Febuxostat Sandoz

Pale yellow to yellow, film-coated, capsule shaped tablets, engraved with "80" on one side and plain on the other.
Each film coated tablet contains febuxostat hemihydrate 82.28 mg equivalent to febuxostat 80 mg. Also contains lactose monohydrate 76.5 mg.
Excipients/Inactive Ingredients: Lactose Monohydrate, Microcrystalline Cellulose (E460), Hydroxypropylcellulose (E463), Croscarmellose Sodium, Colloidal Anhydrous Silica (E551), Magnesium Stearate (E470b), Coating material.

Pharmacotherapeutic group: Antigout preparations, preparations inhibiting uric acid production. ATC code: M04AA03.
Pharmacology: Pharmacodynamics: Mechanism of action: Uric acid is the end product of purine metabolism in humans and is generated in the cascade of hypoxanthine-xanthine-uric acid. Both steps in the previously mentioned transformations are catalysed by xanthine oxidase (XO). Febuxostat is a 2-arylthiazole derivative that achieves its therapeutic effect of decreasing serum uric acid by selectively inhibiting XO. Febuxostat is a potent, non-purine selective inhibitor of XO (NP-SIXO) with an in vitro inhibition Ki value less than one nanomolar. Febuxostat has been shown to potently inhibit both the oxidised and reduced forms of XO. At therapeutic concentrations febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism, namely, guanine deaminase, hypoxanthine guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase or purine nucleoside phosphorylase.
Clinical efficacy and safety: The efficacy of febuxostat was demonstrated in three phase 3 pivotal studies (the two pivotal APEX and FACT studies, and the additional CONFIRMS study, described as follows) that were conducted in 4,101 patients with hyperuricaemia and gout. In each phase 3 pivotal study, febuxostat demonstrated superior ability to lower and maintain serum uric acid levels compared to allopurinol. The primary efficacy endpoint in the APEX and FACT studies was the proportion of patients whose last 3 monthly serum uric acid levels were <6.0 mg/dl (357 μmol/l). In the additional phase 3 CONFIRMS study, for which results became available after the marketing authorisation for febuxostat was first issued, the primary efficacy endpoint was the proportion of patients whose serum urate level was <6.0 mg/dl at the final visit. No patients with organ transplant have been included in these studies (see Precautions).
Post marketing long term studies: CARES Study was a multicenter, randomized, double-blind, non inferiority trial comparing CV outcomes with febuxostat versus allopurinol in patients with gout and a history of major CV disease including MI, hospitalization for unstable angina, coronary or cerebral revascularization procedure, stroke, hospitalized transient ischemic attack, peripheral vascular disease, or diabetes mellitus with evidence of microvascular or macrovascular disease. To achieve sUA less than 6 mg/dL, the dose of febuxostat was titrated from 40 mg up to 80 mg (regardless of renal function) and the dose of allopurinol was titrated in 100 mg increments from 300 to 600 mg in patients with normal renal function and mild renal impairment and from 200 to 400 mg in patients with moderate renal impairment. The primary endpoint in CARES was the time to first occurrence of MACE, a composite of non-fatal MI, non-fatal stroke, CV death and unstable angina with urgent coronary revascularization.
The endpoints (primary and secondary) were analysed according to the intention-to-treat (ITT) analysis including all subjects who were randomized and received at least one dose of double-blind study medication. Overall 56.6% of patients discontinued trial treatment prematurely and 45% of patients did not complete all trial visits. In total, 6,190 patients were followed for a median of 32 months and the median duration of exposure was 728 days for patients in febuxostat group (n 3098) and 719 days in allopurinol group (n 3092). The primary MACE endpoint occurred at similar rates in the febuxostat and allopurinol treatment groups (10.8% vs. 10.4% of patients, respectively; hazard ratio [HR] 1.03; two-sided repeated 95% confidence interval [CI] 0.87-1.23). In the analysis of the individual components of MACE, the rate of CV deaths was higher with febuxostat than allopurinol (4.3% vs. 3.2% of patients; HR 1.34; 95% CI 1.03-1.73). The rates of the 13 other MACE events were similar in the febuxostat and allopurinol groups, i.e. non-fatal MI (3.6% vs. 3.8% of patients; HR 0.93; 95% CI 0.72-1.21), non-fatal stroke (2.3% vs. 2.3% of patients; HR 1.01; 95% CI 0.73-1.41) and urgent revascularization due to unstable angina (1.6% vs. 1.8% of patients; HR 0.86; 95% CI 0.59-1.26). The rate of all-cause mortality was also higher with febuxostat than allopurinol (7.8% vs. 6.4% of patients; HR 1.22; 95% CI 1.01-1.47), which was mainly driven by the higher rate of CV deaths in that group (see Precautions). Rates of adjudicated hospitalization for heart failure, hospital admissions for arrhythmias not associated with ischemia, venous thromboembolic events and hospitalization for transient ischemic attacks were comparable for febuxostat and allopurinol.
