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Uloric

Generic Name: Febuxostat
Class: Antigout Agents
VA Class: MS400
Chemical Name: 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid
Molecular Formula: C16H16N2O3S
CAS Number: 144060-53-7

Medically reviewed on Nov 26, 2018

Introduction

Xanthine oxidase inhibitor.1 2 3 4 5 6 8

Uses for Uloric

Gout

Long-term management of hyperuricemia in patients with gout.1 2 3 4 5 6 7

Goal in management of gout is reduction in serum urate concentrations to levels below the limit of urate solubility (about 6.8 mg/dL).2 4

Not recommended for the management of asymptomatic hyperuricemia.1

Uloric Dosage and Administration

General

  • Acute gout attacks (gout flare) may occur after initiation of febuxostat.1 Consider gout flare prophylaxis with an NSAIA or colchicine; start these agents when febuxostat therapy is initiated.1 Gout flare prophylaxis may be beneficial for up to 6 months.1 During these acute attacks, continue febuxostat and manage the gout flare as appropriate.1

  • Testing for target serum urate concentrations can be performed after 2 weeks of febuxostat therapy.1

Administration

Oral Administration

Administer orally without regard to meals or antacids.1 10

Dosage

Adults

Gout
Oral

Initial dosage is 40 mg once daily.1 Increase dosage to 80 mg once daily in patients who do not achieve serum urate concentrations of <6 mg/dL after 2 weeks of therapy with febuxostat 40 mg once daily.1

Special Populations

Hepatic Impairment

Dosage adjustment not necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1 8 Manufacturer makes no specific dosage recommendations for patients with severe hepatic impairment (Child-Pugh class C).1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not necessary in patients with mild to moderate renal impairment (Clcr 30–89 mL/minute).1 In patients with severe renal impairment (Clcr 15–29 mL/minute), maximum 40 mg once daily.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustment not necessary.1 3 (See Geriatric Use under Cautions.)

Cautions for Uloric

Contraindications

  • Concomitant therapy with azathioprine or mercaptopurine.1 (See Interactions.)

Warnings/Precautions

Acute Gout

Febuxostat initiation may increase frequency of acute gout attacks (gout flare).1 Consider gout flare prophylaxis with an NSAIA or colchicine; start these agents when febuxostat therapy is initiated.1

Cardiovascular Events

May increase risk of potentially fatal cardiovascular thromboembolic events.1 11

Higher rate of cardiovascular thromboembolic events (cardiovascular deaths, nonfatal MI, nonfatal stroke) observed in premarketing studies in patients receiving febuxostat than in patients receiving allopurinol.1 Causal relationship not established.1

Preliminary results from postmarketing cardiovascular safety study in >6000 patients12 showed no increase in composite end point (cardiovascular death, nonfatal MI, nonfatal stroke, or unstable angina requiring urgent coronary revascularization) with febuxostat versus allopurinol, but an increased risk of cardiovascular death and death from all causes with febuxostat.11 FDA will conduct comprehensive review when final study results are available.11

Monitor for signs and symptoms of MI and stroke.1

Hepatic Effects

Fatal and nonfatal hepatic failure reported; causal relationship to drug cannot be excluded.1 Elevations of serum aminotransferase concentrations also reported.1

Perform liver function tests (serum ALT, AST, alkaline phosphatase, and total bilirubin concentrations) prior to initiation of therapy and repeat promptly in patients with manifestations suggestive of liver damage (see Advice to Patients).1 Interrupt therapy if ALT >3 times the ULN and investigate the cause.1 Treat the cause, if possible, to resolution or stabilization.1 If an alternate etiology is not found, do not restart febuxostat.1

Risk for severe drug-related liver injury if no alternate etiology is found and ALT is >3 times the ULN with total bilirubin concentrations >2 times the ULN; do not restart febuxostat in these patients.1 Manufacturer states that febuxostat may be used with caution in patients with lesser elevations of ALT or bilirubin if an alternate probable cause of liver function test abnormalities determined.1

Dermatologic and Hypersensitivity Reactions

Serious dermatologic reactions (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [DRESS]) and hypersensitivity reactions reported.1

Many patients reporting dermatologic reactions to febuxostat also reported similar reactions to prior allopurinol therapy.1 Use with caution in patients with history of dermatologic reactions to allopurinol.1

