ADENURIC 120mg tablets medication leaflet

M04AA03 febuxostat • Musculo-skeletal system | Antigout preparations | Preparations inhibiting uric acid production

General data about ADENURIC 120mg

Substance: febuxostat

Date of last drug list: 01-01-2025

Commercial code: W57781003

Concentration: 120mg

Pharmaceutical form: tablets

Quantity: 28

Product type: original

Price: 64.28 RON

Prescription restrictions: P-RF - Medicines prescription that is retained in the pharmacy (not renewable).

Marketing authorisation

Manufacturer: PATHEON FRANCE - FRANTA

Holder: MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG S.A. - LUXEMBURG

Number: 447/2008/20

Shelf life: 3 years

Concentrations available for febuxostat

120mg, 80mg

Other substances similar to febuxostat

Contents of the package leaflet for the medicine ADENURIC 120mg tablets

1. NAME OF THE MEDICINAL PRODUCT

ADENURIC 120 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 120 mg of febuxostat.

Excipient(s) with known effects:

Each tablet contains 114.75 mg of lactose (as monohydrate)

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablets).

Pale yellow to yellow, film-coated, capsule shaped tablets, engraved with “120” on one side

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

ADENURIC is indicated for the treatment of chronic hyperuricaemia in conditions where uratedeposition has already occurred (including a history, or presence of, tophus and/or gouty arthritis).

ADENURIC is indicated for the prevention and treatment of hyperuricaemia in adult patientsundergoing chemotherapy for haematologic malignancies at intermediate to high risk of Tumor Lysis

Syndrome (TLS).

ADENURIC is indicated in adults.

4.2 Posology and method of administration

Posology

Gout: The recommended oral dose of ADENURIC is 80 mg once daily without regard to food. Ifserum uric acid is > 6 mg/dL (357 µmol/L) after 2-4 weeks, ADENURIC 120 mg once daily may beconsidered.

ADENURIC works sufficiently quickly to allow retesting of the serum uric acid after 2 weeks. Thetherapeutic target is to decrease and maintain serum uric acid below 6 mg/dL (357μmol/L).

Gout flare prophylaxis of at least 6 months is recommended (see section 4.4).

Tumor Lysis Syndrome: The recommended oral dose of ADENURIC is 120 mg once daily withoutregard to food.

ADENURIC should be started two days before the beginning of cytotoxic therapy and continued for aminimum of 7 days; however treatment may be prolonged up to 9 days according to chemotherapyduration as per clinical judgment.

Elderly

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

Renal impairment

The efficacy and safety have not been fully evaluated in patients with severe renal impairment(creatinine clearance <30 mL/min, see section 5.2).

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

Hepatic impairment

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

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

Tumour Lysis Syndrome: in the pivotal Phase III trial (FLORENCE) only subjects with severe hepaticinsufficiency were excluded from trial participation. No dose adjustment was required for enrolledpatients on the basis of hepatic function.

Paediatric population

The safety and the efficacy of ADENURIC in children aged below the age of 18 years have not beenestablished. No data are available.

Method of administration

Oral use

ADENURIC 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 alsosection 4.8).

4.4 Special warnings and precautions for use

Cardio-vascular disorders

Treatment of chronic hyperuricaemia

In patients with pre-existing major cardiovascular diseases (e.g. myocardial infarction, stroke orunstable angina), during the development of the product and in one post registrational study (CARES),a higher number of fatal cardiovascular events were observed with febuxostat when compared toallopurinol.

However, in a subsequent post registrational study (FAST), febuxostat was not inferior to allopurinolin the incidence of both fatal and non-fatal cardiovascular events.

Treatment of this patient group should be exercised cautiously and they should be monitored regularly.

For further details on cardiovascular safety of febuxostat refer to section 4.8 and section 5.1.

Prevention and treatment of hyperuricaemia in patients at risk of TLS

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

Tumor Lysis Syndrome treated with ADENURIC should be under cardiac monitoring as clinicallyappropriate.

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 inthe post-marketing experience. In most cases, these reactions occurred during the first month oftherapy with febuxostat. Some, but not all of these patients reported renal impairment and/or previoushypersensitivity to allopurinol. Severe hypersensitivity reactions, including Drug Reaction with

Eosinophilia and Systemic Symptoms (DRESS) were associated with fever, haematological, renal orhepatic involvement in some cases.

