Febuxostat Krka

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Febuxostat Krka 80 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 80 mg febuxostat.

Excipient(s) with known effect
- lactose: 73 mg

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)

Off pink, oval, biconvex, film-coated tablets scored on one side. Tablet dimension: approximatelly 
16 mm × 8 mm. The score line is only to facilitate breaking for ease of swallowing and not to divide 
into equal doses.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Febuxostat Krka 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 Krka is indicated in adults.

4.2 Posology and method of administration

Posology

The recommended oral dose of Febuxostat Krka 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 Krka 120 mg once daily may be 
considered.

Febuxostat Krka 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.

Hepatic impairment
The efficacy and safety of febuxostat has not been studied in patients with severe hepatic impairment 
(Child Pugh Class C).



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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 efficacy of Febuxostat Krka in children below the age of 18 years have not been 
established. No data are available.

Method of administration

Oral use
Febuxostat Krka 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

Cardiovascular 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.

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.



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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

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 



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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 Krka contains lactose. Patients with rare hereditary problems of galactose intolerance, total 
lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicine 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.

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



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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 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 breastfeeding.

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 Krka 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 



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activities until they are reasonably certain that Febuxostat Krka 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
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



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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 



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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

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antigout preparations, 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 

IJ



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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), febxuostat 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 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)
1results 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 



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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

2

3

4

5

6

7

8

9

10

11

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

M
ea

n 
(±

S
E

M
) 

S
er

u
m

 U
ri

c 
A

ci
d

 L
ev

el
 (

m
g/

dL
)

Week

Febuxostat 80 mg

Allopurinol 

Placebo

Febuxostat 120 mg

Febuxostat 240 mg

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 



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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% 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.



13

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.

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 



14

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.

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



15

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

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 monohydrate
Cellulose, microcrystalline
Hydroxypropylcellulose
Croscarmellose sodium



16

Silica, colloidal hydrated
Magnesium stearate

Film coating

Poly(vinyl alcohol)
Macrogol 3350
Titanium dioxide (E171)
Talc
Iron oxide, red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blister (PVC/PVDC/PVC//Alu): 14, 28, 56 or 84 film-coated tablets, in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

14 film-coated tablets: EU/1/18/1347/001
28 film-coated tablets: EU/1/18/1347/002
56 film-coated tablets: EU/1/18/1347/003
84 film-coated tablets: EU/1/18/1347/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 28 March 2019

10. DATE OF REVISION OF THE TEXT

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



17

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



18

1. NAME OF THE MEDICINAL PRODUCT

Febuxostat Krka 120 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 120 mg febuxostat.

Excipient(s) with known effect
- lactose: 109 mg

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)

Brownish yellow, slightly biconvex, capsule shaped film-coated tablets scored on both sides. Tablet 
dimension: approximatelly 19 mm × 8 mm. The score line is only to facilitate breaking for ease of 
swallowing and not to divide into equal doses.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Febuxostat Krka 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 Krka 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 Krka is indicated in adults.

4.2 Posology and method of administration

Posology

Gout: The recommended oral dose of Febuxostat Krka 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 Krka 120 mg once daily may 
be considered.

Febuxostat Krka 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 reccomended oral dose of  Febuxostat Krka is 120 mg once daily without regard to food. 
Febuxostat Krka 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



19

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 efficacy of Febuxostat Krka in children below the age of 18 years have not been 
established. No data are available.

Method of administration

Oral use
Febuxostat Krka 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

Cardiovascular 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 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



20

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

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.



21

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 Krka contains lactose. Patients with rare hereditary problems of galactose intolerance, total 
lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicine 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 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.



22

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

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



23

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 breastfeeding.

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 Krka 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 Krka 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 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***



24

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
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 



25

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
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. 



26

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

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antigout preparations, 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



27

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), febxuostat 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 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)
1results 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.



28

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

2

3

4

5

6

7

8

9

10

11

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

M
ea

n
 (

±
S

E
M

) 
S

er
um

 U
ri

c 
A

ci
d 

L
ev

el
 (

m
g/

d
L

)

Week

Febuxostat 80 mg

Allopurinol 

Placebo

Febuxostat 120 mg

Febuxostat 240 mg

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 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) 



29

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 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.



30

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.

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 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 (AUCsUA1-8) and change in serum creatinine (sC) level both from 
baseline to Day 8.
Overall, 346 patients with haematological malignancies undergoing chemotherapy and at intermediate 



31

/ 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.

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 



32

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

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.



33

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 monohydrate
Cellulose, microcrystalline
Hydroxypropylcellulose
Croscarmellose sodium
Silica, colloidal hydrated
Magnesium stearate

Film coating

Poly(vinyl alcohol)
Macrogol 3350
Titanium dioxide (E171)
Talc
Iron oxide, yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blister (PVC/PVDC/PVC//Alu): 14, 28, 56 or 84 film-coated tablets, in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.