Discontinue febuxostat if serious dermatologic reactions suspected.1 (see Advice to Patients)

Specific Populations

Pregnancy

Data are inadequate regarding use of febuxostat in pregnant women.1

Animal studies revealed no evidence of fetal harm at exposures greater than those achieved with maximum recommended human dosage.1

Lactation

Distributed into milk in rats.1 Not known whether febuxostat distributes into human milk, affects human milk production, or affects breast-fed infant.1

Consider benefits of breast-feeding and importance of the drug to the woman; also consider any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity of some older patients cannot be ruled out.1

Hepatic Impairment

Not studied in patients with severe hepatic impairment (Child-Pugh class C); caution if used in these individuals.1 Dosage adjustment not needed in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1 8

Renal Impairment

Increased systemic exposure in patients with severe renal impairment; dosage adjustment recommended.1 Dosage adjustment not needed in patients with mild to moderate renal impairment.1 (See Renal Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics: Absorption and Pharmacokinetics: Elimination.)

Not studied in individuals with end-stage renal disease who are undergoing dialysis.1

Secondary Hyperuricemia

Not evaluated in patients with secondary hyperuricemia.1 Not recommended in patients whose rate of urate formation is greatly increased.1

Common Adverse Effects

Liver function abnormalities, nausea, arthralgia, rash.1

Interactions for Uloric

Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, or 3A4; weakly inhibits CYP2D6.1 Does not induce CYP 1A2, 2B6, 2C9, 2C19, or 3A4.1

Metabolized by UGT enzymes, including UGT 1A1, 1A3, 1A9, and 2B7; CYP isoenzymes, including CYP 1A2, 2C8, and 2C9; and non-CYP enzymes.1 Relative contribution of each enzyme isoform to the drug’s metabolism is not clear.1

Drugs Affecting Hepatic Microsomal or Other Enzymes

Drug interactions generally are not expected between febuxostat and inhibitors or inducers of particular enzyme isoforms.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions are unlikely between febuxostat and substrates of these isoenzymes.1

Drugs Metabolized by Xanthine Oxidase

Inhibition of xanthine oxidase by febuxostat may increase plasma concentrations of drugs metabolized by the enzyme, resulting in toxicity.1 (See Contraindications under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Antacids

Pharmacokinetic interaction unlikely1 10

Antineoplastic agents

Not evaluated1

Mercaptopurine: Possible inhibition of mercaptopurine metabolism; possible increase in toxic effects1

No information on safety of concomitant use1

Mercaptopurine: Concomitant use contraindicated1

Azathioprine

Possible inhibition of azathioprine metabolism; possible increase in toxic effects1

Concomitant use contraindicated1

Colchicine

Clinically important pharmacokinetic interaction unlikely1

Dosage adjustment not needed1

Desipramine

Pharmacokinetic interaction not considered clinically important1

Dosage adjustment not expected to be necessary1

Hydrochlorothiazide

Clinically important pharmacokinetic interaction unlikely1

Dosage adjustment not needed1

Indomethacin

Clinically important pharmacokinetic interaction unlikely1 9

Dosage adjustment not needed1 9

Naproxen

Clinically important pharmacokinetic interaction unlikely1 9

Dosage adjustment not needed1 9

Theophylline

Urinary excretion of 1-methylxanthine (major metabolite of theophylline) increased by approximately 400-fold; no effect on theophylline peak concentration or AUC1

Use concomitantly with caution; dosage adjustment of theophylline not necessary1

Long-term safety of 1-methylxanthine exposure not known1

Warfarin

Pharmacokinetic interaction unlikely1

Dosage adjustment not needed1

Uloric Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations of febuxostat are reached in 1–1.5 hours.1 3

Food

Administration with food decreases the rate and extent of absorption of febuxostat; not considered clinically important.1 10

Special Populations

Mild to moderate hepatic impairment: Peak concentrations and AUC are increased by 20–30%; not considered clinically important.1 8

Mild or moderate renal impairment: AUC is increased by 7–18 or 45–49%, respectively; not considered clinically important.1

Severe renal impairment: AUC is increased by 96–98%.1

Distribution

Plasma Protein Binding

99.2%.1

Elimination

Metabolism

Metabolized by conjugation by UGT 1A1, 1A3, 1A9, and 2B7; oxidation by CYP 1A2, 2C8, and 2C9; and metabolism by other enzymes.1

