Podagrel (Capsules) Instructions for Use

Marketing Authorization Holder

Akrikhin Chemical and Pharmaceutical Plant, JSC (Russia)

Contact Information

AKRIKHIN JSC (Russia)

ATC Code

M04AA03 (Febuxostat)

Active Substance

Febuxostat (Rec.INN registered by WHO)

Dosage Forms

	Podagrel	Capsules 80 mg: 30, 32, 60, or 90 pcs.
		Capsules 120 mg: 30, 32, 60, or 90 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 1, dark brown in color; capsule contents – powder from white to white with a grayish or yellowish tint.

Excipients: lactose monohydrate, microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate; hard gelatin capsule [body: titanium dioxide, iron oxide red, iron oxide yellow, iron oxide black, gelatin; cap: titanium dioxide, iron oxide red, iron oxide yellow, iron oxide black, gelatin].

8 pcs. – blister packs (4) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.

Capsules hard gelatin, two-tone, size No. 0: light brown body with a dark brown cap; capsule contents – powder from white to white with a grayish or yellowish tint.

Excipients: lactose monohydrate, microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate; hard gelatin capsule [body: titanium dioxide, iron oxide red, iron oxide yellow, iron oxide black, gelatin; cap: titanium dioxide, iron oxide red, iron oxide yellow, iron oxide black, gelatin].

8 pcs. – blister packs (4) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.

Clinical-Pharmacological Group

Antigout drug that reduces the concentration of uric acid in the blood serum

Pharmacotherapeutic Group

Antigout agent – xanthine oxidase inhibitor

Pharmacological Action

Mechanism of action

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 derivative of 2-arylthiazole and is a potent selective non-purine inhibitor of xanthine oxidase (in vitro inhibition constant is less than 1 nM). The enzyme xanthine oxidase catalyzes two stages of purine metabolism: the oxidation of hypoxanthine to xanthine, and then the oxidation of xanthine to uric acid.

As a result of selective inhibition of xanthine oxidase (oxidized and reduced forms) by febuxostat, the concentration of uric acid in the blood serum decreases.

At therapeutic concentrations, Febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism, such as guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase, or purine nucleoside phosphorylase.

Clinical efficacy and safety

The efficacy of febuxostat was confirmed in 3 pivotal phase III clinical studies involving 4101 patients with hyperuricemia and gout (APEX, FACT, and CONFIRMS).

In each of these phase III studies, the use of febuxostat led to a more effective reduction in uric acid concentration and maintenance of its level in the blood serum compared to 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) over the last 3 months. In the 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 final visit. The APEX study (a study of the efficacy of febuxostat compared to placebo and allopurinol) included 1072 patients. Febuxostat was used in doses of 80 mg, 120 mg, or 240 mg once daily; allopurinol – in doses of 100 mg or 300 mg once daily. The use of febuxostat at a dose of 240 mg (twice the recommended maximum) was studied to assess the safety profile of febuxostat. When using febuxostat at doses of 80 mg and 120 mg, the proportion of patients whose serum uric acid concentration did not exceed 6.0 mg/dL (357 µmol/L) over the last 3 months was 48% and 65%, respectively; when using allopurinol – 22%.

The FACT study (a study of febuxostat compared to allopurinol) included 760 patients. When using febuxostat at doses of 80 mg and 120 mg once daily, or allopurinol at 300 mg/day, the proportion of patients whose serum uric acid concentration did not exceed 6.0 mg/dL (357 µmol/L) over the last 3 months was 53%, 62%, and 21%, respectively. The use of febuxostat led to a rapid decrease in uric acid concentration in the blood plasma; this effect persisted for a long time. A decrease in serum uric acid concentration to less than 6.0 mg/dL (357 µmol/L) was noted as early as the 2nd week of use.

The CONFIRMS study (a study of the safety and efficacy of febuxostat at doses of 40 mg or 80 mg once daily compared to allopurinol at doses of 300 mg or 200 mg once daily in patients with gout and hyperuricemia) included 2269 patients. At least 65% of patients in this study had mild to moderate renal impairment (creatinine clearance 30-89 ml/min). When using febuxostat at a dose of 40 mg or 80 mg, the proportion of patients whose plasma uric acid concentration was less than 6.0 mg/dL at the final visit was 45% and 67%, respectively; when using allopurinol at doses of 300 mg or 200 mg once daily – 42%.