Patients should be advised of the signs and symptoms and monitored closely for symptoms ofallergic/hypersensitivity reactions (see section 4.8). Febuxostat treatment should be immediatelystopped if serious allergic/hypersensitivity reactions, including Stevens-Johnson Syndrome, occursince early withdrawal is associated with a better prognosis. If patient has developedallergic/hypersensitivity reactions including Stevens-Johnson Syndrome and acute anaphylacticreaction/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. Goutflares may occur during initiation of treatment due to changing serum uric acid levels resulting inmobilization of urate from tissue deposits (see sections 4.8 and 5.1). At treatment initiation withfebuxostat flare prophylaxis for at least 6 months with an NSAID or colchicine is recommended (seesection 4.2).

If a gout flare occurs during febuxostat treatment, it should not be discontinued. The gout flare shouldbe managed concurrently as appropriate for the individual patient. Continuous treatment withfebuxostat 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 itstreatment, 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 pivotalclinical study with ADENURIC in the Tumor Lysis Syndrome. As there has been no experience withfebuxostat, its use in patients with Lesch-Nyhan Syndrome is not recommended.

Mercaptopurine/azathioprine

Febuxostat use is not recommended in patients concomitantly treated withmercaptopurine/azathioprine as inhibition of xanthine oxidase by febuxostat may cause increasedplasma concentrations of mercaptopurine/azathioprine that could result in severe toxicity.

Where the combination cannot be avoided, a reduction of the dose of mercaptopurine/azathioprine tothe 20% or less of the previously prescribed dose is recommended in order to avoid possiblehaematological effects (see sections 4.5 and 5.3).

The patients should be closely monitored and the dose of mercaptopurine/azathioprine should besubsequently adjusted based on the evaluation of the therapeutic response and the onset of eventualtoxic effects.

Organ transplant recipients

As there has been no experience in organ transplant recipients, the use of febuxostat in such patients isnot recommended (see section 5.1).

Theophylline

Co-administration of febuxostat 80 mg and theophylline 400mg single dose in healthy subjectsshowed absence of any pharmacokinetic interaction (see section 4.5). Febuxostat 80 mg can be used inpatients 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 inpatients treated with febuxostat (5.0%). Liver function test is recommended prior to the initiation oftherapy 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 withfebuxostat (5.5%) in the long term open label extension studies. Caution is required when febuxostat isused in patients with alteration of thyroid function (see section 5.1).

Lactose

Febuxostat tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the

Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

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 notrecommended. Inhibition of XO by febuxostat may cause increased plasma concentrations of thesedrugs leading to myelotoxicity.

In case of concomitant administration with febuxostat, the dose of mercaptopurine/azathioprine shouldbe reduced to the 20% or less of the previously prescribed dose (see sections 4.4 and 5.3).

The adequacy of the proposed dose adjustment, which was based on a modelling and simulationanalysis from preclinical data in rats, was confirmed by the results of a clinical drug-drug interactionstudy in healthy volunteers, receiving azathioprine 100 mg alone and a reduced dose of azathioprine(25 mg) in combination with febuxostat (40 or 120 mg).

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 patientsundergoing several chemotherapy regimens, including monoclonal antibodies. However, drug-drugand drug-disease interactions were not explored during this study. Therefore, possible interactionswith 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 effecton the pharmacokinetics of rosiglitazone and its metabolite N-desmethyl rosiglitazone, indicating thatfebuxostat is not a CYP2C8 enzyme inhibitor in vivo. Thus, co-administration of febuxostat withrosiglitazone or other CYP2C8 substrates is not expected to require any dose adjustment for thosecompounds.

Theophylline

An interaction study in healthy subjects has been performed with febuxostat to evaluate whether theinhibition 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 QDwith 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 givenconcomitantly. No data is available for febuxostat 120 mg.

Naproxen and other inhibitors of glucuronidation

Febuxostat metabolism depends on Uridine Glucuronosyl Transferase (UGT) enzymes. Medicinalproducts that inhibit glucuronidation, such as NSAIDs and probenecid, could in theory affect theelimination of febuxostat. In healthy subjects concomitant use of febuxostat and naproxen 250mgtwice daily was associated with an increase in febuxostat exposure (Cmax 28%, AUC 41% and t1/226%). In clinical studies the use of naproxen or other NSAIDs/Cox-2 inhibitors was not related to anyclinically significant increase in adverse events.

