Usage
- Febuxostat is prescribed for the chronic management of hyperuricemia in patients with gout. It is specifically indicated for patients who have an inadequate response to a maximally titrated dose of allopurinol, are intolerant to allopurinol, or for whom treatment with allopurinol is not advisable. It is not recommended for asymptomatic hyperuricemia. It is also indicated for the prevention and treatment of hyperuricemia in adult patients undergoing chemotherapy for hematologic malignancies at intermediate to high risk of Tumor Lysis Syndrome (TLS).
- Pharmacological classification: Xanthine oxidase inhibitor.
- Mechanism of action: Febuxostat inhibits xanthine oxidase, the enzyme responsible for converting hypoxanthine to xanthine and xanthine to uric acid. This inhibition reduces uric acid production, thereby lowering serum uric acid levels. It does not affect the synthesis of purines or pyrimidines.
Alternate Names
- International or regional variations: Adenuric.
- Brand names: Uloric.
How It Works
- Pharmacodynamics: Febuxostat reduces serum uric acid levels by selectively inhibiting xanthine oxidase. This leads to a decrease in urate deposition in joints and other tissues, thereby alleviating the symptoms of gout.
- Pharmacokinetics:
- Absorption: Febuxostat is well-absorbed after oral administration, with peak plasma concentrations reached within 1 to 1.5 hours. Administration with food or antacids does not significantly affect its overall absorption.
- Metabolism: Febuxostat undergoes hepatic metabolism via glucuronidation (UGT1A1, UGT1A3, UGT1A9, and UGT2B7) and oxidation (primarily CYP1A2, CYP2C8, and CYP2C9) to inactive metabolites.
- Elimination: Febuxostat is eliminated primarily through hepatic metabolism, with a small portion eliminated renally as unchanged drug or metabolites. The elimination half-life is approximately 5 to 8 hours.
- Mode of action: Febuxostat binds to the molybdopterin cofactor of xanthine oxidase, preventing the conversion of hypoxanthine and xanthine to uric acid.
- Receptor binding, enzyme inhibition, or neurotransmitter modulation: Febuxostat acts through non-competitive inhibition of xanthine oxidase.
- Elimination pathways: Primarily hepatic metabolism via glucuronidation and oxidation to inactive metabolites, followed by biliary and renal excretion.
Dosage
Standard Dosage
Adults:
- Initial dose: 40 mg orally once a day. If serum uric acid (sUA) is >6 mg/dL after 2 weeks, increase to 80 mg orally once a day. Alternatively, an initial dose of 80 mg orally once a day can be given, increased to 120 mg once daily if the serum uric acid is >6 mg/dL after 2-4 weeks.
- Maximum dose: For chronic gout management: 80 mg/day (some sources mention up to 120 mg). For tumor lysis syndrome prevention: 120 mg/day.
- Administration: Oral, with or without food.
Children:
- The safety and effectiveness of febuxostat in pediatric patients under 18 years of age have not been established. Use is not recommended.
Special Cases:
- Elderly Patients: No dose adjustment is necessary.
- Patients with Renal Impairment: Mild to moderate impairment: No adjustment necessary. Severe impairment (CrCl < 30 mL/min): Limit dose to 40 mg once daily.
- Patients with Hepatic Dysfunction: Mild to moderate impairment: No adjustment for mild impairment. Limited information is available for moderate impairment. Severe impairment: Not studied; use with caution. The maximum daily dose for mild impairment is 80 mg.
- Patients with Comorbid Conditions: Cardiovascular disease: use not recommended. Diabetes: Monitor glucose levels as indicated.
Clinical Use Cases
Febuxostat is not indicated for use in clinical cases like intubation, surgical procedures, mechanical ventilation, ICU use or emergency situations.
Dosage Adjustments
As described above, dose adjustments are necessary for renal and hepatic impairment. Monitor liver function tests and serum uric acid levels during therapy. For patients developing elevated ALT levels (more than 3 times the upper limit of normal), interrupt treatment and do not restart without another explanation for ALT abnormalities.
Side Effects
Common Side Effects
- Liver function test abnormalities
- Nausea
- Rash
- Arthralgia
- Gout flares (particularly during initial treatment)
- Diarrhea, headache, edema, fatigue.
Rare but Serious Side Effects
- Cardiovascular thromboembolic events (e.g., myocardial infarction, stroke)
- Hepatic failure (including fatal cases)
- Severe skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis)
- Allergic reactions
- Rhabdomyolysis
Long-Term Effects
Chronic complications from long-term febuxostat use are not well defined. Post-marketing reports indicate cases of impaired hepatic function, including fatal liver failure, and cardiovascular effects. Regular monitoring is important.
Adverse Drug Reactions (ADR)
- As noted above, cardiovascular events, severe hepatic dysfunction, serious skin reactions, and allergic reactions are potentially life-threatening ADRs requiring immediate intervention.
Contraindications
- Hypersensitivity to febuxostat.
- Concomitant use with azathioprine, mercaptopurine, didanosine, or theophylline.
Drug Interactions
- CYP450 interactions: Febuxostat is primarily metabolized by CYP1A2, CYP2C8, and CYP2C9, and may weakly inhibit CYP2D6. It is also a substrate of BCRP (breast cancer resistance protein).