FAST study was a prospective, randomised, open-label, blinded endpoint study comparing the CV safety profile of febuxostat versus allopurinol in patients with chronic hyperuricaemia (in conditions where urate deposition had already occurred) and CV risk factors (i.e. patients 60 years or older and with at least one other CV risk factor). Eligible patients received allopurinol treatment prior to randomization, and dose adjustments were required when needed, according to clinical judgement, EULAR recommendations and the approved posology. At the end of the allopurinol lead-in phase, patients with a sUA level of <0.36 mmol/L (<6 mg/dL) or receiving the maximum tolerated dose or the maximum licensed dose of allopurinol were randomised in a 1:1 ratio to receive either febuxostat or allopurinol treatment. The primary endpoint of the study FAST was the time to the first occurrence of any event included in the Antiplatelet Trialists' Collaborative (APTC) composite endpoint, which included: i) hospitalisation for non-fatal MI/biomarker positive acute coronary syndrome (ACS); ii) non-fatal stroke; iii) death due to a CV event. The primary analysis was based on the on-treatment (OT) approach.
Overall, 6,128 patients were randomized, 3063 to febuxostat and 3065 to allopurinol. In the primary OT analysis, febuxostat was non-inferior to allopurinol in the incidence of the primary endpoint, which occurred in 172 patients (1.72/100 patient years) on febuxostat compared to 241 patients (2.05/100 patient years) on allopurinol, with an adjusted HR 0.85 (95% CI: 0.70, 1.03), p<0.001. The OT analysis for the primary endpoint in the subgroup of patients with a history of MI, stroke or ACS showed no significant difference between treatment groups: there were 65 (9.5%) patients with events in the febuxostat group and 83 (11.8%) patients with events in the allopurinol group; adjusted HR 1.02 (95% CI: 0.74-1.42); p=0.202.
Treatment with febuxostat was not associated with an increase in CV death or all-cause death, overall or in the subgroup of patients with a baseline history of MI, stroke or ACS. Overall, there were fewer deaths in the febuxostat group (62 CV deaths and 108 all-cause deaths), than in the allopurinol group (82 CV deaths and 174 all-cause deaths).
There was a greater reduction in uric acid levels on febuxostat treatment compared to allopurinol treatment.
Pharmacokinetics: In healthy subjects, maximum plasma concentrations (C_max) and area under the plasma concentration time curve (AUC) of febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg to 120 mg. For doses between 120 mg and 300 mg, a greater than dose proportional increase in AUC is observed for febuxostat. There is no appreciable accumulation when doses of 10 mg to 240 mg are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t_½) of approximately 5 to 8 hours.
Population pharmacokinetic/pharmacodynamic analyses were conducted in 211 patients with hyperuricaemia and gout, treated with febuxostat 40-240 mg QD. In general, febuxostat pharmacokinetic parameters estimated by these analyses are consistent with those obtained from healthy subjects, indicating that healthy subjects are representative for pharmacokinetic/pharmacodynamic assessment in the patient population with gout.
Absorption: Febuxostat is rapidly (t_max of 1.0-1.5 h) and well absorbed (at least 84%). After single or multiple oral 80 mg and 120 mg once daily doses, C_max is approximately 2.8-3.2 μg/ml, and 5.0-5.3 μg/ml, respectively. Absolute bioavailability of the febuxostat tablet formulation has not been studied.
Following multiple oral 80 mg once daily doses or a single 120 mg dose with a high fat meal, there was a 49% and 38% decrease in C_max and a 18% and 16% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed where tested (80 mg multiple dose). Thus, febuxostat may be taken without regard to food.
