INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ADENURIC® 80 MG/ADENURIC® 120 MG (ADENURIC® 80 MG/ADENURIC® 120 MG)

Composition:

Active substance: febuxostat;

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

Excipients: lactose monohydrate, hydroxypropylcellulose, microcrystalline cellulose, sodium croscarmellose, magnesium stearate, colloidal anhydrous silicon dioxide, polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

80 mg film-coated tablet: capsule-shaped, film-coated tablets, pale yellow to yellow in colour, with "80" embossed on one side and a breakline on the other side.

The breakline is intended only for tablet splitting to facilitate swallowing and is not intended for dividing the tablet into equal doses.

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

Pharmacotherapeutic group.

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

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

Uric acid is the end product of purine metabolism in humans and is formed during the following reaction: hypoxanthine → xanthine → uric acid. Xanthine oxidase catalyzes both steps of this reaction. Febuxostat is a 2-arylthiazole derivative whose therapeutic effect is related to reduction of serum uric acid concentration by selective inhibition of xanthine oxidase. Febuxostat is a potent and selective non-purine xanthine oxidase inhibitor (NP-SIXO), with an inhibition constant (Ki) in vitro 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 ADENURIC® has been demonstrated in three pivotal phase 3 studies (two main studies, APEX and FACT, and an additional phase 3 study, CONFIRMS, described below), which included 4101 patients with hyperuricemia and gout. In each of these pivotal phase 3 studies, ADENURIC® 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 maintained serum uric acid concentration below 6.0 mg/dL (357 µmol/L) during the last three months of the study. In the additional phase 3 CONFIRMS study, the results of which became available after the initial marketing authorization of ADENURIC®, the primary efficacy endpoint was the proportion of patients with serum uric acid concentration below 6.0 mg/dL at the final visit. Patients who had undergone organ transplantation were not included in these studies (see section "Special precautions").

APEX study: The Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX) was a randomized, double-blind, multicenter study of 28 weeks' duration. A total of 1072 patients were randomized: placebo (n=134), ADENURIC® 80 mg once daily (n=267), ADENURIC® 120 mg once daily (n=269), ADENURIC® 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 ADENURIC® regimens—80 mg once daily and 120 mg once daily—compared to allopurinol at the standard 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).

FACT study: The Febuxostat Allopurinol Controlled Trial (FACT), a phase 3 randomized, double-blind, multicenter study of 52 weeks' duration, randomized a total of 760 patients: ADENURIC® 80 mg once daily (n = 256), ADENURIC® 120 mg once daily (n = 251), and allopurinol 300 mg once daily (n = 253).

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

Table 1 presents the results for the primary efficacy endpoint:

Table 1

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

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 concentration > 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 ADENURIC® was administered, the reduction in serum uric acid concentration was rapid and sustained. A decrease 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 remained consistent 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 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 dose.

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: ADENURIC® 40 mg once daily (n=757), ADENURIC® 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 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 impaired renal function

In the APEX study, efficacy was evaluated in 40 patients with impaired renal function (i.e., baseline serum creatinine concentration > 1.5 mg/dL and ≤ 2.0 mg/dL). Patients randomized to the allopurinol group had their dose reduced to 100 mg once daily. The primary efficacy endpoint was achieved in the ADENURIC® 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 meaningful differences in the reduction of serum uric acid concentration were not observed between healthy volunteers regardless of renal function (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 impaired renal function 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 patients).

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 three visits) was achieved in the ADENURIC® subgroups in 41% of patients (80 mg once daily), 48% of patients (120 mg once daily), and 66% of patients (240 mg once daily), compared to 9% in the allopurinol 300 mg/100 mg once daily group and 0% in the placebo group.

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

Clinical outcomes: proportion of patients requiring gout flare treatment

APEX study: During the 8-week prophylactic period, 36% of patients in the febuxostat 120 mg treatment group required treatment for gout flares, 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% to 55% of patients received treatment for gout flares. Gout flares occurring during the last 4 weeks of the trial (weeks 24–28) were observed in 15% of patients (febuxostat 80, 120 mg), 14% of patients (allopurinol 300 mg), and 20% of patients (placebo).