34

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

14 film-coated tablets: EU/1/18/1347/005
28 film-coated tablets: EU/1/18/1347/006
56 film-coated tablets: EU/1/18/1347/007
84 film-coated tablets: EU/1/18/1347/008

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 28 March 2019

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.



35

ANNEX II

A. MANUFACTURER(S) 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



36

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

KRKA, d.d., Novo mesto
Šmarješka cesta 6
8501 Novo mesto
Slovenia

TAD Pharma GmbH
Heinz-Lohmann-Straße 5
27472 Cuxhaven
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 (PSURs)

The requirements for submission of PSURs 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 marketing authorisation holder (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 or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.



37

ANNEX III

LABELLING AND PACKAGE LEAFLET



38

A. LABELLING



39

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

BOX

1. NAME OF THE MEDICINAL PRODUCT

Febuxostat Krka 80 mg film-coated tablets

febuxostat

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 80 mg febuxostat.

3. LIST OF EXCIPIENTS

Contains lactose.
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

film-coated tablet

14 film-coated tablets
28 film-coated tablets
56 film-coated tablets
84 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral 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



40

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

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

12. MARKETING AUTHORISATION NUMBER(S)

14 film-coated tablets: EU/1/18/1347/001
28 film-coated tablets: EU/1/18/1347/002
56 film-coated tablets: EU/1/18/1347/003
84 film-coated tablets: EU/1/18/1347/004

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Febuxostat Krka 80 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN



41

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

BOX

1. NAME OF THE MEDICINAL PRODUCT

Febuxostat Krka 120 mg film-coated tablets

febuxostat

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 120 mg febuxostat.

3. LIST OF EXCIPIENTS

Contains lactose.
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

film-coated tablet

14 film-coated tablets
28 film-coated tablets
56 film-coated tablets
84 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral 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



42

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

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

12. MARKETING AUTHORISATION NUMBER(S)

14 film-coated tablets: EU/1/18/1347/005
28 film-coated tablets: EU/1/18/1347/006
56 film-coated tablets: EU/1/18/1347/007
84 film-coated tablets: EU/1/18/1347/008

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Febuxostat Krka 120 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN



43

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER (PVC/PVDC/PVC//Alu)

1. NAME OF THE MEDICINAL PRODUCT

Febuxostat Krka 80 mg tablets

febuxostat

2. NAME OF THE MARKETING AUTHORISATION HOLDER

KRKA

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



44

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER (PVC/PVDC/PVC//Alu)

1. NAME OF THE MEDICINAL PRODUCT

Febuxostat Krka 120 mg tablets

febuxostat

2. NAME OF THE MARKETING AUTHORISATION HOLDER

KRKA

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



45

B. PACKAGE LEAFLET



46

Package leaflet: Information for the patient

Febuxostat Krka 80 mg film-coated tablets
Febuxostat Krka 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 Krka is and what it is used for
2. What you need to know before you take Febuxostat Krka
3. How to take Febuxostat Krka
4. Possible side effects
5. How to store Febuxostat Krka
6. Contents of the pack and other information

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

Febuxostat Krka 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 Krka works by reducing uric acid levels. Keeping uric acid levels low by taking Febuxostat 
Krka 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 Krka 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 Krka is for adults.

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

Do not take Febuxostat Krka
- if you are allergic to febuxostat or any of the other ingredients of this medicine (listed in section 

6).

Warnings and precautions
Talk to your doctor or pharmacist before taking Febuxostat Krka:
- if you have or have had heart failure or heart problems or stroke,
- if you have or have had kidney disease and/or serious allergic reaction to Allopurinol (a 

medicine used for the treatment of gout),



47

- 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 Krka, 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 Krka.

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 Krka at any time. If you develop a rash or these skin symptoms, seek 
immediate advice from a doctor and tell 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 before first starting treatment with 
Febuxostat Krka.

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 Krka, 
and especially during the first weeks or months of treatment. It is important to keep taking Febuxostat 
Krka even if you have a flare, as Febuxostat Krka is still working to lower uric acid. Over time, gout 
flares will occur less often and be less painful if you keep taking Febuxostat Krka 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.

Other medicines and Febuxostat Krka
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 Krka 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)



48

Pregnancy and breast-feeding
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.

It is not known if Febuxostat Krka may harm your unborn child. Febuxostat Krka should not be used 
during pregnancy. It is not known if Febuxostat Krka may pass into human breast milk. You should 
not take Febuxostat Krka if you are breast feeding, or if you are planning to breastfeed.

Driving and using machines
Be aware that you may experience dizziness, sleepiness, blurred vision and numbness or tingling 
sensation during treatment with this medicine and should not drive or operate machines if affected.

Febuxostat Krka contains lactose and sodium
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor
before taking this medicinal product.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’.

3. How to take Febuxostat Krka

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.

- The usual dose is one tablet daily. The score line is only there to help you break the tablet if you
have difficulty swallowing it whole.

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

Gout
Febuxostat Krka 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 Krka 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 Krka is available as a 120 mg tablet.
Start taking Febuxostat Krka two days before chemotherapy and continue its use according to your 
doctor’s advice. The treatment is usually short-term.

