FEBUXOSTAT VIVANTA

Posology The recommended oral dose of febuxostat is 80 mg once daily without regard to food. If serum uric acid is > 6 mg/dL (357 μmol/L) after 2-4 weeks, febuxostat 120 mg once daily may be considered. Febuxostat works sufficiently quickly to allow retesting of the serum uric acid after 2 weeks.

The therapeutic target is to decrease and maintain serum uric acid below 6 mg/dL (357 μmol/L). 4). 2). 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).

The recommended dose in patients with mild hepatic impairment is 80 mg. Limited information is available in patients with moderate hepatic impairment. Paediatric population The safety and the efficacy of febuxostat in children aged below the age of 18 years have not been established.

No data are available. Method of administration Oral use Febuxostat tablets should be taken by mouth and can be taken with or without food.

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: 3001 subjects treated at least with a dose from 80 mg to 120 mg) and post-marketing experience are gout flares, liver function abnormalities, diarrhoea, nausea, headache, dizziness, dyspnoea, rash, pruritus,arthralgia, myalgia, pain in extremity, oedema and fatigue.

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

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, post- authorisation safety studies and post-marketing experience 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# Eye disorders Uncommon Blurred vision Rare Retinal artery occlusion# 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# Ear and labyrinth disorders Uncommon Tinnitus Rare Vertigo# Cardiac disorders Uncommon Atrial fibrillation, palpitations, ECG abnormal, arrhytmia# Rare Sudden cardiac death* Vascular disorders Uncommon Hypertension, flushing, hot flush 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# Hepato-biliary 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 morbilliform Musculoskeletal and connective tissue disorders Common Arthralgia, myalgia, pain in extremity# Uncommon Arthritis, musculoskeletal pain, muscle weakness, muscle spasm, muscle tightness, bursitis, joint swelling #, back pain#, musculoskeletal stiffness#, joint stiffness Rare Rhabdomyolysis*, rotator cuff syndrome#, polymyalgia rheumatica# Renal and urinary disorders Uncommon Renal failure, nephrolithiasis, haematuria, pollakiuria, proteinuria, micturition urgency, urinary tract infection# Rare Tubulointerstitial nephritis* Reproductive system and breast disorder Uncommon Erectile dysfunction General disorders and administration site conditions Common Oedema, Fatigue Uncommon Chest pain, chest discomfort, pain#, malaise# Rare Thirst, feeling hot# Investigations Uncommon Blood amylase increase, platelet count decrease, WBC decrease, lymphocyte count decrease, blood creatine increase, blood creatinine increase, haemoglobin decrease, blood urea increase, blood triglycerides increase, blood cholesterol increase, haematocritic decrease, blood lactate dehydrogenase increased, blood potassium increase, INR increased# Rare Blood glucose 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 patients concomitantly treated with colchicine.

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.

1. 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.

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. 1). 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.

8).