Febuxostat is an oral, non-purine selective xanthine oxidase inhibitor (XOI). Febuxostat does not require a dosage adjustment in patients with mild to moderate renal impairment and appears less likely than allopurinol to cause serious hypersensitivity. Febuxostat shares with allopurinol an increased risk of gout flare during therapy initiation, which necessitates the concurrent use of colchicine, NSAIDs, or corticosteroids for prophylaxis against acute gout attacks. A boxed warning in the product label warns about a potential increase in cardiovascular death versus allopurinol. Gout patients with established cardiovascular (CV) disease treated with febuxostat had a higher rate of cardiovascular (CV) death compared to those treated with allopurinol in a CV outcomes study. Because of the increased risk of CV death, febuxostat 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 allopurinol treatment is not advisable. Unlike allopurinol, febuxostat has not been studied in patients with secondary hyperuricemia. Like other chronic gout treatments, the drug is not recommended in patients with asymptomatic hyperuricemia. For chronic gout management, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) guidelines recommend ULT to achieve a target serum uric acid (sUA) level of less than 6 mg/dL to prevent the formation of crystals and to eliminate crystal deposition, thereby dissolving tophi. A lower target (less than 5 mg/dL) is recommended for patients with severe disease. Allopurinol is usually the first-line treatment agent due to effectiveness and cost considerations unless contraindications exist. Allopurinol and febuxostat appear relatively similar in lowering serum urate concentrations and reducing gout flares with long-term (more than 1 year) of monotherapy use. Treatment guidelines recommend combination therapy with a uricosuric (e.g., lesinurad) plus a xanthine oxidase inhibitor (XOI) when treatment goals are not met with an XOI alone. The use of pegloticase is usually reserved for severe, refractory chronic gout.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-May administer without regard to food, meals, or antacid use.
Limit the use of febuxostat to patients who are not treated effectively by, are contraindicated to receive, or experience severe adverse effects due to allopurinol. A large safety clinical trial showed an increased risk of cardiovascular death and all-cause mortality with febuxostat use vs. allopurinol. Instruct patients to recognize the signs and symptoms of myocardial infarction and stroke, and to seek medical help immediately if they experience such symptoms. In a cardiovascular (CV) outcome study (ClinicalTrials.gov identifier NCT01101035), gout patients with established CV disease treated with febuxostat had a higher rate of CV death vs. those treated with allopurinol. The CV outcomes study in patients with gout (CARES) was a randomized, double-blinded, allopurinol-controlled, non-inferiority study conducted to evaluate the risk of major adverse cardiovascular events (MACE) in patients with gout who were treated with febuxostat. The study enrolled patients who had a history of major CV disease, cerebrovascular disease, or diabetes mellitus with micro- and/or macrovascular disease. The primary endpoint was the time to the first occurrence of MACE defined as the composite of CV death, nonfatal MI, nonfatal stroke, or unstable angina with urgent coronary revascularization. The study was designed to exclude a prespecified risk margin of 1.3 for the hazard ratio of MACE. Results showed that febuxostat was non-inferior to allopurinol for the primary endpoint of MACE [HR: 1.03, 95% CI: 0.89, 1.21]. However, there was a significant increase in CV deaths in patients treated with febuxostat (1.5 per 100 patient-years) vs. patients treated with allopurinol (1.1 per 100 patient-years) [HR: 1.34, 95% CI: 1.03, 1.73]. Sudden cardiac death was the most common cause of adjudicated CV deaths in the febuxostat group (83 of 3,098; 2.7%) as compared to the allopurinol group (56 of 3,092; 1.8%). Febuxostat was similar to allopurinol for nonfatal MI, nonfatal stroke, and unstable angina with urgent coronary revascularization. Cardiac events due to thromboembolism occurred at a rate of 0.74 per 100 patient-years (95% CI 0.36 to 1.37) in patients who received febuxostat compared to a rate of 0.60 per 100 patient-years (95% CI 0.16 to 1.53) in patients who received allopurinol. All-cause mortality was higher in the febuxostat group (243 deaths [7.8%]; 2.6 per 100 patient-years) than the allopurinol group (199 deaths [6.4%]; 2.2 per 100 patient-years) [HR: 1.22, 95% CI: 1.01, 1.47], due to a higher rate of CV deaths. In a 5-year open-label trial that included patients with comorbid high blood pressure, hyperlipidemias, obesity, and pre-existing cardiovascular disease, 5% of patients suffered serious cardiac adverse events, including AV block and atrial fibrillation. In the premarketing clinical trials, each of the following cardiovascular adverse events was experienced by less than 1% of all patients taking febuxostat: angina, atrial fibrillation, atrial flutter, cardiac murmur, ECG abnormalities, palpitations, sinus bradycardia, sinus tachycardia, flushing, hypertension, hypotension, and increases in lactate dehydrogenase or creatine phosphokinase.
