Buxstat

Uses

Buxstat is used for the long-term management of Hyperuricemia in patients with gout. It is not recommended for use in the treatment of asymptomatic Hyperuricemia.

Buxstat is also used to associated treatment for these conditions: Chronic, symptomatic Hyperuricemia

How Buxstat works

Gout is a form of acute arthritis that is characterized by the accumulation of crystals of monosodium urate and urate crystals in or around a joint, leading to inflammation and persistent urate crystal deposition in bones, joints, tissues, and other organs that may exacerbate over time. Hyperuricemia is closely related to gout, whereby it may exist for many years before the first clinical attack of gout; thus, aberrated serum uric acid levels and hyperuricemia are believed to be the biochemical aberration involved in the pathogenesis of gout. Xanthine oxidoreductase (XOR) can act as a xanthine oxidase or xanthine dehydrogenase. In humans, it is a critical enzyme for uric acid production as it catalyzes the oxidation reaction steps from hypoxanthine to xanthine and from xanthine to uric acid in the pathway of purine metabolism. Buxstat potently inhibits XOR, blocking both its oxidase and dehydrogenase activities. With high affinity, febuxostat binds to XOR in a molecular channel leading to the molybdenum-pterin active site, where allopurinol demonstrates relatively weak competitive inhibition.

XOR is mainly found in the dehydrogenase form under normal physiological conditions; however, in inflammatory conditions, XOR can be converted into the xanthine oxidase form, which catalyzes reactions that produce reactive oxygen species (ROS), such as peroxynitrite. ROS contribute to vascular inflammation and alterations in vascular function. As febuxostat can inhibit both forms of XOR, it can inhibit ROS formation, oxidative stress, and inflammation. In a rat model, febuxostat suppressed renal ischemia-reperfusion injury by attenuating oxidative stress.

Dosage

Buxstat dosage

The recommended starting dosage of Buxstat is 40 mg once daily. For patients who do not achieve a serum uric acid concentration of less than 6 mg/dL after 2 weeks at the 40 mg dose, Buxstat 80 mg once daily is recommended. Buxstat can be administered without regard to food or antacid use.

Side Effects

The most common adverse events associated with the use of Buxstat may include liver function abnormalities, nausea, arthralgia, and rash.

Toxicity

Oral lowest published toxic dose (TDLO) in humans is 1.82 mg/kg/14D (intermittent). Oral LD₅₀ 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.

Precaution

Gout Flare: An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including Buxstat. If a gout flare occurs during treatment, Buxstat need not be discontinued. Prophylactic therapy (i.e., non-steroidal anti-inflammatory drug (NSAID) or colchicine upon initiation of treatment) may be beneficial for up to six months.

Cardiovascular Events: A higher rate of cardiovascular thromboembolic events was observed in patients treated with febuxostat than allopurinol in clinical trials. Monitor for signs and symptoms of MI and stroke.

Liver Enzyme Elevation: Transaminase elevations have been observed in febuxostat -treated patients. Monitor liver function tests periodically.

Interaction

Concomitant administration of Buxstat with azathioprine, mercaptopurine or theophylline could increase plasma concentrations of these drugs resulting in severe toxicity.

Food Interaction

• Take with or without food. A high fat meal decreases Cmax and AUC in a clinically insignificant way.

Buxstat Drug Interaction

Unknown: aspirin, aspirin, rosuvastatin, apixaban, omega-3 polyunsaturated fatty acids, furosemide, atorvastatin, metoprolol, metoprolol, esomeprazole, amlodipine, omega-3 polyunsaturated fatty acids, acetaminophen, clopidogrel, acetaminophen, multivitamin, cyanocobalamin, ascorbic acid, cholecalciferol, rivaroxaban

Buxstat Disease Interaction

Major: secondary hyperuricemiaModerate: CV disease, renal dysfunction, hepatic impairment

Volume of Distribution

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

Elimination Route

After oral administration, about 85% of febuxostat is absorbed rapidly. T_max ranges from 1 to 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.

Half Life

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

Clearance

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

Elimination Route

Buxstat 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.

Pregnancy & Breastfeeding use

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Buxstat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: It is not known whether this drug is excreted in human milk. Caution should be exercised when Buxstat is administered to a nursing woman.

Contraindication

Buxstat is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline.

Special Warning

Pediatric Use: Safety and effectiveness in pediatric patients under 18 years of age have not been established

Acute Overdose

Febustat was studied in healthy subjects in doses up to 300 mg daily for seven days without evidence of dose-limiting toxicities.

Storage Condition

Keep out of the reach of children. Keep in a cool & dry place, protected from light.

Innovators Monograph

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