Distribution: The apparent steady state volume of distribution (V_ss/F) of febuxostat ranges from 29 to 75 l after oral doses of 10-300 mg. The plasma protein binding of febuxostat is approximately 99.2%, (primarily to albumin), and is constant over the concentration range achieved with 80 mg and 120 mg doses. Plasma protein binding of the active metabolites ranges from about 82% to 91%.
Biotransformation: Febuxostat is extensively metabolised by conjugation via uridine diphosphate glucuronosyltransferase (UDPGT) enzyme system and oxidation via the cytochrome P450 (CYP) system. Four pharmacologically active hydroxyl metabolites have been identified, of which three occur in plasma of humans. In vitro studies with human liver microsomes showed that those oxidative metabolites were formed primarily by CYP1A1, CYP1A2, CYP2C8 or CYP2C9 and febuxostat glucuronide was formed mainly by UGT 1A1, 1A8, and 1A9.
Elimination: Febuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg oral dose of ¹⁴C-labeled febuxostat, approximately 49% of the dose was recovered in the urine as unchanged febuxostat (3%), the acyl glucuronide of the active substance (30%), its known oxidative metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to the urinary excretion, approximately 45% of the dose was recovered in the faeces as the unchanged febuxostat (12%), the acyl glucuronide of the active substance (1%), its known oxidative metabolites and their conjugates (25%), and other unknown metabolites (7%).
Renal impairment: Following multiple doses of 80 mg of febuxostat in patients with mild, moderate or severe renal impairment, the C_max of febuxostat did not change, relative to subjects with normal renal function. The mean total AUC of febuxostat increased by approximately 1.8-fold from 7.5 μg⋅h/ml in the normal renal function group to 13.2 μg.h/ml in the severe renal dysfunction group. The C_max and AUC of active metabolites increased up to 2- and 4-fold, respectively. However, no dose adjustment is necessary in patients with mild or moderate renal impairment.
Hepatic impairment: Following multiple doses of 80 mg of febuxostat in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, the C_max and AUC of febuxostat and its metabolites did not change significantly compared to subjects with normal hepatic function. No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C).
Age: There were no significant changes observed in AUC of febuxostat or its metabolites following multiple oral doses of febuxostat in elderly as compared to younger healthy subjects.
Gender: Following multiple oral doses of febuxostat, the C_max and AUC were 24% and 12% higher in females than in males, respectively. However, weight-corrected C_max and AUC were similar between the genders. No dose adjustment is needed based on gender.
Toxicology: Preclinical safety data: Effects in non-clinical studies were generally observed at exposures in excess of the maximum human exposure.
Pharmacokinetic modelling and simulation of rat data suggests that, when co-administered with febuxostat, the clinical dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose in order to avoid possible haematological effects (see Precautions and Interactions).
Carcinogenesis, mutagenesis, impairment of fertility: In male rats, a statistically significant increase in urinary bladder tumours (transitional cell papilloma and carcinoma) was found only in association with xanthine calculi in the high dose group, at approximately 11 times human exposure. There was no significant increase in any other tumour type in either male or female mice or rats. These findings are considered a consequence of species specific purine metabolism and urine composition and of no relevance to clinical use.
A standard battery of test for genotoxicity did not reveal any biologically relevant genotoxic effects for febuxostat.
Febuxostat at oral doses up to 48 mg/kg/day was found to have no effect on fertility and reproductive performance of male and female rats.
There was no evidence of impaired fertility, teratogenic effects, or harm to the foetus due to febuxostat. There was high dose maternal toxicity accompanied by a reduction in weaning index and reduced development of offspring in rats at approximately 4.3 times human exposure. Teratology studies, performed in pregnant rats at approximately 4.3 times and pregnant rabbits at approximately 13 times human exposure did not reveal any teratogenic effects.

