Adenuric 80 mg film-coated tablets 80 mg No. 28

Instructions for use Adenuric 80 mg film-coated tablets 80 mg No. 28

Composition

active ingredient: febuxostat;

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

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

Dosage form

Film-coated tablets.

Main physicochemical properties:

Film-coated tablet, 80 mg: pale yellow to yellow, capsule-shaped, film-coated tablets, debossed with “80” on one side and a breakline on the other side.

The score line is only intended for breaking the tablet to make it easier to swallow; it is not intended to divide the tablet into equal doses.

Film-coated tablet, 120 mg: pale yellow to yellow, capsule-shaped, film-coated tablets, debossed with “120” on one side and plain 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 during the following reaction: hypoxanthine → xanthine → uric acid. Xanthine oxidase catalyzes both steps of this reaction. Febuxostat is a 2-arylthiazole derivative, the therapeutic effect of which is associated with a decrease in serum uric acid concentration by selective inhibition of xanthine oxidase. Febuxostat is a potent and selective non-purine inhibitor of xanthine oxidase (NP-SIXO), with an in vitro Ki (inhibition constant) of less than 1 nanomolar. Febuxostat has been shown to significantly inhibit the activity of both the oxidized and reduced forms of xanthine oxidase. At therapeutic concentrations, febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism such as guanine deaminase, hypoxanthineguanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase, or purine nucleoside phosphorylase.

Clinical efficacy and safety.

Gout

The efficacy of ADENURIC® was confirmed in three phase 3 pivotal studies (the two pivotal studies APEX and FACT and the additional CONFIRMS study, described below), which included 4,101 patients with hyperuricemia and gout. In each of these pivotal phase 3 studies, ADENURIC® was more effective in lowering serum uric acid levels and maintaining them at an appropriate level compared to allopurinol. The primary efficacy endpoint in the APEX and FACT studies was the proportion of patients whose serum uric acid concentration did not exceed 6.0 mg/dL (357 μmol/L) during the previous three months. In the additional phase 3 CONFIRMS study, the results of which became available after the first approval of ADENURIC®, the primary efficacy endpoint was the proportion of patients whose serum uric acid concentration did not exceed 6.0 mg/dL at the time of the last visit. These studies did not include patients who had undergone organ transplantation (see section "Special warnings and precautions for use").

APEX Study: The Phase 3 Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX) was a randomized, double-blind, multicenter, 28-week study. A total of 1072 patients were randomized to: 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 (2 times the maximum recommended dose).

The APEX study demonstrated a statistically significant superiority of both ADENURIC® 80 mg once daily and ADENURIC® 120 mg once daily treatment regimens compared to allopurinol at the usual dose of 300 mg (n = 258) / 100 mg (n = 10) in reducing serum uric acid concentrations below 6 mg/dL (357 μmol/L) (see Table 1 and Figure 1).

FACT Study: The Febuxostat Allopurinol Controlled Trial (FACT) was a phase 3, randomized, double-blind, multicenter, 52-week study. A total of 760 patients were randomized to: 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 regimens – ADENURIC® 80 mg once daily and ADENURIC® 120 mg once daily – compared to allopurinol at the usual dose of 300 mg in reducing and maintaining serum uric acid concentrations below 6 mg/dL (357 μmol/L).

Table 1 presents the results of the assessment of 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

With ADENURIC®, the reduction in serum uric acid concentration was rapid and sustained. Reductions in serum uric acid concentration to < 6.0 mg/dL (357 μmol/L) were observed as early as the second week of the study and were maintained throughout the course of treatment. Figure 1 shows the mean serum uric acid concentrations over time for each treatment group in both pivotal phase 3 studies.

Note: 509 patients received allopurinol 300 mg once daily; 10 patients with serum creatinine > 1.5 mg/dL and < 2.0 mg/dL received allopurinol 100 mg once daily (10 of 268 patients in the APEX study). Febuxostat 240 mg was administered for safety evaluation at 2 times the maximum recommended dose.

