Liquestia film-coated tablets 80 mg blister No. 28

Instructions Liquestia film-coated tablets 80 mg blister No. 28

Composition

active ingredient: febuxostat;

1 film-coated tablet contains 80 mg of febuxostat;

excipients: microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, croscarmellose sodium, anhydrous lactose, colloidal anhydrous silicon dioxide, magnesium stearate;

film coating: polyvinyl alcohol (E 1203), titanium dioxide (E 171), macrogol 3350 (E 1521), talc (E 553b), iron oxide yellow (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties:

Film-coated tablets, 80 mg: oblong, biconvex, film-coated tablets, pale yellow to yellow, embossed with "80" 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 affect 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 was confirmed in three phase III studies (two pivotal studies, APEX and FACT, and the additional CONFIRMS study, described below), which included 4101 patients with hyperuricemia and gout. In each of these pivotal phase III studies, febuxostat was more effective in lowering serum uric acid levels and maintaining them at an appropriate level compared to allopurinol. The primary efficacy endpoint in the APEX and FACT studies was the proportion of patients with a serum uric acid concentration of less than 6.0 mg/dL (357 μmol/L) during the previous three months. In the additional phase III CONFIRMS study, the results of which became available after the first approval of febuxostat, the primary efficacy endpoint was the proportion of patients with a serum uric acid concentration of less than 6.0 mg/dL at the time of the last visit. Patients who had undergone organ transplantation were excluded from these studies (see section 4.4).

The APEX study: The Phase III Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX) was a randomized, double-blind, multicenter, 28-week study. A total of 1072 patients were randomized to: placebo (n=134), febuxostat 80 mg once daily (n=267), febuxostat 120 mg once daily (n=269), febuxostat 240 mg once daily (n=134), and allopurinol (300 mg once daily (n=258) for patients with baseline serum creatinine ≤ 1.5 mg/dL or 100 mg once daily (n=10) for patients with baseline serum creatinine > 1.5 mg/dL and ≤ 2.0 mg/dL). For safety assessment, febuxostat was administered at a dose of 240 mg (2 times the maximum recommended dose).

The APEX study demonstrated a statistically significant superiority of both treatment regimens: febuxostat 80 mg once daily and febuxostat 120 mg once daily compared to allopurinol at the usual dose of 300 mg (n = 258)/100 mg (n = 10) in reducing serum uric acid concentrations below 6 mg/dL (357 μmol/L) (see Table 1).

FACT Study: The Febuxostat Allopurinol Controlled Trial (FACT) was a phase III, randomized, double-blind, multicenter, 52-week study. A total of 760 patients were randomized to: febuxostat 80 mg once daily (n = 256), febuxostat 120 mg once daily (n = 251), and allopurinol 300 mg once daily (n = 253).

The FACT study demonstrated a statistically significant superiority of both regimens – febuxostat 80 mg once daily and febuxostat 120 mg once daily, compared to allopurinol at the usual dose of 300 mg in reducing and maintaining serum uric acid concentrations below 6 mg/dL (357 μmol/L).

Table 1 presents the results of the assessment of the primary efficacy endpoint.

Table 1

Proportion of patients with serum uric acid concentration < 6.0 mg/dL (357 μmol/L) during the last three monthly visits

Febuxostat's ability to rapidly reduce serum uric acid was rapid and long-lasting. Reductions in serum uric acid to < 6.0 mg/dL (357 μmol/L) were observed as early as the second week of the study and were maintained throughout treatment.

CONFIRMS Study: The CONFIRMS study was a 26-week, randomized, controlled, phase III study conducted to evaluate the safety and efficacy of febuxostat 40 mg and 80 mg compared with allopurinol 300 mg and 200 mg in patients with gout and hyperuricemia. A total of 2269 patients were randomized to receive febuxostat 40 mg once daily (n=757), febuxostat 80 mg once daily (n=756), and allopurinol 300/200 mg once daily (n=756). At least 65% of patients had mild to moderate renal impairment (creatinine clearance 30–89 mL/min). Gout prophylaxis was mandatory for 26 weeks.

The proportion of patients with serum uric acid concentration < 6.0 mg/dL (357 μmol/L) at the last visit was 45% for febuxostat 40 mg, 67% for febuxostat 80 mg, and 42% for allopurinol 300/200 mg, respectively.

