4.1. Therapeutic indications

ELSTABYA 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).

ELSTABYA 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).

ELSTABYA is indicated in adults.

4.2. Posology and method of administration

Posology

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

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

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

Tumor Lysis Syndrome: The recommended oral dose of ELSTABYA is 120 mg once daily without regard to food.

ELSTABYA should be started two days before the beginning of cytotoxic therapy and continued for a minimum of 7 days; however, treatment may be prolonged up to 9 days according to chemotherapy duration as per clinical judgment.

Elderly

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

Renal impairment

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

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

Hepatic impairment

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

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

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

Paediatric population

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

Method of administration

Oral use.

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

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

See also section 4.8.

4.4. Special warnings and precautions for use

Cardio-vascular disorders

Treatment of chronic hyperuricaemia

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

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

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

For further details on cardiovascular safety of febuxostat refer to 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 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 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. This has not been observed in the pivotal clinical study with febuxostat 120 mg 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.

Where the combination cannot be avoided, a reduction of the dose of mercaptopurine/azathioprine to the 20 % or less of the previously prescribed dose is recommended in order to avoid possible haematological effects (see sections 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 400mg 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).

Lactose

ELSTABYA tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product 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 myelo toxicity.

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 sections 4.4 and 5.3) The adequacy of the proposed dose adjustment, which was based on a modelling and simulation analysis from preclinical data in rats, was confirmed by the results of a clinical study in healthy volunteers, receiving azathioprine 100 mg alone and a reduced dose of azathioprine (25 mg) in combination with febuxostat (40 or 120 mg).

Interaction studies of febuxostat with other cytotoxic chemotherapy have not been conducted. 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 medicinal product 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, co-administration of 120 mg febuxostat QD with a single 4 mg oral dose of rosiglitazone had no effect on the pharmacokinetics of rosiglitazone and its metabolite N-desmethyl rosiglitazone, indicating that febuxostat is not a CYP2C8 enzyme inhibitor in vivo. Thus, co-administration of febuxostat with rosiglitazone or other CYP2C8 substrates is not expected to require any dose adjustment for those compounds.

Theophylline

An interaction study in healthy subjects has been performed with febuxostat to evaluate whether the inhibition of XO may cause an increase in the theophylline circulating levels as reported with other XO inhibitors. The results of the study showed that the co-administration of febuxostat 80 mg QD with theophylline 400 mg single dose has no effect on the pharmacokinetics or safety of theophylline.

Therefore no special caution is advised when febuxostat 80 mg and theophylline are given concomitantly.

No data is available for febuxostat 120 mg.

Naproxen and other inhibitors of glucuronidation

Febuxostat metabolism depends on Uridine Glucuronosyl Transferase (UGT) enzymes. Medicinal products that inhibit glucuronidation, such as NSAIDs and probenecid, could in theory affect the elimination of febuxostat. In healthy subjects concomitant use of febuxostat and naproxen 250 mg twice daily was associated with an increase in febuxostat exposure (Cmax 28 %, AUC 41 % and t1/2 26 %). In clinical studies the use of naproxen or other NSAIDs/Cox-2 inhibitors was not related to any clinically significant increase in adverse events.

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

Inducers of glucuronidation

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

Colchicine/indometacin/hydrochlorothiazide/warfarin

Febuxostat can be co-administered with colchicine or indomethacin with no dose adjustment of febuxostat or the co-administered active substance being necessary.

No dose adjustment is necessary for febuxostat when administered with hydrochlorothiazide.

No dose adjustment is necessary for warfarin when administered with febuxostat. Administration of febuxostat (80 mg or 120 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. INR and Factor VII activity were also not affected by the co-administration of febuxostat.

Desipramine/CYP2D6 substrates

Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro. In a study in healthy subjects, 120 mg febuxostat QD resulted in a mean 22 % increase in AUC of desipramine, a CYP2D6 substrate indicating a potential weak inhibitory effect of febuxostat on the CYP2D6 enzyme in vivo.

Thus, co-administration of febuxostat with other CYP2D6 substrates is not expected to require any dose adjustment for those compounds.

Antacids

Concomitant ingestion of an antacid containing magnesium hydroxide and aluminium hydroxide has been shown to delay absorption of febuxostat (approximately 1 hour) and to cause a 32 % decrease in Cmax, but no significant change in AUC was observed. Therefore, febuxostat may be taken without regard to antacid use.

4.6. Fertility, pregnancy and lactation

Pregnancy

Data on a very limited number of exposed pregnancies have not indicated any adverse reactions 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.

ELSTABYA 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. ELSTABYA should not be used while breast-feeding.

Fertility

In animals, reproduction studies up to 48 mg/kg/day showed no dose- dependent adverse reactions on fertility (see section 5.3). The effect of febuxostat on human fertility is unknown.

