Febuxostat Mylan

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 

 

Febuxostat Mylan 80 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each tablet contains 80 mg of febuxostat.  

 

Excipient with known effect 

Each tablet contains 236.0 mg of lactose. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Film-coated tablet. 

 

A yellow, capsule shaped, biconvex tablet approximately 16 x 7 mm, debossed with M on one 

side of the tablet and FX3 on the other side. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred 

(including a history, or presence of, tophus and/or gouty arthritis). Febuxostat Mylan is 

indicated in adults. 

 

4.2 Posology and method of administration 

 

Posology 

 

The recommended oral dose of Febuxostat Mylan 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 Mylan 120 mg once 

daily may be considered. 

 

Febuxostat Mylan 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 section 4.4). 

 

Elderly 

No dose adjustment is required in the elderly (see section 5.2). 

 

Renal impairment 

The efficacy and safety have not been fully evaluated in patients with severe renal impairment 

(creatinine clearance <30 mL/min, see section 5.2). 

 

No dose adjustment is necessary in patients with mild or moderate renal impairment. 

 



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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 Mylan should be taken by mouth and can be taken with or without food. 

 

4.3 Contraindications 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see also 

section 4.8). 

 

4.4 Special warnings and precautions for use 

 

Cardio-vascular disorders 

 

Treatment with febuxostat in patients with pre-existing major cardiovascular diseases (e.g. 
myocardial infarction, stroke or unstable angina) should be avoided, unless no other therapy 

options are appropriate. 

A numerical greater incidence of investigator-reported cardiovascular APTC events (defined 

endpoints from the Anti-Platelet Trialists’ Collaboration (APTC) including cardiovascular 

death, non-fatal myocardial infarction, non-fatal stroke) was observed in the febuxostat total 

group compared to the allopurinol group in the APEX and FACT studies (1.3 vs. 0.3 events per 

100 Patient Years (PYs)), but not in the CONFIRMS study (see section 5.1 for detailed 

characteristics of the studies). The incidence of investigator-reported cardiovascular APTC 

events in the combined Phase 3 studies (APEX, FACT and CONFIRMS studies) was 0.7 vs. 0.6 

events per 100 PYs. In the long-term extension studies the incidences of investigator-reported 

APTC events were 1.2 and 0.6 events per 100 PYs for febuxostat and allopurinol, respectively. 

No statistically significant differences were found and no causal relationship with febuxostat 

was established. Identified risk factors among these patients were a medical history of 

atherosclerotic disease and/or myocardial infarction, or of congestive heart failure. 

In the post registrational CARES trial (see section 5.1 for detailed characteristics of the study) 

the rate of MACE events was similar in febuxostat versus allopurinol treated patients (HR 1.03; 

95% CI 0.87-1.23), but a higher rate of cardiovascular deaths was observed (4.3% vs. 3.2% of 

patients; HR 1.34; 95% CI 1.03-1.73). 

 

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. 

 



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Patients should be advised of the signs and symptoms and monitored closely for symptoms of 

allergic/hypersensitivity reactions (see section 4.8). 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 mobilization of urate from tissue deposits (see section 4.8 and 5.1). At 

treatment initiation with febuxostat flare prophylaxis for at least 6 months with an NSAID or 

colchicine is recommended (see section 4.2). 

 

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 these populations 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. No interaction studies have been performed in humans.  

Where the combination cannot be avoided, a reduction of the dose of 

mercaptopurine/azathioprine is recommended. Based on modelling and simulation analysis of 

data from a pre-clinical study in rats, when coadministered with febuxostat, the dose of 

mercaptopurine/azathioprine should be reduced to the 20 % or less of the previously prescribed 

dose in order to avoid possible haematological effects (see section 4.5 and 5.3). 

 

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 section 5.1). 

 

Theophylline 

 

Co-administration of febuxostat 80 mg and theophylline 400 mg single dose in healthy subjects 

showed absence of any pharmacokinetic interaction (see section 4.5). 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 



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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 section 5.1). 

 

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 section 5.1). 

 

Excipients 

 

Febuxostat Mylan tablets contain lactose. Patients with rare hereditary problems of galactose 

intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this 

medicine. 

 

Febuxostat Mylan tablets contains less than 1 mmol sodium (23 mg) per tablet, that is to say 

essentially ‘sodium-free’. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

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 drugs leading to toxicity. Drug interaction studies of febuxostat with drugs (except 

theophylline) that are metabolized by XO have not been performed in humans. 

Modelling and simulation analysis of data from a pre-clinical study in rats indicates that, in case 

of concomitant administration with febuxostat, the dose of mercaptopurine/azathioprine should 

be reduced to 20% or less of the previously prescribed dose (see section 4.4 and 5.3) 

 

Drug interaction studies of febuxostat with other cytotoxic chemotherapy have not been 

conducted. No data is available regarding the safety of febuxostat during other cytotoxic 

therapy. 

 

Rosiglitazone/CYP2C8 substrates 

 

Febuxostat was shown to be a weak inhibitor of CYP2C8 in vitro. In a study in healthy subjects, 

coadministration 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. 



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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 (Cmax 

28%, AUC 41% and t1/2 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/indometacin/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 Cmax, but no significant change in AUC was observed. Therefore, 

febuxostat may be taken without regard to antacid use. 

 

4.6 Fertility, pregnancy and lactation 

 

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 



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indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal 

development or parturition (see section 5.3). The potential risk for human is unknown. 

Febuxostat should not be used during pregnancy. 

 

Breast-feeding 

 

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 breast-

feeding. 

 

Fertility 

 

In animals, reproduction studies up to 48 mg/kg/day showed no dose-dependent adverse effects 

on fertility (see section 5.3). The effect of febuxostat on human fertility is unknown. 

 

4.7 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. 

 

4.8 Undesirable effects 

 

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-marketing experience are gout flares, liver 

function abnormalities, diarrhoea, nausea, headache, rash and oedema. 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. 

 

Tabulated 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 below. 

 

Within each frequency grouping, adverse reactions are presented in order of decreasing 

seriousness. 

 

Table 1: Adverse reactions in combined phase 3, long-term extension studies and post-

marketing experience 

Blood and lymphatic system 
disorders 

Rare 
Pancytopenia, thrombocytopenia, agranulocytosis* 

Immune system disorders Rare 
Anaphylactic reaction*, drug hypersensitivity* 

Endocrine disorders Uncommon 
Blood thyroid stimulating hormone increased 

Eye disorders Rare 
Blurred vision 

Metabolism and nutrition 
disorders 

Common*** 
Gout flares 

Uncommon 



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Diabetes mellitus, hyperlipidemia, decrease appetite, weight 

increase 
Rare 

Weight decrease, increase appetite, anorexia 
Psychiatric disorders Uncommon 

Libido decreased, insomnia 

Rare 
Nervousness 

Nervous system disorders Common 
Headache 

Uncommon 

Dizziness, paraesthesia, hemiparesis, somnolence, altered taste, 

hypoaesthesia, hyposmia 
Ear and labyrinth disorders Rare 

Tinnitus 
Cardiac disorders Uncommon 

Atrial fibrillation, palpitations, ECG abnormal 

Rare 

Sudden cardiac death* 

Vascular disorders Uncommon 
Hypertension, flushing, hot flush 

Respiratory system disorders Uncommon 
Dyspnoea, bronchitis, upper respiratory tract infection, cough 

Gastrointestinal disorders Common 
Diarrhoea**, nausea 

Uncommon: 

Abdominal pain, abdominal distension, gastro-oesophageal reflux 

disease, vomiting, dry mouth, dyspepsia, constipation, frequent 

stools, flatulence, gastrointestinal discomfort 

Rare 

Pancreatitis, mouth ulceration 
Hepato-biliary disorders Common 

Liver function abnormalities** 

Uncommon 
Cholelithiasis 

Rare 
Hepatitis, jaundice*, liver injury* 

Skin and subcutaneous tissue 

disorders 
Common 

Rash (including various types of rash reported with lower 

frequencies, see below) 

Uncommon 

Dermatitis, urticaria, pruritus, skin discolouration, skin lesion, 

petechiae, rash macular, rash maculopapular, rash papular 
Rare 

Toxic epidermal necrolysis*, Stevens-Johnson Syndrome*, 

angioedema*, drug reaction with eosinophilia and systemic 
symptoms*, generalized rash (serious)*, erythema, exfoliative 

rash, rash follicular, rash vesicular, rash pustular, rash pruritic*, 

rash erythematous, rash morbillifom, alopecia, hyperhidrosis 
Musculoskeletal and connective 
tissue disorders 

Uncommon 

Arthralgia, arthritis, myalgia, musculoskeletal pain, muscle 

weakness, muscle spasm, muscle tightness, bursitis 
Rare 

Rhabdomyolysis*, joint stiffness, musculoskeletal stiffness 
Renal and urinary disorders Uncommon 



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Renal failure, nephrolithiasis, haematuria, pollakiuria, proteinuria 

Rare 
Tubulointerstitial nephritis*, micturition urgency 

Reproductive system and breast 
disorder 

Uncommon 
Erectile dysfunction 

General disorders and 
administration site conditions 

Common 
Oedema 

Uncommon 

Fatigue, chest pain, chest discomfort 
Rare 

Thirst 
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 
Rare 

Blood glucose increase, activated partial thromboplastin time 

prolonged, red blood cell count decrease, blood alkaline 

phosphatase increase, blood creatine phosphokinase increase* 

 
* 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 section 5.1 for incidences of gout flares in the individual Phase 3 randomized 

controlled 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 section 4.4). 

 

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 section 4.2 and 4.4). 

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. 

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting 

system listed in Appendix V. 

 

4.9 Overdose 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 

 

Pharmacotherapeutic group: Antigout preparation, preparations inhibiting uric acid production, 

ATC code: M04AA03 

 

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 above transformations are catalyzed 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 oxidized 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 below) that were 

conducted in 4101 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 section 4.2). 