Primary endpoint in the subgroup of patients with renal impairment

The APEX study evaluated the efficacy of the drug in 40 patients with renal impairment (i.e., baseline serum creatinine > 1.5 mg/dL and ≤ 2.0 mg/dL). These patients, randomized to allopurinol, had their dose reduced to 100 mg once daily. The primary efficacy endpoint was achieved in the febuxostat groups in 44% (80 mg once daily), 45% (120 mg once daily), and 60% (240 mg once daily) compared with 0% in the allopurinol 100 mg once daily and placebo groups.

At the same time, no clinically significant differences in the percentage reduction in serum uric acid concentration were observed in healthy volunteers, regardless of the functional state of the kidneys (58% in the group with normal kidney function and 55% in the group with severe renal impairment).

A prospective analysis of patients with gout and renal impairment in the CONFIRMS study showed that febuxostat was significantly more effective, 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 subjects).

Primary endpoint in the subgroup of patients with serum uric acid concentration ≥ 10 mg/dL

Baseline serum uric acid concentrations ≥ 10 mg/dL were observed in approximately 40% of patients (combined APEX and FACT studies). Among these patients, the primary efficacy endpoint (serum uric acid concentration < 6 mg/dL at the last 3 visits) was achieved in the febuxostat subgroups: 41% of patients (80 mg once daily), 48% of patients (120 mg once daily), and 66% of patients (240 mg once daily) compared with 9% in the allopurinol 300 mg/100 mg once daily group and 0% in the placebo group.

In the CONFIRMS study, the proportion of patients who achieved the primary efficacy endpoint (serum uric acid < 6.0 mg/dL at the last visit) in the group of patients with baseline serum uric acid ≥ 10 mg/dL who received febuxostat 40 mg once daily was 27% (66/249), febuxostat 80 mg once daily – 49% (125/254), and allopurinol 300 mg/200 mg once daily – 31% (72/230).

Clinical outcomes: percentage of patients requiring treatment for gout attacks

APEX study: During the 8-week prophylaxis period, patients in the febuxostat 120 mg treatment group (36%) who required treatment for gout attacks were compared with patients receiving febuxostat 80 mg (28%), allopurinol 300 mg (23%), or placebo (20%). The frequency of attacks was higher after the prophylaxis period and gradually decreased over time. Between 46% and 55% of patients received treatment for gout attacks from week 8 and from week 28. Gout attacks occurring during the last 4 weeks of the trial (weeks 24–28) were observed in 15% of patients (febuxostat 80, 120 mg), 14% of patients (allopurinol 300 mg), and 20% of patients (placebo).

The proportion of patients requiring treatment for gout flares (APEX and FACT studies) was lower in groups where the mean serum uric acid concentration after treatment decreased to < 6.0 mg/dL, < 5.0 mg/dL, or < 4.0 mg/dL compared with groups in which the mean uric acid level was ≥ 6.0 mg/dL in the last 32 weeks of treatment (weeks 20–24 to weeks 49–52).

In the CONFIRMS study, the proportion of patients requiring treatment for gout attacks (1 day every 6 months) was 31% and 25% in the febuxostat 80 mg and allopurinol groups, respectively. There was no difference in the proportion of patients requiring treatment for gout attacks between the febuxostat 80 mg and 40 mg groups.

Long-term extended open-label studies

EXCEL Study (C02-021): The EXCEL study was a 3-year, open-label, multicenter, randomized, allopurinol-controlled, Phase III safety study conducted to evaluate the safety of patients who completed the pivotal Phase III studies (APEX or FACT). A total of 1086 patients were enrolled and received either febuxostat 80 mg once daily (n=649), febuxostat 120 mg once daily (n=292), or allopurinol 300/100 mg once daily (n=145). Approximately 69% of patients did not require therapy adjustment to achieve final stable treatment. Patients with serum uric acid levels > 6.0 mg/dL on three consecutive measurements were excluded from the study.

Serum uric acid levels did not change over time (e.g., 91% and 93% of patients initially treated with febuxostat at doses of 80 mg and 120 mg, respectively, had serum uric acid levels less than 6.0 mg/dL at month 36).

According to three-year follow-up data, less than 4% of patients who required treatment for attacks showed a reduction in gout attack frequency at 16–24 months and 30–36 months (i.e., more than 96% of patients did not require treatment for attacks).

In 46% and 38% of patients receiving final stable treatment with febuxostat 80 or 120 mg once daily, respectively, complete resolution of the primary palpable tophus was observed from baseline to the last visit.