Extended long-term open-label studies

The three-year EXCEL study included 1086 patients who completed the APEX or FACT studies and who took Febuxostat at a dose of 80 mg or 120 mg once daily, or allopurinol 100 mg or 300 mg once daily. The target serum uric acid level achieved with prior febuxostat use was maintained without change throughout the study and did not change over time (in 91% and 93% of patients initially taking Febuxostat at doses of 80 mg and 120 mg, respectively). Less than 4% of patients required treatment for an acute gout attack (i.e., more than 96% of patients did not require treatment for gout attacks) at 16-24 months and 30-36 months. In 46% and 38% of patients continuously taking Febuxostat at doses of 80 mg or 120 mg once daily, respectively, complete resolution of tophi was noted by the final visit.

The five-year FOCUS study 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 the target serum uric acid level of less than 6.0 mg/dL, and 38% of patients required dose adjustment to achieve the target level. The proportion of patients with a serum uric acid concentration of less than 6.0 mg/dL (357 µmol/L) was more than 80%.

Patients with impaired renal function

In the APEX study, Febuxostat was used in 40 patients with impaired renal function (with creatinine >1.5 mg/dL and ≤2.0 mg/dL). In the febuxostat group, the target level was achieved in 44% of patients receiving Febuxostat 80 mg once daily, 45% receiving 120 mg once daily, and 60% receiving 240 mg once daily, compared with 0% in the allopurinol group (100 mg once daily) and the placebo group. No clinically significant differences in the degree of reduction in serum uric acid concentration compared to healthy volunteers were noted (the reduction in uric acid concentration in the group of patients with normal renal function was 58%, in the group with severe renal failure – 55%).

Patients with serum uric acid concentration greater than 10 mg/dL

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

According to the CONFIRMS study, the proportion of patients with a baseline uric acid concentration greater than 10 mg/dL who achieved the primary efficacy endpoint (uric acid concentration less than 6.0 mg/dL at the final visit) was 27% for patients receiving Febuxostat 40 mg once daily; 49% for patients receiving Febuxostat 80 mg once daily; and 31% of patients receiving 300 mg or 200 mg allopurinol once daily.

Patients requiring treatment for an acute gout attack

APEX study: During the 8-week prophylactic period, a larger proportion of patients in the group taking Febuxostat 120 mg/day required treatment for an acute gout attack (36%) than in the groups taking Febuxostat 80 mg (28%), allopurinol 300 mg (23%), and the placebo group (20%). During the prophylactic period, the incidence of acute gout attacks increased, subsequently decreasing over time. From 46% to 55% of patients received treatment for an acute gout attack from week 8 to week 28. Acute gout attacks during the last 4 weeks of the study (weeks 24-28) were observed 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.

FACT study: During the 8-week prophylactic period, a larger proportion of patients in the group taking Febuxostat 120 mg/day required treatment for an acute gout attack (36%) than in the groups taking Febuxostat 80 mg/day (22%), allopurinol 300 mg/day (21%). After the 8-week prophylactic period, the incidence of acute gout attacks increased and then gradually decreased over time (64% and 70% of patients received treatment for a gout flare from week 8 to week 52). Acute gout attacks during the last 4 weeks of the study (weeks 49-52) were observed in 6-8% of patients in the febuxostat group (80 mg, 120 mg), and 11% of patients in the allopurinol group (300 mg).

The proportion of patients requiring treatment for an acute gout attack (APEX and FACT studies) was numerically lower in the groups where the mean serum uric acid concentration was less than 6.0 mg/dL, less than 5.0 mg/dL, or less than 4.0 mg/dL during the last 32 weeks (periods from week 20-24 and from week 49-52), compared to the group where the mean serum uric acid concentration was greater than 6.0 mg/dL.

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

Tumor Lysis Syndrome

The efficacy and safety of febuxostat at a dose of 120 mg for the prevention and treatment of tumor lysis syndrome were studied in the FLORENCE study. Febuxostat demonstrated a more potent and rapid reduction in serum uric acid concentration compared to allopurinol.