 

APEX Study: The Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX) 

was a Phase 3, randomized, double-blind, multicenter, 28-week study. One thousand and 

seventy-two (1072) patients were randomized: placebo (n=134), febuxostat 80 mg QD (n=267), 

febuxostat 120 mg QD (n=269), febuxostat 240 mg QD (n=134) or allopurinol (300 mg QD 

[n=258] for patients with a baseline serum creatinine ≤1.5 mg/dL or 100 mg QD [n=10] for 

patients with a baseline serum creatinine >1.5 mg/dL and ≤2.0 mg/dL). Two hundred and 

forty mg febuxostat (2 times the recommended highest dose) was used as a safety evaluation 

dose. 

 

The APEX study showed statistically significant superiority of both the febuxostat 80 mg QD 

and the febuxostat 120 mg QD treatment arms versus the conventionally used doses of 

allopurinol 300 mg (n = 258) /100 mg (n = 10) treatment arm in reducing the sUA below 

6 mg/dL (357 µmol/L) (see Table 2 and Figure 1). 

 

FACT Study: The Febuxostat Allopurinol Controlled Trial (FACT) Study was a Phase 3, 

randomized, double-blind, multicenter, 52-week study. Seven hundred sixty (760) patients were 

randomized: febuxostat 80 mg QD (n=256), febuxostat C 120 mg QD (n=251), or allopurinol 

300 mg QD (n=253). 

 



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The FACT study showed the statistically significant superiority of both febuxostat 80 mg and 

febuxostat 120 mg QD treatment arms versus the conventionally used dose of allopurinol 

300 mg treatment arm in reducing and maintaining sUA below 6 mg/dL (357 µmol/L). 

 

Table 2 summarises the primary efficacy endpoint results: 

 

Table 2 

Proportion of Patients with Serum Uric Acid Levels <6.0 mg/dL (357 µmol/L) Last Three 

Monthly Visits 

 

Study 

 
Febuxostat 

80 mg QD 

 
Febuxostat 

 120 mg QD 

Allopurinol 
300 / 

100 mg QD1 
APEX 

(28 weeks) 

48%* 

(n=262) 
65%*, # 

(n=269) 
22% 

(n=268) 
FACT 

(52 weeks) 

53%* 

(n=255) 
62%* 

(n=250) 
21% 

(n=251) 
Combined 

Results 

51%* 

(n=517) 
63%*, # 

(n=519) 
22% 

(n=519) 
1 results from subjects receiving either 100 mg QD (n=10: patients with 

serum creatinine >1.5 and ≤2.0 mg/dL) or 300 mg QD (n=509) were pooled 

for analyses. 

* p < 0.001 vs allopurinol, # p < 0.001 vs 80 mg 

 

The ability of febuxostat to lower serum uric acid levels was prompt and persistent. Reduction 

in serum uric acid level to <6.0 mg/dL (357 µmol/L) was noted by the Week 2 visit and was 

maintained throughout treatment. The mean serum uric acid levels over time for each treatment 

group from the two pivotal Phase 3 studies are shown in Figure 1. 

 

Figure 1 Mean Serum Uric Acid Levels in Combined Pivotal Phase 3 Studies 

 
11 

 
10 Placebo 

 
9 

 
8 

 
7 Allopurinol 

 
6 

Febuxostat 80 mg 
 

5 

 
4 

Febuxostat 120 mg 

 

3    
 

Febuxostat 240 mg 

2 

BL   2 4 6 8    12   16   20   24   28   32   36   40   44   48   52 

 
W

e
e

k 
 

BL=baseline       SEM=standard error of the mean 

 

Note: 509 patients received allopurinol 300 mg QD; 10 patients with serum creatinine >1.5 and 

≤2.0 mg/dL were dosed with 100 mg QD. (10 patients out of 268 in APEX study). 

240 mg febuxostat was used to evaluate the safety of febuxostat at twice the recommended 



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highest dose. 

 

CONFIRMS Study: The CONFIRMS study was a Phase 3, randomized, controlled, 26-week 

study to evaluate the safety and efficacy of febuxostat 40 mg and 80 mg, in comparison with 

allopurinol 300 mg or 200 mg, in patients with gout and hyperuricaemia. Two thousand and 

two hundred-sixty nine (2269) patients were randomized: febuxostat 40 mg QD (n=757), 

febuxostat 80 mg QD (n=756), or allopurinol 300/200 mg QD (n=756). At least 65% of the 

patients had mild-moderate renal impairment (with creatinine clearance of 30-89 mL/min). 

Prophylaxis against gout flares was obligatory over the 26-week period. 

 

The proportion of patients with serum urate levels of < 6.0 mg/dL (357 µmol/L) at the final 

visit, was 45% for 40 mg febuxostat, 67% for febuxostat 80 mg and 42% for allopurinol 

300/200 mg, respectively. 

 

Primary endpoint in the sub-group of patients with renal impairment 

The APEX Study evaluated efficacy in 40 patients with renal impairment (i.e., baseline serum 

creatinine > 1.5 mg/dL and ≤2.0 mg/dL). For renally impaired subjects who were randomized 

to allopurinol, the dose was capped at 100 mg QD. Febuxostat achieved the primary efficacy 

endpoint in 44% (80 mg QD), 45% (120 mg QD), and 60% (240 mg QD) of patients compared 

to 0% in the allopurinol 100 mg QD and placebo groups. 

 

There were no clinically significant differences in the percent decrease in serum uric acid 

concentration in healthy subjects irrespective of their renal function (58% in the normal renal 

function group and 55% in the severe renal dysfunction group). 

 

An analysis in patients with gout and renal impairment was prospectively defined in the 

CONFIRMS study, and showed that febuxostat was significantly more efficacious in lowering 

serum urate levels to < 6 mg/dL compared to allopurinol 300 mg/200 mg in patients who had 

gout with mild to moderate renal impairment (65% of patients studied). 

 

Primary endpoint in the sub group of patients with sUA ≥ 10 mg/dL 

Approximately 40% of patients (combined APEX and FACT) had a baseline sUA of ≥ 

10 mg/dL. In this subgroup febuxostat achieved the primary efficacy endpoint (sUA < 

6.0 mg/dL at the last 3 visits) in 41% (80 mg QD), 48% (120 mg QD), and 66% (240 mg QD) 

of patients compared to 9% in the allopurinol 300 mg/100 mg QD and 0% in the placebo 

groups. 

 

In the CONFIRMS study, the proportion of patients achieving the primary efficacy endpoint 

(sUA <6.0 mg/dL at the final visit) for patients with a baseline serum urate level of ≥ 10 mg/dL 

treated with febuxostat 40 mg QD was 27% (66/249), with febuxostat 80 mg QD 49% 

(125/254) and with allopurinol 300 mg/200 mg QD 31% (72/230), respectively. 

 

Clinical Outcomes: proportion of patients requiring treatment for a gout flare 

APEX study: During the 8-week prophylaxis period, a greater proportion of subjects in the 

febuxostat 120 mg (36%) treatment group required treatment for gout flare compared to 

febuxostat 80 mg (28%), allopurinol 300 mg (23%) and placebo (20%). Flares increased 

following the prophylaxis period and gradually decreased over time. Between 46% and 55% of 

subjects received treatment for gout flares from Week 8 and Week 28. Gout flares during the 

last 4 weeks of the study (Weeks 24-28) were observed in 15% (febuxostat 80, 120 mg), 14% 

(allopurinol 300 mg) and 20% (placebo) of subjects. 

 

FACT study: During the 8-week prophylaxis period, a greater proportion of subjects in the 

febuxostat 120 mg (36%) treatment group required treatment for a gout flare compared to both 

the febuxostat 80 mg (22%) and allopurinol 300 mg (21%) treatment groups. After the 8-week 

prophylaxis period, the incidences of flares increased and gradually decreased over time (64% 



13 

 

and 70% of subjects received treatment for gout flares from Week 8-52). Gout flares during the 

last 4 weeks of the study (Weeks 49-52) were observed in 6-8% (febuxostat 80 mg, 120 mg) 

and 11% (allopurinol 300 mg) of subjects. 

 

The proportion of subjects requiring treatment for a gout flare (APEX and FACT Study) was 

numerically lower in the groups that achieved an average post-baseline serum urate level 

<6.0 mg/dL, <5.0 mg/dL, or <4.0 mg/dL compared to the group that achieved an average post-

baseline serum urate level ≥6.0 mg/dL during the last 32 weeks of the treatment period (Week 

20 - Week 24 to Week 49 - 52 intervals). 

 

During the CONFIRMS study, the percentages of patients who required treatment for gout 

flares (Day 1 through Month 6) were 31% and 25% for the febuxostat 80 mg and allopurinol 

groups, respectively. No difference in the proportion of patients requiring treatment for gout 

flares was observed between the febuxostat 80 mg and 40 mg groups. 

 

Long-term, open label extension Studies 

EXCEL Study (C02-021): The Excel study was a three years Phase 3, open label, multicenter, 

randomised, allopurinol-controlled, safety extension study for patients who had completed the 

pivotal Phase 3 studies (APEX or FACT).  A total of 1,086 patients were enrolled: Febuxostat 

80 mg QD (n=649), febuxostat 120 mg QD (n=292) and allopurinol 300/100 mg QD (n=145). 

About 69% of patients required no treatment change to achieve a final stable treatment. 

Patients who had 3 consecutive sUA levels >6.0 mg/dL were withdrawn. 

 

Serum urate levels were maintained over time (i.e. 91% and 93% of patients on initial 

treatment with febuxostat 80 mg and 120 mg, respectively, had sUA <6 mg/dL at Month 36). 

 

Three years data showed a decrease in the incidence of gout flares with less than 4% of patients 

requiring treatment for a flare (i.e. more than 96% of patients did not require treatment for a 

flare) at Month 16-24 and at Month 30-36. 

