Febuxostat

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Clinical Pharmacology

Uric acid is the end product of the metabolism of purines in humans and is formed by the following reaction: hypoxanthine → xanthine → 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. Febuxostat is a potent and selective non-purine xanthine oxidase inhibitor (NP-SIXO), its inhibition constant (Ki) invitro is <1 nm="" febuxostat="" has="" been="" shown="" to="" significantly="" inhibit="" the="" activity="" of="" both="" oxidized="" and="" reduced="" forms="" xanthine="" oxidase="" at="" therapeutic="" concentrations="" affects="" other="" enzymes="" involved="" in="" metabolism="" purines="" or="" pyrimidines="" such="" as="" guanine="" deaminase="" hypoxanthine="" anguanine="" phosphorobosyl="" transferase="" orotidin="" monophosphate="" decarboxylase="" purine="" nucleoside="" phosphorylase="" clinical="" efficacy="" safety:="" br=""> Gout
The efficacy of febuxostat 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 ІІІ, febuxostat 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 mcmol / 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 (AllopurinolandPlacebo-ControlledEfficacyStudyofFebuxostat - APEX) lasted 28 weeks. A total of 1072 patients were randomized: placebo (n = 134), febuxostat in a dose of 80 mg 1 time per day (n = 267), febuxostat at a dose of 120 mg 1 time per day (n = 269), febrasostat at a dose of 240 mg 1 time per 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 concentration> 1.5 and ≤ 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 in both treatment regimens with a febuxostat in a dose of 80 mg 1 time per day and febuxostat in a dose of 120 mg 1 time per day compared with allopurinol in the usual dose of 300 mg (n = 258) / 100 mg (n = 10) in reducing plasma concentration of uric acid <6 mg="" dl="" 357="" mcmol="" l="" table="" 1="" br=""> FACT study. A febuxostat efficacy study with allopurinol control (TheFebuxostatAllopurinolControlledTrial, FACT) Phase III - a randomized, double-blind, multicenter study of 52 weeks duration. A total of 760 patients were randomized into groups: febuxostat at a dose of 80 mg 1 time per day (n = 256), febuxostat 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 (febuxostat at a dose of 80 mg 1 time per day and febuxostat at a dose of 120 mg 1 time per day) compared with allopurinol at the usual dose of 300 mg for reducing and maintaining serum uric acid concentrations <6 mg="" dl="" 357="" mcmol="" l="" br=""> In tab. Figure 1 shows the results of the evaluation of the primary endpoint efficiency.
Table 1
The proportion of patients with a serum uric acid concentration of <6.0 mg="" dl="" 357="" mcmol="" l="" during="" the="" last="" three="" monthly="" visits="" p="">

Study	Fabuxostat at a dose of 80 mg 1 time per day	phebuxostat at a dose of 120 mg once a day	Allopurinol 300/100 mg 1 time per day¹
APEX (28 weeks)	48% * (n = 262)	65%*^{, #} (n = 269)	22% (n = 268)
FACT (52 weeks)	53% * (n = 255)	62% * (n = 250)	21% (n = 251)
Combined Results	51% * (n = 517)	63%*^{, #} (n = 519)	22% (n = 519)

