Febuxostat Drug is an orally available, non-purine inhibitor of xanthine oxidase with uric acid lowering activity. Upon oral administration, febuxostat selectively and noncompetitively inhibits the activity of xanthine oxidase, an enzyme that converts oxypurines, including hypoxanthine and xanthine, into uric acid. By inhibiting xanthine oxidase, uric acid production is reduced and serum uric acid levels are lowered. Febuxostat may provide protection against acute renal failure caused by the excessive release of uric acid that occurs upon massive tumor cell lysis resulting from the treatment of some malignancies.
Febuxostat is a xanathine oxidase (XO) inhibitor indicated in patients with gout suffering from hyperuricemia and is used in its chronic management. Febuxostat is not recommended for the treatment of asymptomatic hyperuricemia. Febuxostat was approved by the FDA in February 2009.
Mechanism of Action of Febuxostat Drug
Febuxostat is a non-purine-selective inhibitor of xanthine oxidase.It works by non-competitively blocking the molybdenum pterin center which is the active site on xanthine oxidase. Xanthine oxidase is needed to successively oxidize both hypoxanthine and xanthine to uric acid. Hence, febuxostat inhibits xanthine oxidase, therefore reducing the production of uric acid. Febuxostat inhibits both oxidized as well as a reduced form of xanthine oxidase because of which febuxostat cannot be easily displaced from the molybdenum pterin site. Febuxostat, a xanthine oxidase inhibitor, achieves its therapeutic effect by decreasing serum uric acid. Febuxostat is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic concentrations.
Indications of Febuxostat Drug
- Chronic, symptomatic Hyperuricemia
- Gout
- Chronic management of symptomatic hyperuricemia in patients with gout
- Gouty arthritis
- Multiple joints pain
- Osteoarthritis with edema
- For the treatment of hyperuricemia in patients with gout.
- Indicated for the treatment of chronic hyperuricemia in conditions where urate deposition has already occurred (including a history, or presence of, tophus and/or gouty arthritis).
- 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.
Contra Indications of Febuxostat Drug
Serious rash
- Postmarketing reports of serious rash and hypersensitivity reactions, including Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms
- Use with caution in patients with a history of stroke or myocardial infarction, preexisting cardiac disease, or other cardiac risk factors. In clinical trials, an increased incidence of thromboembolic cardiac events
- Use febuxostat with caution in patients with severe hepatic disease (Child-Pugh Class C) and in patients with elevated transaminase concentrations. Fatal and non-fatal hepatic failure as well as increases in transaminase concentrations above the upper limit of normal (ULN), specifically AST and ALT, have been observed.
- Use febuxostat with caution in patients with severe renal impairment (CrCl less than 30 mL/minute); dose adjustments are required. In a study of febuxostat in patients with varying degrees of renal function,
- Febuxostat is not recommended in patients with secondary hyperuricemia (e.g., after an organ transplant) or in patients with a greatly increased rate of uric acid synthesis (e.g., those with neoplastic disease, patients on chemotherapy, and patients with Lesch-Nyhan syndrome).
- Limited available data with the use of febuxostat in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes resulting from fetal exposure during pregnancy.
- Febuxostat should be used with caution during breast-feeding. There are no data on the presence of febuxostat in human milk, the effects on the breastfed infant, or the effects on milk production. Febuxostat is present in the milk of lactating rats at up to approximately 7 times the plasma concentration.
Dosages of Febuxostat Drug
- Strengths: 80 mg; 40 mg
Gout
- Initial dose: 40 mg orally once a day
- If serum uric acid level is greater than 6 mg/dL after 2 weeks, increase the dose to 80 mg orally once a day
- Maintenance dose: 40 to 80 mg orally once a day
Side Effects of Febuxostat Drug
The most common
- Acid or sour stomach
- anxiety
- bad, unusual, or unpleasant (after) taste
- blistering, crusting, irritation, itching, or reddening of the skin
- body aches or pain
- nausea,
- rash,
- joint pain,
- gout flares, and
- liver problems.
- stroke,
- heart attack,
- anemia,
- hepatitis,
- hypersensitivity, and
- weight loss.
