Gout patients with established cardiovascular (CV) disease treated with febuxostat had a higher rate of CV death compared to those treated with allopurinol in a CV outcomes study. Consider the risks and benefits of febuxostat when deciding to prescribe or continue patients on febuxostat. Febuxostat 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.
Note: Urate-lowering therapy (ULT) may be initiated during a gout flare or after the flare subsides; concomitant pharmacologic prophylaxis with colchicine, nonsteroidal anti-inflammatory drugs, or a glucocorticoid is recommended for at least the first 3 to 6 months to decrease flare activity (ACR [FitzGerald 2020]).
Hyperuricemia: Oral: Initial: 40 mg once daily; may increase to 80 mg once daily in patients who do not achieve a serum uric acid level <6 mg/dL after 2 weeks. The dose may be increased further to 120 mg once daily if clinically indicated (EULAR [Richette 2017]).
Tumor lysis syndrome, prevention (alternative therapy) (off-label use): Patients at intermediate or high risk for tumor lysis syndrome (TLS):
Note: Aggressive IV hydration should always be initiated prior to cytotoxic therapy in patients at elevated risk for TLS (Coiffier 2008). The optimal dose of febuxostat for the prevention of TLS is not yet established (Bellos 2019).
Oral: 40 to 60 mg once daily (Sharma 2016; Takai 2014; Tamura 2016) or 120 mg once daily (Spina 2015). Begin 1 to 2 days before the start of chemotherapy and continue for up to 14 days until normalization of laboratory evidence of TLS (eg, serum uric acid, serum lactate dehydrogenase) (Coiffier 2008; Sharma 2016; Spina 2015; Tamura 2016).
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function:
CrCl ≥30 mL/minute: No dosage adjustment necessary (manufacturer's labeling).
CrCl <30 mL/minute: Initial: 20 to 40 mg once daily (manufacturer's labeling; expert opinion). Note: Observational studies in patients with hyperuricemia have reported safety and tolerability of 60 and 80 mg/day; a careful titration may be considered in patients unresponsive to standard doses (Kim 2020; Lim 2016; Mayer 2005; Saag 2016; Saag 2019).
Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (highly protein bound): Initial: 20 to 40 mg once daily; no supplemental dose necessary (Choi 2021; expert opinion). Note: A small, retrospective, observational study in patients with hyperuricemia reported safety and tolerability of doses up to 80 mg/day (Lim 2016); a careful titration may be considered in patients unresponsive to standard doses (expert opinion).
Peritoneal dialysis: Unlikely to be dialyzed (highly protein bound): Initial: 20 to 40 mg once daily (Choi 2021; expert opinion). Note: A small, retrospective, observational study in patients with hyperuricemia reported safety and tolerability of doses up to 80 mg/day (Lim 2016); a careful titration may be considered in patients unresponsive to standard doses (expert opinion).
CRRT: Dose as for CrCl <30 mL/minute (expert opinion).
PIRRT (eg, sustained, low-efficiency diafiltration ): Dose as for CrCl <30 mL/minute (expert opinion).
Preexisting hepatic impairment:
Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.
Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use caution.
Hepatotoxicity during treatment:
ALT >3 times ULN (in the clinical context of potential liver injury [eg, fatigue, anorexia, right upper quadrant pain, dark urine, jaundice]): Interrupt febuxostat therapy and evaluate. Do not reinitiate febuxostat if no alternate etiology for liver test abnormalities is identified.
Refer to adult dosing.
Hypersensitivity or severe skin reactions: Discontinue febuxostat if hypersensitivity or severe skin reactions develop.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Uloric: 40 mg, 80 mg
Generic: 40 mg, 80 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Uloric: 80 mg [DSC] [contains fd&c blue #1 (brilliant blue), fd&c blue #2 (indigotine), quinoline (d&c yellow #10) aluminum lake]
Generic: 80 mg
Oral: Administer with or without meals or antacids.
Hyperuricemia: Chronic management of hyperuricemia in patients with gout 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
Limitations of use: Not recommended for treatment of asymptomatic hyperuricemia.
