TAZOTAX

Febuxostat is a non-purine xanthine oxidase (XO) inhibitor.

In early 2008, febuxostat was granted marketing authorization by the European Commission for the treatment of chronic hyperuricemia and gout.

In the following year, the FDA for approved febuxostat for use in the chronic management of hyperuricemia in adult patients with gout who have an inadequate response or intolerance to allopurinol.

Gout is a form of arthritis that is caused by the accumulation of uric acid crystal in or around a joint, leading to inflammation and further deposition of uric acid crystal deposition in bones, joints, tissues, and other organs in the long term.

Gout is closely associated with hyperuricemia.

Febuxostat works by inhibiting the activity of an enzyme that is responsible for the synthesis of uric acid, thereby reducing serum uric acid levels.

In February 2019, a black box warning for febuxostat was added, based on the findings of a post-market clinical study (the CARES trial) where there was an increased risk of cardiovascular (CV) fatal outcomes in patients with gout and known cardiovascular disease treated with febuxostat, when compared to those treated with allopurinol.

The manufacturer and the

FDA advise health professionals to limit the use of febuxostat to second-line therapy in patients who have inadequate response or intolerance to allopurinol, and to avoid the use of febuxostat in patients with cardiovascular diseases. 1, 9.

Febuxostat is indicated for the chronic management of hyperuricemia in adult patients with gout who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or for whom treatment with allopurinol is not advisable.

It is not recommended for the treatment of asymptomatic hyperuricemia 10 or secondary hyperuricemia.

Febuxostat is a novel, selective xanthine oxidase/dehydrogenase inhibitor that works by decreasing serum uric acid in a dose-dependent manner.

In healthy subjects, febuxostat decreased the mean serum uric acid and serum xanthine concentrations, as well as the total urinary uric acid excretion.

Febuxostat at daily doses of 40-80 mg reduced the 24-hour mean serum uric acid concentrations by 40-55%.

Closely related to the drug-induced reduction of serum uric acid levels and mobilization of urate crystals in tissue deposits, febuxostat is associated with gout flares.

Unlike allopurinol and oxypurinol, febuxostat has no inhibitory actions against other enzymes involved in purine and pyrimidine synthesis and metabolism, because it does not structurally resemble purines or pyrimidines.

After oral administration, about 85% of febuxostat is absorbed rapidly.

T max ranges from 1-1.5 hours.

Following once-daily oral administration, C max was approximately 1.6 ± 0.6 mcg/mL at a dose of 40 mg febuxostat and 2.6 ± 1.7 mcg/mL at a dose of 80 mg febuxostat.

A high-fat meal decreased

C max by 49% and AUC by 18%, but there were no clinically significant changes in the ability of febuxostat to decrease serum uric acid concentrations.

The apparent steady-state volume of distribution (V ss /F) of febuxostat ranges from 29-75 L, indicating a low to medium volume of distribution.

Febuxostat is metabolized in the liver by UDP-glucuronosyltransferase (UGT) and Cytochrome P450 (CYP) enzymes, with the relative contribution of each enzyme isoform in the metabolism of febuxostat not fully elucidated.

UGT1A1, UGT1A3, UGT1A9, and UGT2B7 mediate conjugation of febuxostat, 10 which approximately accounts for 22–44% of the metabolism of the total dose administered, to produce the acyl-glucuronide metabolite.

CYP1A2, CYP2C8, CYP2C9, and non-P450 enzymes are responsible for the oxidation reaction, which accounts for 2-8% of the metabolism of the dose.

Oxidation reaction produces 67M-1, 67M-2, and 67M-4, which are pharmacologically active metabolites. 67M-1, 67M-2, and 67M-4 can further undergo glucuronidation and sulfation.

Hydroxy metabolites are present in human plasma at much lower concentrations than the parent drug.

Hover over products below to view reaction partners Febuxostat Febuxostat acyl-glucuronide 67M-1 + 67M-2 67M-4.

Febuxostat is eliminated via both hepatic and renal pathways.

Following oral administration of 80 mg radiolabeled febuxostat, approximately 49% of the dose was recovered in the urine.

In urine, about 3% of the recovered dose accounted for unchanged febuxostat, 30% accounted for the acyl glucuronide metabolite, 13% accounted for oxidative metabolites and their conjugates, and 3% accounted for unidentified metabolites.

Approximately 45% of the total dose was recovered in the feces, where 12% of the dose accounted for the unchanged parent drug.

About 1% accounted for the acyl glucuronide metabolite, 25% accounted for oxidative metabolites and their conjugates, and 7% accounted for unidentified metabolites.

The apparent mean terminal elimination half-life of approximately 5-8 hours.

Following oral administration of single doses of 10-240 mg, the mean apparent total clearance ranged from 10-12 L/h.

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Oral lowest published toxic dose (TDLO) in humans is 1.82 mg/kg/14D (intermittent).