Febuxostat can be co-administered with naproxen with no dose adjustment of febuxostat or naproxenbeing necessary.

Inducers of glucuronidation

Potent inducers of UGT enzymes might possibly lead to increased metabolism and decreased efficacyof febuxostat. Monitoring of serum uric acid is therefore recommended 1-2 weeks after start oftreatment with a potent inducer of glucuronidation. Conversely, cessation of treatment of an inducermight lead to increased plasma levels of febuxostat.

Colchicine/indometacin/hydrochlorothiazide/warfarin

Febuxostat can be co-administered with colchicine or indomethacin with no dose adjustment offebuxostat 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 offebuxostat (80 mg or 120 mg once daily) with warfarin had no effect on the pharmacokinetics ofwarfarin 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 ADENURIC QD resulted in a mean 22% increase in AUC of desipramine, a CYP2D6substrate 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 anydose adjustment for those compounds.

Antacids

Concomitant ingestion of an antacid containing magnesium hydroxide and aluminium hydroxide hasbeen 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 withoutregard 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 offebuxostat on pregnancy or on the health of the foetus/new born child. Animal studies do not indicatedirect or indirect harmful effects with respect to pregnancy, embryonal/foetal development orparturition (see section 5.3). The potential risk for human is unknown. Febuxostat should not be usedduring pregnancy.

Breastfeeding

It is unknown whether febuxostat is excreted in human breast milk. Animal studies have shownexcretion of this active substance in breast milk and an impaired development of suckling pups. A riskto 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 onfertility (see section 5.3). The effect of ADENURIC 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 dangerousactivities until they are reasonably certain that ADENURIC 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 adose from 10 mg to 300 mg), post-authorisation safety studies (FAST study: 3001 subjects treated atleast with a dose from 80 mg to 120 mg) and post-marketing experience in gout patients are goutflares, liver function abnormalities, diarrhoea, nausea, headache, dizziness, dyspnoea, rash,pruritus,arthralgia, myalgia, pain in extremity, oedema and fatigue. These adverse reactions weremostly mild or moderate in severity. Rare serious hypersensitivity reactions to febuxostat, some ofwhich were associated to systemic symptoms, and rare events of sudden cardiac death, have occurredin 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, post-authorisationsafety studies and post-marketing experience in gout patients

Blood and lymphatic system Raredisorders Pancytopenia, thrombocytopenia, agranulocytosis*, anaemia#

Immune system disorders Rare

Anaphylactic reaction*, drug hypersensitivity*

Endocrine disorders Uncommon

Blood thyroid stimulating hormone increased, hypothyroidism#

Eye disorders Uncommon

Blurred vision

Rare

Retinal artery occlusion#

Metabolism and nutrition Common***disorders Gout flares

Uncommon

Diabetes mellitus, hyperlipidemia, decrease appetite, weightincrease

Rare

Weight decrease, increase appetite, anorexia

Psychiatric disorders Uncommon

Libido decreased, insomnia

Rare

Nervousness, depressed mood#, sleep disorder#

Nervous system disorders Common

Headache, dizziness

Uncommon

Paraesthesia, hemiparesis, somnolence, lethargy# altered taste,hypoaesthesia, hyposmia

Rare

Ageusia#, burning sensation#

Ear and labyrinth disorders Uncommon

Tinnitus

Rare

Vertigo#

Cardiac disorders Uncommon

Atrial fibrillation, palpitations, ECG abnormal, left bundle branchblock (see section Tumor Lysis Syndrome), sinus tachycardia (seesection Tumor Lysis Syndrome), arrhythmia#

Rare

Sudden cardiac death*

Vascular disorders Uncommon

Hypertension, flushing, hot flush, haemorrhage (see section

Tumor Lysis Syndrome)

Rare

Circulatory collapse#

Respiratory system disorders Common

Dyspnoea

Uncommon

Bronchitis, upper respiratory tract infection, lower respiratorytract infection#, cough, rhinorrhoea#

Rare

Pneumonia#

Gastrointestinal disorders Common

Diarrhoea**, nausea

Uncommon:

