FEBUXOSTAT: 5,843 Adverse Event Reports & Safety Profile

Febuxostat is a xanthine oxidase inhibitor. The active ingredient in febuxostat tablets is 2-(3-cyano-­4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid hemihydrate, with a molecular weight of 325.38. The empirical formula is C 16 H 16 N 2 O 3 S. ½ H 2 O The chemical structure is: Febuxostat hemihydrate is a non-hygroscopic, white to off white crystalline powder that is freely soluble in dimethylformamide; soluble in tetrahydrofuran; sparingly soluble in acetone and ethanol. The melting range is 203°C to 208°C. Febuxostat tablets for oral use contain the active ingredient, febuxostat hemihydrate, and are available in two dosage strengths, 40 mg and 80 mg. Inactive ingredients include colloidal silicon dioxide, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium croscarmellose. Febuxostat tablets are coated with Opadry II, green. The components of Opadry II, green are D&C yellow #10 aluminium lake, FD&C blue #1/ Brilliant blue FCF aluminum lake, FD&C blue #2/ Indigo Carmine AL, Macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, titanium dioxide. chemicalstructure

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. Febuxostat tablets are not recommended for the treatment of asymptomatic hyperuricemia. 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. Febuxostat tablets are xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in 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 )

AND ADMINISTRATION

• Recommended dosage is 40 mg or 80 mg once daily. The recommended starting dosage is 40 mg once daily. For patients who do not achieve a serum uric acid (sUA) less than 6 mg/dL after 2 weeks, the recommended dosage is 80 mg once daily. ( 2.1 )
• Patients with severe renal impairment: Limit the dosage to 40 mg once daily. ( 2.2 , 8.6 )
• Flare prophylaxis is recommended upon initiation of febuxostat tablets. ( 2.4 )
• Can be administered without regard to food or antacid use. ( 2.1 )

2.1 Recommended Dosage 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. Concurrent prophylactic treatment with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.2 )]</span>.

2.2 Dosage Recommendations in Patients with Renal Impairment and Hepatic Impairment The recommended dosage of febuxostat tablets is limited to 40 mg once daily in patients with severe renal impairment. No dose modification is necessary when administering febuxostat tablets in patients with mild or moderate renal impairment <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]</span> . No dosage modification is necessary in patients with mild to moderate hepatic impairment <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )]</span> .

2.3 Serum Uric Acid Level Monitoring 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> .

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 )

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 tablets, and at least 0.5% greater than placebo, are liver function abnormalities, nausea, arthralgia, and rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 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 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 Adverse Reactions Placebo Febuxostat Tablets allopurinol* (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 tablets 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.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of febuxostat tablets. 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 epidermal necrolysis.

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. 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 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 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 Consider the risks and benefits of febuxostat when deciding to prescribe or continue patients on febuxostat 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. 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.

5.2 Gout 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)].

5.3 Hepatic 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . 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.

5.4 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. 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 tablets with XO substrate drugs, azathioprine or mercaptopurine could increase plasma concentrations of these drugs resulting in severe toxicity. ( 7 )

7.1 Xanthine Oxidase Substrate Drugs Febuxostat tablet 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>. Therefore, use with caution when coadministering febuxostat tablets with theophylline. A drug interaction study of febuxostat tablets and azathioprine, also metabolized by XO, showed an increase in exposure of 6-mercaptopurine which may lead to toxicity <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Drug interaction studies of febuxostat tablets with other drugs that are metabolized by XO (e.g., mercaptopurine) have not been conducted. Febuxostat tablets are contraindicated in patients being treated with azathioprine or mercaptopurine <span class="opacity-50 text-xs">[see Contraindications (4) ]</span>.

7.2 Cytotoxic Chemotherapy Drugs Drug interaction studies of febuxostat tablets with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of febuxostat tablets during cytotoxic chemotherapy.

7.3 In Vivo Drug Interaction Studies Based on drug interaction studies in healthy patients, febuxostat tablets do not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>. Therefore, febuxostat tablets may be used concomitantly with these medications.