Adenuric, 80 mg 28 pcs

Antipodagrelating agent – xanthine oxidase inhibitor

Pharmacodynamics

. Uric acid is the end product of purine metabolism in the human body, formed as a result of the hypoxanthine-xanthine uric acid reaction cascade. Febuxostat is a 2-arylthiazole derivative and is a strong selective non-purine xanthine oxidase inhibitor (in vitro inhibition constant is less than 1 nM). The enzyme xanthine oxidase catalyzes two stages of purine metabolism: oxidation of hypoxanthine to xanthine and then oxidation of xanthine to uric acid.

As a result of selective inhibition of xanthine oxidase (oxidized and reduced forms) by febuxostat it causes decrease of uric acid concentration in blood serum.

In therapeutic concentrations febuxostat does not inhibit other enzymes involved in the metabolism of purines or pyrimidines, such as guanine deaminase, hypoxanguanine phosphorybosyltransferase, orotate phosphorybosyltransferase, oro-tidinmonophosphate decarboxylase or purine-nucleoside phosphorylase.

Clinical efficacy and safety profile

Gout

The efficacy and safety of febuxostat has been confirmed in three baseline phase III clinical studies involving 4,101 patients with hyperuricemia and gout ( APEX , FACT and CONFIRMS ).

In each of these studies, use of febuxostat resulted in a more effective reduction in uric acid concentration and maintenance of serum levels compared with allopurinol.

The primary 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 past three months. In an additional CONFIRMS study, the primary endpoint was the proportion of patients whose serum uric acid concentration was less than 6.0 mg/dL at the last visit. These studies did not include patients who had undergone organ transplantation.

The double-blind, randomized, multicenter, 28-week APEX study (investigating the effectiveness of febuxostat versus placebo and allopurinol) enrolled 1,072 patients. Febuxostat was used in doses of 80 mg, 120 mg, or 240 mg once daily; allopurinol was used in a dose of 300 mg once daily in patients with baseline plasma creatinine ≤1.5 mg/dL and in a dose of 100 mg once daily in patients with baseline plasma creatinine >1.5 mg/dL and ≤2.0 mg/dL.

The use of febuxostat at a dose of 240 mg (twice the recommended maximum) was studied to evaluate the safety profile of febuxostat. When febuxostat was used at doses of 80 mg and 120 mg once daily for 28 weeks, the proportion of patients whose serum uric acid concentrations did not exceed 6.0 mg/dL (357 µmol/L) during the past three months was 48% and 65%, respectively, with allopurinol use at 22%. A double-blind, randomized, multicenter, 52-week FACT study (study of febuxostat versus allopurinol) enrolled 760 patients. Febuxostat was used in doses of 80 mg or 120 mg once daily; allopurinol was used in a dose of 300 mg once daily.

When febuxostat 80 mg and 120 mg once daily for 52 weeks, the proportion of patients whose serum uric acid concentrations did not exceed 6.0 mg/dL (357 µmol/L) during the past three months was 53% and 62%, respectively, and when allopurinol was used was 21%.

Administration of febuxostat led to a rapid decrease in plasma uric acid concentration; this effect persisted for a long time.

Decrease of uric acid concentration in blood serum less than 6.0 mg/dl (357 µmol/L) was noted as early as the second week of use (FACT study), this concentration was maintained throughout the period of febuxostat use.

A total of 2,269 patients were enrolled in the randomized, controlled, 26-week CONFIRMS study (studying the safety and effectiveness of febuxostat at doses of 40 mg and 80 mg once daily versus allopurinol at doses of 300 mg or 200 mg once daily in patients with gout and hyperuricemia). At least 65% of patients in this study had mild to moderate renal function impairment (creatinine clearance 30-89 mL/min).

The proportion of patients with plasma uric acid concentrations less than 6.0 mg/dL at the last visit was 45% and 67%, respectively, for febuxostat 40 mg and 80 mg, and 42% for allopurinol 300 mg/200 mg.

Extended long-term open-label studies

A three-year open-label, multicenter, randomized, expanded EXCEL safety study with allopurinol as a comparison included 1,086 patients (who completed the APEX or FACT study ) who were taking febuxostat at a dose of 80 mg once daily, febuxostat at 120 mg once daily or allopurinol 300 mg (for patients with baseline plasma creatinine ≤1.5 mg/dL) and 100 mg (for patients with baseline plasma creatinine >1.5 mg/dL and ≤2.0 mg/dL) once daily. Approximately 69% of patients did not require dose adjustment to establish a definitive stable regimen.