FACT study: During the 8-week prophylactic period, 36% of patients in the febuxostat 120 mg treatment group required treatment for gout flares, 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 to 52). Gout flares during the last 4 weeks of the trial (weeks 49–52) were observed in 6–8% of patients (febuxostat 80 mg, 120 mg) and 11% of patients (allopurinol 300 mg).

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

During the CONFIRMS study, the proportion of patients requiring treatment for gout flares (1 day every 6 months) was 31% and 25% in the 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): The EXCEL study was a 3-year, open-label, multicenter, randomized, extended, allopurinol-controlled phase 3 safety study conducted to evaluate safety in patients who completed the pivotal phase 3 studies (APEX or FACT). A total of 1086 patients were included in the study: ADENURIC® 80 mg once daily (n=649), ADENURIC® 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 exceeded 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 80 mg and 120 mg doses, respectively, had serum uric acid levels < 6.0 mg/dL at month 36).

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

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

The FOCUS study (TMX-01-005) was a 5-year, open-label, multicenter, extended phase 2 safety study conducted in patients who completed the 4-week double-blind febuxostat dosing period 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 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 trials, minor changes in liver function parameters were observed in patients receiving febuxostat (5.0%). The frequency of these changes was similar to that observed with allopurinol (4.2%) (see section "Special precautions"). 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 precautions").

Post-marketing long-term studies

The CARES study was a multicenter, randomized, double-blind, non-inferiority trial comparing cardiovascular outcomes with febuxostat versus allopurinol in patients with gout and a history of major cardiovascular diseases, including myocardial infarction, hospitalization for unstable angina, coronary or cerebral revascularization procedures, stroke, hospitalization for transient ischemic attack, peripheral vascular disease, or diabetes with signs of microangiopathy or macroangiopathy. To achieve sUA levels below 6 mg/dL, febuxostat dose was titrated from 40 mg to 80 mg (independent of renal function), while allopurinol dose 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 intention-to-treat (ITT) analysis, including all subjects who were randomized and received at least one dose of study drug during the double-blind trial.

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, with a mean exposure duration of 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 mortality 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 due to 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 higher cardiovascular mortality in this group (see section "Special precautions").

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 masking, comparing the cardiovascular safety profile of febuxostat and allopurinol in patients with chronic hyperuricemia (in conditions where urate deposition has already occurred) and cardiovascular risk factors (CV risk factors) (i.e., patients aged 60 years or older and with at least one additional CV risk factor). Patients meeting study inclusion criteria received allopurinol treatment prior to randomization and, if needed, had their dose 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 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-received approach.

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

In the primary analysis of treatment-received patients, febuxostat was non-inferior to allopurinol regarding the frequency 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 hazard ratio [HR] of 0.85 (95% CI: 0.70, 1.03), p < 0.001. The treatment-received analysis for the primary endpoint in the subgroup of patients with prior MI, stroke, or ACS did not show a significant difference between treatment groups: 65 (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 (CV) 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 CV deaths and 108 non-CV deaths) compared to the allopurinol group (82 CV deaths and 174 non-CV deaths).

Treatment with febuxostat resulted in greater reduction in uric acid levels compared to allopurinol treatment.

Tumor Lysis Syndrome (TLS)