 

46% and 38%, of patients on final stable treatment of febuxostat 80 or 120 mg QD, 

respectively, had complete resolution of the primary palpable tophus from baseline to the Final 

Visit. 

 

FOCUS Study (TMX-01-005) was a 5 years Phase 2, open-label, multicenter, safety extension 

study for patients who had completed the febuxostat 4 weeks of double blind dosing in study 

TMX-00-004. 

 

116 patients were enrolled and received initially febuxostat 80 mg QD. 62% of patients 

required no dose adjustment to maintain sUA <6 mg/dL and 38% of patients required a dose 

adjustment to achieve a final stable dose. 

 

The proportion of patients with serum urate levels of <6.0 mg/dL (357 µmol/L) at the final visit 

was greater than 80% (81-100%) at each febuxostat dose. 

 

During the phase 3 clinical studies, mild liver function test abnormalities were observed in 

patients treated with febuxostat (5.0%). These rates were similar to the rates reported on 

allopurinol (4.2%) (see section 4.4). Increased TSH values (>5.5 µIU/mL) were observed in 

patients on long-term treatment with febuxostat (5.5%) and patients with allopurinol (5.8%) in 

the long term open label extension studies (see section 4.4). 

 

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 



14 

 

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 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 section 4.4). 

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. 

 

5.2 Pharmacokinetic properties 

 

In healthy subjects, maximum plasma concentrations (Cmax) 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 (t1/2) 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 (tmax of 1.0-1.5 h) and well absorbed (at least 84%). After single or 

multiple oral 80 and 120 mg once daily doses, Cmax 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. 

 



15 

 

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 Cmax and an 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 (Vss/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 

and 120 mg doses. Plasma protein binding of the active metabolites ranges from about 82% to 

91%. 

 

Biotransformation 

 

Febuxostat is extensively metabolized 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 Cmax 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 Cmax 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 Cmax 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 



16 

 

 

Following multiple oral doses of febuxostat, the Cmax and AUC were 24% and 12% higher in 

females than in males, respectively. However, weight-corrected Cmax and AUC were similar 

between the genders. No dose adjustment is needed based on gender. 

 

5.3 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 section 

4.4 and 4.5). 

 

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. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Tablet core 

 

Lactose 

Microcrystalline cellulose 

Magnesium stearate 

Hydroxypropylcellulose 

Croscarmellose sodium 

Colloidal hydrated silica 

Colloidal anhydrous silica 

Crospovidone 

Talc 

 

Tablet coating 



17 

 

 

Hypromellose 

Titanium dioxide (E171)  

Ethylcellulose 

Iron oxide yellow (E172) 

Triacetin 

Iron oxide black (E172) 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

2 years. 

For bottles: After first opening use within 180 days 

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special storage conditions. 

 

6.5 Nature and contents of container 

 

(PVC/oPA/Alu)/Alu (desiccant embedded) blisters of 14, 28, 84 tablets, calendar blisters of 28, 

84 tablets and perforated unit dose blisters of 28 x 1 tablets. 

 

(PVC/oPA/Alu)/Alu blisters of 14, 28, 42 tablets, calendar blisters of 28 tablets and perforated 

unit dose blisters of 28 x 1 tablets and multipacks of 84 (2 packs of 42) tablets. 

 

HDPE bottle with polypropylene (PP) screw cap closure with desiccant containing 28 or 84 

tablets. 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal 

 

No special requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

117 Allee des Parcs 

69 800 Saint Priest 

France 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/17/1194/001 

EU/1/17/1194/002 

EU/1/17/1194/003 

EU/1/17/1194/004 

EU/1/17/1194/005 

EU/1/17/1194/006 



18 

 

EU/1/17/1194/007 

EU/1/17/1194/008 

EU/1/17/1194/017 

EU/1/17/1194/018 

EU/1/17/1194/019 

EU/1/17/1194/020 

EU/1/17/1194/021 

EU/1/17/1194/022 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 15 June 2017 

 

 

10. DATE OF REVISION OF THE TEXT 

 

Detailed information on this medicinal product is available on the website of the European 

Medicines Agency http://www.ema.europa.eu 

 

http://www.ema.europa.eu/


19 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Febuxostat Mylan 120 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each tablet contains 120 mg of febuxostat. 

 

Excipient with known effect 

Each tablet contains 354.0 mg of lactose 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Film-coated tablet. 

 

A yellow, capsule shaped, biconvex tablet, approximately 18 x 8 mm, debossed with M on one 

side of the tablet and FX4 on the other side. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Febuxostat Mylan 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 Mylan 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 Mylan is indicated in adults. 

 

4.2 Posology and method of administration 

 

Posology 

 

Gout 

The recommended oral dose of Febuxostat Mylan 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 Mylan 120 mg once 

daily may be considered. 

 

Febuxostat Mylan 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 section 4.4). 

 

Tumor Lysis Syndrome 

The recommended oral dose of Febuxostat Mylan is 120 mg once daily without regard to food. 

 



20 

 

Febuxostat Mylan 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 section 5.2). 

 

Renal impairment 

The efficacy and safety have not been fully evaluated in patients with severe renal impairment 

(creatinine clearance <30 mL/min, see section 5.2). 

 

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). 

 

Gout: The recommended dose in patients with mild hepatic impairment is 80 mg. Limited 

information is available in patients with moderate hepatic impairment. 

 

Tumour Lysis Syndrome: in the pivotal Phase III trial (FLORENCE) only subjects with severe 

hepatic insufficiency were excluded from trial participation. No dose adjustment was required 

for enrolled patients on the basis of hepatic function. 

 

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 Mylan should be taken by mouth and can be taken with or without food. 

 

4.3 Contraindications 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see also 

section 4.8). 

 

4.4 Special warnings and precautions for use 

 

Cardio-vascular disorders 

 

Treatment of chronic hyperuricaemia 

 

Treatment with febuxostat in patients with pre-existing major cardiovascular diseases (e.g. 

myocardial infarction, stroke or unstable angina) should be avoided, unless no other therapy 

options are appropriate.  

A numerical greater incidence of investigator-reported cardiovascular APTC events (defined 

endpoints from the Anti-Platelet Trialists’ Collaboration (APTC) including cardiovascular 

death, non-fatal myocardial infarction, non-fatal stroke) was observed in the febuxostat total 

group compared to the allopurinol group in the APEX and FACT studies (1.3 vs. 0.3 events per 

100 Patient Years (PYs)), but not in the CONFIRMS study (see section 5.1 for detailed 

characteristics of the studies). The incidence of investigator-reported cardiovascular APTC 

events in the combined Phase 3 studies (APEX, FACT and CONFIRMS studies) was 0.7 vs. 0.6 



21 

 

events per 100 PYs. In the long-term extension studies the incidences of investigator-reported 

APTC events were 1.2 and 0.6 events per 100 PYs for febuxostat and allopurinol, respectively. 

No statistically significant differences were found and no causal relationship with febuxostat 

was established. Identified risk factors among these patients were a medical history of 

atherosclerotic disease and/or myocardial infarction, or of congestive heart failure. 

In the post registrational CARES trial (see section 5.1 for detailed characteristics of the study) 

the rate of MACE events was similar in febuxostat versus allopurinol treated patients (HR 

1.03;95% CI 0.87-1.23), but a higher rate of cardiovascular deaths was observed (4.3% vs. 3.2% 

of patients; HR 1.34; 95% CI 1.03-1.73). 

 

Prevention and treatment of hyperuricaemia in patients at risk of TLS 

 

Patients undergoing chemotherapy for haematologic malignancies at intermediate to high risk of 

Tumor Lysis Syndrome treated with febuxostat should be under cardiac monitoring as clinically 

appropriate. 

 

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 section 4.8). 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 mobilization of urate from tissue deposits (see sections 4.8 and 5.1). At 

treatment initiation with febuxostat flare prophylaxis for at least 6 months with an NSAID or 

colchicine is recommended (see section 4.2). 

 

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. This has not been observed 

in the pivotal clinical study with febuxostat in the Tumor Lysis Syndrome. As there has been no 

experience with febuxostat, its use in patients with Lesch-Nyhan Syndrome is not 

recommended. 

 

Mercaptopurine/azathioprine 



22 

 

 

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. No interaction studies have been performed in humans. 

Where the combination cannot be avoided, a reduction of the dose of 

mercaptopurine/azathioprine is recommended. Based on modelling and simulation analysis of 

data from a pre-clinical study in rats, when coadministered with febuxostat, the dose of 

mercaptopurine/azathioprine should be reduced to the 20% or less of the previously prescribed 

dose in order to avoid possible haematological effects (see section 4.5 and 5.3). 

 

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 section 5.1). 

 

Theophylline 

 

Co-administration of febuxostat 80 mg and theophylline 400 mg single dose in healthy subjects 

showed absence of any pharmacokinetic interaction (see section 4.5). 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 section 5.1). 

 

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 section 5.1). 

 

Excipients 

 

Febuxostat Mylan tablets contain lactose. Patients with rare hereditary problems of galactose 

intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this 

medicine. 

 

Febuxostat Mylan tablets contains less than 1 mmol sodium (23 mg) per tablet, that is to say 

essentially ‘sodium-free’. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Mercaptopurine/azathioprine 

 



23 

 

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 drugs leading to toxicity. Drug interaction studies of febuxostat with drugs (except 

theophylline) that are metabolized by XO have not been performed in humans. 

Modelling and simulation analysis of data from a pre-clinical study in rats, indicates that, 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 section 4.4 and 5.3). 

 

Drug interaction studies of febuxostat with other cytotoxic chemotherapy have not been 

conducted.  

 

In the Tumor Lysis Syndrome pivotal trial febuxostat 120 mg daily was administered to patients 

undergoing several chemotherapy regimens, including monoclonal antibodies. However, drug-

drug and drug-disease interactions were not explored during this study. Therefore, possible 

interactions with any concomitantly administered cytotoxic drug cannot be ruled out. 

