INSTRUCTION for medical use of the medicinal product DENOFIX (DENOFIX)

Composition:

Active substance: febuxostat;

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

Excipients: lactose monohydrate, microcrystalline cellulose (E460), hydroxypropylcellulose (E463), sodium croscarmellose, colloidal anhydrous silicon dioxide (E551), magnesium stearate (E470b);

Film coating: polyvinyl alcohol (E1203), talc (E553b), titanium dioxide (E171), macrogol 3350 (E1521), methacrylic acid copolymer (type A), iron oxide yellow (E172), sodium hydrogencarbonate (E500(ii)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Film-coated tablets 80 mg: capsule-shaped, film-coated tablets, pale yellow to yellow in color, with "80" imprinted on one side and smooth on the other side;

Film-coated tablets 120 mg: capsule-shaped, film-coated tablets, pale yellow to yellow in color, with "120" imprinted on one side and smooth on the other side.

Pharmacotherapeutic group. Medicinal products for the treatment of gout. Medicinal products inhibiting uric acid production.

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 through selective inhibition of 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 inhibit other enzymes involved in purine or pyrimidine metabolism, such as guanidase, hypoxanthine-guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase, or purine nucleoside phosphorylase.

Efficacy and Safety

Gout. The efficacy of febuxostat has been confirmed in three Phase 3 studies (two pivotal studies, APEX and FACT, and an additional study, CONFIRMS, described below), involving 4,101 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 target levels. The primary efficacy endpoint in the APEX and FACT studies was the proportion of patients who achieved a serum uric acid concentration of ≤ 6.0 mg/dL (357 µmol/L) during the last three months of the study. 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 ≤ 6.0 mg/dL at the last visit. Patients who had undergone organ transplantation were not included in these studies (see section "Special Warnings and Precautions for Use").

APEX Study. The Phase 3 Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX) was a randomized, double-blind, multicenter study of 28 weeks' duration. A total of 1,072 patients were randomized to receive: 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).

The APEX study demonstrated statistically significant superiority of both febuxostat treatment regimens—80 mg once daily and 120 mg once daily—compared to standard-dose allopurinol (300 mg/100 mg) in reducing serum uric acid concentration to below 6 mg/dL (357 µmol/L) (see Table 1 and Figure 1 below).

FACT Study. The Phase 3 Febuxostat Allopurinol Controlled Trial (FACT) was a randomized, double-blind, multicenter study of 52 weeks' duration. A total of 760 patients were randomized to receive: febuxostat 80 mg once daily (n = 256), febuxostat 120 mg once daily (n = 251), or 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 standard-dose allopurinol (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 compared with allopurinol # p < 0.001 compared with 80 mg dose

When febuxostat was administered, serum uric acid concentration decreased rapidly and remained low for a long time. Reduction of 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. 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 pooled 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 out 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 conducted 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 (creatinine clearance 30–89 mL/min). Prophylaxis of gout flares was mandatory throughout the 26 weeks.

