Macleods Pharmaceuticals Limited

Febuxostat tablets 40 mg

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Generic for Febuxostat

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FEBUXOSTAT TABLETS 40 MG 40 MG FILM 3334227407

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40 mg

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TL;DR — Quick Summary

Key facts from the full medication guide below

BOXED WARNING 1 INDICATIONS & USAGE 2 DOSAGE & ADMINISTRATION 2.1 Recommended Dosage 2.2 Dosage Recommendations in Patients with Renal Impairment and Hepatic Impairment

🩺What it's for

Febuxostat 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. Limitations of Use: Febuxostat is not recommended for the treatment of asymptomatic hyperuricemia.

💊How to take it

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.

ℹ️Common side effects

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 in > 1% of patients treated with febuxostat, and at least 0.5% greater than placebo, are liver function abnormalities, nausea, arthralgia, and rash.

⚠️Serious risks

WARNING : CARDIOVASCULAR DEATH Gout patients with established cardiovascular (CV) disease treated with febuxostat 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 when deciding to prescribe or continue patients on febuxostat.

📋Interactions & cautions

Concomitant administration of febuxostat with XO substrate drugs, azathioprine or mercaptopurine could increase plasma concentrations of these drugs resulting in severe toxicity.

📦Storage & missed dose

Febuxostat 40 mg tablets are green, biconvex, round, film- coated tablets debossed with "M 87" on one side and plain on the other side and supplied as: NDC Number Size 33342-274-07 bottles of 30 Tablets 33342-274-10 bottles of 90 Tablets 33342-274-15 bottles of 500 Tablets Febuxostat 80 mg tablets are green, biconvex, teardrop-shaped, film-coated tablets debossed with "M 88" on one side and plain on the other side and supplied as: NDC Number Size 33342-275-07 bottles of 30 Tablets 33342-275-10…

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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 40 mg or 80 mg daily. For febuxostat 40 mg, 559 patients were treated for 6 months. For febuxostat 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 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 6 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 in Patients Receiving Placebo in Controlled Studies Adverse Reactions Placebo Febuxostat 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 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. 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, hematemesis, 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-Barr 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.

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 - 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 - 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.