 

Rosiglitazone/CYP2C8 substrates 

 

Febuxostat was shown to be a weak inhibitor of CYP2C8 in vitro. In a study in healthy subjects, 

coadministration 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 (Cmax 

28%, AUC 41% and t1/2 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/indometacin/hydrochlorothiazide/warfarin 



24 

 

 

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 Cmax, but no significant change in AUC was observed. Therefore, 

febuxostat may be taken without regard to antacid use. 

 

4.6 Fertility, pregnancy and lactation 

 

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 section 5.3). The potential risk for human is unknown. 

Febuxostat should not be used during pregnancy. 

 

Breast-feeding 

 

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 breast-

feeding. 

 

Fertility 

 

In animals, reproduction studies up to 48 mg/kg/day showed no dose-dependent adverse effects 

on fertility (see section 5.3). The effect of febuxostat on human fertility is unknown. 

 

4.7 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. 

 



25 

 

4.8 Undesirable effects 

 

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-marketing experience in gout patients are gout 

flares, liver function abnormalities, diarrhoea, nausea, headache, rash and oedema. 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. 

 

Tabulated 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 below. 

The frequencies are based on studies and post-marketing experience in gout patients. 

 

Within each frequency grouping, adverse reactions are presented in order of decreasing 

seriousness. 

 

Table 1: Adverse reactions in combined phase 3, long-term extension studies and post-

marketing experience in gout patients. 

Blood and lymphatic system 

disorders 
Rare 

Pancytopenia, thrombocytopenia, agranulocytosis* 
Immune system disorders Rare 

Anaphylactic reaction*, drug hypersensitivity* 
Endocrine disorders Uncommon 

Blood thyroid stimulating hormone increased 
Eye disorders Rare 

Blurred vision 
Metabolism and nutrition 

disorders 
Common*** 

Gout flares 
Uncommon 

Diabetes mellitus, hyperlipidemia, decrease appetite, weight 

increase 
Rare 

Weight decrease, increase appetite, anorexia 
Psychiatric disorders Uncommon 

Libido decreased, insomnia 
Rare 

Nervousness 
Nervous system disorders Common 

Headache 
Uncommon 

Dizziness, paraesthesia, hemiparesis, somnolence, altered taste, 

hypoaesthesia, hyposmia 
Ear and labyrinth disorders Rare 

Tinnitus 
Cardiac disorders Uncommon 

Atrial fibrillation, palpitations, ECG abnormal, left bundle branch 

block (see section Tumor Lysis Syndrome), sinus tachycardia (see 

section Tumor Lysis Syndrome) 

Rare 

Sudden cardiac death* 
Vascular disorders Uncommon 



26 

 

Hypertension, flushing, hot flush, haemorrhage (see section Tumor 

Lysis Syndrome) 
Respiratory system disorders Uncommon 

Dyspnoea, bronchitis, upper respiratory tract infection, cough 
Gastrointestinal disorders Common 

Diarrhoea**, nausea 

Uncommon: 

Abdominal pain, abdominal distension, gastro-oesophageal reflux 

disease, vomiting, dry mouth, dyspepsia, constipation, frequent 

stools, flatulence, gastrointestinal discomfort 
Rare 

Pancreatitis, mouth ulceration 
Hepato-biliary disorders Common 

Liver function abnormalities** 

Uncommon 
Cholelithiasis 

Rare 
Hepatitis, jaundice*, liver injury* 

Skin and subcutaneous tissue 
disorders 

Common 

Rash (including various types of rash reported with lower 

frequencies, see below) 

Uncommon 

Dermatitis, urticaria, pruritus, skin discolouration, skin lesion, 

petechiae, rash macular, rash maculopapular, rash papular 
Rare 

Toxic epidermal necrolysis*, Stevens-Johnson Syndrome*, 

angioedema*, drug reaction with eosinophilia and systemic 

symptoms*, generalized rash (serious)*, erythema, 

exfoliative rash, rash follicular, rash vesicular, rash 

pustular, rash pruritic*, rash erythematous, rash 

morbillifom, alopecia, hyperhidrosis 
Musculoskeletal and connective 

tissue disorders 
Uncommon 

Arthralgia, arthritis, myalgia, musculoskeletal pain, muscle 

weakness, muscle spasm, muscle tightness, bursitis 

Rare 

Rhabdomyolysis*, joint stiffness, musculoskeletal stiffness 
Renal and urinary disorders Uncommon 

Renal failure, nephrolithiasis, haematuria, pollakiuria, proteinuria 
Rare 

Tubulointerstitial nephritis*, micturition urgency 
Reproductive system and breast 

disorder 
Uncommon 

Erectile dysfunction 
General disorders and 

administration site conditions 
Common 

Oedema 
Uncommon 

Fatigue, chest pain, chest discomfort 

Rare 
Thirst 

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 



27 

 

Rare 

Blood glucose increased, activated partial thromboplastin time 

prolonged, red blood cell count decrease, blood alkaline 

phosphatase increase, blood creatine phosphokinase increase* 
* 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 section 5.1 for incidences of gout flares in the individual Phase 3 randomized 

controlled 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 section 4.4). 

 

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 section 4.2 and 4.4). 

 

Tumor Lysis Syndrome 

 

Summary of the safety profile 

 

In the randomized, double-blind, Phase 3 pivotal FLORENCE (FLO-01) study comparing 

febuxostat with allopurinol (346 patients undergoing chemotherapy for haematologic 

malignancies and at intermediate-to-high risk of TLS), only 22 (6.4%) patients overall 

experienced adverse reactions, namely 11 (6.4%) patients in each treatment group. The majority 

of adverse reactions were either mild or moderate. 

 
Overall, the FLORENCE trial did not highlight any particular safety concern in addition to the 
previous experience with febuxostat in gout, with the exception of the following three adverse 
reactions (listed above in table 1). 

 

Cardiac disorders: 

Uncommon: Left bundle branch block, sinus tachycardia 

 

Vascular disorders:  

Uncommon: haemorrhage 

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. 

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting 

system listed in Appendix V. 

 

4.9 Overdose 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


28 

 

 

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

 

5.1 Pharmacodynamic properties 
 

Pharmacotherapeutic group: Antigout preparation, preparations inhibiting uric acid production, 

ATC code: M04AA03 

 
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 above transformations are catalyzed 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 oxidized 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 
 

Gout 
 

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 below) that were 

conducted in 4101 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 section 4.2). 

 

APEX Study: The Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX) 

was a Phase 3, randomized, double-blind, multicenter, 28-week study. One thousand and 

seventy-two (1072) patients were randomized: placebo (n=134), febuxostat 80 mg QD (n=267), 

febuxostat 120 mg QD (n=269), febuxostat 240 mg QD (n=134) or allopurinol (300 mg QD 

[n=258] for patients with a baseline serum creatinine ≤1.5 mg/dL or 100 mg QD [n=10] for 

patients with a baseline serum creatinine >1.5 mg/dL and ≤2.0 mg/dL). Two hundred and 

forty mg febuxostat (2 times the recommended highest dose) was used as a safety evaluation 

dose. 

 
The APEX study showed statistically significant superiority of both the febuxostat 80 mg QD 

and the febuxostat 120 mg QD treatment arms versus the conventionally used doses of 

allopurinol 300 mg (n=258) /100 mg (n = 10) treatment arm in reducing the sUA below 

6 mg/dL (357 µmol/L) (see Table 2 and Figure 1). 

 

FACT Study: The Febuxostat Allopurinol Controlled Trial (FACT) Study was a Phase 3, 

randomized, double-blind, multicenter, 52-week study. Seven hundred sixty (760) patients were 



29 

 

randomized: febuxostat 80 mg QD (n=256), febuxostat 120 mg QD (n=251), or allopurinol 

300 mg QD (n=253). 

 

The FACT study showed the statistically significant superiority of both febuxostat 80 mg and 

febuxostat 120 mg QD treatment arms versus the conventionally used dose of allopurinol 

300 mg treatment arm in reducing and maintaining sUA below 6 mg/dL (357 µmol/L). 

 

Table 2 summarises the primary efficacy endpoint results: 

 

Table 2 

Proportion of Patients with Serum Uric Acid Levels <6.0 mg/dL (357 µmol/L) Last Three 

Monthly Visits 

 

Study 

 

Febuxostat 

80 mg QD 

 

Febuxostat 

120 mg QD 

Allopurinol 

300 / 

100 mg QD1 

APEX 

(28 weeks) 

48%* 

(n=262) 

65%*, # 

(n=269) 

22% 

(n=268) 

FACT 

(52 weeks) 

53%* 

(n=255) 

62%* 

(n=250) 

21% 

(n=251) 

Combined 

Results 

51%* 

(n=517) 

63%*, # 

(n=519) 

22% 

(n=519) 
1 results from subjects receiving either 100 mg QD (n=10: patients with 

serum creatinine >1.5 and ≤2.0 mg/dL) or 300 mg QD (n=509) were pooled 

for analyses. 

* p < 0.001 vs allopurinol, # p < 0.001 vs 80 mg 

 
The ability of febuxostat to lower serum uric acid levels was prompt and persistent. Reduction 
in serum uric acid level to <6.0 mg/dL (357 µmol/L) was noted by the Week 2 visit and was 
maintained throughout treatment. The mean serum uric acid levels over time for each treatment 
group from the two pivotal Phase 3 studies are shown in Figure 1. 
 



30 

 

M
ea

n
 (

±
S

E
M

) 
S

er
u

m
 U

ri
c 

A
ci

d
 L

ev
el

 (
m

g
/d

L
) 

Figure 1 Mean Serum Uric Acid Levels in Combined Pivotal Phase 3 Studies 
 

11 

 

10 Placebo 
 

9 

 
8 

 
7 Allopurinol 

 

6 
Febuxostat 80 mg 

 

5 

 
4 

Febuxostat 120 mg 

 

3    
 

Febuxostat 240 mg 

2 
BL   2 4 6 8    12   16   20   24   28   32   36   40   44   48   52 

 
W
e
e
k 

 
BL=baseline       SEM=standard error of the mean 

 

Note: 509 patients received allopurinol 300 mg QD; 10 patients with serum creatinine >1.5 and 

≤2.0 mg/dL were dosed with 100 mg QD. (10 patients out of 268 in APEX study). 

