INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EUROFEB (EUROFEB)

Composition:

Active substance: febuxostat;

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

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

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: film-coated tablets, oblong-shaped, biconvex, pale yellow to yellow in color, with "80" or "120" engraved on one side and smooth surface on the other side.

Pharmacotherapeutic group. Medicinal products for the treatment of gout. Uric acid synthesis inhibitors. ATC code M04AA03.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Uric acid is the end product of purine metabolism in humans and is formed through the following reaction: hypoxanthine → xanthine → uric acid. Xanthine oxidase catalyzes both steps of this reaction. Febuxostat is a 2-arylthiazole derivative, and its therapeutic effect is related to reducing serum uric acid concentration by selectively inhibiting xanthine oxidase. Febuxostat is a potent and selective non-purine inhibitor of xanthine oxidase (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 inhibit other enzymes involved in purine or pyrimidine metabolism, such as guanidine deaminase, hypoxanthine-guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase, or purine nucleoside phosphorylase.

Clinical efficacy and safety

Gout

The efficacy of febuxostat was confirmed in three pivotal phase 3 studies (two main studies, APEX and FACT, and an additional study, CONFIRMS, described below), which included 4101 patients with hyperuricemia and gout. In each of these pivotal phase 3 studies, febuxostat was more effective than allopurinol in lowering and maintaining serum uric acid concentration at the desired level. The primary efficacy endpoint in the APEX and FACT studies was the proportion of patients who maintained serum uric acid concentration below 6.0 mg/dL (357 µmol/L) during the last three months. In the additional phase 3 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 below 6.0 mg/dL at the last visit. Patients who had undergone organ transplantation were not included in these studies (see section "Special precautions").

Study APEX. The phase 3 Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX) was a randomized, double-blind, multicenter trial lasting 28 weeks. 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), or allopurinol 300 mg once daily (n=258) for patients with baseline serum creatinine concentration ≤ 1.5 mg/dL, or 100 mg once daily (n=10) for patients with baseline serum creatinine concentration > 1.5 mg/dL and ≤ 2.0 mg/dL. For safety assessment, febuxostat was administered at a dose of 240 mg (twice the maximum recommended dose).

Study APEX demonstrated a statistically significant advantage 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 below 6 mg/dL (357 µmol/L) (see Table 1 and Figure 1).

Study FACT. The phase 3 Febuxostat Allopurinol Controlled Trial (FACT) was a randomized, double-blind, multicenter study lasting 52 weeks. A total of 760 patients were randomized: febuxostat 80 mg once daily (n=256), febuxostat 120 mg once daily (n=251), or allopurinol 300 mg once daily (n=253).

Study FACT demonstrated a statistically significant advantage of both febuxostat regimens—80 mg once daily and 120 mg once daily—compared to allopurinol at the usual dose of 300 mg in reducing and maintaining serum uric acid concentration below 6 mg/dL (357 µmol/L).

Table 1 presents the results of the primary efficacy endpoint assessment.

Table 1

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

Study	Febuxostat 80 mg once daily	Febuxostat 120 mg once daily	Allopurinol 300/100 mg once daily1
APEX (28 weeks)	48 %* (n=262)	65 %*, # (n=269)	22 % (n=268)
FACT (52 weeks)	53 %* (n=255)	62 %* (n=250)	21 % (n=251)
Pooled results	51 %* (n=517)	63 %*, # (n=519)	22 % (n=519)
1 Results from patients receiving 100 mg once daily (n = 10: patients with baseline serum creatinine > 1.5 mg/dL and ≤ 2.0 mg/dL) or 300 mg once daily (n=509) were combined in the analysis. * p < 0.001 vs allopurinol, # p < 0.001 vs 80 mg dose.

When febuxostat was administered, the reduction in 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 treatment. Figure 1 shows mean serum uric acid concentrations over time for each treatment group in both pivotal phase 3 studies.

Figure 1

Mean serum uric acid concentrations from combined pivotal studies (phase 3)

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 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 randomized, controlled phase 3 trial of 26 weeks duration, 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 2269 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 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% for febuxostat 40 mg, 67% for febuxostat 80 mg, and 42% for allopurinol 300/200 mg, respectively.

