What are the potential side effects of allopurinol (xanthine oxidase inhibitor)?

Allopurinol Side Effects

Allopurinol can cause several significant side effects, with skin rash being the most common adverse reaction that can sometimes progress to severe and potentially fatal hypersensitivity reactions, particularly in patients with renal impairment or those carrying the HLA-B*58:01 allele. 1

Common Side Effects (Incidence ≥1%)

• Skin rash (most frequent adverse reaction) - can range from mild maculopapular eruptions to severe exfoliative dermatitis 1
• Gastrointestinal disturbances - diarrhea, nausea 1
• Liver enzyme elevations - increased alkaline phosphatase, SGOT/SGPT 1
• Acute gout attacks following initiation of therapy (historically 6%, now <1% with gradual dose titration) 1

Severe Hypersensitivity Reactions

• Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome/Drug Hypersensitivity Syndrome (DHS) - potentially life-threatening reaction characterized by: 1

  • Fever
  • Severe skin rash
  • Elevated leukocyte and eosinophil counts
  • Lymphadenopathy
  • Multi-organ involvement (hepatic, renal, cardiac, gastrointestinal, lymphatic, pulmonary, ophthalmic)

• Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) - severe cutaneous reactions with high mortality rates 1, 2

  • Risk factors include HLA-B*58:01 allele (particularly in Han-Chinese, Korean, and Thai populations) 3
  • Symptoms typically develop within approximately 1 week of starting therapy 1

Less Common Side Effects (Incidence <1%)

Gastrointestinal

• Hepatotoxicity - hepatic necrosis, granulomatous hepatitis, hepatomegaly 1
• Hyperbilirubinemia, cholestatic jaundice 1
• Vomiting, abdominal pain, gastritis, dyspepsia 1

Hematologic

• Thrombocytopenia, eosinophilia, leukocytosis, leukopenia 1
• Rare cases of aplastic anemia, agranulocytosis, pancytopenia 1

Renal

• Acute renal failure, particularly in patients with pre-existing kidney disease 4
• Xanthine crystal deposition in renal tubules (due to inhibition of xanthine oxidase) 3

Neurological

• Peripheral neuropathy, neuritis, paresthesia, somnolence 1
• Drowsiness (patients should be cautioned when engaging in activities requiring alertness) 1

Cardiovascular

• Necrotizing angiitis, vasculitis 1

Other

• Myopathy, arthralgias 1
• Taste loss/perversion 1

Drug Interactions

• Reduced clearance of purine-based chemotherapeutic agents (6-mercaptopurine, azathioprine) - requires 65-75% dose reduction of these medications 3, 1
• Reduced clearance of high-dose methotrexate 3
• Contraindicated with cyclophosphamide and other cytotoxic agents due to increased bone marrow suppression 3
• Potential interactions with dicumarol, thiazide diuretics, chlorpropamide, and cyclosporine 3
• Increased risk of hypersensitivity reactions in patients with decreased renal function receiving thiazides concurrently 1
• Increased risk of skin rash with concurrent use of ampicillin or amoxicillin 1
• Increased risk of adverse events with concomitant use of colchicine or statins 5

Risk Factors for Adverse Reactions

• Renal impairment (requires dose reduction) 3
• HLA-B*58:01 allele (particularly in Han-Chinese, Korean, and Thai populations) 3, 6
• Recent initiation of therapy (most reactions occur within first weeks) 1, 6
• Concomitant use of certain medications (colchicine, statins) 5

Monitoring and Management

• Discontinue allopurinol immediately at the first sign of skin rash or other hypersensitivity reactions 1
• Monitor liver function in patients with pre-existing liver disease 1
• Reduce dose by at least 50% in patients with renal insufficiency 3
• Consider HLA-B*58:01 testing before initiating therapy in high-risk ethnic groups 3
• Start with low doses (100 mg daily) and titrate gradually to minimize risk of acute gout attacks 3