The target serum uric acid concentration level (less than 6.0 dL) achieved with prior febuxostat use did not change over time (91% and 93% of patients who initially took febuxostat at doses, respectively, 80 mg/mg and 120 mg, had serum uric acid concentrations less than 6.0 mg/dL at month 36 of use).

At three-year follow-up, there was a reduction in the incidence of gout attacks at months 16-24 and 30-36. Less than 4% of patients required treatment for an acute gout attack (i.e., more than 96% of patients did not need treatment for a gout attack). In 46% and 38% of patients taking febuxostat continuously, respectively, at a dose of 80 and 120 mg once daily, complete disappearance of tophi palpable at the initial visit was noted by the last visit.

The five-year open-label, multicenter, expanded safety study FOCUS (Phase II) included 116 patients who initially received febuxostat at a dose of 80 mg once daily for 4 weeks. In 62% of patients, no dose adjustment was required to maintain a target serum uric acid concentration of less than 6.0 mg/dL, and 38% of patients required dose adjustment to achieve target levels. At the last study visit, the proportion of patients whose serum uric acid concentration was less than 6.0 mg/dL (357 μmol/L) was greater than 80% (81-100%) at each study dose of febuxostat.

Effectiveness and safety profile in patients with impaired renal function

Febuxostat was used in 40 patients with impaired renal function (with creatinine >1.5 mg/dL and ≤2.0 mg/dL) in the APEX study. In patients with impaired renal function randomized to the allopurinol group, the dose of the latter was limited to 100 mg per day. In the febuxostat group, the primary endpoint was achieved in 44% of patients receiving febuxostat at a dose of 80 mg once daily, in 45% receiving 120 mg once daily, and in 60% receiving 240 mg once daily compared with 0% in the allopurinol group (100 mg once daily) and placebo group. There were no clinically significant differences in degree of decrease of uric acid concentration in blood serum in comparison with healthy volunteers (decrease of uric acid concentration in the group of patients with normal renal function was 58%, in the group with severe renal insufficiency – 55%).

A prospective analysis in the CONFIRMS study demonstrated significantly greater efficacy of febuxostat in reducing serum uric acid concentrations below 6 mg/dL, compared with allopurinol at a dose of 300 mg/ 200 mg in patients with gout and mild to moderate renal insufficiency (the proportion of these patients in the study was 65%).

The primary endpoint in a subgroup of patients with serum uric acid concentrations greater than 10 mg/dL

A baseline serum uric acid concentration greater than 10 mg/dL was noted in approximately 40% of patients enrolled in the APEX and FACT studies . Among these patients, the primary endpoint (uric acid concentration less than 6 mg/dL in the last 3 visits) was achieved in 41% of patients taking febuxostat at a dose of 80 mg once daily, in 48% of patients taking febuxostat at a dose of 120 mg once daily, and in 66% of patients taking febuxostat at a dose of 240 mg once daily compared with 9% in the allopurinol 300 mg/100 mg group and 0% in the placebo group.

According to the CONFIRMS study, the proportion of patients achieving the primary efficacy endpoint (uric acid concentration less than 6.0 mg/dL at the last visit) in the group of patients with a baseline serum uric acid concentration greater than 10 mg/dL receiving 40 mg febuxostat once daily was 27%, 80 mg once daily was 49% and 300 mg or 200 mg allopurinol once daily was 31%.

Percentage of patients needing treatment for an acute gout attack

The APEX Study: During the 8-week prevention period, a higher proportion of patients (36%) needed treatment for an acute gout attack in the group taking febuxostat at a dose of 120 mg daily than in the groups taking febuxostat at 80 mg (28%), allopurinol at 300 mg (23%) and the placebo group (20%). The incidence of acute gout attacks increased during the prophylactic period, subsequently decreasing over time. Between 46% and 55% of patients were treated for an acute gout attack from week 8 to week 28. Acute gout attacks during the last four weeks of the study (weeks 24-28) occurred in 15% of patients in the febuxostat group (80 mg, 120 mg), 14% of patients in the allopurinol group (300 mg), and 20% of patients in the placebo group.

The FACT Study : During the 8-week prophylactic period, a higher proportion of patients (36%) needed treatment for an acute gout attack in the group taking febuxostat at a dose of 120 mg daily than in the groups taking febuxostat at 80 mg daily (22%), allopurinol at 300 mg daily (21%). After an 8-week prophylactic period, the incidence of acute gout attacks increased and then gradually decreased over time (64% and 70% of patients were treated for gout exacerbations from weeks 8 through 52). Acute gout attacks during the last four weeks of the study (weeks 49-52) occurred in 6-8% of patients in the febuxostat group (80 mg, 120 mg), and in 11% of patients in the allopurinol group (300 mg).

