Efstat

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EFSTAT

Composition:

Active substance: febuxostat (febuxostat);

1 film-coated tablet contains febuxostat 80 mg or 120 mg;

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

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: film-coated tablets, oblong-shaped, biconvex, from pale yellow to yellow in color, with "80" or "120" engraved on one side and a smooth surface on the other.

Pharmacotherapeutic group. Medicinal products for the treatment of gout. Medicinal products that inhibit uric acid formation. Febuxostat. ATC code M04A A03.

Pharmacological properties.

Pharmacodynamics.

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 whose therapeutic effect is related to decreasing serum uric acid concentration by selectively inhibiting xanthine oxidase. Febuxostat is a potent and selective non-purine inhibitor of xanthine oxidase, with an in vitro inhibition constant (Ki) of less than 1 nM. It has been demonstrated that febuxostat significantly inhibits the activity of both oxidized and reduced forms of xanthine oxidase. At therapeutic concentrations, febuxostat does not affect other enzymes involved in purine or pyrimidine metabolism, such as guanidine deaminase, hypoxanthine-guanine phosphoribosyltransferase, orotidin monophosphate decarboxylase, or purine nucleoside phosphorylase.

Pharmacokinetics.

In healthy volunteers, maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) increased proportionally with dose after single and multiple doses of febuxostat ranging from 10 mg to 120 mg. At doses from 120 mg to 300 mg, the increase in AUC was greater than proportional to dose. No significant accumulation of febuxostat was observed after repeated doses of 10–240 mg every 24 hours. The predicted mean terminal elimination half-life (t1/2) of febuxostat was approximately 5–8 hours.

Absorption. Febuxostat is rapidly (tmax – 1.0–1.5 hours) and well (84%) absorbed. After single and multiple oral doses of 80 mg or 120 mg once daily, Cmax was 2.8–3.2 μg/mL and 5.0–5.3 μg/mL, respectively. The absolute bioavailability of febuxostat tablets has not been analyzed. When multiple doses of 80 mg once daily or a single 120 mg dose were administered with a high-fat meal, Cmax decreased by 49% and 38%, and AUC decreased by 18% and 16%, respectively. However, this was not associated with clinically significant changes in the extent of plasma uric acid reduction (after multiple 80 mg doses). Therefore, the drug can be administered regardless of food intake.

Distribution. The predicted steady-state volume of distribution (Vss/F) of febuxostat ranges from 29 L to 75 L after oral administration of 10–300 mg. The extent of plasma protein binding (primarily to albumin) is 99.2% and does not change with dose escalation from 80 mg to 120 mg. For active metabolites of febuxostat, the extent of plasma protein binding ranges from 82% to 91%.

Metabolism. Febuxostat is extensively metabolized via conjugation by uridine diphosphate-glucuronosyltransferase (UGT) enzymes and oxidation by cytochrome P450 (CYP) enzymes. Four pharmacologically active hydroxyl metabolites of febuxostat have been identified, three of which were detected in plasma. In vitro studies using human liver microsomes demonstrated that these oxidized metabolites are formed predominantly by CYP1A1, CYP1A2, CYP2C8, and CYP2C9, whereas febuxostat glucuronide is formed mainly by UGT1A1, 1A8, and 1A9.

Excretion. Febuxostat is eliminated via both hepatic and renal routes. After oral administration of 14C-febuxostat 80 mg, approximately 49% was excreted in urine as unchanged febuxostat (3%), the acyl glucuronide 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 feces as unchanged febuxostat (12%), acyl glucuronide of the active substance (1%), known oxidized metabolites and their conjugates (25%), and other unknown metabolites (7%).

Special patient groups

Renal impairment.

After repeated administration of febuxostat 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. 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. Cmax and AUC of active metabolites increased 2- and 4-fold, respectively. However, dose adjustment of the drug is not required in patients with mild, moderate, or severe renal impairment.

Hepatic impairment.

After repeated administration of febuxostat 80 mg, no significant changes in Cmax and AUC of febuxostat and its metabolites were observed in patients with mild (Child–Pugh class A) or moderate (Child–Pugh class B) hepatic impairment compared to patients with normal liver function. The drug has not been studied in patients with severe hepatic impairment (Child–Pugh class C).