Similar to other agents used to treat hyperuricemia, gout flare may occur after febuxostat initiation; prophylactic therapy with an NSAID or colchicine for up to six months may be beneficial. Continue febuxostat therapy during gout flare, adding either an NSAID or colchicine acutely. In a 5-year open-label clinical trial, 47% of all patients experienced gout flare; approximately 7% of patients withdrew from the study due to gout flare. The presence of tophi may be predictive of an increased risk of gout flare; after 12 months of therapy, less than 10% of patients without baseline tophi reported gout flare compared to 31% of patients with baseline tophi. During the course of therapy, the incidence of treated gout flare decreased from greater than 25% of patients at the peak incidence of 4 months to none at 60 months; however, this data may be biased by a 50% premature discontinuation of study patients. Arthralgia was reported in 1.1% of patients who received febuxostat 40 mg/day, in 0.7% of patients who received febuxostat 80 mg/day, and in 0.7% of patients who received allopurinol 100-300 mg/day (allopurinol dose was dependent on renal function). Less than 1% of patients who received febuxostat in doses ranging from 40-240 mg daily experienced arthritis; joint stiffness or swelling; muscle weakness, spasms, twitching, or tightness; musculoskeletal pain or stiffness; or myalgia. Advise patients to report unusual or persistent muscle pain and/or weakness as rhabdomyolysis has been reported during post-marketing use of febuxostat. Creatine increases were noted in < 1% of patients during clinical trials.
Renal system adverse events have been noted during febuxostat therapy. In clinical trials, less than 1% of patients experienced renal or urinary disorders. Adverse events included hematuria, nephrolithiasis, polyuria, proteinuria, renal failure (unspecified), renal insufficiency, pyuria (or sterile pyuria), urinary urgency, and urinary incontinence. Tubulointerstitial nephritis (interstitial nephritis) has been reported in post-marketing experience. Renal failure also has occurred in patients with gouty nephropathy independent of hyperuricemia therapy. Patients with secondary hyperuricemia (i.e. patients post-organ transplant and those with neoplastic disease) have a greatly increased rate of urate formation. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and caliculi. Febuxostat use in patients with secondary hyperuricemia has not been studied and use is not recommended. As with allopurinol, it is advisable for patients to maintain a urine output >= 2 L/day in an attempt to avoid the formation of xanthine calculi under the influence of xanthine oxidase inhibitor therapy and to help prevent renal precipitation of urates in patients receiving concurrent uricosuric agents. Abnormal laboratory parameters noted in < 1% of patients include creatinine and blood urea increases, BUN/creatinine ratio increases, and urinary casts.
Myelosuppression occurred rarely, less than 1%, in study patients taking febuxostat. Adverse events included anemia, idiopathic thrombocytopenic purpura, leukocytosis, leukopenia, lymphopenia, neutropenia, pancytopenia, splenomegaly, and thrombocytopenia. Increases in MCV, in addition to decreases in hemoglobin and hematocrit have been noted in < 1% of patients.
Nausea was reported in 1.1-1.3% of patients in clinical trials, while vomiting occurred in < 1%. Other adverse GI, metabolic, or nutritional effects that occurred in less than 1% of patients taking febuxostat in clinical trials include abdominal pain or distension, xerostomia, flatulence, diarrhea, gastritis, gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain, hyperchlohydria, hematochezia, oral ulceration, pancreatitis, peptic ulcer, constipation, dyspepsia, hematemesis, weight gain or weight loss, anorexia, appetite stimulation, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperamylasemia, hypokalemia, hyperkalemia, hypernatremia, bicarbonate decreases, and TSH increases.