The proportion of patients needing treatment for an acute gout attack (APEX and FACT studies ) was numerically lower in the groups with a mean serum uric acid concentration of less than 6.0 mg/dL, less than 5.0 mg/dL, or less than 0 mg/dL in the past 32 weeks (periods 20-24 weeks and 49-52 weeks) compared with the group where the mean serum uric acid concentration was greater than 6.0 mg/dL.

In the CONFIRMS study, the proportion of patients needing treatment for an acute gout attack (from day 1 to month 6) was 31% and 25% in the febuxostat 80 mg and allopurinol 200/300 mg groups, respectively. In the febuxostat 80 mg and febuxostat 40 mg groups, there were no differences between the proportions of patients needing treatment for an acute gout attack.

Tumor Decay Syndrome

The efficacy and safety of febuxostat for the prevention and treatment of tumor decay syndrome were studied in a randomized, double-blind phase III study, FLORENCE . Febuxostat demonstrated a more potent and rapid reduction in serum uric acid concentration compared to allopurinol with no adverse effect on renal function.

The study included 346 patients with hemoblastosis who had received cytostatic therapy and had a moderate to high risk of developing tumor decay syndrome. Patients received febuxostat at a dose of 120 mg once daily or allopurinol 200-600 mg daily to evaluate the ability of febuxostat to maintain serum uric acid concentration and to evaluate the effect of febuxostat on renal function. Patients who met the inclusion criteria for the study had to be candidates for allopurinol treatment or were unable to be treated with febuxostat.

The primary endpoints were the area under the concentration-time curve ( AUC ) of uric acid in serum and the change in serum creatinine over 8 days.

The mean area under the concentration-time curve was statistically significantly less in the febuxostat group than in the allopurinol group.

The mean serum uric acid concentration 24 hours after starting febuxostat and at all subsequent measurements was significantly lower than in the allopurinol group.

There were no statistically significant differences in the effect of febuxostat and allopurinol on plasma creatinine content.

The frequency of tumor decay syndrome with febuxostat and allopurinol was not statistically different either by laboratory diagnostic criteria or by clinical criteria.

The incidence of drug-related effects and the incidence of adverse reactions were 67.6% versus 64.7%, and 6.4% versus 6.4% in the febuxostat group and allopurinol group, respectively.

In the FLORENCE study in patients in whom allopurinol was planned, febuxostat demonstrated greater control of serum uric acid concentration compared with allopurinol. There are currently no data to compare febuxostat with rasburicase.

The efficacy and safety of febuxostat in patients with severe acute tumor decay syndrome (for example, in patients in whom other treatment regimens aimed at reducing uric acid concentration were ineffective) has not been studied.

Pharmacokinetics

A population-based analysis of pharmacokinetics and pharmacodynamics included data from a study involving 211 patients with hyperuricemia and gout who received febuxostat at a dose of 40 to 240 mg once daily. The obtained pharmacokinetic parameters of febuxostat were comparable to those of healthy volunteers, which allows us to consider the data of pharmacokinetic and pharmacodynamic studies involving healthy volunteers to be representative of the population of patients with gout.

Absorption

After oral administration, febuxostat is rapidly and almost completely (at least 84% of the dose taken) absorbed from the gastrointestinal tract. At multiple administration of febuxostat in dose of 80 mg or single dose of 120 mg concomitantly with fatty food maximum plasma concentration of febuxostat (C max ) was decreased by 49% and 38%, and AUC – by 18% and 16%, respectively. However, this had no effect on the clinical efficacy of decreasing uric acid concentration in blood serum (when taking febuxostat repeatedly at a dose of 80 mg), in this regard, febuxostat can be taken regardless of meals.

C max is reached 1.0-1.5 hours after oral administration and is 2.8-3.2 mcg/ml in a single oral dose of 80 mg and 5.0-5.3 mcg/ml in a single 120 mg dose. Absolute bioavailability of febuxostat in tablet form has not been studied.

No cumulation was observed in repeated oral administration of febuxostat in doses of 10 mg – 240 mg once daily.

Linearity/’non-linearity Pharmacokinetics

In healthy volunteers, Cmax and AUC increase linearly with increasing dose between 10 mg and 120 mg when administered once or repeatedly orally with febuxostat, and a greater than dose-proportional increase in AUC is noted in the dose range between 120 mg and 300 mg.