1Results among patients who received 100 mg 1 time per day (n = 10: patients with baseline serum creatinine concentration> 1.5 and ≤ 2.0 mg / dL) or 300 mg 1 time per day (n = 509), during analysis were combined.
* p <0.001 compared="" with="" allopurinol="" p="" 0="" 001="" to="" a="" dose="" of="" 80="" mg="" br=""> Fabuxostat quickly reduced the serum concentration of uric acid, and this effect persisted for a long time. The decrease in plasma uric acid concentration <6.0 mg="" dl="" 357="" mol="" l="" was="" noted="" already="" on="" the="" 2nd="" week="" of="" study="" and="" persisted="" thereafter="" during="" treatment="" br=""> CONFIRMS study. A randomized controlled phase III study of CONFIRMS for a period of 26 weeks was performed to evaluate the safety and efficacy of Febuxostat at doses of 40 and 80 mg compared with allopurinol at 300 and 200 mg for patients with gout and hyperuricemia. A total of 2269 patients were randomized: febuxostat at a dose of 40 mg 1 time per day (n = 757), febuxostat at a dose of 80 mg 1 time per day (n = 756) and allopurinol 300/200 mg once a day (n = 756). At least 65% of patients had impaired mild to moderate renal function (with a creatinine clearance of 30–89 ml / min). Prevention of gout attacks was mandatory for 26 weeks.
The proportion of patients with a serum uric acid concentration of <6.0 mg="" dl="" 357="" mol="" l="" on="" the="" last="" visit="" was="" 45="" for="" febuxostat="" 40="" 67="" 80="" and="" 42="" allopurinol="" 300="" 200="" respectively="" br=""> Primary endpoint in a subgroup of patients with impaired renal function
In the APEX study, the efficacy of the drug was evaluated in 40 patients with impaired renal function (with initial serum creatinine concentration> 1.5 and ≤ 2.0 mg / dL). These patients, randomized to the group of allopurinol, the dose of the drug was reduced to 100 mg 1 time per day. The primary endpoint of efficacy was achieved in febuxostat groups in 44% (80 mg 1 time per day), 45% (120 mg 1 time per day), and 60% (240 mg 1 time per day) of patients compared to 0% in groups allopurinol 100 mg 1 time per day and placebo.
At the same time, there were no clinically significant differences in the decrease in serum uric acid concentration in healthy volunteers in percent, regardless of the renal function (58% in the group with normal renal function and 55% in the group with severe renal impairment).
A prospective analysis of patients with gouty and renal dysfunction using the CONFIRMS study showed that febuxostat was significantly more effective: serum uric acid levels were reduced <6.0 mg="" dl="" compared="" to="" allopurinol="" 300="" 200="" in="" patients="" with="" gout="" and="" impaired="" renal="" mild="" moderate="" 65="" of="" subjects="" br=""> Primary endpoint in a subgroup of patients with a serum uric acid concentration ≥10 mg / dL
An initial serum uric acid concentration of ≥10 mg / dL was observed in approximately 40% of patients (combined studies of APEX and FACT). Among these patients, the primary efficacy endpoint (serum uric acid concentration <6 mg="" dl="" in="" the="" last="" 3="" visits="" was="" achieved="" febuxostat="" groups="" 41="" 80="" 1="" time="" per="" day="" 48="" 120="" and="" 66="" 240="" of="" patients="" compared="" with="" 9="" allopurinol="" group="" 300="" 100="" 0="" placebo="" br=""> According to a CONFIRMS study, the proportion of patients who reached the primary endpoint of efficacy (with a serum uric acid concentration <6.0 mg="" dl="" on="" the="" last="" visit="" in="" group="" with="" baseline="" plasma="" uric="" acid="" concentration="" 10="" who="" received="" a="" febuxostat="" 40="" once="" day="" it="" was="" 27="" 66="" 249="" 80="" 1="" time="" per="" -="" 49="" 125="" 254="" and="" allopurinol="" 300="" 200="" 31="" 72="" 230="" respectively="" br=""> Clinical results: percentage of patients requiring therapy for gout attacks
APEX study. During the 8-week prophylactic period, the data of patients from the therapeutic group of febuxostat 120 mg (36%), who required therapy for attacks of gout, was compared with those of patients who used Febuxostat 80 mg (28%), allopurinol 300 mg (23%) or placebo (20%).The frequency of attacks was higher after the prophylactic period and gradually decreased with time. In 46–55% of patients, gout attacks were treated from the 8th and 28th weeks. Gout attacks that occurred during the last 4 weeks of testing (24–28 weeks) were noted in 15% (febuxostat 80 and 120 mg), 14% (allopurinol 300 mg) and 20% (placebo) of patients.
FACT study. During the 8-week prophylactic period, the data of patients from the therapeutic group of febuxostat 120 mg (36%), who required therapy for attacks of gout, were compared with those of the two therapeutic groups who used Febuxostat 80 mg (22%) or allopurinol 300 mg ( 21%). After an 8-week prophylactic period, the frequency of attacks increased and gradually decreased over time (64 and 70% of patients receiving treatment for bouts of gout from week 8 to week 52). Gout attacks during the last 4 weeks of testing (49–52 weeks) were reported in 6–8% (febuxostat 80 and 120 mg) and 11% (allopurinol 300 mg) of patients.
The proportion of patients requiring treatment for exacerbations of gout (the APEX and FACT study) was lower in groups where the average concentration of uric acid in the blood serum decreased to <6.0 after="" treatment="" 5="" 0="" or="" 4="" mg="" dl="" compared="" to="" groups="" in="" which="" the="" average="" uric="" acid="" level="" was="" 6="" last="" 32="" weeks="" of="" from="" 20="" 24="" 49="" 52="" br=""> During the CONFIRMS study, the proportion of patients requiring treatment for gout attacks (1 day every 6 months) was 31% and 25% in the groups that received 80 mg Febuxostat and Allopurinol respectively. There was no difference in the ratio of patients who required treatment for gout attacks between the groups that used Febuxostat 80 and 40 mg.