- Clinically significant interactions: Increased levels of azathioprine, mercaptopurine, didanosine, and theophylline. Co-administration with these drugs is contraindicated due to risk of severe toxicity. Interactions with other medications, including rosuvastatin, methotrexate and others should be considered, however, no dosage adjustments are needed when coadministering naproxen, colchicine, indomethacin, hydrochlorothiazide, warfarin, or desipramine.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Australian TGA category: B1. US FDA: Not Assigned.
- Insufficient data available on use in pregnant women to inform drug-related risk. Animal studies do not indicate direct or indirect harmful effects. Potential risk for humans is unknown. Febuxostat should not be used during pregnancy unless the benefits outweigh the risks.
- It is unknown whether febuxostat is excreted in human breast milk. Animal studies have shown excretion in breast milk and impaired development in suckling offspring. Breastfeeding is not recommended while taking febuxostat.
Drug Profile Summary
- Mechanism of Action: Xanthine oxidase inhibitor, reducing uric acid production.
- Side Effects: Liver function abnormalities, nausea, rash, gout flares, joint pain, cardiovascular events (rare but serious).
- Contraindications: Hypersensitivity, concomitant use with azathioprine, mercaptopurine, didanosine, or theophylline.
- Drug Interactions: Azathioprine, mercaptopurine, didanosine, and theophylline (contraindicated); multiple moderate and minor interactions with other medications; monitor for potential drug interactions.
- Pregnancy & Breastfeeding: Not recommended unless potential benefit outweighs risk.
- Dosage: Adults: Initially 40 mg once daily, may increase to 80 mg; maximum dose 80 mg for gout, 120 mg for tumor lysis syndrome. Not recommended for children. Renal/hepatic adjustments needed.
- Monitoring Parameters: Serum uric acid, liver function tests (ALT, AST, bilirubin), complete blood count, renal function. For patients with cardiovascular risks, monitor cardiovascular status as well.
Popular Combinations
- Prophylactic co-administration with an NSAID or colchicine during initiation of febuxostat therapy (up to six months) to minimize gout flares.
Precautions
- General Precautions: Assess liver and kidney function, cardiovascular history, and concomitant medications before initiating therapy. Monitor for adverse events, especially gout flares, hepatic effects, and cardiovascular symptoms.
- Specific Populations: As noted above, caution should be used in pregnancy and breastfeeding, and use is not recommended in children. Dose adjustment is necessary for patients with renal or hepatic impairment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Febuxostat?
A: Adults: Initial dose is 40 mg once daily. May be increased to 80 mg once daily if serum uric acid remains > 6 mg/dL after two weeks. Some patients may begin at 80 mg daily and increase up to 120 mg daily if serum uric acid remains above target after 2-4 weeks. Maximum daily dose is generally 80 mg for gout, 120 mg for tumor lysis syndrome. Pediatric use is not recommended. Renal and hepatic adjustments may be required.
Q2: How does Febuxostat differ from Allopurinol?
A: Both are xanthine oxidase inhibitors, but febuxostat is a non-purine analog, while allopurinol is a purine analog. Febuxostat may be more effective in lowering sUA in some patients and is an alternative for those who cannot tolerate or do not respond to allopurinol. It is also associated with a different side effect profile.
Q3: What should be done if a gout flare occurs during Febuxostat treatment?
A: Febuxostat should not be discontinued. The gout flare should be managed concurrently with appropriate medications (e.g., NSAIDs, colchicine). Prophylactic treatment with an NSAID or colchicine is recommended during treatment initiation and can be continued for up to six months to minimize flares.
Q4: Is Febuxostat safe for patients with cardiovascular disease?
A: Febuxostat is not recommended for patients with a history of significant cardiovascular disease (e.g., myocardial infarction, stroke, unstable angina) due to an observed increased risk of cardiovascular events in some studies.
Q5: Are there any specific dietary restrictions with Febuxostat?
A: Febuxostat can be taken with or without food. However, general dietary recommendations for gout management, such as limiting purine-rich foods (e.g., organ meats, shellfish) and alcohol intake, still apply.
Q6: What are the most serious side effects of Febuxostat?
A: Rare but serious side effects include cardiovascular thromboembolic events (myocardial infarction, stroke), liver failure, severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), and allergic reactions. Patients should be advised to seek immediate medical attention if these occur.
Q7: Can Febuxostat be used during pregnancy or breastfeeding?
A: Febuxostat is generally not recommended during pregnancy or breastfeeding due to limited human data and potential risks identified in animal studies. It is not known if febuxostat crosses the placenta or is excreted into breast milk. Use only if benefits clearly outweigh the risks.
Q8: How long does it take for Febuxostat to start working?
A: Febuxostat lowers serum uric acid levels relatively quickly. Serum uric acid levels can be rechecked as early as two weeks after initiating therapy to assess the effectiveness of the initial dose.
Q9: Can Febuxostat be crushed or split?
A: While some tablets can be split or crushed, it is generally recommended to take febuxostat tablets whole as prescribed. It’s always best to check the specific product labeling or consult a pharmacist before modifying the form of the medication.
Q10: What is the role of Febuxostat in Tumor Lysis Syndrome?
A: Febuxostat at a dose of 120 mg daily is indicated for the prevention and treatment of hyperuricemia in patients undergoing chemotherapy for hematological malignancies at intermediate to high risk of Tumor Lysis Syndrome. It is typically initiated two days before the beginning of cytotoxic therapy and continued for a minimum of 7 days, potentially up to 9 days, depending on the chemotherapy duration.