Distribution

The apparent volume of distribution at equilibrium ranges from 29 L to 75 L after oral administration of 10 to 300 mg of febuxostat. The degree of binding to plasma proteins (mainly to albumin) reaches 99.2%, and does not change when the dose is increased from 80 mg to 120 mg. For active metabolites the degree of binding to plasma proteins varies from 82% to 91%.

Metabolism

Febuxostat is metabolized by conjugation involving uridine diphosphate-glucuronyl transferase (UDFGT) and oxidation involving cytochrome P450 ( CYP ) enzymes. Four pharmacologically active hydroxyl metabolites have been isolated, of which three are found in human plasma. In in vitro studies on human liver microsomes showed that oxidized metabolites are formed predominantly under the influence of CYP 1 A 1, CYP 1 A 2, CYP 2 C 8 or CYP 2 C 9 isoenzymes, while febuxostat glucuronide is formed mainly under the influence of UGT 1A1, UGT 1A8 and UGT 1A9 isoenzymes.

Excretion

Febuxostat and its metabolites are excreted through the intestine and kidneys.

After oral administration of 14C radioisotope-labeled febuxostat at a dose of 80 mg, approximately 49% is excreted by the kidneys: unchanged – about 3%, as acyl glucuronide – 30%, as oxidized metabolites and their conjugates – 13%, as other metabolites – 3%.

About 45% of febuxostat is excreted through the intestine: as unchanged febuxostat – 12%, acylglucuronide – 1%, oxidized metabolites and their conjugates – 25%, other metabolites – 7%. Each half-life of febuxostat (T½) is 5-8 hours.

Farmacokinetics in special groups

Patients with renal impairment

Multiple oral doses of 80 mg febuxostat in patients with mild, moderate, or severe renal impairment did not change Cmax compared with healthy volunteers.

In patients with severe renal failure, the mean total AUC of febuxostat increased approximately 1.8-fold – (13.2 mcg/ml) compared to healthy volunteers (7.5 mcg h/ml); Cmax and AUC of pharmacologically active febuxostat metabolites increased 2 and 4-fold, respectively. Thus, in patients with renal insufficiency of mild or moderate severity no dose adjustment of the drug is required.

Patients with hepatic insufficiency

No significant changes in Cmax and AUC of febuxostat and its metabolites in patients with mild hepatic insufficiency (Child-Pugh class A: 5-6 points) and moderate (Child-Pugh class B: 7-9 points) severity compared to healthy volunteers. No studies of febuxostat pharmacokinetics have been conducted in patients with severe hepatic impairment (Child-Pugh grade C: 10-15 points).

Elderly age

No significant changes in the AUC of febuxostat and its metabolites were observed in elderly patients compared to young healthy volunteers during multiple oral administration of febuxostat.

Gender

In repeated oral administration of febuxostat, the Cmax and AUC of febuxostat were 24% and 12% higher in women than in men, respectively. However, the Cmax and AUC values adjusted for patient weight were similar for both groups. Thus, there is no need to adjust the dose of the drug depending on the gender of the patient.

Indications

Chronic hyperuricemia in conditions accompanied by deposition of urate crystals (in the presence of tophi and/or gouty arthritis, including a history).

The treatment and prevention of hyperuricaemia in adult patients undergoing cytostatic therapy for hemoblastosis with a moderate to high risk of tumor decay syndrome (120 mg dosage only).

Adenuric^® is indicated for use in adults.

Active ingredient

Febuxostat

Composition

Core:

Active ingredient:

febuxostat – 80.0 mg.

Auxiliary substances:

Lactose monohydrate – 76.50 mg,

Hyprolose – 12.00 mg, <

Microcrystalline cellulose (Avicel PH 101) – 129.00 mg,

Microcrystalline cellulose ( Avicel PH 102) – 172.50 mg,

croscarmellose sodium – 25.00 mg,

magnesium stearate – 2.50 mg,

colloidal silica aqueous – 2.50 mg.

Film Coating:

Opadray^®II Yellow 85 F 42129, consisting of: polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, iron oxide yellow dye (E 172) – 20.84 mg.

How to take, the dosage

Oral. Adenuric® is taken once a day, regardless of meals.

Phagra

The recommended starting dose is 80 mg of Febuxostat once a day.

After 2-4 weeks, it is recommended to monitor serum uric acid concentration; if the index exceeds 6 mg/dL (357 µmol/L), the drug dose may be increased to 120 mg once daily.

Decrease of uric acid concentration in serum against the background of Adenuric® use is quick enough, therefore uric acid concentration control may be performed after 2 weeks after the beginning of the drug administration. The goal of treatment is decrease and maintenance of uric acid concentration in serum less than 6 mg/dl (357 µmol/l).

