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

Composition:

Active substance: febuxostat;

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

Excipients:

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

coating Insta Moistshield Aqua II yellow: polyethylene glycol, talc, titanium dioxide (E 171), yellow iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Tablets of 80 mg: capsule-shaped, biconvex, film-coated tablets, yellow in color, with "F 19" engraved on one side and smooth on the other side.

Tablets of 120 mg: capsule-shaped, biconvex, film-coated tablets, yellow in color, with "F 20" engraved on one side and smooth on the other side.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

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

Clinical efficacy and safety

Gout

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

APEX trial. The phase 3 Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX) was a randomized, double-blind, multicenter study lasting 28 weeks. A total of 1072 patients were randomized: placebo (n=134), febuxostat 80 mg once daily (n=267), febuxostat 120 mg once daily (n=269), febuxostat 240 mg once daily (n=134), or allopurinol 300 mg once daily (n=258) for patients with baseline serum creatinine concentration ≤1.5 mg/dL, or 100 mg once daily (n=10) for patients with baseline serum creatinine concentration >1.5 mg/dL and ≤2.0 mg/dL. For safety assessment, febuxostat was administered at a dose of 240 mg (twice the maximum recommended dose).

The APEX trial demonstrated a statistically significant advantage of both febuxostat 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 to below 6 mg/dL (357 µmol/L) (see Table 1 and Figure 1).

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

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

Table 1 presents the results for the primary efficacy endpoint.

Table 1

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

The reduction in serum uric acid concentration with febuxostat was rapid and sustained. Decreased serum uric acid concentration to < 6.0 mg/dL (357 µmol/L) was observed as early as the second week of the study and persisted throughout treatment. Figure 1 shows mean serum uric acid concentrations over time for each treatment group in both pivotal phase 3 studies.

Figure 1

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

Note: 509 patients received allopurinol 300 mg once daily; 10 patients with serum creatinine concentration > 1.5 mg/dL and < 2.0 mg/dL received allopurinol 100 mg once daily (10 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 2269 patients were randomized: febuxostat 40 mg once daily (n=757), febuxostat 80 mg once daily (n=756), and allopurinol 300/200 mg once daily (n=756). At least 65% of patients had mild to moderate renal impairment (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% for febuxostat 40 mg, 67% for febuxostat 80 mg, and 42% for allopurinol 300/200 mg, respectively.

Primary efficacy endpoint in the subgroup of patients with renal impairment

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

Clinically significant differences in the percentage reduction of serum uric acid concentration were not observed in healthy volunteers regardless of renal function (58% in the group with normal renal function and 55% in the group with severe renal impairment).

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

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

Baseline serum uric acid concentration ≥ 10 mg/dL was observed in approximately 40% of patients (combined APEX and FACT studies). Among these patients, the primary efficacy endpoint (serum uric acid concentration < 6.0 mg/dL at the last 3 visits) was achieved in the febuxostat subgroup in 41% of patients (80 mg once daily), 48% 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 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: percentage of patients requiring treatment for gout flares

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

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

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

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

Long-term open-label extension studies

EXCEL study (C02-021). The EXCEL study was a 3-year, open-label, multicenter, randomized, allopurinol-controlled phase 3 safety extension study conducted to evaluate safety in patients who completed the pivotal phase 3 studies (APEX or FACT). A total of 1086 patients were included in the study: febuxostat 80 mg once daily (n=649), febuxostat 120 mg once daily (n=292), and allopurinol 300/100 mg once daily (n=145). Approximately 69% of patients did not require dose adjustment to achieve final stable treatment. Patients whose serum uric acid concentration was > 6.0 mg/dL in three consecutive measurements were excluded from the study.

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

Based on 3-year follow-up data, in less than 4% of patients requiring treatment for flares, a reduction in gout flare frequency was observed at 16–24 months and 30–36 months (i.e., over 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, phase 2 safety extension study conducted in patients who completed a 4-week double-blind dose-titration period of febuxostat in the TMX-00-004 trial. The study included 116 patients initially receiving febuxostat 80 mg once daily. For 62% of patients, no dose adjustment was required to maintain serum uric acid concentration below 6.0 mg/dL, while 38% of patients required dose adjustment to achieve final stable concentration.