4.7. Effects on ability to drive and use machines

Somnolence, dizziness, paraesthesia and blurred vision have been reported with the use of febuxostat. Patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that ELSTABYA 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), post-authorisation safety studies (FAST study: 3 001 subjects treated at least with a dose from 80 mg to 120 mg) and post-marketing experience in gout patients are gout flares, liver function abnormalities, diarrhoea, nausea, headache, dizziness, dyspnoea, rash, pruritus, arthralgia, myalgia, pain in extremity, oedema and fatigue.

These adverse reactions were mostly mild or moderate in severity. Rare serious hypersensitivity reactions to febuxostat, some of which were associated to systemic symptoms, and rare events of sudden cardiac death have occurred in the post-marketing experience.

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-authorisation safety studies and post-marketing experience in gout patients

Blood and lymphatic system disorders

Rare

Pancytopenia, thrombocytopenia, agranulocytosis*, anaemia#

Immune system disorders

Rare

Anaphylactic reaction*, drug hypersensitivity*

Endocrine disorders

Uncommon

Blood thyroid stimulating hormone increased, hypothyroidism#

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, depressed mood#, sleep disorder#

Nervous system disorders

Common

Headache, dizziness

Uncommon

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

Rare

Ageusia#, burning sensation#

Eye disorders

Uncommon

Blurred vision

Rare

Retinal artery occlusion#

Ear and labyrinth disorders

Uncommon

Tinnitus

Rare

Vertigo#

Cardiac disorders

Uncommon

Atrial fibrillation, palpitations, ECG abnormal, arrhythmia#, 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)

Rare

Circulatory collapse#

Respiratory system disorders

Common

Dyspnoea

Uncommon

Bronchitis, upper respiratory tract infection, lower respiratory tract 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#

Hepatobiliary disorders

Common

Liver function abnormalities**

Uncommon

Cholelithiasis

Rare

Hepatitis, jaundice*, liver injury* cholecystitis#

Skin and subcutaneous tissue disorders

Common

Rash (including various types of rash reported with lower frequencies, see below), pruritus

Uncommon

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

Rare

Toxic epidermal necrolysis*, Stevens- Johnson Syndrome*, angioedema*, drug reaction with eosinophilia and systemic symptoms*, generalized rash (serious)*, exfoliative rash, rash follicular, rash vesicular, rash pustular, rash erythematous, rash morbillifom

Musculoskeletal and connective tissue disorders

Common

Arthralgia, pain in extremity#

Uncommon

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

Rare

Rhabdomyolysis*, rotator cuff syndrome#, polymyalgia rheumatica#

Renal and urinary disorders

Uncommon

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

Rare

Tubulointerstitial nephritis*

Reproductive system and breast disorders

Uncommon

Erectile dysfunction

General disorders and administration site conditions

Common

Oedema, fatigue

Uncommon

Chest pain, chest discomfort, pain#, malaise#

Rare

Thirst, feeling hot#

Investigations

Uncommon

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

Rare

Blood glucose increase, activated partial thromboplastin time prolonged, red blood cell count decrease, blood alkaline phosphatase increase, blood creatine phosphokinase increase*

Injury, poisoning and procedural complications

Uncommon

Contusion#

* Adverse reactions coming from post-marketing experience

** Treatment-emergent non-infective diarrhoea and abnormal liver function tests in the combined Phase 3 studies are more frequent in patientsconcomitantly treated with colchicine.

*** See section 5.1 for incidences of gout flares in the individual Phase 3 randomized controlled studies.

# Adverse reactions coming from post-authorisation safety studies

Description of selected adverse reactions

Rare serious hypersensitivity reactions to febuxostat, including Stevens- Johnson Syndrome, Toxic epidermal necrolysis and anaphylactic reaction/shock, have occurred in the post-marketing experience. Stevens- Johnson Syndrome and Toxic epidermal necrolysis are characterised by progressive skin rashes associated with blisters or mucosal lesions and eye irritation. Hypersensitivity reactions to febuxostat can be associated to the following symptoms: skin reactions characterised by infiltrated maculopapular eruption, generalised or exfoliative rashes, but also skin lesions, facial oedema, fever, haematologic abnormalities such as thrombocytopenia and eosinophilia, and single or multiple organ involvement (liver and kidney including tubulointerstitial nephritis) (see section 4.4).

Gout flares were commonly observed soon after the start of treatment and during the first months. Thereafter, the frequency of gout flare decreases in a time-dependent manner. Gout flare prophylaxis is recommended (see section 4.2 and 4.4).

Tumor Lysis Syndrome

Summary of the safety profile

In the randomized, double-blind, Phase 3 pivotal FLORENCE (FLO-01) study comparing febuxostat with allopurinol (346 patients undergoing chemotherapy for haematologic malignancies and at intermediate-to-high risk of TLS), only 22 (6.4 %) patients overall experienced adverse reactions, namely 11 (6.4 %) patients in each treatment group. The majority of adverse reactions were either mild or moderate.

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

Cardiac disorders:

Uncommon: Left bundle branch block, sinus tachycardia

Vascular disorders:

Uncommon: haemorrhage

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to United Kingdom's Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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