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

FLORENCE was a randomized (1:1), double-blind, controlled phase III study comparing ADENURIC® 120 mg once daily with allopurinol 200–600 mg daily (mean daily allopurinol dose [± standard deviation]: 349.7 ± 112.90 mg) under controlled serum uric acid concentration conditions. Eligible patients were candidates for allopurinol treatment or lacked access to rasburicase. Primary endpoints were the area under the serum uric acid concentration 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/high risk of developing TLS were enrolled. The mean AUC sUA1-8 (mg × h/dL) was significantly lower with ADENURIC® (514.0 ± 225.71 vs. 708.0 ± 234.42; least squares mean difference: -196.794 [95% confidence interval: -238.600; -154.988]; p < .0001). Additionally, mean serum uric acid levels were significantly lower with ADENURIC® starting from the first 24 hours of treatment and at any subsequent time point. No statistically significant differences were observed in mean serum creatinine levels (%) between ADENURIC® and allopurinol (-0.83 ± 26.98 vs. -4.92 ± 16.70, respectively; least squares mean difference: 4.0970 [95% confidence interval: -0.6467; 8.8406]; p=0.0903). Regarding secondary endpoints, no statistically significant differences were observed in the incidence of laboratory-confirmed TLS (8.1% and 9.2% for ADENURIC® and allopurinol, respectively; relative risk: 0.875 [95% confidence interval: 0.4408; 1.7369]; p=0.8488) or clinical tumor lysis syndrome (1.7% and 1.2% for ADENURIC® and allopurinol, respectively; relative risk: 0.994 [95% confidence interval: 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 ADENURIC® and allopurinol, respectively. In the FLORENCE study, ADENURIC® demonstrated superior and faster action in reducing serum uric acid levels compared to allopurinol. Data comparing ADENURIC® and 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 after single and multiple doses of febuxostat in the range of 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 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 ADENURIC® 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 reach maximum concentration] 1.0–1.5 hours) and well absorbed (at least 84%). After single and multiple oral doses of febuxostat 80 mg or 120 mg once daily, Cmax 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 repeated administration at 80 mg or single administration 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 repeated administration at 80 mg). Thus, ADENURIC® can be administered regardless of food intake.

Distribution. The predicted volume of distribution at steady state (Vss/F) for febuxostat ranges from 29 to 75 L after oral administration at doses of 10–300 mg. The degree of febuxostat binding to plasma proteins (primarily albumin) is 99.2% and does not change with increasing dose from 80 mg to 120 mg. For active metabolites of febuxostat, the degree of plasma protein binding 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 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, while febuxostat glucuronide is formed mainly by UGT1A1, 1A8, and 1A9.

Elimination. 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 repeated administration of ADENURIC® 80 mg, no changes in Cmax of febuxostat were observed in patients with mild, moderate, or severe renal impairment compared to patients with normal renal function. The mean total AUC of febuxostat increased 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-fold and 4-fold, respectively. However, dose adjustment of the medicinal product is not required in patients with mild or moderate renal impairment.

Hepatic impairment.

With repeated administration of ADENURIC® 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 study of the medicinal product in patients with severe hepatic impairment (Child-Pugh class C) has not been conducted.

Age.

With repeated oral administration of ADENURIC®, 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 ADENURIC®, 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.

ADENURIC® 80 mg and ADENURIC® 120 mg:

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

ADENURIC® 120 mg:

Treatment and prevention of hyperuricaemia in adult patients undergoing chemotherapy for haematological malignancies with moderate or high risk of tumour lysis syndrome (TLS).

ADENURIC® is indicated for adult patients.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Mercaptopurine/azathioprine.

Due to its mechanism of action, febuxostat inhibits xanthine oxidase; therefore, concomitant use is not recommended. Inhibition of xanthine oxidasi may increase plasma concentrations of both drugs, potentially causing myelotoxic reactions. If 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, was 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 interaction studies of febuxostat with other cytotoxic chemotherapy have not been conducted. In the pivotal study, patients with TLS receiving multiple chemotherapy regimens, including monoclonal antibodies, were administered febuxostat 120 mg. 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 4 mg rosiglitazone did not affect the pharmacokinetics of rosiglitazone or its metabolite N-desmethylrosiglitazone, demonstrating that febuxostat does not inhibit CYP2C8 in vivo. Therefore, concomitant administration of febuxostat with rosiglitazone or other CYP2C8 substrates does not require dose adjustment.

Theophylline.

A drug interaction study with febuxostat was conducted in healthy volunteers to evaluate the potential for increased circulating theophylline levels due to xanthine oxidase inhibition, as observed with other xanthine oxidase inhibitors. Results showed that concomitant 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 UDP-glucuronosyltransferase enzyme. Medicinal products that inhibit glucuronidation, such as NSAIDs and probenecid, may theoretically affect febuxostat elimination. In healthy volunteers, concomitant administration of febuxostat and naproxen 250 mg twice daily resulted in increased exposure to febuxostat (Cmax increased by 28%, AUC by 41%, t1/2 by 26%). In clinical trials, use of naproxen and other NSAIDs/COX-2 inhibitors was not associated with clinically significant increase in adverse reactions.