240 mg febuxostat was used to evaluate the safety of febuxostat at twice the recommended 

highest dose. 

 
CONFIRMS Study: The CONFIRMS study was a Phase 3, randomized, controlled, 26-week 

study to evaluate the safety and efficacy of febuxostat 40 mg and 80 mg, in comparison with 

allopurinol 300 mg or 200 mg, in patients with gout and hyperuricaemia. Two thousand and 

two hundred-sixty nine (2269) patients were randomized: febuxostat 40 mg QD (n=757), 

febuxostat 80 mg QD (n=756), or allopurinol 300/200 mg QD (n=756). At least 65% of the 

patients had mild-moderate renal impairment (with creatinine clearance of 30-89 mL/min). 

Prophylaxis against gout flares was obligatory over the 26-week period. 

 

The proportion of patients with serum urate levels of < 6.0 mg/dL (357 µmol/L) at the final 

visit, was 45% for 40 mg febuxostat, 67% for febuxostat 80 mg and 42% for allopurinol 

300/200 mg, respectively. 

 
Primary endpoint in the sub-group of patients with renal impairment 

The APEX Study evaluated efficacy in 40 patients with renal impairment (i.e., baseline serum 

creatinine > 1.5 mg/dL and ≤2.0 mg/dL). For renally impaired subjects who were randomized 

to allopurinol, the dose was capped at 100 mg QD. Febuxostat achieved the primary efficacy 

endpoint in 44% (80 mg QD), 45% (120 mg QD), and 60% (240 mg QD) of patients compared 

to 0% in the allopurinol 100 mg QD and placebo groups. 

 
There were no clinically significant differences in the percent decrease in serum uric acid 

concentration in healthy subjects irrespective of their renal function (58% in the normal renal 

function group and 55% in the severe renal dysfunction group). 

 
An analysis in patients with gout and renal impairment was prospectively defined in the 

CONFIRMS study, and showed that febuxostat was significantly more efficacious in lowering 

serum urate levels to < 6 mg/dL compared to allopurinol 300 mg/200 mg in patients who had 



31 

 

gout with mild to moderate renal impairment (65% of patients studied). 

 
Primary endpoint in the sub group of patients with sUA ≥ 10 mg/dL 

Approximately 40% of patients (combined APEX and FACT) had a baseline sUA of ≥ 

10 mg/dL. In this subgroup febuxostat achieved the primary efficacy endpoint (sUA < 

6.0 mg/dL at the last 3 visits) in 41% (80 mg QD), 48% (120 mg QD), and 66% (240 mg QD) 

of patients compared to 9% in the allopurinol 300 mg/100 mg QD and 0% in the placebo 

groups. 

 
In the CONFIRMS study, the proportion of patients achieving the primary efficacy endpoint 

(sUA <6.0 mg/dL at the final visit) for patients with a baseline serum urate level of ≥ 10 mg/dL 

treated with febuxostat 40 mg QD was 27% (66/249), with febuxostat 80 mg QD 49% 

(125/254) and with allopurinol 300 mg/200 mg QD 31% (72/230), respectively. 

 
Clinical Outcomes: proportion of patients requiring treatment for a gout flare 

Apex study: During the 8-week prophylaxis period, a greater proportion of subjects in the 

febuxostat 120 mg (36%) treatment group required treatment for gout flare compared to 

febuxostat 80 mg (28%), allopurinol 300 mg (23%) and placebo (20%). Flares increased 

following the prophylaxis period and gradually decreased over time. Between 46% and 55% of 

subjects received treatment for gout flares from Week 8 and Week 28. Gout flares during the 

last 4 weeks of the study (Weeks 24-28) were observed in 15% (febuxostat 80, 120 mg), 14% 

(allopurinol 300 mg) and 20% (placebo) of subjects. 

 
Fact study: During the 8-week prophylaxis period, a greater proportion of subjects in the 

febuxostat 120 mg (36%) treatment group required treatment for a gout flare compared to both 

the febuxostat 80 mg (22%) and allopurinol 300 mg (21%) treatment groups. After the 8-week 

prophylaxis period, the incidences of flares increased and gradually decreased over time (64% 

and 70% of subjects received treatment for gout flares from Week 8-52). Gout flares during the 

last 4 weeks of the study (Weeks 49-52) were observed in 6-8% (febuxostat 80 mg, 120 mg) 

and 11% (allopurinol 300 mg) of subjects. 

 
The proportion of subjects requiring treatment for a gout flare (APEX and FACT Study) was 

numerically lower in the groups that achieved an average post-baseline serum urate level 

<6.0 mg/dL, <5.0 mg/dL, or <4.0 mg/dL compared to the group that achieved an average post-

baseline serum urate level ≥6.0 mg/dL during the last 32 weeks of the treatment period (Week 

20-Week 24 to Week 49 - 52 intervals). 

 
During the CONFIRMS study, the percentages of patients who required treatment for gout 

flares (Day 1 through Month 6) were 31% and 25% for the febuxostat 80 mg and allopurinol 

groups, respectively. No difference in the proportion of patients requiring treatment for gout 

flares was observed between the febuxostat 80 mg and 40 mg groups. 

 
Long-term, open label extension Studies 

EXCEL Study (C02-021): The Excel study was a three years Phase 3, open label, multicenter, 

randomised, allopurinol-controlled, safety extension study for patients who had completed the 

pivotal Phase 3 studies (APEX or FACT). A total of 1,086 patients were enrolled: Febuxostat 

80 mg QD (n=649), febuxostat 120 mg QD (n=292) and allopurinol 300/100 mg QD (n=145). 

About 69% of patients required no treatment change to achieve a final stable treatment. 

Patients who had 3 consecutive sUA levels >6.0 mg/dL were withdrawn. 

 

Serum urate levels were maintained over time (i.e. 91% and 93% of patients on initial 

treatment with febuxostat 80 mg and 120 mg, respectively, had sUA <6 mg/dL at Month 36). 

 
Three years data showed a decrease in the incidence of gout flares with less than 4% of patients 

requiring treatment for a flare (i.e. more than 96% of patients did not require treatment for a 



32 

 

flare) at Month 16-24 and at Month 30-36. 

 
46% and 38%, of patients on final stable treatment of febuxostat 80 or 120 mg QD, 

respectively, had complete resolution of the primary palpable tophus from baseline to the Final 

Visit. 

 
FOCUS Study (TMX-01-005) was a 5 years Phase 2, open-label, multicenter, safety extension 

study for patients who had completed the febuxostat 4 weeks of double blind dosing in study 

TMX-00-004. 116 patients were enrolled and received initially febuxostat 80 mg QD. 62% of 

patients required no dose adjustment to maintain sUA <6 mg/dL and 38% of patients required a 

dose adjustment to achieve a final stable dose. 

 

The proportion of patients with serum urate levels of <6.0 mg/dL (357 µmol/L) at the final visit 

was greater than 80% (81-100%) at each febuxostat dose. 

 
During the phase 3 clinical studies, mild liver function test abnormalities were observed in 

patients treated with febuxostat (5.0%). These rates were similar to the rates reported on 

allopurinol (4.2%) (see section 4.4). Increased TSH values (>5.5 µIU/mL) were observed in 

patients on long-term treatment with febuxostat (5.5%) and patients with allopurinol (5.8%) in 

the long term open label extension studies (see section 4.4). 

 
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 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 section 4.4). 

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. 



33 

 

 
Tumor Lysis Syndrome 

The efficacy and safety of febuxostat in the prevention and treatment of Tumor Lysis 

Syndrome was evaluated in the FLORENCE (FLO-01) study. Febuxostat C showed a superior 

and faster urate lowering activity compared to allopurinol. 

 

FLORENCE was a randomized (1:1), double blind, phase III, pivotal trial comparing 

febuxostat 120 mg once daily with allopurinol 200 to 600 mg daily (mean allopurinol daily 

dose [± standard deviation]: 349.7 ± 112.90 mg) in terms of control of serum uric acid level. 

Eligible patients had to be candidates for allopurinol treatment or have no access to rasburicase. 

Primary endpoints were serum uric acid area under the curve (AUC sUA1-8) and change in 

serum creatinine (sC) level both from baseline to Day 8. 

 

Overall, 346 patients with haematological malignancies undergoing chemotherapy and at 

intermediate/high risk of Tumor Lysis Syndrome were included. Mean AUC sUA1-8 (mgxh/dl) 

was significantly lower with febuxostat (514.0 ± 225.71 vs 708.0 ± 234.42; least square means 

difference: -196.794 [95% confidence interval: -238.600 ; -154.988]; p < .0001). Furthermore, 

the mean serum uric acid level was significantly lower with febuxostat since the first 24 hours 

of treatment and at any following time point. No significant difference in mean serum 

creatinine change (%) occurred between febuxostat and allopurinol (-0.83 ± 26.98 vs -4.92 ± 

16.70 respectively; least square means difference: 4.0970 [95% confidence interval: -0.6467 ; 

8.8406]; p=0.0903). With regard to secondary endpoints, no significant difference was detected 

in terms of incidence of laboratory TLS (8.1% and 9.2% in febuxostat and allopurinol arm, 

respectively; relative risk: 0.875 [95% confidence interval: 0.4408 ; 1.7369]; p=0.8488) nor of 

clinical TLS (1.7% and 1.2% in febuxostat and allopurinol arm, respectively; relative risk: 

0.994 [95% confidence interval: 0.9691 ; 1.0199]; p=1.0000).  Incidence of overall treatment-

emergent signs and symptoms and adverse drug reactions was 67.6% vs 64.7% and 6.4% vs 

6.4% with febuxostat and allopurinol respectively. In the FLORENCE study febuxostat 

demonstrated a superior control of serum uric acid level compared to allopurinol in patients 

scheduled to receive the latter drug. No data comparing febuxostat with rasburicase are 

currently available. The efficacy and safety of febuxostat has not been established in patients 

with acute severe TLS, e.g. in patients who failed on other urate lowering therapies. 