Long-term extended open research
EXCEL Study (C 02-021). The EXCEL study is a 3-year open multicenter randomized advanced allopurinol-controlled phase III safety study, which was conducted to assess the safety of patients who completed the main phase III studies (APEX or FACT). A total of 1086 patients were included in the study: febuxostat at a dose of 80 mg 1 time per day (n = 649), febuxostat at a dose of 120 mg 1 time per day (n = 292) or allopurinol 300/100 mg 1 time per day (n = 145 ). Approximately 69% of patients did not need treatment adjustment to achieve a final stable result. Patients whose plasma uric acid concentration was> 6.0 mg / dL for three consecutive measurements were excluded from the study.
The level of serum uric acid concentration did not change over time (for example, 91 and 93% of patients who first used Febuxostat at doses of 80 and 120 mg, respectively, had serum uric acid concentration levels of <6.0 mg="" dl="" per="" 36th="" month="" br=""> According to a 3-year follow-up, less than 4% of patients requiring treatment for gout attacks experienced a decrease in the frequency of gout attacks at the 16–24th and 30–36th month (that is, more than 96% of patients need in the treatment of gout attacks is absent).
In 46 and 38% of patients who received the final stable treatment with febuxostat at a dose of 80 or 120 mg, respectively, 1 time per day, there was a complete disappearance of the primary palpable tophus.
The FOCUS study (TMX-01-005) is a 5-year open multicenter advanced phase II safety study that was conducted with the participation of patients who completed the use of febuxostat for 4 weeks in double dosage in a blind test of TMX-01-004. The study included 116 patients who received an 80 mg first-course injections at least once a day. In 62% of patients, to maintain the serum concentration of uric acid at a level of <6.0 mg="" dl="" dose="" adjustment="" was="" not="" required="" and="" 38="" of="" patients="" to="" achieve="" a="" final="" stable="" concentration="" br=""> The proportion of patients with uric acid concentrations in plasma <6.0 mg="" dl="" 357="" mcmol="" l="" during="" the="" last="" visit="" was=""> 80% (81-100%) for each of the groups by dose of febuxostat.
In the third phase of clinical studies in patients treated with febuxostat, minor changes in hepatic parameters were recorded (5.0%). The frequency of these changes is similar to that of allopurinol (4.2%). In long-term, open-ended, extended studies in patients who received Febuxostat (5.5%) or allopurinol (5.8%) for a long time, there was an increase in the level of TSH (> 5.5 mcIU / ml).
Tumor Lysis Syndrome (SLO)
The efficacy and safety of the use of the febuxostat drug for the prevention and treatment of SLO was evaluated in the FLORENCE study (FLO-01). Fabuxostat has shown better and faster action in reducing urate levels than allopurinol.
FLORENCE was a randomized (1: 1) double-blind, Phase III phase support study conducted to compare febuxostat 120 mg once daily and allopurinol 200–300 mg / day (average daily dose of allopurinol ± standard deviation: 349.7 ± 112.90 mg) in terms of monitoring the concentration of uric acid in the serum. Selected patients had to be candidates for treatment with allopurinol or did not have access to rasburrikase. The primary endpoints consisted of serum uric acid AUC (AUC sUA1–8) and changes in serum creatinine level (sC) from day 1 to day 8 each.
The study included 346 patients with hematological malignant neoplasms receiving chemotherapy with an average / high degree of risk of developing SLO. The mean AUC value of sUA1–8 mg · h / dl was significantly lower when using a fabuxostat (514.0 ± 225.71 compared to 708.0 ± 234.42; least squares mean difference: –196.794 [95% confidence interval ( CI) –238,600 ... –154.988]; p = 0.0001). In addition, the mean serum uric acid level was significantly lower with the use of Feboxostat, starting from the first 24 hours of treatment and at any subsequent point in time. There were no statistically significant differences in the mean serum creatinine content (%) between febuxostat and allopurinol (–0.83 ± 26.98 compared to –4.92 ± 16.70, respectively; the least squares for the difference: 4.0970 [95 % CI –0.6467; 8.8406]; p = 0.0903). Taking into account secondary endpoints, no statistically significant differences in the incidence of laboratory-confirmed LES were observed (8.1 and 9.2% for febuxostat and allopurinol, respectively; relative risk (RR) 0.875 [95% CI 0.4408-1.7369]; p = 0.8488) and there was no clinical picture of tumor collapse (1.7 and 1.2% for febuxostat and allopurinol, respectively; OR 0.994 [95% CI 0.9691; 1,0199]; p = 1.0000) . The frequency of all signs and symptoms that occurred during treatment, as well as adverse reactions was 67.6% compared to 64.7% and 6.4% compared to 6.4% for febuxostat and allopurinol, respectively. In the FLORENCE study, febuxostat demonstrated a better and faster effect on reducing serum uric acid levels compared to allopurinol. Data for comparison of febuxostat and rasburrikazy currently not available. The efficacy and safety of fabuxostat has not been established for patients with acute severe SLO, for example, for patients who do not have other types of therapy to reduce urates.
Preclinical safety data
The described effects of the drug, noted in clinical studies with exposure, many times exceed the maximum exposure in humans.
Carcinogenesis, mutagenesis, impaired fertility