The FOCUS study (TMX-01-005) was a 5-year, open-label, multicenter, Phase II safety extension study conducted in patients who completed the 4-week double-blind febuxostat dosing in study TMX-00-004. The study included 116 patients who initially received febuxostat 80 mg once daily. 62% of patients did not require dose adjustment to maintain serum uric acid levels below 6.0 mg/dL, and 38% of patients required dose adjustment to achieve final steady-state levels.

The proportion of patients with serum uric acid levels less than 6.0 mg/dL (357 μmol/L) at the last visit was greater than 80% (81–100%) for each febuxostat dose group.

In phase III clinical trials, minor changes in liver function tests (5.0%) were observed in patients treated with febuxostat. The incidence of these changes was similar to that of allopurinol (4.2%) (see section 4.4). In long-term open-label extension studies, increases in TSH (> 5.5 μIU/mL) were observed in patients treated with febuxostat (5.5%) or allopurinol (5.8%) for extended periods (see section 4.4).

Tumor lysis syndrome (TLS)

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

The study included 346 patients with hematological malignancies receiving chemotherapy and at intermediate/high risk of developing SLE. The mean AUC sUA1-8 (mg x h/dL) was significantly lower with febuxostat (514.0 ± 225.71 vs. 708.0 ± 234.42; LS mean difference: -196.794 [95% CI: -238.600, -154.988]; p < 0.0001). In addition, the mean serum uric acid level was significantly lower with febuxostat, starting from the first 24 hours of treatment and at any time point thereafter. There were no statistically significant differences in mean serum creatinine (%) between febuxostat and allopurinol (-0.83 ± 26.98 vs. -4.92 ± 16.70, respectively; LS mean difference: 4.0970 [95% CI: -0.6467, 8.8406]; p=0.0903). Regarding secondary endpoints, there were no statistically significant differences in the incidence of laboratory-confirmed SLE (8.1% and 9.2% for febuxostat and allopurinol, respectively; relative risk: 0.875 [95% confidence interval: 0.4408, 1.7369]; p=0.8488) and no clinical tumor lysis syndrome (1.7% and 1.2% for febuxostat and allopurinol, respectively; relative risk: 0.994 [95% confidence interval: 0.9691, 1.0199]; p=1.0000). The incidence of all treatment-emergent signs and symptoms and adverse reactions was 67.6% versus 64.7% and 6.4% versus 6.4% for febuxostat and allopurinol, respectively. In the FLORENCE study, febuxostat demonstrated superior and faster serum uric acid-lowering activity compared with allopurinol. Data comparing febuxostat and rasburicase are currently unavailable. The efficacy and safety of febuxostat have not been established in patients with acute severe GSD, for example, in patients in whom other urate-lowering therapies have failed.

Pharmacokinetics

In healthy volunteers, the maximum plasma concentration (Cmax) and area under the curve (AUC) increased in a dose-proportional manner after single and multiple doses of febuxostat in the range of 10 mg to 120 mg. At doses of 120 mg to 300 mg, the increase in AUC was greater than dose-proportional. There was no accumulation of febuxostat when doses of 10–240 mg were administered every 24 hours. The estimated mean terminal elimination half-life (t1/2) of febuxostat was approximately 5–8 hours. A population pharmacokinetic/pharmacodynamic analysis was performed on data obtained from 211 patients with hyperuricemia and gout who received febuxostat in doses of 40–240 mg once daily. Overall, the pharmacokinetic parameter values obtained were similar to those in healthy volunteers, which is a good model for assessing the pharmacokinetics/pharmacodynamics of the drug in patients with gout.

Absorption. Febuxostat is rapidly (tmax (time to maximum concentration) – 1.0–1.5 hours) and well (at least 84%) absorbed. With single and multiple oral administration of febuxostat at doses of 80 mg or 120 mg 1 time per day, 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 analyzed. With multiple administration at a dose of 80 mg 1 time per day or with a single administration at a dose of 120 mg in combination with a fatty meal, Cmax was reduced by 49% and 38%, and AUC – by 18% and 16%, respectively. However, this was not accompanied by clinically significant changes in the degree of reduction in plasma uric acid levels (with multiple administration at a dose 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 to 75 L after oral administration at a dose of 10–300 mg. The degree of binding to plasma proteins (mainly albumin) is 99.2% and does not change with increasing dose from 80 mg to 120 mg. For the active metabolites of febuxostat, the degree of binding to plasma proteins ranges from 82 to 91%.

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

Elimination: Febuxostat is eliminated from the body via the liver and kidneys. Following oral administration of 80 mg 14C-febuxostat, approximately 49% was excreted in the urine as unchanged febuxostat (3%), acylglucuronide of the active substance (30%), known oxidized metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to renal excretion, approximately 45% was excreted in the feces as unchanged febuxostat (12%), acylglucuronide of the active substance (1%), known oxidized metabolites and their conjugates (25%), and other unknown metabolites (7%).

