Podagrat

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PODOGRAT (PODAGRAT)

Composition:

Active substance: febuxostat;

One film-coated tablet contains febuxostat hemihydrate equivalent to 80 mg or 120 mg of febuxostat;

Excipients: lactose monohydrate; microcrystalline cellulose, hydroxypropylcellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, polyvinyl alcohol, talc, titanium dioxide (E 171), polyethylene glycol, methacrylic acid copolymer (type A), yellow iron oxide (E 172), sodium bicarbonate.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: capsule-shaped, film-coated tablets, from pale yellow to yellow, with embossing "80" or "120" on one side and smooth on the other.

Pharmacotherapeutic group.

Medicinal products for the treatment of gout. Medicinal products inhibiting uric acid production. 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 whose therapeutic effect is related to reducing serum uric acid concentration by selectively inhibiting xanthine oxidase. Febuxostat is a potent and selective non-purine xanthine oxidase inhibitor (NP-SIXO), with an in vitro inhibition constant (Ki) of less than 1 nanomole. 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 inhibit other enzymes involved in purine or pyrimidine metabolism, such as guanidine deaminase, hypoxanthine-guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase, or purine nucleoside phosphorylase.

Clinical Efficacy and Safety

Gout

The efficacy of febuxostat was demonstrated in three pivotal phase 3 studies (two pivotal APEX and FACT studies and the additional CONFIRMS study), which included patients with hyperuricemia and gout. In each of these pivotal studies, febuxostat demonstrated superior ability to reduce serum uric acid concentration and maintain it at target levels compared to allopurinol.

APEX Study: A study evaluating the efficacy of febuxostat with allopurinol and placebo control (Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat, APEX), lasting 28 weeks.

The APEX study showed statistically significant superiority in both febuxostat treatment groups (80 mg once daily and 120 mg once daily) compared to the allopurinol treatment group (standard dose of 300 mg/100 mg) in reducing serum uric acid concentration below 6 mg/dL (357 µmol/L).

FACT Study: A study evaluating the efficacy of febuxostat with allopurinol control (Febuxostat Allopurinol Controlled Trial, FACT), lasting 52 weeks.

The FACT study showed statistically significant superiority in both febuxostat treatment groups (80 mg once daily and 120 mg once daily) compared to the allopurinol treatment group (standard dose of 300 mg) in reducing and maintaining serum uric acid concentration below 6 mg/dL (357 µmol/L).

CONFIRMS Study: The CONFIRMS study, lasting 26 weeks, was conducted to evaluate the safety and efficacy of febuxostat at doses of 40 mg and 80 mg compared to allopurinol at doses of 300 mg and 200 mg in patients with gout and hyperuricemia.

A prospectively planned analysis of data from patients with gout and impaired renal function in the CONFIRMS study showed that febuxostat was statistically significantly more effective in reducing serum uric acid levels to < 6.0 mg/dL compared to allopurinol 300 mg/200 mg in patients with gout and mild to moderate renal impairment (65% of the studied patients).

Post-marketing Long-term Studies

The CARES study compared cardiovascular outcomes with febuxostat versus allopurinol in patients with gout and a history of major cardiovascular diseases, including myocardial infarction, hospitalization for unstable angina, coronary or cerebral revascularization procedures, stroke, hospitalization for transient ischemic attack, peripheral vascular disease, or diabetes with signs of microangiopathy or macroangiopathy.

The rate of cardiovascular mortality was higher in the febuxostat group than in the allopurinol group.

The all-cause mortality rate was also higher in the febuxostat group than in the allopurinol group, primarily due to higher cardiovascular mortality in this group (see section "Special Warnings and Precautions for Use").

Rates of hospitalization for heart failure, hospitalization for non-ischemic arrhythmia, venous thromboembolic events, and hospitalization for transient ischemic attacks were comparable between febuxostat and allopurinol.

Pharmacokinetics.

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

A population pharmacokinetic/pharmacodynamic analysis was performed using data from patients with hyperuricemia and gout who received febuxostat at doses of 40–240 mg once daily. Overall, the obtained pharmacokinetic parameters of febuxostat were consistent with those in healthy individuals, indicating that healthy individuals are representative for assessing the pharmacokinetics/pharmacodynamics of the drug in patients with gout.