A statistically significant increase in the incidence of bladder tumors (transitional cell papilloma and carcinoma) was observed only in male rats in the maximum dose group (approximately 11 times the exposure in humans) and was associated with the deposition of xanthine crystals.No probable increase in the incidence of development of other tumors was found in studies on male and female mice and rats. These changes were considered as a manifestation of the characteristics of purine metabolism and composition of urine and had no clinical significance.
In standard genotoxicity studies, no biologically significant genotoxic effects of febuxostat were noted.
Febuxostat at doses up to 48 mg / kg / day orally did not affect fertility and reproductive function in male and female rats.
Data on impaired fertility, teratogenic effects or harmful effects on the fetus is not received. At exposure 4.3 times higher than recommended for humans, the rats showed increased toxicity for the female with a subsequent decrease in the weaning rate of the breastfeeding and slowing the development of the offspring. In studies on pregnant rats with exposures 4.3 times higher than those recommended for humans, and pregnant rabbits with exposures 13 times higher than those recommended for humans, no drug teratogenic effects were observed.
Pharmacokinetics. In healthy volunteers, Cmax and AUC increased in proportion to the dose after single and repeated use of Febuxostat at doses of 10–120 mg. At doses of 120–300 mg, the increase in AUC was greater than proportional to the dose. At doses of 10–240 mg every 24 h, no accumulation of fabuxostat was noted. The estimated mean terminal T½ of febuxostat was approximately 5–8 h.
A population-based analysis of pharmacokinetics / pharmacodynamics was carried out according to data obtained with the participation of 211 patients with hyperuricemia and gout who used febuxostat in doses of 40–240 mg once a day. In general, the obtained values of pharmacokinetic parameters were similar to those in healthy volunteers, which, therefore, are a good model for evaluating the pharmacokinetics / pharmacodynamics of the drug in patients with gout.
Suction. Fabuxostat is fast (tmax [time to reach Cmax] - 1.0–1.5 h) and well (84%) absorbed. With single and repeated use of fabuxostat orally in doses of 80 mg or 120 mg 1 time per day, Cmax is respectively 2.8–3.2 and 5.0–5.3 mcg / ml. The absolute bioavailability of fabuxostat was not analyzed. With repeated use in a dose of 80 mg 1 time per day or with a single use at a dose of 120 mg in combination with fatty foods, Cmax decreased by 49 and 38%, and AUC - by 18 and 16%, respectively. However, this was not accompanied by clinically significant changes in the degree of reduction of plasma uric acid levels (with repeated use at a dose of 80 mg). Thus, the drug can be used regardless of the meal.
Distribution. The estimated volume of distribution in the equilibrium state (Vss / F) for fabuxostat varies from 29 to 75 liters after oral administration at a dose of 10-300 mg. The degree of binding to plasma proteins (mainly albumin) is 99.2% and does not change with increasing doses from 80 to 120 mg. For active metabolites of febuxostat, the degree of binding to plasma proteins ranges from 82 to 91%.
Metabolism. Febuxostat is actively metabolized by conjugation with the participation of uridine phosphate gluconyl transferase (UDP-gluconyl transferase) and oxidation with the participation of cytochrome P450 (CYP) enzymes. A total of 4 pharmacologically active hydroxyl metabolites of fabuxostat have been described; 3 of them were detected in humans in the blood plasma. Studies of invitro on human liver microsomes have shown that these oxidized metabolites are formed mainly under the action of CYP A1, CYP A2, CYP 2C8 and CYP 2C9, whereas febuxostat glucuronide is formed mainly under the action of UDP-gluconyltransferase 1A1, 1A8, 1A9.
Derivation. Fabuxostat is secreted from the body by the liver and kidneys. After ingestion of 14C-fabuxostat at a dose of 80 mg, approximately 49% were excreted with urine in unchanged form of febuxostat (3%), acylglucuronide (30%), known oxidized metabolites and their conjugates (13%), and other unknown metabolites (3%).In addition to renal excretion, approximately 45% was excreted in the feces as unchanged febuxostat (12%), acylglucuronide (1%), known oxidized metabolites and their conjugates (25%), and other unknown metabolites (7%).
Special groups of patients. Renal failure. With repeated use of febuxostat at a dose of 80 mg, there was no change in Сmaxfebuksostat in patients with mild, moderate or severe renal insufficiency compared with patients with normal renal function. The mean total febuxostat AUC increased by about 1.8 times from 7.5 mcg / h / ml in patients with normal renal function to 13.2 mcg / h / ml in those with severe renal insufficiency. Cmax and AUC of active metabolites increased 2 and 4 times, respectively. However, in patients with renal insufficiency, mild, moderate or severe dosage adjustment is not required.
Liver dysfunction. With repeated use of febuxostat at a dose of 80 mg, there were no significant changes in Cmax and AUC of febuxostat and its metabolites in patients with mild to moderate (class A and B on the Child-Pugh scale) degree of hepatic insufficiency compared with patients with normal liver function. Studies of the drug in patients with severe hepatic insufficiency (class C on the Child-Pugh scale) were not conducted.
Age. With repeated oral administration of febuxostat, there were no significant changes in febuxostat AUC and its metabolites in elderly patients compared with young healthy volunteers.
Floor. With repeated oral administration of FebuxostCmax and AUC of Febuxostat, women were, respectively, 24% and 12% higher than men. However, Cmax and AUC, adjusted for body weight, were similar for both groups, therefore, a dose of febuxostat depending on gender is not required.

