Febuxostat

Pharmacologic Category

Antigout Agent; Xanthine Oxidase Inhibitor

Dosing: Adult

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]).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

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: Adult

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.

Calculations

Use: Labeled Indications

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.

* See Uses in AHFS Essentials for additional information.

Comparative Efficacy

FEBUXOSTAT

Clinical Practice Guidelines

3e Initiative, "Guidelines for the Management of Gout," 2014

ACR, "Guidelines for the Management of Gout," June 2020

EULAR, "2016 Updated Recommendations for the Management of Gout," 2016

Administration: Oral

Administer with or without meals or antacids.

Storage/Stability

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

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to lower uric acid in the blood in people with gout.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Joint pain

• Nausea

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• Chest pain

• Fast heartbeat

• Abnormal heartbeat

• Shortness of breath

• Dizziness

• Passing out

• Headache

• Swollen glands

• Flu-like signs

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Contraindications

Concurrent use with azathioprine or mercaptopurine

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

Warnings/Precautions

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 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.

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.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

In clinical trials, no clinically significant differences in safety or effectiveness were observed in elderly subjects. See dosage adjustment for renal impairment.

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

Breast-Feeding Considerations

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.

Briggs' Drugs in Pregnancy & Lactation

Febuxostat

Adverse Reactions

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%)

Frequency not defined: Endocrine & metabolic: Acute gout attack

<1%, postmarketing, and/or case reports: Abdominal distention, abdominal pain, abnormal electroencephalogram, abnormal gait, abnormal hepatic function tests, abnormal skin odor, aggressive behavior, agitation, agranulocytosis, alopecia, altered sense of smell, anaphylaxis, anemia, angina pectoris, angioedema, anorexia, anxiety, arthritis, asthenia, atrial fibrillation, atrial flutter, blood coagulation test abnormality, blurred vision, bronchitis, bruise, casts in urine, cerebral infarction (lacunar), cerebrovascular accident, chest discomfort, chest pain, cholecystitis, cholelithiasis, constipation, cough, deafness, decreased appetite, decreased libido, decreased mental acuity, decreased serum bicarbonate, decreased urine output, dehydration, depression, dermatitis, diabetes mellitus, drowsiness, drug reaction with eosinophilia and systemic symptoms, dry nose, dysgeusia, dyspepsia, dyspnea, ecchymoses, ECG abnormality, eczema, edema, eosinophilia, epistaxis, equilibrium disturbance, erectile dysfunction, erythema multiforme, exfoliation of skin, fatigue, feeling abnormal, flatulence, flu-like symptoms, flushing, frequent bowel movements, gastric hyperacidity, gastritis, gastroesophageal reflux disease, gastrointestinal distress, gingival pain, Guillain-Barré syndrome, gynecomastia, hair discoloration, headache, heart murmur, hematemesis, hematochezia, hematuria, hemiparesis, hepatic disease, hepatic failure, hepatitis, hepatomegaly, herpes zoster, hirsutism, hot flash, hypercholesterolemia, hyperglycemia, hyperhidrosis, hyperlipidemia, hypersensitivity reaction, hypertension, hypertonia, hypertriglyceridemia, hypoesthesia, hypokalemia, hypotension, immune thrombocytopenia, increased amylase, increased appetite, increased blood urea nitrogen, increased creatine phosphokinase in blood specimen, increased lactate dehydrogenase, increased LDL cholesterol, increased MCV, increased serum alkaline phosphatase, increased serum creatinine, increased serum glucose, increased serum potassium, increased serum sodium, increased thirst, increased thyroid stimulating hormone level, increased urine output, insomnia, interstitial nephritis, irritability, jaundice, joint stiffness, joint swelling, lethargy, leukocytosis, leukocyturia, leukopenia, liver steatosis, lymphocytopenia, mass, mastalgia, migraine, muscle rigidity, muscle spasm, muscle twitching, musculoskeletal pain, myalgia, myasthenia, nephrolithiasis, nervousness, neutropenia, oral mucosa ulcer, pain, palpitations, pancreatitis, pancytopenia, panic attack, paranasal sinus hypersecretion, paresthesia, peptic ulcer, personality changes, petechia, pharyngeal edema, pollakiuria, prolonged partial thromboplastin time, prolonged prothrombin time, prostate specific antigen increase, proteinuria, pruritus, psychotic symptoms, purpuric disease, renal failure syndrome, renal insufficiency, respiratory congestion, rhabdomyolysis, sinus bradycardia, skin discoloration, skin lesion, skin photosensitivity, sneezing, splenomegaly, Stevens-Johnson syndrome, tachycardia, throat irritation, thrombocytopenia, tinnitus, toxic epidermal necrolysis, transient ischemic attacks, tremor, upper respiratory tract infection, urinary incontinence, urinary urgency, urticaria (including dermographism), vertigo, vomiting, weight gain, weight loss, xerostomia

* See Cautions in AHFS Essentials for additional information.