Febuxostat is indicated for the treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred (including a history, or presence of, tophus and/or gouty arthritis).
Febuxostat is indicated for the prevention and treatment of hyperuricaemia in adult patients undergoing chemotherapy for haematologic malignancies at intermediate to high risk of Tumor Lysis Syndrome (TLS).
Febuxostat is indicated in adults.

Posology: Gout: The recommended oral dose of febuxostat is 80 mg once daily without regard to food. If serum uric acid is >6 mg/dl (357 μmol/l) after 2-4 weeks, febuxostat 120 mg once daily may be considered.
Febuxostat works sufficiently quickly to allow retesting of the serum uric acid after 2 weeks. The therapeutic target is to decrease and maintain serum uric acid below 6 mg/dl (357 μmol/l). Gout flare prophylaxis of at least 6 months is recommended (see Precautions).
Tumor Lysis Syndrome: The recommended oral dose of Febuxostat is 120 mg once daily without regard to food.
Febuxostat should be started two days before the beginning of cytotoxic therapy and continued for a minimum of 7 days; however treatment may be prolonged up to 9 days according to chemotherapy duration as per clinical judgment.
Elderly: No dose adjustment is required in the elderly (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: The efficacy and safety have not been fully evaluated in patients with severe renal impairment (creatinine clearance <30 ml/min, see Pharmacology: Pharmacokinetics under Actions). No dose adjustment is necessary in patients with mild or moderate renal impairment.
Hepatic impairment: The efficacy and safety of febuxostat has not been studied in patients with severe hepatic impairment (Child Pugh Class C).
The recommended dose in patients with mild hepatic impairment is 80 mg. Limited information is available in patients with moderate hepatic impairment.
Paediatric population: The safety and the efficacy of febuxostat in children aged below the age of 18 years have not been established. No data are available.
Method of administration: Oral use.
Febuxostat should be taken by mouth and can be taken with or without food.

Patients with an overdose should be managed by symptomatic and supportive care.

Hypersensitivity to the active substance or to any of the excipients (see also Adverse Reactions).