Indications

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.
Azurix at a dose of 120 mg
Treatment and prevention of hyperuricemia in adult patients undergoing chemotherapy for hematologic malignancies with a moderate or high risk of ALS.
Azurix is indicated for adult patients.

Febuxostat is marketed under different brands and generic names, and comes in different dosage forms:

Brand name	Manufacturer	Country	Dosage form
Azurix			pills
Adenurik	Menarini-von Hayden GmbH	Germany	pills

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Dosage and Administration

Gout. The recommended dose of Azurix is 80 mg orally once a day, regardless of the meal. If the concentration of uric acid in the blood serum exceeds 6 mg / dL (357 μmol / l) after 2–4 weeks of treatment, the dose of Azurix can be increased to 120 mg once daily.
The effect of the drug occurs quite 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="" mcmol="" l="" br=""> The duration of prevention of gout attacks is at least 6 months.
SLO. The recommended dose of Azurix is 120 mg orally once a day, regardless of the meal. Azurix should be started 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, mild or moderate dose adjustment is not required. In patients with severe impaired renal function (creatinine clearance <30 ml="" min="" the="" efficacy="" and="" safety="" of="" drug="" has="" not="" been="" adequately="" studied="" br=""> 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.
Elderly patients. For this category of patients, dose adjustment is not required.
Patients undergoing organ transplantation. Experience of using fabuxostat in this category of patients is not, therefore, the use of the drug is not shown.
Mode of application
For oral administration.
Azurix is administered orally, regardless of the meal.

Adverse reactions

The most frequent adverse reactions in clinical studies (4072 patients using a dose of 10 to 300 mg) and in the process of post-marketing observation in patients with gout were exacerbations (attacks) of gout, abnormal liver function, diarrhea, nausea, headache, rashes and swelling. These reactions were in most cases mild and moderate severity. During post-marketing surveillance, there were reports of serious hypersensitivity reactions to fabuxostat, some of which were accompanied by systemic reactions.
In tab. 2 indicates adverse reactions by frequency of occurrence and severity (in descending order) that occurred during clinical studies and in the post-marketing period, and are classified as follows: often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1000 to <1/100) and rarely (from ≥1 / 10 000 to <1/1000).
table 2
Adverse reactions that occurred in the third phase of combined randomized extended long-term studies and in the period of post-marketing follow-up in patients with gout

