Irbesartan - Drug Monograph

Introduction

Irbesartan is an angiotensin II receptor blocker (ARB) used primarily in the management of hypertension and diabetic nephropathy. As a selective antagonist of the angiotensin II type 1 (AT1) receptor, it represents a cornerstone therapy in cardiovascular and renal protection strategies. First approved by the FDA in 1997, irbesartan has established itself as an effective antihypertensive agent with additional renoprotective benefits in patients with type 2 diabetes mellitus.

Mechanism of Action

Irbesartan selectively blocks the binding of angiotensin II to the AT1 receptor found in vascular smooth muscle, adrenal glands, and other tissues. By inhibiting angiotensin II-mediated vasoconstriction, aldosterone secretion, and sympathetic nervous system activation, irbesartan produces:

• Vasodilation of arterial and venous vessels
• Reduced peripheral vascular resistance
• Decreased blood pressure
• Attenuation of angiotensin II-induced renal damage

Unlike ACE inhibitors, irbesartan does not inhibit kininase II, avoiding the accumulation of bradykinin responsible for cough and angioedema associated with ACE inhibitors.

Indications

• Hypertension: Alone or in combination with other antihypertensive agents
• Diabetic nephropathy in patients with type 2 diabetes mellitus and hypertension

• Heart failure (when ACE inhibitors are not tolerated)
• Proteinuric chronic kidney disease
• Cardiovascular risk reduction in patients with left ventricular hypertrophy

Dosage and Administration

• Initial dose: 150 mg once daily
• Maintenance dose: 150-300 mg once daily
• Maximum dose: 300 mg daily

• Recommended dose: 300 mg once daily

• Renal impairment: No dosage adjustment necessary
• Hepatic impairment: No dosage adjustment necessary
• Geriatric patients: No dosage adjustment necessary
• Volume-depleted patients: Consider lower starting dose (75 mg)

• Can be taken with or without food
• Tablets should be swallowed whole with water
• Consistent timing daily recommended for optimal blood pressure control

Pharmacokinetics

• Rapidly absorbed with bioavailability of 60-80%
• Peak plasma concentrations reached within 1.5-2 hours
• Food does not significantly affect absorption

• Volume of distribution: 53-93 L
• Protein binding: approximately 90% (primarily to albumin and α1-acid glycoprotein)
• Crosses placental barrier and present in breast milk

• Primarily metabolized by cytochrome P450 2C9 (CYP2C9)
• Glucuronidation via UGT1A3 and UGT1A1
• No active metabolites identified

• Terminal elimination half-life: 11-15 hours
• Excretion: Approximately 20% renal, 80% fecal
• Not significantly removed by hemodialysis

Contraindications

• Hypersensitivity to irbesartan or any component of the formulation
• Concomitant use with aliskiren in patients with diabetes
• Pregnancy (second and third trimesters)
• Severe hepatic impairment (Child-Pugh class C)

Warnings and Precautions

• Category D in second and third trimesters
• Discontinue immediately when pregnancy detected
• Associated with fetal injury and death

• May cause acute renal failure in susceptible patients
• Monitor renal function in patients with renal artery stenosis
• Use caution in patients with severe congestive heart failure

• Risk increased with potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes
• Monitor potassium levels, especially in elderly and patients with renal impairment

• May occur in volume-depleted patients
• Correct volume depletion prior to administration

• Use caution in patients with biliary obstruction disorders

Drug Interactions

• Aliskiren: Contraindicated in diabetic patients due to increased risk of renal impairment, hyperkalemia, and hypotension
• Lithium: Increased lithium concentrations and toxicity risk
• NSAIDs: May diminish antihypertensive effect and increase risk of renal impairment
• Potassium-sparing diuretics: Increased risk of hyperkalemia
• ACE inhibitors: Increased risk of hyperkalemia, hypotension, and renal impairment

• Warfarin: Potential interaction requiring INR monitoring
• CYP2C9 inhibitors (fluconazole, amiodarone): May increase irbesartan concentrations

Adverse Effects

• Dizziness (4-6%)
• Fatigue (3-4%)
• Musculoskeletal pain (3-4%)
• Upper respiratory infection (3-4%)
• Diarrhea (3%)

• Orthostatic hypotension
• Hyperkalemia
• Increased serum creatinine
• Headache
• Dyspepsia
• Rash

• Angioedema (rare, <0.1%)
• Acute renal failure
• Severe hypotension
• Hepatotoxicity
• Neutropenia (rare)

Monitoring Parameters

• Blood pressure (sitting, standing)
• Renal function (serum creatinine, eGFR)
• Electrolytes (potassium, sodium)
• Liver function tests
• Pregnancy test in women of childbearing potential

• Blood pressure at 2-4 weeks after initiation or dose adjustment
• Renal function and electrolytes within 2-4 weeks after initiation and periodically thereafter
• Potassium levels more frequently in at-risk patients
• Signs and symptoms of hypotension, especially in volume-depleted patients
• Pregnancy status in women of childbearing potential

Patient Education

• Take medication at the same time each day
• Do not stop taking without consulting healthcare provider
• Report any signs of pregnancy immediately
• Regular blood pressure monitoring is essential
• Avoid potassium supplements or salt substitutes unless prescribed

• Dizziness or lightheadedness, especially when standing up
• Swelling of face, lips, tongue, or throat
• Difficulty breathing or swallowing
• Unusual fatigue or weakness
• Signs of infection (fever, sore throat)
• Decreased urine output

• Maintain regular follow-up appointments
• Adhere to recommended dietary modifications
• Limit alcohol consumption
• Regular physical activity as tolerated
• Smoking cessation counseling if applicable

References

1. FDA Prescribing Information: Avapro (irbesartan) tablets. Revised 2022. 2. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. J Am Coll Cardiol. 2018;71(19):e127-e248. 3. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851-860. 4. Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet. 2000;355(9204):637-645. 5. Micromedex Solutions. Irbesartan. Truven Health Analytics, Ann Arbor, MI. Accessed 2023. 6. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. Irbesartan. Updated 2023.