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

Composition

Core:

Active ingredient:

febuxostat – 80.0 mg.

Auxiliary substances:

Lactose monohydrate – 76.50 mg,

Hyprolose – 12.00 mg,

How to take, the dosage

Interaction

Special Instructions

Contraindications

With caution:

Side effects

Overdose

Similarities