Febuxostat: Package Insert and Label Information

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.

4 CONTRAINDICATIONS

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.

5.4 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 tablets. Discontinue febuxostat tablets if serious skin reactions are suspected [see Patient Counseling Information (17)]. Many of these patients had reported previous similar skin reactions to allopurinol. Febuxostat tablets should be used with caution in these patients.

6 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)]

6.1 Clinical 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 2757 patients with hyperuricemia and gout were treated with febuxostat tablets 40 mg or 80 mg daily. For febuxostat tablets 40 mg, 559 patients were treated for ≥6 months. For febuxostat tablets 80 mg, 1377 subjects 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 3098 patients were treated with febuxostat tablets 40 mg or 80 mg daily; of these, 2155 patients were treated for ≥1 year and 1539 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 tablets treatment groups and at least 0.5% greater than placebo.

Table 1: Adverse Reactions Occurring in ≥1% of Patients Treated with Febuxostat tablets and at Least 0.5% Greater than Seen in Patients Receiving Placebo in Controlled Studies
Placebo Febuxostat tablets allopurinol*
Adverse Reactions (N=134) 40 mg daily (N=757) 80 mg daily (N=1279) (N=1277)
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 1122 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 tablets 40 mg, 1.2% of febuxostat tablet 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 tablets 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 tablets, 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 tablets. 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.

Cardiac Disorders: angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia.

Ear and Labyrinth Disorders: deafness, tinnitus, vertigo.

Eye Disorders: vision blurred.
Gastrointestinal Disorders: abdominal distention, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis, gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain, haematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis, peptic ulcer, vomiting.



General Disorders and Administration Site Conditions: asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst.

Hepatobiliary Disorders: cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly.

Immune System Disorder: hypersensitivity.

Infections and Infestations: herpes zoster.

Procedural Complications: contusion.

Metabolism and Nutrition Disorders: anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased.
Musculoskeletal and Connective Tissue Disorders: arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia.

Nervous System Disorders: altered taste, balance disorder, cerebrovascular accident, Guillain-Barré syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor.

Psychiatric Disorders: agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change.

Renal and Urinary Disorders: hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence.

Reproductive System and Breast Changes: breast pain, erectile dysfunction, gynecomastia.

Respiratory, Thoracic and Mediastinal Disorders: bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection.

Skin and Subcutaneous Tissue Disorders: alopecia, angio-edema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria.


Vascular Disorders: flushing, hot flush, hypertension, hypotension.

Laboratory Parameters: activated partial thromboplastin time prolonged, creatine increased, bicarbonate decreased, sodium increased, EEG abnormal, glucose increased, cholesterol increased, triglycerides increased, amylase increased, potassium increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin decreased, MCV increased, RBC decreased, creatinine increased, blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased, alkaline phosphatase increased, LDH increased, PSA increased, urine output increased/decreased, lymphocyte count decreased, neutrophil count decreased, WBC increased/decreased, coagulation test abnormal, low density lipoprotein (LDL) increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein.

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