If you take more Febuxostat Krka 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 Krka
If you miss a dose of Febuxostat Krka 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 Krka
Do not stop taking Febuxostat Krka without the advice of your doctor even if you feel better. If you 
stop taking Febuxostat Krka 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



49

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.

The 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).

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

Uncommon (may affect up to 1 in 100 people):
- 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 

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 

(hemorrhage, 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 (may affect up to 1 in 1,000 people):
- 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 



50

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
- 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 Krka

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.

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 Krka contains
- The active substance is febuxostat.

Each film-coated tablet contains 80 mg febuxostat.
Each film-coated tablet contains 120 mg febuxostat.

- The other ingredients are lactose monohydrate, microcrystalline cellulose, 



51

hydroxypropylcellulose, croscarmellose sodium, colloidal hydrated silica and magnesium 
stearate in the tablet core and poly(vinyl alcohol), macrogol 3350, titanium dioxide (E171), talc, 
yellow iron oxide (E172) - only for 120 mg film-coated tablets and red iron oxide (E172) - only 
for 80 mg film-coated tablets in the film coating.
See section 2 "Febuxostat Krka contains lactose and sodium".

What Febuxostat Krka looks like and contents of the pack
Febuxostat Krka 80 mg film-coated tablets (tablets) are off pink, oval, biconvex, film-coated tablets 
scored on one side. Tablet dimension: approximatelly 16 mm × 8 mm. The score line is only to 
facilitate breaking for ease of swallowing and not to divide into equal doses.
Febuxostat Krka 120 mg film-coated tablets (tablets) are brownish yellow, slightly biconvex, capsule 
shaped film-coated tablets scored on both sides. Tablet dimension: approximatelly 19 mm × 8 mm. 
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

Febuxostat Krka is available in boxes containing 14, 28, 56 or 84 film-coated tablets in blisters.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

Manufacturer
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
TAD Pharma GmbH, Heinz-Lohmann-Straße 5, 27472 Cuxhaven, Germany

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
KRKA Belgium, SA.
Tél/Tel: + 32 (0) 487 50 73 62

Lietuva
UAB KRKA Lietuva
Tel: + 370 5 236 27 40

България
КРКА България ЕООД
Teл.: + 359 (02) 962 34 50

Luxembourg/Luxemburg
KRKA Belgium, SA.
Tél/Tel: + 32 (0) 487 50 73 62 (BE)

Česká republika
KRKA ČR, s.r.o.
Tel: + 420 (0) 221 115 150

Magyarország
KRKA Magyarország Kereskedelmi Kft.
Tel.: + 36 (1) 355 8490

Danmark
KRKA Sverige AB
Tlf: + 46 (0)8 643 67 66 (SE)

Malta
E. J. Busuttil Ltd.
Tel: + 356 21 445 885

Deutschland
TAD Pharma GmbH
Tel: + 49 (0) 4721 606-0

Nederland
KRKA Belgium, SA.
Tel: + 32 (0) 487 50 73 62 (BE)

Eesti
KRKA, d.d., Novo mesto Eesti filiaal
Tel: + 372 (0) 6 671 658

Norge
KRKA Sverige AB
Tlf: + 46 (0)8 643 67 66 (SE)

Ελλάδα
QUALIA PHARMA S.A.
Τηλ: + 30 210 6256177

Österreich
KRKA Pharma GmbH, Wien
Tel: + 43 (0)1 66 24 300

España
KRKA Farmacéutica, S.L.

Polska
KRKA-POLSKA Sp. z o.o.



52

Tel: + 34 911 61 03 81 Tel.: + 48 (0)22 573 7500

France
KRKA France Eurl
Tél: + 33 (0)1 57 40 82 25

Portugal
KRKA Farmacêutica, Sociedade Unipessoal Lda.
Tel: + 351 (0)21 46 43 650

Hrvatska
KRKA - FARMA d.o.o.
Tel: + 385 1 6312 100

România
KRKA Romania S.R.L., Bucharest
Tel: + 4 021 310 66 05

Ireland
KRKA Pharma Dublin, Ltd.
Tel: + 353 1 293 91 80

Slovenija
KRKA, d.d., Novo mesto
Tel: + 386 (0) 1 47 51 100

Ísland
LYFIS ehf.
Sími: + 354 534 3500

Slovenská republika
KRKA Slovensko, s.r.o.
Tel: + 421 (0) 2 571 04 501

Italia
KRKA Farmaceutici Milano S.r.l.
Tel: + 39 02 3300 8841

Suomi/Finland
KRKA Finland Oy
Puh/Tel: + 358 20 754 5330

Κύπρος
Kipa Pharmacal Ltd.
Τηλ: + 357 24 651 882

Sverige
KRKA Sverige AB
Tel: + 46 (0)8 643 67 66 (SE)

Latvija
KRKA Latvija SIA
Tel: + 371 6 733 86 10

United Kingdom
Krka UK Ltd.
Tel: +44 (0)207 400 3352

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) 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