face, lips, and/or tongue) has been reported rarely in postmarketing use. Photosensitivity.

Musculoskeletal: muscle pain, muscle weakness, myositis and rhabdomyolysis have been reported in patients receiving ARBs. Myalgia.

Renal: impaired renal function including cases of renal failure in patients at risk (see 7 Warnings and Precautions, Renal).

Skin: psoriasis (and psoriasis exacerbation).

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

The interaction of IRBESARTAN with individual behavioural risks (e.g. cigarette smoking, cannabis use, and/or alcohol consumption) has not been studied.

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

2 Contraindications and 7 Warnings and Precautions, Cardiovascular.

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

9.5. Drug-Food Interactions

This drug may be taken with or without food.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

10 Clinical Pharmacology

10.1 Mechanism of Action

Irbesartan antagonizes angiotensin II by blocking AT₁ receptors.

Angiotensin II is the primary vasoactive hormone in the renin-angiotensin system. 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 AT₁ receptor found in many tissues. Irbesartan has no agonist activity at the AT₁ receptor. AT₂ receptors have been found in many tissues, but to date they have not been associated with cardiovascular homeostasis. Irbesartan has essentially no affinity for the AT₂ receptors.

Irbesartan does not inhibit angiotensin converting enzyme, also known as kinase 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.

10.2 Pharmacodynamics

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.

Hypertensive patients: Angiotensin II receptor inhibition following chronic administration of irbesartan causes 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 decline following irbesartan administration; however, at recommended dose, serum potassium levels are not significantly affected.

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

The BP 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. In controlled trials, there was essentially no change in average heart rate in patients treated with irbesartan.

There was no rebound effect after withdrawal of irbesartan.

Race: Black hypertensive patients had a smaller BP response to irbesartan monotherapy than caucasians.

10.3 Pharmacokinetics

Absorption

Irbesartan is an orally active agent. The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60% - 80%. Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range with an average terminal elimination half-life of 11-15 hours. Following oral administration, peak plasma concentrations are attained at 1.5-2 hours after dosing. Steady-state concentrations are achieved within 3 days.

Distribution

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

The average volume of distribution of irbesartan is 53-93 liters. Total plasma and renal clearances are in the range of 157-176 mL/min and 3.0-3.5 mL/min, respectively.

Metabolism

Irbesartan is metabolized via glucuronide conjugation, and oxidation primarily by the cytochrome P-450 isoenzyme CYP 2C9. Metabolism of irbesartan by CYP 3A4 is negligible. In addition, irbesartan is not metabolized by the following isoenzymes: CYP 1A1, 1A2, 2A6, 2B6, 2D6, 2E1.

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

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.

Special Populations and Conditions

• Geriatrics: In subjects > 65 years of age, irbesartan elimination half-life was not significantly altered, but AUC and C_max values 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_max 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 tablets should be stored between 15°C and 30°C.

Part 2: Scientific Information

13 Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance: irbesartan

Chemical Name: 2-butyl-3-[(2¹-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,3-diazaspiro [4,4] non-1-en-4-one.

Molecular formula and molecular mass: C₂₅ H₂₈ N₆O, 428.5 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.

14 Clinical Trials

14.1 Clinical Trials by Indication

Two trials were done to investigate the effects of Irbesartan tablet in patients with hypertension and type 2 diabetic nephropathy, the IDNT and IRMA 2 trials.

IDNT:

The Irbesartan Diabetic Nephropathy Trial (IDNT) was a multicenter, randomized, controlled, double-blind, morbidity and mortality trial comparing irbesartan, amlodipine and placebo. In 1715 hypertensive patients with type 2 diabetes (proteinuria ≥900 mg/day and serum creatinine 1.0-3.0 mg/dL) the long-term effects (mean 2.6 years) of irbesartan on the progression of renal disease and all-cause mortality were examined. In addition, as a secondary endpoint, the effect of irbesartan on the risk of fatal or non-fatal cardiovascular events was assessed. The most important exclusion criteria were: onset of type II diabetes mellitus at <20 years of age, renovascular occlusive disease affecting both kidneys or a solitary kidney, and unstable angina pectoris.

