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In the randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with ULORIC(0.74 per100 P-Y [95%Confidence Interval(CI)0.36-1.37])than allopurinol (0.60 per100 P-Y [95% CI0.16-1.53])[see ADVERSE REACTIONS]. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of myocardial infarction (MI) and stroke.
There have been post marketing reports of fatal and non-fatal hepatic failure in patient staking ULORIC, although the reports contain insufficient information necessary to establish the probable cause. During randomized controlled studies, transaminase elevations greater than three times the upper limit of normal (ULN) were observed(AST:2%, 2%, andALT:3%, 2%in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted[see CLINICAL PHARMACOLOGY].
Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than three times the upper limit of the reference range), ULORIC treatment should be interrupted and investigation done to establish the probable cause. ULORIC should not be restarted in these patients without another explanation for the liver test abnormalities.
Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury and should not be restarted on ULORIC. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with ULORIC can be used with caution.
Patient Counseling Information
See FDA-Approved Patient Labeling (PATIENT INFORMATION)
Patients should be advised of the potential benefits and risks of ULORIC. Patients should be informed about the potential for gout flares, elevated liver enzymes and adverse cardiovascular events after initiation of ULORIC therapy.
Patients should be instructed to inform their healthcare professional if they develop a rash, chest pain, shortness of breath or neurologic symptoms suggesting a stroke. Patients should be instructed to inform their healthcare professional of any other medications they are currently taking with ULORIC, including over-the-counter medications.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two-year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of urinary bladder was observed at 24 mg/kg (25 times the human plasma exposure at maximum recommended human dose of 80 mg/day) and 18.75 mg/kg (12.5 times the human plasma exposure at 80 mg/day) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder.
Febuxostat showed a positive mutagenic response in a chromosomal aberration assay in a Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. Febuxostat was negative in the in vitro Ames assay and chromosomal aberration test in human peripheral lymphocytes, and L5178Y mouse lymphoma cell line, and in vivo tests in mouse micronucleus, rat unscheduled DNA synthesis and rat bone marrow cells.
Impairment of Fertility
Febuxostat at oral doses up to 48 mg/kg/day (approximately 35 times the human plasma exposure at 80 mg/day) had no effect on fertility and reproductive performance of male and female rats.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. ULORIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Febuxostat was not teratogenic in rats and rabbits at oral doses up to 48 mg/kg (40 and 51 times the human plasma exposure at 80 mg/day for equal body surface area, respectively) during organogenesis. However, increased neonatal mortality and a reduction in the neonatal body weight gain were observed when pregnant rats were treated with oral doses up to 48 mg/kg (40 times the human plasma exposure at 80 mg/day) during organogenesis and through lactation period.
Febuxostat is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ULORIC is administered to a nursing woman.
Safety and effectiveness in pediatric patients under 18 years of age have not been established.
No dose adjustment is necessary in elderly patients. Of the total number of subjects in clinical studies of ULORIC, 16% were 65 and over, while 4% were 75 and over. Comparing subjects in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out. The Cmax and AUC24 of febuxostat following multiple oral doses of ULORIC in geriatric subjects ( ≥ 65 years) were similar to those in younger subjects (18 to 40 years) [see CLINICAL PHARMACOLOGY].
No dose adjustment is necessary in patients with mild or moderate renal impairment (Clcr 30 to 89 mL/min). The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended.
There are insufficient data in patients with severe renal impairment (Clcr less than 30 mL/min); therefore, caution should be exercised in these patients [see CLINICAL PHARMACOLOGY].
No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); therefore, caution should be exercised in these patients [see CLINICAL PHARMACOLOGY].
No studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); ULORIC is not recommended for use in patients whom the rate of urate formation is greatly increased (e.g., malignant disease and its treatment, Lesch-Nyhan syndrome). The concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 2/24/2016
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