Allopurinol

Allopurinol, a xanthine oxidase inhibitor, is a urate-lowering medication.

Allopurinol is FDA approved for the following indications:

1. Gout
2. Prevention of tumor lysis syndrome
3. Prevention of recurrent calcium nephrolithiasis in patients with hyperuricosuria 

Other non-FDA approved indications include Lesch-Nyhan syndrome-associated hyperuricemia and the prevention of recurrent uric acid nephrolithiasis.[1]

American College of Rheumatology recommends initiating urate-lowering therapy such as allopurinol in patients with an established diagnosis of gouty arthritis in the following situations:

1. Frequent attacks of acute gouty arthritis, defined as equal to or more than two attacks per year
2. Chronic kidney disease stage 2 or worse
3. Presence of tophi or tophus on clinical exam or imaging
4. History of nephrolithiasis

It is important to note that asymptomatic hyperuricemia is not an indication of allopurinol or any urate-lowering therapy.[1]

Allopurinol undergoes metabolism in the liver, where it transforms into its pharmacologically active metabolite, oxypurinol. The half-life of allopurinol is 1 to 2 hours, and oxypurinol is about 15 hours. Both allopurinol and oxypurinol are renally excreted. Allopurinol and oxypurinol both inhibit xanthine oxidase, an enzyme in the purine catabolism pathway that converts hypoxanthine to xanthine to uric acid.

Allopurinol administration can be in two forms, either oral or intravenous (IV). While oral administration is the standard route for gout and uric acid or calcium oxalate nephrolithiasis, IV allopurinol is for the prevention of tumor lysis syndrome and management of cancer therapy-induced hyperuricemia in patients who cannot tolerate oral therapy.

For long-term gout treatment, the recommended starting dose of allopurinol is 100 mg daily, to be escalated by 100 mg every 2 to 5 weeks until achieving the target serum uric acid. American College of Rheumatology recommends target uric acid of less than 6.0 mg/dL for all patients with gout, and less than 5.0 mg/dL in patients with tophaceous gout. The maximum daily allopurinol dose is 800 mg. Following the patient reaching the target serum uric acid level, the required dose of allopurinol to achieve the target serum uric acid level should continue indefinitely.[1]

In patients with renal insufficiency (chronic kidney disease stage 4 and greater), allopurinol should start at 50 mg daily dose, and the dose shall be escalated by 50 mg every 2 to 5 weeks until reaching the target serum uric acid.[2] allopurinol and oxypurinol both are dialyzable, and in patients end-stage renal disease on hemodialysis or peritoneal dialysis, allopurinol can be initiated at 50 mg on alternate days to be given post dialysis, with cautious dose escalation to achieve target serum uric acid.

For prevention of tumor lysis syndrome, allopurinol shall be initiated 2 to 3 days before starting chemotherapy and continued until 3 to 7 days after chemotherapy. Doses for oral allopurinol is 300 mg/m^2/day in three divided doses every 8 hours, maximum 800 mg daily, and for IV allopurinol is 200 to 400 mg/m2 daily single doses or 2 to 3 divided doses.

Allopurinol dosing is 300 mg oral daily for the prevention of recurrent uric acid or calcium nephrolithiasis.

Allopurinol is a relatively safe medication, although adverse effects can occur.

Due to the destabilization of intra-articular uric acid microtophi on the initiation of any urate-lowering therapy, there is an increased incidence of acute gouty flares, especially during the initial few months. To prevent this, patients should start an anti-inflammatory agent such as colchicine, nonsteroidal anti-inflammatory drug (NSAID), or low dose prednisone (only in patients who cannot take colchicine or NSAIDs) before or at the same time as initiating allopurinol.[3]

Maculopapular pruritic rash, gastrointestinal adverse effects, including nausea and diarrhea, are other common adverse effects. Laboratory abnormalities, including transaminitis and elevated serum alkaline phosphatase, leukopenia, and thrombocytopenia, can occur. Other less common and rare adverse effects include liver necrosis, granulomatous hepatitis, cholestatic jaundice, interstitial nephritis, and vasculitis. 

Allopurinol hypersensitivity syndrome (AHS) is a rare severe adverse effect of allopurinol with an incidence of about 1 in 1000, with a high mortality rate of 20% to 25%. The mechanism is a T-cell mediated immune reaction to oxypurinol. The highest risk is in the first few months of therapy, especially with higher starting doses of allopurinol. Concurrent diuretics, especially thiazide use, renal insufficiency stage 3, or higher, are major risk factors. Patients of Korean, Han Chinese, and Thai descent with HLA-B*5801 genotype are at a very high risk of AHS. Clinical features of AHS include Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, hepatocellular injury, acute kidney injury, fever, leukocytosis, and eosinophilia. Management is supportive. Lowering the starting dose of allopurinol to less than 100 mg daily in all patients, and less than 50  mg daily in patients with chronic kidney disease stage 3 or worse can lower the risk of AHS.

Several drug interactions exist with allopurinol. The most important drug interaction is with azathioprine and 6-mercaptopurine, both of which are metabolized by the enzyme xanthine oxidase. Use of any xanthine oxidase inhibitor such as allopurinol in a patient on azathioprine or 6-mercaptopurine can cause severe agranulocytosis and pancytopenia.

Presence of HLA-B*5801 genotype in patients of Korean descent with chronic kidney disease stage 3 or worse, or in patients of Han Chinese or Thai descent irrespective of renal function, is an especially high risk of AHS (hazard ratio of several hundred). American College of Rheumatology recommends screening this population for HLA-B*5801 genotype using the polymerase chain reaction (PCR) testing before initiating allopurinol, and if positive, using an alternative urate-lowering therapy. However, universal HLA-B*5801 allopurinol screening is not recommended given the significantly lower HLA-B*5801 prevalence and hazard ratio in other populations.