Dear buyers! Unfortunately, we are currently unable to accept the application to Canada and are revoking the license. Keep an eye on the site to see if there are any updates from Canada.
Main physicochemical properties: capsule-shaped tablets, film-coated, pale yellow to yellow in color, embossed with "80" or "120" on one side and plain on the other.
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 febuxostat has been demonstrated in three pivotal phase 3 studies (two pivotal studies, APEX and FACT, and an additional study, CONFIRMS), which included patients with hyperuricemia and gout. In each of these pivotal studies, febuxostat demonstrated superior ability to lower and maintain serum uric acid levels compared to allopurinol.
APEX study: Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX) 28-week study.
The APEX study showed a statistically significant advantage in both the febuxostat 80 mg once daily and febuxostat 120 mg once daily treatment groups compared to the treatment group receiving allopurinol at the usual dose of 300 mg/100 mg in reducing serum uric acid concentrations below 6 mg/dL (357 μmol/L).
FACT study: a 52-week study of the efficacy of febuxostat with allopurinol control (Febuxostat Allopurinol Controlled Trial, FACT).
The FACT study showed a statistically significant advantage in both the febuxostat 80 mg once daily and febuxostat 120 mg once daily treatment groups compared to the treatment group receiving allopurinol at the usual dose of 300 mg in reducing and maintaining serum uric acid concentrations below 6 mg/dL (357 μmol/L).
CONFIRMS study: The CONFIRMS study was a 26-week study conducted to evaluate the safety and efficacy of febuxostat at doses of 40 mg and 80 mg compared with allopurinol at doses of 300 mg and 200 mg in patients with gout and hyperuricemia.
A prospectively planned analysis of data from patients with gout and renal impairment in the CONFIRMS study showed that febuxostat was statistically significantly more effective in 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 patients studied).
Post-registration long-term studies
The CARES study 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.
The incidence of cardiovascular deaths was higher in the febuxostat group than in the allopurinol group.
The incidence of all-cause mortality was also higher in the febuxostat group than in the allopurinol group, 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.
In healthy volunteers, the maximum plasma concentration (Cmax) and the area under the plasma uric acid concentration-time curve (AUC) increased in a dose-proportional manner after single and multiple doses of febuxostat in the range of 10 mg to 120 mg. The increase in AUC was more than dose-proportional when febuxostat was administered in the range of 120 mg to 300 mg. No accumulation of febuxostat was observed when doses of 10 mg to 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 in patients with hyperuricemia and gout who used febuxostat at doses of 40-240 mg 1 time per day. In general, the obtained values of the pharmacokinetic parameters of febuxostat are consistent with those in healthy subjects, indicating that healthy subjects are representative for the assessment of 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 febuxostat at 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.
With repeated oral administration of 80 mg once daily or with 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 levels (with repeated administration of 80 mg). Thus, febuxostat can be used regardless of food intake.
Distribution
The estimated steady-state volume of distribution (Vss/F) for febuxostat ranges from 29 L to 75 L after oral administration of 10–300 mg. The extent of plasma protein binding of febuxostat (primarily albumin) is 99.2% and is stable over the concentration range achieved with doses of 80 mg or 120 mg. For the active metabolites of febuxostat, the extent of plasma protein binding ranges from 82% to 91%.
Metabolism
Febuxostat is extensively metabolized by conjugation via the uridine diphosphate glucuronyltransferase (UDP-glucuronyltransferase) enzyme system and oxidation via the cytochrome P450 (CYP) system. A total of 4 pharmacologically active hydroxyl metabolites of febuxostat have been identified, 3 of which 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-glucuronyltransferases 1A1, 1A8 and 1A9.
Breeding
Febuxostat is eliminated from the body via the liver and kidneys. After oral administration of 14C-febuxostat at a dose of 80 mg, approximately 49% was excreted in the urine as unchanged febuxostat (3%), acylglucuronide of the active substance (30%), its known oxidized metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to urinary excretion, approximately 45% of the dose was excreted in the feces as unchanged febuxostat (12%), acylglucuronide of the active substance (1%), its known oxidized metabolites and their conjugates (25%), and other unknown metabolites (7%).