Febuxostat may be administered concomitantly with naproxen without dose adjustment.

Inducers of glucuronidation.

Potent inducers of UDP-glucuronosyltransferase enzyme 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, febuxostat plasma levels 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. 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 ADENURIC® 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.

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 drug development and in one post-marketing study (CARES), a higher number of cardiovascular adverse events with fatal outcome were observed in patients with pre-existing major 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), 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 and with regular monitoring.

For further information 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 hematologic malignancies with moderate or high risk of TLS who are receiving ADENURIC® should be under cardiologist supervision when clinically indicated.

Allergy/hypersensitivity to medicinal products.

In the context of post-marketing surveillance, rare cases of serious allergic reactions/hypersensitivity reactions, including life-threatening Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute anaphylactic reactions/shock, have been reported. In 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), in some cases were accompanied by fever, hematological, renal, or hepatic impairment.

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

Acute gout flare (gout attack).

Treatment with febuxostat should only be initiated during the intercritical period, after resolution of an acute gout attack. 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 therapy, concomitant administration of non-steroidal 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 attack should be administered concurrently. With prolonged use of febuxostat, the frequency and severity of gout attacks decrease.

Xanthine deposition.

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

Azathioprine/mercaptopurine.

Febuxostat is not recommended for patients who are concurrently receiving azathioprine/mercaptopurine, as febuxostat's inhibition of xanthine oxidase may increase plasma concentrations of mercaptopurine/azathioprine, potentially leading to severe toxicity.

If co-administration cannot be avoided, it is recommended to reduce the dose of mercaptopurine/azathioprine 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 occurrence of potential toxic effects.

Organ transplant recipients.

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 disorders.

During 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 treatment and during therapy as clinically indicated.

Thyroid disorders.

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

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., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

Limited experience with febuxostat use during pregnancy indicates no adverse effects on pregnancy course or fetal/neonatal health. Animal studies did not reveal any direct or indirect harmful effects on pregnancy, embryonic/fetal development, or delivery. The potential risk for 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 ADENURIC® on human reproductive function is unknown.

Ability to influence reaction speed when driving or operating machinery.

Cases of somnolence, dizziness, paresthesia, and visual disturbances have been reported during febuxostat treatment. Therefore, patients taking ADENURIC® should be cautious when driving or operating machinery until they are certain that these adverse reactions do not affect them.

Method of Administration and Dosage.

Dosage

Gout.

The recommended dose of ADEURIC® 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 ADEURIC® to 120 mg once daily should be considered. The effect of the drug manifests rapidly, allowing repeat measurement of serum uric acid concentration after 2 weeks. The goal of treatment is to reduce serum uric acid concentration and maintain it 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 ADEURIC® is 120 mg once daily orally, regardless of food intake.

ADEURIC® 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 group.

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.

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

Method of Administration

For oral use.

ADEURIC® is administered orally, regardless of food intake.

Children.

The safety and efficacy of ADEURIC® in children under 18 years of age have not been established. Data on use are lacking.

Overdose.

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

Adverse reactions.

Summary of safety profile.

The most commonly reported adverse reactions in clinical trials (4072 patients receiving doses from 10 mg to 300 mg), post-marketing safety studies (FAST study: 3001 participants receiving at least 80 mg to 120 mg), 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 mild to moderate in severity. During post-marketing surveillance, rare cases of serious hypersensitivity reactions to febuxostat have been reported, some of which were accompanied by systemic reactions, as well as rare events of sudden cardiac death.

The table below lists adverse reactions observed with febuxostat use in patients, categorized 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 trials and post-marketing experience in patients with gout.

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.