The proportion of patients with serum uric acid concentration below 6.0 mg/dL (357 µmol/L) at the last visit was over 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 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%) for prolonged periods (see section "Special precautions").

Tumor Lysis Syndrome (TLS)

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

FLORENCE was a randomized (1:1), double-blind, controlled phase III study comparing febuxostat 120 mg once daily with allopurinol 200–600 mg daily (mean daily dose of allopurinol ± standard deviation: 349.7 ± 112.90 mg) under controlled serum uric acid (sUA) conditions. Eligible patients were candidates for allopurinol treatment or had no access to rasburicase. Primary endpoints were the area under the serum uric acid concentration-time curve (AUC sUA1–8) and change in serum creatinine (sCr) from day 1 to day 8.

A total of 346 patients with hematologic malignancies receiving chemotherapy and at intermediate/high risk of developing TLS were enrolled. The mean AUC sUA1–8 (mg × h/dL) was significantly lower with febuxostat (514.0 ± 225.71 vs. 708.0 ± 234.42; least squares mean difference: –196.794 [95% CI (confidence interval): –238.600; –154.988]; p < 0.0001). Additionally, mean serum uric acid levels were significantly lower with febuxostat starting from the first 24 hours of treatment and at any subsequent time point. No statistically significant differences in mean serum creatinine (%) were observed 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, no statistically significant differences were observed in the incidence of laboratory-confirmed TLS (8.1% vs. 9.2% for febuxostat and allopurinol, respectively; relative risk: 0.875 [95% CI: 0.4408; 1.7369]; p = 0.8488) or clinical TLS (1.7% vs. 1.2% for febuxostat and allopurinol, respectively; relative risk: 0.994 [95% CI: 0.9691; 1.0199]; p = 1.0000). The frequency of all treatment-emergent adverse events and adverse reactions was 67.6% vs. 64.7% and 6.4% vs. 6.4% for febuxostat and allopurinol, respectively. In the FLORENCE study, febuxostat demonstrated superior and faster urate-lowering action compared to allopurinol. Data comparing febuxostat 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 plasma concentration-time curve (AUC) increased proportionally with dose after single and multiple doses of febuxostat from 10 mg to 120 mg. At doses from 120 mg to 300 mg, AUC increased more than proportionally to dose. With repeated administration of 10–240 mg every 24 hours, no accumulation of febuxostat was observed. The predicted mean terminal elimination half-life (t1/2) of febuxostat was approximately 5–8 hours. A population pharmacokinetic/pharmacodynamic analysis was performed based on data from 211 patients with hyperuricemia and gout receiving Febumax at doses of 40–240 mg once daily. Overall, the obtained pharmacokinetic parameter values corresponded to those in healthy volunteers, which 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 of 80 mg or single administration of 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 of 80 mg). Thus, Febumax can be administered regardless of food intake.

Distribution. The predicted steady-state volume of distribution (Vss/F) for febuxostat ranges from 29 to 75 L after oral administration of 10–300 mg. The extent of 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 for active metabolites of febuxostat ranges from 82% to 91%.

Metabolism. Febuxostat is extensively metabolized via conjugation by uridine diphosphate glucuronosyltransferases (UDP-glucuronosyltransferases) and oxidation by cytochrome P450 (CYP) enzymes. 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 primarily by CYP1A1, CYP1A2, CYP2C8, or CYP2C9, whereas febuxostat glucuronide is formed mainly by UDP-glucuronosyltransferase 1A1, 1A8, and 1A9.

Excretion. Febuxostat is eliminated via the liver and kidneys. After oral administration of 14C-febuxostat 80 mg, approximately 49% was excreted in urine as unchanged febuxostat (3%), active substance acylglucuronide (30%), known oxidized metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to renal excretion, approximately 45% 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 Febumax 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 × 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 2- 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 Febumax 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 Febumax, 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, Cmax and AUC of febuxostat in women were 24% and 12% higher, respectively, than in men. However, Cmax and AUC corrected for body weight were similar in both groups; therefore, dose adjustment of febuxostat based on gender is not required.

Studies

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

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

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

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

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

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

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

All-cause mortality 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").