 
5.2 Pharmacokinetic properties 

 
In healthy subjects, maximum plasma concentrations (Cmax) 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 (t1/2) 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 (tmax of 1.0-1.5 h) and well absorbed (at least 84%). After single or 

multiple oral 80 and 120 mg once daily doses, Cmax 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. 



34 

 

 
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 Cmax 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 (Vss/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 

and 120 mg doses. Plasma protein binding of the active metabolites ranges from about 82% to 

91%. 

 
Biotransformation 

 

Febuxostat is extensively metabolized 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 Cmax 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 Cmax 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 Cmax 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. 

 



35 

 

Gender 

 

Following multiple oral doses of febuxostat, the Cmax and AUC were 24% and 12% higher in 

females than in males, respectively. However, weight-corrected Cmax and AUC were similar 

between the genders. No dose adjustment is needed based on gender. 

 

5.3 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 section 

4.4 and 4.5). 

 

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. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 
6.1 List of excipients 

 
Tablet core 

 

Lactose 

Microcrystalline cellulose 

Magnesium stearate 

Hydroxypropylcellulose 

Croscarmellose sodium 

Colloidal hydrated silica 

Colloidal anhydrous silica 

Crospovidone 

Talc 

 



36 

 

Tablet coating 

 

Hypromellose 

Titanium dioxide (E171) 

Ethylcellulose 

Iron oxide yellow (E172) 

Triacetin 

Iron oxide black (E172) 

 
6.2 Incompatibilities 

 
Not applicable. 

 
6.3 Shelf life 

 
2 years. 

For bottles: After first opening use within 180 days 

 
6.4 Special precautions for storage 

 
This medicinal product does not require any special storage conditions. 

 

6.5 Nature and contents of container 

 
(PVC/oPA/Alu)/Alu (desiccant embedded) blisters of 14, 28, 84 tablets, calendar blisters of 28, 

84 tablets and perforated unit dose blisters of 28 x 1 tablets. 

 

(PVC/oPA/Alu)/Alu blisters of 14, 28, 42 tablets, calendar blisters of 28 tablets and perforated 

unit dose blisters of 28 x 1 tablets and multipacks of 84 (2 packs of 42) tablets. 

 

HDPE bottle with polypropylene (PP) screw cap closure with desiccant containing 28 or 84 

tablets. 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal 

 
No special requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 
Mylan S.A.S. 

117 Allee des Parcs 

69 800 Saint Priest 

France 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/17/1194/009 

EU/1/17/1194/010 

EU/1/17/1194/011 

EU/1/17/1194/012 

EU/1/17/1194/013 



37 

 

EU/1/17/1194/014 

EU/1/17/1194/015 

EU/1/17/1194/016 

EU/1/17/1194/023 

EU/1/17/1194/024 

EU/1/17/1194/025 

EU/1/17/1194/026 

EU/1/17/1194/027 

EU/1/17/1194/028 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 
Date of first authorisation: 15 June 2017 

 

 

10. DATE OF REVISION OF THE TEXT 

 
Detailed information on this medicinal product is available on the website of the European 

Medicines Agency http://www.ema.europa.eu 

  

http://www.emea.europa.eu/


38 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURERS RESPONSIBLE FOR BATCH 

RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING 

SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF 

THE MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD 

TO THE SAFE AND EFFECTIVE USE OF THE 

MEDICINAL PRODUCT 



39 

 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturers responsible for batch release 

 

Mylan Hungary Kft 

Mylan utca 1 

H-2900 Komárom 

Hungary 

 

McDermott Laboratories Limited trading as Gerard Laboratories 

35/36 Baldoyle Industrial Estate 

Grange Road 

Dublin 13 

Ireland 

 

Mylan Germany GmbH 

Zweigniederlassung Bad Homburg v. d. Hoehe, Benzstrasse 1 

Bad Homburg v. d. Hoehe 

Hessen, 61352,  

Germany 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  

 

Medicinal product subject to medical prescription. 

 

 

C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

• Periodic Safety Update Reports 
 

The requirements for submission of periodic safety update reports for this medicinal 

product are set out in the list of Union reference dates (EURD list) provided for under 

Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the 

European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   

 

• Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions 

detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and 

any agreed subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile 



40 

 

or as the result of an important (pharmacovigilance or risk minimisation) milestone being 

reached. 

  



41 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



42 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

  



43 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

OUTER CARTON (BLISTERS AND BOTTLES) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Febuxostat Mylan 80 mg film-coated tablets  

febuxostat  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

Each tablet contains 80 mg febuxostat. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains lactose. 

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

[Blisters] 

14 film-coated tablets 

28 film-coated tablets 

42 film-coated tablets 

84 film-coated tablets 

28 x 1 film-coated tablets 

28 film-coated tablets (calendar) 

84 film-coated tablets (calendar) 

 

[Bottles] 

28 film-coated tablets  

84 film-coated tablets  

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For oral use. 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 

OUT OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 



44 

 

 

 

8. EXPIRY DATE 

 

EXP 

For bottles: After first opening use within 180 days 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL 

PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL 

PRODUCTS, IF APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

117 Allee des Parcs 

69 800 Saint Priest 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/17/1194/001 

EU/1/17/1194/002 

EU/1/17/1194/003 

EU/1/17/1194/004 

EU/1/17/1194/005 

EU/1/17/1194/006 

EU/1/17/1194/007 

EU/1/17/1194/008 

EU/1/17/1194/017 

EU/1/17/1194/018 

EU/1/17/1194/019 

EU/1/17/1194/020 

EU/1/17/1194/021 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 



45 

 

 

 

 

16. INFORMATION IN BRAILLE 

 

Febuxostat Mylan 80 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 



46 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

OUTER CARTON OF MULTIPACK (WITH BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Febuxostat Mylan 80 mg film-coated tablets 

 

febuxostat  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

Each tablet contains 80 mg febuxostat. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains lactose. 

 

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Multipack: 84 (2 packs of 42) film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For oral use. 

 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 

OUT OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 



47 

 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL 

PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL 

PRODUCTS, IF APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

117 Allee des Parcs 

69 800 Saint Priest 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/17/1194/022 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Febuxostat Mylan 80 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



48 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

INNER CARTON OF MULTIPACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Febuxostat Mylan 80 mg film-coated tablets 

 

febuxostat  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

Each tablet contains 80 mg febuxostat. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains lactose. 

 

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

42 film-coated tablets 

 

Components of a multipack, can’t be sold separately. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For oral use. 

 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 

OUT OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



49 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL 

PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL 

PRODUCTS, IF APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

117 Allee des Parcs 

69 800 Saint Priest 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/17/1194/022 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Febuxostat Mylan 80 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

  



50 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  

 

BOTTLE LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Febuxostat Mylan 80 mg film-coated tablets  

febuxostat  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

Each tablet contains 80 mg febuxostat. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains lactose. 

See the package leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

28 film-coated tablets  

84 film-coated tablets  

 

 

5. METHOD AND ROUTE OF ADMINISTRATION 

 

For oral use. 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 

OUT OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

After first opening use within 180 days 

 

 



51 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL 

PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL 

PRODUCTS, IF APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

117 Allee des Parcs 

69 800 Saint Priest 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/17/1194/007 

EU/1/17/1194/008 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

  



52 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Febuxostat Mylan 80 mg film-coated tablets  

febuxostat  

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

[For calendar blisters only]: 

MON 

TUE 

WED 

THU 

FRI 

SAT 

SUN 

 

  



53 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

OUTER CARTON (BLISTERS AND BOTTLES) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Febuxostat Mylan 120 mg film-coated tablets  

febuxostat  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

Each tablet contains 120 mg febuxostat. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains lactose. 

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

[Blisters] 

14 film-coated tablets 

28 film-coated tablets 

42 film-coated tablets 

84 film-coated tablets 

28 x 1 film-coated tablets 

28 film-coated tablets (calendar) 

84 film-coated tablets (calendar) 

 

[Bottles] 

28 film-coated tablets  

84 film-coated tablets  

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For oral use. 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 

OUT OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 



54 

 

 

 

8. EXPIRY DATE 

 

EXP 

For bottles: After first opening use within 180 days 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL 

PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL 

PRODUCTS, IF APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

117 Allee des Parcs 

69 800 Saint Priest 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/17/1194/009 

EU/1/17/1194/010 

EU/1/17/1194/011 

EU/1/17/1194/012 

EU/1/17/1194/013 

EU/1/17/1194/014 

EU/1/17/1194/015 

EU/1/17/1194/016 

EU/1/17/1194/023 

EU/1/17/1194/024 

EU/1/17/1194/025 

EU/1/17/1194/026 

EU/1/17/1194/027 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 



55 

 

 

 

 

16. INFORMATION IN BRAILLE 

 

Febuxostat Mylan 120 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



56 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF MULTIPACK (WITH BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Febuxostat Mylan 120 mg film-coated tablets 

 

febuxostat  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

Each tablet contains 120 mg febuxostat. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains lactose. 

 

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Multipack: 84 (2 packs of 42) film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For oral use. 

 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 

OUT OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 



57 

 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL 

PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL 

PRODUCTS, IF APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

117 Allee des Parcs 

69 800 Saint Priest 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/17/1194/028 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Febuxostat Mylan 120 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

  



58 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

INNER CARTON OF MULTIPACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Febuxostat Mylan 120 mg film-coated tablets 

 

febuxostat  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

Each tablet contains 120 mg febuxostat. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains lactose. 

