INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LIQUESTIA® (LIQUESTIA)

Composition:

Active substance: febuxostat;

One film-coated tablet contains 80 mg or 120 mg of febuxostat;

Excipients: microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, sodium croscarmellose, anhydrous lactose, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: polyvinyl alcohol (E 1203), titanium dioxide (E 171), macrogol 3350 (E 1521), talc (E 553b), yellow iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Film-coated tablets, 80 mg: elongated, biconvex, film-coated tablets, pale yellow to yellow in colour, with "80" embossed on one side and smooth on the other;

Film-coated tablets, 120 mg: elongated, biconvex, film-coated tablets, pale yellow to yellow in colour, with "120" embossed on one side and smooth on the other.

Pharmacotherapeutic group.

Medicinal products for the treatment of gout. Medicinal products that inhibit uric acid formation. ATC code M04A A03.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Uric acid is the end product of purine metabolism in humans and is formed during the following reaction: hypoxanthine → xanthine → uric acid. Xanthine oxidase catalyzes both steps of this reaction. Febuxostat is a 2-arylthiazole derivative whose therapeutic effect is related to reduction of serum uric acid concentration by selectively inhibiting xanthine oxidase. Febuxostat is a potent and selective non-purine xanthine oxidase inhibitor (NP-SIXO), with an in vitro inhibition constant (Ki) of less than 1 nanomolar. Febuxostat has been shown to significantly inhibit the activity of both oxidized and reduced forms of xanthine oxidase. At therapeutic concentrations, febuxostat does not affect other enzymes involved in purine or pyrimidine metabolism, such as guaninedeaminase, hypoxanthine-guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase, or purine nucleoside phosphorylase.

Clinical efficacy and safety

Gout. The efficacy of febuxostat has been demonstrated in three pivotal phase III studies (two pivotal studies APEX and FACT, and an additional study CONFIRMS, described below), involving 4101 patients with hyperuricemia and gout. In each of these pivotal phase III studies, febuxostat was more effective than allopurinol in lowering and maintaining serum uric acid concentration at appropriate levels. The primary efficacy endpoint in the APEX and FACT studies was the proportion of patients who had serum uric acid concentrations ≤ 6.0 mg/dL (357 µmol/L) during the last three months. In the additional phase III CONFIRMS study, whose results became available after the initial approval of febuxostat, the primary efficacy endpoint was the proportion of patients with serum uric acid concentration ≤ 6.0 mg/dL at the last visit. Patients who had undergone organ transplantation were not included in these studies (see section "Special precautions").

APEX study: The Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX) was a randomized, double-blind, multicenter study of 28 weeks' duration. A total of 1072 patients were randomized: placebo (n=134), febuxostat 80 mg once daily (n=267), febuxostat 120 mg once daily (n=269), febuxostat 240 mg once daily (n=134), and allopurinol 300 mg once daily (n=258) for patients with baseline serum creatinine concentration ≤ 1.5 mg/dL or allopurinol 100 mg once daily (n=10) for patients with baseline serum creatinine concentration > 1.5 mg/dL and ≤ 2.0 mg/dL. Febuxostat 240 mg (twice the maximum recommended dose) was administered to assess safety.

The APEX study demonstrated statistically significant superiority of both febuxostat regimens—80 mg once daily and 120 mg once daily—compared to allopurinol at the usual dose of 300 mg (n=258)/100 mg (n=10) in reducing serum uric acid concentration to below 6 mg/dL (357 µmol/L) (see Table 1 below). Figure 1 shows mean serum uric acid concentrations over time for each treatment group in both pivotal phase III studies.

Figure 1. Mean serum uric acid concentrations from combined pivotal studies (Phase III)

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Note: 509 patients received allopurinol 300 mg once daily; 10 patients with serum creatinine concentration > 1.5 mg/dL and < 2.0 mg/dL received allopurinol 100 mg once daily (10 out of 268 patients in the APEX study). Febuxostat 240 mg was administered to assess safety at a dose twice the maximum recommended.

FACT study: The Febuxostat Allopurinol Controlled Trial (FACT), a phase III study, was a randomized, double-blind, multicenter study of 52 weeks' duration. A total of 760 patients were randomized: febuxostat 80 mg once daily (n=256), febuxostat 120 mg once daily (n=251), and allopurinol 300 mg once daily (n=253).

The FACT study demonstrated statistically significant superiority of both febuxostat regimens—80 mg once daily and 120 mg once daily—compared to allopurinol 300 mg once daily in reducing and maintaining serum uric acid concentration below 6 mg/dL (357 µmol/L).

Table 1 presents the results for the primary efficacy endpoint.

Table 1

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

The ability of febuxostat to rapidly reduce serum uric acid concentration was rapid and sustained. Reduction in serum uric acid concentration to < 6.0 mg/dL (357 µmol/L) was observed as early as the second week of the study and persisted throughout the treatment period.