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

Gender. During repeated oral administration of febuxostat, Cmax and AUC of febuxostat in women were 24% and 12% higher, respectively, than in men. However, Cmax and AUC corrected for body weight were similar between the two groups; therefore, dose adjustment of febuxostat based on gender is not required.

Clinical characteristics.

Indications.

For 80 mg and 120 mg dosage forms

Treatment of chronic hyperuricemia associated with diseases characterized by deposition of urate crystals, particularly in the presence of tophi and/or current or past history of gouty arthritis.

For 120 mg dosage form

Treatment and prevention of hyperuricemia in adult patients undergoing chemotherapy for hematologic malignancies with moderate or high risk of tumor lysis syndrome (TLS).

The medicinal product is indicated for adult patients.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Mercaptopurine/azathioprine.

Due to its mechanism of action, febuxostat inhibits xanthine oxidase; therefore, its concomitant use with mercaptopurine and azathioprine is not recommended. Inhibition of xanthine oxidase may lead to increased plasma concentrations of these drugs, potentially causing toxic reactions. Clinical studies on the interaction between febuxostat and medicinal products metabolized by xanthine oxidase have not been conducted in humans.

Modeling and simulation analysis of preclinical data in rats indicates that if febuxostat is co-administered, doses of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose (see section "Special precautions for use").

Interactions of febuxostat during cytotoxic chemotherapy have not been studied.

In clinical trials, patients with TLS received febuxostat 120 mg with various chemotherapy regimens, including monoclonal antibodies. However, drug–drug and drug–disease interactions were not specifically investigated in these studies. Therefore, potential interactions with any concomitantly administered cytotoxic medicinal products cannot be excluded.

Rosiglitazone/CYP2C8 substrates.

Febuxostat is a weak inhibitor of CYP2C8 in vitro. In a study in healthy volunteers, concomitant administration of 120 mg febuxostat once daily and a single 4 mg dose of rosiglitazone did not affect the pharmacokinetics of rosiglitazone or its metabolite N-desmethyl rosiglitazone. Thus, febuxostat does not inhibit the CYP2C8 enzyme in vivo. Therefore, dose adjustment is not required when febuxostat is used concomitantly with rosiglitazone or other CYP2C8 substrates.

Theophylline.

An interaction study with febuxostat was conducted in healthy volunteers to evaluate the potential for increased circulating theophylline levels due to xanthine oxidase inhibition, as observed with other xanthine oxidase inhibitors. Results showed that concomitant administration of febuxostat 80 mg and theophylline 400 mg did not result in any pharmacokinetic interaction or impact on theophylline safety. Therefore, febuxostat 80 mg can be used concomitantly with theophylline without special precautions. Data on the use of febuxostat 120 mg are not available.

Naproxen and other inhibitors of glucuronidation.

Febuxostat metabolism depends on the activity of the enzyme UDP-glucuronosyltransferase. Medicinal products that inhibit glucuronidation, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and probenecid, may theoretically alter febuxostat elimination. In healthy volunteers, co-administration of febuxostat and naproxen 250 mg twice daily resulted in increased exposure to febuxostat (Cmax by 28%, AUC by 41%, t1/2 by 26%). In clinical trials, 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 dose adjustment of either medicinal product.

Inducers of glucuronidation.

Potent inducers of UDP-glucuronosyltransferase may enhance the metabolism and reduce the efficacy of febuxostat. In patients receiving potent inducers of glucuronidation, plasma uric acid levels should be monitored 1–2 weeks after initiation of concomitant therapy. Upon discontinuation of the glucuronidation inducer, plasma levels of febuxostat may increase.

Colchicine/indomethacin/hydrochlorothiazide/warfarin.

Febuxostat can be used concomitantly with colchicine or indomethacin without dose adjustment of either drug.

Dose adjustment of febuxostat is not required when used concomitantly with hydrochlorothiazide.

