Febuxostat

Chemical formula: C₁₆H₁₆N₂O₃S  Molecular mass: 316.375 g/mol  PubChem compound: 134018

Interactions

Febuxostat interacts in the following cases:

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.

CYP2D6 substrates

Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro. In a study in healthy subjects, 120 mg febuxostat 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.

Severe renal impairment

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

Severe hepatic impairment

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

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.

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.

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.

Cardiovascular disorders

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.

Organ transplant recipients

As there has been no experience in organ transplant recipients, the use of febuxostat in such patients is not recommended.

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. The potential risk for human is unknown. Febuxostat should not be used during pregnancy.

Nursing mothers

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.

Carcinogenesis, mutagenesis and fertility

Fertility

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

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 does not adversely affect performance.

Adverse reactions


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 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, 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
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, 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.
# 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).

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.

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