Continuing Education Activity

Allopurinol, a xanthine oxidase inhibitor, is a urate-lowering medication that is FDA approved for managing gout, preventing tumor lysis syndrome, and preventing 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. It is important to note that asymptomatic hyperuricemia is not an indication of allopurinol or any urate-lowering therapy. This activity outlines the indications, mechanism, pharmacology, contraindications, and adverse events associated with allopurinol drug therapy.

Objectives:

• Identify the various indications, both approved and off-label, for allopurinol therapy.
• Describe the potential adverse effects of allopurinol.
• Summarize the mechanism of action of allopurinol.
• Review the importance of coordinating and collaborating among various disciplines in an interprofessional health team to coordinate care and management to enhance outcomes for patients receiving allopurinol therapy.

Indications

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 recurrent uric acid nephrolithiasis prevention.[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]

Van Liere E. et al. conducted a study on using low-dose azathioprine and allopurinol (LDAA) to treat inflammatory bowel disease. Allopurinol was added to azathioprine to improve its tolerability. The investigators found that LDAA was better tolerated in patients compared with standard azathioprine monotherapy.[2]

Mechanism of Action

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.

Schmidt A. et al. conducted a clinical trial on the analgesic effects of allopurinol in patients undergoing hysterectomy. The investigators found that allopurinol given as a pre-anesthetic agent reduced pain scores 2 hours after surgery.[3]

Fagundes A. et al. conducted a study (12 women) on allopurinol treatment in patients with fibromyalgia.[4] Allopurinol treatment reduced pain. However, in a larger study (N = 31 for allopurinol and N = 29 for placebo), allopurinol did not demonstrate analgesic properties in fibromyalgia patients.[5]

Hsu F. et al. found evidence that medium to high doses of allopurinol reduced colorectal cancer risk in patients.[6]

Park S. et al. found that allopurinol was renoprotective in patients with hyperuricemia and chronic kidney disease compared to febuxostat treatment.[7]

Prieto-Moure B. et al. conducted research on small intestine ischemia-reperfusion injury of Wistar rats and the role of allopurinol and dantrolene in preventing oxygen-free radical damage. The researchers found that the allopurinol and dantrolene combination provided antioxidant effects, which decreased the oxygen-free radical damage caused by the ischemia-reperfusion in the rat's small intestines.[8]

Administration

Allopurinol administration can be in two forms: 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 the target serum uric acid is achieved. 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 concentration, the required dose of allopurinol to achieve the target serum uric acid concentration should continue indefinitely.[1]

In patients with renal insufficiency (chronic kidney disease stage 4 and greater), allopurinol should start at a 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.[9] Allopurinol and oxypurinol are both dialyzable. In patients with end-stage renal disease on hemodialysis or peritoneal dialysis, allopurinol can be initiated at 50 mg on alternate days and be given post dialysis, with cautious dose escalation to achieve target serum uric acid.

To prevent 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 are 300 mg/m^2/day in three divided doses every 8 hours, a maximum of 800 mg daily, and 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.

Adverse Effects

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

Due to the destabilization of intra-articular uric acid microtophi on initiating 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.[10]

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

Fontana R. et al. conducted research on eleven patients with suspected allopurinol-induced liver damage. The researchers found that hepatoxicity was associated with the following alleles: HLA-B*58:01, HLA-B*53:01, and HLA-A*34:02. The median age was 60 years, 54% were men, and 63% were African-American.[11]

Allopurinol maintenance therapy may increase thyroid-stimulating hormone, which might result from subclinical hypothyroidism.[12]

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.[13] 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. Wong C et al. conducted pharmacogenomic testing (HLA-B*58:01 allele) on patients with chronic kidney disease before initiating allopurinol treatment.[14] The pharmacogenomic screening prevents allergic skin reactions, and it is cost-effective.

Lavu A. et al. reported on a patient with Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) caused by allopurinol. The patient’s clinical presentation gradually resolved with the discontinuation of allopurinol therapy. The patient was found to have the HLA-B*58:01 allele. The investigators recommend pharmacogenomic testing for the HLA-B*58:01 allele before initiating allopurinol therapy to prevent SJS and TEN in susceptible patients.[15]

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

Contraindications

The presence of 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 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.

Monitoring

Complete blood count, liver function tests, renal function, and serum uric acid levels shall be measured every 2 to 5 weeks while titrating the dose until achieving the target serum uric acid level and every six months thereafter. Patients need counseling about the signs and symptoms of AHS with a recommendation to discontinue allopurinol promptly if they develop skin rash concerning AHS, especially early in therapy. 

The manufacturer recommends that patients on allopurinol discontinue the drug for one week before breastfeeding. However, the mother could continue allopurinol therapy in exclusively breastfed babies with careful monitoring of the child for allergic reactions and complete blood counts.[16]

Enhancing Healthcare Team Outcomes

Allopurinol is a relatively safe drug that has been used for over half a century. Still, recent studies in gout have shown significant underutilization of this agent and suboptimal dose use, insufficient to reach target serum uric acid concentrations in a considerable proportion of gout patients. A problem with allopurinol treatment for gout is therapy adherence. Emad Y. et al. found that the most common reason for lack of patient adherence to pharmacotherapy is: "patients wanting to lead a normal life."[17] This is an opportunity for healthcare professionals to improve pharmacotherapy adherence.

Contrary to the common belief, recent studies have shown that allopurinol is safe in severe chronic kidney disease and can impede the progression of renal disease in patients with gout and chronic kidney disease.[18][19] Using allopurinol in patients with gout is also associated with lower all-cause mortality and other adverse cardiovascular events, including readmissions due to congestive heart failure.[19][20][21][22] American College of Rheumatology recommends allopurinol as one of the first-line agents of urate-lowering therapy for gout management. Several studies report that allopurinol reduced cardiovascular events. However, research by Suissa S. et al. concludes that these studies contained time-related biases and, thus, allopurinol does not provide cardiovascular protection.[23]

There are, however, potential rare though severe adverse effects associated with allopurinol. The use of allopurinol requires management by an interprofessional healthcare team that includes clinicians (MDs, DOs, NPs, PAs), nurses, and pharmacists. Clinicians initiating allopurinol therapy should ensure no drug interactions and that xanthine oxidase inhibitor therapy is the optimal choice; if necessary, a pharmacist consult can assist in this evaluation. Pharmacists can also verify dosing and provide additional patient counsel regarding how to take the drug. The nursing team shall assist with verifying patient adherence and helping to monitor for adverse events and therapeutic effectiveness. All team members should document their observations in the patient's permanent health record, and be prepared to reach out to other team members when necessary, so alterations to the therapeutic regimen can be made. The best chance for allopurinol to have therapeutic success with minimal adverse events is via an interprofessional team approach. [Level 5]