The study included 346 patients with hematological malignancies who were undergoing cytostatic therapy and who had a moderate to high risk of developing tumor lysis syndrome. Patients took Febuxostat at a dose of 120 mg once daily or allopurinol 200-600 mg/day. The primary endpoints were: AUC of serum uric acid and change in serum creatinine content over 8 days. The mean AUC of uric acid was statistically significantly smaller in the febuxostat group. The mean serum uric acid concentration 24 hours after the start of febuxostat use and at all subsequent measurements was significantly lower than in the allopurinol group. No statistically significant differences in the effect of Febuxostat and allopurinol on plasma creatinine content were noted.

When assessing secondary endpoints, the incidence of tumor lysis syndrome with febuxostat and allopurinol use did not differ statistically, either by laboratory diagnostic criteria or by clinical criteria.

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

In the FLORENCE study, in patients for whom allopurinol use was planned, Febuxostat demonstrated more pronounced control over serum uric acid concentration compared to allopurinol.

There are currently no data to compare Febuxostat with rasburicase.

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

Preclinical safety data

In preclinical data obtained from standard studies of pharmacological safety, toxicity upon repeated administration, genotoxicity, carcinogenic potential, and reproductive and ontogenetic toxicity, no particular harm to humans was identified.

Pharmacokinetics

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

Absorption

After oral administration, Febuxostat is rapidly and almost completely (at least 84% of the administered dose) absorbed from the gastrointestinal tract. When febuxostat was taken multiple times at a dose of 80 mg or a single dose of 120 mg simultaneously with a fatty meal, the C_max of febuxostat in plasma decreased by 49% and 38%, respectively, and AUC by 18% and 16%. However, this did not affect the clinical efficacy of reducing serum uric acid concentration (with multiple doses of febuxostat 80 mg), therefore Febuxostat can be taken regardless of food intake.

C_max is reached 1.0-1.5 hours after a single or multiple oral administration and is 2.8-3.2 µg/ml when taking a dose of 80 mg and 5.0-5.3 µg/ml when taking a dose of 120 mg. The absolute bioavailability of febuxostat in tablet form has not been studied.

No accumulation was observed with multiple oral administration of febuxostat at doses of 10-240 mg once daily.

Distribution

The apparent V_d at steady state varies from 29 L to 75 L after oral administration of 10-300 mg of febuxostat. The degree of binding to plasma proteins (mainly 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 glucuronosyltransferase (UDP-GT) and oxidation involving cytochrome P450 (CYP) enzymes. Four pharmacologically active hydroxyl metabolites were isolated, three of which are found in human plasma. In vitro studies on human liver microsomes have shown that oxidized metabolites are formed primarily under the influence of CYP1A1, CYP1A2, CYP2C8, or CYP2C9 isoenzymes, while febuxostat glucuronide is formed mainly under the influence of UGT1A1, UGT1A8, and UGT1A9 isoenzymes.

Elimination

Febuxostat and its metabolites are eliminated from the body through the intestines and kidneys. After oral administration of ¹⁴C-radiolabeled 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%.

Approximately 45% of febuxostat is excreted through the intestines: as unchanged febuxostat – 12%, acyl glucuronide – 1%, oxidized metabolites and their conjugates – 25%, other metabolites – 7%. The apparent T_1/2 of febuxostat is 5-8 hours.

Linearity (non-linearity)

In healthy volunteers, with single or multiple oral administration of febuxostat, C_max and AUC increase linearly with increasing dose in the range from 10 mg to 120 mg, and in the dose range from 120 mg to 300 mg, an increase in AUC greater than proportional to the dose is noted.

Special patient groups

Patients with impaired renal function. With multiple oral administration of febuxostat at a dose of 80 mg in patients with mild, moderate, or severe renal failure, C_max did not change compared to healthy volunteers. In patients with severe renal failure, the mean total AUC of febuxostat increased approximately 1.8-fold (13.2 µg×h/ml) compared to healthy volunteers (7.5 µg×h/ml); C_max and AUC of pharmacologically active metabolites of febuxostat increased 2 and 4 times, respectively. Thus, in patients with mild or moderate renal failure, no dose adjustment of the drug is required.