Abdominal pain, abdominal pain upper #, abdominal distension,gastro-oesophageal reflux disease, vomiting, dry mouth,dyspepsia, constipation, frequent stools, flatulence,gastrointestinal discomfort, mouth ulceration, lip swelling #,pancreatitis

Rare

Gastrointestinal perforation #, stomatitis#

Hepato-biliary disorders Common

Liver function abnormalities**

Uncommon

Cholelithiasis

Rare

Hepatitis, jaundice*, liver injury*, cholecystitis#

Skin and subcutaneous tissue Commondisorders Rash (including various types of rash reported with lowerfrequencies, see below), pruritus

Uncommon

Dermatitis, urticaria, skin discolouration, skin lesion, petechiae,rash macular, rash maculopapular, rash papular, hyperhidrosis,alopecia, eczema #, erythema, night sweats #, psoriasis#, rashpruritic#

Rare

Toxic epidermal necrolysis*, Stevens-Johnson Syndrome*,angioedema*, drug reaction with eosinophilia and systemicsymptoms*, generalized rash (serious)*, exfoliative rash, rashfollicular, rash vesicular, rash pustular, rash erythematous, rashmorbillifom

Musculoskeletal and connective Commontissue disorders Arthralgia, myalgia, pain in extremity#

Uncommon

Arthritis, musculoskeletal pain, muscle weakness, muscle spasm,muscle tightness, bursitis, joint swelling #, back pain #,musculoskeletal stiffness#, joint stiffness

Rare

Rhabdomyolysis*, rotator cuff syndrome #, polymyalgiarheumatica#

Renal and urinary disorders Uncommon

Renal failure, nephrolithiasis, haematuria, pollakiuria, proteinuria,micturition urgency, urinary tract infection#

Rare

Tubulointerstitial nephritis*

Reproductive system and breast Uncommondisorder Erectile dysfunction

General disorders and Commonadministration site conditions Oedema, Fatigue

Uncommon

Chest pain, chest discomfort, pain #, malaise#

Rare

Thirst, feeling hot#

Investigations Uncommon

Blood amylase increase, platelet count decrease, WBC decrease,lymphocyte count decrease, blood creatine increase, bloodcreatinine increase, haemoglobin decrease, blood urea increase,blood triglycerides increase, blood cholesterol increase,haematocritic decrease, blood lactate dehydrogenase increased,blood potassium increase, INR increased#

Rare

Blood glucose increase, activated partial thromboplastin timeprolonged, red blood cell count decrease, blood alkalinephosphatase increase, blood creatine phosphokinase increase*

Injury, poisoning and procedural Uncommoncomplications Contusion#

* Adverse reactions coming from post-marketing experience

** Treatment-emergent non-infective diarrhoea and abnormal liver function tests in thecombined 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 randomizedcontrolled studies.# Adverse reactions coming from post-authorisation safety studies

Description of selected adverse reactions

Rare serious hypersensitivity reactions to febuxostat, including Stevens-Johnson Syndrome, Toxicepidermal necrolysis and anaphylactic reaction/shock, have occurred in the post-marketing experience.

Stevens-Johnson Syndrome and Toxic epidermal necrolysis are characterised by progressive skinrashes associated with blisters or mucosal lesions and eye irritation. Hypersensitivity reactions tofebuxostat can be associated to the following symptoms: skin reactions characterised by infiltratedmaculopapular eruption, generalised or exfoliative rashes, but also skin lesions, facial oedema, fever,haematologic abnormalities such as thrombocytopenia and eosinophilia, and single or multiple organinvolvement (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 prophylaxisis 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 febuxostatwith allopurinol (346 patients undergoing chemotherapy for haematologic malignancies and atintermediate-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 mildor moderate.

Overall, the FLORENCE trial did not highlight any particular safety concern in addition to theprevious experience with ADENURIC in gout, with the exception of the following three adversereactions (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. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted 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 preparation, preparations inhibiting uric acid production, ATCcode: M04AA03

Mechanism of action

Uric acid is the end product of purine metabolism in humans and is generated in the cascade ofhypoxanthine → xanthine → uric acid. Both steps in the above transformations are catalyzed byxanthine oxidase (XO). Febuxostat is a 2-arylthiazole derivative that achieves its therapeutic effect ofdecreasing serum uric acid by selectively inhibiting XO. Febuxostat is a potent, non-purine selectiveinhibitor of XO (NP-SIXO) with an in vitro inhibition Ki value less than one nanomolar. Febuxostathas been shown to potently inhibit both the oxidized and reduced forms of XO. At therapeuticconcentrations febuxostat does not inhibit other enzymes involved in purine or pyrimidinemetabolism, namely, guanine deaminase, hypoxanthine guanine phosphoribosyltransferase, orotatephosphoribosyltransferase, orotidine monophosphate decarboxylase or purine nucleosidephosphorylase.

Clinical efficacy and safety

Gout

The efficacy of ADENURIC was demonstrated in three Phase 3 pivotal studies (the two pivotal APEXand FACT studies, and the additional CONFIRMS study, described below) that were conducted in4101 patients with hyperuricaemia and gout. In each phase 3 pivotal study, ADENURIC demonstratedsuperior ability to lower and maintain serum uric acid levels compared to allopurinol. The primaryefficacy endpoint in the APEX and FACT studies was the proportion of patients whose last 3 monthlyserum 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 ADENURIC was first issued,the primary efficacy endpoint was the proportion of patients whose serum urate level was < 6.0 mg/dLat the final visit. No patients with organ transplant have been included in these studies (see section4.2).

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), ADENURIC 80 mg QD (n=267), ADENURIC 120 mg

QD (n=269), ADENURIC 240 mg QD (n=134) or allopurinol (300 mg QD [n=258] for patients with abaseline serum creatinine ≤1.5 mg/dL or 100 mg QD [n=10] for patients with a baseline serumcreatinine >1.5 mg/dL and ≤2.0 mg/dL). Two hundred and forty mg febuxostat (2 times therecommended highest dose) was used as a safety evaluation dose.

The APEX study showed statistically significant superiority of both the ADENURIC 80 mg QD andthe ADENURIC 120 mg QD treatment arms versus the conventionally used doses of allopurinol300 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:

ADENURIC 80 mg QD (n=256), ADENURIC 120 mg QD (n=251), or allopurinol 300 mg QD(n=253).

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

ADENURIC 120 mg QD treatment arms versus the conventionally used dose of allopurinol 300 mgtreatment 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

Allopurinol

Study ADENURIC ADENURIC 300 /80 mg QD 120 mg QD 100 mg QD1

APEX 48% * 65% *, # 22%(28 weeks) (n=262) (n=269) (n=268)

FACT 53%* 62%* 21%(52 weeks) (n=255) (n=250) (n=251)

Combined 51%* 63%*, # 22%

Results (n=517) (n=519) (n=519)1 results from subjects receiving either 100 mg QD (n=10: patients withserum creatinine >1.5 and ≤2.0 mg/dL) or 300 mg QD (n=509) were pooledfor analyses.

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

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

Figure 1 Mean Serum Uric Acid Levels in Combined Pivotal Phase 3 Studies10 Placebo7 Allopurinol

ADENURIC 80 mg

ADENURIC 120 mg

ADENURIC 240 mg

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

Week

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 recommendedhighest dose.

Mean (±SEM) Serum Uric Acid Level (mg/dL)

CONFIRMS Study: The CONFIRMS study was a Phase 3, randomized, controlled, 26-week study toevaluate the safety and efficacy of febuxostat 40 mg and 80 mg, in comparison with allopurinol300 mg or 200 mg, in patients with gout and hyperuricaemia. Two thousand and two hundred-sixtynine (2269) patients were randomized: ADENURIC 40 mg QD (n=757), ADENURIC 80 mg QD(n=756), or allopurinol 300/200 mg QD (n=756). At least 65% of the patients had mild-moderate renalimpairment (with creatinine clearance of 30-89 mL/min). Prophylaxis against gout flares wasobligatory 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, was45% 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 serumcreatinine > 1.5 mg/dL and ≤2.0 mg/dL). For renally impaired subjects who were randomized toallopurinol, the dose was capped at 100 mg QD. ADENURIC achieved the primary efficacy endpointin 44% (80 mg QD), 45% (120 mg QD), and 60% (240 mg QD) of patients compared to 0% in theallopurinol 100 mg QD and placebo groups.

There were no clinically significant differences in the percent decrease in serum uric acidconcentration in healthy subjects irrespective of their renal function (58% in the normal renal functiongroup and 55% in the severe renal dysfunction group).

An analysis in patients with gout and renal impairment was prospectively defined in the CONFIRMSstudy, 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 moderaterenal 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. Inthis subgroup ADENURIC achieved the primary efficacy endpoint (sUA < 6.0 mg/dL at the last 3visits) in 41% (80 mg QD), 48% (120 mg QD), and 66% (240 mg QD) of patients compared to 9% inthe 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 withfebuxostat 40 mg QD was 27% (66/249), with febuxostat 80 mg QD 49% (125/254) and withallopurinol 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 febuxostat120 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 andgradually decreased over time. Between 46% and 55% of subjects received treatment for gout flaresfrom Week 8 and Week 28. Gout flares during the last 4 weeks of the study (Weeks 24-28) wereobserved 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 febuxostat120 mg (36%) treatment group required treatment for a gout flare compared to both the febuxostat80 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 subjectsreceived 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) ofsubjects.

The proportion of subjects requiring treatment for a gout flare (APEX and FACT Study) wasnumerically 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 uratelevel ≥6.0 mg/dL during the last 32 weeks of the treatment period (Week 20-Week 24 to Week 49 - 52intervals).

During the CONFIRMS study, the percentages of patients who required treatment for gout flares (Day1 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 betweenthe 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: ADENURIC 80 mg QD(n=649), Adenuric 120 mg QD (n=292) and allopurinol 300/100 mg QD (n=145). About 69 % ofpatients required no treatment change to achieve a final stable treatment. Patients who had 3consecutive 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 withfebuxostat 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 patientsrequiring 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, hadcomplete 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 studyfor 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 nodose adjustment to maintain sUA <6 mg/dL and 38% of patients required a dose adjustment to achievea final stable dose.

The proportion of patients with serum urate levels of <6.0 mg/dL (357 µmol/L) at the final visit wasgreater than 80% (81-100%) at each febuxostat dose.

During the phase 3 clinical studies, mild liver function test abnormalities were observed in patientstreated 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-termtreatment with febuxostat (5.5%) and patients with allopurinol (5.8%) in the long term open labelextension studies (see section 4.4).

Post Marketing long term studies

CARES Study was a multicenter, randomized, double-blind, non inferiority trial comparing CVoutcomes with febuxostat versus allopurinol in patients with gout and a history of major CVdisease including MI, hospitalization for unstable angina, coronary or cerebral revascularizationprocedure, stroke, hospitalized transient ischemic attack, peripheral vascular disease, or diabetesmellitus with evidence of microvascular or macrovascular disease. To achieve sUA less than 6mg/dL, the dose of febuxostat was titrated from 40 mg up to 80 mg (regardless of renalfunction) and the dose of allopurinol was titrated in 100 mg increments from 300 to 600 mg inpatients with normal renal function and mild renal impairment and from 200 to 400 mg inpatients 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-blindstudy medication.

Overall 56.6% of patients discontinued trial treatment prematurely and 45% of patients did notcomplete all trial visits.

In total, 6,190 patients were followed for a median of 32 months and the median duration of exposurewas 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 treatmentgroups (10.8% vs. 10.4% of patients, respectively; hazard ratio [HR] 1.03; two-sided repeated 95%confidence interval [CI] 0.89-1.21).

In the analysis of the individual components of MACE, the rate of CV deaths was higher withfebuxostat than allopurinol (4.3% vs. 3.2% of patients; HR 1.34; 95% CI 1.03-1.73). The rates of theother 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 thanallopurinol (7.8% vs. 6.4% of patients; HR 1.22; 95% CI 1.01-1.47), which was mainly driven by thehigher rate of CV deaths in that group (see section 4.4).

Rates of adjudicated hospitalization for heart failure, hospital admissions for arrhythmias notassociated with ischemia, venous thromboembolic events and hospitalization for transient ischemicattacks were comparable for febuxostat and allopurinol.