Prevention of acute attacks of gout is recommended for at least 6 months.

Tumor Decay Syndrome

The recommended dose is 120 mg of febuxostat once daily regardless of meals. Adenuric® should be started two days before the start of cytostatic therapy. The duration of Adenuric® use should be at least 7 days. Depending on the duration of chemotherapy Adenuric® may be increased up to 9 days.

Elderly patients

No adjustment of the drug dose is required.

Patients with hepatic insufficiency

Phodagra.

In patients with mild hepatic impairment (Child-Pugh grade A: 5-6 points) the recommended dose of the drug is 80 mg once a day. Experience of using the drug in moderate hepatic insufficiency is limited.

Tumor decay syndrome

In the FLORENCE study no dose adjustment of febuxostat depending on liver function was required (patients with severe hepatic insufficiency were not included in the study).

Studies of efficacy and safety of febuxostat in patients with severe hepatic impairment (Child-Pugh grade C: 10-15 points) were not conducted.

Patients with renal insufficiency

In patients with mild to moderate renal insufficiency no dose adjustment is required.

In patients with renal insufficiency of severe severity (creatinine clearance < 30 ml/min) efficacy and safety of the drug have been insufficiently studied.

Interaction

Mercaptopurine/azathioprine

Simultaneous use with mercaptopurine, azathioprine is not recommended because inhibition of xanthine oxidase by febuxostat may lead to increased plasma concentration of mercaptopurine, azathioprine and increase their toxic effects. There have been no studies on the interaction of febuxostat and substances metabolized with xanthine oxidase.

Cytostatics

No studies have been conducted to study the drug interaction of febuxostat and cytostatic drugs. In the FLORENCE study, febuxostat at a dose of 120 mg was used for tumor decay syndrome in patients who had undergone cytostatic therapy of various types (including monoclonal antibody therapy). Nevertheless, since there have been no studies of drug interaction between febuxostat and cytotoxic drugs, potential interaction of febuxostat with simultaneously used cytotoxic chemopreparations cannot be excluded.

Rosiglitazone/substrates of CYP 2 C 8 isoenzyme

According to in vitro data febuxostat is a weak inhibitor of CYP 2 C 8 isoenzyme. No changes in pharmacokinetic parameters of rosiglitazone and its metabolite N-dysmethyl rosiglitazone were observed in healthy volunteers, which indicates that febuxostat has no inhibitory properties of CYP 2 C 8 isoenzyme in vivo when administered simultaneously with a single dose of 4 mg of rosiglitazone. When concomitant use of febuxostat and rosiglitazone (or other substrates of CYP 2 C 8 isoenzyme) no dose adjustment is required.

Theophylline

When using other xanthine oxidase inhibitors concomitantly with theophylline, an increase in plasma concentration of theophylline was noted. During concomitant use in healthy volunteers febuxostat in dose of 80 mg once per day and single dose of theophylline 400 mg no changes in pharmacokinetic parameters or tolerability of theophylline were observed, thus in concomitant use of febuxostat in dose of 80 mg and theophylline no special precautions are required. Studies of concomitant use of febuxostat at a dose of 120 mg and theophylline have not been conducted.

Naproxen and other glucuronidation inhibitors

The metabolism of febuxostat depends on the activity of the enzyme uridine diphosphate-glucuronyltransferase (UDFGT). Drugs that inhibit the glucuronidation process, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and probenicid, can theoretically affect the excretion of Febuxostat.

In healthy volunteers, concomitant use of febuxostat and naproxen at a dose of 250 mg twice daily resulted in a 28% increase in Cmax of febuxostat, a 41% increase in AUC and a 26% increase in T½.

In clinical trials concomitant use of febuxostat and naproxen or other NSAIDs/COG-2 inhibitors was not accompanied by clinically significant increase in the frequency of side effects. Dose adjustment in concomitant use of febuxostat and naproxen is not required.

Glucuronization inducers

Concomitant use of febuxostat with strong glucuronization inducers may increase its metabolism and decrease its effectiveness. With concomitant use it is necessary to monitor serum uric acid concentration 1-2 weeks after the start of therapy. If glucuronidation inducer is cancelled, Cmax increase of febuxostat is possible.

Colchicine/indomethacin/hydrochlorthiazide/warfarin

Febuxostat can be used simultaneously with colchicine or indomethacin without dose adjustment.

There is also no need for dose adjustment of febuxostat in concomitant use with hydrochlorthiazide.