CONFIRMS study: The CONFIRMS study was a randomized, controlled Phase III trial lasting 26 weeks, designed to evaluate the safety and efficacy of febuxostat at doses of 40 mg and 80 mg compared to allopurinol at doses of 300 mg and 200 mg in patients with gout and hyperuricemia. A total of 2,269 patients were randomized: febuxostat 40 mg once daily (n=757), febuxostat 80 mg once daily (n=756), and allopurinol 300/200 mg once daily (n=756). At least 65% of patients had mild to moderate renal impairment (with creatinine clearance of 30–89 mL/min). Prophylaxis for gout flares was mandatory throughout the 26 weeks.

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

Primary endpoint in the subgroup of patients with renal impairment. The APEX study evaluated drug efficacy in 40 patients with renal impairment (i.e., baseline serum creatinine concentration > 1.5 mg/dL and ≤ 2.0 mg/dL). Patients randomized to the allopurinol group had their dose reduced to 100 mg once daily. The primary efficacy endpoint was achieved in febuxostat treatment groups in 44% of patients (80 mg once daily), 45% (120 mg once daily), and 60% (240 mg once daily), compared to 0% in the allopurinol 100 mg once daily and placebo groups.

Clinically significant differences in the percentage reduction of serum uric acid concentration were not observed between healthy volunteers regardless of renal function status (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 demonstrated that febuxostat was significantly more effective: serum uric acid levels decreased to < 6.0 mg/dL compared to allopurinol 300 mg/200 mg in patients with gout and mild to moderate renal impairment (65% of subjects).

Primary endpoint in the subgroup of patients with baseline serum uric acid concentration ≥ 10 mg/dL. Baseline serum uric acid concentration ≥ 10 mg/dL was observed in approximately 40% of patients (combined APEX and FACT studies). Among these patients, the primary efficacy endpoint (serum uric acid concentration < 6 mg/dL at the last three visits) was achieved in the febuxostat subgroups: 41% of patients (80 mg once daily), 48% of patients (120 mg once daily), and 66% of patients (240 mg once daily), compared to 9% in the allopurinol 300 mg/100 mg once daily 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 the last visit) in the subgroup of patients with baseline serum uric acid concentration ≥ 10 mg/dL, receiving febuxostat 40 mg once daily, was 27% (66/249), febuxostat 80 mg once daily—49% (125/254), allopurinol 300 mg/200 mg once daily—31% (72/230).

Clinical outcomes: percentage of patients requiring treatment for gout flares

APEX study: During the 8-week prophylactic period, 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 flares was higher after the prophylactic period and gradually decreased over time. From week 8 to week 28, 46% to 55% of patients required treatment for gout flares. Gout flares occurring during the last 4 weeks of the trial (weeks 24–28) were observed in 15% of patients (febuxostat 80 mg, 120 mg), 14% of patients (allopurinol 300 mg), and 20% of patients (placebo).

FACT study: During the 8-week prophylactic period, 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%) or allopurinol 300 mg (21%). During the 8-week prophylactic period, the frequency of flares increased and then gradually decreased over time (64% and 70% of patients receiving treatment for gout flares from week 8 to week 52). Gout flares during the last 4 weeks of the trial (weeks 49–52) were observed in 6–8% of patients (febuxostat 80 mg, 120 mg) and 11% of patients (allopurinol 300 mg).

The proportion of patients requiring treatment for 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 compared to groups where the mean uric acid level was ≥ 6.0 mg/dL during the last 32 weeks of treatment (from weeks 20–24 to weeks 49–52).

During the CONFIRMS study, the proportion of patients requiring treatment for gout flares (1 day every 6 months) was 31% and 25% in the groups receiving febuxostat 80 mg and allopurinol, respectively. No differences were observed in the proportion of patients requiring treatment for gout flares between the groups receiving febuxostat 80 mg and 40 mg.

Long-term extension open-label studies. EXCEL study (C02-021): EXCEL was a three-year, open-label, multicenter, randomized, extension, allopurinol-controlled Phase III safety study conducted to evaluate safety in patients who completed the main Phase III studies (APEX or FACT). A total of 1,086 patients were included in the study, receiving: febuxostat 80 mg once daily (n = 649), febuxostat 120 mg once daily (n = 292), or allopurinol 300/100 mg once daily (n = 145). Approximately 69% of patients did not require dose adjustment to achieve final stable treatment. Patients whose serum uric acid concentration exceeded 6.0 mg/dL in three consecutive measurements were excluded from the study.

Serum uric acid concentrations over time remained unchanged (e.g., in 91% and 93% of patients initially receiving febuxostat at doses of 80 mg and 120 mg, respectively, serum uric acid concentrations were less than 6.0 mg/dL at month 36).