Kidney failure
With multiple doses of febuxostat at a dose of 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 × h/mL in patients with normal renal function to 13.2 μg × h/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
Multiple dosing of febuxostat at a dose of 80 mg did not show significant changes in Cmax and AUC of febuxostat and its metabolites in patients with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment compared to subjects with normal hepatic function. The drug has not been studied in patients with severe (Child-Pugh Class C) hepatic impairment.
Age
After multiple oral doses of febuxostat, no significant changes in AUC of febuxostat and its metabolites were observed in elderly patients compared to healthy younger volunteers.
Sex
After multiple oral doses of febuxostat, 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. No dose adjustment is necessary based on gender.
Indication
Gout 80 mg and 120 mg:
Gout is indicated for the treatment of chronic hyperuricemia in diseases accompanied by the deposition of urate crystals (including the presence of tophi and/or gouty arthritis at present or in history).
Gout is indicated for the prevention and treatment of hyperuricemia in adult patients receiving chemotherapy for hematological malignancies at moderate or high risk of tumor lysis syndrome (TLS).
The medicine 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 its concomitant use with these drugs is not recommended. Inhibition of xanthine oxidase by febuxostat may lead to increased plasma concentrations of both drugs, which may cause myelotoxicity.
When co-administered with 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 data in rats, 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 mg or 120 mg).
There are no data on the safety of febuxostat during cytotoxic chemotherapy.
Interaction studies of febuxostat with other cytotoxic chemotherapy agents have not been conducted.
In a pivotal study, patients with SLE who had received multiple chemotherapy regimens, including monoclonal antibodies, were given febuxostat at a dose of 120 mg daily. However, drug-drug and drug-disease interactions were not investigated in this study. Therefore, the possibility of interactions with any concomitantly administered cytotoxic drugs cannot be excluded.
Rosiglitazone/CYP2C8 substrates
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 is not an inhibitor of the CYP2C8 enzyme in vivo. Therefore, co-administration of febuxostat and rosiglitazone or other CYP2C8 substrates does not require any dose adjustment for these medicinal products.
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, similar to that 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 once daily was co-administered with a single dose of theophylline 400 mg. Therefore, febuxostat 80 mg can be co-administered with theophylline without any special precautions. There are no data available for febuxostat 120 mg.
Naproxen and other glucuronidation inhibitors
Febuxostat metabolism is dependent on the activity of enzymes of the UDP-glucuronyltransferase family. 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 or other NSAIDs/cyclooxygenase-2 (COX-2) inhibitors was not associated with any clinically significant increase in adverse reactions.
Febuxostat can be used concomitantly with naproxen without dose adjustment.
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 1–2 weeks after starting treatment. Conversely, when the glucuronidation inducer is discontinued, febuxostat plasma levels may increase.
Febuxostat can be used concomitantly with colchicine or indomethacin without dose adjustment of febuxostat or the concomitantly administered active substance.
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 the latter. The use of febuxostat (80 mg or 120 mg once daily) with warfarin in healthy volunteers did not affect the pharmacokinetics of the latter. Concomitant use with febuxostat also did not affect the international normalized ratio (INR) and factor VII activity.
In vitro data indicate that febuxostat is a weak inhibitor of CYP2D6. In a study in healthy volunteers receiving 120 mg of febuxostat once daily, an average increase of 22% in the AUC of desipramine (a CYP2D6 substrate) was observed, indicating that febuxostat has a weak inhibitory effect on the CYP2D6 enzyme in vivo. Therefore, concomitant use of febuxostat with other CYP2D6 substrates does not require any dose adjustment for these medicinal products.
Antacids
When administered orally with antacids containing magnesium hydroxide and aluminum hydroxide, a delay in the absorption of febuxostat (approximately 1 hour) and a 32% decrease in Cmax were observed, but no significant change in AUC was observed. Therefore, febuxostat can be used with antacids.