 

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

42 film-coated tablets 

 

Components of a multipack, can’t be sold separately. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For oral use. 

 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 

OUT OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



59 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL 

PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL 

PRODUCTS, IF APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

117 Allee des Parcs 

69 800 Saint Priest 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/17/1194/028 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Febuxostat Mylan 120 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

  



60 

 

 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  

 

BOTTLE LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Febuxostat Mylan 120 mg film-coated tablets  

febuxostat  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

Each tablet contains 120 mg febuxostat. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains lactose. 

See the package leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablets 

 

28 film-coated tablets  

84 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For oral use. 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 

OUT OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

After first opening use within 180 days 

 



61 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL 

PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL 

PRODUCTS, IF APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

117 Allee des Parcs 

69 800 Saint Priest 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/17/1194/015 

EU/1/17/1194/016 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

 

  



62 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Febuxostat Mylan 120 mg film-coated tablets  

febuxostat  

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

[For calendar blisters only]: 

MON 

TUE 

WED 

THU 

FRI 

SAT 

SUN 

 

  



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B. PACKAGE LEAFLET 



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Package leaflet: Information for the patient 

 

Febuxostat Mylan 80 mg film-coated tablets  

Febuxostat Mylan 120 mg film-coated tablets  

febuxostat 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 

 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm 

them, even if their signs of illness are the same as yours. 

- If you get any side effects talk to your doctor or pharmacist. This includes any possible 
side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Febuxostat Mylan is and what it is used for 
2. What you need to know before you take Febuxostat Mylan 
3. How to take Febuxostat Mylan 
4. Possible side effects 
5. How to store Febuxostat Mylan 
6. Contents of the pack and other information 
 

 

1. What Febuxostat Mylan is and what it is used for 

 

Febuxostat Mylan tablets contain the active substance febuxostat and are used to treat gout, 

which is associated with an excess of a chemical called uric acid (urate) in the body. In some 

people, the amount of uric acid builds up in the blood and may become too high to remain 

soluble. When this happens, urate crystals may form in and around the joints and kidneys. These 

crystals can cause sudden, severe pain, redness, warmth and swelling in a joint (known as a gout 

attack). Left untreated, larger deposits called tophi may form in and around joints. These tophi 

may cause joint and bone damage. 

 

Febuxostat Mylan works by reducing uric acid levels. Keeping uric acid levels low by taking 

Febuxostat Mylan once every day stops crystals building up, and over time it reduces 

symptoms. Keeping uric acid levels sufficiently low for a long enough period can also shrink 

tophi. 

 

Febuxostat Mylan 120 mg tablets are also used to treat and prevent high blood levels of uric 

acid that may occur when you start to receive chemotherapy for blood cancers. 

When chemotherapy is given, cancer cells are destroyed, and uric acid levels increase in the 

blood accordingly, unless the formation of uric acid is prevented. 

 

Febuxostat Mylan is for adults. 

 

 

2. What you need to know before you take Febuxostat Mylan  

 

Do not take Febuxostat Mylan 

• If you are allergic to febuxostat or any of the other ingredients of this medicine (listed in 
section 6). 

 



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Warnings and precautions 

 

Talk to your doctor before taking Febuxostat Mylan: 

• If you have or have had heart failure, heart problems or stroke 

• If you have or have had renal disease and/or serious allergic reaction to allopurinol (a 
medication used for the treatment of Gout) 

• If you have or have had liver disease or liver function test abnormalities 

• If you are being treated for high uric acid levels as a result of Lesch-Nyhan syndrome (a 
rare inherited condition in which there is too much uric acid in the blood) 

• If you have thyroid problems. 
 

Should you experience allergic reactions to Febuxostat Mylan, stop taking this medicine (see 

also section 4). Possible symptoms of allergic reactions might be: 

- rash including severe forms (e.g. blisters, nodules, itchy, exfoliative rash), itchiness 
- swelling of limbs or face 
- difficulties in breathing 
- fever with enlarged lymph nodes 
- but also serious life threatening allergic conditions with cardiac and circulatory arrest. 

Your doctor might decide to permanently stop treatment with Febuxostat Mylan. 

 

There have been rare reports of potentially life-threatening skin rashes (Stevens-Johnson 

Syndrome) with the use of febuxostat, appearing initially as reddish target-like spots or circular 

patches often with central blister on the trunk. It may also include ulcers in the mouth, throat, 

nose, genitals and conjunctivitis (red and swollen eyes). The rash may progress to widespread 

blistering or peeling of the skin. 

 

If you have developed Stevens-Johnson Syndrome with the use of febuxostat, you must not be 

re-started on Febuxostat Mylan at any time. If you develop a rash or these skin symptoms, seek 

immediate advice from a doctor and tell them that you are taking this medicine. 

 

If you are having a gout attack at the moment (a sudden onset of severe pain, tenderness, 

redness, warmth and swelling in a joint), wait for the gout attack to subside first before starting 

treatment with Febuxostat Mylan. 

 

For some people, gout attacks may flare up when starting certain medicines that control uric 

acid levels. Not everyone gets flares, but you could get a flare-up even if you are taking 

Febuxostat Mylan, and especially during the first weeks or months of treatment. It is important 

to keep taking Febuxostat Mylan even if you have a flare, as Febuxostat Mylan is still working 

to lower uric acid. Over time, gout flares will occur less often and be less painful if you keep 

taking Febuxostat Mylan every day. 

 

Your doctor will often prescribe other medicines, if they are needed, to help prevent or treat the 

symptoms of flares (such as pain and swelling in a joint). 

 

In patients with very high urate levels (e.g. those undergoing cancer chemotherapy), treatment 

with uric acid-lowering medicines could lead to the build-up of xanthine in the urinary tract, 

with possible stones, even though this has not been observed in patients being treated with 

febuxostat for Tumor Lysis Syndrome. 

 

Your doctor may ask you to have blood tests to check that your liver is working normally. 

 

Children and adolescents 

 

Do not give this medicine to children under the age of 18 because the safety and efficacy have 

not been established. 



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Other medicines and Febuxostat Mylan 

 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines, including medicines obtained without a prescription. 

It is especially important to tell your doctor or pharmacist if you are taking medicines 

containing any of the following substances as they may interact with Febuxostat Mylan and 

your doctor may wish to consider necessary measures: 

• Mercaptopurine (used to treat cancer) 

• Azathioprine (used to reduce immune response) 

• Theophylline (used to treat asthma) 
 

Pregnancy and breast-feeding 

 

It is not known if febuxostat may harm your unborn child. Febuxostat Mylan should not be used 

during pregnancy. It is not known if febuxostat may pass into human breast milk. You should 

not use Febuxostat Mylan if you are breast-feeding, or if you are planning to breast-feed. 

 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, 

ask your doctor or pharmacist for advice before taking this medicine. 

 

Driving and using machines 

 

Be aware that you may experience dizziness, sleepiness, blurred vision and numbness or 

tingling sensation during treatment and should not drive or operate machines if affected. 

 

Lactose and Sodium content 

 

Febuxostat Mylan tablets contain lactose (a type of sugar). If you have been told by your doctor 

that you have an intolerance to some sugars, contact your doctor before taking this medicine. 

 

Febuxostat Mylan contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 

‘sodium-free’ 

 

3. How to take Febuxostat Mylan 

 

Always take this medicine exactly as your doctor has told you. Check with your doctor or 

pharmacist if you are not sure. 

 

• The usual dose is one tablet daily. The back of the calendar blister pack is marked with 
the days of the week to help you check that you have taken a dose each day. 

• The tablets should be taken by mouth and can be taken with or without food. 
 

Gout 

Febuxostat Mylan is available as either an 80 mg tablet or a 120 mg tablet. Your doctor will 

have prescribed the strength most suitable for you. 

 

Continue to take Febuxostat Mylan every day even when you are not experiencing gout flare or 

attack. 

 

Prevention and treatment of high uric acid levels in patients undergoing cancer chemotherapy 

Febuxostat Mylan is available as a 120 mg tablet. 

Start taking Febuxostat Mylan two days before chemotherapy and continue its use according to 

your doctor’s advice. Usually treatment is short-term. 

 



67 

 

If you take more Febuxostat Mylan than you should 

 

In the event of an accidental overdose ask your doctor what to do, or contact your nearest 

accident and emergency department. 

 

If you forget to take Febuxostat Mylan 

 

If you miss a dose of Febuxostat Mylan take it as soon as you remember unless it is almost time 

for your next dose, in which case miss out the forgotten dose and take your next dose at the normal 

time. Do not take a double dose to make up for a forgotten dose. 

 

If you stop taking Febuxostat Mylan 

 

Do not stop taking Febuxostat Mylan without the advice of your doctor even if you feel better. 

If you stop taking Febuxostat Mylan your uric acid levels may begin to rise and your symptoms 

may worsen due to the formation of new crystals of urate in and around your joints and kidneys. 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Stop taking this medicine and contact your doctor immediately or go to an emergency 

department nearby if the following rare (may affect up to 1 in 1,000 people) side effects occur, 

because a serious allergic reaction might follow: 

• anaphylactic reactions, drug hypersensitivity (see also section 2 “Warnings and 
precautions”) 

• potentially life-threatening skin rashes characterised by formation of blisters and 
shedding of the skin and inner surfaces of body cavities, e.g. mouth and genitals, painful 

ulcers in the mouth and/or genital areas, accompanied by fever, sore throat and fatigue 

(Stevens- Johnson Syndrome/ Toxic Epidermal Necrolysis), or by enlarged lymph nodes, 

liver enlargement, hepatitis (up to liver failure), raising of the white-cells count in the 

blood (drug reaction with eosinophilia and systemic symptoms-DRESS) (see section 2) 

• generalised skin rashes 
 

Other side effects which are not mentioned above are listed below. 

