Febuxostat

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Listed in ZINC15

Breast Feeding; Lactation; Milk, Human; Antigout Agents; Gout Suppressants

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

183.6 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID8048650]

180.6 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

179.28 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

This chemical does not meet GHS hazard criteria for 5.9% (1 of 17) of reports.

Warning

H302 (88.2%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P263, P264, P270, P273, P301+P317, P318, P319, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 17 reports by companies from 7 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Liver test abnormalities have been reported to occur in 2% to 13% (average ~3.5%) of patients receiving febuxostat, but the levels are generally mild-to-moderate and self-limited. The height, nature and timing of these abnormalities have not been described. However, liver test elevations were the major reason for febuxostat discontinuation for adverse events (~2%) in clinical trials, despite the fact that no cases of jaundice or acute hepatitis were reported. Since its approval and more wide-scale use, there have been several individual case reports of liver injury attributed to febuxostat. Most cases have been marked by serum aminotransferase elevations without jaundice arising within days of starting febuxostat, including enzyme elevations in the setting of DRESS syndrome. At least one instance of a mixed-cholestatic hepatitis without immunoallergic features, arising after several months of treatment has been described. The product label for febuxostat lists hepatic steatosis, hepatitis and hepatomegaly as potential side effects. Furthermore, several cases of acute liver failure during febuxostat therapy have been reported to pharmacovigilance databases. Another unrelated, nonpurine xanthine oxidase inhibitor (benzbromarone) was not approved for use in the United States because of its potential for hepatic toxicity.

M04AA03

M - Musculo-skeletal system

QM - Musculo-skeletal system

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 to 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.

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. Febuxostat 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.