Patients were randomized to receive once daily irbesartan 75 mg (N=579), amlodipine 2.5 mg (N=567), or matching placebo (N=569). Patients were then titrated to a maintenance dose of 300 mg irbesartan, 10 mg amlodipine, or placebo as tolerated. Additional antihypertensive agents for the 3 study arms [excluding ACE inhibitors, other angiotensin II receptor blockers (ARBs) and calcium channel blockers (CCBs)] were added as needed to help achieve a BP goal of ≤ 135/85 mmHg in all groups, or a 10 mmHg reduction in systolic blood pressure (SBP) if baseline was >160 mmHg. Of the total of 579 patients randomized to irbesartan, 442 completed the double blind phase. All analyses were conducted on the intent to treat (ITT) patient population.

IDNT Primary Endpoint

Time to Doubling of Serum Creatinine, ESRD, or Death

Table 4

Primary Composite Endpoint Comparison (IDNT)

Event

Number (%) of Subjects Relative Risk

Placebo

N=569

Irbesartan N=579

Amlodipine N=567

Estimate

(% Reduction)

95%

Confidence Interval

p

Irbesartan vs. Placebo

Primary

Composite

Endpoint*

222 (39.0) 189 (32.6) - 0.80 (20) 0.66-0.97 0.023

Irbesartan vs. Amlodipine

Primary

Composite

Endpoint*

• 189 (32.6) 233 (41.1) 0.77 (23) 0.63-0.93 0.006

* First occurrence of any of the following: doubling of serum creatinine, end-stage renal disease (ESRD) or all-cause mortality

Irbesartan demonstrated a 20% relative risk reduction (absolute risk reduction 6.4%) in the composite primary endpoint (1^st occurrence of any of the following: doubling of serum creatinine, end-stage renal disease (ESRD) or all-cause mortality) compared to placebo (p=0.023), and a 23% relative risk reduction (absolute risk reduction 8.5%) compared to amlodipine (p=0.006). When the individual components of the primary composite endpoint were analysed, no effect in all-cause mortality and no significant effect on time to ESRD were observed. However, a significant reduction in doubling of serum creatinine was observed. Irbesartan decreased the progression of renal disease in patients with chronic renal insufficiency and overt proteinuria. Irbesartan also produced significant reduction in the rate of urine excretion of protein and albumin relative to placebo or amlodipine (p<0.001 for both comparisons). Similar BP was achieved in the irbesartan 300 mg and amlodipine 10 mg groups.

Treatment with irbesartan reduced the occurrence of sustained doubling of serum creatinine as a separate endpoint (33%) with an absolute risk reduction of 6.8%.

The risk of developing a doubling of serum creatinine or ESRD was reduced by 26% relative to placebo with an absolute risk reduction of 6.2% and by 34% relative to amlopidine with an absolute risk reduction of 10.0% (pooled risk reduction 30%, p=0.0005). This renal protective effect of irbesartan appeared to be independent of systemic BP reduction.

There was no significant difference in the assessment of fatal or non-fatal cardiovascular events (cardiovascular death, non-fatal myocardial infarction, hospitalization for heart failure, permanent neurologic deficit attributed to stroke, or above-the-ankle amputation) among the 3 treatment groups.

Safety data from this trial are reported in the 8 Adverse Reactions section.

IRMA 2

The study of the Effects of Irbesartan on MicroAlbuminuria in Hypertensive Patients with Type 2 Diabetes Mellitus (IRMA 2) was a multicenter, randomized, placebo-controlled, double-blind morbidity study, conducted in 590 hypertensive patients with type 2 diabetes, microalbuminuria (20-200 mcg/min; 30-300mg/day) and normal renal function (serum creatinine ≤1.5 mg/dL in males and ≤1.1 mg/dL in females). Screening of urine for albumin has revealed that patients with microalbuminuria have a 10 - 20 fold higher risk of developing diabetic nephropathy than patients with normoalbuminuria. Of the 590 patients, 201 received placebo, 195 received irbesartan 150 mg and 194 patients received irbesartan 300 mg.

The primary endpoint was the long-term effects (2 years) of irbesartan on the progression to clinical (overt) proteinuria (urinary albumin excretion rate [AER] >200 mcg/min [>300mg/day] and an increase in AER of ≥ 30% from baseline). In addition, after 1 and 2 years of treatment, the effect of irbesartan on the change in overnight AER and the change in 24-hour creatinine clearance was assessed. The most important exclusion criteria were: onset of type II diabetes mellitus at <20 years of age, renovascular occlusive disease affecting both kidneys or a solitary kidney and unstable angina pectoris.