In healthy patients, maximum plasma concentrations (Cmax) and AUC of febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg (0.25 times the lowest recommended dosage) to 120 mg (1.5 times the maximum recommended dosage). There is no accumulation when therapeutic doses are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t1/2) of approximately 5 to 8 hours. Febuxostat pharmacokinetic parameters for patients with hyperuricemia and gout estimated by population pharmacokinetic analyses were similar to those estimated in healthy patients. Absorption The absorption of radiolabeled febuxostat following oral dose administration was estimated to be at least 49% (based on total radioactivity recovered in urine). Maximum plasma concentrations of febuxostat occurred between 1 and 1.5 hours postdose. After multiple oral 40 mg and 80 mg once daily doses, Cmax is approximately 1.6 0.6 mcg/mL (N=30), and 2.6 1.7 mcg/mL (N=227), respectively. Absolute bioavailability of the febuxostat tablet has not been studied. Following multiple 80 mg once daily doses with a high fat meal, there was a 49% decrease in Cmax and an 18% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed (58% fed vs. 51% fasting). Thus, febuxostat may be taken without regard to food. Concomitant ingestion of an antacid containing magnesium hydroxide and aluminum hydroxide with an 80 mg single dose of febuxostat has been shown to delay absorption of febuxostat (approximately one hour) and to cause a 31% decrease in Cmax and a 15% decrease in AUC . As AUC rather than Cmax was related to drug effect, change observed in AUC was not considered clinically significant. Therefore, febuxostat may be taken without regard to antacid use. Distribution The mean apparent steady state volume of distribution (Vss/F) of febuxostat was approximately 50 L (CV ~40%). The plasma protein binding of febuxostat is approximately 99.2% (primarily to albumin), and is constant over the concentration range achieved with 40 mg and 80 mg doses. Metabolism Febuxostat is extensively metabolized by both conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes including UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and oxidation via cytochrome P450 (CYP) enzymes including CYP1A2, 2C8 and 2C9 and non-P450 enzymes. The relative contribution of each enzyme isoform in the metabolism of febuxostat is not clear. The oxidation of the isobutyl side chain leads to the formation of four pharmacologically active hydroxy metabolites, all of which occur in plasma of humans at a much lower extent than febuxostat. In urine and feces, acyl glucuronide metabolites of febuxostat (~35% of the dose), and oxidative metabolites, 67M-1 (~10% of the dose), 67M-2 (~11% of the dose), and 67M-4, a secondary metabolite from 67M-1 (~14% of the dose), appeared to be the major metabolites of febuxostat in vivo. Elimination Febuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg oral dose of 14C-labeled febuxostat, approximately 49% of the dose was recovered in the urine as unchanged febuxostat (3%), the acyl glucuronide of the drug (30%), its known oxidative metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to the urinary excretion, approximately 45% of the dose was recovered in the feces as the unchanged febuxostat (12%), the acyl glucuronide of the drug (1%), its known oxidative metabolites and their conjugates (25%), and other unknown metabolites (7%). The apparent mean terminal elimination half-life (t1/2) of febuxostat was approximately 5 to 8 hours. Specific Populations Geriatric Patients The Cmax and AUC of febuxostat and its metabolites following multiple oral doses of febuxostat in geriatric patients ( 65 years) were similar to those in younger patients (18 to 40 years). In addition, the percent decrease in serum uric acid concentration was similar between elderly and younger patients. No dose adjustment is necessary in geriatric patients [see Use in Specific Populations (8.5)]. Patients with Renal Impairment In a dedicated phase I pharmacokinetics study, following multiple 80 mg doses of febuxostat in healthy patients with mild (Clcr 50 to 80 mL/min), moderate (Clcr 30 to 49 mL/min) or severe renal impairment (Clcr 10 to 29 mL/min), the Cmax of febuxostat did not change relative to patients with normal renal function (Clcr greater than 80 mL/min). AUC and half-life of febuxostat increased in patients with renal impairment in comparison to patients with normal renal function, but values were similar among three renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in patients with renal impairment compared to those with normal renal function. Mean Cmax and AUC values for three active metabolites increased up to two and four-fold, respectively. However, the percent decrease in serum uric acid concentration for patients with renal impairment was comparable to those with normal renal function (58% in normal renal function group and 55% in the severe renal function group). Based on population pharmacokinetic analysis, following multiple 40 mg or 80 mg doses of febuxostat, the mean oral clearance (CL/F) values of febuxostat in patients with gout and mild (n=334), moderate (n=232) or severe (n=34) renal impairment were decreased by 14%, 34%, and 48%, respectively, compared to patients with normal (n=89) renal function. The corresponding median AUC values of febuxostat at steady-state in patients with renal impairment were increased by 18%, 49%, and 96% after 40 mg dose, and 7%, 45% and 98% after 80 mg dose, respectively, compared to patients with normal renal function. Febuxostat has not been studied in end stage renal impairment patients who are on dialysis. Patients with Hepatic Impairment Following multiple 80 mg doses of febuxostat