Adverse reactions : תופעות לוואי

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: 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          Rare disorders                           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, 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, arrhythmia#
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       Common disorders                          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     Common tissue 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 #, 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     Uncommon disorder                           Erectile dysfunction
General disorders and              Common administration 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, 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              Uncommon procedural complications           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.
*** 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).

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/ and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com