Febuxostat with Hydroxyurea: Managing Hyperuricemia
Febuxostat is used alongside hydroxyurea to prevent or treat hyperuricemia (elevated uric acid), which occurs because hydroxyurea causes rapid cell turnover and can temporarily impair renal tubular function, both of which elevate serum uric acid levels. 1
Mechanism of Hyperuricemia with Hydroxyurea
- Hydroxyurea causes temporary impairment of renal tubular function accompanied by elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine 1
- The medication increases cell turnover as part of its therapeutic mechanism, releasing purines that are metabolized to uric acid 1
- This elevation in serum uric acid may require dosage adjustment of uricosuric medication or xanthine oxidase inhibitors 1
Role of Febuxostat
- Febuxostat is a potent, non-purine selective xanthine oxidase inhibitor that blocks the enzyme responsible for converting purines to uric acid 2, 3
- It demonstrates superior ability to lower and maintain serum urate levels below 6 mg/dL compared with conventional doses of allopurinol 2
- Dose adjustment appears unnecessary in patients with mild to moderate renal or hepatic insufficiency, making it particularly useful in sickle cell disease patients who may have compromised kidney function 2
Clinical Context in Sickle Cell Disease
- Hydroxyurea is dosed at 15-20 mg/kg/day initially, titrating to maximum tolerated dose of 20-35 mg/kg/day 4
- The medication should be continued without interruption unless dose-limiting myelosuppression occurs 5
- Monitoring includes complete blood count with reticulocyte count every 2-4 weeks during dose titration and every 1-3 months on stable dosing 5
Alternative: Allopurinol
- Allopurinol is the traditional first-line xanthine oxidase inhibitor with over 40 years of safety data 1, 2
- However, febuxostat may be preferred in patients with renal insufficiency (common in sickle cell disease) or those who cannot tolerate allopurinol 2, 6
- Febuxostat at 40 mg daily has been shown to increase estimated glomerular filtration rate in patients with stage 3/4 chronic kidney disease over 12 months of treatment 6
Important Caveats
- The most common adverse reactions with febuxostat include abnormal liver function tests, headache, diarrhea, nausea, vomiting, and abdominal pain 2, 3
- Febuxostat carries an FDA black box warning regarding cardiovascular death risk in patients with established cardiovascular disease, though this remains controversial 1
- For patients with cardiovascular disease history, switching to allopurinol should be considered if febuxostat is being used 1
- Prophylaxis with colchicine or NSAIDs is required when initiating febuxostat, as aggressive uric acid lowering triggers gout flares for a prolonged period 2