Cardiovascular disorders: In patients with pre-existing major cardiovascular diseases (e.g. myocardial infarction, stroke or unstable angina), during the development of the product and in one post registrational study (CARES), higher number of fatal cardiovascular events were observed with febuxostat when compared to allopurinol.
However, in a subsequent post registrational study (FAST), febuxostat was not inferior to allopurinol in the incidence of both fatal and non-fatal cardiovascular events.
Treatment of this patient group should be exercised cautiously and they should be monitored regularly. For further details on cardiovascular safety of febuxostat refer to Adverse Reactions and Pharmacology: Pharmacodynamics under Actions.
Medicinal product allergy/hypersensitivity: Rare reports of serious allergic/hypersensitivity reactions, including life-threatening Stevens-Johnson syndrome, toxic epidermal necrolysis and acute anaphylactic reaction/shock, have been collected in the post-marketing experience. In most cases, these reactions occurred during the first month of therapy with febuxostat. Some, but not all of these patients reported renal impairment and/or previous hypersensitivity to allopurinol. Severe hypersensitivity reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS) were associated with fever, haematological, renal or hepatic involvement in some cases.
Patients should be advised of the signs and symptoms and monitored closely for symptoms of allergic/hypersensitivity reactions (see Adverse Reactions). Febuxostat treatment should be immediately stopped if serious allergic/hypersensitivity reactions, including Stevens-Johnson syndrome, occur since early withdrawal is associated with a better prognosis. If patient has developed allergic/hypersensitivity reactions including Stevens-Johnson syndrome and acute anaphylactic reaction/shock, febuxostat must not be re-started in this patient at any time.
Acute gouty attacks (gout flare): Febuxostat treatment should not be started until an acute attack of gout has completely subsided. Gout flares may occur during initiation of treatment due to changing serum uric acid levels resulting in mobilisation of urate from tissue deposits (see Adverse Reactions and Pharmacology: Pharmacodynamics under Actions). At treatment initiation with febuxostat flare prophylaxis for at least 6 months with an NSAID or colchicine is recommended (see Dosage & Administration).
If a gout flare occurs during febuxostat treatment, it should not be discontinued. The gout flare should be managed concurrently as appropriate for the individual patient. Continuous treatment with febuxostat decreases frequency and intensity of gout flares.
Xanthine deposition: In patients in whom the rate of urate formation is greatly increased (e.g. malignant disease and its treatment, Lesch-Nyhan syndrome) the absolute concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract.
As there has been no experience with febuxostat, its use in patients with Lesch-Nyhan syndrome is not recommended.
Mercaptopurine/azathioprine: Febuxostat use is not recommended in patients concomitantly treated with mercaptopurine/azathioprine as inhibition of xanthine oxidase by febuxostat may cause increased plasma concentrations of mercaptopurine/azathioprine that could result in severe toxicity. Where the combination cannot be avoided, a reduction of the dose of mercaptopurine/azathioprine to the 20% or less of the previously prescribed dose is recommended in order to avoid possible haematological effects (see Interactions and Pharmacology: Toxicology: Preclinical safety data under Actions).
The patients should be closely monitored and the dose of mercaptopurine/azathioprine should be subsequently adjusted based on the evaluation of the therapeutic response and the onset of eventual toxic effects.
Organ transplant recipients: As there has been no experience in organ transplant recipients, the use of febuxostat in such patients is not recommended (see Pharmacology: Pharmacodynamics under Actions).
Theophylline: Co-administration of febuxostat 80 mg and theophylline 400 mg single dose in healthy subjects showed absence of any pharmacokinetic interaction (see Interactions). Febuxostat 80 mg can be used in patients concomitantly treated with theophylline without risk of increasing theophylline plasma levels. No data is available for febuxostat 120 mg.
Liver disorders: During the combined phase 3 clinical studies, mild liver function test abnormalities were observed in patients treated with febuxostat (5.0%). Liver function test is recommended prior to the initiation of therapy with febuxostat and periodically thereafter based on clinical judgment (see Pharmacology: Pharmacodynamics under Actions).
Thyroid disorders: Increased TSH values (>5.5 μIU/ml) were observed in patients on long-term treatment with febuxostat (5.5%) in the long term open label extension studies. Caution is required when febuxostat is used in patients with alteration of thyroid function (see Pharmacology: Pharmacodynamics under Actions).
Lactose-intolerant patients: This 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.
Effects on ability to drive and use machines: Somnolence, dizziness, paraesthesia and blurred vision have been reported with the use of febuxostat. Patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that febuxostat does not adversely affect performance.

Pregnancy: Data on a very limited number of exposed pregnancies have not indicated any adverse effects of febuxostat on pregnancy or on the health of the foetus/new born child. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development or parturition (see Pharmacology: Toxicology: Preclinical safety data). The potential risk for human is unknown. Febuxostat should not be used during pregnancy.
Breastfeeding: It is unknown whether febuxostat is excreted in human breast milk. Animal studies have shown excretion of this active substance in breast milk and an impaired development of suckling pups. A risk to a suckling infant cannot be excluded. Febuxostat should not be used while breastfeeding.
Fertility: In animals, reproduction studies up to 48 mg/kg/day showed no dose-dependent adverse effects on fertility (see Pharmacology: Toxicology: Preclinical safety data). The effect of febuxostat on human fertility is unknown.