The proportion of patients with 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. 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). These patients randomized to the allopurinol group received a reduced dose of 100 mg once daily. The primary efficacy endpoint was achieved in the febuxostat 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 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 of results obtained in patients with gout and renal impairment during the CONFIRMS study showed that febuxostat was significantly more effective: serum uric acid concentration decreased to a level < 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 < 6.0 mg/dL at the last three visits) was achieved in the febuxostat subgroups 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, patients in the febuxostat 120 mg treatment group (36 %) requiring treatment for gout flares were compared to patients receiving febuxostat 80 mg (28 %), allopurinol 300 mg (23 %), and placebo (20 %). The frequency of flares increased after the prophylactic period and gradually decreased over time. From weeks 8 to 28, 46 % to 55 % of patients were treated for gout flares. Gout flares during the last 4 weeks of the trial (weeks 24–28) were observed in 15 % of patients receiving febuxostat (80, 120 mg), 14 % of patients receiving allopurinol (300 mg), and 20 % of patients receiving 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 to patients in both febuxostat 80 mg (22 %) and allopurinol 300 mg (21 %) treatment groups. After the 8-week prophylactic period, flare frequency increased and gradually decreased over time (64 % and 70 % of patients receiving treatment for gout flares from weeks 8 to 52). Gout flares during the last 4 weeks of the trial (weeks 49–52) were observed in 6–8 % of patients receiving febuxostat 80 mg or 120 mg and in 11 % of patients receiving 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 febuxostat 80 mg and allopurinol groups, 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) — a three-year, open-label, multicenter, randomized phase 3 extension study comparing febuxostat with allopurinol, conducted to evaluate safety in patients who had previously participated in pivotal phase 3 studies (APEX or FACT). A total of 1,086 patients were enrolled in the study, receiving 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 a final stable treatment regimen. Patients whose serum uric acid concentrations were > 6.0 mg/dL in three consecutive measurements were excluded from the study.

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

According to three-year follow-up data, in less than 4 % of patients requiring treatment for flares, a reduction in gout flare frequency was observed at months 16–24 and 30–36 (i.e., more than 96 % of patients did not require 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 2 safety extension study conducted in patients who completed a 4-week double-blind dose-titration period with febuxostat in the TMX-00-004 trial. The study included 116 patients who initially received 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 a 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 more than 80 % (81–100 %) in each febuxostat treatment group.

In phase 3 clinical trials, minor changes in liver 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, elevated TSH (thyroid-stimulating hormone) 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 serious 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. To achieve a uric acid level below 6 mg/dL, the febuxostat dose was titrated from 40 mg to 80 mg (regardless of renal function), and the allopurinol dose 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 MACE (major adverse cardiovascular events), including 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 the trial treatment prematurely, and 45 % of patients did not complete all planned study visits.

A total of 6,190 patients were followed for 32 months; mean duration of exposure was 728 days in the febuxostat group (n = 3,098) and 719 days in the allopurinol group (n = 3,092).

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

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

The incidence of all-cause mortality was also higher in the febuxostat group than in the allopurinol group — 7.8 % vs. 6.4 % (RR 1.22; 95 % CI 1.01–1.47), primarily due to higher cardiovascular mortality in this group (see section «Special instructions»).

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

The FAST study was a prospective, randomized, open-label trial with endpoint masking, comparing the cardiovascular safety profile of febuxostat and allopurinol in patients with chronic hyperuricemia (in conditions where urate deposition has already occurred) and risk factors for cardiovascular disease (CVD) (i.e., patients aged 60 years or older and with at least one additional CVD risk factor). Patients meeting the study inclusion 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 regimen. At the end of the allopurinol lead-in phase, patients with serum uric acid concentration (sUA) < 0.36 mmol/L (< 6 mg/dL) or patients receiving the maximum tolerated dose or maximum allowed dose of allopurinol were randomized in a 1:1 ratio to receive either febuxostat or allopurinol. The primary endpoint of the FAST study was time to first occurrence of any event included in the Antiplatelet Trialists’ Collaborative (APTC) endpoint, specifically:

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

The primary analysis was based on the treatment-received approach.

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

According to the primary analysis of data from patients who received treatment, febuxostat was non-inferior to allopurinol regarding the incidence of the primary endpoint, which occurred in 172 patients (1.72 per 100 patient-years) in the febuxostat group compared to 241 patients (2.05 per 100 patient-years) in the allopurinol group, with an adjusted risk ratio [RR] 0.85 (95 % CI 0.70–1.03), p < 0.001. The treatment-received analysis showed no significant difference between treatment groups in the incidence of the primary endpoint in the subgroup of patients with a history of MI, stroke, or ACS: 65 (9.5 %) patients with primary endpoint events in the febuxostat group and 83 (11.8 %) patients in the allopurinol group; adjusted risk ratio [RR] 1.02 (95 % CI 0.74–1.42), p = 0.202.