Absorption

Febuxostat is rapidly (tmax [time to reach maximum concentration] 1.0–1.5 hours) and well absorbed (at least 84%). 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 studied.

With repeated oral administration at 80 mg once daily or single administration at 120 mg 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 degree of serum uric acid reduction (with repeated 80 mg dosing). Therefore, febuxostat can be administered regardless of food intake.

Distribution

The predicted steady-state volume of distribution (Vss/F) for febuxostat ranges from 29 L to 75 L after oral administration of 10–300 mg. The extent of binding of febuxostat to plasma proteins (primarily albumin) is 99.2% and remains stable across the concentration range achieved with 80 mg or 120 mg doses. Protein binding of active metabolites of febuxostat ranges from 82% to 91%.

Metabolism

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

Excretion

Febuxostat is eliminated via both hepatic and renal pathways. After oral administration of 14C-febuxostat at a dose of 80 mg, approximately 49% was excreted in urine as unchanged febuxostat (3%), the acyl glucuronide of the active substance (30%), its known oxidized metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to urinary excretion, approximately 45% of the dose was excreted in feces as unchanged febuxostat (12%), the acyl glucuronide of the active substance (1%), its known oxidized metabolites and their conjugates (25%), and other unknown metabolites (7%).

Renal Impairment

With repeated administration of febuxostat at 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 by 2 and 4 times, respectively. However, dose adjustment is not required in patients with mild or moderate renal impairment.

Hepatic Impairment

With repeated administration of febuxostat at 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 individuals with normal liver function. The use of the drug in patients with severe hepatic impairment (Child-Pugh class C) has not been studied.

Age

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

Gender

With repeated oral administration of febuxostat, Cmax and AUC of febuxostat in women were 24% and 12% higher, respectively, than in men. However, body weight-adjusted Cmax and AUC were similar between the two groups. Dose adjustment based on gender is not required.

Clinical characteristics.

Indications.

Prophrag 80 mg and 120 mg:

Prophrag is indicated for the treatment of chronic hyperuricemia in conditions associated with urate crystal deposition (including presence of tophi and/or current or past history of gouty arthritis).

Prophrag 120 mg:

Prophrag is indicated for the prevention and treatment of hyperuricemia in adult patients receiving chemotherapy for hematological 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 listed in the section "Composition".

Interaction with other medicinal products and other forms of interaction.

Mercaptopurine/azathioprine

Due to its mechanism of action, febuxostat inhibits xanthine oxidase; therefore, concomitant use with these medicinal products is not recommended. Inhibition of xanthine oxidase by febuxostat may lead to increased plasma concentrations of both drugs, potentially causing myelotoxic reactions.

If co-administration with febuxostat is necessary, the dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose (see section "Special warnings and precautions for use").

The adequacy of this proposed dose adjustment, based on modeling and simulation analysis of preclinical data in rats, has been confirmed by results of a clinical drug interaction study in healthy volunteers who received azathioprine 100 mg alone and a reduced dose of azathioprine (25 mg) in combination with febuxostat (40 mg or 120 mg).

There are no data on the safety of febuxostat use during cytotoxic chemotherapy.

Drug interaction studies between febuxostat and other cytotoxic chemotherapeutic agents have not been conducted.

In the pivotal study, patients with TLS receiving multiple chemotherapy regimens, including monoclonal antibodies, were administered febuxostat 120 mg once daily. However, drug–drug and drug–disease interactions were not specifically investigated in this study. 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 febuxostat 120 mg once daily and a single oral dose of rosiglitazone 4 mg did not affect the pharmacokinetics of rosiglitazone or its metabolite N-desmethylrosiglitazone, demonstrating that febuxostat is not an inhibitor of CYP2C8 in vivo. Therefore, co-administration of febuxostat with rosiglitazone or other CYP2C8 substrates does not require dose adjustment of these medicinal products.

Theophylline

A drug interaction study in healthy volunteers was conducted to evaluate the potential effect of xanthine oxidase inhibition on increasing circulating levels of theophylline, as observed with other xanthine oxidase inhibitors. Results showed that concomitant administration of febuxostat 80 mg once daily and a single 400 mg dose of theophylline resulted in no pharmacokinetic interaction or impact on theophylline safety. Thus, febuxostat at a dose of 80 mg can be used concomitantly with theophylline without special precautions. Data on concomitant use of febuxostat 120 mg are not available.

Naproxen and other inhibitors of glucuronidation

Febuxostat metabolism depends on the activity of UDP-glucuronosyltransferase enzymes. Medicinal products that inhibit glucuronidation, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and probenecid, may theoretically affect febuxostat elimination. In healthy volunteers, concomitant administration of febuxostat and naproxen 250 mg twice daily resulted in increased febuxostat exposure (Cmax increased by 28%, AUC by 41%, t1/2 by 26%). However, in clinical trials, the use of naproxen or other NSAIDs/COX-2 inhibitors was not associated with any clinically significant increase in adverse reactions.

Febuxostat may be co-administered with naproxen without dose adjustment.

Inducers of glucuronidation

Potent inducers of UDP-glucuronosyltransferase enzyme may enhance febuxostat metabolism and reduce its efficacy. In patients taking potent inducers of glucuronidation, plasma uric acid levels should be monitored 1–2 weeks after initiation of treatment. Conversely, upon discontinuation of the glucuronidation inducer, plasma levels of febuxostat may increase.

Colchicine/indomethacin/hydrochlorothiazide/warfarin

Febuxostat may be co-administered with colchicine or indomethacin without dose adjustment of febuxostat or the concomitantly administered active substance.

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

Concomitant administration of febuxostat with warfarin does not require a change in warfarin dosage. Administration of febuxostat (80 mg or 120 mg once daily) with warfarin in healthy volunteers did not affect the pharmacokinetics of warfarin. Concomitant use with febuxostat also had no effect on 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 involving healthy volunteers receiving febuxostat 120 mg once daily, an average increase in AUC of desipramine (a CYP2D6 substrate) by 22% was observed, indicating weak inhibitory effect of febuxostat on CYP2D6 in vivo. Therefore, concomitant administration of febuxostat with other CYP2D6 substrates does not require dose adjustment of these medicinal products.

Antacids

Concomitant oral administration with antacids containing magnesium hydroxide and aluminum hydroxide results in delayed absorption of febuxostat (by approximately 1 hour) and a 32% reduction in Cmax; however, no significant change in AUC was observed. Therefore, febuxostat may be administered with antacid agents.

Special precautions for use.

Cardiovascular diseases

In patients with serious cardiovascular diseases (e.g., myocardial infarction, stroke, or unstable angina), a higher number of life-threatening cardiovascular events were observed with febuxostat compared to allopurinol during drug development and in one post-marketing study (CARES).

However, a subsequent post-marketing study (FAST) showed that febuxostat was non-inferior to allopurinol regarding the frequency of both life-threatening and non-life-threatening cardiovascular events.

Treatment of this patient group should be carried out with caution and their condition should be monitored regularly.

In the APEX and FACT studies, a numerical increase in cardiovascular events (Anti-Platelet Trialists’ Collaboration (APTC) — defined as composite endpoints including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) was observed in the overall febuxostat group compared to the allopurinol group (1.3 vs. 0.3 events per 100 patient-years), unlike in the CONFIRMS study (see section "Pharmacodynamics"). The frequency of cardiovascular events (APTC) based on pooled data from phase 3 studies (APEX, FACT, and CONFIRMS) was 0.7 vs. 0.6 events per 100 patient-years. In long-term extension studies, investigator-reported cardiovascular events by APTC criteria occurred at a rate of 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 was established. Identified risk factors in these patients included a history of atherosclerosis and/or myocardial infarction, or congestive heart failure.

In the post-marketing CARES study, the incidence of MACE (major adverse cardiovascular events) was similar in the febuxostat and allopurinol groups (HR 1.03; 95% CI 0.89–1.21), but a higher rate of cardiovascular mortality was observed (4.3% vs. 3.2% of patients; HR 1.34; 95% CI 1.03–1.73).

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

Patients receiving chemotherapy for hematological malignancies with moderate or high risk of TLS who are treated with the medicinal product Podagrat should, when clinically indicated, be under cardiologist supervision.

Drug allergy/hypersensitivity

During post-marketing surveillance, rare cases of serious allergic reactions/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. Renal function impairment and/or prior hypersensitivity to allopurinol were observed in several patients. Severe hypersensitivity reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), in some cases were associated with fever, hematological abnormalities, and changes in kidney or liver function.

Patients should be informed about the signs and symptoms of hypersensitivity/allergic reactions and should be closely monitored for the development of such symptoms (see section "Adverse reactions"). Febuxostat must be discontinued immediately if serious allergic reactions/hypersensitivity reactions, including Stevens-Johnson syndrome, occur, as early discontinuation improves prognosis. Re-administration of febuxostat is contraindicated in patients who have experienced allergic reactions/hypersensitivity reactions, including Stevens-Johnson syndrome, or acute anaphylactic reaction/shock.

Gout flares

Treatment with febuxostat should only be initiated after complete resolution of an acute gout attack. Initiation of treatment may provoke gout flares due to changes in serum uric acid levels resulting from mobilization of urate deposits from tissues. At the beginning of febuxostat treatment, concomitant administration of NSAIDs or colchicine for at least 6 months is recommended to prevent gout flares.

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

Xanthine deposition

In patients with markedly increased 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, which in rare cases may lead to xanthine deposition in the urinary tract. Due to lack of treatment experience, febuxostat is not recommended for these patient groups. This was not observed in the pivotal clinical study of febuxostat in TLS. Due to limited experience, febuxostat is not recommended for patients with Lesch-Nyhan syndrome.

mercaptopurine/azathioprine

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

If combination therapy cannot be avoided, a reduction in the dose 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 therapeutic response and potential toxic effects.

Patients who have undergone organ transplantation

As there is no experience with febuxostat use in patients who have undergone organ transplantation, administration of the medicinal product is not indicated in this patient population.

Theophylline

Concomitant administration of a single 80 mg dose of febuxostat and a single 400 mg dose of theophylline did not show any pharmacokinetic interactions (see section "Interaction with other medicinal products and other forms of interaction"). Febuxostat at a dose of 80 mg can be administered concomitantly with theophylline without risk of increased plasma theophylline concentrations. Data on the use of febuxostat at a dose of 120 mg are not available.

Hepatic impairment

Pooled data from phase 3 clinical trials showed minor abnormalities in liver function parameters (5.0%) in patients receiving febuxostat. Therefore, liver function tests should be performed before initiating febuxostat therapy and periodically during treatment as clinically indicated.

Thyroid function

During long-term open-label extension studies, increased TSH levels (> 5.5 mU/mL) were observed in 5.5% of patients receiving long-term febuxostat treatment. Therefore, febuxostat should be used with caution in patients with thyroid dysfunction.

Lactose

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

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., it is essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

Very limited experience with febuxostat use during pregnancy indicates no adverse effects on pregnancy course or fetal/neonatal health. Animal studies did not show any direct or indirect harmful effects of the drug on pregnancy, embryonic/fetal development, or parturition. The potential risk for humans is unknown. Febuxostat should not be used during pregnancy.

Breastfeeding

It is unknown whether febuxostat passes into human breast milk. Animal studies have shown that the active substance is excreted in milk and has a negative effect on the development of suckling offspring. The risk to breastfed infants cannot be excluded. Febuxostat should not be used during breastfeeding.

Fertility

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

Ability to influence reaction rate when driving or operating machinery.

Cases of somnolence, dizziness, paresthesia, and blurred vision have been reported during febuxostat use. Therefore, patients taking the medicinal product Podagrat should exercise caution when driving or operating machinery until they are certain that the drug does not cause the aforementioned adverse reactions.

Method of Administration and Dosage.

Dosage

Gout. The recommended dose of febuxostat is 80 mg once daily, administered orally, regardless of food intake. If serum uric acid concentration exceeds 6 mg/dL (357 µmol/L) after 2–4 weeks of treatment, dose escalation to 120 mg once daily should be considered.

The effect of febuxostat develops rapidly, allowing serum uric acid levels to be re-assessed after 2 weeks. The goal of treatment is to reduce and maintain serum uric acid concentration below 6 mg/dL (357 µmol/L).

The recommended duration of prophylaxis of gout attacks is at least 6 months.

Tumor Lysis Syndrome. The recommended dose of febuxostat is 120 mg once daily, administered orally, regardless of food intake.

Treatment with the medicinal product Podagrat should be initiated two days prior to the start of cytotoxic therapy and continued for at least 7 days. However, the duration of therapy may be extended up to 9 days depending on the duration of chemotherapy and clinical assessment.

Elderly Patients

Dose adjustment in elderly patients is not required.

Renal Impairment

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

Hepatic Impairment

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

Gout. The recommended dose in patients with mild hepatic impairment is 80 mg. Experience with the use of the medicinal product in patients with moderate hepatic impairment is limited.

Tumor Lysis Syndrome. In clinical trials (Phase III), only patients with severe hepatic impairment were excluded. For patients included in the studies, dose adjustment based on hepatic function status was not required.

Method of Administration

For oral use.

The medicinal product Podagrat is administered orally, regardless of food intake.

Children

The safety and efficacy of febuxostat in children under 18 years of age have not been established. Data on use are lacking.

Overdose.

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

Adverse Reactions

Summary of safety profile

The most commonly reported adverse reactions in clinical trials (4072 participants who received at least one dose of the drug ranging from 10 mg to 300 mg) and in post-marketing safety studies (FAST study: 3001 participants who received at least one dose of the drug ranging from 80 mg to 120 mg), as well as from post-marketing experience, include gout flares, liver function test abnormalities, diarrhea, nausea, headache, dizziness, dyspnea, rash, pruritus, arthralgia, myalgia, limb pain, edema, and fatigue. These adverse reactions were mostly mild or moderate in severity. Post-marketing experience has revealed rare cases of serious hypersensitivity reactions to febuxostat (some of which were associated with systemic reactions) and rare events of sudden cardiac death.

The table below lists adverse reactions observed in patients treated with febuxostat, classified as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000).

Frequency estimates are based on data from clinical trials and post-marketing experience in patients with gout.

Within each category, adverse reactions are listed in descending order of severity.

Adverse reactions observed from pooled data of long-term extension Phase 3 trials, post-marketing safety studies, and post-marketing experience:

*Adverse reactions observed during post-marketing experience with the medicinal product.

**Non-infectious diarrhea and abnormal liver function test results occurring during therapy, as observed in clinical studies, were more frequent in patients receiving concomitant colchicine therapy.

***See section "Pharmacodynamics" for frequency of gout flares (attacks).

#Adverse reactions observed in post-authorization safety studies.

Description of selected adverse reactions

During post-marketing experience with the medicinal product, 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 blister formation (possible skin detachment) or mucosal involvement and eye mucosa irritation. Hypersensitivity reactions to febuxostat may present with symptoms such as skin reactions characterized by sudden infiltrated maculopapular rashes, generalized or exfoliative rashes, skin lesions, facial swelling, fever, blood test abnormalities such as thrombocytopenia and eosinophilia, and involvement of individual 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 therapy. Subsequently, the frequency of gout attacks decreased over time. Prophylaxis of acute gout attacks is recommended.

Tumor Lysis Syndrome (TLS)

Overview of the drug safety profile

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

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

Cardiac disorders:

Uncommon: left bundle branch block, sinus tachycardia.

Vascular disorders:

Uncommon: hemorrhage.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 4 years.

Storage conditions. No special storage conditions required. Keep out of reach and sight of children.

Packaging. 14 film-coated tablets in a blister; 2, 4, or 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Rontis Hellas Medical and Pharmaceutical Products S.A.

Manufacturer's address and location of operations.

Larissa Industrial Area, P.O. Box 3012, Larissa, 41 500, Greece.