Tumor lysis syndrome, prevention (alternative therapy)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
1% to 10%:
Dermatologic: Skin rash (2%)
Gastrointestinal: Nausea (1%)
Hepatic: Hepatic insufficiency (5% to 7%), increased serum alanine aminotransferase (3%), increased serum aspartate aminotransferase (2%)
Neuromuscular & skeletal: Arthralgia (≤1%)
<1%:
Cardiovascular: Angina pectoris, atrial fibrillation, atrial flutter, chest pain, ECG abnormality, edema, flushing, heart murmur, hypertension, hypotension, increased serum creatine kinase, palpitations, sinus bradycardia, tachycardia
Dermatologic: Abnormal skin odor, alopecia, dermatitis, ecchymoses, eczema, exfoliation of skin, hair discoloration, hyperhidrosis, pruritus, skin discoloration, skin lesion, skin photosensitivity, urticaria (including dermographism)
Endocrine & metabolic: Decreased libido, decreased serum bicarbonate, dehydration, diabetes mellitus, gynecomastia, hirsutism, hot flash, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, hypokalemia, increased lactate dehydrogenase, increased LDL cholesterol, increased serum potassium, increased serum sodium, increased thirst, increased thyroid stimulating hormone level, weight gain, weight loss
Gastrointestinal: Abdominal distention, abdominal pain, anorexia, cholecystitis, cholelithiasis, constipation, decreased appetite, dysgeusia, dyspepsia, flatulence, frequent bowel movements, gastric hyperacidity, gastritis, gastroesophageal reflux disease, gastrointestinal distress, gingival pain, hematemesis, hematochezia, increased amylase, increased appetite, oral mucosa ulcer, pancreatitis, peptic ulcer, vomiting, xerostomia
Genitourinary: Decreased urine output, erectile dysfunction, hematuria, increased urine output, mastalgia, pollakiuria, prostate specific antigen increase, proteinuria, urinary incontinence, urinary urgency
Hematologic & oncologic: Anemia, blood coagulation test abnormality, bruise, immune thrombocytopenia, increased MCV, leukocytosis, leukocyturia, leukopenia, lymphocytopenia, neutropenia, pancytopenia, petechia, prolonged partial thromboplastin time, prolonged prothrombin time, purpuric disease, splenomegaly, thrombocytopenia
Hepatic: Hepatitis, hepatomegaly, increased serum alkaline phosphatase, liver steatosis
Hypersensitivity: Angioedema, hypersensitivity reaction
Infection: Herpes zoster infection
Nervous system: Abnormal electroencephalogram, abnormal gait, agitation, altered sense of smell (decreased), anxiety, asthenia, balance impairment, cerebral infarction (lacunar), cerebrovascular accident, decreased mental acuity, depression, drowsiness, fatigue, feeling abnormal, Guillain-Barré syndrome, headache, hemiparesis, hypertonia, hypoesthesia, insomnia, irritability, lethargy, migraine, myasthenia, nervousness, pain, panic attack, paresthesia, personality changes, transient ischemic attacks, tremor, vertigo
Neuromuscular & skeletal: Arthritis, increased creatine phosphokinase in blood specimen, joint stiffness, joint swelling, muscle rigidity, muscle spasm, muscle twitching, musculoskeletal pain, myalgia
Ophthalmic: Blurred vision
Otic: Deafness, tinnitus
Renal: Casts in urine, increased blood urea nitrogen, increased serum creatinine, nephrolithiasis, renal failure syndrome
Respiratory: Bronchitis, cough, dry nose, dyspnea, epistaxis, flu-like symptoms, paranasal sinus hypersecretion, pharyngeal edema, respiratory congestion, sneezing, throat irritation, upper respiratory tract infection
Miscellaneous: Mass
Frequency not defined: Endocrine & metabolic: Acute gout attack
Postmarketing:
Dermatologic: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Han 2020)
Hematologic & oncologic: Agranulocytosis (Poh 2017), eosinophilia
Hepatic: Hepatic failure, hepatic injury (acute; Bohm 2016), jaundice (Bohm 2016)
Hypersensitivity: Anaphylaxis, drug reaction with eosinophilia and systemic symptoms (Paschou 2016), fixed drug eruption (Oda 2016)
Nervous system: Psychotic symptoms (including aggressive behavior)
Neuromuscular & musculoskeletal: Polymyositis (eosinophilic; Chahine 2017); rhabdomyolysis (Kang 2014)
Renal: Interstitial nephritis
Concurrent use with azathioprine or mercaptopurine
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to febuxostat or any component of the formulation.
Concerns related to adverse effects:
• Cardiovascular death: [US Boxed Warning]: Gout patients with established cardiovascular (CV) disease had a higher rate of CV death when treated with febuxostat compared to patients treated with allopurinol in a CV outcomes study. Febuxostat should only be used in patients who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or when treatment with allopurinol is not advisable. Consider risks and benefits when prescribing or continuing febuxostat therapy. Consider prophylactic low-dose aspirin in patients with a history of CV disease. Monitor patients for signs and symptoms of CV events (White 2018).
• Hepatic failure: Postmarketing cases of hepatic failure (both fatal and nonfatal) have been reported (causal relationship has not been established). In controlled studies, significant hepatic transaminase elevations (>3 × ULN) have occurred (causal relationship not established). Liver function tests should be evaluated at baseline and periodically thereafter; evaluate liver function tests promptly in patients experiencing signs and symptoms of hepatic injury (eg, fatigue, anorexia, right upper quadrant pain, dark urine, jaundice). Interrupt therapy in patients who develop abnormal liver function tests (eg, ALT >3 × ULN); permanently discontinue use if no other explanation for the abnormalities is elucidated and in patients who develop ALT >3 × ULN and serum total bilirubin >2 × ULN. All other patients may be cautiously restarted on febuxostat.