Blood and lymphatic system	Rarely: pancytopenia, thrombocytopenia
The immune system	Rarely: anaphylactic reactions , hypersensitivity to the drug
From the endocrine system	Infrequently: increased levels of thyroid-stimulating blood hormone
On the part of the organ of vision	Seldom: blurred vision
On the part of nutrition and metabolism	Often ***: exacerbation (attacks) of gout Infrequently: diabetes, hyperlipidemia, loss of appetite, weight gain Seldom: decrease in body weight, increase in appetite, anorexia
From the psyche	Infrequently: decrease in a libido, sleeplessness Seldom: nervousness
From the nervous system and sensory organs	Often: headache Infrequently: dizziness, paresthesias, hemiparesis, drowsiness, change in taste, increase in pain threshold, weakening of smell
From the organ of hearing and the labyrinth	Seldom: tinnitus
Since the cardiovascular system	Infrequently: atrial fibrillation, palpitations, abnormalities on ECG, AH, hot flashes with a sensation of heat For fabuxostat at a dose of 120 mg: blockade of the left leg of the bundle of His, ventricular tachycardia, bleeding (see section SLO)
On the part of the respiratory system	Infrequently: shortness of breath, bronchitis, upper respiratory tract infections, cough
From the digestive system	Often: diarrhea **, nausea Infrequently: abdominal pain, bloating, gastroesophageal reflux disease, vomiting, dry mouth, dyspepsia, constipation, frequent defecation, flatulence, stomach or intestinal discomfort Rarely: pancreatitis, mouth ulcers
Liver and biliary tract	Often: abnormal liver function ** Infrequently: cholelithiasis Rarely: hepatitis, jaundice , liver failure
From the skin and its derivatives	Often: rashes (including rashes with a lower incidence) Infrequently: dermatitis, urticaria, pruritus, discoloration of the skin, skin damage, petechiae, spotted rash, maculopapular and papular rash Rare: toxic epidermal necrolysis * Stevens - Johnson , angioedema , drug reactions, accompanied by eosinophilia and systemic symptoms , generalized rash (severe) , erythema, exfoliative rash, follicular rash, vesicular rash, pustular rash, itching rashes *, erythematous rashes, core-like rash, alopecia, increased sweating
From the musculoskeletal system and connective tissue	Infrequently: joint pain, arthritis, muscle pain, musculoskeletal pain, muscle weakness, muscle cramps, muscle stiffness, bursitis Rarely: rhabdomyolysis *, joint stiffness, musculoskeletal stiffness
Kidney and urinary tract	Infrequently: renal failure, urolithiasis, hematuria, pollakiuria, proteinuria Seldom: tubulointerstitial nephritis *, frequent urge to urinate
Reproductive system and mammary glands	Seldom: violation of an erection
On the part of the body as a whole	Often: swelling Infrequently: increased fatigue, chest pain, feeling of discomfort in the chest Rarely: thirst
Additional research methods	Infrequently: an increase in the level of amylase in the blood, a decrease in the number of platelets, a decrease in the number of leukocytes in the blood, a decrease in the number of lymphocytes in the blood, an increase in the level of creatinine in the blood, a decrease in the level of hemoglobin in the blood, an increase in the TG level in the blood, an increase in the cholesterol level in the blood, a decrease in hematocrit, increased levels of LDH in the blood, increased levels of potassium in the blood. Rarely: an increase in blood glucose, lengthening of activated partial thromboplastin time, a decrease in the number of erythrocytes in the blood, an increase in alkaline alkaline phase in the blood

* Adverse reactions noted within postmarketing analysis.
** Diarrhea and abnormal liver function tests that required therapy were noted during clinical studies and developed more frequently in patients who received concomitant colchicine therapy.
***Cm. section PHARMACOLOGICAL PROPERTIES regarding the frequency of gout attacks that occurred in the third phase of individual randomized controlled trials.
Description of individual adverse reactions
As part of post-marketing surveillance, there were reports of rare cases of serious hypersensitivity reactions to febuxostat, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylactic reactions / shock. Stevens-Johnson syndrome and toxic epidermal necrolysis are characterized by progressive skin rashes with bullous lesions of the skin or mucosa and irritation of the mucous membrane of the eye. Hypersensitivity reactions to febuxostat can be manifested by the following symptoms: a skin reaction in the form of an infiltrated maculopapular rash, a generalized or exfoliative rash, thrombocytopenia, and lesions of individual organs or several organs (liver and kidney, including tubulo-interstitial nephritis).
Exacerbation (attacks) of gout is usually noted soon after the start of treatment and during the first months of therapy. The incidence of gout attacks has decreased over time. When using fabuxostat, prevention of acute attacks of gout is recommended.
SLO
Security Profile Summary
In the course of a randomized, double-blind reference study of the third phase FLORENCE (FLO-01), which compared febuxostat and allopurinol (346 patients receiving chemotherapy for hematological malignancies with a moderate or high risk of SLO), only in 22 (6.4%) patients developed adverse reactions, namely, 11 (6.4%) patients in each treatment group. Most adverse reactions were mild or moderate. In general, during the FLORENCE study, there were no additional suspicions regarding the safety of using fabuxostat in patients with gout, with the exception of the three side reactions listed below (see Table 2).
Since the cardiovascular system: infrequently - the blockade of the left bundle of His, ventricular tachycardia; sometimes bleeding.
Reports of possible adverse reactions. Reports of possible adverse reactions after registration of the drug play an important role. This allows you to continue to monitor the benefit / risk ratio for this drug.

Hypersensitivity to the active substance or any other auxiliary component of the drug.

