Pharmacologic Category

Pharmacology

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

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)

Excretion

Urine (~49% mostly as metabolites, 3% as unchanged drug); feces (~45% mostly as metabolites, 12% as unchanged drug)

Time to Peak

Plasma: 1 to 1.5 hours

Half-Life Elimination

~5 to 8 hours

Protein Binding

~99%, primarily to albumin

Special Populations: Gender

Following multiple oral doses, Cmax and AUC are 30% and 14% higher in women than men, respectively.

Use: Labeled Indications

Hyperuricemia: Chronic management of hyperuricemia in patients with gout.

Limitations of use: Not recommended for treatment of asymptomatic hyperuricemia.

Contraindications

Concurrent use with azathioprine or mercaptopurine

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to febuxostat or any component of the formulation.

Dosing: Adult

Note: It is recommended to take an NSAID or colchicine with initiation of therapy and may continue for up to 6 months to help prevent gout flares. If a gout flare occurs, febuxostat does not need to be discontinued.

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 (ACR guidelines [Khanna 2012]; EULAR [Richette 2017]).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild to moderate impairment (CrCl 30 to 89 mL/minute): No dosage adjustment necessary.

Severe impairment (CrCl <30 mL/minute): Maximum dose: 40 mg once daily.

Dialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). A small pharmacokinetic study involving an extremely limited number of Japanese hemodialysis patients (n=3) receiving 10 to 20 mg/day showed that pharmacokinetics were not altered (Hira 2015).

Dosing: 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.

Administration

Administer with or without meals or antacids.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

AzaTHIOprine: Febuxostat may increase the serum concentration of AzaTHIOprine. Avoid combination

Didanosine: Febuxostat may increase the serum concentration of Didanosine. Avoid combination

Mercaptopurine: Febuxostat may increase the serum concentration of Mercaptopurine. Avoid combination

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. 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. Exceptions: Dyphylline. Monitor therapy

Adverse Reactions

1% to 10%:

Dermatologic: Skin rash (1% to 2%)

Gastrointestinal: Nausea (1%)

Hepatic: Liver function abnormalities (5% to 7%)

Neuromuscular & skeletal: Arthralgia (1%)

<1% (Limited to important or life-threatening): Abnormal electroencephalogram, abnormal gait, aggressive behavior, agitation, agranulocytosis, alopecia, anaphylaxis, anemia, angina pectoris, angioedema, anorexia, anxiety, arthralgia, atrial fibrillation, atrial flutter, blurred vision, bruise, cardiac failure, cerebral infarction, cerebrovascular accident, cerebrovascular accident, cholecystitis, cholelithiasis, constipation, deafness, decreased hematocrit, decreased libido, decreased serum bicarbonate, decreased urine output, dehydration, depression, dermatitis, diabetes mellitus, DRESS syndrome, dysgeusia, dyspepsia, dyspnea, ECG abnormality, eczema, edema, eosinophilia, epistaxis, erectile dysfunction, erythema multiforme, flu-like symptoms, flushing, gastritis, gastroesophageal reflux disease, gingival pain, Guillain-Barré syndrome, gynecomastia, hair discoloration, heart murmur, hematemesis, hematochezia, hematuria, hemiparesis, hepatic failure, hepatitis, hepatomegaly, herpes zoster, hirsutism, hot flash, hyperacidity, hypercholesterolemia, hyperglycemia, hyperhidrosis, hyperkalemia, hyperlipidemia, hypernatremia, hypersensitivity reaction, hypertension, hypertriglyceridemia, hypokalemia, hypotension, immune thrombocytopenia, increased amylase, increased blood urea nitrogen, increased creatine phosphokinase, increased lactate dehydrogenase, increased MCV, increased serum alkaline phosphatase, increased serum creatinine, increased thyroid stimulating hormone level, increased urine output, interstitial nephritis, jaundice, joint swelling, lethargy, leukocytosis, leukopenia, liver steatosis, lymphocytopenia, migraine, muscle spasm, muscle twitching, myalgia, myocardial infarction, nephrolithiasis, neutropenia, oral mucosa ulcer, pain, palpitations, pancreatitis, pancytopenia, panic attack, paresthesia, peptic ulcer, personality changes, petechia, pharyngeal edema, pollakiuria, prolonged partial thromboplastin time, prolonged prothrombin time, prostate specific antigen increase, proteinuria, psychotic symptoms, renal failure, respiratory tract infection, rhabdomyolysis, sinus bradycardia, skin discoloration, skin photosensitivity, splenomegaly, Stevens-Johnson syndrome, tachycardia, thrombocytopenia, tinnitus, toxic epidermal necrolysis, transient ischemic attacks, tremor, urinary incontinence, urinary tract infection, urticaria (including dermographism), vertigo, vomiting, weakness, weight gain, weight loss

Warnings/Precautions

Concerns related to adverse effects:

• 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 x 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 x ULN); permanently discontinue use if no other explanation for the abnormalities is elucidated and in patients who develop ALT >3 x ULT and serum total bilirubin >2 x 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.

• Thromboembolic events: MI, stroke and cardiovascular deaths were reported at a slightly increased rate versus allopurinol in controlled studies (a causal relationship has not been established). Patients should be monitored for signs and symptoms of MI or stroke.

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.

Monitoring Parameters

Liver function tests at baseline and then periodically, serum uric acid levels (as early as 2 weeks after initiation); signs/symptoms of MI or stroke, signs/symptoms of hypersensitivity or severe skin reactions

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience joint pain or nausea. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), angina, swollen glands, or shortness of breath (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.