Patients with impaired liver function. With multiple oral administration of febuxostat at a dose of 80 mg, no significant changes in the C_max and AUC parameters of febuxostat and its metabolites were noted in patients with mild (Child-Pugh class A (5-6 points)) and moderate (Child-Pugh class B (7-9 points)) hepatic impairment compared to healthy volunteers. Pharmacokinetic studies of febuxostat have not been conducted in patients with severe hepatic impairment (Child-Pugh class C (10-15 points)).

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

Gender. With repeated oral administration of febuxostat, the C_max and AUC of febuxostat in women were 24% and 12% higher, respectively, than in men. However, the C_max and AUC values adjusted for patient body weight were similar for both groups. Therefore, no dose adjustment of the drug based on patient gender is required.

Preclinical safety data

In preclinical data obtained from standard studies of pharmacological safety, toxicity with repeated administration, genotoxicity, carcinogenic potential, reproductive and ontogenetic toxicity, no particular risk to humans was identified.

Indications

Podagrel is indicated for use in adults for

• Treatment of chronic hyperuricemia in conditions accompanied by deposition of urate crystals (in the presence of tophi and/or gouty arthritis, including in the medical history);
• Prevention and treatment of chronic hyperuricemia in adult patients undergoing cytostatic therapy for hemoblastoses with a moderate to high risk of tumor lysis syndrome (only for the 120 mg dosage).

ICD codes

Dosage Regimen

The recommended starting dose is 80 mg of febuxostat once daily. If the serum uric acid concentration exceeds 6 mg/dL (357 µmol/L) after 2-4 weeks, the drug dose can be increased to 120 mg once daily. The reduction in serum uric acid concentration during the use of Podagrel occurs quite rapidly, therefore, monitoring of uric acid concentration can be performed 2 weeks after starting the drug. The goal of treatment is to reduce and maintain the serum uric acid concentration below 6 mg/dL (357 µmol/L).

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

In elderly patients, no dose adjustment of the drug is required.

In patients with mild to moderate renal impairment, no dose adjustment is required. In patients with severe renal impairment (CrCl <30 mL/min), the efficacy and safety of the drug have not been sufficiently studied.

In patients with mild hepatic impairment (Child-Pugh class A (5-6 points)), the recommended dose of the drug is 80 mg once daily. Experience with the drug in moderate hepatic impairment is limited. Studies of the efficacy and safety of febuxostat in patients with severe hepatic impairment (Child-Pugh class C (10-15 points)) have not been conducted.

The safety and efficacy of febuxostat in children and adolescents under 18 years of age have not been established.

Method of administration

Orally.

The drug is used once daily, regardless of food intake.

Adverse Reactions

The most frequent adverse effects in patients with gout when using febuxostat, based on clinical trials (4072 patients taking Febuxostat in doses from 10 mg to 300 mg) and post-marketing surveillance data, were: gout attack, impaired liver function, diarrhea, headache, nausea, skin rash, and edema. In most cases, these phenomena were characterized as mild or moderate in severity.

During post-marketing surveillance, rare cases of hypersensitivity reactions to Febuxostat have been reported, in some cases accompanied by systemic symptoms.

Possible adverse effects are listed below according to the WHO classification by descending frequency of occurrence: very common (≥1/10); common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), including isolated reports; frequency unknown (frequency cannot be estimated from available data). The frequency of adverse effects is based on data from clinical trials and post-marketing experience in patients with gout.

* Adverse effects observed during post-marketing surveillance

** Non-infectious diarrhea and liver disorders observed in Phase III studies were more frequent with concomitant use of colchicine

*** Additional information regarding the development of acute gout attacks (see section “Pharmacological action”)

Description of selected adverse reactions

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

Stevens-Johnson syndrome and toxic epidermal necrolysis are characterized by the occurrence of a progressive skin rash combined with bullous skin or mucous membrane lesions, as well as eye irritation.

Hypersensitivity reactions to Febuxostat may also manifest with the following symptoms: skin reactions characterized by infiltrative maculo-papular eruptions; generalized or exfoliative rash, as well as skin lesions, facial edema, fever, hematopoietic system disorders such as thrombocytopenia and eosinophilia, and involvement of one or more organs (liver and kidneys, including tubulointerstitial nephritis).