Application features
Cardiovascular diseases
In patients with serious cardiovascular disease (e.g., myocardial infarction, stroke, or unstable angina), a higher number of life-threatening cardiovascular events were observed with febuxostat compared to allopurinol during drug development and in one post-marketing study (CARES).
However, a subsequent post-marketing study (FAST) showed that febuxostat was non-inferior to allopurinol in terms of the incidence of life-threatening and non-life-threatening cardiovascular events.
Treatment of this group of patients should be carried out with caution and their condition should be monitored regularly.
In the APEX and FACT studies, there was a quantitative increase in the number of cardiovascular events (Anti-Platelet Trialists' Collaboration (APTC)) (endpoints defined in the antiplatelet therapy (APTC) group, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) in the overall febuxostat group compared to the allopurinol group (1.3 versus 0.3 events per 100 patient-years), in contrast to the CONFIRMS study (see section "Pharmacodynamics"). The incidence of cardiovascular events (APTC) in the pooled phase 3 studies (APEX, FACT and CONFIRMS studies) was 0.7 versus 0.6 events per 100 patient-years. In long-term extension studies, the incidence of investigator-reported cardiovascular events according to APTC criteria was 1.2 and 0.6 per 100 patient-years for febuxostat and allopurinol, respectively. The differences were not statistically significant and a causal relationship between these events and febuxostat was not established. Risk factors identified in these patients included a history of atherosclerosis and/or myocardial infarction, or congestive heart failure.
In the post-marketing CARES study, the incidence of MACE (major adverse cardiovascular events) 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 receiving chemotherapy for hematological malignancies with moderate or high risk of SLE and using the drug Podagrat should be under the supervision of a cardiologist if clinically indicated.
Drug allergy/hypersensitivity
During post-marketing surveillance, there have been rare reports of serious allergic/hypersensitivity reactions, including life-threatening Stevens-Johnson syndrome, toxic epidermal necrolysis and acute anaphylactic reactions/shock. In most cases, these reactions occurred within the first month of febuxostat use. Several patients had a history of renal impairment and/or hypersensitivity to allopurinol. Severe hypersensitivity reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), were in some cases accompanied by fever, blood, renal or hepatic changes.
Patients should be informed of the signs and symptoms of hypersensitivity/allergic reactions and should be closely monitored for the development of symptoms of such reactions (see section 4.8). If serious allergic/hypersensitivity reactions, including Stevens-Johnson syndrome, occur, febuxostat should be discontinued immediately, as early discontinuation improves the prognosis. If a patient develops allergic/hypersensitivity reactions, including Stevens-Johnson syndrome, and acute anaphylactic reaction/shock, then re-administration of febuxostat is contraindicated in such patients.
Episodes of exacerbation (attack) of gout
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 a significant increase in urate formation (for example, against the background of malignant diseases 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. Due to the lack of experience with febuxostat, its use is not recommended for these categories of patients. This was not observed in the pivotal clinical study of the use of febuxostat in SLP. Due to limited experience, febuxostat is not recommended for 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 toxic reactions. 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, when febuxostat is co-administered, the dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose 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
Since there is no experience with the use of febuxostat in patients who have undergone organ transplantation, the drug is not indicated for use in this category of patients.
Theophylline
Concomitant administration of febuxostat 80 mg and theophylline 400 mg as a single dose did not show any pharmacokinetic interactions (see section 4.5). Febuxostat 80 mg can be administered to patients concomitantly with theophylline without the risk of increased theophylline plasma concentrations. There are no data available for febuxostat 120 mg.
Liver disorders
In pooled phase 3 clinical trials, mild abnormalities in liver function tests (5.0%) were observed in patients treated with febuxostat. Therefore, it is recommended that liver function tests be monitored prior to initiation of febuxostat therapy and periodically during treatment as clinically indicated.
Thyroid disorders
In long-term open-label extension studies, 5.5% of patients treated with febuxostat for long-term treatment experienced elevations in TSH (> 5.5 μIU/mL). Therefore, febuxostat should be used with caution in patients with thyroid dysfunction.
