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

From the Guidelines

Allopurinol commonly causes side effects that patients should be aware of before starting treatment, with the most serious being a severe hypersensitivity reaction called allopurinol hypersensitivity syndrome, which can be life-threatening. The most common adverse event with allopurinol is rash, and most serious adverse effects associated with allopurinol are rare, mild, and reversible; however, fatal hypersensitivity reactions have also been reported with the drug 1. More common side effects include skin rashes (which occur in about 2% of patients), gastrointestinal issues like nausea, vomiting, diarrhea, and abdominal pain. Some patients experience headaches, dizziness, drowsiness, or altered taste. Allopurinol can also cause liver function abnormalities and may increase the risk of acute gout attacks when first starting therapy. Blood disorders like reduced white blood cell counts or platelets occur rarely.

• Key points to consider when prescribing allopurinol include:
  • Starting with a low dose (typically 100mg daily) and gradually increasing to minimize side effects
  • Taking the medication after meals to reduce stomach upset
  • Adjusting dosing for patients with impaired kidney function
  • Considering HLA-B*5801 screening in selected patients sub-populations at elevated risk for allopurinol hypersensitivity syndrome
  • Monitoring for signs of severe hypersensitivity reaction, such as skin rash, fever, liver damage, kidney problems, and seeking immediate medical attention if these occur
  • Being aware of the potential for increased risk of side effects in patients with kidney disease
  • Considering alternative treatments, such as febuxostat, in patients who are intolerant or have contraindications to allopurinol 1. Patients should be advised to seek immediate medical attention if they experience any signs of a severe hypersensitivity reaction, such as a skin rash or fever, while taking allopurinol.

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 can be severe and life-threatening. Some of the known side effects include:

• Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are immune-mediated disease processes that can involve almost every organ system 3, 4, 5, 6, 7
• Hypersensitivity reactions, ranging from mild cutaneous eruption to more severe clinical manifestations such as allopurinol hypersensitivity syndrome 5
• Severe cutaneous adverse reactions, which can be categorized based on the area of skin involvement 4
• Acute renal failure and hemodynamic compromise, especially in patients with concomitant acute viral illness 4

Risk Factors for Side Effects

Several risk factors have been identified for the development of serious cutaneous reactions associated with allopurinol use, including:

• Ethnicity, with Asian and African American patients being at higher risk 6, 7
• HLA-B∗5801 genotype 6
• Kidney impairment 3, 6
• Allopurinol starting dose 6
• Concomitant diuretic use 6

Prevention and Treatment

Strategies to reduce the risk of side effects include:

• Screening for HLA-B∗5801 in high-risk individuals 6
• Commencing allopurinol at a low dose 6
• Educating patients about the signs and symptoms of severe cutaneous adverse reactions, and what to do if they occur 6
• Cessation of allopurinol and supportive care in cases of severe cutaneous adverse reactions 6