Drug interactions

Mercaptopurin / azathioprine. In accordance with the mechanism of action of fabuxostat, which consists in the ability to suppress xanthine oxidase, its simultaneous use with mercaptopurine / azathioprine is not recommended. Inhibition of xanthine oxidase can lead to an increase in the concentration of both drugs in the blood plasma, which can cause a toxic reaction. There were no studies on the interaction of febuxostat with drugs metabolized by xanthine oxidase.
There is no data on the safety of their simultaneous use in cytotoxic therapy.
In the course of the study, patients with SLOs with several chemotherapy regimens were administered Febuxostat at a dose of 120 mg, including monoclonal antibodies. However, during this study, the interactions “drug - drug” and “drug - disease” were not investigated. Therefore, the possibility of interaction with any cytotoxic drugs, with their combined prescription, cannot be ruled out.
Rosiglitazone / CYP 2C8 Substrates. Febuxostat is a weak inhibitor of CYP 2C8 invitro. In a study involving healthy volunteers, the simultaneous administration of 120 mg of Febuxostat 1 time per day and 4 mg of rosiglitazone in a single dose did not affect the pharmacokinetics of rosiglitazone and its metabolite N-desmethylrosiglitazone, which demonstrates that febuxostat does not inhibit the CYP 2C8 invivo enzyme. Thus, the simultaneous administration of febuxostat and rosiglitazone or other CYP 2C8 substrates does not require dose adjustment for these drugs.
Theophylline.A study was conducted of the interaction of febuxostat with the participation of healthy volunteers to evaluate the effect of inhibition of xanthine oxidase on the increase in theophylline level in the circulating blood, observed with other inhibitors of xanthine oxidase. The results showed that the simultaneous use of febuxostat at a dose of 80 mg and theophylline at a dose of 400 mg showed no pharmacokinetic interactions or an effect on the safety of theophylline. Fabuxostat at a dose of 80 mg can be used simultaneously with theophylline without special reservations. Data on the use of fabuxostat at a dose of 120 mg are not available.
Naproxen and other glucuronization inhibitors. Febuxostat metabolism depends on the activity of UDP-glucuronyltransferase. Drugs that suppress the process of glucuronization, such as NSAIDs and probenecid, can theoretically alter the excretion of fabuxostat. In healthy volunteers with the simultaneous use of febuxostat and naproxen 250 mg 2 times a day, the increased effect of febuxostat was observed (Cmax is 28%, AUC - 41%, T½ - 26%). In clinical studies, the use of naproxen and other NSAIDs / COX-2 inhibitors was not accompanied by a clinically significant increase in severity and an increase in the incidence of adverse reactions. Thus, febuxostat can be used simultaneously with naproxen without changing their dose.
Glucuronization inhibitors. Powerful inducers of UDP-glucuronyltransferase can enhance metabolism and reduce the effectiveness of febuxostat. In patients who use powerful inducers of glucuronization, it is recommended to monitor the level of uric acid in the blood plasma after 1–2 weeks of simultaneous therapy. When the inducer of glucuronization is canceled, an increase in the level of febuxostat in the blood plasma is possible.
Colchicine / Indomethacin / Hydrochlorothiazide / Warfarin. Febuxostat can be used simultaneously with colchicine or indomethacin without changing the dose of drugs. There is also no need to correct the dose of fabuxostat when used in combination with hydrochlorothiazide. The simultaneous use of fabuxostat with warfarin does not require changing the dose of the latter. The use of fabuxostat (80 or 120 mg 1 time per day) with warfarin does not affect the pharmacokinetics of the latter. Simultaneous use with febuxostat also did not affect the international normalized attitude and activity of factor VII.
Desipramine / CYP 2D6 substrates. According to the data obtained by invitro, febuxostat is a weak inhibitor of CYP 2D6. In studies involving healthy volunteers who received 120 mg of Febuksostat, a 22% increase in the desucramine AUC (CYP 2D6 substrate) was observed, indicating a weak inhibitory effect of febuxostat in vivo. Thus, with simultaneous use of fabuxostat and CYP 2D6 substrates, there is no need to change their doses.
Antacid agents. With simultaneous use with antacids containing magnesium hydroxide and aluminum hydroxide, inhibition of febuxostat absorption is observed (approximately by 1 hour) and Cmax decrease by 32%, however, the AUC of febuxostat does not change significantly, therefore febuxostat can be combined with the use of antacids.