CONFIRMS Study: The CONFIRMS study was a 26-week, randomized, controlled, phase 3 study conducted to evaluate the safety and efficacy of febuxostat 40 mg and 80 mg compared with allopurinol 300 mg and 200 mg in patients with gout and hyperuricemia. A total of 2,269 patients were randomized to: 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). Gout flare prophylaxis was mandatory for 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 endpoint in the subgroup of patients with renal impairment

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

At the same time, no clinically significant differences in the percentage reduction in serum uric acid concentration were observed in healthy volunteers, regardless of the functional state of the kidneys (58% in the group with normal kidney function and 55% in the group with severe renal impairment).

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

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

Baseline serum uric acid concentrations ≥ 10 mg/dL were 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 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 with 9% in the allopurinol 300 mg/100 mg once daily group and 0% in the placebo group.

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

Clinical outcomes: percentage of patients requiring treatment for gout attacks

FACT Study: During the 8-week prophylaxis period, patients in the febuxostat 120 mg treatment group (36%) who required treatment for gout attacks were compared with patients in both treatment groups, febuxostat 80 mg (22%) and allopurinol 300 mg (21%). After the 8-week prophylaxis period, the frequency of attacks increased and gradually decreased over time (64% and 70% of patients treated for gout attacks from weeks 8–52). Gout attacks 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 with groups in which the mean uric acid level was ≥ 6.0 mg/dL in the last 32 weeks of treatment (weeks 20–24 to weeks 49–52).

In the CONFIRMS study, the proportion of patients requiring treatment for gout attacks (1 day every 6 months) was 31% and 25% in the febuxostat 80 mg and allopurinol groups, respectively. There was no difference in the proportion of patients requiring treatment for gout attacks between the febuxostat 80 mg and 40 mg groups.

Long-term extended open-label studies

EXCEL Study (C02-021): The EXCEL study was a three-year, open-label, multicenter, randomized, allopurinol-controlled, phase 3 safety study conducted to evaluate the safety of patients who completed the pivotal phase 3 studies (APEX or FACT). A total of 1086 patients were enrolled 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 therapy adjustment to achieve final stable treatment. Patients with serum uric acid levels > 6.0 mg/dL on three consecutive measurements were excluded from the study.

Serum uric acid levels did not change over time (e.g., 91% and 93% of patients initially treated with febuxostat at doses of 80 mg and 120 mg, respectively, had serum uric acid levels < 6.0 mg/dL at month 36).

According to three-year follow-up data, less than 4% of patients who required treatment for attacks showed a reduction in the frequency of gout attacks at 16–24 months and 30–36 months (i.e., more than 96% of patients did not require treatment for attacks).

In 46% and 38% of patients receiving final stable treatment with febuxostat 80 or 120 mg once daily, respectively, complete resolution of the primary palpable tophus was observed from baseline to the last visit.

The FOCUS study (TMX-01-005) was a 5-year, open-label, multicenter, Phase 2 safety extension study conducted in patients who completed the 4-week double-blind febuxostat dosing in study TMX-00-004. The study included 116 patients who initially received febuxostat 80 mg once daily. 62% of patients did not require dose adjustment to maintain serum uric acid levels below 6.0 mg/dL, and 38% of patients required dose adjustment to achieve final steady-state levels.

The proportion of patients with serum uric acid levels less than 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 tests were observed in patients treated with febuxostat (5.0%). The incidence of these changes was similar to that observed with allopurinol (4.2%) (see section 4.4). In long-term open-label extension studies, elevations in TSH (> 5.5 μIU/mL) were observed in patients treated with febuxostat (5.5%) or allopurinol (5.8%) for extended periods (see section 4.4).

Post-registration long-term studies

The CARES study was a multicenter, randomized, double-blind, non-inferiority trial that compared 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 mellitus with evidence of microangiopathy or macroangiopathy. To achieve sUA levels of less than 6 mg/dL, the febuxostat dose was titrated from 40 mg to 80 mg (regardless of renal function), and the allopurinol dose was titrated in 100 mg increments from 300 to 600 mg for patients with normal renal function and mild renal impairment and from 200 to 400 mg for patients with moderate renal impairment.

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

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

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

The primary endpoint of MACE was observed with 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).

When analyzing the individual components of MACE, the incidence 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 incidence of other MACE events was similar in the febuxostat and allopurinol groups, i.e. nonfatal myocardial infarction (3.6% vs. 3.8% of patients; HR 0.93; 95% CI 0.72–1.21), nonfatal 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), mainly due to the higher cardiovascular mortality rate in this group (see section 4.4).

