SAFETY DATA

Adverse reactions in gout patients including those with CKD through stage 3 in phase 2 and 3 clinical studies1,2

Over 4000 patients studied, some for over 5 years3

Adverse reactions occurring in ≥1% of ULORIC-treated patients and at least 0.5% greater than seen in patients receiving placebo in phase 3 controlled studies1*

Safety chart

Safety profile evaluated in gout patients with CKD through stage 41-3

  • No renal dose adjustments required for patients with CKD through stage 31
  • The dose of ULORIC is limited to 40 mg once daily in patients with severe renal impairment1

Kidney function should be a key consideration when selecting a urate-lowering therapy4

CKD=chronic kidney disease; CKD4=CKD stage 4; Clcr=creatinine clearance; sUA=serum uric acid.

*ULORIC 80 mg and allopurinol were included in the CONFIRMS, APEX, and FACT studies. Placebo was included only in APEX, and ULORIC 40 mg was included only in CONFIRMS.2,5,6

Of the patients who received allopurinol, 10 received 100 mg, 145 received 200 mg, and 1122 received 300 mg, based on level of renal impairment.1

indication

Indication

ULORIC is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in adult 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. ULORIC is not recommended for the treatment of asymptomatic hyperuricemia.  

The CARES Study

Review the safety data

Results of a randomized, double-blind, post-marketing safety study of patients with gout and a history of major cardiovascular (CV) disease1

  • ULORIC was noninferior to allopurinol in the study primary endpoint of incident of MACE1
  • Patients receiving ULORIC experienced a higher rate of CV death, a secondary endpoint. The biological plausibility of CV death associated with ULORIC is unclear1,7
  • In other secondary endpoints, rates of nonfatal MI, nonfatal stroke, and UA with urgent coronary revascularization were similar among the ULORIC and allopurinol groups1,7

CARES study patient population

  • Patients included in the study were diagnosed with gout and had a history of major CV disease, cerebrovascular disease, or diabetes mellitus with micro- and/or macrovascular disease1
  • Study enrollment took place over 7 years and median on-study follow-up was 2.6 years1,7
  • Mean age was 65 years (range: 44-93 years). Patients had a diagnosis of gout for approximately 12 years, a mean baseline sUA of 8.7 mg/dL, and 90% had experienced at least one gout flare in the past year. CV history included MI (39%), hospitalization for UA (28%), cardiac revascularization (37%), and stroke (14%). Prevalent comorbid conditions were hypertension (92%), hyperlipidemia (87%), diabetes mellitus (55%), diabetes mellitus with micro- or macrovascular disease (39%), and renal impairment (92% with an estimated Clcr 30-89 mL/min)1
  • Patients with CKD4 were excluded from this study.8 In patients with severe renal impairment, limit the dose of ULORIC to 40 mg once daily1

CARES=Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities; CKD=chronic kidney disease; CKD4=CKD stage 4; CI=confidence interval; Clcr=creatinine clearance; MACE=major adverse cardiovascular events (Composite of CV death, nonfatal MI, nonfatal stroke, or UA with urgent coronary revascularization); MI=myocardial infarction; PY=patient years; QD=once a day; sUA=serum uric acid; UA=unstable angina.

Patients initially received ULORIC 40 mg. If sUA ≥6 mg/dL after 2 weeks, patients were titrated to ULORIC 80 mg for the remainder of the study. Patients received ULORIC 40 mg or 80 mg QD regardless of kidney function.7

§Patients with Clcr≥60 mL/min initially received allopurinol 300 mg QD, which was increased by 100 mg monthly if sUA ≥6 mg/dL to a maximum dose of 600 mg QD. Patients with Clcr≥30-<60 mL/min initially received allopurinol 200 mg QD, which was increased by 100 mg monthly if sUA ≥6 mg/dL to a maximum dose of 400 mg QD.7

IMPORTANT SAFETY INFORMATION FOR ULORIC (febuxostat)

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WARNING: CARDIOVASCULAR DEATH

Gout patients with established cardiovascular (CV) disease treated with ULORIC had a higher rate of CV death compared to those treated with allopurinol in a CV outcomes study.

Consider the risks and benefits of ULORIC when deciding to prescribe or continue patients on ULORIC. ULORIC should only be used in patients 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.

  • ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine.
  • Cardiovascular Death: In a CV outcomes study, there was a higher rate of CV death in patients treated with ULORIC compared to allopurinol; in the same study ULORIC was non-inferior to allopurinol for the primary endpoint of major adverse cardiovascular events (MACE). Consider the risks and benefits of ULORIC when deciding to prescribe or continue patients on ULORIC.
  • Gout Flares: An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including ULORIC. If a gout flare occurs during treatment, ULORIC need not be discontinued. Prophylactic therapy (i.e., NSAIDs or colchicine) upon initiation of treatment may be beneficial for up to six months.
  • Hepatic Effects: Postmarketing reports of hepatic failure, sometimes fatal, have been received. Causality cannot be excluded. During randomized controlled studies, transaminase elevations greater than three times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted.
    Obtain liver tests before starting treatment with ULORIC. Use caution in patients with liver disease. If liver injury is detected, promptly interrupt ULORIC and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart treatment if liver injury is confirmed and no alternate etiology can be found.
  • Serious Skin Reactions: Postmarketing reports of serious skin and hypersensitivity reactions, including Stevens-Johnson Syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN) have been reported in patients taking ULORIC. Discontinue ULORIC if serious skin reactions are suspected.
  • Adverse reactions occurring in at least 1% of ULORIC-treated patients, and at least 0.5% greater than placebo, are liver function abnormalities, nausea, arthralgia, and rash. 

INDICATION

ULORIC is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in adult 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. ULORIC is not recommended for the treatment of asymptomatic hyperuricemia.

Please see the complete Prescribing Information, including Medication Guide, for ULORIC.

SHOW REFERENCES HIDE REFERENCES
  1. ULORIC (febuxostat) prescribing information. Takeda Pharmaceuticals.
  2. Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12(2):R63.
  3. Data on file. Takeda Pharmaceuticals.
  4. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology Guidelines for Management of Gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 2012;64(10):1431-1446.
  5. 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(11):1540-1548.
  6. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout [published correction appears in N Engl J Med. 2006;354(14):1533]. N Engl J Med. 2005;353(23):2450-2461.
  7. White WB, Saag KG, Becker MA, et al; for the CARES Investigators. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018;378(13):1200-1210. 
  8. Supplement to: White WB, Saag KG, Becker MA, et al; for the 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.