Concomitant use of febuxostat with warfarin does not require dose adjustment of warfarin. Administration of febuxostat (80 mg or 120 mg once daily) with warfarin does not affect the pharmacokinetics of warfarin. Concomitant use with febuxostat also does not affect the international normalized ratio (INR) or factor VII activity.

Desipramine/CYP2D6 substrates.

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

Therefore, when febuxostat is used concomitantly with CYP2D6 substrates, no dose adjustment is necessary.

Antacids.

When administered concomitantly with antacids containing magnesium hydroxide and aluminum hydroxide, delayed absorption of febuxostat (by approximately 1 hour) and a 32% reduction in Cmax are observed. However, the AUC of febuxostat is not significantly altered; therefore, febuxostat may be co-administered with antacids.

Special precautions for use.

Cardiovascular diseases.

Treatment of chronic hyperuricemia

Patients with pre-existing major cardiovascular diseases (e.g., myocardial infarction, stroke, or unstable angina) should avoid treatment with febuxostat, except when no other appropriate treatment options are available.

In the APEX and FACT studies, an increased number of cardiovascular events [Anti-Platelet Trialists’ Collaboration (APTC)] (defined as endpoints in the APTC combined analysis of antiplatelet therapy, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (1.3 compared to 0.3 events per 100 patient-years)) were reported in the febuxostat group compared to the allopurinol group, unlike in the CONFIRMS study. The incidence of APTC cardiovascular events reported in the studies in combined phase III trials (APEX, FACT, and CONFIRMS) was 0.7 versus 0.6 events per 100 patient-years for febuxostat and allopurinol, respectively. In long-term, large-scale studies, the incidence of these cardiovascular events was 1.2 and 0.6 events per 100 patient-years for febuxostat and allopurinol, respectively. The differences were not statistically significant, and no causal relationship between these events and febuxostat use has been established. Identified risk factors in such patients included conditions resulting from atherosclerosis and/or history of myocardial infarction or congestive heart failure.

Prevention and treatment of hyperuricemia in patients at risk of tumor lysis syndrome (TLS)

Patients undergoing chemotherapy for hematological malignancies with moderate or high risk of TLS who are receiving febuxostat should be under cardiological monitoring when clinically indicated.

Drug allergy/hypersensitivity.

During post-marketing surveillance, rare cases of serious allergic/hypersensitivity reactions, including life-threatening Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute anaphylactic reactions/shock, have been reported. In most cases, such reactions occurred within the first month of febuxostat treatment. Several patients had a history of renal function impairment and/or hypersensitivity to allopurinol. Severe hypersensitivity reactions, including those with eosinophilia and systemic symptoms (DRESS syndrome), in some cases were associated with fever, hematological, renal, or hepatic dysfunction.

Patients should be informed about the signs and symptoms of hypersensitivity/allergy and monitored for the development of such reactions. If serious allergic/hypersensitivity reactions occur, including Stevens-Johnson syndrome, febuxostat must be discontinued immediately, as early discontinuation improves prognosis. Re-administration of febuxostat is contraindicated in patients who have previously experienced allergic/hypersensitivity reactions, including Stevens-Johnson syndrome, or acute anaphylactic reactions/shock.

Acute gout attack (flare-up).

Treatment with febuxostat should only be initiated after an acute gout attack has subsided. Febuxostat may provoke gout flares at the beginning of treatment due to changes in plasma uric acid levels caused by the mobilization of urate from tissue deposits. At the start of febuxostat therapy, it is recommended to co-administer NSAIDs or colchicine for at least 6 months to prevent gout flares.

If a gout flare occurs during febuxostat treatment, the drug should be continued. Appropriate individual therapy for the acute gout attack should be administered concomitantly. With prolonged use of febuxostat, the frequency and severity of gout attacks decrease.

Xanthine deposition.

In patients with accelerated urate production (e.g., due to malignancies and their treatment or in Lesch-Nyhan syndrome), a significant increase in absolute xanthine concentration in urine may occur, potentially leading to xanthine deposition in the urinary tract. This was not observed in the pivotal clinical trial of febuxostat in TLS. Due to limited experience, febuxostat is not indicated in patients with Lesch-Nyhan syndrome.

Mercaptopurine/azathioprine.