Concomitant use of febuxostat (80 mg or 120 mg once daily) with warfarin has no effect on warfarin pharmacokinetics, INR (international normalized ratio) and Factor VII activity in healthy volunteers.

In concomitant use of febuxostat with warfarin no dose adjustment of warfarin is required.

Desipramine/substrates of CYP 2 D 6 isoenzyme

According to data obtained in vitro , febuxostat is a weak inhibitor of CYP 2 D 6 isoenzyme. In investigation in healthy volunteers during the use of febuxostat at the dose of 120 mg once a day there was increase of AUC of desipramine (CYP 2 D 6 isoenzyme substrate) on 22%, that proves a weak inhibitory effect of febuxostat on CYP 2 D 6 isoenzyme in vivo. Thus, no dose adjustment is required when concomitant use of febuxostat and CYP 2 D 6 isoenzyme substrates.

Antacids

When concomitant use with antacids containing magnesium hydroxide or aluminum hydroxide, there is decreased absorption of febuxostat (approximately by 1 hour) and decreased Cmax by 32%, but AUC of febuxostat was not significantly changed. Thus, febuxostat can be taken simultaneously with antacids.

Special Instructions

Acute gout attack

The use of the drug Adenuric® should be started only after the acute attack of gout has subsided. Beginning of Adenuric® medicine use can provoke the development of an acute attack of gout due to the release of urate from tissue depots and subsequent increase of uric acid concentration in blood serum.

For prevention of gout attacks in absence of contraindications it is recommended to use NSAIDs or colchicine concomitantly during at least 6 months.

In case of attack during the period of Adenuric® use the preparation should be continued and a corresponding treatment of an acute attack of gout should be carried out simultaneously.

During long-term use of Adenuric® the frequency and severity of gout attacks decrease.

Deposition of xanthines

In rare cases in patients with accelerated urate formation (e.g. against the background of malignant tumors or in Loesch-Nichan syndrome) a significant increase in the absolute concentration of xanthines in urine may occur, which may be accompanied by their deposition in the urinary tract.

This phenomenon was not observed in patients with tumor decay syndrome when Febuxostat was used in the FLORENCE study. Due to limited data, the use of Adenuric® in patients with Lesch-Nyhan syndrome is not recommended.

Mercaptopurine/azathioprine

Concurrent use with mercaptopurine, azathioprine is not recommended. If concomitant use is necessary, reduction of the dose of mercaptopurine/azathioprine and close medical monitoring is recommended to reduce the toxic effects on the hematopoietic system.

Theophylline

No changes in pharmacokinetic parameters were observed with concomitant use in healthy volunteers of febuxostat at a dose of 80 mg once daily and a single dose of theophylline 400 mg. Thus, concomitant use of febuxostat at a dose of 80 mg and theophylline carries no risk of increasing theophylline plasma concentrations. Studies of concomitant use of febuxostat in dose of 120 mg and theophylline were not conducted.

Patients who had organ transplantation

The use of Adenuric® preparation in patients who had organ transplantation is not recommended due to the lack of experience of use.

Allergic and hypersensitivity reactions

During post-marketing use, there have been rare reports of severe allergic reactions (hypersensitivity reactions), including Stevens-Johnson syndrome, toxicodermal necrolysis, anaphylactic reactions and shock.

In most cases these reactions developed during the first month of use of Adenuric®. Some patients had renal failure and/or hypersensitivity reactions against the background of allopurinol use.

In some cases severe hypersensitivity reactions, including drug reaction syndrome with eosinophilia and systemic symptoms (DRESS), were accompanied by fever, changes in blood parameters, liver or kidney function disorders.

Patients should be informed about possible signs and symptoms of allergic reactions (hypersensitivity reactions), and should be closely monitored for the development of symptoms of allergic reactions / hypersensitivity reactions.

In case of severe allergic/hypersensitivity reactions, including Stevens-Johnson syndrome, Adenuric® should be discontinued immediately (earlier withdrawal is associated with a better prognosis). Repeated use of the drug is not recommended.

Cardiovascular disease

The use of the drug Adenuric® is not recommended in patients with coronary heart disease or congestive heart failure.

In the APEX and FACT studies (as opposed to the CONFIRMS study ), the total febuxostat group compared to the allopurinol group showed an increase in cardiovascular abnormalities as defined by the developed by the Collaborative Analysis of Antiplatelet Therapy (CAAT) group and included cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) of 1.3 compared with 0.3 cases per 100 patient-years.