With multiple administration of febuxostat at a dose of 80 mg, no changes in Cmax of febuxostat were observed 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 x h/mL in patients with normal renal function to 13.2 μg x 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 patients with normal hepatic function. The drug has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

Age.

After multiple oral doses of febuxostat, no significant changes in AUC of febuxostat and its metabolites were observed in elderly patients compared to young healthy volunteers.

Sex.

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

Indication

Liquestia® 80 mg and Liquestia® 120 mg

Treatment of chronic hyperuricemia in diseases accompanied by the deposition of urate crystals, including the presence of tophus and/or gouty arthritis at present or in history.

Liquestia® is indicated for adult patients.

Contraindication

Hypersensitivity to the active substance or to any of the excipients listed in the "Composition" section.

Interaction with other medicinal products and other types of interactions

Mercaptopurine/azathioprine.

According to its mechanism of action, febuxostat inhibits xanthine oxidase, therefore concomitant use is not recommended. Inhibition of xanthine oxidase may lead to increased plasma concentrations of both drugs, which may cause a toxic reaction. Interaction studies of febuxostat with drugs metabolized by xanthine oxidase have not been conducted.

No interaction studies have been conducted with febuxostat during cytotoxic chemotherapy. In the study, febuxostat 120 mg was administered to patients with SLE receiving multiple chemotherapy regimens, including monoclonal antibodies. However, drug-drug and drug-disease interactions were not investigated in this study. Therefore, possible interactions with any concomitantly administered cytotoxic agents 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 dose of 4 mg of rosiglitazone had no effect on the pharmacokinetics of rosiglitazone and its metabolite N-desmethylrosiglitazone, demonstrating that febuxostat does not inhibit the CYP2C8 enzyme in vivo. Therefore, co-administration of febuxostat and rosiglitazone or other CYP2C8 substrates does not require dose adjustment for these drugs.

Theophylline.

An interaction study of febuxostat was conducted in healthy volunteers to assess the effect of xanthine oxidase inhibition on the increase in circulating theophylline levels observed with other xanthine oxidase inhibitors. The results showed that concomitant administration of febuxostat 80 mg and theophylline 400 mg did not show any pharmacokinetic interactions or effects on the safety of theophylline. Therefore, febuxostat 80 mg can be co-administered with theophylline without any special precautions. There are no data available for the 120 mg dose of febuxostat.

Naproxen and other glucuronidation inhibitors.

Febuxostat metabolism is dependent on the activity of the enzyme UDP-glucuronyltransferase. Drugs that inhibit glucuronidation, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and probenecid, could theoretically alter the elimination of febuxostat. In healthy volunteers, concomitant administration of febuxostat and naproxen 250 mg twice daily resulted in an increase in febuxostat exposure (Cmax 28%, AUC 41%, t1/2 26%). In clinical studies, the use of naproxen and other NSAIDs/COX-2 inhibitors was not associated with a clinically significant increase in adverse reactions.

Febuxostat can be used concomitantly with naproxen without changing their doses.

Glucuronidation inducers.

Strong inducers of UDP-glucuronyltransferase may increase the metabolism and reduce the efficacy of febuxostat. In patients receiving strong inducers of glucuronidation, it is recommended to monitor plasma uric acid levels after 1-2 weeks of concomitant therapy. When the inducer of glucuronidation is discontinued, an increase in febuxostat plasma levels may occur.

Colchicine/indomethacin/hydrochlorothiazide/warfarin.

There is also no need to change the dose of febuxostat when used simultaneously with hydrochlorothiazide.

Concomitant use of febuxostat with warfarin does not require a change in the dose of warfarin. Co-administration of febuxostat (80 mg or 120 mg once daily) with warfarin does not affect the pharmacokinetics of warfarin. Co-administration with febuxostat also had no effect on INR and factor VII activity.

Desipramine/CYP2D6 substrates.

In vitro data indicate that febuxostat is a weak inhibitor of CYP2D6. In a study in healthy volunteers receiving 120 mg of febuxostat once daily, a 22% increase in the AUC of desipramine (a CYP2D6 substrate) was observed, indicating that febuxostat is a weak inhibitor of the CYP2D6 enzyme in vivo.

Therefore, there is no need to adjust the doses of febuxostat and CYP2D6 substrates when co-administered.