Febuxostat is not recommended for patients receiving mercaptopurine/azathioprine concurrently, as inhibition of xanthine oxidase by febuxostat may increase plasma concentrations of mercaptopurine/azathioprine, potentially leading to severe toxicity. No human interaction studies have been conducted.

If combination therapy cannot be avoided, a dose reduction of mercaptopurine/azathioprine is recommended. Based on modeling and simulation analysis of preclinical rat data, when febuxostat is co-administered, the dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose to avoid potential hematological effects (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be closely monitored, and the dose of mercaptopurine/azathioprine should be adjusted based on assessment of therapeutic response and potential toxic effects.

Patients who have undergone organ transplantation.

There is no experience with febuxostat use in this patient group; therefore, its use is not recommended.

Theophylline.

Single-dose co-administration of febuxostat 80 mg and theophylline 400 mg did not reveal any pharmacokinetic interaction. Febuxostat 80 mg may be administered concomitantly with theophylline without risk of increasing theophylline plasma concentration. Data on febuxostat 120 mg dose are not available.

Hepatic impairment.

During combined phase III clinical trials, mild changes in liver function parameters were observed in 5.0% of patients receiving febuxostat. Therefore, liver function tests should be performed before initiating febuxostat treatment and during therapy as clinically indicated.

Thyroid disorders.

Elevated TSH (> 5.5 mIU/mL) was observed in 5.5% of patients receiving long-term febuxostat treatment during long-term open-label extension studies. Therefore, febuxostat should be prescribed with caution in patients with thyroid dysfunction.

Important information on excipients.

The medicinal product contains lactose; therefore, it is contraindicated in patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

The medicinal product Efstath contains sodium; therefore, patients on a sodium-restricted diet should use it with caution.

Use during pregnancy or breastfeeding.

Pregnancy.

Limited experience with febuxostat use during pregnancy indicates no adverse effects on pregnancy outcome or fetal/neonatal health. Animal studies did not reveal any direct or indirect harmful effects on pregnancy, embryonal/fetal development, or parturition. The potential risk for humans is unknown. Due to the above, febuxostat is contraindicated during pregnancy.

Breastfeeding period.

It is unknown whether febuxostat passes into human breast milk. Animal studies have shown that febuxostat is excreted in milk and has a negative effect on the development of suckling newborns. The risk of drug transfer into breast milk cannot be excluded. Therefore, febuxostat is contraindicated during breastfeeding.

Fertility.

Fertility studies in animals at a dose of 48 mg/kg/day did not reveal dose-dependent adverse effects. The effect of febuxostat on human reproductive function is unknown.

Ability to influence reaction speed when operating vehicles or machinery.

Reports of somnolence, dizziness, paresthesia, and blurred vision have been reported during febuxostat use. Therefore, patients should exercise caution when driving vehicles or operating machinery until they are certain that these adverse reactions do not occur.

Dosage and Administration

Dosage

Gout.

The recommended dose is 80 mg once daily orally, independent of food intake. If serum uric acid concentration exceeds 6 mg/dL (357 µmol/L) after 2–4 weeks of treatment, increasing the febuxostat dose to 120 mg once daily should be considered. The drug's effect manifests rapidly, allowing repeat measurement of serum uric acid concentration after 2 weeks. The goal of therapy is to reduce and maintain serum uric acid concentration below 6 mg/dL (357 µmol/L).

The duration of gout attack prophylaxis should be at least 6 months.

Tumor Lysis Syndrome (TLS).

The recommended dose is 120 mg once daily, administered orally, independent of food intake. Treatment with the medicinal product Efastat should be initiated two days prior to the start of cytotoxic therapy and continued for at least 7 days; however, administration may be extended up to 9 days depending on the duration of chemotherapy and clinical assessment.

Renal Impairment.

Dose adjustment is not required in patients with mild or moderate renal impairment. The efficacy and safety of the drug have not been adequately studied in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Hepatic Impairment.

The efficacy and safety of febuxostat have not been studied in patients with severe hepatic impairment (Child–Pugh class C).

