Uric acid is the end product of the metabolism of purines in humans and is formed by the following reaction: hypoxanthine â†’ xanthine â†’ uric acid. Xanthine oxidase is a catalyst for both steps of this reaction. Febuxostat is a derivative of 2-arylthiazole. Its therapeutic effect is associated with a decrease in serum uric acid concentration by selectively suppressing xanthine oxidase. Fabuxostat is a potent and selective non-panin inhibitor of xanthine oxidase (NP-SIXO), its in vitro inhibitory constant (Ki) is <1 nM. Febuxostat has been shown to significantly inhibit the activity of both oxidized and reduced forms of xanthine oxidase. At therapeutic concentrations, febuxostat affects other enzymes involved in the metabolism of purines or pyrimidines, such as guanine deaminase, hypoxanthine anguanine phosphoribosyl transferase, orotidin monophosphate decarboxylase or purine nucleoside phosphorylase.
Clinical efficacy and safety
The efficacy of Adenurik was confirmed in phase III of the three main studies (2 main studies of APEX and FACT and an additional study of CONFIRMS, described below), including 4101 patients with hyperuricemia and gout. In each of these basic studies of phase III, Adenurik more effectively reduced the plasma concentration of uric acid and maintained it at the proper level compared to allopurinol. In both studies, the primary endpoint of efficacy was the proportion of patients whose serum uric acid concentration did not exceed 6.0 mg / dL (357 Âµmol / L) during the last 3 months. In an additional phase III CONFIRMS study, the results of which became available after the first registration of the drug, the primary end point of effectiveness was the proportion of patients whose plasma uric acid concentration did not exceed 6.0 mg / dl at the time of the last visit. These studies did not include patients undergoing organ transplantation.
APEX study. A randomized, double-blind, multicenter study of the efficacy of febuxostat with placebo control and allopurinol phase III (Allopurinol and Placebo-Controlled APEX) lasted 28 weeks. A total of 1072 patients were randomized: placebo (n = 134), Adenurik at a dose of 80 mg 1 time per day (n = 267), Adenurik at a dose of 120 mg 1 time per day (n = 269), Adenurik at a dose of 240 mg 1 time day (n = 134) and allopurinol (at a dose of 300 mg 1 time per day (n = 258) in patients with baseline serum creatinine concentration> 1.5 mg / dL or 100 mg 1 time per day (n = 10) in patients with serum creatinine baseline> 1.5 and â‰¤ 2.0 mg / dL). To assess the safety of febuxostat administered at a dose of 240 mg (2 times higher than the maximum recommended dose).
The APEX study showed a statistically significant advantage of both treatment regimens of Adenurik at a dose of 80 mg 1 time per day and Adenurik at a dose of 120 mg 1 time per day compared with allopurinol at a usual dose of 300 mg (n = 258) / 100 mg (n = 10) in reducing the plasma concentration of uric acid <6 mg / dL (357 Î¼mol / l) (Table 1).
FACT study. A febuxostat efficacy study with allopurinol-control (The Febuxostat Allopurinol Controlled Trial, FACT) Phase III - a randomized, double-blind, multicenter study of 52 weeks duration. A total of 760 patients were randomized to groups: Adenurik at a dose of 80 mg 1 time per day (n = 256), Adenurik at a dose of 120 mg 1 time per day (n = 251) and allopurinol 300 mg 1 time per day (n = 253).
The FACT study showed a statistically significant advantage of both regimens (Adenurik at a dose of 80 mg 1 time per day and Adenurik at a dose of 120 mg 1 time per day) compared with allopurinol at a usual dose of 300 mg in reducing and maintaining serum uric acid concentrations <6 mg / for (357 Âµmol / l).
treatment of chronic hyperuricemia in patients with diseases accompanied by deposition of urate crystals, including in the presence of tophi and / or gouty arthritis at present or in history.
Adenurik at a dose of 120 mg
Treatment and prevention of hyperuricemia in adult patients undergoing chemotherapy for hematologic malignant neoplasms with moderate or high risk of SLO.
Adenurik is indicated for adult patients.
gout. The recommended dose of Adenurika is 80 mg 1 time per day orally, regardless of the meal. If the concentration of uric acid in the blood serum exceeds 6 mg / dL (357 Î¼mol / l) after 2-4 weeks of treatment, the dose of Adenurik can be increased to 120 mg once a day.
The effect of the drug occurs fairly quickly, which makes it possible to re-determine the concentration of uric acid after 2 weeks. The goal of treatment is to reduce the concentration of uric acid and maintain it at a level of <6 mg / dL (357 Âµmol / L).
The duration of prevention of gout attacks is at least 6 months.
SLO. The recommended dose of Adenurika is 120 mg orally, once a day, regardless of the meal. The use of Adenurik should begin 2 days before the start of cytotoxic therapy and continue for at least 7 days; however, therapy can be extended to 9 days in accordance with the duration of chemotherapy and clinical evaluation.
Renal failure. Patients with impaired renal function do not require mild or moderate dose adjustment. In patients with severe impaired renal function (creatinine clearance <30 ml / min), the efficacy and safety of the drug has not been adequately studied.
Liver dysfunction. A study of the efficacy and safety of febuxostat in patients with severely impaired liver function (class C on the Child-Pugh scale) was not conducted.
Gout: in mild abnormal liver function, the recommended dose is 80 mg. Experience with the use of the drug in violation of the liver function is moderately limited.
SLO. Only subjects with severe hepatic insufficiency were excluded from the Phase III baseline study (FLORENCE). For patients who were included in the study, dose adjustment due to the state of liver function is not required.
Patients of advanced age. For this category of patients, dose adjustment is not required.
Patients undergoing organ transplantation. Experience in the use of febuxostat in this category of patients is not, therefore, the use of the drug is not shown.