Goutil

Approved Indications:

• Chronic Management of Hyperuricemia in Gout:
  Febuxostat is indicated to lower serum uric acid levels in adult patients with gout who have inadequate response to or intolerance of allopurinol.
• Prevention of Gout Flares:
  Used as a long-term urate-lowering therapy in patients with recurrent attacks of gout, including tophi or joint damage due to uric acid crystal deposition.
• Hyperuricemia in Tumor Lysis Syndrome (off-label):
  Occasionally used off-label for preventing hyperuricemia associated with tumor lysis syndrome (TLS) in cancer patients undergoing chemotherapy.

Important Off-Label Uses:

• As a second-line urate-lowering agent in patients with mild to moderate chronic kidney disease (stage 2 or 3), especially if allopurinol is contraindicated or not tolerated.
• Cardiovascular risk reduction in hyperuricemic patients (investigational and not routinely recommended due to safety concerns).

Adults (General Gout Management):

• Initial dose: 40 mg once daily
• If serum uric acid >6 mg/dL after 2 weeks: Increase to 80 mg once daily
• Maximum dose: 80 mg/day
• Can be taken with or without food.

Prophylaxis of Gout Flares (Initial Phase):

• Co-administer NSAIDs or colchicine for at least 6 months when initiating febuxostat.

Renal Impairment:

• Mild to moderate (CrCl ≥30 mL/min): No dose adjustment needed.
• Severe (CrCl <30 mL/min): Use with caution; limited data available.

Hepatic Impairment:

• Mild (Child-Pugh A): No adjustment required.
• Moderate (Child-Pugh B): Use with caution.
• Severe (Child-Pugh C): Not recommended.

Elderly:

• No specific dosage adjustment required.

Pediatrics:

• Safety and efficacy not established.

Administration Notes:

• Oral administration; tablets should be swallowed whole.
• Continue therapy even during acute gout attacks (add treatment for the attack separately).

Febuxostat is a non-purine selective xanthine oxidase inhibitor. It reduces serum uric acid levels by inhibiting xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and then xanthine to uric acid. By blocking this enzyme, febuxostat decreases uric acid production without affecting other enzymes involved in purine and pyrimidine metabolism, offering a more selective and potent inhibition compared to allopurinol.

• Absorption:
  Rapidly absorbed orally; bioavailability approximately 49%.
• Peak Plasma Concentration (Tmax):
  Reached within 1 to 1.5 hours after oral dose.
• Distribution:
  Highly protein bound (~99.2%), mainly to albumin.
• Metabolism:
  Extensively metabolized in the liver via:
• Uridine diphosphate glucuronosyltransferase (UGT1A1, UGT1A3, UGT1A9)
• CYP450 enzymes: CYP1A2, CYP2C8, and CYP2C9
• Elimination Half-life:
  Approximately 5 to 8 hours
• Excretion:
• Urine (49%) – as metabolites
• Feces (45%) – mainly as metabolites

• Pregnancy:
  Classified as Pregnancy Category C. Animal studies show adverse effects on the fetus; no adequate studies in pregnant women. Use only if potential benefit justifies the potential risk.
• Lactation:
  Unknown whether febuxostat is excreted into human milk. Due to potential for serious adverse reactions in infants, caution is advised; either discontinue the drug or discontinue nursing depending on clinical need.

• Primary Class: Antigout Agent
• Subclass: Xanthine Oxidase Inhibitor (non-purine type)

• Known hypersensitivity to febuxostat or any excipients
• Concomitant use with azathioprine or mercaptopurine
• Severe hepatic impairment (Child-Pugh C)
• History of severe cardiovascular disease (e.g., myocardial infarction or stroke) – use discouraged

• Cardiovascular Risk:
  May increase risk of cardiovascular death compared to allopurinol. Avoid in patients with pre-existing heart disease.
• Gout Flares on Initiation:
  Uric acid mobilization during initiation may trigger gout flares. Prophylaxis is recommended.
• Severe Hypersensitivity Reactions:
  Rare cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and other serious reactions reported.
• Hepatic Impairment:
  Monitor liver function tests periodically during treatment.
• Renal Impairment:
  Use with caution in severe renal impairment.
• Thromboembolic Events:
  Monitor for signs of thrombosis in patients at risk.

Common Adverse Effects:

• Musculoskeletal: Arthralgia, gout flares
• Hepatic: Elevated liver enzymes (ALT/AST)
• Gastrointestinal: Nausea, diarrhea
• Skin: Rash

Less Common or Serious Effects:

• Liver function abnormalities
• Hypersensitivity reactions (rash, facial swelling)
• Cardiovascular events (myocardial infarction, stroke)
• Anemia
• Thrombocytopenia

Rare Effects:

• Severe skin reactions (SJS, TEN)
• Agranulocytosis
• Rhabdomyolysis

Major Interactions:

• Azathioprine / Mercaptopurine:
  Risk of severe toxicity due to inhibition of their metabolism. Contraindicated.
• Theophylline:
  Possible increase in theophylline levels due to CYP inhibition—monitor if co-administered.
• Warfarin:
  Mild elevation of INR reported. Monitor coagulation parameters.

Food & Alcohol:

• No clinically significant food interaction.
• Alcohol may increase uric acid production—limit or avoid.

Metabolism Enzymes Involved:

• CYP1A2, CYP2C8, CYP2C9 (minor involvement)
• UGT enzymes (major pathway)

• FDA Black Box Warning (2019):
  Added for increased risk of cardiovascular death compared to allopurinol; recommend avoiding febuxostat in patients with established cardiovascular disease unless no other treatment options are suitable.
• Updated ACR Gout Guidelines:
  Febuxostat may be used as second-line urate-lowering therapy if allopurinol is not tolerated. Cardiovascular risks must be evaluated prior to initiation.
• EMA Recommendations:
  Similar cardiovascular safety concerns raised; prescribers are advised to use caution in high-risk patients.

• Storage Temperature:
  Store at 20°C to 25°C (68°F to 77°F)
• Allowable Excursion:
  Permitted between 15°C to 30°C (59°F to 86°F)
• Humidity & Light:
  Protect from excessive moisture. Store in a dry place, away from direct light.
• Handling:
  Keep in original container. No special reconstitution or refrigeration required.