Based on three-year follow-up data, in less than 4% of patients requiring treatment for flares, a reduction in gout flare frequency was observed at 16–24 months and 30–36 months (i.e., more than 96% of patients did not require flare treatment).

Complete disappearance of the primary palpable tophus from baseline to the last visit was observed in 46% and 38% of patients receiving final stable treatment with febuxostat at doses of 80 mg and 120 mg once daily, respectively.

The FOCUS study (TMX-01-005) was a five-year, open-label, multicenter, Phase II extension safety study conducted in patients who completed the 4-week double-blind dosing period of febuxostat in the TMX-00-004 trial. The study included 116 patients who initially received febuxostat 80 mg once daily. In 62% of patients, dose adjustment was not required to maintain serum uric acid concentration below 6.0 mg/dL, while 38% of patients required dose adjustment to achieve final stable concentration.

The proportion of patients with serum uric acid concentration below 6.0 mg/dL (357 µmol/L) at the last visit was greater than 80% (81–100%) in each febuxostat dose group.

In Phase III clinical trials, minor changes in liver function parameters were observed in patients receiving febuxostat (5.0%). The frequency of these changes was similar to that with allopurinol (4.2%) (see section "Special instructions"). In long-term open extension studies, elevated TSH [thyrotropin] levels (> 5.5 µIU/mL) were observed in patients receiving febuxostat (5.5%) or allopurinol (5.8%) over a prolonged period (see section "Special instructions").

Post-marketing long-term studies. The CARES study was a multicenter, randomized, double-blind, non-inferiority trial comparing cardiovascular outcomes with febuxostat versus allopurinol in patients with gout and a history of major cardiovascular diseases, including myocardial infarction, hospitalization for unstable angina, coronary or cerebral revascularization procedures, stroke, hospitalization for transient ischemic attack, peripheral vascular disease, or diabetes with signs of microangiopathy or macroangiopathy. To achieve serum uric acid (sUA) levels < 6 mg/dL, the dose of febuxostat was titrated from 40 mg to 80 mg (regardless of renal function), and the dose of allopurinol was titrated in 100 mg increments from 300 to 600 mg for patients with normal renal function and mild renal impairment, and from 200 to 400 mg for patients with moderate renal impairment.

The primary endpoint in the CARES study was time to first occurrence of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and unstable angina requiring urgent coronary revascularization.

Endpoints (primary and secondary) were evaluated using intention-to-treat (ITT) analysis, including all subjects who were randomized and received at least one dose of the study drug during the double-blind trial.

Overall, 56.6% of patients discontinued the trial treatment prematurely, and 45% of patients did not complete all study visits.

In total, 6,190 patients were observed for 32 months, with a mean exposure duration of 728 days in the febuxostat group (n = 3,098) and 719 days in the allopurinol group (n = 3,092).

The primary endpoint occurred at similar rates in the febuxostat and allopurinol treatment groups (10.8% vs. 10.4% of patients, respectively; risk ratio [RR] 1.03; two-sided repeated 95% confidence interval [CI] 0.89–1.21).

In the analysis of individual MACE components, the rate of cardiovascular mortality was higher in the febuxostat group compared to the allopurinol group (4.3% vs. 3.2% of patients; RR 1.34; 95% CI 1.03–1.73). The rates of other MACE components were similar between the febuxostat and allopurinol groups: non-fatal myocardial infarction (3.6% vs. 3.8% of patients; RR 0.93; 95% CI 0.72–1.21), non-fatal stroke (2.3% vs. 2.3% of patients; RR 1.01; 95% CI 0.73–1.41), and urgent revascularization due to unstable angina (1.6% vs. 1.8% of patients; RR 0.86; 95% CI 0.59–1.26).

The all-cause mortality rate was also higher in the febuxostat group compared to the allopurinol group (7.8% vs. 6.4% of patients; RR 1.22; 95% CI 1.01–1.47), primarily driven by higher cardiovascular mortality in this group (see section "Special instructions").

Rates of hospitalization for heart failure, hospitalization for non-ischemic arrhythmia, venous thromboembolic events, and hospitalization for transient ischemic attacks were comparable between the febuxostat and allopurinol groups.

The FAST study was a prospective, randomized, open-label, endpoint-blinded trial comparing the safety profile of febuxostat and allopurinol in cardiovascular diseases in patients with chronic hyperuricemia (in conditions where urate deposition has already occurred) and cardiovascular risk factors (i.e., patients aged 60 years or older with at least one cardiovascular risk factor). Eligible patients received allopurinol treatment prior to randomization, and dose adjustment was required as needed based on clinical assessment, EULAR [European League Against Rheumatism] recommendations, and approved dosing. At the end of the initial allopurinol treatment phase, patients with sUA levels < 0.36 mmol/L (<6 mg/dL) receiving the maximum tolerated or maximum allowed allopurinol dose were randomized in a 1:1 ratio to receive febuxostat or allopurinol. The primary endpoint of the FAST study was time to first occurrence of any event in the composite endpoint, including: 1) hospitalization for non-life-threatening myocardial infarction (MI) / positive biomarker acute coronary syndrome (ACS); 2) non-life-threatening stroke; 3) death due to cardiovascular disorders. The primary analysis was based on on-treatment (OT) analysis.