Primary efficacy endpoint in the subgroup of patients with renal impairment

In the APEX study, efficacy was evaluated in a subgroup of 40 patients with renal impairment (i.e., baseline serum creatinine concentration > 1.5 mg/dL and ≤ 2.0 mg/dL). For such patients randomized to the allopurinol group, the dose was reduced to 100 mg once daily. The primary efficacy endpoint was achieved in the febuxostat group 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 in 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 efficacy 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 < 6.0 mg/dL at the last 3 visits) was achieved in the febuxostat subgroup in 41% of patients (80 mg once daily), 48% (120 mg once daily), and 66% (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 who received febuxostat 40 mg once daily was 27% (66/249), febuxostat 80 mg once daily 49% (125/254), and allopurinol 300 mg/200 mg once daily 31% (72/230).

Clinical outcomes: proportion of patients requiring treatment for gout flares

APEX study. During the 8-week prophylactic period, the proportion of patients in the febuxostat 120 mg treatment group requiring treatment for gout flares was 36%, compared to 28% in the febuxostat 80 mg group, 23% in the allopurinol 300 mg group, and 20% in the placebo group. The flare frequency was higher after the prophylactic period and gradually decreased over time. From week 8 to week 28, 46–55% of patients were treated for gout flares. Gout flares occurring during the last 4 weeks of the trial (24–28 weeks) 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, the proportion of patients in the febuxostat 120 mg treatment group requiring treatment for gout flares was 36%, compared to 22% in the febuxostat 80 mg group and 21% in the allopurinol 300 mg group. After the 8-week prophylactic period, flare frequency increased and then gradually decreased (64% and 70% of patients received treatment for gout flares from weeks 8–52). Gout flares during the last 4 weeks of the trial (49–52 weeks) 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 febuxostat 80 mg and 40 mg groups.

Long-term extension open-label studies

EXCEL study (C02-021). The EXCEL study was a 3-year, open-label, multicenter, randomized, allopurinol-controlled phase 3 safety extension study conducted to evaluate safety in patients who completed the pivotal phase 3 studies (APEX or FACT). A total of 1086 patients were included: febuxostat 80 mg once daily (n=649), febuxostat 120 mg once daily (n=292), and 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 was > 6.0 mg/dL in three consecutive measurements were excluded from the study.

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

Based on 3-year follow-up data, less than 4% of patients requiring treatment for flares showed a decrease in gout flare frequency at months 16–24 and 30–36 (i.e., more than 96% of patients did not require flare treatment).

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

The FOCUS study (TMX-01-005) was a 5-year, open-label, multicenter, phase 2 safety extension study conducted in patients who completed a 4-week double-blind dosing of febuxostat in the TMX-00-004 trial. The study included 116 patients initially receiving febuxostat 80 mg once daily. Dose adjustment was not required in 62% of patients 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%) for each febuxostat dose group.

In phase 3 clinical studies, 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-label extension studies, increases in TSH 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 disease, including myocardial infarction, hospitalization for unstable angina, coronary or cerebral revascularization procedure, stroke, hospitalization for transient ischemic attack, peripheral vascular disease, or diabetes with signs of microangiopathy or macroangiopathy. The dose of febuxostat was titrated from 40 mg to 80 mg (regardless of renal function) to achieve an sUA level < 6 mg/dL, and the dose of allopurinol was titrated in 100 mg increments from 300 to 600 mg for patients with normal renal function or 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 MACE (major adverse cardiovascular events), a composite of non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and unstable angina requiring urgent coronary revascularization.

Endpoints (primary and secondary) were analyzed according to the intention-to-treat (ITT) principle, including all subjects who were randomized and received at least one dose of study drug during the double-blind period.

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

A total of 6190 patients were followed for 32 months; the mean duration of exposure was 728 days in the febuxostat group (n=3098) and 719 days in the allopurinol group (n=3092).

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

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

The all-cause mortality rate was also higher in the febuxostat group than in the allopurinol group (7.8% vs. 6.4% of patients; HR 1.22; 95% CI 1.01–1.47), primarily driven by the higher cardiovascular mortality rate 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 febuxostat and allopurinol.

