FEBUXOSTAT — febuxostat tablet, film coated
Indoco Remedies Limited
WARNING: CARDIOVASCULAR DEATH
Gout patients with established cardiovascular (CV) disease treated with febuxostat tablets had a higher rate of CV death compared to those treated with allopurinol in a CV outcomes study [see Warnings and Precautions (5.1)].
Consider the risks and benefits of febuxostat tablets when deciding to prescribe or continue patients on febuxostat tablets. Febuxostat tablets 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)].
1 INDICATIONS AND USAGE
Febuxostat tablets are 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.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
The recommended febuxostat tablets dosage is 40 mg or 80 mg once daily.
The recommended starting dosage of febuxostat tablets is 40 mg once daily. For patients who do not achieve a serum uric acid (sUA) less than 6 mg/dL after two weeks, the recommended febuxostat tablets dosage is 80 mg once daily.
Febuxostat tablets can be taken without regard to food or antacid use [see Clinical Pharmacology (12.3)].
2.2 Dosage Recommendations in Patients with Renal Impairment and Hepatic Impairment
No dose adjustment is necessary when administering febuxostat tablets in patients with mild or moderate renal impairment.
The recommended dosage of febuxostat tablets is limited to 40 mg once daily in patients with severe renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
No dose adjustment is necessary in patients with mild to moderate hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
2.3 Uric Acid Level
Testing for the target serum uric acid level of less than 6 mg/dL may be performed as early as two weeks after initiating febuxostat tablets therapy.
2.4 Recommended Prophylaxis for Gout Flares
Gout flares may occur after initiation of febuxostat tablets due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended upon initiation of febuxostat tablets. Prophylactic therapy may be beneficial for up to six months [see Clinical Studies (14.1)]. If a gout flare occurs during febuxostat tablets treatment, febuxostat tablets need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient [see Warnings and Precautions (5.2)].
3 DOSAGE FORMS AND STRENGTHS
- 40 mg tablets, light green to green coloured, round, biconvex, film coated tablet debossed with “18” on one side and “I” on the other side.
- 80 mg tablets, light green to green coloured, tear drop shaped, biconvex, film coated tablet debossed with “19” on one side and “I” on the other side.
Febuxostat tablets are contraindicated in patients being treated with azathioprine or mercaptopurine [see Drug Interactions (7)].
5 WARNINGS AND PRECAUTIONS
5.1 Cardiovascular Death
In a cardiovascular (CV) outcome study (ClinicalTrials.gov identifier NCT01101035), gout patients with established CV disease treated with febuxostat tablets 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 tablets. 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 tablets 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 tablets (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 tablets group (83 of 3,098; 2.7%) as compared to the allopurinol group (56 of 3,092; 1.8%). Febuxostat tablets 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 tablets 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 tablets when deciding to prescribe or continue patients on febuxostat tablets [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.
5.2 Gout Flares
After initiation of febuxostat tablets, 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 tablets are initiated, concurrent prophylactic treatment with an NSAID or colchicine is recommended [see Dosage and Administration (2.4)].
5.3 Hepatic Effects
There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking febuxostat tablets, 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 tablets 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 tablets.
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 tablets treatment should be interrupted and investigation done to establish the probable cause. Febuxostat tablets 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 tablets. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with febuxostat tablets can be used with caution.
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