CLASSES

Anti-Gout Agents

BOXED WARNING

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.[35002] 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.[35002] 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.[63967] [35002]

DEA CLASS

Rx

DESCRIPTION

Oral, non-purine selective xanthine oxidase inhibitor (XOI)
Used for the chronic management of gout, usually in patients with inadequate response or who are not candidates for allopurinol treatment
Carries a boxed warning for a potential increase in cardiovascular death vs. allopurinol

COMMON BRAND NAMES

Uloric

HOW SUPPLIED

Febuxostat/Uloric Oral Tab: 40mg, 80mg

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

Doses of up to 120 mg/day PO have been used in clinical trials.

Doses of up to 120 mg/day PO have been used in clinical trials.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

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.

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.

ADMINISTRATION

May administer without regard to food, meals, or antacid use.

STORAGE

Uloric :
- Protect from light
- Store at 20 to 25 degrees C (68 to 77 degrees F); excursions permitted between 15 to 30 degrees C (59 to 86 degrees F) USP Controlled Room Temperature

CONTRAINDICATIONS / PRECAUTIONS

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.[35002] 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.[35002] 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.[63967] [35002]

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.

ADVERSE REACTIONS

AV block / Early / 5.0-5.0
atrial fibrillation / Early / 0-5.0
myocardial infarction / Delayed / 3.6-4.3
stroke / Early / 1.8-1.8
atrial flutter / Early / 0-1.0
bradycardia / Rapid / 0-1.0
thromboembolism / Delayed / 0-1.0
proteinuria / Delayed / 0-1.0
renal failure (unspecified) / Delayed / 0-1.0
pancytopenia / Delayed / 0-1.0
hematemesis / Delayed / 0-1.0
pancreatitis / Delayed / 0-1.0
hyperkalemia / Delayed / 0-1.0
peptic ulcer / Delayed / 0-1.0
cholecystitis / Delayed / 0-1.0
angioedema / Rapid / 0-1.0
Guillain-Barre syndrome / Delayed / 0-1.0
rhabdomyolysis / Delayed / Incidence not known
interstitial nephritis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known

gout / Delayed / 47.0-47.0
elevated hepatic enzymes / Delayed / 4.6-6.6
angina / Early / 0-1.6
sinus tachycardia / Rapid / 0-1.0
hypertension / Early / 0-1.0
palpitations / Early / 0-1.0
hypotension / Rapid / 0-1.0
pyuria / Delayed / 0-1.0
hematuria / Delayed / 0-1.0
nephrolithiasis / Delayed / 0-1.0
urinary incontinence / Early / 0-1.0
lymphopenia / Delayed / 0-1.0
anemia / Delayed / 0-1.0
splenomegaly / Delayed / 0-1.0
neutropenia / Delayed / 0-1.0
leukopenia / Delayed / 0-1.0
thrombocytopenia / Delayed / 0-1.0
hyperglycemia / Delayed / 0-1.0
hyperamylasemia / Delayed / 0-1.0
hypokalemia / Delayed / 0-1.0
oral ulceration / Delayed / 0-1.0
hypernatremia / Delayed / 0-1.0
gastritis / Delayed / 0-1.0
diabetes mellitus / Delayed / 0-1.0
hypertriglyceridemia / Delayed / 0-1.0
dehydration / Delayed / 0-1.0
hypercholesterolemia / Delayed / 0-1.0
constipation / Delayed / 0-1.0
hyperlipidemia / Delayed / 0-1.0
hepatomegaly / Delayed / 0-1.0
cholelithiasis / Delayed / 0-1.0
hepatitis / Delayed / 0-1.0
steatosis / Delayed / 0-1.0
migraine / Early / 0-1.0
depression / Delayed / 0-1.0
impotence (erectile dysfunction) / Delayed / 0-1.0
edema / Delayed / 0-1.0
chest pain (unspecified) / Early / 0-1.0
dyspnea / Early / 0-1.0
blurred vision / Early / 0-1.0
psychosis / Early / Incidence not known

rash / Early / 0.5-1.6
nausea / Early / 1.1-1.3
arthralgia / Delayed / 0.7-1.1
flushing / Rapid / 0-1.0
weakness / Early / 0-1.0
myalgia / Early / 0-1.0
musculoskeletal pain / Early / 0-1.0
polyuria / Early / 0-1.0
urinary urgency / Early / 0-1.0
leukocytosis / Delayed / 0-1.0
abdominal pain / Early / 0-1.0
gastroesophageal reflux / Delayed / 0-1.0
xerostomia / Early / 0-1.0
diarrhea / Early / 0-1.0
weight loss / Delayed / 0-1.0
appetite stimulation / Delayed / 0-1.0
vomiting / Early / 0-1.0
flatulence / Early / 0-1.0
weight gain / Delayed / 0-1.0
anorexia / Delayed / 0-1.0
dyspepsia / Early / 0-1.0
urticaria / Rapid / 0-1.0
hyperhidrosis / Delayed / 0-1.0
photosensitivity / Delayed / 0-1.0
alopecia / Delayed / 0-1.0
purpura / Delayed / 0-1.0
pruritus / Rapid / 0-1.0
petechiae / Delayed / 0-1.0
ecchymosis / Delayed / 0-1.0
skin discoloration / Delayed / 0-1.0
headache / Early / 0-1.0
paresthesias / Delayed / 0-1.0
insomnia / Early / 0-1.0
anxiety / Delayed / 0-1.0
agitation / Early / 0-1.0
hypoesthesia / Delayed / 0-1.0
lethargy / Early / 0-1.0
libido decrease / Delayed / 0-1.0
irritability / Delayed / 0-1.0
tremor / Early / 0-1.0
dysgeusia / Early / 0-1.0
gynecomastia / Delayed / 0-1.0
fatigue / Early / 0-1.0
asthenia / Delayed / 0-1.0
infection / Delayed / 0-1.0
nasal dryness / Early / 0-1.0
cough / Delayed / 0-1.0
epistaxis / Delayed / 0-1.0
throat irritation / Early / 0-1.0
sneezing / Early / 0-1.0
nasal congestion / Early / 0-1.0
tinnitus / Delayed / 0-1.0
vertigo / Early / 0-1.0
dizziness / Early / 1.0

DRUG INTERACTIONS

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.
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.
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.
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.
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.
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.
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.
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.
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.

PREGNANCY AND LACTATION

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.

MECHANISM OF ACTION

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.

PHARMACOKINETICS

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.