Febuxostat

Article Author:
Valerie Gerriets
Article Editor:
Ishwarlal Jialal
Updated:
9/6/2019 10:09:39 PM
PubMed Link:
Febuxostat

Indications

Febuxostat is an inhibitor of the enzyme xanthine oxidase and is FDA-approved for the chronic management of hyperuricemia in patients diagnosed with gout.[1][2]  Due to the finding of an increased risk of death with febuxostat versus allopurinol, the FDA recently recommended limiting the use of febuxostat to patients for which allopurinol is not efficacious or patients who experience severe side effects with allopurinol.[3]

Mechanism of Action

Febuxostat is a non-purine selective inhibitor of the enzyme xanthine oxidase, which is involved in purine catabolism.[4] The xanthine oxidase enzyme catalyzes two reactions that ultimately generate uric acid from hypoxanthine. Febuxostat is a potent, selective inhibitor of xanthine oxidase, forming a stable complex with both the reduced and oxidized form of the enzyme, thereby inhibiting its function. Treatment with febuxostat leads to lower serum uric acid levels in animals and humans.[5] The therapeutic effect of febuxostat has as its basis the ability to lower serum uric acid levels in patients with hyperuricemia, defined by the uric acid serum concentration that exceeds the solubility of uric acid (approximately 7 mg/dL).[6][7] The chemical structure of febuxostat does not resemble either purines or pyrimidine structures, and it does not appear to inhibit other enzymes in the nucleotide catabolic pathways.[8]

Administration

Febuxostat is administered orally with an initial dose of 40 mg per day.[9]  Its administration can be without regard to food or antacid use.  The dose of febuxostat can be increased to 80 mg per day in patients that do not achieve a serum uric acid level of less than 6 mg/dL after 2 weeks of treatment with 40 mg so long as the patient does not have severe renal impairment (defined as a clearance of 15 to 29 mL/min).   Febuxostat is available in both 40 mg, and 80 mg tablet formulations and estimates are that greater than 49% of the dose is absorbed when taken orally.[9] Upon initiating treatment with febuxostat, gout flares may occur.[10]  Therefore, flare prophylaxis with either a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended concurrently with febuxostat treatment and may continue for up to six months.[11][12]

Adverse Effects

Common adverse drug effects (greater than 1% of the febuxostat-treated group based on multiple randomized, controlled clinical studies ranging in length from 6 to 12 months) [10]:

  • Liver function abnormalities, dizziness, arthralgia, nausea, and rash.

Less common adverse effects listed by organ system (less than 1% of the febuxostat-treated group based on multiple randomized, controlled clinical studies) [13][14]:

  • Blood and Lymphatic System: anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia
  • Cardiac: angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia
  • Ear and Eye:  deafness, tinnitus, vertigo, blurred vision
  • Gastrointestinal: abdominal distention, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis, gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain, haematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis, peptic ulcer, vomiting
  • Hepatobiliary: cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly
  • Immune: hypersensitivity, drug reaction with eosinophilia
  • Infections: herpes zoster
  • Metabolism-related: anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased
  • Musculoskeletal: arthritis, joint stiffness, joint swelling, muscle spasms, twitching, weakness, musculoskeletal pain/stiffness, myalgia
  • Nervous System: altered taste, balance disorder, cerebrovascular accident, Guillain-Barre syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor
  • Psychiatric: agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change.
  • Renal: hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence
  • Reproductive: breast pain, erectile dysfunction, gynecomastia
  • Respiratory: bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection
  • Skin and Subcutaneous Tissue: alopecia, angioedema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria
  • Vascular: flushing, hot flush, hypertension, hypotension
  • Altered Laboratory Parameters: activated partial thromboplastin time prolonged, creatine increased, bicarbonate decreased, sodium increased, EEG abnormal, glucose increased, cholesterol increased, triglycerides increased, amylase increased, potassium increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin decreased, MCV increased, RBC decreased, creatinine increased, blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased, alkaline phosphatase increased, LDH increased, PSA increased, urine output increased/decreased, lymphocyte count decreased, neutrophil count decreased, WBC increased/decreased, coagulation test abnormal, low-density lipoprotein (LDL) increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein

Warnings and Precautions

Gout Flares

An increase in gout flares frequently occurs after the initiation of febuxostat.[10] This increase is likely due to the reduction of serum uric acid levels, which mobilizes the urate crystals in tissue deposits. Therefore, flare prophylaxis with either a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended concurrently with febuxostat treatment and may continue for up to six months.  Febuxostat should not be used to treat secondary hyperuricemia or asymptomatic hyperuricemia. 

Cardiovascular Events

In randomized controlled studies, there was a higher rate of cardiovascular deaths as well as non-fatal myocardial infarctions and strokes in the febuxostat-treated group compared with the allopurinol-treated group.[3] Based on this new information, the FDA is limiting the use of febuxostat to patients for which allopurinol is not efficacious or patients who experience severe side effects with allopurinol, and there is now a boxed warning of cardiovascular death.  

Hepatic Effects

In randomized controlled studies, liver function abnormalities were reported, including transaminase elevations greater than three times the upper limit of normal.[15][10] Although this effect has not been shown to be clinically significant, a liver test panel, including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and total bilirubin is recommended prior to initiating febuxostat treatment as a baseline measurement as well as periodically during treatment and in patients experiencing any signs of hepatic injury. 