The FAST study was a prospective, randomized, open-label trial with endpoint adjudication, comparing the cardiovascular safety profile of febuxostat and allopurinol in patients with chronic hyperuricemia (where urate deposition had already occurred) and risk factors for cardiovascular disease (CVD) (i.e., patients aged 60 years or older with at least one additional CVD risk factor). Patients meeting study entry criteria received allopurinol treatment prior to randomization, and if needed, their dose was adjusted based on clinical assessment, European League Against Rheumatism (EULAR) recommendations, and approved dosing guidelines. At the end of the allopurinol lead-in phase, patients with serum uric acid concentration (sUA) < 0.36 mmol/L (< 6 mg/dL) or those receiving the maximum tolerated or maximum allowed allopurinol dose were randomized in a 1:1 ratio to receive either febuxostat or continue allopurinol. The primary endpoint of the FAST study was time to first occurrence of any event included in the Antiplatelet Trialists’ Collaborative (APTC) composite endpoint, including:

• hospitalization for non-fatal myocardial infarction (MI)/acute coronary syndrome (ACS) with positive biomarker response;
• non-fatal stroke;
• death due to cardiovascular complications.

The primary analysis was based on a treatment-emergent approach.

Overall, 6128 patients were randomized, of whom 3063 received febuxostat and 3065 received allopurinol.

In the primary analysis of treatment-emergent patient data, febuxostat was non-inferior to allopurinol regarding the frequency of the primary endpoint, which occurred in 172 patients (1.72/100 patient-years) in the febuxostat group compared to 241 patients (2.05/100 patient-years) in the allopurinol group, with an adjusted hazard ratio [HR] of 0.85 (95% CI: 0.70, 1.03), p < 0.001. The analysis of treatment-emergent patient data for the primary endpoint in the subgroup of patients with prior MI, stroke, or ACS did not show a significant difference between treatment groups: 635 (9.5%) patients with events in the febuxostat group and 83 (11.8%) patients with events in the allopurinol group; adjusted hazard ratio [HR] 1.02 (95% CI: 0.74–1.42); p = 0.202.

Treatment with febuxostat was not associated with increased cardiovascular or all-cause mortality either overall or in the subgroup of patients with prior MI, stroke, or ACS. Overall, fewer deaths occurred in the febuxostat group (62 cardiovascular deaths and 108 deaths from other causes) compared to the allopurinol group (82 cardiovascular deaths and 174 deaths from other causes).

Treatment with febuxostat resulted in greater reduction in uric acid levels 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 urate-lowering effect compared to allopurinol.

FLORENCE was a randomized (1:1), double-blind, controlled phase III trial comparing febuxostat 120 mg once daily with allopurinol 200–600 mg daily (mean daily allopurinol dose [± standard deviation]: 349.7 ± 112.90 mg) under conditions of serum uric acid concentration control. Eligible patients were candidates for allopurinol treatment or had no access to rasburicase. Primary endpoints were the area under the serum uric acid concentration-time curve (AUC sUA1-8) and change in serum creatinine (sCr) 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 enrolled. 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 was no statistically significant difference in mean serum creatinine change (%) 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 was no statistically significant difference in the incidence of laboratory-confirmed TLS (8.1% and 9.2% for febuxostat and allopurinol, respectively; relative risk: 0.875 [95% CI: 0.4408; 1.7369]; p=0.8488) or clinical tumor lysis syndrome (1.7% and 1.2% for febuxostat and allopurinol, respectively; relative risk: 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 serum uric acid-lowering effect compared to allopurinol. Data comparing febuxostat with rasburicase are currently unavailable. 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 to 120 mg. At doses from 120 to 300 mg, the increase in AUC was greater than proportional to dose. With dosing 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 consistent with those in healthy volunteers, which thus serve as 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 80 mg or 120 mg once daily, Cmax was 2.8–3.2 µg/mL and 5.0–5.3 µg/mL, respectively. The absolute bioavailability of febuxostat tablets was not analyzed. With multiple dosing at 80 mg once daily or single dosing at 120 mg in combination 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 serum uric acid reduction (with multiple dosing at 80 mg). Therefore, febuxostat can be administered regardless of food intake.

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

Metabolism. Febuxostat is extensively metabolized via conjugation by uridine diphosphate glucuronosyltransferases (UGT) and oxidation by cytochrome P450 (CYP) enzymes. A total of four pharmacologically active hydroxyl metabolites of febuxostat have been identified, three of which were detected in human plasma. In vitro studies using human liver microsomes indicated that these oxidized metabolites are formed predominantly by CYP1A1, CYP1A2, CYP2C8, or CYP2C9, whereas febuxostat glucuronide is formed mainly by UGT1A1, 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% of the dose 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 multiple dosing 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. Mean total AUC of febuxostat increased by approximately 1.8-fold: from 7.5 µg × hour/mL in patients with normal renal function to 13.2 µg × hour/mL in patients with severe renal impairment. Cmax and AUC of active metabolites increased by 2 and 4 times, respectively. However, dose adjustment of the drug is not required in patients with mild or moderate renal impairment.