Gout attacks are usually observed shortly after starting Podagrel and during the first months of therapy. Subsequently, the frequency of attacks decreases. Prophylaxis of acute gout attacks is recommended.

Tumor lysis syndrome

Summary of the safety profile

In patients receiving chemotherapy for hemoblastoses and having a moderate to high risk of tumor lysis syndrome, the incidence of adverse effects was noted in 6.4% (see section “Pharmacological action”). In most cases, the adverse events were characterized as mild or moderate in severity. Overall, no specific features of the febuxostat safety profile in this patient group were noted in addition to that in gout, except for the following adverse effects: uncommon from the cardiac and vascular systems – left bundle branch block, sinus tachycardia, haemorrhage.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product in order to ensure continuous monitoring of the benefit-risk balance of the medicinal product.

Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to febuxostat and/or any of the excipients included in the drug composition;
• Children under 18 years of age (due to lack of data on efficacy and safety of use in this patient group);
• Pregnancy;
• Breastfeeding period;
• Hereditary galactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome.

With caution

• Severe renal impairment (CrCl <30 mL/min) (efficacy and safety have not been sufficiently studied);
• Hepatic impairment;
• History of serious allergic reactions (hypersensitivity reactions);
• Coronary artery disease;
• Congestive heart failure;
• Thyroid diseases;
• Concomitant use of mercaptopurine/azathioprine (possible increase in plasma concentration of these substances and enhancement of their toxicity);
• Post-organ transplant status (experience with febuxostat is limited);
• Lesch-Nyhan syndrome (experience with febuxostat is limited).

Use in Pregnancy and Lactation

Pregnancy

Due to insufficient data, the potential risk of febuxostat to humans is unknown, therefore the use of febuxostat during pregnancy is contraindicated. There is limited experience with the use of febuxostat during pregnancy, during which no adverse effects on the course of pregnancy and the condition of the fetus/newborn were noted. In animal studies, no direct or indirect adverse effects of the drug on the course of pregnancy, embryonic/fetal development, and the birth process were noted.

Breastfeeding period

There are no data on whether Febuxostat passes into breast milk. In animal studies, it was noted that Febuxostat passes into breast milk and has an adverse effect on the development of suckling offspring. Thus, a risk to breastfed infants cannot be excluded. Therefore, the use of febuxostat is contraindicated during breastfeeding.

There are no data on the effect on fertility.

Use in Hepatic Impairment

In patients with mild hepatic impairment (Child-Pugh class A (5-6 points)), the recommended dose of the drug is 80 mg once daily.

Experience with the drug in moderate hepatic impairment is limited.

Studies of the efficacy and safety of febuxostat in patients with severe hepatic impairment (Child-Pugh class C (10-15 points)) have not been conducted.

Use in Renal Impairment

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

In patients with severe renal impairment (CrCl <30 mL/min), the efficacy and safety of the drug have not been sufficiently studied.

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age (due to lack of data on efficacy and safety of use in this patient group).

Geriatric Use

In elderly patients, no dose adjustment of the drug is required.

Special Precautions

Acute gout attack (gout flare)

Use of Podagrel should be started only after the acute gout attack has resolved. Initiation of Podagrel may provoke an acute gout attack due to the release of urates from tissue depots and subsequent increase in serum uric acid concentration. For the prophylaxis of gout attacks, concomitant use of NSAIDs or colchicine is recommended for at least 6 months.

If a gout attack develops during the use of Podagrel, therapy with the drug should be continued and appropriate treatment for the acute gout attack should be administered simultaneously. With long-term use of Podagrel, the frequency and severity of gout attacks decrease.

Xanthine deposition

In rare cases, in patients with accelerated urate formation (e.g., against the background of malignant neoplasms or in Lesch-Nyhan syndrome), a significant increase in the absolute concentration of xanthines in the urine is possible, which may be accompanied by their deposition in the urinary tract. Due to limited data, the use of Podagrel in patients with Lesch-Nyhan syndrome is not recommended.