Special instructions

Cardiovascular diseases
Treatment of chronic hyperuricemia. Fabuxostat is not recommended for patients with coronary artery disease or congestive heart failure.
In the APEX and FACT studies, an increase in the number of cardiovascular disorders (Anti-PlateletTrialists' Collaboration - APTC) was reported in the total febuxostat group compared with the allopurinol group (determination of endpoints in the combined anti-platelet analysis group (APTC), including including deaths due to cardiovascular disease, non-fatal myocardial infarction, stroke without death, 1.3 compared with 0.3 cases per 100 patient-years), in contrast to the CONFIRMS study.The frequency of cardiovascular disorders (APTC) reported in the studies in combined phase III studies (APEX, FACT and CONFIRMS) was 0.7 compared to 0.6 cases per 100 patient-years for febuxostat and allopurinol, respectively. In the framework of long-term large-scale studies, the reported cardiovascular disorders rate was 1.2 and 0.6 cases per 100 patient-years for febuxostat and allopurinol, respectively. The differences were not statistically significant, and there was no causal relationship between these violations and the use of febuxostat. Risk factors in these patients were diseases resulting from atherosclerosis and / or myocardial infarction, or a history of congestive heart failure.
Prevention and treatment of hyperuricemia in patients at risk of developing SLO
Patients undergoing chemotherapy for hematological malignancies with a moderate or high risk of ALD and using febuxostat, if clinically indicated, are under the supervision of a cardiologist.
Allergy to drugs / hypersensitivity. As part of post-marketing surveillance, there have been rare reports of serious allergic / hypersensitivity reactions, including the life-threatening Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute anaphylactic reactions / shock. In most cases, they occurred within the first month of the use of fabuxostat. In a few patients, renal dysfunction and / or hypersensitivity to allopurinol in history was noted. Severe hypersensitivity reactions, including reactions accompanied by eosinophilia and systemic symptoms (DRESS syndrome), in some cases have been associated with fever, hematological, renal or hepatic insufficiency. Patients should be informed about the symptoms of hypersensitivity / allergy, and they need to be monitored regarding the development of such reactions. If serious allergic / hypersensitivity reactions occur, use of febuxostat should be stopped immediately, since early discontinuation of use improves the prognosis. If the patient has an allergic reaction / hypersensitivity reaction, including Stevens-Johnson syndrome, and acute anaphylactic reactions / shock, then reappointment of febuxostat is contraindicated.
Exacerbation (attack) of gout. Febuxcostat treatment should begin only in the period after the exacerbation of the disease. Fabuxostat can trigger a gout attack at the beginning of treatment by changing the level of uric acid through the release of urates from the depot. At the beginning of treatment with febuxostat, it is recommended to prescribe NSAIDs or colchicine for a period of at least 6 months to prevent gout attacks. At development of an attack against the use of febuxostat treatment is continued. At the same time carry out the appropriate individual therapy of acute gout. With prolonged use of fabuxostat, the frequency and severity of gout attacks are reduced.
Xanthine deposits. In patients with accelerated urate formation (for example, against the background of malignant neoplasms and their treatment or with Lesch-Nyhan syndrome), a significant increase in the absolute concentration of xanthines in the urine, accompanied by their deposition in the urinary tract, is possible. This was not observed in the reference clinical study of febuxostat in SLO. Due to the limited experience of using fabuxostat in this condition, the drug is not indicated for patients.
Mercaptopurin / azathioprine. Fabuxostat is not recommended for use in patients receiving mercaptopurine / azathioprine.
If simultaneous use cannot be avoided, the condition of the patients should be carefully monitored.A dose reduction of mercaptopurine / azathioprine is recommended to avoid possible hematological effects.
Patients undergoing organ transplantation. Experience of using fabuxostat in this category of patients is not, therefore, the use of the drug is not shown.
Theophylline. A single simultaneous use of Febuksostat at a dose of 80 mg and theophylline at a dose of 400 mg did not demonstrate any pharmacokinetic interactions. Febuxostat in a dose of 80 mg can be used simultaneously with theophylline without the risk of increasing theophylline concentration in the blood plasma. Data on the use of fabuxostat at a dose of 120 mg are not available.
Liver disease. During the combined phase III clinical studies, in 5.0% of patients who used febuxostat, minor changes in hepatic parameters were noted, therefore, it is recommended to check functional hepatic indicators before prescribing febuxostat and during treatment if indicated.
Diseases of the thyroid gland. In 5.5% of patients who received a fabuxostat for a long time, an increase in TSH (> 5.5 mcIU / ml) was observed, therefore, the drug should be administered with caution to persons with impaired thyroid function.
Lactose. The drug contains lactose, so for patients with rare hereditary diseases associated with galactose intolerance, lactase deficiency or impaired glucose / galactose absorption, the drug is contraindicated.
Use during pregnancy and lactation. Limited experience with the use of febuxostat during pregnancy indicates the absence of an adverse effect on the course of pregnancy and the health of the fetus / newborn. In the course of animal studies, no direct or indirect adverse effects on the course of pregnancy, the development of the embryo / fetus and the course of childbirth were noted. The potential risk to humans is unknown. In connection with the foregoing, the use of fabuxostat is contraindicated during pregnancy.
It is not known whether Febuksostat penetrates human breast milk. Animal studies have shown that febuxostat penetrates into breast milk and has a negative effect on the development of newborns who are breastfed. In connection with the foregoing, the use of fabuxostat during breastfeeding is contraindicated.
Fertility Fertility studies in animals at a dose of 48 mg / kg / day did not reveal a dose-related dependence of the adverse reactions. The effect of febuxostat on the human reproductive function is unknown.
Children. The use of fabuxostat in children (under the age of 18 years) is not shown due to the lack of experience with its use in pediatrics.
The ability to influence the reaction rate when driving or working with other mechanisms. There were reports of the development of drowsiness, dizziness, paresthesia and impaired visual clarity with the use of febuxostat, so patients using febuxostat are advised to use caution when driving and working with other mechanisms until they are sure that these phenomena are absent.