Common
- Abdominal or stomach fullness or pain
- arm, back, or jaw pain
- nausea
- joint pain
- rash
- inaccurate liver function test results
- black, tarry stools
- bloody nose
- blurred vision
- chest pain or discomfort
Rare
- tiredness
- lack of appetite
- unexplained weight loss
- discomfort in the upper right part of your abdomen
- dark urine
- jaundice (yellowing of your skin or the whites of your eyes)
- chest pain
- shortness of breath
- discomfort in your upper body
- cold sweats
- nausea , vomiting
- sudden dizziness
- sudden, unexplained tiredness
- weakness or numbness in one part or side of your body
- slurred speech
- sudden confusion
- trouble seeing in one or both of your eyes
- sudden trouble walking, dizziness, or loss of balance or coordination
- sudden and unexplainable severe headache
Drug Interactions of febuxostat
Mercaptopurine/azathioprine
On the basis of the mechanism of action of febuxostat on XO inhibition concomitant use is not recommended.
Drug interaction studies of febuxostat with cytotoxic chemotherapy have not been conducted. No data is available regarding the safety of febuxostat during cytotoxic therapy.
Rosiglitazone/CYP2C8 substrates
Febuxostat was shown to be a weak inhibitor of CYP2C8 in vitro. In a study in healthy subjects, coadministration of 120 mg febuxostat QD with a single 4 mg oral dose of rosiglitazone had no effect on the pharmacokinetics of rosiglitazone and its metabolite N-desmethyl rosiglitazone, indicating that febuxostat is not a CYP2C8 enzyme inhibitor in vivo. Thus, co-administration of febuxostat with rosiglitazone or other CYP2C8 substrates is not expected to require any dose adjustment for those compounds.
An interaction study in healthy subjects has been performed with febuxostat to evaluate whether the inhibition of XO may cause an increase in the theophylline circulating levels as reported with other XO inhibitors. The results of the study showed that the co-administration of febuxostat 80 mg QD with theophylline 400 mg single dose has no effect on the pharmacokinetics or safety of theophylline. Therefore no special caution is advised when febuxostat 80 mg and theophylline are given concomitantly. No data is available for febuxostat 120 mg.
Naproxen and other inhibitors of glucuronidation
Febuxostat metabolism depends on Uridine Glucuronosyl Transferase (UGT) enzymes. Medicinal products that inhibit glucuronidation, such as NSAIDs and probenecid, could, in theory, affect the elimination of febuxostat. In healthy subjects, concomitant use of febuxostat and naproxen 250mg twice daily was associated with an increase in febuxostat exposure (Cmax28%, AUC 41%, and t1/2 26%).
Febuxostat can be co-administered with naproxen with no dose adjustment of febuxostat or naproxen being necessary.
Inducers of glucuronidation
Potent inducers of UGT enzymes might possibly lead to increased metabolism and decreased efficacy of febuxostat. Monitoring of serum uric acid is therefore recommended 1-2 weeks after start of treatment with a potent inducer of glucuronidation. Conversely, cessation of treatment of an inducer might lead to increased plasma levels of febuxostat.
Colchicine/indometacin/hydrochlorothiazide/warfarin
Febuxostat can be co-administered with colchicine or indomethacin with no dose adjustment of febuxostat or the co-administered active substance being necessary.
No dose adjustment is necessary for febuxostat when administered with hydrochlorothiazide.
No dose adjustment is necessary for warfarin when administered with febuxostat. Administration of febuxostat (80 mg or 120 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. INR and Factor VII activity were also not affected by the co-administration of febuxostat.
Desipramine/CYP2D6 substrates
Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro. In a study in healthy subjects, 120 mg ADENURIC QD resulted in a mean 22% increase in AUC of desipramine, a CYP2D6 substrate indicating a potential weak inhibitory effect of febuxostat on the CYP2D6 enzyme in vivo. Thus, co-administration of febuxostat with other CYP2D6 substrates is not expected to require any dose adjustment for those compounds.
Concomitant ingestion of an antacid containing magnesium hydroxide and aluminum hydroxide has been shown to delay absorption of febuxostat (approximately 1 hour) and to cause a 32% decrease in Cmax, but no significant change in AUC was observed. Therefore, febuxostat may be taken without regard to antacid use.
- didanosine
- mercaptopurine
- theophylline
Pregnancy & Lactation
FDA Pregnancy Category C
Pregnancy
This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.
Lactation
It is not known if febuxostat passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding.
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