• Gout. In patients with mild hepatic impairment, the recommended dose is 80 mg. Experience with the drug in patients with moderate hepatic impairment is limited.
• Tumor Lysis Syndrome (TLS). Dose adjustment based on hepatic function is not required in patients with mild or moderate hepatic impairment.

Elderly Patients.

Dose adjustment is not required for this patient population.

Patients Who Have Undergone Organ Transplantation.

There is no experience with the use of febuxostat in this patient population; therefore, the use of the drug is not recommended.

Administration Method.

Administer orally, independent of food intake.

Pediatric Patients.

The use of febuxostat in patients under 18 years of age is not recommended due to lack of experience in pediatric populations.

Overdose.

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

Adverse Reactions

The most commonly reported adverse reactions in clinical trials (4072 patients receiving doses from 10 mg to 300 mg) and during post-marketing surveillance in patients with gout were exacerbations (attacks) of gout, liver function abnormalities, diarrhea, nausea, headache, rash, and edema. These reactions were mostly mild to moderate in severity. During post-marketing surveillance, there have been reports of rare cases of serious hypersensitivity reactions to febuxostat, some of which were accompanied by systemic reactions, as well as rare events of sudden cardiac death.

The table below lists adverse reactions observed following administration of febuxostat, classified as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), and rare (≥ 1/10,000 to < 1/1000). Frequency is based on data from clinical studies and post-marketing experience in patients with gout. Within each frequency category, adverse reactions are listed in order of decreasing severity.

Adverse reactions observed in Phase 3 combined randomized, long-term extension studies and during post-marketing surveillance in patients with gout

Table

System Organ Classes	Adverse reactions by frequency
Blood and lymphatic system disorders	Uncommon: pancytopenia, thrombocytopenia, agranulocytosis*, anemia****
Immune system disorders	Uncommon: hypersensitivity reactions, including anaphylactic reactions*.
Endocrine disorders	Uncommon: increased blood levels of thyroid-stimulating hormone, hypothyroidism****.
Eye disorders	Uncommon: blurred vision, retinal artery occlusion****.
Metabolism and nutrition disorders	Common***: exacerbation (attacks) of gout. Uncommon: diabetes mellitus, hyperlipidemia, decreased appetite, weight gain. Rare: weight loss, increased appetite, anorexia.
Psychiatric disorders	Uncommon: decreased libido, insomnia. Rare: nervousness, depressed mood****, sleep disorder****.
Nervous system and sensory disorders	Common: headache, dizziness. Uncommon: paresthesia, hemiparesis, somnolence, lethargy, altered taste perception, reduced sense of smell, hypesthesia. Rare: ageusia****, burning sensation****.
Ear and labyrinth disorders	Uncommon: tinnitus. Rare: vertigo****.
Cardiac disorders	Uncommon: atrial fibrillation, palpitations, ECG abnormalities, left bundle branch block (see section "Tumor lysis syndrome"), sinus tachycardia (see section "Tumor lysis syndrome"). Rare: sudden cardiac death*
Vascular disorders	Uncommon: arterial hypertension, flushing, hot flushes, hemorrhage (see section "Tumor lysis syndrome"). Rare: vascular insufficiency****.
Respiratory, thoracic and mediastinal disorders	Uncommon: dyspnea, bronchitis, upper respiratory tract infections, lower respiratory tract infections****, cough, rhinorrhea****. Rare: pneumonia****.
Gastrointestinal disorders	Common: diarrhea**, nausea. Uncommon: abdominal pain, bloating, gastroesophageal reflux disease, vomiting, dry mouth, dyspepsia, constipation, frequent defecation, flatulence, discomfort in stomach or intestine, oral mucosal ulcers, lip swelling, pancreatitis****. Rare: gastrointestinal perforation****, stomatitis****.
Hepatobiliary disorders	Common: hepatic function abnormalities**. Uncommon: cholelithiasis. Rare: hepatitis, jaundice*, liver injury, cholecystitis****.
Skin and subcutaneous tissue disorders	Common: rash (including rashes with lower frequency of occurrence). Uncommon: dermatitis, urticaria, pruritus, skin discoloration, skin injury, petechiae, maculopapular rash, macular rash, papular rash. Rare: toxic epidermal necrolysis*, Stevens-Johnson syndrome*, angioneurotic edema*, drug reaction with eosinophilia and systemic symptoms (DRESS)*, generalized (serious) rash*, erythema, exfoliative, follicular, vesicular, pustular, pruritic*, erythematous, measles-like rashes, alopecia, increased sweating.
Musculoskeletal and connective tissue disorders	Common: joint pain, muscle pain, limb pain. Uncommon: arthritis, musculoskeletal pain, muscle weakness, muscle cramps, muscle stiffness, bursitis. Rare: rhabdomyolysis*, joint stiffness, musculoskeletal stiffness.
Renal and urinary disorders	Uncommon: renal failure, urolithiasis, hematuria, polyuria, proteinuria. Rare: tubulointerstitial nephritis*, urgent need to urinate.
Reproductive system and breast disorders	Rare: erectile dysfunction.
General disorders	Common: edema. Uncommon: fatigue, chest pain, discomfort in chest. Rare: thirst.
Investigations (laboratory findings)	Uncommon: increased blood amylase levels, decreased platelet count, decreased blood leukocyte count, decreased blood lymphocyte count, increased blood creatinine levels, decreased hemoglobin levels in blood, increased blood urea levels, increased blood triglyceride levels, increased blood cholesterol levels, decreased hematocrit, increased blood lactate dehydrogenase (LDH) levels, increased blood potassium levels. Rare: increased blood glucose levels, prolonged activated partial thromboplastin time, decreased red blood cell count in blood, increased blood alkaline phosphatase levels, increased blood creatine phosphokinase levels*.