Summary of the safety profile: The most commonly reported adverse reactions in clinical trials (4,072 subjects treated at least with a dose from 10 mg to 300 mg) and post-authorisation safety study (FAST study: 3001 subjects treated at least with a dose from 80 mg to 120 mg) and post-marketing experience are gout flares, liver function abnormalities, diarrhoea, nausea, headache, dizziness, dyspnoea, rash, pruritus, arthralgia, myalgia, pain in extremity, oedema and fatigue. These adverse reactions were mostly mild or moderate in severity. Rare serious hypersensitivity reactions to febuxostat, some of which were associated to systemic symptoms, and rare events of sudden cardiac death have occurred in the post-marketing experience.
List of adverse reactions: Common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to <1/1,000) adverse reactions occurring in patients treated with febuxostat are listed as follows.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Adverse reactions in combined phase 3, long-term extension studies post-authorisation safety studies and post-marketing experience: Blood and lymphatic system disorders: Rare: Pancytopenia, thrombocytopenia, agranulocytosis*, anaemia^#.
Immune system disorders: Rare: Anaphylactic reaction*, hypersensitivity*.
Endocrine disorders: Uncommon: Blood thyroid stimulating hormone increased, hypothyroidism^#.
Metabolism and nutrition disorders: Common***: Gout flares.
Uncommon: Diabetes mellitus, hyperlipidaemia, decrease appetite, weight increase.
Rare: Weight decrease, increase appetite, anorexia.
Psychiatric disorders: Uncommon: Libido decreased, insomnia.
Rare: Nervousness, depressed mood^#, sleep disorder^#.
Nervous system disorders: Common: Headache, dizziness.
Uncommon: Paraesthesia, hemiparesis, somnolence, lethargy^#, altered taste, hypoaesthesia, hyposmia.
Rare: Ageusia^#, burning sensation^#.
Eye disorders: Uncommon: Blurred vision.
Rare: Retinal artery occlusion^#.
Ear and labyrinth disorders: Uncommon: Tinnitus.
Rare: Vertigo^#.
Cardiac disorders: Uncommon: Atrial fibrillation, palpitations, ECG abnormal, arrhythmia^#.
Rare: Sudden cardiac death*.
Vascular disorders: Uncommon: Hypertension, flushing, hot flush.
Rare: Circulatory collapse^#.
Respiratory, thoracic and mediastinal disorders: Common: Dyspnoea.
Uncommon: Bronchitis, upper respiratory tract infection, lower respiratory tract infection#, cough, rhinorrhea^#.
Rare: Pneumonia^#.
Gastrointestinal disorders: Common: Diarrhoea**, nausea.
Uncommon: Abdominal pain, abdominal pain upper^#, abdominal distension, gastrooesophageal reflux disease, vomiting, dry mouth, dyspepsia, constipation, frequent stools, flatulence, gastrointestinal discomfort, lip swelling^#, pancreatitis and mouth ulceration.
Rare: Gastrointestinal perforation^#, stomatitis^#.
Hepatobiliary disorders: Common: Liver function abnormalities**.
Uncommon: Cholelithiasis.
Rare: Hepatitis, jaundice*, liver injury*, cholecystitis^#.
Skin and subcutaneous tissue disorders: Common: Rash (including various types of rash reported with lower frequencies, see as follows), pruritus.
Uncommon: Dermatitis, urticaria, skin discolouration, skin lesion, petechiae, rash macular, rash maculopapular, rash popular, hyperhidrosis, alopecia, eczema^#, erythema, night sweats^#, psoriasis#, rash pruritic^#*.