FAST study was a prospective, randomised, open-label, blinded-endpoint study comparing the CVsafety profile of febuxostat versus allopurinol in patients with chronic hyperuricaemia (in conditionswhere urate deposition had already occurred) and CV risk factors (i.e. patients 60 years or older andwith at least one other CV risk factor). Eligible patients received allopurinol treatment prior torandomization, and dose adjustments were required when needed, according to clinical judgement,

EULAR recommendations and the approved posology. At the end of the allopurinol lead-in phase,patients with a sUA level of <0.36 mmol/L (<6 mg/dL) or receiving the maximum tolerated dose orthe maximum licensed dose of allopurinol were randomised in a 1:1 ratio to receive either febuxostator allopurinol treatment. The primary endpoint of the study FAST was the time to the first occurrenceof any event included in the Antiplatelet Trialists’ Collaborative (APTC) composite endpoint, whichincluded: i) hospitalisation for non-fatal MI/biomarker positive acute coronary syndrome (ACS); ii)non-fatal stroke; iii) death due to a CV event. The primary analysis was based on the on-treatment(OT) approach.

Overall, 6,128 patients were randomized, 3063 to febuxostat and 3065 to allopurinol.

In the primary OT analysis, febuxostat was non-inferior to allopurinol in the incidence of the primaryendpoint, which occurred in 172 patients (1.72/100 patient years) on febuxostat compared to 241patients (2.05/100 patient years) on allopurinol, with an adjusted HR 0.85 (95% CI: 0.70, 1.03),p<0.001. The OT analysis for the primary endpoint in the subgroup of patients with a history of MI,stroke or ACS showed no significant difference between treatment groups: there were 65 (9.5%)patients with events in the febuxostat group and 83 (11.8%) patients with events in the allopurinolgroup; adjusted HR 1.02 (95% CI: 0.74-1.42); p=0.202.

Treatment with febuxostat was not associated with an increase in CV death or all-cause death, overallor in the subgroup of patients with a baseline history of MI, stroke or ACS. Overall, there were fewerdeaths in the febuxostat group (62 CV deaths and 108 all-cause deaths), than in the allopurinol group(82 CV deaths and 174 all-cause deaths).

There was a greater reduction in uric acid levels on febuxostat treatment compared to allopurinoltreatment.

Tumor Lysis Syndrome

The efficacy and safety of ADENURIC in the prevention and treatment of Tumor Lysis Syndromewas evaluated in the FLORENCE (FLO-01) study. ADENURIC showed a superior and faster uratelowering activity compared to allopurinol.

FLORENCE was a randomized (1:1), double blind, phase III, pivotal trial comparing ADENURIC 120mg 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 candidatesfor allopurinol treatment or have no access to rasburicase. Primary endpoints were serum uric acid areaunder the curve (AUC sUA1-8) and change in serum creatinine (sC) level both from baseline to Day 8.

Overall, 346 patients with haematological malignancies undergoing chemotherapy and at intermediate/ high risk of Tumor Lysis Syndrome were included. Mean AUC sUA1-8 (mgxh/dl) was significantlylower with ADENURIC (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 acidlevel was significantly lower with ADENURIC since the first 24 hours of treatment and at anyfollowing time point. No significant difference in mean serum creatinine change (%) occurredbetween ADENURIC and allopurinol (-0.83 ± 26.98 vs -4.92 ± 16.70 respectively; least square meansdifference: 4.0970 [95% confidence interval: -0.6467 ; 8.8406]; p=0.0903). With regard to secondaryendpoints, no significant difference was detected in terms of incidence of laboratory TLS (8.1% and9.2% in ADENURIC 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 ADENURIC and allopurinol arm,respectively; relative risk: 0.994 [95% confidence interval: 0.9691 ; 1.0199]; p=1.0000). Incidence ofoverall treatment-emergent signs and symptoms and adverse drug reactions was 67.6% vs 64.7% and6.4% vs 6.4% with ADENURIC and allopurinol respectively. In the FLORENCE study ADENURICdemonstrated a superior control of serum uric acid level compared to allopurinol in patients scheduledto receive the latter drug. No data comparing ADENURIC 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 concentrationtime curve (AUC) of febuxostat increased in a dose proportional manner following single and multipledoses of 10 mg to 120 mg. For doses between 120 mg and 300 mg, a greater than dose proportionalincrease in AUC is observed for febuxostat. There is no appreciable accumulation when doses of10 mg to 240 mg are administered every 24 hours. Febuxostat has an apparent mean terminalelimination half-life (t1/2) of approximately 5 to 8 hours.