Febuxostat treatment was not associated with increased cardiovascular (CV) mortality or all-cause mortality, either overall or in the subgroup of patients with a history of MI, stroke, or ACS. Overall, there were fewer deaths in the febuxostat group (62 CV deaths and 108 non-CV deaths) than in the allopurinol group (82 CV deaths and 174 non-CV deaths).

Febuxostat treatment resulted in greater reduction of 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 action in reducing urate levels compared to allopurinol.

FLORENCE was a randomized (1:1), double-blind, active-controlled phase 3 study 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 curve (AUC sUA1–8) and change in serum creatinine level from day 1 to day 8.

A total of 346 patients with hematologic malignancies receiving chemotherapy and at intermediate/high risk of developing TLS were enrolled. 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, 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 level (%) 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; 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 incidence of treatment-emergent signs and symptoms and adverse reactions was 67.6 % vs. 64.7 % and 6.4 % vs. 6.4 % with 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, for example, in patients for 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 from 10 mg to 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 based on data from 211 patients with hyperuricemia and gout receiving febuxostat at doses of 40–240 mg once daily. Overall, the obtained pharmacokinetic parameter values corresponded to 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 (at least 84 %) absorbed. After single and multiple oral doses of febuxostat at 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 in combination with a fatty 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 repeated administration at 80 mg). Therefore, 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 febuxostat binding to plasma proteins (mainly albumin) is 99.2 % and does not change with increasing dose from 80 mg to 120 mg. The extent of binding to plasma proteins of active metabolites of febuxostat 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 them were detected in human plasma. In vitro studies using human liver microsomes demonstrated 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 at a dose of 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 %).

Special populations

Renal impairment. With repeated administration of febuxostat at a dose of 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 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 at a dose of 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

Denofix, film-coated tablets, 80 mg and 120 mg:

for the treatment of chronic hyperuricemia in diseases associated with urate crystal deposition, particularly in the presence of tophi and/or gouty arthritis, current or in the medical history.

Denofix, film-coated tablets, 120 mg:

for the treatment and prevention of hyperuricemia in adults undergoing chemotherapy for hematologic malignancies with moderate or high risk of tumor lysis syndrome (TLS).

Denofix 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 interactions

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 precautions for use").

The adequacy of this proposed dose adjustment, based on modeling and simulation analysis of preclinical data in rats, was confirmed by results from 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).

Studies on febuxostat interaction with other cytotoxic chemotherapy have not been conducted.

In the pivotal study, patients with TLS receiving various chemotherapy regimens, including monoclonal antibodies, were administered febuxostat 120 mg. However, drug–drug and drug–disease interactions were not specifically evaluated in this study. Therefore, potential interactions with any concomitantly administered cytotoxic agents cannot be excluded.

Rosiglitazone / CYP2C8 substrates

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

Theophylline

A study in healthy volunteers evaluated a potential interaction between febuxostat and theophylline to determine whether febuxostat’s inhibition of xanthine oxidase leads to increased plasma concentrations of theophylline—an effect previously observed with other xanthine oxidase inhibitors. When febuxostat 80 mg and theophylline 400 mg were administered concomitantly, no pharmacokinetic interactions or effects on the safety of theophylline were observed. Thus, febuxostat at a dose of 80 mg can be administered concomitantly with theophylline without special precautions. Data for the 120 mg dose of febuxostat are not available.

Naproxen and other inhibitors of glucuronidation

The 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 affect the elimination of febuxostat. In healthy volunteers, concomitant administration of febuxostat and naproxen 250 mg twice daily resulted in enhanced exposure to febuxostat (Cmax increased by 28%, AUC by 41%, and t1/2 by 26%). In clinical trials, the use of naproxen and other NSAIDs/COX-2 inhibitors was not associated with clinically significant increases in adverse reactions.

Febuxostat may be administered concomitantly with naproxen without dose adjustment.