Rates of readmission for heart failure, hospitalization for arrhythmias not related to ischemia, venous thromboembolic events, and hospitalization for transient ischemic attacks were comparable for febuxostat and allopurinol.

The FAST study was a prospective, randomized, open-label, blinded study comparing the cardiovascular safety profile of febuxostat and allopurinol in patients with chronic hyperuricemia (in the setting where urate deposition has already occurred) and risk factors for cardiovascular disease (CVD) (i.e., patients ≥60 years of age and at least one other CVD risk factor). Eligible patients were treated with allopurinol prior to randomization and had their dose adjusted as needed based on clinical assessment, European League Against Rheumatism (EULAR) guidelines, and the approved dosing regimen. At the end of the allopurinol run-in phase, patients with serum uric acid (sUA) < 0.36 mmol/L (< 6 mg/dL) or patients receiving the maximum tolerated dose or maximum tolerated dose of allopurinol were randomized 1:1 to receive either febuxostat or allopurinol. The primary endpoint of the FAST study was the time to first occurrence of any Antiplatelet Trialists' Collaborative (APTC) composite endpoint, including:

— hospitalization for non-fatal myocardial infarction (MI) / acute coronary syndrome (ACS) with a positive response to biomarkers;

— non-fatal stroke;

— death as a result of cardiovascular complications.

The primary analysis was based on an approach that considered data from patients receiving treatment.

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

In the primary analysis of the treated patients, febuxostat was non-inferior to allopurinol in terms of the incidence of the primary endpoint, which was observed in 172 patients (1.72/100 patient-years) in the febuxostat group compared with 241 patients (2.05/100 patient-years) in the allopurinol group, with an adjusted hazard ratio [HR] of 0.85 (95% CI: 0.70, 1.03), p < 0.001. Analysis of the treated patients for the primary endpoint in the subgroup of patients with a history of MI, stroke, or ACS showed no significant difference between treatment groups: 65 (9.5%) patients with 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.

Febuxostat treatment was not associated with an increase in CVD or non-cardiac mortality overall or in the subgroup of patients with a history of MI, stroke, or ACS. Overall, there were fewer deaths in the febuxostat group (62 CVD deaths and 108 non-cardiac deaths) than in the allopurinol group (82 CVD deaths and 174 non-cardiac deaths).

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

Tumor lysis syndrome (TLS)

FLORENCE was a randomized (1:1), double-blind, pivotal phase III study comparing ADENURIC® 120 mg once daily to allopurinol 200–600 mg daily (mean daily allopurinol dose [± standard deviation]: 349.7 ± 112.90 mg) under controlled conditions for serum uric acid. Eligible patients were candidates for allopurinol or had no access to rasburicase. The primary endpoints were the area under the serum uric acid concentration curve (AUC sUA1-8) and the change in serum creatinine (sC), each from day 1 to day 8.

The study included 346 patients with hematological malignancies receiving chemotherapy and at intermediate/high risk of developing SLE. The mean AUC sUA1-8 (mg × h/dL) was significantly lower with ADENURIC® (514.0 ± 225.71 vs. 708.0 ± 234.42; LS mean difference: -196.794 [95% CI: -238.600, -154.988]; p < .0001). In addition, the mean serum uric acid level was significantly lower with ADENURIC®, starting from the first 24 hours of treatment and at any time point thereafter. There were no statistically significant differences in mean serum creatinine (%) between ADENURIC® and allopurinol (-0.83 ± 26.98 versus -4.92 ± 16.70, respectively; least squares mean for difference: 4.0970 [95% confidence interval: -0.6467, 8.8406]; p=0.0903). Considering the secondary endpoints, there were no statistically significant differences in the incidence of laboratory-confirmed SLE (8.1% and 9.2% for ADENURIC® and allopurinol, respectively; relative risk: 0.875 [95% confidence interval: 0.4408, 1.7369]; p=0.8488) and no 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 incidence of all treatment-emergent signs and symptoms and adverse reactions was 67.6% versus 64.7% and 6.4% versus 6.4% for ADENURIC® and allopurinol, respectively. In the FLORENCE study, ADENURIC® demonstrated superior and more rapid serum uric acid lowering activity compared with allopurinol. Data comparing ADENURIC® and rasburicase are currently unavailable. The efficacy and safety of febuxostat have not been established in patients with acute severe SLE, i.e. patients in whom other urate-lowering therapies have failed.