Fatal and non-fatal hepatic failure has been reported in patients taking febuxostat. Elevated hepatic enzymes were reported in 6.6% and 4.6% of patients who received febuxostat 40 mg and 80 mg daily, respectively. Reversible elevated hepatic enzymes of greater than 3 times the upper limit of normal have been observed in clinical trials, aspartate transaminase (AST) in 2% of patients and alanine transaminase (ALT) in 3% of patients. No relationship between the incidence of transaminase elevations and febuxostat dose was identified. Abnormal liver function test results were the most common adverse event related to febuxostat therapy discontinuation during pre-marketing studies. Obtain liver function tests before initiating febuxostat. After initiation, liver-function testing is recommended at 2 months, 4 months, and periodically thereafter; measure liver function immediately in patients who report symptoms suggestive of liver injury, including fatigue, anorexia, abdominal discomfort, dark urine, or jaundice. Less than 1% of study patients experienced cholelithiasis, cholecystitis, hepatic steatosis, elevated alkaline phosphatase, hepatitis, or hepatomegaly. Abnormal coagulation tests, including prolonged prothrombin or activated partial thromboplastin times have been noted in < 1% of patients.
Hypersensitivity reactions have been reported in clinical trials (less than 1%) and in post-marketing experience with febuxostat. In placebo- and alternative drug-controlled study, rash (unspecified) was reported in 0.5% of patients taking 40 mg/day, 1.6% of patients taking 80 mg/day, 1.6% of patients taking allopurinol 100-300 mg/day, and 0.7% of those on placebo. Serious skin and hypersensitivity reactions including anaphylaxis, anaphylactoid reactions, generalized rash, erythema multiforme, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN). Discontinue febuxostat if a serious skin reaction occurs or is suspected. Many of these patients had reported similar skin reactions to allopurinol. Febuxostat should be used with caution in these patients. Other dermatologic and allergic reactions reported in less than 1% of patients include angioedema, alopecia, dermatitis, dermographism, ecchymosis, eczema, hair color changes, abnormal hair growth, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, abnormal skin odor, and urticaria.
Psychosis, reported as psychotic behavior including aggressive thoughts, has been reported during post-marketing use of febuxostat. Dizziness was reported in > 1% of febuxostat-treated patients during clinical trials, but not at a rate more than 0.5% greater than placebo. The following nervous system and psychiatric adverse reactions were reported in patients who received febuxostat at doses ranging from 40 mg to 240 mg during phase 2 and 3 clinical studies: dysgeusia, balance disorder, cerebrovascular accident, Guillain-Barre syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesias, somnolence, transient ischemic attack, tremor, agitation, anxiety, depression, insomnia, irritability, libido decrease, nervousness, panic attack, and personality changes. Abnormal EEG was noted in < 1% of patients.
Reproductive system adverse reactions reported in < 1% of febuxostat recipients during clinical trials include breast pain, gynecomastia, impotence (erectile dysfunction), and PSA increases.
General disorders reported in < 1% of patients during febuxostat treatment in phase 2 and 3 clinical trials include asthenia, chest pain (unspecified), edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst, herpes zoster, and contusion.
Adverse respiratory effects occurred rarely during febuxostat treatment in clinical trials. Effects reported in < 1% of patients include bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract or nasal congestion, sneezing, throat irritation, and upper respiratory tract infection.
Blurred vision, deafness, tinnitus, and vertigo were noted in < 1% of febuxostat recipients treated with doses ranging from 40 to 240 mg during phase 2 and 3 clinical trials.
Febuxostat is contraindicated in patients being treated with azathioprine or mercaptopurine.
Similar to other xanthine oxidase inhibitor use, gout flare was reported after febuxostat initiation; prophylactic therapy with an NSAID or colchicine for up to 6 months may be beneficial. Use febuxostat more cautiously in patients with baseline tophi as there may be a higher likelihood of gout flare in this population.
Postmarketing reports of serious rash and hypersensitivity reactions, including Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN) have been reported in patients taking febuxostat. Discontinue febuxostat if serious skin reactions are suspected. Many of the patients with these reactions had reported previous similar skin reactions to allopurinol. Febuxostat should be used with caution in these patients.
