Febuxostat tablet is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in adult patients with gout who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or for whom treatment with allopurinol is not advisable. For the safe and effective use of allopurinol, see allopurinol prescribing information. Limitations of Use: Febuxostat tablets are not recommended for the treatment of asymptomatic hyperuricemia.
Febuxostat tablet is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in adult patients with gout who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or for whom treatment with allopurinol is not advisable. ( 1 ) For the safe and effective use of allopurinol, see allopurinol prescribing information. Limitations of Use: Febuxostat tablets are not recommended for the treatment of asymptomatic hyperuricemia.
( 1 )
Contraindications
Febuxostat tablets are contraindicated in patients being treated with azathioprine or mercaptopurine [see Drug Interactions ( 7 ) ]. Febuxostat tablets are contraindicated in patients being treated with azathioprine or mercaptopurine. ( 4 )
Warnings and precautions
Cardiovascular Death: In a CV outcomes study, there was a higher rate of CV death in patients treated with febuxostat compared to allopurinol; in the same study febuxostat was non-inferior to allopurinol for the primary endpoint of major adverse cardiovascular events (MACE). Consider the risks and benefits of febuxostat when deciding to prescribe or continue patients on febuxostat. ( 1 , 5.1 ) Gout Flares: An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including febuxostat.
If a gout flare occurs during treatment, febuxostat need not be discontinued. Prophylactic therapy (i.e., non-steroidal anti-inflammatory drug [NSAID] or colchicine upon initiation of treatment) may be beneficial for up to six months. ( 2.4 , 5.2 ) Hepatic Effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt febuxostat and assess patient for probable cause, then treat cause if possible, to resolution or stabilization.
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Do not restart febuxostat if liver injury is confirmed and no alternate etiology can be found. ( 5.3 ) Serious Skin Reactions: Postmarketing reports of serious skin and hypersensitivity reactions, including Stevens-Johnson Syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN) have been reported in patients taking febuxostat. Discontinue febuxostat if serious skin reactions are suspected.
( 5.4 )
5.1 Cardiovascular Death 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 compared to 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 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 [Hazard Ratio: 1.03, 95% Confidence Interval (CI): 0.89, 1.21]. However, there was a significant increase in CV deaths in patients treated with febuxostat (134 [1.5 per 100 patient-years]) compared to patients treated with allopurinol (100 [1.1 per 100 patient-years]) [Hazard Ratio: 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 [see Clinical Studies ( 14.2 )].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 treatment with allopurinol is not advisable [see Indications and Usage( 1 )].
Consider the risks and benefits of febuxostat when deciding to prescribe or continue patients on febuxostat [see Indications and Usage ( 1 )]. Consider use of prophylactic low-dose aspirin therapy in patients with a history of CV disease. Physicians and patients should remain alert for the development of adverse CV event signs and symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
5.2Gout Flares
After initiation of febuxostat, an increase in gout flares is frequently observed. This increase is due to reduction in serum uric acid levels, resulting in mobilization of urate from tissue deposits. In order to prevent gout flares when febuxostat is initiated, concurrent prophylactic treatment with an NSAID or colchicine is recommended [see Dosage and Administration ( 2.4 ) ].
5.3Hepatic Effects
There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking febuxostat, although the reports contain insufficient information necessary to establish the probable cause. During randomized controlled studies, transaminase elevations greater than three times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in febuxostat and allopurinol-treated patients, respectively).
No dose-effect relationship for these transaminase elevations was noted [see Clinical Pharmacology ( 12.3 ) ]. Obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) as a baseline before initiating febuxostat. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than three times the upper limit of the reference range), febuxostat treatment should be interrupted and investigation done to establish the probable cause. Febuxostat should not be restarted in these patients without another explanation for the liver test abnormalities. Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury and should not be restarted on febuxostat.
For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with febuxostat can be used with caution.
5.4Serious Skin Reactions
Postmarketing reports of serious skin and hypersensitivity reactions, including Stevens-Johnson Syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN) have been reported in patients taking febuxostat. Discontinue febuxostat if serious skin reactions are suspected [see Patient Counseling Information ( 17 ) ]. Many of these patients had reported previous similar skin reactions to allopurinol.
Febuxostat should be used with caution in these patients.
Interactions
Concomitant administration of febuxostat with XO substrate drugs, azathioprine or mercaptopurine could increase plasma concentrations of these drugs resulting in severe toxicity. ( 7 )
7.1Xanthine Oxidase Substrate Drugs
Febuxostat is an XO inhibitor. Based on a drug interaction study in healthy patients, febuxostat altered the metabolism of theophylline (a substrate of XO) in humans [see Clinical Pharmacology ( 12.3 ) ]. Therefore, use with caution when coadministering febuxostat with theophylline. Drug interaction studies of febuxostat with other drugs that are metabolized by XO (e.g., mercaptopurine and azathioprine) have not been conducted.
Inhibition of XO by febuxostat may cause increased plasma concentrations of these drugs leading to toxicity [see Clinical Pharmacology ( 12.3 ) ]. Febuxostat is contraindicated in patients being treated with azathioprine or mercaptopurine [see Contraindications ( 4 ) ].
7.2Cytotoxic Chemotherapy Drugs
Drug interaction studies of febuxostat with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of febuxostat during cytotoxic chemotherapy.