According to pooled data from phase III clinical trials (APEX , FACT and CONFIRMS studies ) the incidence of cardiovascular events was 0.7 compared with an incidence of 0.6 per 100 patient-years.

In long-term large-scale studies, the incidence of cardiovascular abnormalities on GCAAT was 1.2 and 0.6 cases per 100 patient-years for febuxostat and allopurinol, respectively. The differences were not statistically significant, and no causal relationship between these disorders and phebuxostat intake was established.

A history of the following conditions was established as risk factors for these events in patients: atherosclerosis and/or myocardial infarction, or congestive heart failure.

Prevention and treatment of hyperuricemia in patients at risk of tumor decay syndrome

In patients receiving cytostatic therapy of hematoblastosis with moderate to severe risk of tumor decay syndrome the use of Adenuric®, if indicated, should be monitored by a cardiologist.

Hepatic diseases

According to the pooled data of phase III clinical trials when using febuxostat 5% of patients had liver function abnormalities of mild severity.

It is recommended to assess the liver function before prescription of Adenuric® and if indicated – also during the use.

Thyroid disease

In extended long-term, open-label studies, long-term use of febuxostat in 5.5% of patients showed increased thyrotropic hormone concentrations (>5,5 µIU/ml), in connection with this fact patients with thyroid dysfunction should be administered Adenuric® with caution.

Adenuric® contains lactose; therefore it is contraindicated in patients with lactase deficiency, hereditary lactose intolerance, glucose-galactose malabsorption syndrome.

Influence on the ability to drive vehicles and operate machinery

. While taking Adenuric® medicine somnolence, dizziness, paresthesia and blurred vision may occur and, as a consequence, decrease of the reaction and ability to concentrate. That is why during the use of Adenuric® medicine one should be careful while driving vehicles and performing other potentially dangerous activities that require concentration and quick psychomotor reactions.

.

Contraindications

– Hypersensitivity to Febuxostat and/or any of the auxiliary substances;

– children under 18 years of age;

– pregnancy and lactation;

– hereditary galactose intolerance, lactase deficiency and malabsorption syndrome of glucose and galactose.

With caution:

– severe renal insufficiency (creatinine clearance < 30 ml/min) (efficacy and safety have not been studied sufficiently);

– Hepatic insufficiency;

– history of allergic reactions;

– coronary heart disease;

– congestive heart failure;

–

– concomitant use with mercaptopurine/azathioprine (the concentration of these substances in the blood plasma may increase and their toxicity);

– conditions after organ transplantation (experience of Febuxostat use is limited);

– Lech-Nichan syndrome (experience of Febuxostat use is limited).

Side effects

Taking into account the different nature of the course of gout and tumor decay syndrome, the side effects of febuxostat in these nosologies of action are presented separately.

Podagra

The most common side effects in patients with gout when using febuxostat based on clinical studies (4072 patients taking febuxostat in doses from 10 mg to 300 mg) and on post-marketing surveillance data were: gout attack, impaired liver function, diarrhea, headache, nausea, skin rash, and edema. In most cases, these phenomena were characterized by a mild to moderate degree of severity.

Rare cases of hypersensitivity reactions to febuxostat accompanied in some cases by systemic symptoms were registered during the post-marketing observation period.

Possible adverse effects are listed below according to the World Health Organization’s top-down frequency of occurrence: very frequently (≥1/10); frequently (≥1/100,< 1/10), infrequently (≥1/1000,< 1/100), rarely (≥1/10000,< 1/1000), very rarely (< 1/10000), including individual reports.

Frequency of adverse effects is based on data from clinical trials and post-marketing experience with febuxostat.

Blood and lymphatic system

Rarely: pancytopenia, thrombocytopenia.

An immune system

Rare: anaphylactic reactions*, hypersensitivity reactions*.

Nervous system disorders

Frequently: headache;

Infrequently: Dizziness, paresthesia, hemiparesis, somnolence, change in taste perception, hyposthesia, hyposmia (impaired sense of smell).

Endocrine system

Infrequent: increase in plasma thyrotropic hormone (TSH) concentration.

Metabolism and nutrition

Often: gout attacks***;

Infrequently: Diabetes mellitus, hyperlipidemia, decreased appetite, increased body weight;

Rarely: decreased body weight, increased appetite, anorexia.

Mental side

Infrequent: decreased libido, insomnia;

Rare : nervousness.

Sight

Rarely : blurred vision.

Hearing and labyrinth disorders

Rarely : tinnitus.