Inducers of glucuronidation

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

Colchicine/Indomethacin/Hydrochlorothiazide/Warfarin

Febuxostat may be administered concomitantly with colchicine or indomethacin without dose adjustment.

No dose adjustment of febuxostat is required when administered concomitantly with hydrochlorothiazide.

Concomitant administration of febuxostat with warfarin does not require dose adjustment of warfarin. In healthy volunteers receiving febuxostat (80 mg or 120 mg once daily) with warfarin, the pharmacokinetics of warfarin were unchanged. 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 in vivo.

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

Antacids

When administered concomitantly with antacids containing magnesium hydroxide and aluminum hydroxide, delayed absorption of febuxostat (by approximately 1 hour) and a 32% reduction in Cmax are observed; however, the AUC of febuxostat is not significantly altered. Therefore, febuxostat may be administered with antacid products.

Special precautions for use

Cardiovascular diseases

Treatment of chronic hyperuricemia

During drug development and in one post-marketing study (CARES), a higher number of cardiovascular adverse events with fatal outcome were observed in patients with a history of serious cardiovascular diseases (e.g., myocardial infarction, stroke, or unstable angina) treated with febuxostat compared to those treated with allopurinol.

However, in a subsequent post-marketing study (FAST), the frequency of both fatal and non-fatal cardiovascular adverse events with febuxostat was comparable to that observed with allopurinol.

Treatment of this patient group requires caution and regular monitoring.

For further information on 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 hematologic malignancies with moderate or high risk of TLS and receiving febuxostat should, if clinically indicated, be under cardiologist supervision.

Allergy/hypersensitivity to medicinal products

In post-marketing surveillance, rare cases of serious allergic reactions/hypersensitivity reactions have been reported, including life-threatening cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute anaphylactic reactions/shock. These reactions mostly occurred within the first month of febuxostat treatment. Some of these patients had impaired renal function and/or a history of hypersensitivity to allopurinol. Severe hypersensitivity reactions, including those associated with eosinophilia and systemic symptoms (DRESS syndrome), were sometimes 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. In case of serious allergic reactions/hypersensitivity reactions, including Stevens-Johnson syndrome, febuxostat treatment must be discontinued immediately, as early discontinuation improves the prognosis. Re-administration of febuxostat is contraindicated if the patient has experienced an allergic reaction/hypersensitivity reaction, including Stevens-Johnson syndrome or acute anaphylactic reactions/shock.

Acute gout flare

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 nonsteroidal anti-inflammatory drugs (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. Appropriate individual therapy for the acute gout flare should be administered concomitantly. With prolonged febuxostat use, 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 xanthine concentration in urine may occur, which in rare cases may lead to xanthine deposition in the urinary tract. This phenomenon 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.

Combination with mercaptopurine/azathioprine

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

If combination 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 forms of interaction").

Patients should be closely monitored, and the dose of mercaptopurine/azathioprine should be adjusted based on assessment of therapeutic response and signs of potential toxicity.

Patients who have undergone organ transplantation

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

Theophylline

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

Hepatic disorders

In combined phase 3 clinical trials, minor abnormalities in liver function tests were observed in 5.0% of patients receiving febuxostat. Therefore, liver function should be assessed before initiating febuxostat and during treatment as clinically indicated.

Thyroid disorders

During long-term open-label extension studies, an increase in TSH levels (> 5.5 mU/mL) was observed in 5.5% of patients receiving long-term febuxostat treatment. Therefore, febuxostat should be used with caution in patients with thyroid dysfunction.

Warnings regarding certain excipients

Lactose

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

Sodium

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., 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 have not shown any direct or indirect harmful effects of febuxostat on pregnancy, embryonic/fetal development, or parturition. The potential risk for humans is unknown. Therefore, 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 adversely affects the development of suckling newborns. The risk of drug transfer into breast milk cannot be excluded. Febuxostat should not be administered to women during breastfeeding.

Fertility

Animal studies with febuxostat administered at a dose of 48 mg/kg/day did not reveal dose-dependent adverse effects on fertility. The effect of febuxostat on human reproductive function is unknown.

Ability to influence reaction speed when driving or operating machinery.
There have been reports of somnolence, dizziness, paresthesia, and visual disturbances during febuxostat treatment. Therefore, patients taking the medicinal product Denofix are advised to exercise caution when driving or operating machinery until they are certain that these adverse reactions do not affect them.

Dosage and Administration

Dosage

Gout

The recommended dose of the medicinal product Denofix is 80 mg once daily orally, regardless 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 Denofix to 120 mg once daily should be considered. The effect of the medicinal product occurs rapidly, allowing serum uric acid concentration to be re-measured 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 prophylaxis of gout attacks is at least 6 months.

Tumor Lysis Syndrome

The recommended dose of the medicinal product Denofix is 120 mg once daily orally, regardless of food intake.

Treatment with Denofix should be initiated two days prior to the start of cytotoxic therapy and continued for at least 7 days; however, the duration of therapy 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 use of the medicinal product in patients with moderate hepatic impairment is limited.

Tumor Lysis Syndrome (TLS). Only subjects with severe hepatic impairment were excluded from the pivotal phase 3 study (FLORENCE). For patients included in the study, dose adjustment based on hepatic function status was not required.

Administration

The medicinal product Denofix should be administered orally, regardless of food intake.

Children

The safety and efficacy of febuxostat in children (under 18 years of age) have not been established. There is no data available on its use in this population.

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 (4,072 patients receiving doses ranging from 10 mg to 300 mg), post-marketing safety studies (FAST study: 3,001 participants receiving at least an 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, dizziness, dyspnea, rash, pruritus, arthralgia, myalgia, limb pain, edema, and increased fatigue. These adverse reactions were mostly of mild to moderate severity. During post-marketing use, there have been reports of rare cases of serious hypersensitivity reactions to febuxostat, some of which were accompanied by systemic manifestations, as well as rare events of sudden cardiac death.

The adverse reactions observed with febuxostat are listed in the table below. The frequency of adverse reactions is defined according to the following categories: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000).

The frequency of adverse reactions was determined in patients with gout based on data from clinical studies and post-marketing experience with febuxostat. Within each frequency group, adverse reactions are listed in order of decreasing severity.

Table 2. Adverse reactions observed in Phase 3 combined long-term extension studies, post-marketing safety studies, and during post-marketing surveillance in patients with gout