• Hypersensitivity: Hypersensitivity and serious skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS) have been reported, particularly in patients with prior skin reactions to allopurinol; use with caution if a patient has a history of hypersensitivity reaction to allopurinol.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with severe hepatic impairment (Child-Pugh class C); has not been studied.
• Secondary hyperuricemia: Use in secondary hyperuricemia has not been studied; avoid use in patients at increased risk of urate formation (eg, malignancy and its treatment; Lesch-Nyhan syndrome).
Dosage forms specific issues:
• Lactose: Contains lactose.
Other warnings/precautions:
• Appropriate use: Administer concurrently with an NSAID or colchicine (up to 6 months) to prevent gout flare, which may occur upon initiation of therapy. Do not use to treat asymptomatic or secondary hyperuricemia.
Substrate of CYP1A2 (minor), CYP2C8 (minor), CYP2C9 (minor), UGT1A1, UGT1A3, UGT1A9, UGT2B7; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
AzaTHIOprine: Febuxostat may increase the serum concentration of AzaTHIOprine. Risk X: Avoid combination
Didanosine: Febuxostat may increase the serum concentration of Didanosine. Risk X: Avoid combination
Mercaptopurine: Febuxostat may increase the serum concentration of Mercaptopurine. Risk X: Avoid combination
Methotrexate: Febuxostat may enhance the adverse/toxic effect of Methotrexate. Risk C: Monitor therapy
Mitapivat: May decrease the serum concentration of UGT1A1 Substrates. Risk C: Monitor therapy
Pegloticase: Febuxostat may enhance the adverse/toxic effect of Pegloticase. Specifically, Febuxostat may blunt increases in serum urate that would signal an elevated risk of anaphylaxis and infusion reactions. Risk X: Avoid combination
Theophylline Derivatives: Febuxostat may increase serum concentrations of the active metabolite(s) of Theophylline Derivatives. Specifically, concentrations of 1-methylxanthine, a metabolite of unknown clinical importance, may become elevated. Risk C: Monitor therapy
Adverse events were observed in some animal reproduction studies.
It is not known if febuxostat is present in breast milk. According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
LFTs at baseline and then periodically. For gout, monitor serum uric acid levels (as early as 2 weeks after initiation, after each dosage titration), then every 6 months (symptomatic patients or tophi) or every 12 months (all patients on urate-lowering therapy, regardless of symptoms) (FitzGerald 2018). Monitor for signs/symptoms of cardiovascular events and signs/symptoms of hypersensitivity or severe skin reactions.
Uric acid, serum:
Adults:
Normal values:
Males: 3.4 to 7 mg/dL or slightly more
Females: 2.4 to 6 mg/dL or slightly more
Goal during therapy: <6 mg/dL; <5 mg/dL in patients with severe gout (eg, tophi, frequent attacks, chronic arthropathy) (EULAR [Richette 2017]). Levels <3 mg/dL are not recommended long-term (EULAR [Richette 2017]).
Note: Serum uric acid values >7 mg/dL do not necessarily represent clinical gout; the American College of Rheumatology clinical practice guidelines recommend against initiating pharmacologic management of asymptomatic hyperuricemia (ACR [FitzGerald 2020]).
Selectively inhibits xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine to uric acid thereby decreasing uric acid. At therapeutic concentration does not inhibit other enzymes involved in purine and pyrimidine synthesis.
Absorption: ≥49%
Distribution: Vss: ~50 L
Protein binding: ~99%, primarily to albumin
Metabolism: Extensive conjugation via uridine diphosphate glucuronosyltransferases (UGTs) 1A1, 1A3, 1A9, and 2B7 and oxidation via cytochrome P450 (CYP) 1A2, 2C8, and 2C9 as well as non-P450 enzymes. Oxidation leads to formation of active metabolites (67M-1, 67M-2, 67M-4)
Half-life elimination: ~5 to 8 hours
Time to peak, plasma: 1 to 1.5 hours
Excretion: Urine (~49% mostly as metabolites, 3% as unchanged drug); feces (~45% mostly as metabolites, 12% as unchanged drug)
Sex: Following multiple oral doses, Cmax and AUC are 30% and 14% higher in women than men, respectively.
Tablets (Febuxostat Oral)
40 mg (per each): $10.07 - $12.38
80 mg (per each): $10.07 - $12.38
Tablets (Uloric Oral)
40 mg (per each): $13.20
80 mg (per each): $13.20
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