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Instructions for use ADENURIC

Uric acid is the end product of purine metabolism in humans and is formed during the following reaction:

hypoxanthine -> xanthine -> uric acid. At both stages of this reaction, xanthine oxidase acts as a catalyst. Febuxostat is a 2-arylthiazole derivative. Its therapeutic effect is based on reducing serum uric acid concentrations by selectively inhibiting xanthine oxidase. Febuxostat is a potent and selective non-purine xanthine oxidase inhibitor (NP-SIXO) with an in vitro Ki (inhibition constant) of less than 1 nM. Febuxostat has been shown to significantly inhibit the activity of both the oxidized and reduced forms of xanthine oxidase. At therapeutic concentrations, febuxostat does not affect other enzymes involved in purine or pyrimidine metabolism, such as guanine deaminase, hypoxanthine guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase or purine nucleoside phosphorylase.

Clinical efficacy and safety

The effectiveness of Adenuric was confirmed in three phase 3 studies (the two main studies APEX and FACT and the additional study CONFIRMS, described below), which included 4101 patients with hyperuricemia and gout. In each of these pivotal phase 3 studies, Adenuric was more effective in lowering and maintaining serum uric acid concentrations than allopurinol. The primary efficacy endpoint in both studies was the proportion of patients whose serum uric acid concentration did not exceed 6.0 mg/dL (357 μmol/L) during the past three months. In the additional phase 3 CONFIRMS study, the results of which became available after the first marketing authorization of Adenuric, the primary efficacy endpoint was the proportion of patients whose serum uric acid concentration did not exceed 6.0 mg/dL at the last visit. These studies did not include patients who had undergone organ transplantation.

APEX Study: The phase 3 Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX) was a randomized, double-blind, multicenter trial of 28 weeks. A total of 1072 patients were randomized:

placebo (n=134), Adenuric 80 mg once a day (n=267), Adenuric 120 mg once a day (n=269), Adenuric 240 mg once a day (n=134) or allopurinol (300 mg 1 time/day (n=258) for patients with initial serum creatinine concentration ≤1.5 mg/dL or 100 mg 1 time/day (n=10) for patients with initial serum creatinine concentration >1.5 mg/dL and ≤2.0 mg/dL dl). To assess safety, febuxostat was prescribed at a dose of 240 mg (2 times the maximum recommended dose).

The APEX study showed a statistically significant advantage of both treatment regimens Adenuric 80 mg 1 time / day and Adenuric 120 mg 1 time / day compared with allopurinol at the usual dose of 300 mg (n = 258) / 100 mg (n = 10) in reducing serum concentrations uric acid below 6 mg/dL (357 µmol/L).

FACT Study:

The Phase 3 Febuxostat Allopurinol Controlled Trial (FACT) was a randomized, double-blind, multicenter study of 52 weeks duration. A total of 760 patients were randomized:

Adenuric 80 mg once a day (n=256), Adenuric 120 mg once a day (n=251) or allopurinol 300 mg once a day (n=253).

The FACT study showed a statistically significant advantage of both regimens - Adenuric 80 mg 1 time / day and Adenuric 120 mg 1 time / day compared with allopurinol at the usual dose of 300 mg, in reducing and maintaining serum uric acid concentrations below 6 mg / dl (357 μmol /l).

Table 1 presents the results of the primary efficacy endpoint.

Table 1. Proportion of patients with serum uric acid concentration <6.0 mg/dL (357 μmol/L) at the last three monthly visits

Study	ADENURIK 80 mg 1 time/day	ADENURIK 120 mg 1 time/day	Allopurinol 300/100 mg 1 time/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)
1 results among patients receiving 100 mg once daily (n=10: patients with baseline serum creatinine concentration >1.5 mg/dL and ≤2.0 mg/dL) or 300 mg once daily (n=509), during analyzes were combined. * p<0.001 compared with allopurinol # p<0.001 compared with 80 mg dose

Adenuric quickly reduced the serum concentration of uric acid, and this effect persisted for a long time. A decrease in serum uric acid concentration <6.0 mg/dL (357 μmol/L) was observed already in the second week of the study and persisted throughout treatment.

