Allopurinol is a medication primarily used to lower uric acid levels in the body. It is FDA-approved for managing gout, preventing tumor lysis syndrome, and preventing recurrent calcium nephrolithiasis in patients with hyperuricosuria. While not FDA-approved for all uses, it’s also used in Lesch-Nyhan syndrome-associated hyperuricemia and to prevent recurrent uric acid nephrolithiasis. Importantly, asymptomatic hyperuricemia is not a reason to use allopurinol or any urate-lowering therapy.
Approved and Off-Label Uses of Allopurinol
Allopurinol, a xanthine oxidase inhibitor, effectively lowers uric acid levels. Its primary uses include:
- Gout: Allopurinol is a common treatment option for gout, helping to prevent attacks by reducing uric acid levels in the blood.
- Prevention of Tumor Lysis Syndrome: This syndrome occurs when cancer cells break down rapidly, releasing uric acid into the bloodstream. Allopurinol helps prevent the buildup of uric acid, which can damage the kidneys.
- Prevention of Recurrent Calcium Nephrolithiasis: In patients with hyperuricosuria (high levels of uric acid in the urine), allopurinol can help prevent the formation of calcium kidney stones.
Other, non-FDA-approved uses include:
- Lesch-Nyhan Syndrome-Associated Hyperuricemia: This rare genetic disorder leads to high uric acid levels.
- Recurrent Uric Acid Nephrolithiasis Prevention: Allopurinol can prevent the formation of uric acid kidney stones.
The American College of Rheumatology suggests considering urate-lowering therapy, including allopurinol, for gout patients in specific situations:
- Frequent gout attacks (two or more per year)
- Chronic kidney disease (stage 2 or worse)
- Presence of tophi (urate crystal deposits)
- History of nephrolithiasis (kidney stones)
Alt text: A foot displaying signs of gout inflammation and swelling, particularly around the big toe joint.
How Allopurinol Works: Mechanism of Action
Allopurinol is metabolized in the liver to oxypurinol, its active form. Allopurinol has a short half-life of 1 to 2 hours, while oxypurinol’s half-life is around 15 hours. Both are excreted by the kidneys. Allopurinol and oxypurinol work by inhibiting xanthine oxidase, an enzyme involved in purine metabolism. This enzyme converts hypoxanthine to xanthine and then to uric acid. By blocking this enzyme, allopurinol reduces uric acid production.
How is Allopurinol Administered?
Allopurinol is available in oral and intravenous (IV) forms. Oral administration is typical for gout and kidney stone prevention. IV allopurinol is used to prevent tumor lysis syndrome and manage cancer therapy-induced hyperuricemia, particularly when oral medication isn’t tolerated.
For long-term gout management, the starting dose is usually 100 mg daily, increased by 100 mg every 2 to 5 weeks until the target serum uric acid level is reached (below 6.0 mg/dL, or below 5.0 mg/dL for tophaceous gout). The maximum daily dose is 800 mg. The required dose should be continued indefinitely to maintain the target uric acid level.
Patients with renal insufficiency (chronic kidney disease stage 4 or greater) should start at 50 mg daily, increasing by 50 mg every 2 to 5 weeks until the target uric acid level is achieved. For patients on hemodialysis or peritoneal dialysis, allopurinol can be started at 50 mg every other day, given post-dialysis, with careful dose adjustments.
To prevent tumor lysis syndrome, allopurinol should begin 2 to 3 days before chemotherapy and continue for 3 to 7 days afterward. Oral doses are typically 300 mg/m^2/day in three divided doses (maximum 800 mg daily), while IV doses are 200 to 400 mg/m2 daily in single or divided doses.
For preventing recurrent uric acid or calcium nephrolithiasis, the typical oral dose is 300 mg daily.
What are the Potential Adverse Effects of Allopurinol?
Alt text: Chemical structure of allopurinol molecule.
Allopurinol is generally safe, but side effects can occur. Starting urate-lowering therapy can sometimes trigger acute gouty flares due to the destabilization of uric acid crystals. Anti-inflammatory agents like colchicine, NSAIDs, or low-dose prednisone are often prescribed to prevent these flares when starting allopurinol.
Common side effects include maculopapular pruritic rash and gastrointestinal issues like nausea and diarrhea. Laboratory abnormalities such as elevated liver enzymes (transaminitis, alkaline phosphatase), leukopenia, and thrombocytopenia can also occur. Less common and rare side effects include liver necrosis, granulomatous hepatitis, cholestatic jaundice, interstitial nephritis, and vasculitis.
Allopurinol hypersensitivity syndrome (AHS) is a rare but severe adverse reaction with a high mortality rate (20% to 25%). It involves a T-cell-mediated immune response to oxypurinol and is most likely in the first few months of therapy, especially with higher starting doses. Risk factors include concurrent diuretics (especially thiazides), renal insufficiency (stage 3 or higher), and HLA-B*5801 genotype in individuals of Korean, Han Chinese, and Thai descent. AHS symptoms can include Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, hepatocellular injury, acute kidney injury, fever, leukocytosis, and eosinophilia. Management is primarily supportive.
Lowering the starting dose to less than 100 mg daily (or less than 50 mg in patients with chronic kidney disease stage 3 or worse) can reduce the risk of AHS. Pharmacogenomic testing (HLA-B*58:01 allele) before starting allopurinol can help prevent allergic skin reactions in susceptible individuals.
Drug interactions are also important to consider. Allopurinol significantly interacts with azathioprine and 6-mercaptopurine, potentially causing severe agranulocytosis and pancytopenia.
When is Allopurinol Contraindicated?
The 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 (regardless of renal function) significantly increases the risk of AHS. Screening these populations for the HLA-B*5801 genotype before starting allopurinol is recommended. If positive, an alternative urate-lowering therapy should be considered. Universal HLA-B*5801 screening is not generally recommended due to lower prevalence and hazard ratios in other populations.
How Should Patients Be Monitored While Taking Allopurinol?
Complete blood counts, liver function tests, renal function, and serum uric acid levels should be checked every 2 to 5 weeks during dose titration and every six months thereafter. Patients should be educated about the signs and symptoms of AHS and advised to stop allopurinol immediately if they develop a concerning skin rash, particularly early in treatment.
The manufacturer recommends discontinuing allopurinol one week before breastfeeding. However, mothers can continue allopurinol while breastfeeding with careful monitoring of the infant for allergic reactions and blood count changes.
Improving Outcomes with Allopurinol Therapy
Despite being a relatively safe and long-used drug, allopurinol is often underutilized and dosed suboptimally, failing to reach target uric acid levels in many gout patients. Patient adherence is a major challenge. Healthcare professionals can improve adherence by addressing patient concerns and promoting a better understanding of the medication’s benefits.
Recent studies have shown that allopurinol is safe in severe chronic kidney disease and may slow renal disease progression in patients with gout and chronic kidney disease. Allopurinol use in gout patients has also been linked to lower all-cause mortality and fewer cardiovascular events. The American College of Rheumatology recommends allopurinol as a first-line urate-lowering therapy for gout.
However, potential rare but severe adverse effects require careful management. An interprofessional healthcare team, including clinicians, nurses, and pharmacists, is essential for optimizing allopurinol therapy and minimizing risks.