Contraindications

Febuxostat contraindications include patients that are treated with azathioprine or mercaptopurine since xanthine oxidase inhibition enhances serious toxicity such as myelosuppression.[9]

Monitoring

Patient monitoring should include signs and symptoms of MI and stroke as well as liver injury as described above in the warnings and precautions section.[3] Patients with impaired renal function appear to tolerate febuxostat well, and no dose adjustments are necessary. Febuxostat may actually slow the progress of mild or moderate chronic kidney disease.[16][8][17]

Toxicity

There is no known human toxicity with febuxostat treatment.[4]

Enhancing Healthcare Team Outcomes

As with many medications, interprofessional communication and teamwork are necessary when it comes to the administration and monitoring of febuxostat.  With the recent revisions of the FDA guidelines, physicians, nurses and pharmacists need to be particularly aware of current prescribing information.[3] 

As of early 2019, febuxostat is now recommended only for patients with gout who are unable to tolerate allopurinol or if allopurinol lacks efficacy; this is particularly pertinent in patients with cardiovascular disease. Pharmacists should familiarize themselves with the patient's gout medication history, and verify that febuxostat is appropriate. They can also confirm dosing and perform medication reconciliation, alerting the patient's doctor to any concerns. Nursing will be in a position to assess treatment efficacy, patient compliance, and look for medication side effects, reporting any concerns to the treating physician. The healthcare team, consisting of physicians, specialists, specialty-trained nursing, and pharmacy, must work together to ensure that proper dosing and dispensing protocols are in place and be aware of the possibility of adverse effects, which includes informing the patient of the increased risk of gout flares upon treatment with febuxostat and treating the flares appropriately.[10] [Level V]


References

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[2] Takano Y,Hase-Aoki K,Horiuchi H,Zhao L,Kasahara Y,Kondo S,Becker MA, Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life sciences. 2005 Mar 4;     [PubMed PMID: 15698861]
[3] White WB,Saag KG,Becker MA,Borer JS,Gorelick PB,Whelton A,Hunt B,Castillo M,Gunawardhana L, Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. The New England journal of medicine. 2018 Mar 29;     [PubMed PMID: 29527974]
[4] Khosravan R,Grabowski BA,Wu JT,Joseph-Ridge N,Vernillet L, Pharmacokinetics, pharmacodynamics and safety of febuxostat, a non-purine selective inhibitor of xanthine oxidase, in a dose escalation study in healthy subjects. Clinical pharmacokinetics. 2006;     [PubMed PMID: 16884320]
[5] Osada Y,Tsuchimoto M,Fukushima H,Takahashi K,Kondo S,Hasegawa M,Komoriya K, Hypouricemic effect of the novel xanthine oxidase inhibitor, TEI-6720, in rodents. European journal of pharmacology. 1993 Sep 14;     [PubMed PMID: 8243554]
[6] Becker MA,Schumacher HR,MacDonald PA,Lloyd E,Lademacher C, Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout. The Journal of rheumatology. 2009 Jun;     [PubMed PMID: 19286847]
[7] Richette P,Doherty M,Pascual E,Barskova V,Becce F,Castañeda-Sanabria J,Coyfish M,Guillo S,Jansen TL,Janssens H,Lioté F,Mallen C,Nuki G,Perez-Ruiz F,Pimentao J,Punzi L,Pywell T,So A,Tausche AK,Uhlig T,Zavada J,Zhang W,Tubach F,Bardin T, 2016 updated EULAR evidence-based recommendations for the management of gout. Annals of the rheumatic diseases. 2017 Jan;     [PubMed PMID: 27457514]
[8] Mayer MD,Khosravan R,Vernillet L,Wu JT,Joseph-Ridge N,Mulford DJ, Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment. American journal of therapeutics. 2005 Jan-Feb;     [PubMed PMID: 15662289]
[9] Gray CL,Walters-Smith NE, Febuxostat for treatment of chronic gout. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2011 Mar 1;     [PubMed PMID: 21330679]
[10] Bruce SP, Febuxostat: a selective xanthine oxidase inhibitor for the treatment of hyperuricemia and gout. The Annals of pharmacotherapy. 2006 Dec;     [PubMed PMID: 17132810]
[11] Schumacher HR Jr,Becker MA,Wortmann RL,Macdonald PA,Hunt B,Streit J,Lademacher C,Joseph-Ridge N, 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 and rheumatism. 2008 Nov 15;     [PubMed PMID: 18975369]
[12] Jackson RL,Hunt B,MacDonald PA, The efficacy and safety of febuxostat for urate lowering in gout patients ≥65 years of age. BMC geriatrics. 2012 Mar 21;     [PubMed PMID: 22436129]
[13] Schumacher HR Jr,Becker MA,Lloyd E,MacDonald PA,Lademacher C, Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology (Oxford, England). 2009 Feb;     [PubMed PMID: 19141576]
[14] Becker MA,Schumacher HR,Espinoza LR,Wells AF,MacDonald P,Lloyd E,Lademacher C, The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis research     [PubMed PMID: 20370912]
[15] Becker MA,Schumacher HR Jr,Wortmann RL,MacDonald PA,Eustace D,Palo WA,Streit J,Joseph-Ridge N, Febuxostat compared with allopurinol in patients with hyperuricemia and gout. The New England journal of medicine. 2005 Dec 8;     [PubMed PMID: 16339094]
[16] Schumacher HR Jr, Febuxostat: a non-purine, selective inhibitor of xanthine oxidase for the management of hyperuricaemia in patients with gout. Expert opinion on investigational drugs. 2005 Jul;     [PubMed PMID: 16022578]
[17] Zeng XX,Tang Y,Hu K,Zhou X,Wang J,Zhu L,Liu J,Xu J, Efficacy of febuxostat in hyperuricemic patients with mild-to-moderate chronic kidney disease: a meta-analysis of randomized clinical trials: A PRISMA-compliant article. Medicine. 2018 Mar;     [PubMed PMID: 29595642]