Lactose
The medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding
Pregnancy
Very limited experience with the use of febuxostat during pregnancy indicates the absence of any undesirable effects on the course of pregnancy and the health of the fetus/newborn child. Animal studies do not indicate any direct or indirect harmful effects of the drug on the course of pregnancy, embryonal/fetal development or the course of labor. The potential risk for humans is unknown. Febuxostat should not be used during pregnancy.
Breastfeeding period
It is not known whether febuxostat is excreted in human milk. Animal studies have shown that the active substance is excreted in breast milk and has adverse effects on the development of suckling infants. A risk to the breastfed infant cannot be excluded. Febuxostat should not be used during breast-feeding.
Fertility
Animal fertility studies at doses up to 48 mg/kg/day did not reveal any dose-related adverse effects on fertility. The effects of febuxostat on human reproductive function are unknown.
Ability to influence reaction speed when driving vehicles or other mechanisms
There have been reports of drowsiness, dizziness, paresthesia, and blurred vision with febuxostat. Therefore, patients taking Gout are advised to exercise caution when driving or operating machinery until they are certain that the drug does not cause the above-mentioned adverse reactions.
Method of administration and doses
Gout: The recommended dose of febuxostat is 80 mg once daily, administered orally, without regard to food intake. If serum uric acid concentration exceeds 6 mg/dL (357 μmol/L) after 2 to 4 weeks of treatment, an increase in dosage to 120 mg once daily should be considered.
Febuxostat has a rapid onset of action, allowing serum uric acid levels to be re-measured after 2 weeks. The goal of treatment is to reduce serum uric acid levels and maintain them below 6 mg/dL (357 μmol/L).
The recommended duration of gout attack prevention is at least 6 months.
Tumor lysis syndrome: The recommended dose of febuxostat is 120 mg once daily, administered orally, without regard to food intake.
The use of the drug Podagrate should be started two days before the start of cytotoxic therapy and continued for at least 7 days, however, the duration of therapy may be extended to 9 days according to the duration of chemotherapy and clinical assessment.
Elderly patients
Dose adjustment is not required for elderly patients.
Kidney failure
The efficacy and safety of the drug have not been sufficiently studied in patients with severe renal impairment (creatinine clearance < 30 ml/min). No dose adjustment is required for patients with mild or moderate renal impairment.
Liver failure
The efficacy and safety of febuxostat in patients with severe hepatic impairment (Child-Pugh Class C) have not been studied.
Gout: The recommended dose for patients with mild hepatic impairment is 80 mg. Experience in patients with moderate hepatic impairment is limited.
Tumor lysis syndrome. Only patients with severe hepatic impairment were excluded from clinical trials (phase III). No dose adjustment was required for patients included in the study based on liver function.
Method of application
For oral use.
The drug Pudagrat is taken orally, regardless of food intake.
Children.
The safety and efficacy of febuxostat in children under the age of 18 have not been established. There are no data on its use.
Overdose
In case of overdose, symptomatic and supportive therapy is indicated.
Side effects
Summary of safety profile
The most common adverse reactions in clinical trials (4072 subjects who received at least one dose of 10 mg to 300 mg) and post-marketing safety studies (FAST study: 3001 subjects who received at least one dose of 80 mg to 120 mg) and post-marketing experience are gout attacks, liver function tests abnormal, diarrhea, nausea, headache, dizziness, dyspnea, rash, pruritus, arthralgia, myalgia, pain in extremity, edema, and fatigue. These adverse reactions were mostly mild to moderate in severity. In post-marketing experience, rare cases of serious hypersensitivity reactions to febuxostat (some with systemic reactions) and rare cases of sudden cardiac death have been reported.
The table below lists the adverse reactions that occur in patients receiving febuxostat, classified as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000).
The frequency of development is based on research data and post-marketing experience in patients with gout.
Within each grouping, adverse reactions are presented in order of decreasing severity by frequency of occurrence.
Adverse reactions observed in pooled data from long-term phase 3 extension studies, post-marketing safety studies, and post-marketing experience