A total of 6,128 patients were randomized: 3,063 receiving febuxostat and 3,065 receiving allopurinol.

In the primary OT analysis, febuxostat was non-inferior to allopurinol regarding the frequency of the primary endpoint, observed in 172 patients (1.72/100 patient-years) receiving febuxostat compared to 241 patients (2.05/100 patient-years) receiving allopurinol, with an adjusted RR of 0.85 (95% CI: 0.70, 1.03), p < 0.001. The OT analysis for the primary endpoint in the subgroup of patients with a history of MI, stroke, or ACS showed no significant difference between treatment groups: 65 (9.5%) patients with adverse events in the febuxostat group and 83 (11.8%) patients in the allopurinol group; adjusted RR 1.02 (95% CI: 0.74–1.42); p = 0.202.

Treatment with febuxostat was not associated with an increased risk of cardiovascular mortality or all-cause mortality overall and in the subgroup of patients with a history of MI, stroke, or ACS. Overall, fewer deaths occurred in the febuxostat group (62 cases of cardiovascular death and 108 cases of all-cause mortality) compared to the allopurinol group (82 cases of cardiovascular death and 174 cases of all-cause mortality).

Greater reduction in uric acid levels was observed with febuxostat treatment compared to allopurinol treatment.

Tumor lysis syndrome (TLS). The efficacy and safety of febuxostat for the prevention and treatment of TLS were evaluated in the FLORENCE (FLO-01) study. Febuxostat demonstrated superior and faster action in reducing urate levels compared to allopurinol.

FLORENCE was a randomized (1:1), double-blind, active-controlled Phase III trial conducted to compare febuxostat 120 mg once daily with allopurinol 200–600 mg daily (mean daily allopurinol dose ± standard deviation: 349.7 ± 112.90 mg) under controlled serum uric acid concentration conditions. Eligible patients were candidates for allopurinol treatment or had no access to rasburicase. The primary endpoints were the area under the serum uric acid concentration curve (AUC sUA1–8) and change in serum creatinine (sC) from day 1 to day 8.

A total of 346 patients with hematologic malignancies receiving chemotherapy and at intermediate or high risk of developing TLS were included in the study. The mean AUC sUA1–8 (mg×h/dL) was significantly lower with febuxostat (514.0 ± 225.71 vs. 708.0 ± 234.42; least squares mean difference: –196.794 [95% CI: –238.600; –154.988]; p < 0.0001). Additionally, the mean serum uric acid level was significantly lower with febuxostat starting from the first 24 hours of treatment and at any subsequent time point. There were no statistically significant differences in mean serum creatinine (%) between febuxostat and allopurinol (–0.83 ± 26.98 vs. –4.92 ± 16.70, respectively; least squares mean difference: 4.0970 [95% CI: –0.6467; 8.8406]; p = 0.0903). Regarding secondary endpoints, there were no statistically significant differences in the incidence of laboratory-confirmed TLS (8.1% and 9.2% for febuxostat and allopurinol, respectively; RR: 0.875 [95% CI: 0.4408; 1.7369]; p = 0.8488) and clinical tumor lysis syndrome (1.7% and 1.2% for febuxostat and allopurinol, respectively; RR: 0.994 [95% CI: 0.9691; 1.0199]; p = 1.0000). The frequency of all treatment-emergent adverse events and adverse reactions was 67.6% vs. 64.7% and 6.4% vs. 6.4% for febuxostat and allopurinol, respectively. In the FLORENCE study, febuxostat demonstrated superior and faster action in reducing serum uric acid levels compared to allopurinol. Data comparing febuxostat with rasburicase are currently lacking. The efficacy and safety of febuxostat have not been established in patients with acute severe TLS, such as patients in whom other urate-lowering therapies are ineffective.

Pharmacokinetics.

In healthy volunteers, maximum plasma concentration (Cmax) and area under the curve (AUC) increased proportionally with dose after single and multiple doses of febuxostat ranging from 10 mg to 120 mg. At doses from 120 mg to 300 mg, the increase in AUC was greater than proportional to dose. With repeated administration of doses of 10–240 mg every 24 hours, accumulation of febuxostat was not observed. The predicted mean terminal elimination half-life (t1/2) of febuxostat was approximately 5–8 hours. A population pharmacokinetic/pharmacodynamic analysis was conducted using data from 211 patients with hyperuricemia and gout who received febuxostat at doses of 40–240 mg once daily. Overall, the obtained pharmacokinetic parameter values were similar to those in healthy volunteers, providing a good model for evaluating the pharmacokinetics/pharmacodynamics of the drug in patients with gout.

