Febumax tablets 80 mg No. 28

Instructions for Febumax 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, sodium lauryl sulfate, colloidal anhydrous silicon dioxide;

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

Dosage form

Film-coated tablets.

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

120 mg tablets: capsule-shaped, biconvex, film-coated tablets, yellow in color, engraved with "F 20" 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, with an in vitro Ki (inhibition constant) of less than 1 nM. 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 affect other enzymes involved in purine or pyrimidine metabolism, such as guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, orotidine monophosphate decarboxylase, or purine nucleoside phosphorylase.

Clinical efficacy and safety

Gout

The efficacy of febuxostat was confirmed in phase 3 of three pivotal studies (the two pivotal studies APEX and FACT and the additional CONFIRMS study, described below), which included 4101 patients with hyperuricemia and gout. In each of these pivotal phase 3 studies, febuxostat 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 registration of febuxostat, 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. Patients who had undergone organ transplantation were excluded from these studies (see section 4.4).

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), 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 ≤1.5 mg/dL or 100 mg once daily (n=10) for patients with baseline serum creatinine >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 febuxostat 80 mg once daily and febuxostat 120 mg once daily 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: febuxostat 80 mg once daily (n=256), febuxostat 120 mg once daily (n=251), and allopurinol 300 mg once daily (n=253).

The FACT study demonstrated statistically significant superiority of both regimens – febuxostat 80 mg once daily and febuxostat 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

(357 μmol/L) during the last three monthly visits

With febuxostat, the reduction in serum uric acid concentration was rapid and sustained. The reduction in serum uric acid concentration to

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 >1.5 mg/dL and

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 2269 patients were randomized to receive 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). Gout prophylaxis was mandatory for 26 weeks.

The proportion of patients with serum uric acid concentration (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 the febuxostat group in 44% of patients (80 mg once daily), 45% (120 mg once daily), and 60% (240 mg once daily) 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 dysfunction).

A prospective analysis conducted in patients with gout and renal impairment using the CONFIRMS study showed that febuxostat was significantly more effective: serum uric acid levels were reduced to levels

Primary endpoint in the subgroup of patients with 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 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) was 31% (72/230).

Clinical outcomes: percentage of patients requiring treatment for gout attacks

APEX 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 the febuxostat 80 mg group (28%), allopurinol 300 mg group (23%), and placebo group (20%). The frequency of attacks was higher after the prophylaxis period and gradually decreased over time. Between 46 and 55% of patients received treatment for gout attacks from week 8 and from week 28. Gout attacks 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 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, where febuxostat 80 mg (22%) and allopurinol 300 mg were used. 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 -24 weeks (weeks 49–52).

Long-term extended open-label studies

EXCEL Study (C02-021). The EXCEL study was a 3-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: 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 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 of

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).

Tumor lysis syndrome (TLS)

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

FLORENCE was a randomized (1:1), double-blind, pivotal phase III study comparing febuxostat 120 mg once daily to allopurinol 200–600 mg daily (mean daily allopurinol dose [± standard deviation]: 349.7 ± 112.90 mg) in a controlled setting 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 SLP. The mean AUC sUA1-8 (mg × h/dL) was significantly lower with febuxostat (514.0 ± 225.71 vs. 708.0 ± 234.42; LS mean difference: -196.794 [95% CI: -238.600; -154.988]; p 9.2% for febuxostat and allopurinol, respectively; relative risk: 0.875 [95% CI: 0.4408; 1.7369]; p = 0.8488) and there was no clinical tumor lysis syndrome (1.7% and 1.2% for febuxostat and allopurinol, respectively; relative risk: 0.994 [95% CI: 0.9691; 1.0199]; p=1.0000). The incidence of all treatment-emergent signs and symptoms and adverse reactions was 67.6% vs. 64.7% and 6.4% vs. 6.4% for febuxostat and allopurinol, respectively. In the FLORENCE study, febuxostat demonstrated superior and faster serum uric acid-lowering efficacy compared with allopurinol. Data comparing febuxostat and rasburicase are not yet available. The efficacy and safety of febuxostat have not been established in patients with acute severe GSD, i.e., in patients in whom other urate-lowering therapies have failed.

In healthy volunteers, the maximum plasma concentration (Cmax) and the area under the pharmacokinetic 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. No accumulation of febuxostat was observed 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 Febuxostat in doses of 40–240 mg once daily. In general, the obtained values of pharmacokinetic parameters correspond to those in healthy volunteers, which are 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, Febumax 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%.

Metabolism: Febuxostat is extensively metabolized by conjugation via uridine diphosphate glucuronyl transferase (UDP-glucuronyl transferase) and oxidation via cytochrome P450 (CYP) enzymes. A total of 4 pharmacologically active hydroxyl metabolites of febuxostat have been identified; 3 of these have been detected in human plasma. In vitro studies in human liver microsomes have shown that these oxidized metabolites are formed primarily by CYP1A1, CYP1A2, CYP2C8 or CYP2C9, while febuxostat glucuronide is formed primarily by UDP-glucuronyl transferases 1A1, 1A8 and 1A9.

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 repeated administration of Febuxostat 80 mg, there was no change in Cmax of febuxostat 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 for patients with mild or moderate renal impairment.

Liver failure

With repeated administration of Febumax 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 insufficiency compared to patients with normal hepatic function. The drug has not been studied in patients with severe hepatic insufficiency (Child-Pugh Class C).