Elimination Route

Excreted in urine (49%) and feces (45%), principally as metabolites.1

Half-life

5–8 hours.1

Special Populations

Pharmacokinetic values in geriatric adults similar to those in younger adults.1 3

Mild, moderate, or severe renal impairment: Clearance is decreased 14, 34, or 48%, respectively.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Febuxostat inhibits xanthine oxidase, the enzyme that catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid.1 3 By blocking uric acid production, febuxostat decreases serum concentrations of uric acid.1 2 3

  • Febuxostat has minimal effects on other enzymes involved in purine and pyrimidine synthesis and metabolism.1 2

Advice to Patients

  • Importance of reading patient information provided by the manufacturer.1

  • Importance of informing patients that gout flares may initially increase when starting treatment with febuxostat and that medications to help reduce flares may be taken regularly for the first few months after initiation.1 Advise patients that they should not discontinue febuxostat therapy if such flares occur.1

  • Risk of adverse hepatic effects.1 Importance of promptly reporting any symptoms suggestive of liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).1

  • Risk of severe dermatologic or hypersensitivity reactions.1 Importance of notifying clinician at the earliest onset of any manifestations of severe dermatologic or hypersensitivity reactions (e.g., rash; red and painful skin; peeling or blistering of the skin; swelling or blistering of the lips, eyes, or mouth; difficulty swallowing or breathing).1

  • Possible risk of cardiovascular thromboembolic events.1 Importance of seeking immediate medical attention if chest pain, shortness of breath, or symptoms suggestive of stroke develop.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products and any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Febuxostat

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

40 mg

Uloric

Takeda

80 mg

Uloric

Takeda

AHFS DI Essentials™. © Copyright 2018, Selected Revisions November 26, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Takeda Pharmaceuticals America. Uloric (febuxostat) tablets prescribing information. Deerfield, Il; 2018 Feb.

2. Becker MA, Schumacher HR, Wortmann RL et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005; 353:2450-61. http://www.ncbi.nlm.nih.gov/pubmed/16339094?dopt=AbstractPlus

3. Khosravan R, Kukulka MJ, Wu J-T et al. The effect of age and gender on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol. 2008; 48:1014-24. http://www.ncbi.nlm.nih.gov/pubmed/18635756?dopt=AbstractPlus

4. Schumacher HR, Becker MA, Wortmann RL et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008; 59:1540-8. http://www.ncbi.nlm.nih.gov/pubmed/18975369?dopt=AbstractPlus

5. Becker MA, Schumacher HR, MacDonald PA et al. Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout. J Rheumatol. 2009; 36:1273-82. http://www.ncbi.nlm.nih.gov/pubmed/19286847?dopt=AbstractPlus

6. Anon. Febuxostat (Uloric) for chronic treatment of gout. Med Lett Drugs Ther. 2009; 51:37-8.

7. Becker M, Schumacher HR, Espinoza L et al. A phase 3 randomized, controlled, multicenter, double-blind trial (RCT) comparing efficacy and safety of daily febuxostat (FEB) and allopurinol (ALLO) in subjects with gout. 2008 annual meeting American College of Rheumatology, San Francisco.

8. Khosravan R, Grabowski BA, Mayer MD et al. The effect of mild and moderate hepatic impairment on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol. 2006; 46:88-102. http://www.ncbi.nlm.nih.gov/pubmed/16397288?dopt=AbstractPlus

9. Khosravan R, Wu J-T, Joseph-Ridge N et al. Pharmacokinetic interactions of concomitant administration of febuxostat and NSAIDs. J Clin Pharmacol. 2006; 46:855-66. http://www.ncbi.nlm.nih.gov/pubmed/16855070?dopt=AbstractPlus

10. Khosravan R, Grabowski B, Wu J-T et al. Effect of food or antacid on pharmacokinetics and pharmacodynamics of febuxostat in healthy subjects. Br J Clin Pharmacol. 2007; 65:355-63. http://www.ncbi.nlm.nih.gov/pubmed/17953718?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2291255&blobtype=pdf

11. US Food and Drug Administration. FDA drug safety communication: Uloric (febuxostat): FDA to evaluate increased risk of heart-related death. From FDA website https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm585281.htm

12. US National Library of Medicine. Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities (CARES). From clinical trials.gov website. Updated 2017 Aug 11. https://clinicaltrials.gov/ct2/show/NCT01101035

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