Because of the increased risk of cardiovascular mortality, febuxostat 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. Use febuxostat with caution in patients with a history of stroke or myocardial infarction, preexisting cardiac disease, or other cardiac risk factors. Consider the risks and benefits of febuxostat when deciding to prescribe or continue patients on the drug. Consider the use of prophylactic low-dose aspirin therapy in patients with a history of cardiovascular (CV) disease. Physicians and patients should remain alert for adverse CV signs and symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. In a cardiovascular (CV) outcome study (ClinicalTrials.gov identifier NCT01101035), gout patients with established CV disease treated with febuxostat had a higher rate of CV death vs. those treated with allopurinol. The CV outcomes study in patients with gout (CARES) was a randomized, double-blinded, allopurinol-controlled, non-inferiority study conducted to evaluate the risk of major adverse cardiovascular events (MACE) in patients with gout who were treated with febuxostat. The study enrolled patients who had a history of major CV disease, cerebrovascular disease, or diabetes mellitus with micro- and/or macrovascular disease. The primary endpoint was the time to the first occurrence of MACE defined as the composite of CV death, nonfatal MI, nonfatal stroke, or unstable angina with urgent coronary revascularization. The study was designed to exclude a prespecified risk margin of 1.3 for the hazard ratio of MACE. Results showed that febuxostat was non-inferior to allopurinol for the primary endpoint of MACE [HR: 1.03, 95% CI: 0.89, 1.21]. However, there was a significant increase in CV deaths in patients treated with febuxostat (1.5 per 100 patient-years) vs. patients treated with allopurinol (1.1 per 100 patient-years) [HR: 1.34, 95% CI: 1.03, 1.73]. Sudden cardiac death was the most common cause of adjudicated CV deaths in the febuxostat group (83 of 3,098; 2.7%) as compared to the allopurinol group (56 of 3,092; 1.8%). Febuxostat was similar to allopurinol for nonfatal MI, nonfatal stroke, and unstable angina with urgent coronary revascularization.
Use febuxostat with caution in patients with severe hepatic disease (Child-Pugh Class C) and in patients with elevated transaminase concentrations. Fatal and non-fatal hepatic failure as well as increases in transaminase concentrations above the upper limit of normal (ULN), specifically AST and ALT, have been observed. No relationship between the incidence of transaminase elevations and febuxostat dose was identified. Obtain liver function tests (ALT, AST, alkaline phosphatase, and total bilirubin) prior to febuxostat initiation. After the initiation of febuxostat therapy, liver-function testing is recommended at 2 months, 4 months, and periodically thereafter. Liver function should be assessed immediately in patients with symptoms suggestive of liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. If abnormal liver function is detected (ALT more than 3 times the ULN), interrupt febuxostat therapy to determine probable cause; do not restart febuxostat in these patients without an alternative explanation for abnormal liver function. Patients with ALT more than 3 times the ULN and bilirubin more than 2 times the ULN with no alternative explanations may experience severe drug-induced liver injury and should not be restarted on febuxostat. Febuxostat may be restarted with caution in patients with lower elevations of ALT or bilirubin with alternative probable cause.
Use febuxostat with caution in patients with severe renal impairment (CrCl less than 30 mL/minute); dose adjustments are required in patients with CrCl 15 to 29 mL/minute. Febuxostat has not been studied in patients with end-stage renal failure receiving dialysis. In a study of febuxostat in patients with varying degrees of renal function, the renal elimination of febuxostat and metabolites was inversely related to the degree of renal impairment.
Febuxostat is not recommended in patients with secondary hyperuricemia (e.g., after organ transplant) or in patients with a greatly increased rate of uric acid synthesis (e.g., those with neoplastic disease, patients on chemotherapy, and patients with Lesch-Nyhan syndrome). Febuxostat inhibits uric acid formation but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and caliculi. Febuxostat use has not been studied in these populations.