Hepatic impairment

With multiple dosing 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 multiple oral dosing of febuxostat, no significant changes in AUC of febuxostat and its metabolites were observed in elderly patients compared to younger healthy volunteers.

Gender

With multiple oral dosing 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 between the two groups; therefore, dose adjustment of febuxostat based on gender is not required.

Clinical characteristics

Indications

EUROFEB at a dose of 80 mg and 120 mg

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

EUROFEB at a dose of 120 mg

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

EUROFEB is indicated for adult patients.

Contraindications

Hypersensitivity to the active substance or to any of the other 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. When febuxostat is administered concomitantly, doses of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose (see section "Special warnings and precautions 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 in healthy volunteers who received azathioprine 100 mg alone and reduced-dose azathioprine (25 mg) in combination with febuxostat (40 or 120 mg). Drug–drug and drug–disease interactions have not been studied during cytotoxic chemotherapy. In the pivotal study, patients with TLS received febuxostat 120 mg with various chemotherapy regimens, including monoclonal antibodies. However, drug–drug and drug–disease interactions were not specifically investigated in this study. Therefore, potential interactions with any co-administered cytotoxic agents cannot be excluded.

Rosiglitazone/CYP2C8 substrates

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

Theophylline

A drug interaction study in healthy volunteers was conducted to evaluate the potential for xanthine oxidase inhibition to increase circulating theophylline levels, as observed with other xanthine oxidase inhibitors. Results showed that co-administration of febuxostat 80 mg and theophylline 400 mg resulted in no pharmacokinetic interactions or effects on theophylline safety. Thus, febuxostat 80 mg may be administered concomitantly with theophylline without special precautions. Data for febuxostat 120 mg are not available.

Naproxen and other inhibitors of glucuronidation

Febuxostat metabolism depends on the activity of the enzyme UDP-glucuronosyltransferase. Medicinal products that inhibit glucuronidation, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and probenecid, could theoretically affect febuxostat elimination. In healthy volunteers, co-administration of febuxostat with naproxen 250 mg twice daily resulted in increased exposure to febuxostat (Cmax increased by 28%, AUC by 41%, t1/2 by 26%). In clinical studies, the use of naproxen and other NSAIDs/COX-2 inhibitors was not associated with clinically significant increases in adverse reactions.

Febuxostat may be co-administered with naproxen without dose adjustment.

Inducers of glucuronidation

Potent inducers of the enzyme 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 may be co-administered with colchicine or indomethacin without dose adjustment.

Dose adjustment of febuxostat is also not required when co-administered with hydrochlorothiazide.

Concomitant administration 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 or factor VII activity.

Desipramine/CYP2D6 substrates

In vitro data indicate that febuxostat is a weak inhibitor of CYP2D6. In studies in 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 in vivo.

Therefore, no dose adjustment is required when febuxostat is co-administered with CYP2D6 substrates.

Antacids

Concomitant administration with antacids containing magnesium hydroxide and aluminium 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 may be administered with antacids.

Special precautions for use

Cardiovascular diseases

Treatment of chronic hyperuricemia

During the development of the medicinal product and in one post-marketing study (CARES), a higher number of cardiovascular adverse events leading to death were observed in patients with pre-existing major cardiovascular diseases (e.g., myocardial infarction, stroke, or unstable angina) treated with febuxostat compared to allopurinol.

However, in a subsequent post-marketing study (FAST), febuxostat was non-inferior to allopurinol regarding the frequency of both fatal and non-fatal cardiovascular adverse events. Treatment of this patient group should be performed cautiously with regular monitoring.

For further details on the cardiovascular safety of febuxostat, see sections "Adverse reactions" and "Pharmacodynamics".

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 febuxostat should, when clinically indicated, be under cardiologist supervision.

Allergy/hypersensitivity to medicinal products

In the context of post-marketing surveillance, rare cases of serious allergic/hypersensitivity reactions have been reported, including life-threatening Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute anaphylactic reactions/shock. In most cases, such reactions occurred within the first month of febuxostat treatment. Renal function impairment and/or history of allopurinol hypersensitivity were observed in several, but not all, patients. Severe hypersensitivity reactions, including those associated with eosinophilia and systemic symptoms (DRESS syndrome), were in some cases accompanied by fever, hematological, renal, or hepatic dysfunction.