in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an average of 20% to 30% increase was observed for both Cmax and AUC24 (total and unbound) in hepatic impairment groups compared to patients with normal hepatic function. In addition, the percent decrease in serum uric acid concentration was comparable between different hepatic groups (62% in healthy group, 49% in mild hepatic impairment group, and 48% in moderate hepatic impairment group). No dose adjustment is necessary in patients with mild or moderate hepatic impairment. No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients [see Use in Specific Populations (8.7)]. Male and Female Patients Following multiple oral doses of febuxostat, the Cmax and AUC24 of febuxostat were 30% and 14% higher in females than in males, respectively. However, weight-corrected Cmax and AUC were similar between the genders. In addition, the percent decrease in serum uric acid concentrations was similar between genders. No dose adjustment is necessary based on gender. Racial Groups No specific pharmacokinetic study was conducted to investigate the effects of race. Drug Interaction Studies Effect of Febuxostat on Other Drugs Xanthine Oxidase Substrate Drugs-Azathioprine, Mercaptopurine Febuxostat is an XO inhibitor. A drug interaction study of febuxostat and azathioprine has been conducted [see Drug Interactions (7)]. Inhibition of XO by febuxostat caused increased plasma concentrations of 6-mercaptopurine, a metabolite of azathioprine, which may lead to toxicity. Drug interaction studies of febuxostat with other drugs that are metabolized by XO (e.g., mercaptopurine) have not been conducted. Febuxostat is contraindicated in patients being treated with azathioprine or mercaptopurine [see Contraindications (4) and Drug Interactions (7)]. Azathioprine and mercaptopurine undergo metabolism via three major metabolic pathways, one of which is mediated by XO. Concomitant administration of allopurinol [a xanthine oxidase inhibitor] with azathioprine or mercaptopurine has been reported to substantially increase plasma concentrations of these drugs. Because febuxostat is a xanthine oxidase inhibitor, it could inhibit the XO-mediated metabolism of mercaptopurine leading to increased plasma concentrations of mercaptopurine that could result in severe toxicity. P450 Substrate Drugs In vitro studies have shown that febuxostat does not inhibit P450 enzymes CYP1A2, 2C9, 2C19, 2D6, or 3A4 and it also does not induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 at clinically relevant concentrations. As such, pharmacokinetic interactions between febuxostat and drugs metabolized by these CYP enzymes are unlikely. Effect of Other Drugs on Febuxostat Febuxostat is metabolized by conjugation and oxidation via multiple metabolizing enzymes. The relative contribution of each enzyme isoform is not clear. Drug interactions between febuxostat and a drug that inhibits or induces one particular enzyme isoform is in general not expected. In Vivo Drug Interaction Studies Azathioprine Concomitant use of febuxostat and azathioprine is contraindicated. Coadministration with febuxostat (40 mg or 120 mg QD) reduced the apparent clearance of mercaptopurine, a XO substrate, by 83.2% to 83.8% following a single oral dose of azathioprine, a prodrug of 6-mercaptopurine. No significant differences were observed in the extent of inhibition of 6-mercaptopurine metabolism by febuxostat 40 mg and 120 mg Colchicine No dose adjustment is necessary for either febuxostat or colchicine when the two drugs are coadministered. Administration of febuxostat (40 mg once daily) with colchicine (0.6 mg twice daily) resulted in an increase of 12% in Cmax and 7% in AUC24 of febuxostat. In addition, administration of colchicine (0.6 mg twice daily) with febuxostat (120 mg daily) resulted in a less than 11% change in Cmax or AUC of colchicine for both AM and PM doses. These changes were not considered clinically significant. Naproxen No dose adjustment is necessary for febuxostat or naproxen when the two drugs are coadministered. Administration of febuxostat (80 mg once daily) with naproxen (500 mg twice daily) resulted in a 28% increase in Cmax and a 40% increase in AUC of febuxostat. The increases were not considered clinically significant. In addition, there were no significant changes in the Cmax or AUC of naproxen (less than 2%). Indomethacin No dose adjustment is necessary for either febuxostat or indomethacin when these two drugs are coadministered. Administration of febuxostat (80 mg once daily) with indomethacin (50 mg twice daily) did not result in any significant changes in Cmax or AUC of febuxostat or indomethacin (less than 7%). Hydrochlorothiazide No dose adjustment is necessary for febuxostat when coadministered with hydrochlorothiazide. Administration of febuxostat (80 mg) with hydrochlorothiazide (50 mg) did not result in any clinically significant changes in Cmax or AUC of febuxostat (less than 4%), and serum uric acid concentrations were not substantially affected. Warfarin No dose adjustment is necessary for warfarin when coadministered with febuxostat. Administration of febuxostat (80 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy patients. INR and Factor VII activity were also not affected by the coadministration of febuxostat. Desipramine Coadministration of drugs that are CYP2D6 substrates (such as desipramine) with febuxostat are not expected to require dose adjustment. Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro and in vivo. Administration of febuxostat (120 mg once daily) with desipramine (25 mg) resulted in an increase in Cmax (16%) and AUC (22%) of desipramine, which was associated with a 17% decrease in the 2-hydroxydesipramine to desipramine metabolic ratio (based on AUC).