Population pharmacokinetic/pharmacodynamic analyses were conducted in 211 patients withhyperuricaemia and gout, treated with ADENURIC 40-240 mg QD. In general, febuxostatpharmacokinetic parameters estimated by these analyses are consistent with those obtained fromhealthy subjects, indicating that healthy subjects are representative forpharmacokinetic/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 oral80 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, therewas a 49% and 38% decrease in Cmax and a 18% and 16% decrease in AUC, respectively. However, noclinically significant change in the percent decrease in serum uric acid concentration was observedwhere tested (80 mg multiple dose). Thus, ADENURIC 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 oraldoses of 10-300 mg. The plasma protein binding of febuxostat is approximately 99.2%, (primarily toalbumin), and is constant over the concentration range achieved with 80 and 120 mg doses. Plasmaprotein 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. Fourpharmacologically active hydroxyl metabolites have been identified, of which three occur in plasma ofhumans. In vitro studies with human liver microsomes showed that those oxidative metabolites wereformed primarily by CYP1A1, CYP1A2, CYP2C8 or CYP2C9 and febuxostat glucuronide wasformed 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 theirconjugates (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%), theacyl 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 ADENURIC in patients with mild, moderate or severe renalimpairment, the Cmax of febuxostat did not change, relative to subjects with normal renal function. Themean total AUC of febuxostat increased by approximately 1.8-fold from 7.5 µg⋅h/mL in the normalrenal function group to 13.2 µg.h/mL in the severe renal dysfunction group. The Cmax and AUC ofactive metabolites increased up to 2- and 4-fold, respectively. However, no dose adjustment isnecessary in patients with mild or moderate renal impairment.

Hepatic impairment

Following multiple doses of 80 mg of ADENURIC in patients with mild (Child-Pugh Class A) ormoderate (Child-Pugh Class B) hepatic impairment, the Cmax and AUC of febuxostat and itsmetabolites did not change significantly compared to subjects with normal hepatic function. Nostudies 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 followingmultiple oral doses of ADENURIC in elderly as compared to younger healthy subjects.

Gender

Following multiple oral doses of ADENURIC, the Cmax and AUC were 24% and 12% higher infemales than in males, respectively. However, weight-corrected Cmax and AUC were similar betweenthe 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 humanexposure.

Pharmacokinetic modelling and simulation of rat data suggests that, when co-administered withfebuxostat, the clinical dose of mercaptopurine/azathioprine should be reduced to 20% or less of thepreviously 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 papillomaand carcinoma) was found only in association with xanthine calculi in the high dose group, atapproximately 11 times human exposure. There was no significant increase in any other tumour typein either male or female mice or rats. These findings are considered a consequence of species specificpurine 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 effectsfor febuxostat.

Febuxostat at oral doses up to 48 mg/kg/day was found to have no effect on fertility and reproductiveperformance of male and female rats.

There was no evidence of impaired fertility, teratogenic effects, or harm to the foetus due tofebuxostat. There was high dose maternal toxicity accompanied by a reduction in weaning index andreduced development of offspring in rats at approximately 4.3 times human exposure. Teratologystudies, performed in pregnant rats at approximately 4.3 times and pregnant rabbits at approximately13 times human exposure did not reveal any teratogenic effects.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Magnesium stearate

Hydroxypropylcellulose

Croscarmellose sodium

Silica, colloidal hydrated

Tablet coating

Opadry II, Yellow, 85F42129 containing:

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogols 3350

Talc

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Clear (Aclar/PVC/Aluminium or PVC/PE/PVDC/Aluminium) blister of 14 tablets.

ADENURIC 120 mg is available in pack sizes of 14, 28, 42, 56, 84 and 98 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Menarini International Operations Luxembourg S.A.1, Avenue de la Gare, L-1611 Luxembourg

Luxembourg

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/447/003

EU/1/08/447/004

EU/1/08/447/009

EU/1/08/447/010

EU/1/08/447/011

EU/1/08/447/012

EU/1/08/447/019

EU/1/08/447/020

EU/1/08/447/021

EU/1/08/447/022

EU/1/08/447/023

EU/1/08/447/024

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 April 2008

Date of latest renewal: 20 December 2012

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