What are the side effects of allopurinol?

Allopurinol Side Effects

Allopurinol's most serious side effect is a potentially life-threatening hypersensitivity syndrome with a 25% mortality rate, though skin rash remains the most frequent adverse reaction requiring immediate drug discontinuation. 1, 2

Severe and Life-Threatening Reactions

Allopurinol Hypersensitivity Syndrome (AHS)

• This syndrome carries a 25% mortality rate and represents the most dangerous complication of allopurinol therapy. 1
• The syndrome manifests as fever, severe skin rash (including exfoliative, urticarial, and purpuric lesions), elevated eosinophil counts, lymphadenopathy, and multi-organ dysfunction affecting hepatic, renal, cardiac, gastrointestinal, and pulmonary systems. 2
• Stevens-Johnson syndrome, generalized vasculitis, and irreversible hepatotoxicity can occur as part of severe hypersensitivity reactions. 2
• Symptoms typically develop within approximately 1 week of initiating therapy, though longer latency periods have been reported. 2

Critical Action Required

• Treatment must be discontinued immediately at the first appearance of skin rash or other signs suggesting an allergic reaction. 2

Common Side Effects

Dermatologic Reactions

• Skin rash is the most frequent adverse reaction to allopurinol, occurring in less than 1% of patients with current dosing protocols (down from historical rates of 3%). 2
• Reactions range from pruritic maculopapular eruptions to severe exfoliative dermatitis. 2
• The incidence of skin rash increases significantly in patients with renal insufficiency. 2

Gastrointestinal Effects

• Diarrhea, nausea, and elevated alkaline phosphatase and liver transaminases (SGOT/SGPT) occur at rates less than 1%. 2

Acute Gout Attacks

• Paradoxical acute gout attacks following initiation now occur in less than 1% of patients when proper dosing protocols are followed (down from historical rates of 6%). 1, 2

High-Risk Populations and Genetic Factors

HLA-B*58:01 Genetic Variant

• Genetic testing for HLA-B*58:01 is recommended before initiating allopurinol in high-risk ethnic groups to prevent severe hypersensitivity reactions. 1, 3
• This variant is particularly prevalent in Han-Chinese, Korean, and Thai populations, dramatically increasing hypersensitivity risk regardless of kidney function. 1, 3
• Korean patients with stage 3 or worse chronic kidney disease have higher prevalence of this variant. 1

Renal Impairment

• Patients with decreased renal function have increased risk of hypersensitivity reactions, particularly when receiving concurrent thiazide diuretics. 2, 4
• Dose reduction of at least 50% is mandatory in patients with renal insufficiency. 1, 3

Significant Drug Interactions

Chemotherapeutic Agents

• Allopurinol requires 65-75% dose reduction of 6-mercaptopurine or azathioprine when used concomitantly. 1, 3, 2
• Allopurinol is contraindicated with cyclophosphamide and other cytotoxic agents due to increased bone marrow suppression. 1, 3

Other Medications

• Concurrent ampicillin or amoxicillin increases the frequency of skin rash. 2, 4
• Documented interactions exist with dicumarol, thiazide diuretics, chlorpropamide, and cyclosporine. 1

Less Common Adverse Effects (Incidence <1%)

Systemic Reactions

• Fever, headache, ecchymosis. 2
• Necrotizing angiitis and vasculitis. 2

Hepatic Effects

• Reversible hepatotoxicity with asymptomatic rises in alkaline phosphatase or transaminases occurs in some patients. 2
• Liver dysfunction was documented in 69% of hospitalized patients with allopurinol adverse reactions. 5

Hematologic Abnormalities

• Leukocytosis (62% of adverse reaction cases), eosinophilia (54%), and mild leukopenia. 2, 5

Renal Effects

• Renal impairment occurred in 54% of hospitalized patients with allopurinol adverse reactions. 5

Risk Mitigation Strategies

Dosing Protocol

• Start with low doses (100 mg daily) and titrate gradually using 100 mg increments to minimize acute gout attacks. 6, 1, 3
• This gradual titration strategy explains the dramatic reduction in adverse event rates compared to historical fixed-dose approaches. 6, 2

Monitoring Requirements

• Periodic liver function tests are recommended during early therapy stages, especially in patients with pre-existing liver disease. 2
• Evaluate liver function if anorexia, weight loss, or pruritus develop. 2

Special Precautions

• Patients should be alerted about potential drowsiness affecting activities requiring alertness. 2
• Exercise particular caution when combining allopurinol with thiazides in patients with decreased renal function. 2