Cardiac side

Infrequent: atrial fibrillation, palpitations, ECG changes, left bundle Gis block (see section “Tumor decay syndrome”), sinus tachycardia (see section “Tumor decay syndrome”).

vascular disorders

Infrequent: increase in blood pressure, blood rushes to the face, fever, hemorrhages (see section “Tumor decay syndrome”).

Respiratory system, chest and mediastinal organs

Infrequent: dyspnea, bronchitis, upper respiratory tract infections, cough, chest pain, discomfort in the chest.

Gastrointestinal tract

Frequently: diarrhea**, nausea;

Infrequently: Abdominal pain, bloating, gastroesophageal reflux disease, vomiting, dry oral mucosa, dyspeptic phenomena, constipation, frequent stools, flatulence, abdominal discomfort;

Rarely: pancreatitis, ulcerative stomatitis.

Liver and biliary tract side

Frequently: Impaired liver function**;

Infrequent : cholelithiasis;

Rarely: hepatitis, jaundice*, liver damage*.

Sides of the skin and subcutaneous tissues

Frequently: skin rash (including various types of rash mentioned below with lower frequency);

Infrequently: Dermatitis, urticaria, pruritus, skin discoloration, skin lesions, petechiae, macular rash, maculopapular rash, papular rash;

Rarely: toxic dermal necrolysis*, Stevens-Johnson syndrome*, angioedema*, drug reaction with eosinophilia and systemic symptoms* (see (see section “Cautions”), severe forms of generalized rash*, erythema, exfoliative rash, follicular rash, vesicular rash, pustular rash, pruritic rash*, erythematous rash, crust-like rash, alopecia, hyperhidrosis.

Musculoskeletal system

Infrequent: Arthralgia, arthritis, myalgia, musculoskeletal pain, muscle weakness, muscle spasm, muscle tension, bursitis;

Rarely: rhabdomyolysis*, joint stiffness, muscle stiffness.

Renal and urinary tract disorders

Infrequent: Renal failure, nephrolithiasis, hematuria, pollakiuria, proteinuria;

Rarely: tubulointerstitial nephritis*, imperative urge to urinate.

Reproductive system disorders

Infrequent: erectile dysfunction.

General disorders:

Frequently: edema;

Infrequently: increased fatigue;

Rarely: thirst.

Influence on the results of laboratory and instrumental studies

Infrequent: increased plasma amylase activity, decreased platelet count, decreased leukocyte count, decreased lymphocyte count, increased plasma creatine and creatinine, decreased hemoglobin, increased plasma urea concentration, increased plasma triglyceride concentration, increased plasma cholesterol concentration, decreased hematocrit, increased plasma lactate dehydrogenase activity, increased plasma potassium concentration.

Rarely: increase in plasma glucose concentration, prolongation of activated partial thromboplastin time, decreased number of red blood cells, increased plasma alkaline phosphatase activity.

* Side effects observed during post-marketing surveillance.

** Non-infectious diarrhea and liver disorders observed in phase III studies were more common with concomitant use of colchicine.

*** Additional information regarding the development of acute gout attacks in “Special Indications”.

Description of Individual Adverse Effects

During post-marketing use, there have been rare reports of severe allergic reactions (hypersensitivity reactions), including Stevens-Johnson syndrome, toxicodermal necrolysis, anaphylactic reactions and shock.

Stevens-Johnson syndrome and toxicodermal necrolysis are characterized by the occurrence of a progressive skin rash combined with bullous lesions of the skin or mucosa, as well as eye irritation. Hypersensitivity reactions to febuxostat may also manifest as the following symptoms: skin reactions characterized by infiltrative maculopapular rashes; generalized or exfoliative rash, as well as skin lesions, facial edema, fever, disorders of the blood forming organs, such as thrombocytopenia and eosinophilia, as well as involvement of one or more organs (liver and kidney, including tubulointerstitial nephritis).

Gout attacks are usually observed soon after initiation of Adenuric® and during the first months of therapy. Later the frequency of attacks decreases. Prevention of the development of acute gout attacks is recommended.

Tumor Decay Syndrome

In the FLORENCE study, side effects were noted in 22 patients (6.4%). In both groups (febuxostat group and allopurinol group), the incidence of adverse events was similar (11 patients each, 6.4%). In most cases, the adverse events were characterized by mild to moderate severity. In general, with the exception of the three side effects listed below from the FLORENCE study, no features of the safety profile of febuxostat in addition to that of gout were noted.

Cardiac side

Infrequent: Left bundle branch block, sinus tachycardia.

vascular disorders

Infrequent: hemorrhages (see section “Tumor decay syndrome”).

Overdose

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

Similarities

Azurix, Febuxostat NW