Blood and lymphatic system disorders	Rare Pancytopenia, thrombocytopenia, agranulocytosis*, anemia#
Immune system disorders	Rare Anaphylactic reactions, hypersensitivity to the drug
Endocrine disorders	Uncommon Elevated blood thyroid-stimulating hormone levels, hypothyroidism#
Eye disorders	Uncommon Blurred vision Rare Retinal artery occlusion#
Metabolism and nutrition disorders	Common*** Exacerbation (attacks) of gout Uncommon Diabetes mellitus, hyperlipidemia, decreased appetite, weight gain Rare Weight loss, increased appetite, anorexia
Psychiatric disorders	Uncommon Decreased libido, insomnia Rare Nervousness, depressed mood#, sleep disorder#
Nervous system disorders	Common Headache, dizziness Uncommon Paresthesia, hemiparesis, somnolence, lethargy#, altered taste sensation, hypoesthesia, reduced sense of smell Rare Ageusia#, burning sensation#
Ear and labyrinth disorders	Uncommon Tinnitus Rare Vertigo#
Cardiac disorders	Uncommon Atrial fibrillation, palpitations, ECG abnormalities, arrhythmia#, left bundle branch block (see section "Tumor lysis syndrome" below), sinus tachycardia (see section "Tumor lysis syndrome" below) Rare Sudden cardiac death*
Vascular disorders	Uncommon Arterial hypertension, flushing, hot flushes, bleeding (see section "Tumor lysis syndrome" below) Rare Circulatory collapse#
Respiratory, thoracic and mediastinal disorders	Common Dyspnea Uncommon Bronchitis, upper respiratory tract infections, lower respiratory tract infections#, cough, rhinorrhea# Rare Pneumonia#
Gastrointestinal disorders	Common Diarrhea**, nausea Uncommon Abdominal pain, upper abdominal pain#, abdominal distension, gastroesophageal reflux disease, vomiting, dry mouth, dyspepsia, constipation, frequent defecation, flatulence, discomfort in stomach or intestine, oral ulcers, lip swelling#, pancreatitis Rare Gastrointestinal perforation#, stomatitis#
Hepatobiliary disorders	Common Liver function test abnormalities** Uncommon Cholelithiasis Rare Hepatitis, jaundice, liver failure, cholecystitis#
Skin and subcutaneous tissue disorders	Common Rash (some forms with lower frequency are listed below), pruritus Uncommon Dermatitis, urticaria, skin discoloration, skin injury, petechiae, maculopapular rash, papular rash, increased sweating, alopecia, eczema#, erythema, night sweats#, psoriasis#, itchy rash# Rare Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, drug reaction with eosinophilia and systemic symptoms (DRESS), generalized rash (serious)*, exfoliative rash, follicular rash, vesicular rash, pustular rash, erythematous rash, morbilliform rash
Musculoskeletal and connective tissue disorders	Common Arthralgia, myalgia, limb pain# Uncommon Arthritis, musculoskeletal pain, muscle weakness, muscle spasms, muscle stiffness, bursitis, joint swelling#, back pain#, musculoskeletal stiffness#, joint stiffness Rare Rhabdomyolysis*, shoulder rotator cuff syndrome#, polymyalgia rheumatica#
Renal and urinary disorders	Uncommon Renal failure, nephrolithiasis, hematuria, polyuria, proteinuria, urinary urgency, urinary tract infections# Rare Tubulointerstitial nephritis*
Reproductive system and breast disorders	Uncommon Erectile dysfunction
General disorders and administration site conditions	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 white blood cell count, decreased lymphocyte count, elevated creatine levels in blood, elevated serum creatinine, decreased hemoglobin levels, elevated blood urea nitrogen, elevated triglycerides in blood, elevated cholesterol in blood, decreased hematocrit, elevated lactate dehydrogenase (LDH) in blood, elevated potassium in blood, increased international normalized ratio (INR)# Rare Elevated blood glucose, prolonged activated partial thromboplastin time, decreased red blood cell count, elevated alkaline phosphatase in blood, elevated creatine phosphokinase in blood*
Injuries	Uncommon Contusion#

* Adverse reactions observed during post-marketing surveillance.

** Diarrhea and abnormal liver function tests requiring therapy, 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 trials.

Adverse reactions identified during post-authorization safety studies.

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 of acute gout flares is recommended when initiating febuxostat therapy.

Tumor lysis syndrome

Summary of safety profile

In the randomized, double-blind, active-controlled phase 3 FLORENCE (FLO-01) study comparing febuxostat and allopurinol (346 patients undergoing chemotherapy for hematologic malignancies with moderate or high risk of TLS), adverse reactions were observed in only 22 (6.4%) patients, specifically in 11 (6.4%) patients in each treatment group. Most adverse reactions were of mild or moderate severity.

Overall, during the FLORENCE study, no additional safety concerns were identified with 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 suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, 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. 4 years.

Storage conditions

No special storage conditions required. Keep out of reach and sight of children.

Packaging

14 film-coated tablets in a blister. 2 blisters in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Rontis Hellas Medical and Pharmaceuticals Products S.A.

Manufacturer's address and place of business

Larissa Industrial Area, P.O. Box 3012, Larissa, 41 500, Greece.