Irbesartan 300 mg demonstrated a 70% relative risk reduction (absolute risk reduction 9.8%) in the development of clinical (overt) proteinuria compared to placebo (p=0.0004). Relative risk reduction in the development of proteinuria with 150 mg irbesartan was not statistically significant. The slowing of progression to clinical (overt) proteinuria was evident as early as 3 months and continued over the 2 year period.

IRMA 2 Primary Endpoint

Time to Overt Proteinuria

Table 5

Time to occurrence of Overt Proteinuria

(Irbesartan 300 mg vs. Placebo Comparison) (IRMA 2)

Event

Number (%) of Subjects Relative Risk

Placebo

N=201

Irbesartan N=195

Estimate

(% Reduction)

95%

Confidence

Interval

p

Primary

Endpoint 30 (14.9) 10 (5.2) 0.295 (70) 0.144 -

0.606 0.0004

Regression to normoalbuminuria (<20 mcg/min; <30 mg/day) was more frequent in the irbesartan 300 mg group (34%) than in the placebo group (21%). Irbesartan 300 mg reduced the level of urinary albumin excretion at 24 months by 43% (p=0.0001).

IRMA 2

Normalization of Urinary Albumin Excretion Rate

Safety data from this trial has been reported in the 8 Adverse Reactions section.

14.3 Comparative Bioavailability Studies

A randomized, two-way, single-dose, crossover comparative bioavailability study of IRBESARTAN 300 mg tablets (Sivem Pharmaceuticals ULC) and Avapro^TM 300 mg tablets (sanofi-aventis Canada Inc.) was conducted in healthy, adult, male subjects under fasting conditions. Comparative bioavailability data from 37 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

Irbesartan

(1 x 300 mg)

Geometric Mean

Arithmetic Mean (CV %)

Parameter Test¹ Reference² % Ratio of

Geometric Means

90% Confidence

Interval

AUC_T

(ng·h/mL)

18573.7 19393.7 (31.8)

20387.9

21159.6 (31.1) 91.1 85.3 – 97.3

AUC_I

(ng·h/mL)

22158.1 22967.2 (26.8)

22966.2

23718.1 (26.0) 96.5 90.8 – 102.6

Cmax

(ng/mL)

4243.6

4429.0 (30.2)

3784.7

3947.6 (29.3) 112.1 105.7 – 119.0

Tmax3

(h) 1.0 (0.5 – 4.0) 1.3 (0.5 – 5.0)

T½4

(h) 13.5 (54.5) 12.1 (37.6)

¹IRBESARTAN (irbesartan) tablets, 300 mg (Sivem Pharmaceuticals ULC)

² Avapro^TM (irbesartan) tablets, 300 mg (sanofi-aventis, Canada Inc.)

³ Expressed as the median (range) only

⁴ Expressed as the arithmetic mean (CV %) only

15 Microbiology

No microbiological information is required for this drug product.

16 Non-Clinical Toxicology

General Toxicology

Table 6 : Acute Toxicity

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

Mouse M (5)

F (5)

IP 200-2000

Rat M (5)

F (5)

IP 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/m² basis, respectively.

Table 7: Subacute and Chronic Toxicity

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 was 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.

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.

Species/

Strain

Sex (N/Dose) Dose

(mg/kg/day)

Route Time Effects

• One high-dose animal presented a marked heart hypertrophy with marked ECG changes on D1 and D10 suggesting that it was a pre-existing 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 bodyweight 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

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

PO 26 weeks • Slight reduction of bodyweight 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.

Species/

Strain

Sex (N/Dose) Dose

(mg/kg/day)

Route Time Effects

Monkey M (5) - F (5)

[main study]

M (3) - F (3)

[reversibility

study for control

and high dose

groups)]

0, 10, 30, 90 PO 6 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.

Monkey M (5)

F (5)

0, 20, 100, 500 PO 52 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 bodyweight gain and erythrocyte

  parameters at doses ≥100 mg/kg/day.

Subacute and Chronic Toxicity (Cont’d)

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 workload 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.

Genotoxicity

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).

Carcinogenicity

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.

Reproduction and developmental toxicology

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.

17 Supporting Product Monographs

1. 1. ^PrAVAPRO, Irbesartan tablets, 75, 150 and 300 mg, control 294898, product monograph, Sanofi-Aventis Canada Inc. 2025-07-25