Age

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

Sex

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

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 mg to 600 mg for patients with normal renal function and mild renal impairment and from 200 mg to 400 mg for patients with moderate renal impairment.

The primary endpoint in the CARES study was the 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 with urgent coronary revascularization.

Endpoints (primary and secondary) were analyzed according to the intention-to-treat (ITT) analysis, including all patients who were randomized and received at least one dose of the drug in 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) [CI] 0.89–1.21).

When analyzing the individual components of MACE, the incidence of cardiovascular deaths 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 accepted hospitalization 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.

Indication

Febumax 80 mg and Febumax 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.

Febumax 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).

Febumax is indicated for adult patients.

Contraindication

Hypersensitivity to the active substance or to any of the excipients of the drug.

Interaction with other medicinal products and other types of interactions

Mercaptopurine/azathioprine

According 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 toxic reactions. Interaction studies of febuxostat with drugs (except theophylline) metabolized by xanthine oxidase have not been conducted in humans.

Modelling and simulation analysis of preclinical data in rats indicates that when febuxostat is co-administered, the dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose (see section 4.4).

Interaction studies with febuxostat during other cytotoxic chemotherapy have not been conducted. In the pivotal study, febuxostat was administered at a dose of 120 mg 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.

Febuxostat is a weak inhibitor of CYP2C8 in vitro. In a study in healthy volunteers, co-administration 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.

Naproxen and other glucuronidation inhibitors

Febuxostat metabolism is dependent on the activity of the enzyme UDP-glucuronyltransferase. Drugs that inhibit glucuronidation, such as nonsteroidal anti-inflammatory drugs (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/cyclooxygenase-2 (COX-2) inhibitors was not associated with a clinically significant increase in adverse reactions.

Febuxostat can be used concomitantly with naproxen without changing the doses of these drugs.

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, an increase in febuxostat plasma levels may occur.

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. The use of febuxostat in healthy volunteers (80 mg or 120 mg once daily) with warfarin does not affect the pharmacokinetics of the latter. Concomitant use with febuxostat also had no effect on international normalized ratio (INR) and factor VII activity.

Desipramine/CYP2D6 substrates

In vitro data indicate that febuxostat is a weak inhibitor of CYP2D6. In a study in healthy volunteers receiving 120 mg Febuxostat 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

Patients with pre-existing underlying cardiovascular disease (e.g. myocardial infarction, stroke or unstable angina) should avoid treatment with febuxostat unless there are no other appropriate treatment options.

In the CARES study (for detailed study characteristics, see the Pharmacodynamics section), the incidence of MACE was similar in the febuxostat and allopurinol groups (HR 1.03; 95% CI 0.89–1.21), but there was a higher incidence of cardiovascular death (4.3% vs. 3.2% of patients; HR 1.34; 95% CI 1.03–1.73).

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 Febumax should be under the supervision of a cardiologist if clinically indicated.

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. Several, but not all, patients had a history of renal impairment and/or hypersensitivity to allopurinol. Severe hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), have been associated with fever, haematological, renal or hepatic failure in some cases.

Patients should be informed of the signs and symptoms of hypersensitivity/allergy and monitored for the development of such reactions. Febuxostat should be discontinued immediately if serious allergic/hypersensitivity reactions, including Stevens-Johnson syndrome, occur, as early discontinuation improves the prognosis. If a patient develops an allergic/hypersensitivity reaction, including Stevens-Johnson syndrome, and acute anaphylactic reactions/shock, then re-administration of febuxostat is contraindicated.

Gout flare-up (attack)

Febuxostat treatment should only be initiated after an exacerbation of the disease. Febuxostat may precipitate a gout attack at the start of treatment by altering serum uric acid levels due to release of urate from the depot. At the start of treatment with febuxostat, it is recommended to prescribe colchicine for at least 6 months to prevent gout attacks.

If a gout attack develops while taking febuxostat, treatment is continued. At the same time, appropriate individual therapy for gout exacerbation is carried out. With prolonged use of febuxostat, the frequency and severity of gout attacks are reduced.

Xanthine deposition

In patients with accelerated urate formation (for example, against the background of malignant neoplasms and their treatment or in Lesch-Nyhan syndrome), a significant increase in the absolute concentration of xanthines in the urine is possible, which in rare cases is accompanied by their deposition in the urinary tract. This was not observed in the pivotal clinical study of Febumax in SLP. Due to limited experience, febuxostat is not indicated in patients with Lesch-Nyhan syndrome.

Mercaptopurine/azathioprine

Febuxostat is not recommended for use in patients receiving concomitant mercaptopurine/azathioprine, as inhibition of xanthine oxidase by febuxostat may result in increased plasma concentrations of mercaptopurine/azathioprine, which may lead to severe toxicity. No interaction studies have been conducted in humans.

If the combination cannot be avoided, it is recommended to reduce the dose of mercaptopurine/azathioprine. Based on modelling and simulation analysis of preclinical data in rats, the dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose when febuxostat is co-administered to avoid possible haematological effects (see section 4.5). Patients should be closely monitored and the dose of mercaptopurine/azathioprine should be adjusted subsequently based on the assessment of the therapeutic response and the occurrence of possible toxic effects.

Patients who have undergone organ transplantation

There is no experience with the use of febuxostat in this category of patients, therefore the use of the drug is not indicated.

Theophylline

A single concomitant administration of febuxostat 80 mg and theophylline 400 mg did not show any pharmacokinetic interactions. Febuxostat 80 mg can be administered concomitantly with theophylline without the risk of increased theophylline concentrations.