What are the considerations for initiating allopurinol (xanthine oxidase inhibitor) therapy?

From the Guidelines

Allopurinol should be started at a low dose of 100mg daily and gradually increased by 100mg every 2-4 weeks until reaching the target serum uric acid level (typically <6 mg/dL) or a maximum dose of 800mg daily. Before initiating therapy, baseline renal function, liver function, and complete blood count should be checked 1. Importantly, allopurinol should be started with prophylactic colchicine (0.6mg once or twice daily) or a low-dose NSAID for 3-6 months to prevent gout flares that commonly occur when uric acid levels are changing 1. Patients should be counseled that allopurinol may initially trigger gout attacks despite prophylaxis, but they should continue taking the medication. Allopurinol works by inhibiting xanthine oxidase, the enzyme responsible for converting hypoxanthine to xanthine and xanthine to uric acid, thereby reducing serum uric acid levels. Dose adjustments are necessary for patients with renal impairment 1. Regular monitoring of uric acid levels every 2-4 weeks during dose titration and then every 6 months once at target is recommended, along with periodic assessment of renal and liver function 1.

Some key considerations when initiating allopurinol therapy include:

• Starting with a low dose and gradually increasing as needed to minimize the risk of adverse effects 1
• Monitoring renal function and adjusting the dose accordingly 1
• Using prophylactic colchicine or NSAIDs to prevent gout flares 1
• Counseling patients on the potential for initial gout attacks despite prophylaxis 1
• Regularly monitoring uric acid levels and adjusting the dose as needed to achieve the target level 1

It's also important to note that allopurinol is generally well-tolerated, but can cause adverse effects such as rash, hepatitis, and eosinophilia 1. In patients with renal impairment, the maximum dosage of allopurinol should be adjusted to creatinine clearance, and alternative treatments such as febuxostat or benzbromarone may be considered if the target serum uric acid level cannot be achieved 1.

From the FDA Drug Label

General An increase in acute attacks of gout has been reported during the early stages of administration of allopurinol tablets, even when normal or subnormal serum uric acid levels have been attained. In addition, it is recommended that the patient start with a low dose of allopurinol tablets (100 mg daily) and increase at weekly intervals by 100 mg until a serum uric acid level of 6 mg/dL or less is attained but without exceeding the maximum recommended dose (800 mg per day). Patients with decreased renal function require lower doses of allopurinol tablets than those with normal renal function. Lower than recommended doses should be used to initiate therapy in any patients with decreased renal function and they should be observed closely during the early stages of administration of allopurinol tablets

The considerations for initiating allopurinol therapy include:

• Starting with a low dose (100 mg daily) and increasing at weekly intervals by 100 mg until a serum uric acid level of 6 mg/dL or less is attained
• Not exceeding the maximum recommended dose (800 mg per day)
• Using lower doses in patients with decreased renal function
• Monitoring patients closely during the early stages of administration, especially those with decreased renal function
• Being aware of the potential for increased acute attacks of gout during the early stages of administration 2
• Assessing the need for prophylactic colchicine to prevent gouty attacks 2

From the Research

Considerations for Initiating Allopurinol Therapy

• The decision to initiate allopurinol therapy should be based on the patient's serum uric acid (SUc) levels, renal function, and presence of gouty tophi or chronic urate arthropathy 3.
• The starting dose of allopurinol should be low, with a gradual increase to achieve the target SUc level, to minimize the risk of adverse reactions such as gouty flares 4.
• The risk of allopurinol hypersensitivity syndrome (AHS) is increased with higher starting doses, particularly in patients with renal impairment, and a starting dose of 1.5 mg per unit of estimated GFR may be associated with a reduced risk of AHS 4.
• Initiating allopurinol during an acute gout attack does not appear to prolong the duration of the attack, and low-dose allopurinol can be started during an acute attack in patients who meet criteria for starting urate-lowering therapy and have normal renal function 5.
• In patients with chronic kidney disease (CKD), low-dose allopurinol may promote greater serum urate lowering compared to normal kidney function, but the treatment challenge may be posed by a possible drug ceiling effect 6.
• Predictors of gout flares when starting allopurinol using the "start-low go-slow" dose escalation strategy include a gout flare in the month before starting allopurinol, allopurinol 100 mg starting dose, and serum urate ≥0.36 mmol/L at month 6 7.

Dosing Considerations

• The initial dose of allopurinol should be 100 mg/day, with gradual increases every 4 weeks until the target SUc level is achieved or adverse effects occur 3.
• The dose of allopurinol should be adjusted based on renal function, with lower doses recommended for patients with impaired renal function 4.
• The use of anti-inflammatory prophylaxis when starting allopurinol may be best targeted at patients who have had a gout flare in the month before starting allopurinol and are commencing allopurinol 100 mg daily 7.

Patient Selection

• Patients with primary gout, normal renal function, and no relevant liver disease are suitable candidates for allopurinol therapy 3.
• Patients with CKD may require lower doses of allopurinol and closer monitoring of serum urate levels 6.
• Patients with a history of gouty flares, particularly in the month before starting allopurinol, may require anti-inflammatory prophylaxis when starting allopurinol 7.