Dosing & Uses
Dosage Forms & Strengths
tablet
- 40mg
- 80mg
Chronic Gout
Indicated for chronic management of hyperuricemia in patients with gout who have an inadequate response to optimal allopurinol therapy, who are intolerant to allopurinol, or for whom treatment is not advisable
Initial dose: 40 mg PO qDay
May increase to 80 mg PO qDay after 2 wk if serum uric acid <6 mg/dL is not achieved
Dosage Modifications
Renal impairment
- Mild to moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
- Severe (CrCl <30 mL/min): Not to exceed 40 mg/day
Hepatic impairment
- Mild to moderate (Child-Pugh class A or B): Dosage adjustment not necessary
- Severe (Child-Pugh class C): Data not available; use with caution
Prophylaxis for gout flares during treatment
- Upon initiation, recommend for flare prophylaxis with a nonsteroidal anti-inflammatory drug (NSAID) or colchicine
- Prophylactic therapy may be beneficial for up to 6 months
- If a gout flare occurs, managed gout flare concurrently; treatment does not need to be discontinued
Dosing Considerations
Limitation of use: Not recommended for the treatment of asymptomatic hyperuricemia
Perform serum uric acid level as early as 2 weeks after initiating therapy
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
1-10%
Liver function abnormalities (4.6-6.6%)
Rash (0.5-1.6%)
Nausea (1.1-1.3%)
Arthralgia (0.7-1.1%)
>1%
Blood and lymphatic system disorders: Anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia
Cardiac disorders: Angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia
Ear and labyrinth disorders: Deafness, tinnitus, vertigo
Eye disorders: Vision blurred
Gastrointestinal disorders: Abdominal distention, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis, gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain, hematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis, peptic ulcer, vomiting
General disorders and administration site conditions: Asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst
Hepatobiliary disorders: Cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly
Immune system disorder: Hypersensitivity
Infections and infestations: Herpes zoster
Procedural complications: Contusion
Metabolism and nutrition disorders: Anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased
Musculoskeletal and connective tissue disorders: Arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia
Nervous system disorders: Altered taste, balance disorder, cerebrovascular accident, Guillain-Barré syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor
Psychiatric disorders: Agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change
Renal and urinary disorders: Hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence
Reproductive system and breast changes: Breast pain, erectile dysfunction, gynecomastia
Respiratory, thoracic and mediastinal disorders: Bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection
Skin and subcutaneous tissue disorders: Alopecia, angio edema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria
Vascular disorders: Flushing, hot flush, hypertension, hypotension
Laboratory parameters: Activated partial thromboplastin time prolonged, creatine increased, bicarbonate decreased, sodium increased, EEG abnormal, glucose increased, cholesterol increased, triglycerides increased, amylase increased, potassium increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin decreased, MCV increased, RBC decreased, creatinine increased, blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase increased, alkaline phosphatase increased, LDH increased, PSA increased, urine output increased/decreased, lymphocyte count decreased, neutrophil count decreased, WBC increased/decreased, coagulation test abnormal, low density lipoprotein increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein
Postmarketing Reports
Immunologic: Anaphylaxis, anaphylactic reaction
Musculoskeletal: Rhabdomyolysis
Hepatobiliary: Hepatic failure (some fatal), jaundice, serious cases of abnormal LFT results, liver disorders
Psychiatric: Psychotic behavior, including aggressive thoughts
Renal and urinary: Tubulointerstitial nephritis
Dermatologic: Generalized rash, Stevens-Johnson syndrome, hypersensitivity skin reactions, drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN)
Blood and lymphatic system disorders: Agranulocytosis, eosinophilia
Warnings
Black Box Warnings
Cardiovascular death
- Patients with established cardiovascular (CV) disease treated with febuxostat had a higher rate of CV death compared with those treated with allopurinol in a CV outcomes study
