Febuxostat

Pronunciation

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
Brands: Uloric

Introduction

Xanthine oxidase inhibitor.1 2 3 4 5 6 8

Uses for Febuxostat

Gout

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

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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

Febuxostat 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

Administered 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

Dosage adjustment is not needed in patients with mild to moderate renal or hepatic impairment.1 8

Cautions for Febuxostat

Contraindications

  • Concomitant therapy with azathioprine, mercaptopurine, or theophylline.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

Higher rate of cardiovascular thromboembolic events (cardiovascular deaths, nonfatal MI, nonfatal stroke) in patients receiving febuxostat than in patients receiving allopurinol.1 Causal relationship not established.1 Monitor for signs and symptoms of MI and stroke.1

Hepatic Effects

Elevations of serum transaminase concentrations reported.1 Perform liver function tests during therapy (e.g., at month 2 and 4 of therapy and then periodically).1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use with caution in nursing women.1

Pediatric Use

Safety and efficacy have not been 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

Dosage adjustment based on age not needed.1 3

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

Insufficient date in patients with severe renal impairment (Clcr <30 mL/minute); caution if used in these individuals.1 Dosage adjustment not needed in patients with mild to moderate renal impairment (Clcr 30–89 mL/minute).1

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 Febuxostat

Febuxostat does not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2C9, 2C19, or 3A4; febuxostat is a weak inhibitor of CYP2D6.1 Febuxostat does not induce CYP1A2, 2B6, 2C9, 2C19, 3A4.1

Febuxostat is metabolized by conjugation by glucuronosyltransferase (uridine diphosphoglucuronosyltransferase, UDP-glucuronate β-D-glucuronosyltransferase [acceptor-unspecific], UGT) enzymes, including UGT1A1, UGT1A3, UGT1A9, and UGT2B7, as well as by oxidation by CYP isoenzymes, including CYP1A2, 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 if administered concomitantly, resulting in toxicity.1 (See Contraindications.)

Specific Drugs

Drug

Interaction

Comments

Antacids

Pharmacokinetic interaction unlikely1 10

Antineoplastic agents

Not evaluated1

Mercaptopurine: Inhibition of mercaptopurine metabolism; possible increase in toxic effects1

No information on safety of concomitant use1

Mercaptopurine: Concomitant use contraindicated1

Azathioprine

Inhibition of azathioprine metabolism; possible increase in toxic effects1

Concomitant use contraindicated1

Colchicine

Clinically important pharmacokinetic interaction unlikely1

Dosage adjustment not needed

Desipramine

Pharmacokinetic interaction not considered clinically important1

Dosage adjustment not expected to be necessary1

Hydrochlorothiazide

Clinically important pharmacokinetic interaction unlikely1

Dosage adjustment not needed

Indomethacin

Clinically important pharmacokinetic interaction unlikely1

Dosage adjustment not needed

Naproxen

Clinically important pharmacokinetic interaction unlikely1

Dosage adjustment not needed

Theophylline

Inhibition of theophylline metabolism; possible increase in toxic effects1

Concomitant use contraindicated1

Warfarin

Pharmacokinetic interaction unlikely1

Dosage adjustment not needed

Febuxostat 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

Distribution

Plasma Protein Binding

99.2%.1

Elimination

Metabolism

Febuxostat is metabolized by uridine diphosphate-glucuronosyltransferase (UGT) 1A1, 1A3, 1A9, 2B7, CYP 1A2, 2C8, 2C9, and 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

Extent of absorption and half-life increased in individuals with renal impairment; not considered clinically important.1

Extent of absorption increased in individuals with mild to moderate hepatic impairment; not considered clinically important.1 8

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

  • Possibility of gout flares, liver function abnormalities, and cardiovascular events.1

  • Importance of informing clinician of rash, chest pain, shortness of breath, or symptoms suggestive of stroke.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.

Febuxostat

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

40 mg

Uloric

Takeda

80 mg

Uloric

Takeda

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Uloric 40MG Tablets (TAKEDA PHARMACEUTICALS): 30/$192.40 or 90/$547.04

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Takeda Pharmaceuticals America. Uloric (febuxostat) tablets prescribing information. Deerfield, Il; 2009 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. [PubMed 16339094]

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. [PubMed 18635756]

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. [PubMed 18975369]

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. [PubMed 19286847]

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. [PubMed 16397288]

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. [PubMed 16855070]

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. [PubMed 17953718]

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