How should the dose of allopurinol be adjusted in patients with impaired renal function?

From the Guidelines

Allopurinol dosing should be adjusted in patients with impaired renal function to prevent toxicity, with the maximum dose adjusted according to creatinine clearance, as recommended by the 2016 updated EULAR evidence-based recommendations for the management of gout 1. The adjustment of allopurinol dose in patients with renal impairment is crucial to minimize the risk of severe cutaneous adverse reactions (SCARs), which have a high mortality rate of 25-30% 1. Key considerations for dose adjustment include:

• Starting with a low dose and gradually titrating upwards to achieve target serum uric acid levels, typically <6 mg/dL
• Monitoring renal function, liver enzymes, and complete blood count regularly during dose adjustments
• Being aware of the increased risk of SCARs in patients with renal impairment and the potential for febuxostat to be a therapeutic alternative in these patients 1
• Following local Summary of Product Characteristics for dose recommendations in renal disease, as they may differ across countries 1 The most recent and highest quality study, the 2016 updated EULAR evidence-based recommendations for the management of gout, provides guidance on adjusting the maximum dose of allopurinol according to creatinine clearance in patients with renal impairment 1. Some key points to consider when adjusting the dose include:
• For patients with creatinine clearance (CrCl) 60-90 mL/min, start with 200-300 mg daily
• For CrCl 30-60 mL/min, use 200 mg daily
• For CrCl 15-30 mL/min, use 100 mg daily
• For CrCl <15 mL/min, start with 100 mg every other day or 50 mg daily It is essential to note that the dose recommendations may vary depending on the patient's specific condition and the availability of therapeutic alternatives, such as febuxostat or pegloticase 1.

From the FDA Drug Label

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 In patients with severely impaired renal function or decreased urate clearance, the half-life of oxipurinol in the plasma is greatly prolonged. Therefore, a dose of 100 mg per day or 300 mg twice a week, or perhaps less, may be sufficient to maintain adequate xanthine oxidase inhibition to reduce serum urate levels Allopurinol and its primary active metabolite, oxipurinol, are eliminated by the kidneys; therefore, changes in renal function have a profound effect on dosage In patients with decreased renal function or who have concurrent illnesses which can affect renal function such as hypertension and diabetes mellitus, periodic laboratory parameters of renal function, particularly BUN and serum creatinine or creatinine clearance, should be performed and the patient’s dosage of allopurinol tablets reassessed With a creatinine clearance of 10 to 20 mL/min, a daily dosage of 200 mg of allopurinol tablets is suitable. When the creatinine clearance is less than 10 mL/min, the daily dosage should not exceed 100 mg. With extreme renal impairment (creatinine clearance less than 3 mL/min) the interval between doses may also need to be lengthened

The dose of allopurinol should be adjusted in patients with renal impairment as follows:

• For patients with a creatinine clearance of 10 to 20 mL/min, a daily dosage of 200 mg is suitable.
• For patients with a creatinine clearance less than 10 mL/min, the daily dosage should not exceed 100 mg.
• For patients with extreme renal impairment (creatinine clearance less than 3 mL/min), the interval between doses may also need to be lengthened. It is also recommended to start with a low dose and gradually increase as needed, while monitoring renal function and serum uric acid levels 2 2. Key considerations for dose adjustment include:
• Renal function: Patients with decreased renal function require lower doses of allopurinol.
• Serum uric acid levels: The dose of allopurinol should be adjusted to maintain serum uric acid levels within the normal range.
• Concurrent illnesses: Patients with concurrent illnesses that can affect renal function, such as hypertension and diabetes mellitus, should be monitored closely.

From the Research

Allopurinol Dose Adjustment in Renal Impairment

• The dose of allopurinol should be adjusted in patients with impaired renal function to minimize the risk of adverse events, including allopurinol hypersensitivity syndrome (AHS) 3.
• The adjustment of allopurinol dose should be based on creatinine clearance, rather than plasma creatinine levels, as the latter may not accurately reflect renal function 4.
• Current guidelines recommend gradual introduction of allopurinol, with close monitoring of serum uric acid concentrations, and dose escalation above recommended levels may be considered in patients with severe disease and persistent hyperuricemia 3.

Dose Adjustment Strategies

• One study suggests that the initial dosage of allopurinol should be low, particularly in patients with renal impairment, and then increased slowly until plasma concentrations of urate are sufficient to dissolve monosodium urate crystals (≤ 0.36 mmol/L) 5.
• Another study found that dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricemia in patients with gout, and that higher doses may be necessary to achieve target serum urate levels 6.
• Increasing the dose of allopurinol above the proposed creatinine clearance-based dose has been shown to be effective and safe in patients with chronic gout, including those with renal impairment 7.

Key Considerations

• Patients with renal impairment are at increased risk of AHS, and careful monitoring is necessary when adjusting allopurinol doses in these patients 3, 4.
• The use of allopurinol dose escalation should be individualized, taking into account the patient's renal function, serum urate levels, and other factors 5, 6, 7.
• Further research is needed to clarify the safety and efficacy of allopurinol dose escalation in patients with renal impairment 3, 6, 7.