What are the potential side effects of irbesartan (angiotensin II receptor antagonist) in an adult patient with a history of hypertension or diabetic nephropathy?

Side Effects of Irbesartan

Irbesartan is generally well-tolerated with an adverse event profile similar to placebo in most patients, though specific monitoring for hyperkalemia and renal function changes is essential, particularly in patients with diabetic nephropathy. 1, 2

Common Side Effects in Hypertensive Patients

In placebo-controlled trials of over 4,300 hypertensive patients, irbesartan demonstrated minimal side effects 2:

• Diarrhea occurred in 3% of irbesartan patients versus 2% with placebo 2
• Dyspepsia/heartburn affected 2% versus 1% with placebo 2
• Fatigue was reported in 4% versus 3% with placebo 2
• Dry cough occurred at the same rate as placebo (2.8% vs 2.7%), unlike ACE inhibitors which commonly cause this side effect 2

Serious Side Effects in Diabetic Nephropathy Patients

The most clinically significant adverse effect is hyperkalemia, which occurs substantially more frequently in patients with diabetic nephropathy 2:

• Hyperkalemia (potassium >6.0 mEq/L) occurred in 18.6% of irbesartan-treated patients versus 6.0% with placebo in the IDNT trial 2
• Discontinuation due to hyperkalemia was necessary in 2.1% of irbesartan patients versus 0.4% with placebo 2

Orthostatic Effects in Diabetic Nephropathy

Patients with diabetic nephropathy experienced increased orthostatic symptoms compared to placebo 2:

• Dizziness: 10.2% versus 6.0% 2
• Orthostatic dizziness: 5.4% versus 2.7% 2
• Orthostatic hypotension: 5.4% versus 3.2% 2

Rare but Serious Post-Marketing Adverse Reactions

The following have been reported during post-approval surveillance, though causality is not always established 2:

• Allergic reactions: Urticaria, angioedema (involving face, lips, pharynx, tongue), anaphylactic shock 2
• Hepatic effects: Increased liver function tests, jaundice, hepatitis 2
• Hematologic: Thrombocytopenia 2
• Other: Increased CPK, tinnitus 2

Critical Warnings and Monitoring Requirements

Fetal Toxicity

Irbesartan must be discontinued immediately when pregnancy is detected, as drugs acting on the renin-angiotensin system cause fetal renal dysfunction, oligohydramnios, fetal lung hypoplasia, skeletal deformations, and neonatal complications including skull hypoplasia, anuria, hypotension, renal failure, and death 2.

Hypotension Risk

Volume- or salt-depleted patients (especially those on high-dose diuretics) are at risk for symptomatic hypotension upon irbesartan initiation 2. Correct volume depletion before starting therapy or use a lower starting dose 2.

Renal Function Impairment

Monitor renal function periodically, particularly in high-risk patients 2:

• Patients with renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion may develop acute renal failure 2
• A modest rise in serum creatinine (10-20%) after initiation is expected and hemodynamic, not indicative of kidney injury unless persistent 1
• Consider withholding or discontinuing therapy if clinically significant renal function decline occurs 2
• The KDIGO guidelines recommend continuing therapy unless creatinine rises by more than 30% within 4 weeks of initiation or dose increase 1

Monitoring Protocol

Check serum creatinine and potassium within 2-4 weeks after initiation or dose increase 1:

• Halve the dose if potassium rises to >5.5 mmol/L 3
• Stop irbesartan immediately if potassium rises to ≥6.0 mmol/L 3
• Halve the dose if creatinine rises to >220 μmol/L (2.5 mg/dL) 3
• Stop immediately if creatinine rises to >310 μmol/L (3.5 mg/dL) 3

Common Pitfalls to Avoid

Never combine irbesartan with ACE inhibitors or direct renin inhibitors, as this increases risks of hypotension, hyperkalemia, and acute renal failure without additional cardiovascular benefit 1, 4.

Counsel patients to temporarily hold irbesartan during intercurrent illness, volume depletion, bowel preparation for colonoscopy, or prior to major surgery to prevent acute kidney injury 4.

Avoid potassium-sparing diuretics or potassium supplements in patients taking irbesartan, especially those with CKD or diabetes, due to compounded hyperkalemia risk 3.

Clinical Context

Despite these potential side effects, the KDIGO 2020 guidelines emphasize that ACE inhibitors and ARBs are generally well-tolerated, and the recommendation to use these agents places high value on their renoprotective and cardiovascular benefits while acknowledging the need for monitoring 1. The renoprotective effects in diabetic nephropathy are substantial, with irbesartan reducing the risk of doubling serum creatinine by 33% compared to placebo in the IDNT trial 1, 5.