Pharmacokinetics.

In healthy volunteers, the maximum plasma concentration (Cmax) and area under the curve (AUC) increased in a dose-proportional manner after single and multiple doses of febuxostat in doses from 10 mg to 120 mg. At doses from 120 mg to 300 mg, the increase in AUC was greater than dose-proportional. There was no accumulation of febuxostat when doses of 10–240 mg were administered every 24 hours. The estimated mean terminal elimination half-life (t1/2) of febuxostat was approximately 5–8 hours. A population pharmacokinetic/pharmacodynamic analysis was performed on data obtained from 211 patients with hyperuricemia and gout who received ADENURIC® in doses of 40–240 mg once daily. In general, the obtained values of pharmacokinetic parameters correspond to those in healthy volunteers, who therefore represent a good model for assessing the pharmacokinetics/pharmacodynamics of the drug in patients with gout.

Absorption. Febuxostat is rapidly (tmax (time to maximum concentration) 1.0–1.5 hours) and well (at least 84%) absorbed. After single and multiple oral doses of 80 mg or 120 mg once daily, Cmax is 2.8–3.2 μg/mL and 5.0–5.3 μg/mL, respectively. The absolute bioavailability of febuxostat tablets has not been studied. After multiple doses of 80 mg once daily or a single dose of 120 mg in combination with a fatty meal, Cmax was reduced by 49% and 38%, and AUC was reduced by 18% and 16%, respectively. However, this was not accompanied by clinically significant changes in the degree of reduction in serum uric acid (with multiple doses of 80 mg). Thus, ADENURIC® can be used regardless of food intake.

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

Elimination: Febuxostat is eliminated from the body via the liver and kidneys. Following oral administration of 80 mg of 14C-febuxostat, approximately 49% was excreted in the urine as unchanged febuxostat (3%), acylglucuronide of the active substance (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 the feces as unchanged febuxostat (12%), acylglucuronide of the active substance (1%), known oxidized metabolites and their conjugates (25%), and other unknown metabolites (7%).

Kidney failure.

With multiple doses of ADENURIC® at a dose of 80 mg, no changes in Cmax of febuxostat were observed in patients with mild, moderate or severe renal impairment compared to patients with normal renal function. The 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. The Cmax and AUC of the active metabolites increased 2- and 4-fold, respectively. However, no dose adjustment is required in patients with mild or moderate renal impairment.

Liver failure.

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

Age.

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

Sex.

After multiple oral doses of ADENURIC®, febuxostat Cmax and AUC were 24% and 12% higher in females than in males, respectively. However, weight-adjusted Cmax and AUC were similar in both groups, and no dose adjustment of febuxostat is necessary based on gender.

Indication

ADENURIC® 80 mg and ADENURIC® 120 mg:

Treatment of chronic hyperuricemia in diseases accompanied by the deposition of urate crystals, including the presence of tophus and/or gouty arthritis at present or in history.

ADENURIC® 120 mg:

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

ADENURIC® is indicated for adult patients.

Contraindication

Hypersensitivity to the active substance or to any other excipient of the drug listed in the "Composition" section.

Interaction with other medicinal products and other types of interactions

Mercaptopurine/azathioprine.

Due to its mechanism of action, febuxostat inhibits xanthine oxidase, therefore concomitant use is not recommended. Inhibition of xanthine oxidase may lead to increased plasma concentrations of both drugs, which may cause myelotoxicity. In case of concomitant administration of febuxostat, the dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose (see section 4.4).

The adequacy of the proposed dose adjustment, which was based on modeling and simulation analysis of preclinical rat data, was confirmed by the results of a clinical drug interaction study in healthy volunteers receiving azathioprine 100 mg alone and a reduced dose of azathioprine (25 mg) in combination with febuxostat (40 or 120 mg).

