Allopurinol is a xanthine oxidase inhibitor, representing a cornerstone of long-term pharmacological management for chronic hyperuricemia. It is the most frequently prescribed urate-lowering therapy (ULT) globally, prized for its well-established efficacy, safety profile, and cost-effectiveness. This medication works by fundamentally altering the underlying metabolic pathway responsible for uric acid production, offering a proactive rather than reactive approach to conditions like gout and specific types of kidney stones. Its use is a mainstay in rheumatology, nephrology, and oncology supportive care protocols.

Features

• Active Pharmaceutical Ingredient (API): Allopurinol.
• Pharmacological Class: Xanthine oxidase inhibitor.
• Available Formulations: Oral tablets (100 mg and 300 mg are most common).
• Mechanism of Action: Competitively inhibits the enzyme xanthine oxidase, which is responsible for the conversion of hypoxanthine to xanthine and xanthine to uric acid.
• Bioavailability: Approximately 90% following oral administration.
• Half-life: Allopurinol: 1-2 hours; its active metabolite, oxypurinol: 18-30 hours (allowing for once-daily dosing).
• Primary Excretion Route: Renal.
• Prescription Status: Prescription-only medication in most jurisdictions.

Benefits

• Prophylaxis of Gout Attacks: Significantly reduces the frequency and severity of acute gout flares over the long term by maintaining serum urate levels below the saturation point for crystal formation (<6 mg/dL or <360 μmol/L).
• Prevention of Tophus Formation: Leads to the gradual dissolution of existing urate crystal deposits (tophi) and prevents the formation of new, debilitating tophi in joints and soft tissues.
• Reduction of Uric Acid Nephrolithiasis Risk: Effective in preventing the formation of uric acid kidney stones in patients with hyperuricosuria.
• Management of Tumor Lysis Syndrome (TLS): Used prophylactically in patients with certain cancers (e.g., leukemias, lymphomas) undergoing chemotherapy to prevent the rapid release and consequent hyperuricemia that can lead to acute kidney injury.
• Long-Term Renal Protection: By controlling hyperuricemia, it may help mitigate associated chronic kidney disease progression in susceptible individuals, though this is an area of ongoing research.
• Improved Quality of Life: Provides patients with chronic gout the freedom from unpredictable, painful attacks, allowing for normal daily activities and improved joint function over time.

Common use

Allopurinol is primarily indicated for:

• Chronic Gout: The management of signs and symptoms of primary or secondary gout, including acute attacks, tophi, joint destruction, and uric acid lithiasis. It is not a treatment for an acute gout attack but is used for long-term prophylaxis.
• Recurrent Uric Acid Stone Formation: Prevention of stone formation in patients with recurrent uric acid calculi and/or hyperuricosuria.
• Prophylaxis of Hyperuricemia: Associated with cancer chemotherapy for hematological malignancies (e.g., leukemias, lymphomas) and in patients with certain enzyme deficiencies (e.g., Lesch-Nyhan syndrome) that cause overproduction of uric acid.

Dosage and direction

Dosage is highly individualized based on the indication, serum uric acid levels, and renal function. Treatment is typically initiated at a low dose and titrated upwards.

• Gout & Hyperuricemia:
  • Initial Dose: 100 mg once daily.
  • Maintenance Dose: Commonly 200-300 mg daily for mild gout. For more severe cases, doses may be increased by 100 mg every 2-4 weeks until a serum uric acid target of <6 mg/dL is achieved. The maximum recommended daily dose is 800 mg, though most patients are controlled on 200-400 mg daily. Doses above 300 mg should be administered in divided doses.
• Prevention of TLS in Oncology:
  • Adults: 600-800 mg daily, starting 1-2 days before initiation of chemotherapy, in divided doses (200-300 mg TID).
  • Children (for TLS): 10-20 mg/kg/day in divided doses (max 400 mg/day).
• Renal Impairment: Dose adjustment is mandatory. A common guideline is to reduce the daily dose (e.g., 100 mg/day for CrCl 10-20 mL/min; 100 mg every other day for CrCl 3-10 mL/min). Dosing should be guided by a clinician familiar with the patient’s complete renal profile.
• Administration: Tablets should be taken orally with a full glass of water. To minimize the potential for gastric irritation, it is recommended to take it after a meal. Consistent and adequate hydration (2-3 liters of fluid per day, unless contraindicated) is crucial to help excrete uric acid and prevent xanthine crystalluria.

Precautions

• Initiation Flare: The initiation of allopurinol therapy is frequently associated with an increase in acute gout attacks. This is due to the mobilization of urate from tissue deposits as serum levels fall. Prophylaxis with an NSAID (e.g., naproxen) or colchicine is strongly recommended for at least the first 3-6 months of therapy.
• Renal Function: Must be assessed prior to initiation and monitored periodically during therapy. Dose adjustments are critical in patients with impaired renal function to minimize the risk of severe adverse reactions.
• Hepatic Function: Use with caution in patients with pre-existing liver disease or history of hepatic impairment. Periodic liver function tests are advised.
• CBC Monitoring: As allopurinol can cause bone marrow suppression, complete blood counts should be monitored periodically, especially during the first few months of therapy.
• Hypersensitivity: Patients should be informed of the signs of severe hypersensitivity reactions (see Side Effects) and instructed to discontinue the drug immediately and seek medical attention if they occur.
• Asymptomatic Hyperuricemia: Allopurinol is not generally recommended for the treatment of asymptomatic hyperuricemia.

