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

From the Guidelines

Allopurinol can cause several side effects, with the most common being skin rash, which occurs in about 2% of patients, as well as stomach upset, nausea, diarrhea, and drowsiness, as reported in a study published in the Annals of Internal Medicine 1.

Common Side Effects

• Skin rash
• Stomach upset
• Nausea
• Diarrhea
• Drowsiness

Serious Side Effects

• Severe skin reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis
• Liver problems
• Kidney issues
• Bone marrow suppression Some patients may experience joint pain when first starting allopurinol, which is actually due to mobilization of urate crystals as uric acid levels decrease, as noted in a study published in the Annals of Internal Medicine 1. This is not an allergic reaction but rather a sign the medication is working.

Recommendations for Use

• Patients should start at a low dose (typically 100mg daily) and gradually increase to minimize side effects, as recommended in a clinical practice guideline from the American College of Physicians 1.
• Those with kidney disease need dose adjustments.
• It's essential to drink plenty of water while taking allopurinol to prevent kidney stones.
• If a rash develops, especially with fever, mouth sores, or eye irritation, medical attention should be sought immediately as this could indicate a severe hypersensitivity reaction.
• Regular blood tests to monitor liver and kidney function are recommended, particularly during the first few months of treatment, as suggested in a study published in the Annals of Internal Medicine 1.

Special Considerations

• Persons with the HLA-B*5801 haplotype, which is prevalent in Asian persons and in Korean persons with stage 3 or worse chronic kidney disease, may have an increased risk for serious adverse effects with allopurinol, as reported in a study published in the Annals of Internal Medicine 1.
• The most commonly reported adverse events from limited trials of febuxostat were abdominal pain, diarrhea, and musculoskeletal pain, as noted in a study published in the Annals of Internal Medicine 1.

From the FDA Drug Label

The most frequent adverse reaction to allopurinol tablets is skin rash. Skin reactions can be severe and sometimes fatal Therefore, treatment with allopurinol tablets should be discontinued immediately if a rash develops Most Common Reactions* Probably Causally Related:

• Gastrointestinal: Diarrhea, nausea, alkaline phosphatase increase, SGOT/SGPT increase.
• Metabolic and Nutritional: Acute attacks of gout.
• Skin and Appendages: Rash, maculopapular rash Incidence Less Than 1% Probably Causally Related:
• Body As a Whole: Ecchymosis, fever, headache.
• Cardiovascular: Necrotizing angiitis, vasculitis
• Gastrointestinal: Hepatic necrosis, granulomatous hepatitis, hepatomegaly, hyperbilirubinemia, cholestatic jaundice, vomiting, intermittent abdominal pain, gastritis, dyspepsia.
• Hemic and Lymphatic: Thrombocytopenia, eosinophilia, leukocytosis, leukopenia.
• Musculoskeletal: Myopathy, arthralgias.
• Nervous: Peripheral neuropathy, neuritis, paresthesia, somnolence.
• Respiratory: Epistaxis
• Skin and Appendages: Erythema multiforme exudativum (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), hypersensitivity vasculitis, purpura, vesicular bullous dermatitis, exfoliative dermatitis, eczematoid dermatitis, pruritus, urticaria, alopecia, onycholysis, lichen planus.
• Special Senses: Taste loss/perversion.
• Urogenital: Renal failure, uremia

The side effects of allopurinol include:

• Skin reactions: rash, maculopapular rash, erythema multiforme exudativum (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome)
• Gastrointestinal: diarrhea, nausea, alkaline phosphatase increase, SGOT/SGPT increase, hepatic necrosis, granulomatous hepatitis, hepatomegaly, hyperbilirubinemia, cholestatic jaundice, vomiting
• Metabolic and Nutritional: acute attacks of gout
• Cardiovascular: necrotizing angiitis, vasculitis
• Hemic and Lymphatic: thrombocytopenia, eosinophilia, leukocytosis, leukopenia
• Musculoskeletal: myopathy, arthralgias
• Nervous: peripheral neuropathy, neuritis, paresthesia, somnolence
• Respiratory: epistaxis
• Urogenital: renal failure, uremia 2

From the Research

Side Effects of Allopurinol

The side effects of allopurinol, a xanthine oxidase inhibitor, are as follows:

• Severe skin reactions, including exfoliative rash and Stevens-Johnson syndrome, which can be life-threatening 3, 4, 5, 6, 7
• Gout attacks, especially during the first two months of treatment 3
• Diarrhea and nausea, which are common early side effects 6
• Hepatic disorders, with treatment withdrawals due to hepatic disorders being more frequent with febuxostat than with allopurinol 3
• Cardiac disorders, with severe cardiac disorders being 4 to 5 times more frequent with febuxostat than with allopurinol 3
• Haematological and thyroid disorders, although the adverse effects of febuxostat are poorly documented 3
• Cutaneous disorders, with the relative frequency of severe cutaneous disorders with febuxostat and allopurinol not being well known 3

Risk Factors for Side Effects

Several risk factors for allopurinol-related side effects have been identified, including:

• Ethnicity 4, 5
• HLA-B*5801 genotype 4, 5
• Kidney impairment 4, 5
• Allopurinol starting dose 4
• Concomitant diuretic use 4
• Recent introduction of allopurinol 5
• Presence of the HLA-B*58:01 allele 5
• Factors that influence the drug concentration 5
• Impaired renal function, ampicillin and thiazide diuretics, which increase the risk of serious hypersensitivity reactions 7