Note:

509 patients received allopurinol at a dose of 300 mg once a day;

10 patients with serum creatinine concentrations >1.5 mg/dL and <2.0 mg/dL received allopurinol 100 mg once daily (10 of 268 patients in the APEX study). Febuxostat 240 mg was administered to assess safety at a dose twice the maximum recommended.

CONFIRMS Study:

The CONFIRMS study was a 26-week, randomized, controlled phase 3 trial conducted to evaluate the safety and efficacy of febuxostat 40 mg and 80 mg compared with allopurinol 300 mg and 200 mg in patients with gout and hyperuricemia. A total of 2269 patients were randomized:

Adenuric 40 mg once a day (n=757), Adenuric 80 mg once a day (n=756), or allopurinol 300/200 mg once a day (n=756). At least 65% of patients had mild to moderate renal impairment (creatinine clearance 30-89 ml/min). Prophylaxis for gout attacks was mandatory for more than 26 weeks.

The proportion of patients with serum uric acid concentrations <6.0 mg/dL (357 μmol/L) at the last visit was 45% for febuxostat 40 mg, 67% for febuxostat 80 mg, and 42% for allopurinol 300/200 mg, respectively.

Primary endpoint in the subgroup of patients with renal impairment

The APEX study evaluated the efficacy of the drug in 40 patients with impaired renal function (i.e., with baseline serum creatinine concentrations >1.5 mg/dL and ≤2.0 mg/dL). In such patients randomized to the allopurinol group, the dose of the drug was reduced to 100 mg 1 time/day. The primary endpoint of efficacy was achieved in the Adenuric groups in 44% of patients (80 mg 1 time/day), 45% (120 mg 1 time/day) and 60% (240 mg 1 time/day) compared to 0% in groups allopurinol 100 mg once a day and placebo.

However, there were no clinically significant differences in the percentage decrease in serum uric acid concentration in healthy participants, regardless of the functional status of the kidneys (58% in the group with normal renal function and 55% in the group with severe renal impairment).

A prospective analysis conducted in patients with gout and renal impairment using the CONFIRMS study showed that febuxostat was significantly more effective, with serum uric acid levels reduced <6.0 mg/dL compared with allopurinol 300/200 mg in patients with gout and renal impairment. mild to moderate renal dysfunction (65% of subjects).

Primary endpoint in the subgroup of patients with serum uric acid concentration ≥10 mg/dL

Baseline serum uric acid concentrations ≥10 mg/dL were observed in approximately 40% of patients (combined APEX and FACT studies). Among these patients, the primary efficacy endpoint (serum uric acid concentration less than 6 mg/dL in the last 3 visits) was achieved in the Adenuric groups in 41% of patients (80 mg 1 time / day), in 48% of patients (120 mg 1 time / day). day) and in 66% of patients (240 mg 1 time/day) compared with 9% in the allopurinol 300/100 mg 1 time/day group and 0% in the placebo group.

According to the CONFIRMS study, the proportion of patients achieving the primary efficacy endpoint (serum uric acid concentration <6.0 mg/dL at last visit) in the group of patients with baseline serum uric acid concentration ≥10 mg/dL receiving febuxostat 40 mg once a day day, respectively, amounted to 27% (66/249), febuxostat 80 mg 1 time/day - 49% (125/254), and allopurinol 300 mg/200 mg 1 time/day - 31% (72/230).

Clinical outcomes: percentage of patients requiring treatment for gout attacks

APEX Study:

During the 8-week prophylaxis period, a greater proportion of patients in the febuxostat 120 mg treatment group (36%) requiring treatment for gout flares were compared with patients receiving febuxostat 80 mg (28%), allopurinol 300 mg (23%), or placebo ( 20%). The frequency of attacks was higher after the prophylactic period and gradually decreased over time. From 46% to 55% of subjects were treated for gout attacks from week 8 and week 28. Gout attacks occurring during the last 4 weeks of the trial (weeks 24–28) occurred in 15% of patients (febuxostat 80, 120 mg), 14% of patients (allopurinol 300 mg) and 20% of patients (placebo).