Absorption. Febuxostat is rapidly (tmax [time to maximum concentration] 1.0–1.5 hours) and well absorbed (at least 84%). After single and multiple oral doses of febuxostat 80 mg or 120 mg once daily, Cmax is 2.8–3.2 µg/mL and 5.0–5.3 µg/mL, respectively. The absolute bioavailability of febuxostat tablets has not been analyzed. With repeated administration at 80 mg once daily or single administration at 120 mg with a high-fat meal, Cmax decreased by 49% and 38%, and AUC decreased by 18% and 16%, respectively. However, this was not associated with clinically significant changes in the degree of reduction of plasma uric acid levels (with repeated administration at 80 mg). Thus, febuxostat can be administered independently of food intake.

Distribution. The predicted steady-state volume of distribution (Vss/F) of febuxostat ranges from 29 to 75 L after oral administration of 10–300 mg. The extent of plasma protein binding (primarily to albumin) is 99.2% and does not change with increasing dose from 80 mg to 120 mg. For active metabolites of febuxostat, the extent of plasma protein binding ranges from 82% to 91%.

Metabolism. Febuxostat is extensively metabolized via conjugation by uridine diphosphate-glucuronosyltransferases (UDP-glucuronosyltransferases) and oxidation by cytochrome P450 (CYP) enzymes. Four pharmacologically active hydroxyl metabolites of febuxostat have been described, three of which have been identified in human plasma. In vitro studies using human liver microsomes showed that these oxidized metabolites are formed predominantly by CYP1A1, CYP1A2, CYP2C8, and CYP2C9, while febuxostat glucuronide is formed primarily by UDP-glucuronosyltransferase 1A1, 1A8, and 1A9.

Excretion. Febuxostat is eliminated via the liver and kidneys. After oral administration of 14C-febuxostat 80 mg, approximately 49% was excreted in urine as unchanged febuxostat (3%), active substance acylglucuronide (30%), known oxidized metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to renal excretion, approximately 45% was excreted in feces as unchanged febuxostat (12%), active substance acylglucuronide (1%), known oxidized metabolites and their conjugates (25%), and other unknown metabolites (7%).

Renal impairment. With repeated administration of febuxostat 80 mg, no changes in Cmax of febuxostat were observed in patients with mild, moderate, or severe renal impairment compared to patients with normal renal function. The mean total AUC of febuxostat increased approximately 1.8-fold from 7.5 µg×h/mL in patients with normal renal function to 13.2 µg×h/mL in patients with severe renal impairment. Cmax and AUC of active metabolites increased 2-fold and 4-fold, respectively. However, dose adjustment of the drug is not required in patients with mild or moderate renal impairment.

Hepatic impairment. With repeated administration of febuxostat 80 mg, no significant changes in Cmax and AUC of febuxostat and its metabolites were observed in patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment compared to patients with normal liver function. The drug has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Age. With repeated oral administration of febuxostat, no significant changes in AUC of febuxostat and its metabolites were observed in elderly patients compared to young healthy volunteers.

Gender. With repeated oral administration of febuxostat, Cmax and AUC of febuxostat in women were 24% and 12% higher, respectively, than in men. However, Cmax and AUC adjusted for body weight were similar in both groups; therefore, dose adjustment of febuxostat based on gender is not required.

Clinical characteristics.

Indications.

Uloric® 80 mg and Uloric® 120 mg

Treatment of chronic hyperuricemia in diseases associated with deposition of urate crystals, including presence of tophi and/or current or past history of gouty arthritis.

Uloric® 120 mg

Treatment and prevention of hyperuricemia in adult patients undergoing chemotherapy for hematologic malignancies with moderate or high risk of tumor lysis syndrome (TLS).

The medicinal product Uloric® is indicated for adult patients.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".

Interaction with other medicinal products and other forms of interaction.

Mercaptopurine/azathioprine.

Due to its mechanism of action, febuxostat inhibits xanthine oxidase; therefore, concomitant use is not recommended. Inhibition of xanthine oxidase may lead to increased plasma concentrations of both drugs, potentially causing myelotoxic reactions.

If co-administration with febuxostat is necessary, the dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose (see section "Special instructions for use").

The adequacy of this proposed dose adjustment, based on modeling and simulation analysis of preclinical data in rats, has been confirmed by results of a clinical drug interaction study involving healthy volunteers who received azathioprine 100 mg alone and reduced dose azathioprine (25 mg) in combination with febuxostat (40 or 120 mg).

There are no safety data on the use of febuxostat during cytotoxic chemotherapy.

Studies on the interaction of febuxostat with other cytotoxic chemotherapeutic agents have not been conducted.