Limited available data with the use of febuxostat in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes resulting from fetal exposure during pregnancy. The results of animal studies using approximately 40 and 51 times, respectively, the exposure at the maximum recommended human dose (MRHD) indicate that febuxostat is not teratogenic in rats and rabbits during organogenesis. In pre- and postnatal development studies of pregnant female rats dosed orally from gestation through lactation, febuxostat had no effects on delivery or growth and development of offspring at a dose approximately 11 times the MRHD. However, increased neonatal mortality and decreased neonatal weight gain were noted in the presence of maternal toxicity at a dose approximately 40 times the MRHD. Febuxostat does cross the placenta following oral administration to pregnant rats.
Febuxostat should be used with caution during breast-feeding. There are no data on the presence of febuxostat in human milk, the effects on the breastfed infant, or the effects on milk production. Febuxostat is present in the milk of lactating rats at up to approximately 7 times the plasma concentration. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for febuxostat and any potential adverse effects on the breastfed infant from febuxostat or from the underlying maternal condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For the treatment of chronic hyperuricemia in persons with gout (gouty arthritis):
Oral dosage:
Adults: 40 mg PO once daily, initially. Increase the dose to 80 mg PO once daily after 2 weeks in persons who do not achieve a serum uric acid concentration less than 6 mg/dL. Gout flares may occur after initiation of febuxostat due to changing serum uric acid concentrations resulting in mobilization of urate from tissue deposits and prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended upon initiation of febuxostat. Prophylactic therapy may be beneficial for up to 6 months. If a gout flare occurs during febuxostat treatment, febuxostat does not need to be discontinued; manage the gout flare concurrently as appropriate. Febuxostat is not recommended for asymptomatic hyperuricemia.
Maximum Dosage Limits:
-Adults
Doses of up to 120 mg/day PO have been used in clinical trials.
-Geriatric
Doses of up to 120 mg/day PO have been used in clinical trials.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustment is needed in patients with mild to moderate hepatic impairment. Caution is recommended in patients with severe hepatic impairment (Child-Pugh Class C); no studies have been done in this population and specific dose recommendations are not available.
If liver function test abnormalities develop during treatment: Interrupt treatment and establish the probable cause. Do not restart febuxostat without another explanation for the LFT abnormalities. Patients who have serum ALT more than 3 times the upper limit of normal (ULN) with serum total bilirubin more than 2 times the ULN without alternative etiologies are at risk for severe drug-induced liver injury. Discontinue febuxostat and do not restart the drug. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment can be used with caution.
Patients with Renal Impairment Dosing
CrCl 30 to 89 mL/minute: No dosage adjustment needed.
CrCl 15 to 29 mL/minute: Do not exceed 40 mg PO once daily.
CrCl less than 15 mL/minute: Febuxostat has not been studied in end-stage renal impairment patients who are on dialysis.
*non-FDA-approved indication
Alkylating agents: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Antimetabolites: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Azathioprine: (Contraindicated) The use of febuxostat with azathioprine is contraindicated. Febuxostat inhibits xanthine oxidase (XO) and is expected to greatly increase the concentrations of drugs metabolized substantially by this enzyme, such as azathioprine. Inhibition of XO by febuxostat may cause increased plasma concentrations of azathioprine, leading to serious toxicity. Drug interaction studies of febuxostat with azathioprine have not been conducted.
Busulfan: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Carmustine, BCNU: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Chlorambucil: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Cladribine: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Clofarabine: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Dacarbazine, DTIC: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Estramustine: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Fludarabine: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Folate analogs: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Hydroxyurea: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Lomustine, CCNU: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Mechlorethamine, Nitrogen Mustard: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Melphalan Flufenamide: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Melphalan: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Mercaptopurine, 6-MP: (Contraindicated) The use of febuxostat with mercaptopurine is contraindicated. Febuxostat inhibits xanthine oxidase (XO) and is expected to greatly increase the concentrations of drugs metabolized substantially by this enzyme, such as mercaptopurine. Inhibition of XO by febuxostat may cause increased plasma concentrations of mercaptopurine, 6-MP, leading to serious toxicity. Drug interaction studies of febuxostat with mercaptopurine have not been conducted.