FACT Study:

During the 8-week prophylaxis period, a greater proportion of patients in the febuxostat 120 mg treatment group (36%) requiring treatment for gout flares were compared with both treatment groups receiving febuxostat 80 mg (22%) and allopurinol 300 mg (21%). After the 8-week prophylaxis period, the frequency of attacks increased and gradually decreased over time (64% and 70% of subjects treated for gout attacks from 8-52 weeks). Gout attacks during the last 4 weeks of the trial (49-52 weeks) were observed in 6-8% of patients (febuxostat 80 mg, 120 mg), and in 11% of patients (allopurinol 300 mg).

The proportion of patients requiring relief of gout flares (APEX and FACT studies) was lower in groups where the mean serum uric acid concentration after treatment decreased to <6.0 mg/dL, <5.0 mg/dL, or <4.0 mg/dL by compared with groups in which the mean uric acid level was >6.0 mg/dL in the last 32 weeks of treatment (from 20-24 weeks to 49-52 weeks).

During the CONFIRMS study, the percentage of patients who required treatment for gout flares (1 day at 6 months) was 31% and 25% in the febuxostat 80 mg and allopurinol groups, respectively. There was no difference in the proportion of patients who required treatment for gout attacks between the febuxostat 80 mg and febuxostat 40 mg groups.

Long-term extended open-label studies

EXCEL Study (C02-021):

The Excel study is a three-year, open-label, multicenter, randomized, extension, allopurinol-controlled, phase 3 safety study that was conducted to evaluate safety in patients enrolled in the pivotal phase 3 trials (APEX or FACT). A total of 1086 patients were included in the study:

Adenuric 80 mg once a day (n=649), Adenuric 120 mg once a day (n=292) or allopurinol 300/100 mg once a day (n=145). In about 69% of patients, no adjustment of therapy was required to achieve final stable treatment. Patients whose serum uric acid levels were >6.0 mg/dL on three consecutive measurements were excluded from the study.

Serum uric acid levels did not change over time (eg, 91% and 93% of patients initially treated with febuxostat 80 mg and 120 mg, respectively, had serum uric acid levels less than 6.0 mg/dL at month 36) .

According to three-year follow-up, less than 4% of patients who required treatment for attacks had a decrease in the frequency of gout attacks at 16-24 months and 30-36 months (i.e., more than 96% of patients did not need treatment for attacks) .

In 46% and 38% of patients receiving definitive stable treatment with febuxostat 80 or 120 mg once daily, respectively, there was complete resolution of primary palpable tophi from baseline to final visit.

The FOCUS study (TMX-01-005) was a five-year, open-label, multicenter, phase 2 safety extension study conducted in patients who completed 4 weeks of double-blind febuxostat dosing in the TMX-01-004 trial. 116 patients were included who initially received febuxostat 80 mg once a day. In 62% of patients, no dose adjustment was required to maintain a serum uric acid concentration of less than 6.0 mg/dL, and 38% of patients required a dose adjustment to achieve a final stable dose.

The proportion of patients with a serum uric acid level less than 6.0 mg/dL (357 μmol/L) at the last visit was more than 80% (81-100%) for each dose of febuxostat.

In phase 3 clinical trials, minor changes in liver function tests (5.0%) were observed in patients receiving febuxostat. The frequency of these changes was similar to that for allopurinol (4.2%). In long-term, open-label extension studies, patients receiving febuxostat (5.5%) or allopurinol (5.8%) for a long time had increased TSH levels (>5.5 μIU/ml).

Preclinical safety data

The described effects of the drug were observed in preclinical studies at exposures many times higher than 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 highest dose group (approximately 11 times the human exposure) and was associated with xanthine crystal deposition. There was no significant increase in the incidence of other tumors in studies on male and female mice and rats. The noted changes were considered as a manifestation of the characteristics of purine metabolism and urine composition and had no clinical significance.

No biologically significant genotoxic effects of febuxostat were observed in standard genotoxicity studies.

Febuxostat in doses up to 48 mg/kg/day orally did not affect fertility and reproductive function in male and female rats.

There is no evidence of impaired fertility, teratogenic effects or harmful effects on the fetus. At exposures 4.3 times higher than recommended for humans, increased maternal toxicity was observed in rats, followed by decreased weaning rates and delayed offspring development. In studies on pregnant rats with exposure 4.3 times higher than recommended for humans, and on pregnant rabbits with exposure 13 times higher than recommended for humans, no teratogenic effects of the drug were noted.