Rosiglitazone / CYP2C8 substrates.

Febuxostat is a weak inhibitor of CYP2C8 in vitro. In a study, concomitant administration of 120 mg febuxostat once daily and a single oral dose of 4 mg rosiglitazone in healthy volunteers did not affect the pharmacokinetics of rosiglitazone or its metabolite N-desmethylrosiglitazone, demonstrating that febuxostat does not inhibit the CYP2C8 enzyme in vivo. Therefore, concomitant administration of febuxostat with rosiglitazone or other CYP2C8 substrates does not require dose adjustment of these drugs.

Theophylline. An interaction study with febuxostat was conducted in healthy volunteers to evaluate the potential effect of xanthine oxidase inhibition on increased circulating levels of theophylline, as observed with other xanthine oxidase inhibitors. Concomitant administration of febuxostat 80 mg and theophylline 400 mg did not result in any pharmacokinetic interactions or impact on the safety of theophylline. Thus, febuxostat 80 mg can be used concomitantly with theophylline without special precautions. Data on febuxostat 120 mg dose are not available.

Naproxen and other inhibitors of glucuronidation.

Metabolism of febuxostat depends on the activity of the enzyme UDP-glucuronosyltransferase. Medicinal products that inhibit glucuronidation, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and probenecid, may theoretically alter the elimination of febuxostat. In healthy volunteers, concomitant administration of febuxostat and naproxen 250 mg twice daily resulted in enhanced effect of febuxostat (Cmax increased by 28%, AUC by 41%, t1/2 (half-life) by 26%). During clinical trials, the use of naproxen and other NSAIDs/COX-2 inhibitors was not associated with clinically significant increase in adverse reactions.

Febuxostat can be used concomitantly with naproxen without changing the doses of either drug.

Inducers of glucuronidation.

Potent inducers of UDP-glucuronosyltransferase may enhance metabolism and reduce the efficacy of febuxostat. In patients receiving potent inducers of glucuronidation, plasma uric acid levels should be monitored 1–2 weeks after initiation of concomitant therapy. Upon discontinuation of the glucuronidation inducer, plasma levels of febuxostat may increase.

Colchicine/indomethacin/hydrochlorothiazide/warfarin.

Febuxostat can be used concomitantly with colchicine or indomethacin without changing the doses of these drugs.

Dose adjustment of febuxostat is also not required when used concomitantly with hydrochlorothiazide.

Concomitant use of febuxostat with warfarin does not require dose adjustment of the latter. Administration of febuxostat (80 mg or 120 mg once daily) with warfarin in healthy volunteers did not affect the pharmacokinetics of warfarin. Concomitant use with febuxostat also had no effect on INR (International Normalized Ratio) or factor VII activity.

Desipramine / CYP2D6 substrates.

In vitro data indicate that febuxostat is a weak inhibitor of CYP2D6. In studies involving healthy volunteers receiving 120 mg febuxostat once daily, an increase in AUC of desipramine (a CYP2D6 substrate) by 22% was observed, indicating weak inhibitory effect of febuxostat on CYP2D6 enzyme in vivo.

Thus, when febuxostat is used concomitantly with CYP2D6 substrates, there is no need to change their doses.

Antacids.

Concomitant use with antacids containing magnesium hydroxide and aluminum hydroxide results in delayed absorption of febuxostat (by approximately 1 hour) and a 32% reduction in Cmax; however, the AUC of febuxostat is not significantly altered. Therefore, febuxostat can be combined with antacid agents.

Special precautions for use.

Cardiovascular diseases.

In patients with serious cardiovascular diseases (e.g., myocardial infarction, stroke, or unstable angina), a higher number of life-threatening cardiovascular events were observed with febuxostat compared to allopurinol during drug development and in one post-marketing study (CARES).

However, a subsequent post-marketing study (FAST) demonstrated that febuxostat was non-inferior to allopurinol regarding the incidence of both life-threatening and non-life-threatening cardiovascular events.

Treatment of this patient group should be carried out with caution and their condition should be monitored regularly. For more detailed information on the cardiovascular safety of febuxostat, see sections "Pharmacodynamics" and "Undesirable effects".

Prevention and treatment of hyperuricemia in patients at risk of tumor lysis syndrome (TLS).

Patients undergoing chemotherapy for hematological malignancies with moderate or high risk of TLS who are receiving the medicinal product Lekvestia® should be under cardiologist supervision when clinically indicated.

Allergy/hypersensitivity to medicinal products.

Rare cases of serious allergic reactions/hypersensitivity reactions, including life-threatening Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute anaphylactic reactions/shock, have been reported in post-marketing surveillance. These reactions mostly occurred within the first month of febuxostat treatment. Renal impairment and/or history of allopurinol hypersensitivity were present in several, but not all, patients. Severe hypersensitivity reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have in some cases been associated with fever, hematological disorders, and renal or hepatic insufficiency.

