What are the side effects of allopurinol in patients, particularly those with a history of kidney (renal) disease or liver disease?

Side Effects of Allopurinol

The most critical side effect of allopurinol is hypersensitivity reaction, which can manifest as skin rash and progress to life-threatening conditions including Stevens-Johnson syndrome, generalized vasculitis, irreversible hepatotoxicity, and death—allopurinol must be discontinued immediately at the first sign of skin rash. 1

Common Side Effects

Dermatologic Reactions

• Rash is the most common adverse event with allopurinol and serves as a warning sign for potentially severe hypersensitivity reactions 2
• Skin manifestations can range from simple maculopapular rashes and hives to severe exfoliative, urticarial, and purpuric lesions 1, 3
• Patients should discontinue allopurinol immediately and contact their physician at the first sign of skin rash, painful urination, blood in urine, eye irritation, or swelling of lips or mouth 1

Gastrointestinal Effects

• Patients may experience gastric irritation, which can be minimized by taking allopurinol after meals 1

Neurologic Effects

• Drowsiness occurs occasionally, requiring patients to exercise caution when engaging in activities requiring alertness 1
• Headache and dizziness have been reported 3
• Rare cases of drug-induced meningitis with severely reduced consciousness have been documented 3

Paradoxical Gout Flares

• An increase in acute gout attacks commonly occurs during early allopurinol therapy, even when serum uric acid levels normalize 1
• This paradox results from mobilization of urate deposits from tissues, causing fluctuations in serum uric acid levels 1
• Prophylactic colchicine or NSAIDs should be given when initiating allopurinol to suppress these attacks 1

Serious and Life-Threatening Side Effects

Hypersensitivity Syndrome

• Fatal hypersensitivity reactions have been reported despite allopurinol's 40+ year safety history 2
• The allopurinol hypersensitivity syndrome is characterized by fever, rash, decreased renal function, hepatocellular injury, leukocytosis, and eosinophilia 4
• Mortality from allopurinol hypersensitivity is substantial—22 of 80 documented cases (27.5%) resulted in death 4
• Stevens-Johnson syndrome (erythema multiforme exudativum) and generalized vasculitis represent severe manifestations 1

Hematologic Effects

• Bone marrow depression affecting one or more cell lines can occur, typically in patients receiving concomitant drugs with similar potential 1
• This complication can develop as early as 6 weeks or as late as 6 years after initiating therapy 1

Hepatotoxicity

• Reversible clinical hepatotoxicity has been documented 1
• Asymptomatic elevations in serum alkaline phosphatase or transaminases may occur 1
• Patients with pre-existing liver disease require periodic liver function tests during early therapy 1
• Development of anorexia, weight loss, or pruritus warrants liver function evaluation 1

Renal Effects

• Some patients with pre-existing renal disease or poor urate clearance show rises in BUN during allopurinol administration 1
• Renal failure associated with allopurinol has been observed in patients with hyperuricemia secondary to neoplastic diseases 1
• Albuminuria has been observed in patients with chronic glomerulonephritis and chronic pyelonephritis 1

Special Population Considerations

Patients with Renal Impairment

• Patients with decreased renal function require dose reductions—starting at 50 mg daily for stage 4 or worse CKD 2
• In severely impaired renal function, oxipurinol half-life is greatly prolonged, potentially requiring doses as low as 100 mg daily or 300 mg twice weekly 1
• The FDA recommends at least 50% dose reduction in patients with renal insufficiency 5
• Renal function monitoring (BUN, serum creatinine, creatinine clearance) should be performed periodically, especially in patients with concurrent conditions affecting renal function like hypertension or diabetes 1

High-Risk Ethnic Groups

• Persons with HLA-B*5801 haplotype have increased risk for serious adverse effects 2
• This haplotype is prevalent in Han Chinese, Thai, and Korean populations (particularly those with stage 3 or worse CKD) 2
• Rapid PCR-based HLA-B*5801 screening should be considered before initiating allopurinol in these high-risk populations 2, 5

Patients on Thiazide Diuretics

• The occurrence of hypersensitivity reactions may be increased in patients with decreased renal function receiving thiazides and allopurinol concurrently 1
• Renal function should be monitored even in the absence of renal failure when combining these medications 1
• Dosage levels should be conservatively adjusted if diminished renal function is detected 1

Critical Drug Interactions Causing Adverse Effects

Purine Antimetabolites

• Concomitant use with mercaptopurine or azathioprine requires 65-75% dose reduction of the chemotherapeutic agent due to severe myelotoxicity risk 5, 6, 1
• Allopurinol is contraindicated with cyclophosphamide and other cytotoxic agents due to increased bone marrow suppression 5

Anticoagulants

• Allopurinol prolongs the half-life of dicumarol, requiring prothrombin time reassessment 1
• Warfarin may require increased dosing and more frequent INR monitoring 6

Antibiotics

• Concomitant use with ampicillin or amoxicillin carries certain risks, and patients should be monitored for hypersensitivity reactions, particularly skin rashes 6, 1
• If rash develops, the risk-benefit of continuing both medications should be reassessed 6

Other Medications

• Colchicine use is an independent risk factor for allopurinol-induced adverse events (odds ratio 3.11) 7
• Statin use increases risk of adverse events (odds ratio 2.10) 7

Clinical Risk Factors for Adverse Events

• Chronic kidney disease (present in 46% of patients with adverse events vs 30% of controls) 7
• Hypertension (42% vs 30%) 7
• Concurrent use of angiotensin receptor blockers (27% vs 15%) 7

Prevention and Monitoring Strategies

• Start with low doses (100 mg daily, or 50 mg daily in stage 4+ CKD) and titrate gradually at weekly intervals 2, 1
• Maintain adequate fluid intake to yield at least 2 liters daily urinary output to prevent xanthine calculi formation 1
• Maintain neutral or slightly alkaline urine 1
• Monitor serum uric acid levels to guide dosing adjustments 1
• Patients should be observed closely during early stages of therapy, particularly those with impaired renal function 1