Patients should be informed about the signs and symptoms of hypersensitivity/allergy and should be monitored for the development of such reactions. Febuxostat must be discontinued immediately upon the occurrence of serious allergic/hypersensitivity reactions, including Stevens-Johnson syndrome, as early discontinuation improves prognosis. Re-administration of febuxostat is contraindicated if the patient has experienced an allergic/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 urates from tissue deposits. At the start of febuxostat treatment, prophylactic administration of NSAIDs or colchicine for at least 6 months is recommended 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 febuxostat use, the frequency and severity of gout flares decrease.

Xanthine deposition

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

Azathioprine/mercaptopurine

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

If co-administration cannot be avoided, the dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose to prevent potential hematological effects (see section "Interaction with other medicinal products and other types of interactions").

Patients should be closely monitored, and the dose of mercaptopurine/azathioprine should be adjusted based on assessment of therapeutic response and the occurrence of possible toxic effects.

Patients who have undergone organ transplantation

There is no experience with the use of febuxostat in this patient population; therefore, the use of the drug is not recommended.

Theophylline

Single-dose co-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 plasma theophylline concentrations. Data for febuxostat 120 mg are not available.

Hepatic impairment

In the combined phase 3 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 and during treatment as clinically indicated.

Thyroid disorders

During long-term open extension studies, elevated TSH levels (> 5.5 mU/L) were observed in 5.5% of patients receiving long-term febuxostat. Therefore, the drug should be used with caution in patients with thyroid function disorders.

Lactose

The medicinal product contains lactose. It is contraindicated in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., it is essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

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

Breastfeeding

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 doses up to 48 mg/kg/day did not reveal any dose-dependent adverse effects. The effect of febuxostat on human reproductive function is unknown.

Ability to influence reaction speed when driving or operating machinery

Cases of somnolence, dizziness, paresthesia, and visual blurring have been reported during febuxostat treatment. Therefore, patients taking febuxostat should exercise caution when driving or operating machinery until they are certain that such adverse reactions do not affect them.

Dosage and Administration

Dosage

Gout

The recommended dose of EUROFEB 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, the dose of EUROFEB may be increased to 120 mg once daily. The effect of the drug manifests rapidly, allowing serum uric acid levels to be re-evaluated after 2 weeks. The goal of treatment is to reduce serum uric acid concentration and maintain it at a level below

6 mg/dL (357 µmol/L).

The recommended duration of gout attack prophylaxis is at least 6 months.

Tumor Lysis Syndrome (TLS)

The recommended dose of EUROFEB is 120 mg once daily orally, independent of food intake.

EUROFEB 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 drug 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 drug in patients with moderate hepatic impairment is limited.

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 is not required.

Administration

For oral use.

EUROFEB should be administered orally, independent of food intake.

Children

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

Overdose

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

Adverse Reactions

Summary of safety profile

The most commonly reported adverse reactions in clinical trials (4072 patients receiving doses from 10 mg to 300 mg), post-marketing safety studies (FAST study: 3001 subjects receiving at least 80 mg to 120 mg dose), and during post-marketing surveillance in patients with gout were gout flares (attacks), hepatic function abnormalities, diarrhea, nausea, headache, rash, edema, dizziness, dyspnea, pruritus, arthralgia, myalgia, limb pain, edema, and increased fatigue. These adverse reactions were mostly mild or 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, and rare events of sudden cardiac death.

The table below lists adverse reactions observed in patients treated with febuxostat, classified as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), and rare (≥ 1/10,000 to < 1/1000). Frequency is based on clinical trial data 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 3 combined long-term extension studies, post-marketing safety studies, and post-marketing surveillance in patients with gout