* Adverse reactions observed during post-marketing surveillance.

** Diarrhea and abnormal liver function test results requiring treatment, observed during clinical trials, occurred more frequently in patients receiving concomitant colchicine therapy.

*** Gout flares (attacks) usually occurred shortly after initiation of treatment and during the first months of treatment. The frequency of gout attacks decreased over time.

**** Adverse reactions identified in post-marketing safety studies.

Description of selected adverse reactions.

During post-marketing surveillance, rare cases of serious hypersensitivity reactions to febuxostat have been reported, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylactic reactions/shock. Stevens-Johnson syndrome and toxic epidermal necrolysis are characterized by progressive skin rash with bullous lesions of the skin or mucous membranes and irritation of the ocular mucosa. Hypersensitivity reactions to febuxostat may present with symptoms such as skin reactions including infiltrated maculopapular rash, generalized or exfoliative rash, skin lesions, facial swelling, fever, other disorders such as thrombocytopenia and eosinophilia, and involvement of individual organs or multiple organs (liver and kidneys, including tubulointerstitial nephritis).

Gout flares (attacks) usually occurred shortly after initiation of treatment and during the first months of treatment. The frequency of gout attacks decreased over time. Prophylaxis of acute gout attacks is recommended following initiation of febuxostat therapy.

Tumor lysis syndrome (TLS)

Summary of safety profile.

In the randomized, double-blind, active-controlled phase 3 FLORENCE (FLO-01) study comparing febuxostat with allopurinol in 346 patients undergoing chemotherapy for hematologic malignancies with moderate or high risk of TLS, adverse reactions were observed in only 22 (6.4%) patients (11 [6.4%] in each treatment group). Most adverse reactions were of mild or moderate severity.

Overall, during the FLORENCE study, no additional safety concerns were identified with febuxostat use in patients with gout, except for the three adverse reactions listed below (see table).

Cardiac disorders:

Uncommon: left bundle branch block, ventricular tachycardia.

Vascular disorders:

Uncommon: hemorrhage.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report any suspected adverse reactions and/or lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.

14 tablets in a blister; 2 blisters per carton.

Prescription status. Prescription only.

Marketing authorization holder. JSC "Pharmaceutical company "Darnitsya".

Address of the marketing authorization holder and location of its business operations.

13, Boryspilska Street, Kyiv, 02093, Ukraine.

Manufacturer. Generics S.A.

Location of manufacturer and address of its business operations.

18 Km Merendzonos Avenue, Pallini, 153 51, Greece.