What is the most common side effect of allopurinol (xanthine oxidase inhibitor) in an adult patient with a history of gout or hyperuricemia?

Most Common Side Effect of Allopurinol

The most common adverse effect of allopurinol is skin rash, occurring in less than 1% of patients with current usage patterns, though early studies reported rates up to 3%. 1

Primary Side Effect Profile

Skin reactions represent the most frequent adverse event associated with allopurinol therapy. 2 The FDA drug label explicitly states that "the most frequent adverse reaction to allopurinol tablets is skin rash," though it emphasizes that treatment must be discontinued immediately if a rash develops due to potential severity. 1

Historical Context and Current Incidence

• Early clinical studies reported skin rash rates of approximately 3% among patients treated for 3 to 34 months. 1
• Current usage patterns show skin reactions occurring in less than 1% of patients, representing a significant decrease from historical rates. 1
• The explanation for this reduction is not fully understood but may relate to more gradual therapy initiation and improved dosing strategies. 1

Other Common Adverse Effects

Beyond skin reactions, the FDA label identifies several other adverse effects that were historically reported at rates greater than 1% but now occur less frequently:

Gastrointestinal Effects

• Diarrhea, nausea, and elevated alkaline phosphatase/liver enzymes were among the most common reactions in early studies. 1
• In hospitalized patients, diarrhea occurred in 0.3% of allopurinol recipients. 3

Acute Gout Flares

• Early studies reported acute gout attacks following allopurinol initiation in an average of 6% of patients. 1
• Current usage suggests this incidence has diminished to less than 1%, likely due to more gradual dose escalation and concurrent prophylactic therapy. 1
• Among hospitalized patients, acute gout exacerbation was troublesome in only 1 in 600 exposed patients (0.17%). 3

Hematological Abnormalities

• Represented the most frequent non-cutaneous adverse effect in hospitalized patients, occurring in 0.6% of recipients. 3
• Drug fever occurred in 0.3% of hospitalized patients. 3

Critical Safety Considerations

Severe Cutaneous Reactions

While rare, allopurinol can cause life-threatening hypersensitivity reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome, which carry a 25% mortality rate. 2, 1 These severe reactions are characterized by:

• Fever, severe skin rash, and eosinophilia 1
• Multi-organ involvement (hepatic, renal, cardiac systems) 1
• Symptoms typically developing within 1 week but potentially occurring with longer latency 1

High-Risk Populations

• Patients with the HLA-B*5801 haplotype have an 80-580 fold increased risk of allopurinol hypersensitivity. 2
• This allele has 6-7% frequency in Asian populations (particularly East Asian descent) and 1% in European populations. 2
• The incidence of skin rash is increased in patients with renal insufficiency. 1
• Concurrent use with ampicillin or amoxicillin increases rash frequency. 1

Clinical Implications

Monitoring Strategy

Patients should be counseled about skin reactions at therapy initiation and instructed to discontinue allopurinol immediately if rash develops. 1 The American College of Rheumatology recommends considering HLA-B*5801 testing before initiating therapy in Southeast Asian and African American patients. 4

Dose-Related Effects

• Adverse effects demonstrate dose-related patterns, with higher doses associated with increased risk. 3
• Dose reduction of 50% or more is recommended in renal failure to minimize toxicity risk. 4

Prophylaxis for Gout Flares

To minimize the risk of acute gout attacks during allopurinol initiation, the American College of Physicians recommends prophylactic therapy with low-dose colchicine or NSAIDs for more than 8 weeks when starting urate-lowering therapy. 2