Mercaptopurine/azathioprine

Concomitant use with mercaptopurine, azathioprine is not recommended.

If concomitant use is necessary, to reduce the toxic effect on the hematopoietic system, a reduction in the dose of mercaptopurine/azathioprine and careful medical supervision are recommended.

Theophylline

With concomitant use of febuxostat at a dose of 80 mg once daily and a single dose of theophylline 400 mg in healthy volunteers, no changes in pharmacokinetic parameters were noted. Thus, concomitant use of febuxostat at a dose of 80 mg and theophylline does not carry a risk of increased plasma theophylline concentration. The study of concomitant use of febuxostat at a dose of 120 mg and theophylline has not been conducted.

Patients who have undergone organ transplantation

Use of Podagrel in patients who have undergone organ transplantation is not recommended due to lack of experience.

Allergic reactions and hypersensitivity reactions

During post-registration use, there have been rare reports of severe allergic reactions (hypersensitivity reactions), including life-threatening Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylactic reactions, and shock.

In most cases, these reactions developed within the first month of using Podagrel. Some patients had renal impairment and/or a history of hypersensitivity reactions to allopurinol.

In some cases, severe hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, were accompanied by fever, changes in blood parameters, and impaired liver or kidney function.

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

If severe allergic reactions/hypersensitivity reactions occur, including Stevens-Johnson syndrome, it is necessary to immediately discontinue the use of Podagrel (earlier discontinuation is associated with a better prognosis). If a patient has previously experienced severe allergic reactions or hypersensitivity reactions, including Stevens-Johnson syndrome, acute anaphylactic reactions/shock, re-administration of the drug is not recommended.

Cardiovascular Diseases

The use of Podagrel is not recommended in patients with coronary artery disease or congestive heart failure. In the APEX and FACT studies (unlike the CONFIRMS study) (see the “Pharmacological Action” section), an increase in the number of cardiovascular disorders, defined according to the system developed by the Anti-Platelet Trialists’ Collaboration (APTC) and including death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, was observed in the overall febuxostat group compared to the allopurinol group – 1.3 compared to 0.3 cases per 100 patient-years. According to pooled data from Phase III clinical studies (APEX, FACT, and CONFIRMS studies), the frequency of cardiovascular disorders was 0.7 compared to 0.6 cases per 100 patient-years.

In long-term large-scale studies, the frequency of APTC cardiovascular events was 1.2 and 0.6 cases per 100 patient-years for febuxostat and allopurinol, respectively. The differences were not statistically significant, and a causal relationship between these events and febuxostat intake was not established.

The following conditions in the patient’s medical history were identified as risk factors for the development of these events: atherosclerosis and/or myocardial infarction, or congestive heart failure.

Liver Diseases

According to pooled data from Phase III clinical studies, mild liver function impairment was observed in 5% of patients using febuxostat.

It is recommended to monitor liver function at the beginning of Podagrel use and periodically thereafter if clinical manifestations occur.

Thyroid Diseases

In extended long-term open-label studies, with long-term use of febuxostat, an increase in TSH concentration (>5.5 µIU/mL) was observed in 5.5% of patients; therefore, Podagrel should be used with caution in patients with impaired thyroid function.

Lactose

The drug contains lactose monohydrate. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take Podagrel.

Effect on Ability to Drive and Operate Machinery

When using Podagrel, drowsiness, dizziness, paresthesia, and blurred vision may occur, and consequently, a decrease in reaction time and ability to concentrate may occur; therefore, caution must be exercised when driving vehicles and engaging in other potentially hazardous activities that require concentration and speed of psychomotor reactions while using Podagrel.

Overdose

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

Drug Interactions

Mercaptopurine/azathioprine

Given the mechanism of action of febuxostat, based on the inhibition of xanthine oxidase, concomitant use is not recommended. Inhibition of xanthine oxidase by febuxostat may lead to an increase in the plasma concentration of mercaptopurine and azathioprine and an enhancement of their toxic effects. Studies on the interaction of febuxostat with substances metabolized by xanthine oxidase have not been conducted.