The number of hospitalizations for heart failure, hospitalizations for non-ischemic arrhythmia, venous thromboembolic events, and hospitalizations for transient ischemic attacks were comparable with 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 risk factors for cardiovascular disease (i.e., patients aged 60 years or older with at least one additional risk factor). Patients meeting the inclusion criteria received allopurinol treatment prior to randomization and, if necessary, had their dose adjusted based on clinical assessment, European League Against Rheumatism (EULAR) recommendations, and approved dosing regimen. At the end of the allopurinol run-in phase, patients with serum uric acid concentration (sUA) < 0.36 mmol/L (< 6 mg/dL) or those 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 composite endpoint, specifically:

• 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 the treatment-received approach.

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

In the primary analysis of treatment-received data, febuxostat was non-inferior to allopurinol regarding the frequency of the primary endpoint, which occurred in 172 patients (1.72/100 patient-years) in the febuxostat group compared to 241 patients (2.05/100 patient-years) in the allopurinol group, with adjusted hazard ratio [HR] 0.85 (95% CI: 0.70, 1.03), p < 0.001. The analysis of treatment-received data for the primary endpoint in the subgroup of patients with prior MI, stroke, or ACS did not show a significant difference between treatment groups: 65 (9.5%) patients with adverse events in the febuxostat group and 83 (11.8%) patients 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 an increased risk of cardiovascular mortality or all-cause mortality, either overall or in the subgroup of patients with prior MI, stroke, or ACS. Overall, fewer deaths occurred in the febuxostat group (62 cardiovascular deaths and 108 deaths from other causes) than in the allopurinol group (82 cardiovascular deaths and 174 deaths from other causes).

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

Clinical Characteristics.

Indications.

Febumex 80 mg and Febumex 120 mg:

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

Febumex 120 mg:

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

Febumex is indicated for adult patients.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Mercaptopurine/azathioprine

Due to its mechanism of action, febuxostat inhibits xanthine oxidase; therefore, concomitant use is not recommended. Inhibition of xanthine oxidase may lead to increased plasma concentrations of both drugs, potentially causing myelotoxic reactions. If co-administration is necessary, 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 rat study data, has been confirmed by results of a clinical drug interaction study in healthy volunteers who received azathioprine 100 mg alone and a reduced dose of azathioprine (25 mg) in combination with febuxostat (40 mg or 120 mg). Drug interaction studies between febuxostat and 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 concomitantly administered cytotoxic agents cannot be excluded.

Rosiglitazone/CYP2C8 substrates

Febuxostat is a weak inhibitor of CYP2C8 in vitro. In a study conducted in 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, demonstrating that febuxostat does not inhibit CYP2C8 in vivo. Thus, co-administration of febuxostat with rosiglitazone or other CYP2C8 substrates does not require dose adjustment of these agents.

Theophylline

A drug interaction study in healthy volunteers was conducted to evaluate the potential for increased circulating levels of theophylline 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 safety concerns regarding theophylline. Therefore, febuxostat 80 mg may be administered concomitantly with theophylline without special precautions. Data on concomitant use of febuxostat 120 mg are not available.

Naproxen and other inhibitors of glucuronidation

Metabolism of febuxostat depends on the activity of the enzyme UDP-glucuronosyltransferase. Medicinal products that inhibit glucuronidation, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and probenecid, may theoretically affect the elimination of febuxostat. 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, 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 of either drug.

Inducers of glucuronidation

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

Colchicine/indomethacin/hydrochlorothiazide/warfarin

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

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 the international normalized ratio (INR) 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 febuxostat 120 mg 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 necessary for CYP2D6 substrates when co-administered with febuxostat.

Antacids

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

Special precautions for use.

Cardiovascular diseases

Treatment of chronic hyperuricemia

In patients with pre-existing major cardiovascular diseases (e.g., myocardial infarction, stroke, or unstable angina), a higher number of cardiovascular deaths were observed in the febuxostat group compared to the allopurinol group during the drug development phase and in one post-marketing study (CARES).

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

Treatment of patients with pre-existing cardiovascular diseases should be performed with caution, and such patients should undergo regular monitoring.

For further details on the cardiovascular safety of febuxostat, see section "Adverse reactions".