Antacids.

When used simultaneously with antacids containing magnesium hydroxide and aluminum hydroxide, a delay in the absorption of febuxostat (approximately 1 hour) and a decrease in Cmax by 32% are noted, however, the AUC of febuxostat does not change significantly, therefore febuxostat can be combined with the use of antacids.

Application features

Cardiovascular diseases.

Treatment of chronic hyperuricemia

Febuxostat is not recommended for use in patients with ischemic heart disease or congestive heart failure.

In the APEX and FACT studies, an increase in the number of cardiovascular events (Anti-Platelet Trialists' Collaboration (APTC)) (endpoints defined in the antiplatelet therapy (APTC) analysis group, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) was reported 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. The incidence of cardiovascular events (APTC) reported in the combined phase III studies (APEX, FACT, and CONFIRMS studies) was 0.7 versus 0.6 events per 100 patient-years. In long-term large-scale studies, the incidence of cardiovascular events reported 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. Identified risk factors in these patients included conditions resulting from atherosclerosis and/or a history of myocardial infarction or congestive heart failure.

Prevention and treatment of hyperuricemia in patients at risk of developing Gout

Patients undergoing chemotherapy for hematological malignancies with moderate or high risk of SLP and using Liquestia® are under the supervision of a cardiologist if clinically indicated.

Allergy/hypersensitivity to medications.

There have been rare reports of serious allergic/hypersensitivity reactions, including life-threatening Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute anaphylactic reactions/shock, during post-marketing surveillance. Most of these reactions occurred within the first month of febuxostat use. Several, but not all, patients had a history of renal impairment and/or hypersensitivity to allopurinol. Severe hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), have been associated with fever, hematologic, renal, or hepatic failure in some cases.

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

Exacerbation (attack) of gout.

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

If an 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.

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

Mercaptopurine/azathioprine.

Febuxostat is not recommended for use in patients receiving concomitant mercaptopurine/azathioprine.

If the combination cannot be avoided, patients should be closely monitored. It is recommended to reduce the dose of mercaptopurine or azathioprine to avoid possible hematological effects.

Patients who have undergone organ transplantation.

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

Theophylline.

A single concomitant administration of febuxostat 80 mg and theophylline 400 mg did not show any pharmacokinetic interactions. Febuxostat 80 mg can be co-administered with theophylline without risk of increased theophylline plasma concentrations. There are no data available for febuxostat 120 mg.

Liver disease.

In the combined phase III clinical trials, minor changes in liver function tests were observed in 5.0% of patients treated with febuxostat, therefore it is recommended to check liver function tests before prescribing febuxostat and during treatment if indicated.

Thyroid disease.

Elevated TSH (> 5.5 μIU/mL) was observed in 5.5% of patients receiving febuxostat for a long time in long-term open-label extension studies. Therefore, the drug should be prescribed 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.

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 Liquestia® are advised to exercise caution when driving or operating machinery until they are certain that they have not experienced any of the above-mentioned side effects.

Use during pregnancy or breastfeeding

Pregnancy

Limited experience with the use of febuxostat during pregnancy indicates that there is no adverse effect of the drug on the course of pregnancy and the health of the fetus/newborn. Animal studies have not indicated direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development or parturition. 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 febuxostat is excreted in breast milk and has adverse effects on the development of nursing infants. A risk of excretion into breast milk cannot be excluded. Febuxostat should not be used during breast-feeding.

Fertility

Animal fertility studies at a dose of 48 mg/kg/day did not reveal any dose-related adverse reactions. The effect of Liquestia® on human reproductive function is unknown.

Method of administration and doses

Dosage

Gout.

The recommended dose of Liquestia® is 80 mg once daily orally, without regard to meals. If serum uric acid levels exceed 6 mg/dL (357 μmol/L) after 2–4 weeks of treatment, an increase in the dose of Liquestia® to 120 mg once daily should be considered. The effect of the drug is quite rapid, which allows for repeated determination of uric acid levels after 2 weeks. The goal of treatment is to reduce uric acid levels and maintain them below 6 mg/dL (357 μmol/L).

The duration of prevention of gout attacks is at least 6 months.

Tumor lysis syndrome (TLS).

The recommended dose of Liquestia® is 120 mg once daily orally, regardless of food intake.

Liquestia® 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.

No dose adjustment is required for this category of patients.

Kidney failure.

In patients with severe renal impairment (creatinine clearance <30 ml/min), the efficacy and safety of the drug have not been sufficiently studied. In patients with mild or moderate renal impairment,