Interaction studies with febuxostat during other cytotoxic chemotherapy have not been performed. In a pivotal study, febuxostat 120 mg was administered to patients with SLE receiving multiple chemotherapy regimens, including monoclonal antibodies. However, drug-drug and drug-disease interactions were not investigated in this study. Therefore, the possibility of 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 in healthy volunteers, coadministration of 120 mg of febuxostat once daily with a single oral dose of 4 mg of rosiglitazone had no effect on the pharmacokinetics of rosiglitazone and its metabolite N-desmethylrosiglitazone, demonstrating that febuxostat does not inhibit CYP2C8 in vivo. Therefore, concomitant administration of febuxostat and rosiglitazone or other CYP2C8 substrates does not require dose adjustment for these drugs.

Theophylline.

An interaction study of febuxostat was conducted in healthy volunteers to assess the effect of xanthine oxidase inhibition on the increase in circulating theophylline levels observed with other xanthine oxidase inhibitors. The results of the study showed that there was no pharmacokinetic interaction or effect on the safety of theophylline when febuxostat 80 mg was co-administered with theophylline 400 mg. Therefore, febuxostat 80 mg can be co-administered with theophylline without any special precautions. There are no data available for the 120 mg dose of febuxostat.

Febuxostat metabolism is dependent on the activity of the enzyme UDP-glucuronyltransferase. Drugs that inhibit glucuronidation, such as NSAIDs and probenecid, could theoretically affect the elimination of febuxostat. In healthy volunteers, concomitant administration of febuxostat and naproxen 250 mg twice daily resulted in an increase in febuxostat exposure (Cmax 28%, AUC 41%, t1/2 26%). In clinical studies, the use of naproxen and other NSAIDs/COX-2 inhibitors was not associated with a clinically significant increase in adverse reactions.

Febuxostat can be used concomitantly with naproxen without changing their doses.

Glucuronidation inducers.

Strong inducers of the enzyme UDP-glucuronyltransferase may increase the metabolism and reduce the efficacy of febuxostat. In patients receiving strong inducers of glucuronidation, it is recommended to monitor plasma uric acid levels after 1–2 weeks of concomitant therapy. When the inducer of glucuronidation is discontinued, febuxostat plasma levels may increase.

Colchicine/indomethacin/hydrochlorothiazide/warfarin.

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

There is also no need to change the dose of febuxostat when used simultaneously with hydrochlorothiazide.

Concomitant use of febuxostat with warfarin does not require a change in the dose of warfarin. In healthy volunteers, the use of febuxostat (80 mg or 120 mg once daily) with warfarin did not affect the pharmacokinetics of warfarin. Concomitant use with febuxostat also had no effect on INR and 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 of ADENURIC® once daily, a 22% increase in the AUC of desipramine (a CYP2D6 substrate) was observed, indicating that febuxostat is a weak inhibitor of the CYP2D6 enzyme in vivo.

Therefore, there is no need to adjust the doses of febuxostat and CYP2D6 substrates when co-administered.

Antacids.

When used simultaneously with antacids containing magnesium hydroxide and aluminum hydroxide, a delay in the absorption of febuxostat (approximately 1 hour) and a decrease in Cmax by 32% are noted, however, the AUC of febuxostat does not change significantly, therefore febuxostat can be used with antacids.

Application features

Cardiovascular diseases.

Treatment of chronic hyperuricemia

During drug development and in one post-marketing study (CARES), patients with pre-existing underlying cardiovascular disease (e.g., myocardial infarction, stroke, or unstable angina) experienced a higher incidence of fatal cardiovascular events with febuxostat compared to allopurinol.

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

Treatment of this group of patients should be carried out with caution and regular supervision.

For more information on the cardiovascular safety of febuxostat, see the sections “Adverse Reactions” and “Pharmacodynamics”.

Prevention and treatment of hyperuricemia in patients at risk of developing Gout

Patients undergoing chemotherapy for hematological malignancies with moderate or high risk of SLP and using ADENURIC®, if clinically indicated, are under the supervision of a cardiologist.

Allergy/hypersensitivity to medications.

There have been rare reports of serious allergic/hypersensitivity reactions, including life-threatening Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute anaphylactic reactions/shock, during post-marketing surveillance. The majority of these reactions occurred within the first month of febuxostat use. A few, but not all, patients experienced