Patients should be informed about the signs and symptoms of hypersensitivity/allergy and monitored for the development of such reactions. If serious allergic reactions/hypersensitivity reactions occur, including Stevens-Johnson syndrome, febuxostat must be discontinued immediately, as early discontinuation improves the prognosis. Re-administration of febuxostat is contraindicated in patients who have previously experienced an allergic reaction/hypersensitivity reaction, including Stevens-Johnson syndrome, or acute anaphylactic reactions/shock.

Acute gout flare (gout attack).

Treatment with febuxostat should only be initiated after an acute gout flare has subsided. Febuxostat may provoke gout flares at the beginning of treatment due to changes in serum uric acid levels caused by mobilization of urate from tissue deposits. At the start of febuxostat treatment, prophylactic therapy with NSAIDs or colchicine is recommended for at least 6 months to prevent gout flares.

If a gout flare occurs during febuxostat treatment, the treatment should be continued. Concomitant appropriate individual therapy for the acute gout flare should be administered. With prolonged use of febuxostat, the frequency and severity of gout flares decrease.

Xanthine deposition.

In patients with accelerated urate production (e.g., due to malignancies and their treatment or in Lesch-Nyhan syndrome), a significant increase in absolute urinary xanthine concentration may occur, which in rare cases may lead to xanthine deposition in the urinary tract. This was not observed in the pivotal clinical trials of febuxostat in TLS. Due to limited experience with febuxostat use, it is not recommended for patients with Lesch-Nyhan syndrome.

Mercaptopurine/azathioprine.

Concomitant use of febuxostat with mercaptopurine/azathioprine is not recommended, as inhibition of xanthine oxidase by febuxostat may increase plasma concentrations of mercaptopurine/azathioprine and lead to severe toxicity.

If combination therapy cannot be avoided, patients should be closely monitored. A dose reduction of mercaptopurine or azathioprine to 20% or less of the previously prescribed dose is recommended to avoid potential hematological effects (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be carefully monitored, and the dose of mercaptopurine/azathioprine should be adjusted according to therapeutic response and potential toxic effects.

Patients who have undergone organ transplantation.

There is no experience with the use of febuxostat in this patient group; therefore, the use of the medicinal product is not recommended.

Theophylline.

Single concomitant administration of febuxostat 80 mg and theophylline 400 mg showed no pharmacokinetic interactions. Febuxostat 80 mg may be administered concomitantly with theophylline without risk of increased theophylline plasma concentrations. Data for febuxostat 120 mg are not available.

Hepatic impairment.

During combined phase III clinical trials, minor changes in liver function parameters were observed in 5.0% of patients receiving febuxostat. Therefore, liver function tests are recommended before initiating febuxostat treatment and during therapy when clinically indicated.

Thyroid disorders.

Elevated TSH levels (> 5.5 mU/mL) were observed in 5.5% of patients receiving long-term febuxostat treatment during long-term open-label extension studies. Therefore, the medicinal product should be prescribed with caution in patients with thyroid dysfunction.

Lactose.

The medicinal product contains lactose. If a patient has been diagnosed with intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

Limited experience with febuxostat use during pregnancy indicates no adverse effects on pregnancy course or fetal/neonatal health. Animal studies did not reveal any direct or indirect harmful effects on pregnancy, embryonic/fetal development, or parturition. The potential risk for humans is unknown. Febuxostat should not be used during pregnancy.

Breastfeeding period

It is unknown whether febuxostat passes into human breast milk. Animal studies have shown that febuxostat is excreted in milk and has a negative effect on the development of suckling newborns. The risk of drug transfer into breast milk cannot be excluded. Febuxostat should not be used during breastfeeding.

Fertility

Fertility studies in animals at a dose of 48 mg/kg/day did not reveal dose-dependent adverse effects. The effect of the medicinal product Lekvestia® on human reproductive function is unknown.

Ability to influence reaction rate when driving or operating machinery.

Cases of somnolence, dizziness, paresthesia, and blurred vision have been reported during febuxostat treatment. Therefore, patients taking the medicinal product Lekvestia® are advised to exercise caution when driving or operating machinery until they are certain that these adverse effects do not occur.

Method of Administration and Dosage.

Dosage

Gout. The recommended dose of the medicinal product Lyquestia® is 80 mg once daily orally, independent of food intake. If serum uric acid concentration exceeds 6 mg/dL (357 µmol/L) after 2–4 weeks of treatment, increasing the dose of Lyquestia® to 120 mg once daily should be considered. The effect of the drug manifests quite rapidly, allowing repeat measurement of serum uric acid concentration after 2 weeks. The goal of treatment is to reduce serum uric acid concentration and maintain it below 6 mg/dL (357 µmol/L).

The duration of gout attack prophylaxis should be at least 6 months.