- Evaluate risks and benefits when prescribing febuxostat or continuing treatment
Contraindications
Coadministration with azathioprine or mercaptopurine
Cautions
After initiation, an increase in gout flares is frequently observed; increase is due to reduction in serum uric acid levels, resulting in mobilization of urate from tissue deposits
Not tested for secondary hyperuricemia; not recommended in patients whose rate of urate formation is greatly increased (eg, malignant disease and its treatment, Lesch-Nyhan syndrome)
Postmarketing reports of serious skin and hypersensitivity reactions reported; discontinue if serious skin reactions are suspected; caution in patients who reported previous similar skin reactions to allopurinol
Postmarketing reports of fatal and nonfatal hepatic failure; may increase liver enzyme activity; obtain LFTs at baseline, and do not initiate if alanine aminotransferase is 3x ULN with total bilirubin >2x ULN
Serious skin and hypersensitivity reactions, including Stevens-Johnson Syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN) reported; discontinue therapy if serious skin reactions suspected; many patients reported previous similar skin reactions to allopurinol; use caution in these patients
Cardiovascular death
- A cardiovascular (CV) outcome study (ClinicalTrials.gov identifier NCT01101035) in patients with a history of major CV disease, cerebrovascular disease, or diabetes mellitus with micro- and/or macrovascular disease showed that febuxostat had a significantly higher incidence of CV deaths compared with allopurinol
- Most common cause of adjudicated CV deaths in the febuxostat group was sudden cardiac death compared with the allopurinol group; similar results to allopurinol were observed for nonfatal MI, nonfatal stroke, and unstable angina with urgent coronary revascularization (see Black Box Warnings)
- Because of increased risk of CV death, drug should only be used in patients who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or for whom treatment with allopurinol is not advisable
Drug interaction overview
- Xanthine oxidase substrates
- Febuxostat inhibits xanthine oxidase (XO)
- Based on a drug interaction study in healthy patients, febuxostat altered the metabolism of theophylline in humans; caution if coadministered
- Other drugs that are metabolized by XO (eg, mercaptopurine and azathioprine) have not been conducted; XO inhibition may increase plasma concentrations of these drugs leading to toxicity (see Contraindications)
Pregnancy & Lactation
Pregnancy
Limited available data in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes
Animal data
- No adverse developmental effects observed in embryo-fetal development studies with oral administration of febuxostat to pregnant rats and rabbits during organogenesis at doses that produced maternal exposures up to 40 and 51 times, respectively, the exposure at the maximum recommended human dose (MRHD)
- No adverse developmental effects observed in a pre- and postnatal development study with administration of febuxostat to pregnant rats from organogenesis through lactation at an exposure ~11 times the MRHD
Lactation
There are no data on presence of febuxostat in human milk, effects on breastfed infant, or on milk production; drug is present in rat milk
Consider the developmental and health benefits of breastfeeding along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from therapy or from underlying maternal condition
Pregnancy Categories
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Pharmacology
Mechanism of Action
Xanthine oxidase inhibitor; inhibits conversion of hypoxanthine to xanthine to uric acid; at therapeutic dosages, decreases production of uric acid without disrupting synthesis of vital purines and pyrimidines
Absorption
Absorption: 49%
Peak plasma concentration: ~1.6 mcg/mL (40-mg dose); 2.6 mcg/mL (80-mg dose)
Peak plasma time: 1-1.5 hr
Following multiple 80 mg qDay doses with a high fat meal, peak plasma concentration decreased by 49% and AUC decreased by 18%
Distribution
Protein bound: 99.2%
Vd: 50 L
Metabolism
Metabolized by UGT1A1, UGT1A3, UGT1A9, and UGT2B7; oxidized by CYP1A2, CYP2C8, and CYP2C9; also metabolized by non-CYP450 enzymes
Elimination
Half-life: 5-8 hr
Excretion: Feces (45%; 12% unchanged; 25% their conjugates; 7% other unknown metabolites), urine (49%; 3% unchanged)
Administration
Oral Administration
Take without regard to food or antacid use
Storage
Protect from light
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
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Patient Handout
Formulary
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