LD is 300 mg/kg in mice, 3200 mg/kg in rabbits, and 980 mg/kg in rats.

No dose-limiting toxicities were observed with febuxostat administered at doses up to 300 mg daily for seven days in healthy subjects.

There are no reports of overdose of febuxostat in clinical studies and there is no known antidote.

Overdose should be managed by symptomatic and supportive care.

Febuxostat tablets are contraindicated in patients being treated with azathioprine or mercaptopurine.

Recommended dosage is 40 mg or 80 mg once daily.

The recommended starting dosage is 40 mg once daily.

For patients who do not achieve a serum uric acid (sUA) less than 6 mg/dL after 2 weeks, the recommended dosage is 80 mg once daily.

Patients with severe renal impairment

Limit the dosage to 40 mg once daily.

Flare prophylaxis is recommended upon initiation of febuxostat tablets.

Can be administered without regard to food or antacid use. 2.1 Recommended Dosage The recommended febuxostat tablets dosage is 40 mg or 80 mg once daily.

The recommended starting dosage of febuxostat tablets is 40 mg once daily.

For patients who do not achieve a serum uric acid (sUA) less than 6 mg/dL after two weeks, the recommended febuxostat tablets dosage is 80 mg once daily.

Febuxostat tablets can be taken without regard to food or antacid use.

Concurrent prophylactic treatment with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended. 2.2 Dosage Recommendations in Patients with Renal Impairment and Hepatic Impairment The recommended dosage of febuxostat tablets is limited to 40 mg once daily in patients with severe renal impairment.

No dose modification is necessary when administering febuxostat tablets in patients with mild or moderate renal impairment.

No dosage modification is necessary in patients with mild to moderate hepatic impairment. 2.3 Serum Uric Acid Level Monitoring Testing for the target serum uric acid level of less than 6 mg/dL may be performed as early as two weeks after initiating febuxostat tablets therapy. 2.4 Recommended Prophylaxis for Gout Flares Gout flares may occur after initiation of febuxostat tablets due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits.

Flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended upon initiation of febuxostat tablets.

Prophylactic therapy may be beneficial for up to six months.

If a gout flare occurs during febuxostat tablets treatment, febuxostat tablets need not be discontinued.

The gout flare should be managed concurrently, as appropriate for the individual patient.

Tablets 40 mg are light yellow to yellow color, biconvex round shaped film-coated tablets debossed with “FEB” on one side and “40” on the other side.

Bottle of 30’s NDC 59651-113-30 Bottle of 90’s NDC 59651-113-90 Bottle of 500’s NDC 59651-113-05 Febuxostat Tablets 80 mg are light yellow to yellow color, biconvex oval shaped film-coated tablets debossed with “FEB” on one side and “80” on the other side.

Bottle of 30’s NDC 59651-114-30 Bottle of 90’s NDC 59651-114-90 Bottle of 100’s NDC 59651-114-01 Bottle of 500’s NDC 59651-114-05 Store at 20° to 25°C (68° to 77°F) .

Protect from light.

Limited available data with febuxostat use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes.

No adverse developmental effects were observed in embryo-fetal development studies with oral administration of febuxostat to pregnant rats and rabbits during organogenesis at doses that produced maternal exposures up to and 51 times, respectively, the exposure at the maximum recommended human dose (MRHD).

No adverse developmental effects were observed in a pre.

• and postnatal development study with administration of febuxostat to pregnant rats from organogenesis through lactation at an exposure approximately 11 times the MRHD.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days to 17, febuxostat was not teratogenic and did not affect fetal development or survival at exposures up to approximately 40 times the MRHD (on an AUC basis at maternal oral doses up to 48 mg/kg/day).

In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation Days to 18, febuxostat was not teratogenic and did not affect fetal development at exposures up to approximately 51 times the MRHD (on an AUC basis at maternal oral doses up to 48 mg/kg/day).

In a pre.

• and postnatal development study in pregnant female rats dosed orally from gestation Day 7 through lactation Day 20, febuxostat had no effects on delivery or growth and development of offspring at a dose approximately 11 times the MRHD (on an AUC basis at a maternal oral dose of 12 mg/kg/day).

However, increased neonatal mortality and a reduction in neonatal body weight gain were observed in the presence of maternal toxicity at a dose approximately 40 times the MRHD (on an AUC basis at a maternal oral dose of 48 mg/kg/day).

Febuxostat crossed the placental barrier following oral administration to pregnant rats and was detected in fetal tissues.

Safety and effectiveness of febuxostat in pediatric patients have not been established.

No dose adjustment is necessary in elderly patients.

Of the total number of patients in Studies 1, 2, and 3 (clinical studies of febuxostat in the treatment of gout) , 16% were and over, while 4% were and over.

Comparing patients in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out.

The C max and

AUC of febuxostat following multiple oral doses of febuxostat in geriatric patients (≥65 years) were similar to those in younger patients (18 to 40 years) .