7.3In Vivo Drug Interaction Studies Based
on drug interaction studies in healthy patients, febuxostat does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine [see Clinical Pharmacology ( 12.3 ) ]. Therefore, febuxostat may be used concomitantly with these medications.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Limited available data with febuxostat use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. No adverse developmental effects were observed in embryo-fetal development studies with oral administration of febuxostat to pregnant rats and rabbits during organogenesis at doses that produced maternal exposures up to 40 and 51 times, respectively, the exposure at the maximum recommended human dose (MRHD).
No adverse developmental effects were observed in a pre- and postnatal development study with administration of febuxostat to pregnant rats from organogenesis through lactation at an exposure approximately 11 times the MRHD (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days 7 to 17, febuxostat was not teratogenic and did not affect fetal development or survival at exposures up to approximately 40 times the MRHD (on an AUC basis at maternal oral doses up to 48 mg/kg/day).
In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation Days 6 to 18, febuxostat was not teratogenic and did not affect fetal development at exposures up to approximately 51 times the MRHD (on an AUC basis at maternal oral doses up to 48 mg/kg/day). In a pre- and postnatal development study in pregnant female rats dosed orally from gestation Day 7 through lactation Day 20, febuxostat had no effects on delivery or growth and development of offspring at a dose approximately 11 times the MRHD (on an AUC basis at a maternal oral dose of 12 mg/kg/day).
However, increased neonatal mortality and a reduction in neonatal body weight gain were observed in the presence of maternal toxicity at a dose approximately 40 times the MRHD (on an AUC basis at a maternal oral dose of 48 mg/kg/day). Febuxostat crossed the placental barrier following oral administration to pregnant rats and was detected in fetal tissues.
Adverse reactions
The following serious adverse reactions are described elsewhere in the prescribing information:
Cardiovascular Death [see Warnings and Precautions ( 5.1 ) ]
Hepatic Effects [see Warnings and Precautions ( 5.3 ) ]
Serious Skin Reactions [see Warnings and Precautions ( 5.4 )] Adverse reactions occurring in at least 1% of patients treated with febuxostat, and at least 0.5% greater than placebo, are liver function abnormalities, nausea, arthralgia, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In Phase 2 and 3 clinical studies, a total of 2,757 patients with hyperuricemia and gout were treated with febuxostat 40 mg or 80 mg daily. For febuxostat 40 mg, 559 patients were treated for ≥6 months.
For febuxostat 80 mg, 1,377 patients were treated for ≥6 months, 674 patients were treated for ≥1 year and 515 patients were treated for ≥2 years. In the CARES study, a total of 3,098 patients were treated with febuxostat 40 mg or 80 mg daily; of these, 2,155 patients were treated for ≥1 year and 1,539 were treated for ≥2 years [see Clinical Studies ( 14.2 ) ]. Most Common Adverse Reactions In three randomized, controlled clinical studies (Studies 1, 2 and 3), which were six to 12 months in duration, the following adverse reactions were reported by the treating physician as related to study drug.
Table 1 summarizes adverse reactions reported at a rate of at least 1% in febuxostat treatment groups and at least 0.5% greater than placebo. Table 1: Adverse Reactions Occurring in ≥ 1% of Patients Treated with Febuxostat and at Least 0.5% Greater than Seen in Patients Receiving Placebo in Controlled Studies Adverse Reactions Placebo Febuxostat allopurinol * (N=134) 40 mg daily (N=757) 80 mg daily (N=1,279) (N=1,277) Liver Function Abnormalities 0.7% 6.6% 4.6% 4.2% Nausea 0.7% 1.1% 1.3% 0.8% Arthralgia 0% 1.1% 0.7% 0.7% Rash 0.7% 0.5% 1.6% 1.6% * Of the patients who received allopurinol, 10 received 100 mg, 145 received 200 mg, and 1,122 received 300 mg, based on level of renal impairment.
The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of febuxostat 40 mg, 1.2% of febuxostat 80 mg, and in 0.9% of patients treated with allopurinol. In addition to the adverse reactions presented in Table 1, dizziness was reported in more than 1% of patients treated with febuxostat although not at a rate more than 0.5% greater than placebo. In the CARES study, liver function abnormalities and diarrhea were reported in more than 1% of patients treated with febuxostat, although not at a rate more than 0.5% greater than allopurinol.
Less Common Adverse Reactions In clinical studies the following adverse reactions occurred in less than 1% of patients and in more than one subject treated with doses ranging from 40 mg to 240 mg of febuxostat. This list also includes adverse reactions (less than 1% of patients) associated with organ systems from Warnings and Precautions. Blood and Lymphatic System Disorders: anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia.
The following adverse reactions have been identified during postapproval use of febuxostat. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: agranulocytosis, eosinophilia. Hepatobiliary Disorders: hepatic failure (some fatal), jaundice, serious cases of abnormal liver function test results, liver disorder.
Immune System Disorders: anaphylaxis, anaphylactic reaction. Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis. Psychiatric Disorders: psychotic behavior including aggressive thoughts. Renal and Urinary Disorders: tubulointerstitial nephritis. Skin and Subcutaneous Tissue Disorders: generalized rash, Stevens-Johnson Syndrome, hypersensitivity skin reactions, erythema multiforme, drug reaction with eosinophilia and systemic symptoms, toxic epider
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Composition
Active ingredients
FEBUXOSTAT 40MG
Strengths and forms
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