Methotrexate: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Mitoxantrone: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Natural Antineoplastics: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Nelarabine: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Pegaspargase: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Pegloticase: (Major) Oral urate-lowering medications, including allopurinol, febuxostat, probenecid, and sulfinpyrazone may potentially blunt the rise of serum uric acid levels in patients taking pegloticase. Since patients who have lost therapeutic response to pegloticase are at higher risk of developing anaphylaxis and infusion reactions, oral urate-lowering therapy should be discontinued prior to pegloticase initiation and withheld during the course of treatment.
Pemetrexed: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Pralatrexate: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Procarbazine: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Rosuvastatin: (Moderate) Do not exceed a rosuvastatin dose of 20 mg once daily if concomitant use of febuxostat is necessary. Concomitant use may increase rosuvastatin exposure and the risk for rosuvastatin-related adverse reactions, such as myopathy and rhabdomyolysis. Coadministration with febuxostat increased rosuvastatin exposure more than 1.9-fold.
Rosuvastatin; Ezetimibe: (Moderate) Do not exceed a rosuvastatin dose of 20 mg once daily if concomitant use of febuxostat is necessary. Concomitant use may increase rosuvastatin exposure and the risk for rosuvastatin-related adverse reactions, such as myopathy and rhabdomyolysis. Coadministration with febuxostat increased rosuvastatin exposure more than 1.9-fold.
Streptozocin: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Temozolomide: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Theophylline, Aminophylline: (Moderate) Use caution if febuxostat and aminophylline are used concurrently. Aminophylline is converted to the active form, theophylline, in the body. By inhibiting xanthine oxidase, febuxostat alters theophylline metabolism. Monitor theophylline concentrations. In a study conducted in healthy adults, coadministration of febuxostat (80 mg PO daily) resulted in increased theophylline Cmax (6%) and AUC (6.5%). These changes were not considered statistically significant. An approximately 400-fold increase in the amount of 1-methylxanthine (a major metabolite of theophylline) excreted in the urine was also noted. Since the long-term safety of exposure to 1-methylxanthine in humans is unknown, use with caution when coadministering febuxostat with aminophylline. (Moderate) Use caution if febuxostat and theophylline are used concurrently. By inhibiting xanthine oxidase, febuxostat alters theophylline metabolism. Monitor theophylline concentrations. In a study conducted in healthy adults, coadministration of febuxostat (80 mg PO daily) resulted in increased theophylline Cmax (6%) and AUC (6.5%). These changes were not considered statistically significant. An approximately 400-fold increase in the amount of 1-methylxanthine (a major metabolite of theophylline) excreted in the urine was also noted. Since the long-term safety of exposure to 1-methylxanthine in humans is unknown, use with caution when coadministering febuxostat with theophylline.
Thioguanine, 6-TG: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Thiotepa: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Vinblastine: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Vincristine Liposomal: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Vincristine: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Vinorelbine: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Febuxostat is a non-purine selective inhibitor of both the oxidized and reduced forms of xanthine oxidase. Similar to allopurinol, febuxostat blocks the metabolism of hypoxanthine and xanthine (oxypurines) to uric acid, thus reducing uric acid blood and urine concentrations. In contrast, uricosuric agents increase the urinary excretion of uric acid. Xanthine oxidase inhibition is dose dependent.
Febuxostat appears to be more selective for xanthine oxidase than allopurinol. In vitro study with febuxostat has shown no significant effects on the activities of the following enzymes of purine and pyrimidine metabolism: guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine-5V-monophosphate decarboxylase, and purine nucleoside phosphorylase. Further differentiating this drug from allopurinol, the structure of febuxostat does not resemble purines or pyrimidines.