From blood and lymphatic system	Uncommon Pancytopenia, thrombocytopenia, agranulocytosis*, anemia#
From immune system	Uncommon Anaphylactic reactions*, hypersensitivity to the drug*
From endocrine system	Uncommon Elevated blood thyroid-stimulating hormone levels, hypothyroidism#
From eye organs	Uncommon Blurred vision Uncommon Retinal artery occlusion#
From metabolism and nutrition	Common*** Exacerbation (attacks) of gout Uncommon Diabetes mellitus, hyperlipidemia, decreased appetite, weight gain Rare Weight loss, increased appetite, anorexia
From psyche	Uncommon Decreased libido, insomnia Rare Nervousness, depressed mood#, sleep disorder#
From nervous system	Common Headache, dizziness Uncommon Paresthesia, hemiparesis, somnolence, lethargy#, altered taste sensation, hypesthesia, reduced sense of smell Rare Ageusia#, burning sensation#
From ear and labyrinthine organs	Uncommon Tinnitus Rare Vertigo#
From cardiac system	Uncommon Atrial fibrillation, palpitations, ECG abnormalities, left bundle branch block (see section "Tumor lysis syndrome"), sinus tachycardia (see section "Tumor lysis syndrome"), arrhythmia# Rare Sudden cardiac death*
From vascular system	Uncommon Arterial hypertension, flushing, hot flushes, bleeding (see section "Tumor lysis syndrome") Rare Circulatory collapse#
From respiratory system	Common Dyspnea Uncommon Bronchitis, upper respiratory tract infections, lower respiratory tract infection#, cough, rhinorrhea# Rare Pneumonia#
From gastrointestinal tract	Common Diarrhea**, nausea Uncommon Abdominal pain, abdominal distension, gastroesophageal reflux disease, vomiting, dry mouth, dyspepsia, constipation, frequent defecation, flatulence, discomfort in stomach or intestine, upper abdominal pain#, mouth ulcers, lip swelling# Rare Gastrointestinal perforation#, stomatitis#
From liver and biliary system	Common Liver function abnormalities** Uncommon Cholelithiasis Rare Hepatitis, jaundice*, liver failure*, cholecystitis#
From skin and subcutaneous tissue	Common Rash (including rashes with lower frequency, see below), pruritus Uncommon Dermatitis, urticaria, skin discoloration, skin injury, petechiae, macular rash, maculopapular rash, papular rash, increased sweating, alopecia, eczema#, erythema, night sweats#, psoriasis#, itchy rash# Rare Toxic epidermal necrolysis*, Stevens-Johnson syndrome*, angioedema*, drug reactions with eosinophilia and systemic symptoms (DRESS)*, generalized (serious) rashes*, exfoliative rash, follicular rash, vesicular rash, pustular rash, erythematous rash, measles-like rash
From musculoskeletal and connective tissue	Common Joint pain, muscle pain, limb pain# Uncommon Arthritis, musculoskeletal pain, muscle weakness, muscle cramps, muscle stiffness, bursitis, joint swelling#, back pain#, musculoskeletal stiffness#, joint stiffness Rare Rhabdomyolysis*, shoulder rotator cuff syndrome#, polymyalgia rheumatica#
From kidneys and urinary system	Uncommon Renal failure, urolithiasis, hematuria, polyuria, proteinuria, urinary urgency, urinary tract infection# Rare Tubulointerstitial nephritis*
From reproductive system and mammary glands	Uncommon Erectile dysfunction
General disorders	Common Edema, fatigue Uncommon Chest pain, chest discomfort, pain#, malaise# Rare Thirst, feeling of warmth#
Investigations	Uncommon Elevated blood amylase levels, decreased platelet count, decreased blood leukocyte count, decreased blood lymphocyte count, elevated creatine levels in blood, elevated blood creatinine levels, decreased blood hemoglobin levels, elevated blood urea levels, elevated blood triglyceride levels, elevated blood cholesterol levels, decreased hematocrit, elevated blood lactate dehydrogenase (LDH) levels, elevated blood potassium levels, elevated international normalized ratio (INR)# Rare Elevated blood glucose levels, prolonged activated partial thromboplastin time, decreased red blood cell count, elevated blood alkaline phosphatase levels, elevated blood creatine phosphokinase levels*
Injuries, poisonings and procedural complications	Uncommon Contusion#

* Adverse reactions observed during post-marketing surveillance.

** Diarrhea and abnormalities in liver function tests requiring treatment, observed in phase 3 studies, occurred more frequently in patients receiving concomitant colchicine therapy.

*** See section "Pharmacodynamics" for the frequency of gout flares observed in phase 3 individual randomized controlled studies.

Adverse reactions reported 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 skin lesions or mucosal involvement and irritation of the ocular mucosa. 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, controlled phase 3 study FLORENCE (FLO-01), comparing febuxostat and allopurinol in 346 patients undergoing chemotherapy for hematologic malignancies with moderate or high risk of TLS, adverse reactions were reported in only 22 (6.4%) patients—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 marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging. 14 tablets in a blister; 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. GenePharm S.A.

Manufacturer's address and location of operations.

18th km Marathon Avenue, Pallini Attiki, 15351, Greece.