Rare: Toxic epidermal necrolysis*, Stevens-Johnson syndrome*, angioedema*, drug reaction with eosinophilia and systemic symptoms*, generalised rash (serious)*, exfoliative rash, rash follicular, rash vesicular, rash pustular, rash erythematous, rash morbilliform.
Musculoskeletal and connective tissue disorders: Common: Arthralgia, myalgia, pain in extremity^#.
Uncommon: Arthritis, musculoskeletal pain, muscle weakness, muscle spasm, muscle tightness, bursitis, joint swelling^#, back pain^#, musculoskeletal stiffness^#, joint stiffness.
Rare: Rhabdomyolysis*, rotator cuff syndrome^#, polymyalgia rheumatica^#.
Renal and urinary disorders: Uncommon: Renal failure, nephrolithiasis, haematuria, pollakiuria, proteinuria, micturition urgency, urinary tract infection^#.
Rare: Tubulointerstitial nephritis*.
Reproductive system and breast disorder: Uncommon: Erectile dysfunction.
General disorders and administration site conditions: Common: Oedema, fatigue.
Uncommon: Chest pain, chest discomfort, pain^#, malaise^#.
Rare: Thirst, feeling hot^#.
Investigations: Uncommon: Blood amylase increase, platelet count decrease, WBC decrease, lymphocyte count decrease, blood creatine increase, blood creatinine increase, haemoglobin decrease, blood urea increase, blood triglycerides increase, blood cholesterol increase, haematocritic decrease, blood lactate dehydrogenase increased, blood potassium increase, INR increased^#.
Rare: Blood glucose increased, activated partial thromboplastin time prolonged, red blood cell count decrease, blood alkaline phosphatase increase, blood creatine phosphokinase increase*.
Injury, poisoning and procedural complications: Uncommon: Contusion^#.
* Adverse reactions coming from post-marketing experience.
** Treatment-emergent non-infective diarrhoea and abnormal liver function tests in the combined Phase 3 studies are more frequent in patients concomitantly treated with colchicine.
*** See Pharmacology: Pharmacodynamics under Actions for incidences of gout flares in the individual Phase 3 randomised controlled studies.
# Adverse reactions coming from post-authorisation safety studies.
Description of selected adverse reactions: Rare serious hypersensitivity reactions to febuxostat, including Stevens-Johnson syndrome, toxic epidermal necrolysis and anaphylactic reaction/shock, have occurred in the post-marketing experience. Stevens-Johnson syndrome and toxic epidermal necrolysis are characterised by progressive skin rashes associated with blisters or mucosal lesions and eye irritation. Hypersensitivity reactions to febuxostat can be associated to the following symptoms: skin reactions characterised by infiltrated maculopapular eruption, generalised or exfoliative rashes, but also skin lesions, facial oedema, fever, haematologic abnormalities such as thrombocytopenia and eosinophilia, and single or multiple organ involvement (liver and kidney including tubulointerstitial nephritis) (see Precautions).
Gout flares were commonly observed soon after the start of treatment and during the first months. Thereafter, the frequency of gout flare decreases in a time-dependent manner. Gout flare prophylaxis is recommended (see Dosage & Administration and Precautions).
Cardiac disorders: Uncommon: Left bundle branch block, sinus tachycardia.
Vascular disorders: Uncommon: Haemorrhage.