Febuxostat is administered orally. It is 99.2% plasma protein bound and has a calculated apparent volume of distribution at steady state of approximately 0.7 L/kg. Febuxostat is extensively metabolized by both conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes, including UGT1A1, UGT1A3, UGT1A9, and UGT2B7, and oxidation via cytochrome P450 enzymes, including CYP1A2, CYP2C8, and CYP2C9 and non-P450 enzymes. The relative contribution of each enzyme isoform in metabolism is not clear. The oxidation of the isobutyl side chain leads to the formation of 4 pharmacologically active metabolites, all of which are found in human plasma at significantly lower concentrations than that of febuxostat. Febuxostat is eliminated by both hepatic and renal pathways. Analysis of renal excretion revealed that within 24 hours, approximately 49% was eliminated in the urine; 3% was excreted as febuxostat, 30% as the acyl glucuronide, 13% as known oxidative metabolites and their conjugates, and 3% as unknown metabolites. In addition to the urinary excretion, approximately 45% of the dose was recovered in the feces, 12% as unchanged febuxostat, 1% as the acyl glucuronide, 25% as known oxidative metabolites and their conjugates, and 7% as other unknown metabolites. The elimination half-life is 5 to 8 hours. Serum urate concentrations decrease in a dose-dependent fashion. Steady-state serum uric acid concentration may be reached within 7 days of therapy initiation.
Affected cytochrome P450 isoenzymes and drug transporters: UGT1A1, UGT1A3, UGT1A9, UGT2B7, CYP1A2, CYP2C8, and CYP2C9
Febuxostat is not expected to interact with drugs that either alter or depend on CYP. While it is a weak inhibitor of CYP2D6 both in vitro and in vivo, in vitro studies have shown that at clinically relevant concentrations, it does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP3A4. Clinically significant interactions between febuxostat and drugs that inhibit or induce one particular enzyme isoform are generally not expected. Febuxostat is extensively metabolized by both conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes, including UGT1A1, UGT1A3, UGT1A9, and UGT2B7, and oxidation via cytochrome P450 enzymes, including CYP1A2, CYP2C8, and CYP2C9 and non-P450 enzymes. The relative contribution of each enzyme isoform in metabolism is not clear.
-Route-Specific Pharmacokinetics
Oral Route
Approximately 49% of an orally administered dose is absorbed with peak febuxostat plasma concentrations occurring between 1 to 1.5 hours post-dose. Administration with food does not appear to affect efficacy. Multiple once daily administrations with a high-fat meal resulted in lower febuxostat Cmax and AUC; however, no clinically significant change in the serum uric acid concentration reduction was observed. Cmax and AUC of febuxostat are dose proportional over a dose range of 10 to 120 mg.
-Special Populations
Hepatic Impairment
No dosage adjustments are needed for patients with mild to moderate hepatic impairment. Febuxostat has not been studied in patients with Child-Pugh Class C hepatic impairment or in patients with comorbid hepatic and renal impairment.
Renal Impairment
In a dedicated phase I pharmacokinetics study, following multiple 80 mg doses of ULORIC in healthy patients with mild (CrCl 50 to 80 mL/minute), moderate (CrCl 30 to 49 mL/minute) or severe renal impairment (CrCl 10 to 29 mL/minute), the Cmax of febuxostat did not change relative to patients with normal renal function (CrCl more than 80 mL/min). The AUC and half-life of febuxostat increased in patients with renal impairment in comparison to patients with normal renal function, but values were similar among the 3 renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in patients with renal impairment compared to those with normal renal function. Mean Cmax and AUC values for the 3 active metabolites increased up to 2-and 4-fold, respectively. However, the percent decrease in serum uric acid concentration for patients with renal impairment was comparable to those with normal renal function (58% in normal renal function group and 55% in the severe renal function group). Among patients with gout and mild, moderate or severe renal impairment, the mean oral clearance of febuxostat was decreased by 14%, 34%, and 48%, respectively, compared to patients with normal renal function. The corresponding median AUC values of febuxostat at steady-state in patients with renal impairment were increased by 18%, 49%, and 96% after 40 mg dose, and 7%, 45% and 98% after 80 mg dose, respectively, compared to patients with normal renal function.
Pediatrics
Safety and efficacy has not been established in patients under 18 years of age.
Geriatric
No clinically significant differences were noted in the pharmacokinetics, pharmacodynamics, and safety of febuxostat based on age.
Gender Differences
No clinically significant differences were noted in the pharmacokinetics, pharmacodynamics, and safety of febuxostat based on gender in adult populations.
Ethnic Differences
Race-based statistically significant differences in febuxostat efficacy were reported in a 5-year open-label trial, with 87% of Caucasian patients reaching target serum urate concentrations of < 6 mg/dL compared to 65% of non-Caucasian patients (p = 0.025).