Metabolism/Transport Effects

Substrate of UGT1A1

Drug Interactions Open Interactions

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

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. Exceptions: Dyphylline. Risk C: Monitor therapy

Monitoring Parameters

LFTs at baseline and then periodically; 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); signs/symptoms of cardiovascular events; signs/symptoms of hypersensitivity or severe skin reactions

Reference Range

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]).

Advanced Practitioners Physical Assessment/Monitoring

Obtain liver function tests at baseline and monitor them periodically. Obtain serum uric acid at 2 weeks after initiation. Obtain baseline renal function; dosage adjustment may be needed. Assess for signs and symptoms of MI, stroke, hypersensitivity, or severe skin reactions. Assess for gout flares and effectiveness of treatment.

Nursing Physical Assessment/Monitoring

Check ordered labs and report abnormalities. Educate patient about increased risk of gout flares after initiation, signs and symptoms of MI and stroke, and signs of hypersensitivity or skin reactions; instruct patient to report.

Dosage Forms: US

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

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Uloric: 80 mg [contains brilliant blue fcf (fd&c blue #1), fd&c blue #2 (indigotine), fd&c yellow #10 aluminum lake]

Generic: 80 mg

Anatomic Therapeutic Chemical (ATC) Classification

M04AA03

Generic Available (US)

Yes

Pricing: US

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

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

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.

Pharmacodynamics/Kinetics

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)

Pharmacodynamics/Kinetics: Additional Considerations

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

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation) and taste alteration has been reported in <1% of patients.

Effects on Bleeding

No information available to require special precautions

Index Terms

TEI-6720; TMX-67

FDA Approval Date

February 13, 2009

References

Bruce SP. Febuxostat: A Selective Xanthine Oxidase Inhibitor for the Treatment of Hyperuricemia and Gout. Ann Pharmacother. 2006;40(12):2187-2194.

FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthritis Care Res (Hoboken). 2020;72(6):744-760. doi:10.1002/acr.24180[PubMed 32391934]

FitzGerald JD, Mikuls TR, Neogi T, et al. Development of the American College of Rheumatology electronic clinical quality measures for gout. Arthritis Care Res (Hoboken). 2018;70(5):659-671. doi:10.1002/acr.23500[PubMed 29649348]

Hira D, Chisaki Y, Noda S, et al. Population pharmacokinetics and therapeutic efficacy of febuxostat in patients with severe renal impairment. Pharmacology. 2015;96(1-2):90-98. doi: 10.1159/000434633.[PubMed 26183164]

Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76(1):29-42. doi: 10.1136/annrheumdis-2016-209707.[PubMed 27457514]

Sivera F, Andres M, Carmona L, et al. Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative. Ann Rheum Dis. 2014;73(2):328-335.[PubMed 23868909]

Uloric (febuxostat) [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; February 2019.

Uloric (febuxostat) [product monograph]. Oakville, Ontario, Canada: Takeda Canada Inc; September 2019.

White WB, Saag KG, Becker MA, et al; CARES Investigators. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018;378(13):1200-1210. doi: 10.1056/NEJMoa1710895.[PubMed 29527974]

Zhang W, Doherty M, Bardin T, et al; EULAR Standing Committee for International Clinical Studies Including Therapeutics. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65(10):1312-1324.[PubMed 16707532]

Brand Names: International

Adenuric (AT, AU, BE, BH, CY, CZ, DE, DK, EE, ES, FR, GB, GR, HR, HU, IE, IT, LB, LT, LU, LV, MT, NL, NZ, PL, PT, RO, SE, SI, SK, TR); Agout (LB, SA); Atenurix (PH); Fabuzest (IN); Febsan (PH); Febuday (LK); Feburic (EG, HK, ID, IL, JP, KR, MY, PH, SG, TH, TW, VN); Febus (BD); Febux (BD); Febuxtat (AR); Fexorin (KR); Fexurix (CL); Furic (PH); Goclio (VN); Goustat (BD); Goutex (CO); Goutil (BD); Goutseal-40 (ZW); Goutseal-80 (ZW); Mebux (PH); Rui Yang (CN); Turazive (CR, DO, GT, HN, NI, PA, SV); Urica (PH); Urostat (BD); Zurig (IN)

Last Updated 10/7/20

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