Mercaptopurine/azathioprine: On the basis of the mechanism of action of febuxostat on XO inhibition concomitant use is not recommended. Inhibition of XO by febuxostat may cause increased plasma concentrations of these active substances leading to myelotoxicity.
In case of concomitant administration with febuxostat, the dose of mercaptopurine/ azathioprine should be reduced to the 20% or less of the previously prescribed dose (see Precautions and Pharmacology: Toxicology: Preclinical safety data).
The adequacy of the proposed dose adjustment, which was based on a modelling and simulation analysis from preclinical data in rats, was confirmed by the results of a clinical drug-drug interaction study in healthy volunteers, receiving azathioprine 100 mg alone and a reduced dose of azathioprine (25 mg) in combination with febuxostat (40 or 120 mg).
Interaction studies of febuxostat with other cytotoxic chemotherapy have not been conducted.
No data is available regarding the safety of febuxostat during cytotoxic therapy.
Rosiglitazone/CYP2C8 substrates: Febuxostat was shown to be a weak inhibitor of CYP2C8 in vitro. In a study in healthy subjects, co-administration of 120 mg febuxostat QD with a single 4 mg oral dose of rosiglitazone had no effect on the pharmacokinetics of rosiglitazone and its metabolite N-desmethyl rosiglitazone, indicating that febuxostat is not a CYP2C8 enzyme inhibitor in vivo. Thus, co-administration of febuxostat with rosiglitazone or other CYP2C8 substrates is not expected to require any dose adjustment for those compounds.
Theophylline: An interaction study in healthy subjects has been performed with febuxostat to evaluate whether the inhibition of XO may cause an increase in the theophylline circulating levels as reported with other XO inhibitors. The results of the study showed that the co-administration of febuxostat 80 mg QD with theophylline 400 mg single dose has no effect on the pharmacokinetics or safety of theophylline. Therefore no special caution is advised when febuxostat 80 mg and theophylline are given concomitantly. No data is available for febuxostat 120 mg.
Naproxen and other inhibitors of glucuronidation: Febuxostat metabolism depends on uridine glucuronosyl transferase (UGT) enzymes. Medicinal products that inhibit glucuronidation, such as NSAIDs and probenecid, could in theory affect the elimination of febuxostat. In healthy subjects concomitant use of febuxostat and naproxen 250 mg twice daily was associated with an increase in febuxostat exposure (C_max 28%, AUC 41% and t_½ 26%). In clinical studies the use of naproxen or other NSAIDs/Cox-2 inhibitors was not related to any clinically significant increase in adverse events.
Febuxostat can be co-administered with naproxen with no dose adjustment of febuxostat or naproxen being necessary.
Inducers of glucuronidation: Potent inducers of UGT enzymes might possibly lead to increased metabolism and decreased efficacy of febuxostat. Monitoring of serum uric acid is therefore recommended 1-2 weeks after start of treatment with a potent inducer of glucuronidation. Conversely, cessation of treatment of an inducer might lead to increased plasma levels of febuxostat.
Colchicine/indomethacin/hydrochlorothiazide/warfarin: Febuxostat can be co-administered with colchicine or indomethacin with no dose adjustment of febuxostat or the co-administered active substance being necessary.
No dose adjustment is necessary for febuxostat when administered with hydrochlorothiazide.
No dose adjustment is necessary for warfarin when administered with febuxostat. Administration of febuxostat (80 mg or 120 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. INR and Factor VII activity were also not affected by the co-administration of febuxostat.
Desipramine/CYP2D6 substrates: Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro. In a study in healthy subjects, 120 mg febuxostat QD resulted in a mean 22% increase in AUC of desipramine, a CYP2D6 substrate indicating a potential weak inhibitory effect of febuxostat on the CYP2D6 enzyme in vivo. Thus, co-administration of febuxostat with other CYP2D6 substrates is not expected to require any dose adjustment for those compounds.
Antacids: Concomitant ingestion of an antacid containing magnesium hydroxide and aluminium hydroxide has been shown to delay absorption of febuxostat (approximately 1 hour) and to cause a 32% decrease in C_max, but no significant change in AUC was observed. Therefore, febuxostat may be taken without regard to antacid use.

Incompatibilities: Not applicable.
Special precautions for disposal and other handling: No special requirements for disposal.

Do not store above 30°C.

Hyperuricemia & Gout Preparations

M04AA03 - febuxostat ; Belongs to the class of preparations inhibiting uric acid production. Used in the treatment of gout.

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