Tumor Lysis Syndrome (TLS). The recommended dose of the medicinal product Lyquestia® is 120 mg once daily orally, independent of food intake.

Administration of Lyquestia® should be initiated two days prior to the start of cytotoxic therapy and continued for at least 7 days; however, the duration of treatment may be extended up to 9 days depending on the duration of chemotherapy and clinical assessment.

Elderly patients. Dose adjustment is not required for this patient population.

Renal impairment. The efficacy and safety of the medicinal product have not been sufficiently studied in patients with severe renal impairment (creatinine clearance < 30 mL/min). Dose adjustment is not required in patients with mild or moderate renal impairment.

Hepatic impairment. The efficacy and safety of febuxostat have not been studied in patients with severe hepatic impairment (Child–Pugh class C).

Gout. In patients with mild hepatic impairment, the recommended dose is 80 mg. Experience with the medicinal product in patients with moderate hepatic impairment is limited.

Tumor Lysis Syndrome (TLS). In the pivotal phase III study (FLORENCE), only subjects with severe hepatic impairment were excluded. For patients included in the study, dose adjustment based on hepatic function was not required.

Method of Administration

For oral use.

Lyquestia® is administered orally, independent of food intake.

Children.

Safety and efficacy of Lyquestia® in children (under 18 years of age) have not been established. Data on use are lacking.

Overdose.

In case of overdose, symptomatic and supportive therapy is indicated.

Adverse Reactions

Summary of Safety Profile

The most commonly reported adverse reactions in clinical trials (4072 patients receiving doses from 10 to 300 mg), post-marketing safety studies (FAST study: 3001 patients receiving doses from 80 to 120 mg), and during post-marketing surveillance in patients with gout were gout flares, hepatic function abnormalities, diarrhea, nausea, headache, dizziness, dyspnea, rash, pruritus, arthralgia, myalgia, limb pain, edema, and fatigue. These reactions were mostly mild to moderate in severity. During post-marketing surveillance, there have been reports of rare cases of serious hypersensitivity reactions to febuxostat, some of which were accompanied by systemic reactions, as well as rare cases of sudden cardiac death.

Table 2 lists the adverse reactions observed in patients treated with febuxostat. Adverse reactions are classified by frequency as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), and rare (≥ 1/10000 to < 1/1000). Frequency is based on clinical trials and post-marketing experience in patients with gout.

Within each frequency category, adverse reactions are listed in order of decreasing severity.

Table 2.

Adverse reactions observed during Phase III combined extension long-term studies, post-marketing safety studies, and post-marketing surveillance in patients with gout.

* Adverse reactions identified from post-marketing experience.

** Diarrhea requiring treatment and abnormal liver function tests observed in Phase III studies occurred more frequently in patients receiving concomitant colchicine therapy.

*** See section "Pharmacodynamics" for frequency of gout flares observed in Phase III of individual randomized controlled trials.

Adverse reactions observed during post-approval safety monitoring.

Description of selected adverse reactions.

During post-marketing surveillance, rare cases of serious hypersensitivity reactions to febuxostat have been reported, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylactic reactions/shock. Stevens-Johnson syndrome and toxic epidermal necrolysis are characterized by progressive skin rash with bullous lesions of the skin or mucous membranes and mucosal irritation of the eyes. Hypersensitivity reactions to febuxostat may present with symptoms such as skin reactions characterized by infiltrated maculopapular rashes, generalized or exfoliative rashes, skin lesions, facial swelling, fever, hematological disorders such as thrombocytopenia and eosinophilia, and involvement of single or multiple organs (liver and kidneys, including tubulointerstitial nephritis).

Gout flares were commonly observed shortly after initiation of treatment and during the first months of therapy. The frequency of gout flares decreased over time. Prophylaxis for acute gout flares is recommended when initiating febuxostat therapy.

Tumor lysis syndrome (TLS).

Summary of safety profile.

In a randomized, double-blind, active-controlled Phase III FLORENCE (FLO-01) study comparing febuxostat and allopurinol in 346 patients undergoing chemotherapy for hematologic malignancies with moderate or high risk of TLS, only 22 (6.4%) patients experienced adverse reactions, with 11 (6.4%) in each treatment group. The majority of adverse reactions were of mild or moderate severity.

Overall, during the FLORENCE study, no additional safety concerns were identified for febuxostat use in patients with gout, except for the three adverse reactions listed below (see Table 2).

Cardiac disorders: uncommon — left bundle branch block, sinus tachycardia.

Vascular disorders: uncommon — hemorrhage.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. This medicinal product does not require special storage conditions.

Keep out of reach and sight of children.

Packaging. 14 tablets in a blister. 2 or 4 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak" (packaging of bulk product manufactured by GenePharm S.A., Greece).

Address of the manufacturer and location of business operations.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.