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

Patients undergoing chemotherapy for hematological malignancies with moderate or high risk of TLS who are receiving Febumax should, when clinically indicated, be under cardiologist supervision.

Allergy/hypersensitivity to medicinal products

During 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 should be 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 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, 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 flare should be administered concurrently. 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 has not been observed in the pivotal clinical trial of febuxostat in TLS. Due to limited experience, febuxostat is not recommended for patients with Lesch-Nyhan syndrome.

Azathioprine/mercaptopurine

Febuxostat is not recommended for patients concurrently receiving azathioprine/mercaptopurine, as inhibition of xanthine oxidase by febuxostat may increase plasma concentrations of mercaptopurine/azathioprine, potentially leading to severe toxicity. If combination therapy cannot be avoided, the dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose to avoid 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 the occurrence of possible toxic effects.

Organ transplant recipients

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 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 on the use of febuxostat 120 mg are not available.

Hepatic impairment

In combined phase 3 clinical trials, minor changes in liver function parameters were observed in 5.0% of patients receiving febuxostat. Therefore, liver function tests are recommended before initiating febuxostat and during treatment as clinically indicated.

Thyroid disorders

During long-term open-label extension studies, increased TSH levels (> 5.5 mIU/L) were observed in 5.5% of patients receiving long-term febuxostat treatment. Therefore, febuxostat should be used with caution in patients with thyroid dysfunction.

Lactose

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

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 have not shown any direct or indirect adverse effects on pregnancy, embryonic/fetal development, or parturition. 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 into breast milk and has a negative effect on the development of suckling neonates. 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 of 48 mg/kg/day did not reveal dose-dependent adverse effects. 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 this medication should exercise caution when driving or operating machinery until they are certain that these adverse reactions do not affect them.

Method of Administration and Dosage

Dosage

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

The recommended duration of treatment for the prevention of gout attacks is at least 6 months.

Tumor Lysis Syndrome (TLS)

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

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

Elderly Patients

Dose adjustment is not required for this patient group.

Renal Impairment

The efficacy and safety of the drug have not been adequately 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 drug in patients with moderate hepatic impairment is limited.

Tumor Lysis Syndrome (TLS)

Dose adjustment is required in patients with severe hepatic impairment.

Method of Administration

For oral use.

Febumax is administered orally, independent of food intake.

Children

Safety and efficacy of the drug 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 volunteers receiving doses from 80 mg to 120 mg), and during post-marketing surveillance in patients with gout were gout flares, hepatic function abnormalities, diarrhea, nausea, headache, dizziness, dyspnea, rash, pruritus, arthralgia, myalgia, limb pain, edema, and increased fatigue. These adverse reactions were mostly mild or moderate in severity. During post-marketing surveillance, there have been reports of rare cases of serious hypersensitivity reactions to febuxostat, some of which were accompanied by systemic reactions, as well as rare events of sudden cardiac death.

The table below lists adverse reactions observed in patients treated with febuxostat, classified as follows: common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), and rare (≥1/10,000 to <1/1,000). Frequency is based on data from clinical trials and post-marketing experience in patients with gout.

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

Table 2

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

* Adverse reactions observed during post-marketing surveillance.

** Diarrhea and abnormal liver function test results requiring treatment, observed during clinical trials, occurred more frequently in patients receiving concomitant colchicine therapy.

*** Gout flares (attacks) usually occurred shortly after initiation of treatment and during the first months of treatment. The frequency of gout flares decreased over time.

Adverse reactions identified from post-marketing 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, including of the eyes. Hypersensitivity reactions to febuxostat may present with symptoms such as skin reactions including infiltrated maculopapular rash, generalized or exfoliative rash, 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 (attacks) were usually observed shortly after initiation of treatment and during the first months of treatment. The frequency of gout flares decreased over time. Prophylaxis for acute gout flares is recommended after initiation of febuxostat therapy.

Tumor Lysis Syndrome (TLS)

Summary of safety profile

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

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

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

Vascular disorders — uncommon: hemorrhage.

Reporting of suspected adverse reactions

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

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Packaging.

14 tablets per blister; 2 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

MACLEODS PHARMACEUTICALS LIMITED.

Manufacturer's address and location of manufacturing site.

Village Theda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.