Cytostatics

Studies on the drug interaction of febuxostat and cytostatic drugs have not been conducted. Nevertheless, since studies on drug disease and drug interaction of febuxostat with cytotoxic drugs have not been conducted, a potential interaction of febuxostat with concurrently used cytotoxic chemotherapeutic agents cannot be excluded.

Rosiglitazone/substrates of the CYP2C8 isoenzyme

According to in vitro data, Febuxostat is a weak inhibitor of the CYP2C8 isoenzyme. In healthy volunteers, with the simultaneous use of 120 mg febuxostat once daily and a single 4 mg dose of rosiglitazone, no changes in the pharmacokinetic parameters of rosiglitazone and its metabolite N-desmethylrosiglitazone were noted, indicating that febuxostat does not have CYP2C8 isoenzyme inhibitory properties in vivo. No dose adjustment is required when febuxostat and rosiglitazone (or other substrates of the CYP2C8 isoenzyme) are used concomitantly.

Theophylline

A drug interaction study of febuxostat was conducted in healthy volunteers to assess whether inhibition of xanthine oxidase could lead to an increase in the plasma concentration of theophylline, as noted with other xanthine oxidase inhibitors. The study results demonstrated that with the simultaneous use of febuxostat at a dose of 80 mg once daily and a single 400 mg dose of theophylline, no changes in the pharmacokinetic parameters or tolerability of theophylline were observed. Thus, no special precautions are required when febuxostat at a dose of 80 mg and theophylline are used concomitantly. The study of the simultaneous use of febuxostat at a dose of 120 mg and theophylline has not been conducted.

Naproxen and other glucuronidation inhibitors

The metabolism of febuxostat depends on the activity of the enzyme uridine diphosphate glucuronosyltransferase (UDP-GT). Drugs that inhibit the glucuronidation process, for example, NSAIDs and probenecid, could theoretically affect the excretion of febuxostat. In healthy volunteers, with the simultaneous use of febuxostat and naproxen at a dose of 250 mg twice daily, an increase in the C_max of febuxostat by 28%, AUC by 41%, and T_1/2 by 26% was observed. In clinical studies, the use of naproxen or other NSAIDs/COX-2 inhibitors was not accompanied by a clinically significant increase in the frequency of adverse reactions. Concomitant use of febuxostat and naproxen or other NSAIDs/COX-2 inhibitors was not accompanied by a clinically significant increase in the frequency of adverse reactions. No dose adjustment is required when febuxostat and naproxen are used concomitantly.

Glucuronidation inducers

When febuxostat is used concomitantly with strong inducers of glucuronidation, its metabolism may be enhanced and its efficacy reduced. When used concomitantly, monitoring of serum uric acid concentration is necessary 1-2 weeks after the start of therapy. Upon discontinuation of a glucuronidation inducer, an increase in the C_max of febuxostat is possible.

Colchicine/indomethacin/hydrochlorothiazide/warfarin

Febuxostat can be used concomitantly with colchicine or indomethacin without dose adjustment. No dose adjustment of febuxostat is required when used concomitantly with hydrochlorothiazide. Concomitant use of febuxostat (80 mg or 120 mg once daily) with warfarin did not affect the pharmacokinetics of warfarin in healthy volunteers, INR, and factor VII activity. No dose adjustment of warfarin is required when used concomitantly with febuxostat.

Desipramine/substrates of the CYP2D6 isoenzyme

According to data obtained in vitro, Febuxostat is a weak inhibitor of the CYP2D6 isoenzyme. In a study in healthy volunteers, against the background of febuxostat use at a dose of 120 mg once daily, an increase in the AUC of desipramine (a substrate of the CYP2D6 isoenzyme) by 22% was noted, indicating a weak inhibitory effect of febuxostat on the CYP2D6 isoenzyme in vivo. Thus, no dose adjustment is required when febuxostat and substrates of the CYP2D6 isoenzyme are used concomitantly.

Antacids

When used concomitantly with antacids (medicinal products that neutralize stomach acid) containing magnesium hydroxide or aluminum hydroxide, a decrease in the absorption of febuxostat (by approximately 1 hour) and a decrease in C_max by 32% were noted; however, the AUC of febuxostat did not change significantly. Thus, Febuxostat can be taken concomitantly with antacids.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 2 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.