FEBUXOSTAT
Clinical safety rating: caution
Comprehensive clinical and safety monograph for FEBUXOSTAT (FEBUXOSTAT).
Febuxostat is a non-purine selective inhibitor of xanthine oxidase (XO). It inhibits both oxidized and reduced forms of XO, thereby reducing the conversion of hypoxanthine to xanthine and xanthine to uric acid, leading to decreased serum uric acid levels.
| Metabolism | Primarily metabolized by conjugation via UDP-glucuronosyltransferases (UGT1A1, UGT1A3, UGT1A9, and UGT2B7) and oxidation via cytochrome P450 (CYP) enzymes, including CYP1A2, CYP2C8, and CYP2C9, with minor contribution from CYP3A4/5. |
| Excretion | Renal: 1-3% unchanged; biliary/fecal: ~50% as metabolites (acyl glucuronides, oxidative metabolites); other: ~49% metabolized and eliminated via multiple pathways including biliary and direct intestinal excretion of unchanged drug. |
| Half-life | Terminal elimination half-life: 5-8 hours in healthy subjects; prolonged in renal impairment (e.g., up to 9.6 hours in moderate impairment). Clinical context: dosing interval is once daily, consistent with half-life. |
| Protein binding | 99% (primarily to albumin; minor binding to alpha-1-acid glycoprotein). |
| Volume of Distribution | Approximately 0.7 L/kg (indicating distribution into total body water; not extensively tissue-bound). |
| Bioavailability | Oral: at least 49% (absolute bioavailability not established; estimated based on mass balance studies). |
| Onset of Action | Oral: Reduction in serum urate observed within 2 weeks; full effect by 4-6 weeks. |
| Duration of Action | Duration of action: 24 hours (once-daily dosing maintains urate reduction). Clinical note: steady-state achieved in ~5-7 days. |
| Molecular Weight | 316.34 |
40 mg orally once daily; may increase to 80 mg orally once daily if serum urate goal not achieved after 2 weeks.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR 30-89 mL/min). For severe renal impairment (eGFR <30 mL/min), limited data; use with caution, not recommended in dialysis. |
| Liver impairment | Child-Pugh Class A or B: no dose adjustment. Child-Pugh Class C: not recommended (no studies). |
| Pediatric use | Not approved for pediatric use; safety and efficacy not established. |
| Geriatric use | No specific dose adjustment required; use with caution due to potential for decreased renal function. |
| 1st trimester | Insufficient human data; animal studies show no teratogenicity at therapeutic doses, but avoid unless clearly needed. |
| 2nd trimester | Insufficient human data; avoid unless benefit outweighs risk. |
| 3rd trimester | Insufficient human data; avoid unless benefit outweighs risk. |
Clinical note
Comprehensive clinical and safety monograph for FEBUXOSTAT (FEBUXOSTAT).
| Placental transfer | Probable transfer due to low molecular weight; exact degree unknown. |
| Breastfeeding | No human data on excretion in breast milk. The manufacturer recommends caution; consider alternative urate-lowering therapy if breastfeeding. |
| Lactation Rating |
■ FDA Black Box Warning
Increased risk of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent revascularization in patients with established cardiovascular disease (based on the CARES trial). Febuxostat should be avoided in patients with a history of myocardial infarction or stroke, unless no other therapy is appropriate.
| Serious Effects |
Concomitant use with azathioprineConcomitant use with mercaptopurineConcomitant use with theophylline
| Precautions | Cardiovascular events (see black box warning); hepatotoxicity (elevated liver enzymes, hepatic failure); gout flares upon initiation (prophylaxis recommended); renal impairment (dose adjustment for severe impairment); hypersensitivity reactions (including Stevens-Johnson syndrome); thyroid function abnormalities (elevated TSH). |
| Food/Dietary | No specific food interactions are reported, but high-purine foods (red meat, organ meats, shellfish) and alcohol may increase serum urate and counteract drug efficacy; advise moderation and limit intake during therapy. |
Loading safety data…
| L3 (Moderately Safe) based on limited animal data and low expected exposure due to high protein binding. |
| Teratogenic Risk | Pregnancy Category C. No adequate studies in pregnant women. In animal studies, febuxostat caused developmental toxicity (reduced fetal weight, increased skeletal variations) at maternal toxic doses. First trimester: unknown risk; avoid unless benefits outweigh risks. Second/third trimester: limited data; potential for fetal harm based on animal findings. |
| Fetal Monitoring | Monitor hepatic function (ALT, AST) and renal function (serum creatinine). Also monitor uric acid levels and signs of gout flares. No specific fetal monitoring required, but consider ultrasound for fetal growth if used in pregnancy. |
| Fertility Effects | In animal studies, no impairment of fertility was observed. Human data lacking; theoretical risk of reversible reproductive dysfunction based on drug class. |
| Clinical Pearls | Febuxostat is a non-purine selective xanthine oxidase inhibitor indicated for chronic management of hyperuricemia in gout. It is contraindicated with concomitant azathioprine, mercaptopurine, or theophylline due to risk of toxicity. Initiate at 40 mg daily; titrate to 80 mg if serum urate not at target after 2 weeks. Monitor for gout flares during initiation; provide prophylactic NSAIDs or colchicine for at least 6 months. Cardiovascular risk: increased risk of cardiovascular death vs allopurinol in patients with history of CV disease; avoid as first-line or in patients with prior MI or stroke. Assess liver function tests at baseline and periodically; discontinue if persistent elevation >3x ULN or signs of liver injury. Not recommended in patients with severe hepatic impairment (Child-Pugh C). |
| Patient Advice | Take exactly as prescribed; do not skip doses or stop without consulting your doctor. · You may experience gout flares during the first few months; continue your medication and take prescribed anti-inflammatory drugs as directed. · Report any signs of heart attack or stroke (chest pain, shortness of breath, weakness on one side of body, slurred speech) immediately. · Avoid alcohol, especially beer, which can increase uric acid levels and trigger gout flares. · Inform your doctor if you are taking azathioprine, mercaptopurine, or theophylline; these are not safe to take with febuxostat. · If you have a history of heart attack, stroke, or heart disease, discuss alternative treatments with your doctor. · Seek medical attention for signs of liver injury (yellow skin/eyes, dark urine, abdominal pain, persistent nausea). · Stay hydrated to help prevent kidney stones; aim for 8-10 glasses of water daily unless otherwise advised. · Do not crush or chew tablets; swallow whole with water. |