Contraindications

Allopurinol is contraindicated in patients with:

• A history of a severe hypersensitivity reaction to allopurinol or any component of the formulation (e.g., Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [DRESS]).
• Patients who are currently being treated with didanosine.

Possible side effect

Side effects can range from common and mild to rare and life-threatening.

• Common (>1%): Skin rash (maculopapular), nausea, vomiting, diarrhea, headache, drowsiness.
• Less Common: Metallic taste, alopecia, fever, eosinophilia, elevated liver enzymes (AST/ALT).
• Rare but Serious (<0.1%):
  • Severe Cutaneous Adverse Reactions (SCARs): Including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). These are medical emergencies.
  • Allopurinol Hypersensitivity Syndrome (AHS): A severe, multisystem reaction characterized by fever, rash (which can progress to exfoliative, urticarial, or purpuric lesions), eosinophilia, hepatitis, worsening renal function, and leukocytosis. Mortality is high (20-30%).
  • Hepatotoxicity: Ranging from transient transaminase elevations to granulomatous hepatitis, hepatic necrosis, and hepatic failure.
  • Bone Marrow Suppression: Including agranulocytosis, aplastic anemia, thrombocytopenia, and leukopenia.
  • Vasculitis.

Drug interaction

Allopurinol and its metabolite oxypurinol interact with several important medications:

• Azathioprine & 6-Mercaptopurine: Allopurinol potently inhibits the metabolism (xanthine oxidase pathway) of these immunosuppressants, leading to dramatically increased levels and profound myelosuppression. The dose of azathioprine/6-MP must be reduced to 25% of the usual dose if co-administered with allopurinol.
• Didanosine: Concurrent use is contraindicated. Allopurinol may increase didanosine concentrations, increasing the risk of toxicity (pancreatitis, neuropathy).
• Warfarin: Allopurinol may potentiate the anticoagulant effect of warfarin, increasing the risk of bleeding. Close monitoring of INR is required.
• ACE Inhibitors (e.g., captopril, enalapril): Co-administration may increase the risk of hypersensitivity reactions, particularly Stevens-Johnson Syndrome.
• Diuretics (especially Thiazides): May increase the incidence of hypersensitivity reactions to allopurinol. They also contribute to hyperuricemia, which may necessitate a higher allopurinol dose.
• Ampicillin/Amoxicillin: Increased incidence of skin rash when used concomitantly with allopurinol.
• Cyclophosphamide: Allopurinol may enhance the bone marrow toxicity of cyclophosphamide.
• Theophylline: Allopurinol may increase serum theophylline levels, potentially leading to toxicity.

Missed dose

• If a dose is missed, it should be taken as soon as it is remembered.
• However, if it is almost time for the next scheduled dose, the missed dose should be skipped, and the regular dosing schedule resumed.
• Do not double the dose to make up for a missed one.

Overdose

• Symptoms: Severe nausea, vomiting, diarrhea, and dizziness. In massive overdose, acute renal failure secondary to xanthine crystalluria and bone marrow suppression may occur.
• Management: There is no specific antidote for allopurinol overdose. Treatment is supportive and symptomatic. Gastric lavage or activated charcoal may be considered if presented early. Forced diuresis and alkalinization of urine may help prevent xanthine crystal deposition in the kidneys. Hemodialysis may be effective in removing allopurinol and oxypurinol, especially in patients with renal impairment.

Storage

• Store at controlled room temperature (20°-25°C or 68°-77°F).
• Protect from light and moisture.
• Keep in the original container, tightly closed.
• Keep out of reach of children and pets.
• Do not use after the expiration date printed on the packaging.

Disclaimer

This information is for educational and informational purposes only and does not constitute medical advice. It is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition or medication. Never disregard professional medical advice or delay in seeking it because of something you have read here. The author and publisher are not responsible for any specific health or allergy needs that may require medical supervision and are not liable for any damages or negative consequences from any treatment, action, application, or preparation, to any person reading or following the information in this document.

Reviews

• Clinical Consensus: Allopurinol is universally regarded by rheumatologists and nephrologists as a first-line, foundational therapy for the long-term management of gout and hyperuricemia. Its decades of use provide a robust evidence base for its efficacy and safety when used appropriately.
• Patient Perspectives: Patient reviews are often mixed, largely due to the experience of initial flares upon starting therapy. Those who are properly counseled on the need for prophylactic anti-inflammatory medication and who persist with treatment consistently report life-changing outcomes: freedom from debilitating pain, resolution of tophi, and a return to normal function. The most significant negative reviews typically stem from experiences with rare but severe hypersensitivity reactions.
• Overall: It remains the most cost-effective and widely studied urate-lowering agent available, earning its status as the gold standard against which newer therapies are measured.