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  • CLASSES

    Anti-gout Preparations, Plain

    DEA CLASS

    Rx

    DESCRIPTION

    Oral, non-purine selective inhibitor of xanthine oxidase; FDA approved in February 2009 for the chronic treatment of hyperuricemia in patients with gout.

    COMMON BRAND NAMES

    Uloric

    HOW SUPPLIED

    Uloric Oral Tab: 40mg, 80mg

    DOSAGE & INDICATIONS

    For the chronic management of hyperuricemia in patients with gout.
    NOTE: In clinical trials, gout flare was commonly reported after febuxostat initiation; prophylactic therapy with an NSAID or colchicine for up to 6 months may be beneficial.
    Oral dosage
    Adults

    40 mg PO daily. The dose may be increased to 80 mg PO daily if the serum uric acid concentration is greater than 6 mg/dL after 2 weeks of therapy. Higher doses were studied, though not FDA approved. In a 52-week randomized controlled trial, 120 mg PO daily resulted in 62% of patients achieving a serum urate concentration < 6 mg/dL at the last 3 monthly measures; 53% of those receiving febuxostat 80 mg PO daily and 21% of patients receiving allopurinol 300 mg PO daily achieved the same (p < 0.001 for each febuxostat treated group vs. allopurinol group); the rate of study discontinuation due to adverse effects was 9.2% in the febuxostat 120mg/day group, 6.2% in the febuxostat 80mg/day group, and 3.1% in the allopurinol 300 mg/day group.

    MAXIMUM DOSAGE

    Adults

    Specific maximum dosage information is not available; doses of up to 120 mg PO daily have been used in clinical trials.

    Elderly

    Specific maximum dosage information is not available; doses of up to 120 mg PO daily have been used in clinical trials.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is needed in patients with mild to moderate hepatic impairment. Although caution is recommended in patients with severe hepatic impairment (Child-Pugh Class C), specific recommendations for febuxostat dosage adjustment are not available.

    Renal Impairment

    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

    Oral Administration

    Administer without regard to meals or antacid use.

    STORAGE

    Uloric :
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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 (see Adverse Reactions).

    Cardiac disease, myocardial infarction, stroke

    Use with caution in patients with a history of stroke or myocardial infarction, preexisting cardiac disease, or other cardiac risk factors. In clinical trials, an increased incidence of thromboembolic cardiac events (cardiovascular deaths, non-fatal myocardial infarction, and non-fatal stroke) was reported in patients taking febuxostat (0.74 per 100 patient years, CI 0.36 to 1.37) compared to those taking allopurinol (0.60 per 100 patient years, CI 0.16 to 1.53). An additional safety trial was conducted in 6,000 patients with gout treated with either febuxostat or allopurinol. The primary outcome was a combination of heart-related death, non-fatal myocardial infarction, non-fatal stroke, and inadequate blood supply to the heart requiring urgent surgery. Preliminary data show that febuxostat did not increase the risk of these combined events; however, when evaluated separately, febuxostat showed an increased risk of heart-related deaths and death from all causes compared to allopurinol. Instruct patients to recognize the signs and symptoms of myocardial infarction and stroke, and to seek medical help immediately if they experience such symptomology.

    Hepatic disease

    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, 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 > 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 > 3 times the ULN and bilirubin > 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.

    Renal impairment

    Use febuxostat with caution in patients with severe renal impairment (CrCl less than 30 mL/minute); dose adjustments are required. 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. Further, a statistically significant linear relationship was identified between measured creatinine clearance and febuxostat AUC (unbound), and between measured creatinine clearance and febuxostat half-life. Plasma uric acid concentrations decreased and adverse events occurred at similar rates regardless of renal impairment. Febuxostat has not been studied in patients receiving dialysis.

    Chemotherapy, Lesch-Nyhan syndrome, neoplastic disease, secondary hyperuricemia

    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.

    Pregnancy

    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.

    Breast-feeding

    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

    Severe

    atrial fibrillation / Early / 0-5.0
    AV block / Early / 5.0-5.0
    atrial flutter / Early / 0-1.0
    bradycardia / Rapid / 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
    myocardial infarction / Delayed / Incidence not known
    stroke / Early / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known

    Moderate

    gout / Delayed / 47.0-47.0
    elevated hepatic enzymes / Delayed / 4.6-6.6
    sinus tachycardia / Rapid / 0-1.0
    angina / Early / 0-1.0
    hypotension / Rapid / 0-1.0
    palpitations / Early / 0-1.0
    hypertension / Early / 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

    Mild

    rash (unspecified) / 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
    petechiae / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    urticaria / Rapid / 0-1.0
    hyperhidrosis / Delayed / 0-1.0
    skin discoloration / Delayed / 0-1.0
    ecchymosis / Delayed / 0-1.0
    alopecia / Delayed / 0-1.0
    photosensitivity / Delayed / 0-1.0
    purpura / 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

    Aldesleukin, IL-2: (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.
    Alemtuzumab: (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.
    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.
    Altretamine: (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.
    Anthracyclines: (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.
    Antitumor antibiotics: (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.
    Arsenic Trioxide: (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: (Severe) Although not formally studied, the coadministration of febuxostat and azathioprine is contraindicated. By inhibiting xanthine oxidase, febuxostat inhibits azathioprine metabolism. As a result, the activity and myelosuppressive effects of azathioprine will be enhanced. Azathioprine toxicity can be life-threatening.
    Bacillus Calmette-Guerin Vaccine, BCG: (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.
    Bevacizumab: (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.
    Bexarotene: (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.
    Camptothecin 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.
    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.
    Cyclophosphamide: (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.
    Denileukin Diftitox: (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.
    Desipramine: (Minor) Although febuxostat is a weak inhibitor of CYP2D6 and desipramine is a CYP2D6 substrate, coadministration is not expected to require dosage adjustment of either medication. Febuxostat 120 mg given with desipramine 25 mg led to a 16% increase in desipramine maximum serum concentration (Cmax) and a 22% increase in desipramine plasma area under the curve (AUC). This relates to a 17% decrease in desipramine metabolism. Consider monitoring for a change in desipramine effect if febuxostat is initiated or discontinued in patients stable on desipramine therapy.
    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.
    Ibritumomab Tiuxetan: (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.
    Ifosfamide: (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.
    Interferon Alfa-2a: (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.
    Interferon Alfa-2b: (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.
    Interferon Alfa-2b; Ribavirin: (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: (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: (Severe) Although not formally studied, the coadministration of febuxostat and mercaptopurine, 6-MP is contraindicated. 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 caliculi. The myelosuppressive effects and other side effects of 6-MP will also be enhanced. Febuxostat is not indicated for the treatment of hyperuricemia secondary to chemotherapy.
    Methoxsalen: (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.
    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.
    Pentostatin: (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.
    Porfimer: (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.
    Pyrimidine 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.
    Signal Transduction Inhibitors: (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.
    Sunitinib: (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.
    Taxanes: (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.
    Thalidomide: (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) Although no dosing adjustments are recommended, use caution if febuxostat and theophylline, aminophylline are used concurrently. By inhibiting xanthine oxidase, febuxostat alters theophylline metabolism. 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. The long-term effects of this increased exposure are unknown.
    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.
    Tositumomab: (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.
    Tretinoin, ATRA: (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.
    Vorinostat: (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

    Pregnancy

    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.

    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.