From the blood and lymphatic system	Uncommon Pancytopenia, thrombocytopenia, agranulocytosis*, anemia#
From the immune system	Uncommon Anaphylactic reactions*, hypersensitivity to the drug*
From the endocrine system	Uncommon Elevated blood thyroid-stimulating hormone levels, hypothyroidism#
From the eye organs	Uncommon Blurred vision Rare Retinal artery occlusion#
From the metabolism and nutrition	Common*** Exacerbation (attacks) of gout Uncommon Diabetes mellitus, hyperlipidemia, decreased appetite, weight gain Rare Weight loss, increased appetite, anorexia
From the psyche	Uncommon Decreased libido, insomnia Rare Nervousness, depressed mood#, sleep disorder#
From the nervous system	Common Headache, dizziness Uncommon Paraesthesia, hemiparesis, somnolence, lethargy#, altered taste sensation, hypoaesthesia, reduced sense of smell Rare Ageusia#, burning sensation#
From the ear and labyrinthine system	Uncommon Tinnitus Rare Vertigo#
From the cardiac system	Uncommon Atrial fibrillation, palpitations, ECG abnormalities, left bundle branch block (see section "Tumour lysis syndrome"), sinus tachycardia (see section "Tumour lysis syndrome"), arrhythmia# Rare Sudden cardiac death*
From the vascular system	Uncommon Arterial hypertension, flushing, hot flushes, haemorrhage (see section "Tumour lysis syndrome") Rare Circulatory collapse#
From the respiratory system	Common Dyspnoea Uncommon Bronchitis, upper respiratory tract infections, lower respiratory tract infection#, cough, rhinorrhoea# Rare Pneumonia#
From the gastrointestinal tract	Common Diarrhoea**, nausea Uncommon Abdominal pain, upper abdominal pain#, bloating, gastroesophageal reflux disease, vomiting, dry mouth, dyspepsia, constipation, frequent defecation, flatulence, discomfort in stomach or intestine, mouth ulcers, lip swelling#, pancreatitis Rare Gastrointestinal perforation#, stomatitis#
From the liver and biliary system	Common Liver function abnormalities** Uncommon Cholelithiasis Rare Hepatitis, jaundice*, hepatic failure*, cholecystitis#
From the skin and subcutaneous tissue	Common Rash (including rashes with lower frequency, see below), pruritus Uncommon Dermatitis, urticaria, skin discoloration, skin injury, petechiae, maculopapular rash, maculopapular eruptions, papular eruptions, increased sweating, alopecia, eczema#, erythema, night sweats#, psoriasis#, pruritic rash# Rare Toxic epidermal necrolysis*, Stevens-Johnson syndrome*, angioedema*, drug reactions with eosinophilia and systemic symptoms*, generalized rash (serious)*, exfoliative rash, follicular rash, vesicular rash, pustular rash, erythematous rash, measles-like rash
From the 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 the kidneys and urinary system	Uncommon Renal failure, nephrolithiasis, haematuria, polyuria, proteinuria, urinary urgency, urinary tract infections# Rare Tubulointerstitial nephritis*
From the reproductive system and breast	Uncommon Erectile dysfunction
General disorders	Common Oedema, increased fatigue Uncommon Chest pain, chest discomfort, pain#, malaise# Rare Thirst, feeling of heat#
Investigations	Uncommon Elevated blood amylase levels, decreased platelet count, decreased white blood cell count, decreased lymphocyte count, elevated creatine levels in blood, elevated creatinine levels in blood, decreased haemoglobin levels, elevated blood urea levels, elevated blood triglyceride levels, elevated blood cholesterol levels, decreased haematocrit, elevated lactate dehydrogenase (LDH) levels in blood, elevated potassium levels in blood, elevated international normalized ratio (INR)# Rare Elevated blood glucose levels, prolonged activated partial thromboplastin time, decreased red blood cell count, elevated alkaline phosphatase levels in blood, elevated creatine phosphokinase levels in blood*
Injury, poisoning and procedural complications	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 during phase 3 individual randomized controlled studies.

Adverse reactions reported during post-marketing 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 against acute gout flares is recommended when initiating febuxostat therapy.

Tumor Lysis Syndrome (TLS)

Summary of safety profile

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

Overall, during the FLORENCE study, no additional safety concerns were identified for the use of ADENURIC® 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 of 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 and patients, or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

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

Storage conditions.

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

Packaging.

14 film-coated tablets in a blister; 2, 4, or 6 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Menarini-von Heyden GmbH.

Manufacturer's address.

Leipziger Strasse 7-13, 01097 Dresden, Germany.

Marketing Authorization Holder.

Menarini International Operations Luxembourg S.A.

Address of the Marketing Authorization Holder.

1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.