 

Common side effects (may affect up to 1 in 10 people) are: 

• abnormal liver test results 

• diarrhoea 

• headache 

• rash (including various types of rash, please see below under “uncommon” and “rare” 
sections) 

• nausea 

• increase in gout symptoms 

• localised swelling due to retention of fluids in tissues (oedema) 
 

Uncommon side effects (may affect up to 1 in 100 people) are: 

• decreased appetite, change in blood sugar levels (diabetes) of which a symptom may be 
excessive thirst, increased blood fat levels, weight increase 

• loss of sex drive 

• difficulty in sleeping, sleepiness 

• dizziness, numbness, tingling, reduced or altered sensation (hypoesthesia, hemiparesis or 



68 

 

paraesthesia), altered sense of taste, diminished sense of smell (hyposmia) 

• abnormal ECG heart tracing, irregular or rapid heartbeats, feeling your heart beat 
(palpitation) 

• hot flushes or flushing (e.g. redness of the face or neck), increased blood pressure, 
bleeding (haemorrhage, seen only in patients taking chemotherapy for blood disorders) 

• cough, shortness of breath, chest discomfort or pain, inflammation of nasal passage 
and/or throat (upper respiratory tract infection), bronchitis 

• dry mouth, abdominal pain/discomfort or wind, heartburn/indigestion, constipation, more 
frequent passing of stools, vomiting, stomach discomfort 

• itching, hives, skin inflammation, skin discoloration, small red or purple spots on the 
skin, small, flat red spots on the skin, flat, red area on the skin that is covered with small 

confluent bumps, rash, areas of redness and spots on the skin, other type of skin 

conditions 

• muscle cramp, muscle weakness, pain/ache in muscles/joints, bursitis or arthritis 
(inflammation of joints usually accompanied by pain, swelling and/or stiffness), pain in 

extremity, back pain, muscle spasm 

• blood in the urine, abnormal frequent urination, abnormal urine tests (increased level of 
proteins in the urine), a reduction in the ability of the kidneys to function properly 

• fatigue, chest pain, chest discomfort 

• stones in the gallbladder or in bile ducts (cholelithiasis) 

• increase in blood thyroid stimulating hormone (TSH) level 

• changes in blood chemistry or amount of blood cells or platelets (abnormal blood test 
results) 

• kidney stones 

• erectile difficulties 
 

Rare side effects (may affect up to 1 in 1,000 people) are: 

• muscle damage, a condition which on rare occasions can be serious. It may cause muscle 
problems and particularly, if at the same time, you feel unwell or have a high temperature 

it may be caused by an abnormal muscle breakdown. Contact your doctor immediately if 

you experience muscle pain, tenderness or weakness 

• severe swelling of the deeper layers of the skin, especially around the lips, eyes, genitals, 
hands, feet or tongue, with possible sudden difficult breathing 

• high fever in combination with measles-like skin rash, enlarged lymph nodes, liver 
enlargement, hepatitis (up to liver failure), raising of the white-cells count in the blood 

(leukocytosis, with or without eosinophilia) 

• reddening of the skin (erythema), rash in various types (e.g. itchy, with white spots, with 
blisters, with blisters containing pus, with shedding of the skin, measles-like rash), 

widespread erythema, necrosis, and bullous detachment of the epidermis and mucous 

membranes, resulting in exfoliation and possible sepsis (Stevens-Johnson 

Syndrome/Toxic epidermal necrolysis) 

• nervousness 

• feeling thirsty 

• ringing in the ears 

• blurred vision, change in vision 

• hair loss 

• mouth ulceration 

• inflammation of the pancreas: common symptoms are abdominal pain, nausea and 
vomiting 

• increased sweating 

• weight decrease, increased appetite, uncontrolled loss of appetite (anorexia) 

• muscle and/or joint stiffness 

• abnormally low blood cell counts (white or red blood cells or platelets) 

• urgent need to urinate 



69 

 

• changes or decrease in urine amount due to inflammation in the kidneys (tubulointerstitial 
nephritis) 

• inflammation of the liver (hepatitis) 

• yellowing of the skin (jaundice) 

• liver damage 

• increased level of creatine phosphokinase in blood (an indicator of muscle damage) 

• sudden cardiac death 
 

 

Reporting of side effects 

 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national 

reporting system listed in Appendix V. By reporting side effects you can help provide more 

information on the safety of this medicine. 

 

 

5. How to store Febuxostat Mylan 

 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the packaging after ‘EXP.’ The 

expiry date refers to the last day of that month. 

For bottles, after first opening use within 180 days 

This medicine does not require any special storage conditions. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 

how to throw away medicines you no longer use. These measures will help protect the 

environment. 

 

 

6. Contents of the pack and other information 

 

What Febuxostat Mylan contains 

 

The active substance is febuxostat. Each tablet contains 80 mg or 120 mg of febuxostat. 

 

The other ingredients are: 

Tablet core: lactose (see section 2, “Febuxostat Mylan contains lactose”), microcrystalline 

cellulose, magnesium stearate, hydroxypropylcellulose, croscarmellose sodium, colloidal 

hydrated silica, colloidal anhydrous silica, crospovidone and talc. 

Film-coating: hypromellose, titanium dioxide (E171), ethylcellulose, iron oxide yellow (E172), 

triacetin and iron oxide black (E172). 

 

What Febuxostat Mylan looks like and contents of the pack 

 

Febuxostat Mylan film-coated tablets are yellow, capsule shaped, biconvex tablets. The 80 mg 

tablets are marked with M on one side of the tablet and FX3 on the other side. The 120 mg 

tablets are marked with M on one side of the tablet and FX4 on the other side. 

 

Febuxostat Mylan 80 mg and 120 mg film-coated tablets are available in blister packs of 14, 28, 

42 and 84 tablets, calendar blister packs of 28 and 84 tablets, and perforated unit dose blister 

packs of 28 x 1 tablets and in multipacks of 84 film-coated tablets comprising 2 packs, each 

containing 42 film-coated tablets. 

 

Febuxostat Mylan 80 mg and 120 mg film-coated tablets are available in plastic bottles of 28 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


70 

 

and 84 tablets.  

Not all pack sizes may be marketed. 

 

 

Marketing Authorisation Holder 

Mylan S.A.S. 

117 Allee des Parcs 

69 800 Saint Priest 

France 

 

Manufacturer 

Mylan Hungary Kft 

Mylan utca 1 

H-2900 Komárom 

Hungary 

 

McDermott Laboratories Limited trading as Gerard Laboratories 

35/36 Baldoyle Industrial Estate 

Grange Road 

Dublin 13 

Ireland 

 

Mylan Germany GmbH 

Zweigniederlassung Bad Homburg v. d. Hoehe, Benzstrasse 1 

Bad Homburg v. d. Hoehe 

Hessen, 61352,  

Germany 

 

For any information about this medicine, please contact the local representative of the 

Marketing 

Authorisation Holder. 

 

België/Belgique/Belgien 

Mylan bvba/sprl 

Tél/Tel: + 32 (0)2 658 61 00 

 

Lietuva 

BGP Products UAB 

Tel: +370 5 205 1288 

 

България 

Майлан ЕООД 

Тел: +359 2 44 55 400 

Luxembourg/Luxemburg 

Mylan bvba/sprl 

Tel: + 32 (0)2 658 61 00 

(Belgique/Belgien) 

Česká republika 

Mylan Healthcare CZ s.r.o. 

Tel: +420 222 004 400 

 

Magyarország 

Mylan EPD Kft 

Tel: + 36 1 465 2100 

Danmark 

Mylan Denmark ApS 

Tel: +45 28 11 69 32 

 

Malta 

V.J. Salomone Pharma Ltd 

Tel: + 356 21 22 01 74 

Deutschland 

Mylan Healthcare GmbH  

Tel: +49 800 0700 800 

 

Nederland 

Mylan BV 

Tel: +31 (0)20 426 3300 

Eesti 

BGP Products Switzerland GmbH Eesti filiaal 

Norge 

Mylan Healthcare Norge AS 



71 

 

Tel: + 372 6363 052 

 

Tel: + 47 66 75 33 00 

 

Ελλάδα  

Generics Pharma Hellas ΕΠΕ  

Τηλ: +30 210 993 6410  

 

Österreich 

Arcana Arzneimittel GmbH 

Tel: +43 1 416 2418 

 

España 

Mylan Pharmaceuticals, S.L 

Tel: + 34 900 102 712 

 

Polska 

Mylan Healthcare Sp. z o.o. 

Tel: + 48 22 546 64 00 

France 

Mylan S.A.S 

Tel: +33 4 37 25 75 00 

 

Portugal 

Mylan, Lda. 

Tel: + 351 21 412 72 56 

 

Hrvatska 

Mylan Hrvatska d.o.o. 

Tel: +385 1 23 50 599 

 

România 

BGP Products SRL 

Tel: +40 372 579 000 

 

Ireland 

Mylan Ireland Limited 

Tel: +353 (0) 87 1694982 

 

Slovenija 

Mylan Healthcare d.o.o 

Tel: + 386 1 23 63 180 

 

Ísland 

Icepharma hf  

Tel: +354 540 8000 

 

Slovenská republika 

Mylan s.r.o. 

Tel: +421 2 32 199 100 

 

Italia 

Mylan Italia S.r.l 

Tel: + 39 02 612 46921 

 

Suomi/Finland 

Mylan Finland OY 

Puh/Tel: +358 20 720 9555 

 

Κύπρος 

Varnavas Hadjipanayis Ltd  

Τηλ: +357 2220 7700 

 

Sverige 

Mylan AB  

Tel: + 46 855 522 750 

Latvija 

Mylan Healthcare SIA 

Tel: +371 676 055 80 

 

United Kingdom 

Generics [UK] Ltd 

Tel: +44 1707 853000 

 

This leaflet was last revised in 

 

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency website 

http://www.ema.europa.eu. 

 

http://www.ema.europa.eu./

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET