Feblorica

APPROVED

Order of the Ministry of Health of Ukraine __________ №_____
Registration Certificate №_________________________

INSTRUCTION FOR MEDICAL USE
FEBLORIKA (FEBLORIKA)

Composition:

Active substance: febuxostat;

One film-coated tablet contains febuxostat 40 mg or 80 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;

Coating: Opadry white YS-1-7040.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical characteristics: film-coated tablets, round, biconvex, white to almost white, with a smooth surface.

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

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Uric acid is the end product of purine metabolism in humans and is formed in the cascade hypoxanthine → xanthine → uric acid. Both steps of the above transformations are catalyzed by xanthine oxidase (XO). Febuxostat is a 2-arylthiazole derivative that achieves its therapeutic effect of lowering serum uric acid levels by selectively inhibiting XO, with in vitro Ki values in the range of 0.6–10 nM. Febuxostat is a non-purine selective inhibitor of XO (NP-SIXO) that potently inhibits both oxidized and reduced forms of XO.

Effect on concentrations of uric acid and xanthine

In healthy volunteers, febuxostat caused a dose-dependent reduction in 24-hour mean serum uric acid concentrations and an increase in 24-hour mean serum xanthine concentrations. In addition, a decrease in total daily urinary excretion of uric acid and an increase in total daily urinary excretion of xanthine were observed. The percentage reduction in mean 24-hour serum uric acid concentration was approximately 55% after administration of an 80 mg daily dose.

Effect on cardiac repolarization

The effect of febuxostat on cardiac repolarization, assessed by QTc interval, was evaluated in healthy volunteers and patients with gout. At steady state, febuxostat at doses up to 300 mg daily (3.75 times the maximum recommended daily dose) did not demonstrate any effect on QTc interval.

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 in the range of 10 to 120 mg. Accumulation of febuxostat after administration of 10–240 mg doses every 24 hours was not observed. The predicted mean terminal elimination half-life (t1/2) of febuxostat was approximately 5–8 hours.

Absorption. Absorption of radiolabeled febuxostat after oral administration of the drug was at least 49% (based on total radioactivity excreted in urine). Cmax of febuxostat was observed between 1 and 1.5 hours after dosing. After multiple oral doses of 40 mg and 80 mg once daily, Cmax was approximately 1.6 ± 0.6 µg/mL (N=30) and 2.6 ± 1.7 µg/mL (N=227), respectively. Absolute bioavailability of febuxostat has not been studied. Following multiple doses of 80 mg once daily taken with a high-fat meal, Cmax decreased by 49% and AUC by 18%. However, this was not associated with clinically significant changes in the degree of reduction of plasma uric acid levels (with multiple 80 mg dosing). Therefore, the drug may be administered regardless of food intake.

Distribution. The predicted steady-state volume of distribution (Vss/F) for febuxostat was approximately 50 L (CV~40%). The extent of binding of febuxostat to plasma proteins (primarily albumin) is 99.2% and does not change with dose escalation from 40 mg to 80 mg.

Metabolism. Febuxostat is extensively metabolized via conjugation by uridine diphosphate-glucuronosyltransferase (UGT) enzymes, including UGT1A1, UGT1A3, UGT1A9, and UGT2B7, and via oxidation by cytochrome P450 (CYP) enzymes, including CYP1A2, 2C8, and 2C9, as well as by non-CYP enzymes. The relative contribution of each enzyme isoform to febuxostat metabolism is unknown. Oxidation of the isobutyl side chain leads to the formation of four pharmacologically active hydroxymetabolites, all of which are present in human plasma at much lower levels than febuxostat.

The main metabolites of febuxostat in vivo in urine and feces are febuxostat acylglucuronide metabolites (~35% of dose) and oxidative metabolites: 67M-1 (~10% of dose), 67M-2 (~11% of dose), and 67M-4 and a secondary metabolite from 67M-1 (~14% of dose).

Excretion. Febuxostat is eliminated via both hepatic and renal pathways. After oral administration of 14C-febuxostat 80 mg, approximately 49% was excreted in urine as unchanged febuxostat (3%), febuxostat acylglucuronide (30%), known oxidative metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to renal excretion, approximately 45% of the drug was excreted in feces as unchanged febuxostat (12%), febuxostat acylglucuronide (1%), known oxidative metabolites and their conjugates (25%), and other unknown metabolites (7%).

Post-marketing long-term studies

The CARES study was a non-inferiority cardiovascular safety trial comparing cardiovascular outcomes with febuxostat versus allopurinol in patients with gout and established cardiovascular disease, including history of myocardial infarction, hospitalization for unstable angina, coronary or cerebral revascularization procedure, stroke, hospitalization for transient ischemic attack, peripheral vascular disease, or diabetes with signs of microangiopathy or macroangiopathy.

The primary endpoint in the CARES study was time to first occurrence of major adverse cardiovascular events (MACE), including non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and unstable angina requiring urgent revascularization.

Endpoints (primary and secondary) were analyzed according to the intention-to-treat (ITT) principle, including all subjects who were randomized and received at least one dose of study drug during the double-blind phase.

In the analysis of individual MACE components, the rate of cardiovascular mortality was higher in the febuxostat group than in the allopurinol group (4.3% vs. 3.2% of patients). The rates of other MACE were similar between the febuxostat and allopurinol groups: non-fatal myocardial infarction (3.6% vs. 3.8% of patients), non-fatal stroke (2.3% vs. 2.3% of patients), and urgent revascularization for unstable angina (1.6% vs. 1.8% of patients).

The rate of all-cause mortality was also higher in the febuxostat group than in the allopurinol group (7.8% vs. 6.4% of patients), primarily driven by higher cardiovascular mortality in this group (see section "Special 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.

Special patient groups

Renal impairment

With multiple dosing of febuxostat 80 mg, no changes in Cmax of febuxostat were observed in patients with mild and moderate renal impairment compared to patients with normal renal function. Mean total AUC of febuxostat increased approximately 1.8-fold compared to patients with normal renal function. Cmax and AUC of active metabolites increased 2- and 4-fold, respectively. However, the percentage reduction in serum uric acid concentration in patients with renal impairment was comparable to that in patients with normal renal function (58% in the normal renal function group and 55% in the severe renal impairment group).

Based on population pharmacokinetic analysis after multiple doses of febuxostat 40 mg or 80 mg, mean CL/F values of febuxostat in patients with gout and mild (n=334), moderate (n=232), or severe (n=34) renal impairment decreased by 14%, 34%, and 48%, respectively, compared to patients with normal (n=89) renal function. Corresponding mean AUC values of febuxostat in patients with renal impairment were increased by 18%, 49%, and 96% after 40 mg dose and by 7%, 45%, and 98% after 80 mg dose, respectively, compared to patients with normal renal function.

The use of febuxostat in patients with end-stage renal disease on dialysis has not been studied.

Hepatic impairment

With multiple dosing of febuxostat 80 mg, no clinically significant changes in Cmax and AUC of febuxostat and its metabolites were observed 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 clinically significant changes in AUC of febuxostat and its metabolites were observed in elderly patients compared to young healthy volunteers.

Gender. During multiple oral administration of febuxostat, Cmax and AUC of febuxostat in females were 30% and 14% higher, respectively, than in males. However, body weight-adjusted Cmax and AUC were similar between the two groups; therefore, dose adjustment based on gender is not required.

Clinical characteristics.

Indications.

For 40 mg and 80 mg dosage

Treatment of chronic hyperuricemia in patients with gout who have had insufficient response to allopurinol or who are intolerant to allopurinol.

Contraindications.

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

Contraindicated in patients receiving treatment with azathioprine or mercaptopurine.

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. Studies on the interaction of febuxostat with medicinal products metabolized by xanthine oxidase have not been conducted.

Studies on febuxostat interaction during cytotoxic chemotherapy have not been performed.

Rosiglitazone/CYP2C8 substrates

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

Theophylline

An interaction study with febuxostat was conducted in healthy volunteers to evaluate the impact of xanthine oxidase inhibition on increased circulating levels of theophylline, 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 interactions or effects on the safety of theophylline. Therefore, febuxostat at a dose of 80 mg can be administered concomitantly with theophylline without special precautions.

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 the elimination of febuxostat. In healthy volunteers, co-administration of febuxostat with naproxen 250 mg twice daily resulted in enhanced exposure to febuxostat (Cmax increased 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 clinically significant increases 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 these medicinal products.

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

Concomitant use of febuxostat with warfarin does not require dose adjustment of warfarin. Administration of febuxostat 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 involving healthy volunteers receiving febuxostat once daily, an increase in AUC of desipramine (a CYP2D6 substrate) by 22% was observed, indicating weak inhibitory effect of febuxostat on CYP2D6 in vivo.

Thus, when febuxostat is used concomitantly with CYP2D6 substrates, there is no need to adjust their doses.

Antacids

Concomitant use 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, the AUC of febuxostat is not significantly altered. Therefore, febuxostat may be co-administered with antacid products.

Special precautions for use.

Gout attacks

At the beginning of febuxostat treatment, gout flares are commonly observed due to changes in serum uric acid levels.

To prevent gout flares during febuxostat therapy, concomitant prophylactic treatment with NSAIDs or colchicine is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Prophylactic therapy for flares may last up to 6 months. If a gout flare occurs during febuxostat treatment, febuxostat should not be discontinued.

Cardiovascular disorders

In the post-marketing CARES study involving patients with gout who had a history of serious cardiovascular disease, cerebrovascular disease, or diabetes with micro- and/or macrovascular complications, a higher rate (134 [1.5 per 100 patient-years]) of cardiovascular death was observed in patients receiving febuxostat compared to those receiving allopurinol (100 [1.1 per 100 patient-years]) [hazard ratio: 1.34, 95% CI: 1.03; 1.73]. The primary endpoint of major adverse cardiovascular events (MACE) [composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and unstable angina requiring urgent coronary revascularization] was similar for febuxostat and allopurinol [hazard ratio: 1.03, 95% CI: 0.89; 1.21]. Febuxostat was similar to allopurinol in terms of non-fatal myocardial infarction, non-fatal stroke, and unstable angina requiring urgent coronary revascularization.

In the initial phase of three randomized controlled trials involving patients with gout, a higher incidence of cardiovascular thromboembolic events (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) was observed in patients treated with febuxostat [1.09 per 100 PY (95% CI 0.44–2.24)] compared to allopurinol [0.60 per 100 PY (95% CI 0.16–1.53)].

There have also been reports of a potential increased risk of heart failure in patients with pre-existing cardiovascular disease and/or cardiovascular risk factors. Febuxostat treatment is not recommended in patients with ischemic heart disease or congestive heart failure. Signs and symptoms of myocardial infarction, stroke, and heart failure should be closely monitored.

When deciding whether to initiate or continue febuxostat treatment, the risks and benefits of febuxostat should be carefully considered. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if such symptoms occur.

Febuxostat should only be used in patients who have an inadequate response to or intolerance of allopurinol, or in whom allopurinol treatment is contraindicated.

Drug allergy/hypersensitivity

Serious skin and hypersensitivity reactions, including Stevens-Johnson syndrome, DRESS syndrome, and toxic epidermal necrolysis, as well as acute anaphylactic reactions/shock, have been reported in patients taking febuxostat.

In most cases, such reactions occurred within the first month of febuxostat treatment. Many of these patients had a history of renal dysfunction and/or hypersensitivity to allopurinol. Severe hypersensitivity reactions, including those associated with eosinophilia and systemic symptoms, were sometimes accompanied by fever, hematological, renal, or hepatic dysfunction.

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

Xanthine deposition

In patients with accelerated urate production (e.g., due to malignant neoplasms and their treatment or in Lesch-Nyhan syndrome), a significant increase in absolute urinary xanthine concentration may occur, leading to xanthine deposition in the urinary tract. Due to limited experience with febuxostat in such conditions, the drug is not recommended for these patients.

Patients who have undergone organ transplantation

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

Patients with thyroid disorders

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

Hepatic reactions

During the post-marketing period, cases of fatal and non-fatal hepatic failure have been reported in patients taking febuxostat, although the reports lack sufficient information to establish a probable causal relationship. In randomized controlled trials, elevations in transaminases to more than three times the upper limit of normal (ULN) were observed (aspartate aminotransferase [AST]: 2%, 2%; alanine aminotransferase [ALT]: 3%, 2% with febuxostat and allopurinol, respectively). No dose-response relationship for these transaminase elevations was observed.

Liver function tests (serum ALT, AST, alkaline phosphatase, and total bilirubin) should be assessed before initiating febuxostat therapy.

Liver function should be promptly evaluated in patients who develop symptoms suggestive of liver injury. These symptoms include fatigue, anorexia, upper abdominal discomfort, dark urine, or jaundice. In such clinical context, if liver test abnormalities are detected (ALT more than three times ULN), febuxostat should be discontinued, further investigations conducted, and the probable cause of the reaction determined. Re-initiation of febuxostat is not recommended in these patients unless an alternative explanation for the liver test abnormalities is established.

Patients with serum ALT levels more than three times the reference range and serum total bilirubin more than twice the reference range, without an alternative cause, are at risk of severe drug-induced liver injury. Therefore, febuxostat should not be re-administered to such patients. Caution should be exercised when administering febuxostat to patients with lower elevations in ALT or bilirubin and with a probable alternative cause for the reaction.

Lactose

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

Sodium-containing compounds

The medicinal product contains sodium croscarmellose. Caution should be exercised when administering the drug to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy

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

Breastfeeding

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 the drug passing 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 the speed of reactions when driving or operating machinery.

There have been reports of somnolence, dizziness, paraesthesia, and visual disturbances during febuxostat treatment. Therefore, patients taking febuxostat should exercise caution when driving or operating machinery until they are certain that these adverse reactions do not affect them.

Method of administration and dosage.

Dosage

Gout

The recommended dose is 40 mg or 80 mg once daily, taken orally, independent of food intake. The recommended initial dose is 40 mg once daily.

If serum uric acid concentration exceeds 6 mg/dL (357 µmol/L) after 2 weeks of treatment, increasing the febuxostat dose to 80 mg once daily should be considered.

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

Renal impairment

Dose adjustment is not required in patients with mild or moderate renal impairment. The recommended dose in patients with severe renal impairment is 40 mg.

Hepatic impairment

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

No dose adjustment is required in patients with mild hepatic impairment. Experience with the use of the drug in patients with moderate hepatic impairment is limited.

Elderly patients

Dose adjustment is not required for this patient group.

Method of administration

Administer orally, independent of food intake.

Children

Febuxostat is not recommended for patients under 18 years of age due to lack of experience with its use in pediatric populations.

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 patients receiving doses ranging from 10 mg to 300 mg) and during post-marketing surveillance in patients with gout were gout flares, liver function abnormalities, diarrhea, nausea, headache, rash, and edema. These adverse 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 symptoms, as well as rare occurrences of sudden cardiac death.

The table below lists adverse reactions observed with febuxostat use in patients, categorized as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), and rare (≥ 1/10000 to < 1/1000). Frequency estimates are based on clinical trials 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 long-term extension studies and during post-marketing surveillance in patients with gout

Infections and infestations	Uncommon Herpes zoster, cellulitis, sinusitis, tinea pedis
Blood and lymphatic system disorders	Uncommon Pancytopenia, thrombocytopenia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, splenomegaly, agranulocytosis*, eosinophilia*
Immune system disorders	Uncommon Anaphylactic reactions*, hypersensitivity to the drug*
Endocrine disorders	Uncommon Increased thyroid-stimulating hormone levels
Eye disorders	Uncommon Blurred vision
Metabolism and nutrition disorders	Common*** Exacerbation (attacks) of gout Uncommon decreased/increased appetite, cow's milk intolerance, dehydration, diabetes mellitus, dyslipidemia, gout, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, decreased/increased body weight Uncommon Weight loss, increased appetite, anorexia
Psychiatric disorders	Uncommon Decreased libido, insomnia Rare Agitation, anxiety, depression, irritability, nervousness, panic attacks, personality change, psychotic behavior including aggression*
Nervous system disorders	Common Headache Uncommon Dizziness, paraesthesia, hemiparesis, somnolence, altered taste sensation, hypoaesthesia, reduced sense of smell Rare Loss of balance, cerebrovascular disorder, acute polyradiculitis, hemiparesis, lacunar infarction, lethargy, migraine, transient ischaemic attack, tremor
Ear and labyrinth disorders	Rare Tinnitus
Cardiac disorders	Uncommon Angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormalities, palpitations, sinus bradycardia, tachycardia Rare Myocardial infarction (some fatal)*, heart failure*
Vascular disorders	Uncommon Arterial hypertension/hypotension, flushing, hot flushes
Respiratory, thoracic and mediastinal disorders	Uncommon: dyspnoea, bronchitis, respiratory congestion, sneezing, throat irritation, upper respiratory tract infections, cough, nasal dryness. Rare: epistaxis, hypersecretion of paranasal sinuses, laryngeal oedema, hoarseness
Gastrointestinal disorders	Common Diarrhoea**, nausea Uncommon Abdominal pain, bloating, gastroesophageal reflux disease, vomiting, dry mouth, dyspepsia, constipation, frequent defecation, flatulence, discomfort in stomach or intestine, gastric ulcer, gastritis Rare Pancreatitis, mouth ulcers
Hepatobiliary disorders	Common Liver function abnormalities** Uncommon Cholelithiasis, cholecystitis, steatosis Rare Hepatitis, jaundice*, liver failure (sometimes fatal)*
Skin and subcutaneous tissue disorders	Common Rash (including rashes with lower frequency, see below) Uncommon Dermatitis, urticaria, pruritus, skin discoloration, skin injury, petechiae, maculopapular rash, papular rash Rare Stevens-Johnson syndrome*, DRESS and toxic epidermal necrolysis*, angioedema*, drug reaction with eosinophilia and systemic symptoms (DRESS)*, generalized rash (serious)*, erythema*, exfoliative rash, follicular rash, vesicular rash, pustular rash, pruritic rash*, erythematous rash, morbilliform rash, alopecia, increased sweating, hair color change, abnormal hair growth
Musculoskeletal and connective tissue disorders	Uncommon Joint pain, arthritis, myalgia, musculoskeletal pain, muscle weakness, muscle cramps, muscle stiffness, bursitis, gouty tophus Rare Rhabdomyolysis*, joint stiffness, musculoskeletal stiffness
Renal and urinary disorders	Uncommon Renal failure*, urolithiasis, haematuria, polyuria, proteinuria*, urinary tract and kidney infections Rare Tubulointerstitial nephritis*, persistent urge to urinate
Reproductive system and breast disorders	Uncommon Erectile dysfunction, breast pain, gynaecomastia, mastitis
General disorders and administration site conditions	Common Oedema Uncommon Increased fatigue, chest pain/discomfort, malaise, gait disturbance, influenza-like symptoms, neoplasm (tumour), pain Rare Thirst
Investigations	Uncommon Elevated creatinine, decreased bicarbonate, elevated sodium, EEG abnormalities, elevated cholesterol, elevated triglycerides, elevated amylase, elevated potassium, elevated TSH, elevated platelet count, decreased haematocrit, decreased haemoglobin, decreased red blood cell count, elevated blood urea nitrogen, elevated blood urea nitrogen/creatinine ratio, elevated LDH, elevated PSA Rare Elevated glucose, prolonged activated partial thromboplastin time, elevated mean corpuscular volume, elevated alkaline phosphatase, elevated blood creatine phosphokinase, increased/decreased diuresis, decreased lymphocyte count, decreased neutrophil count, increased/decreased white blood cell count, coagulation test abnormalities, elevated low-density lipoprotein (LDL), prolonged prothrombin time, presence of casts in urine, positive urine test for leukocytes and protein

* Adverse reactions observed during post-marketing surveillance.

** Diarrhea and abnormal liver function test results requiring therapy, observed in phase 3 studies, occurred more frequently in patients receiving concomitant colchicine therapy.

*** See section "Pharmacodynamics" for the frequency of gout flares observed in phase 3 individual randomized controlled trials.

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

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C. Keep out of the reach of children.

Incompatibilities.

Not known.

Packaging. 10 tablets in a blister; 3 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Mankind Pharma Limited, Unit-II.

Manufacturer's address and place of business.

Village Kishanpura, P.O. Jamniwala, Tehsil Paonta Sahib, District Sirmaur 173025, Himachal Pradesh, India.