The efficacy of febuxostat was demonstrated in three randomized, double-blind, controlled trials in patients with hyperuricemia and gout. Hyperuricemia was defined as a baseline serum uric acid level 8 mg/dL. Study 1 (ClinicalTrials.gov identifier NCT00430248) randomized patients to: febuxostat 40 mg daily, febuxostat 80 mg daily, or allopurinol (300 mg daily for patients with estimated creatinine clearance (Clcr) 60 mL/min or 200 mg daily for patients with estimated Clcr 30 mL/min and 59 mL/min). The duration of Study 1 was six months. Study 2 (ClinicalTrials.gov identifier NCT00174915) randomized patients to: placebo, febuxostat 80 mg daily, febuxostat 120 mg daily, febuxostat 240 mg daily or allopurinol (300 mg daily for patients with a baseline serum creatinine 1.5 mg/dL or 100 mg daily for patients with a baseline serum creatinine greater than 1.5 mg/dL and 2 mg/dL). The duration of Study 2 was six months. Study 3 (ClinicalTrials.gov identifier NCT00102440), a one year study, randomized patients to: febuxostat 80 mg daily, febuxostat 120 mg daily, or allopurinol 300 mg daily. Patients who completed Study 2 and Study 3 were eligible to enroll in a Phase 3 long-term extension study in which patients received treatment with febuxostat for over three years. In all three studies, patients received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis. In Study 1 the duration of prophylaxis was six months; in Study 2 and Study 3 the duration of prophylaxis was eight weeks. The efficacy of febuxostat was also evaluated in a four week dose ranging study which randomized patients to: placebo, febuxostat 40 mg daily, febuxostat 80 mg daily, or febuxostat 120 mg daily. Patients who completed this study were eligible to enroll in a long-term extension study in which patients received treatment with febuxostat for up to five years. Patients in these studies were representative of the patient population for which febuxostat use is intended. Table 2 summarizes the demographics and baseline characteristics for the patients enrolled in the studies. Table 2: Patient Demographics and Baseline Characteristics in Study 1, Study 2 and Study 3 Male 95% Race: Caucasian African American 80% 10% Ethnicity: Hispanic or Latino 7% Alcohol User 67% Mild to Moderate Renal Insufficiency (percent with estimated Clcr less than 90 mL/min) 59% History of Hypertension 49% History of Hyperlipidemia 38% BMI 30 kg/m2 63% Mean BMI 33 kg/m2 Baseline sUA 10 mg/dL 36% Mean baseline sUA 9.7 mg/dL Experienced a gout flare in previous year 85% Serum Uric Acid Level less than 6 mg/dL at Final Visit: Febuxostat 80 mg was superior to allopurinol in lowering serum uric acid to less than 6 mg/dL at the final visit. Febuxostat 40 mg daily, although not superior to allopurinol, was effective in lowering serum uric acid to less than 6 mg/dL at the final visit (Table 3) Table 3: Proportion of Patients with Serum Uric Acid Levels less than 6 mg/dL at Final Visit Study* Febuxostat 40 mg daily Febuxostat 80 mg daily allopurinol Placebo Difference in proportion (95% CI) Febuxost at 40 mg vs allopurinol Febuxostat 80 mg vs allopurinol Study 1 (6 months) (N=2268) 45% 67% 42% 3% (-2%, 8%) 25% (20%, 30%) Study 2 (6 months) (N=643) 72% 39% 1% 33% (26%, 42%) Study 3 (12 months) (N=491) 74% 36% 38% (30%, 46%) *Randomization was balanced between treatment groups, except in Study 2 in which twice as many patients were randomized to each of the active treatment groups compared to placebo. In 76% of febuxostat 80 mg patients, reduction in serum uric acid levels to less than 6 mg/dL was noted by the Week 2 visit. Average serum uric acid levels were maintained at 6 mg/dL or below throughout treatment in 83% of these patients. In all treatment groups, fewer patients with higher baseline serum urate levels ( 10 mg/dL) and/or tophi achieved the goal of lowering serum uric acid to less than 6 mg/dL at the final visit; however, a higher proportion achieved a serum uric acid less than 6 mg/dL with febuxostat 80 mg than with febuxostat 40 mg or allopurinol. Study 1 evaluated efficacy in patients with mild to moderate renal impairment (i.e., baseline estimated Clcr less than 90 mL/min). The results in this subgroup of patients are shown in Table 4. Table 4: Proportion of Patients with Serum Uric Acid Levels less than 6 mg/dL in Patients with Mild or Moderate Renal Impairment at Final Visit Febuxostat 40 mg daily (N=479) Febuxostat 80 mg daily (N=503) allopurinol* 300 mg daily (N=501) Difference in Proportion (95% CI) Febuxostat 40 mg vs allopurinol Febuxostat 80 mg vs allopurinol 50% 72% 42% 7% (1%, 14%) 29% (23%, 35%) *Allopurinol patients (n=145) with estimated Clcr 30 mL/min and Clcr 59 mL/min were dosed at 200 mg daily.

A randomized, double-blind, allopurinol-controlled CV outcomes study (CARES) was conducted to evaluate the CV risk of febuxostat (NCT01101035). The study compared the risk of MACE between patients treated with febuxostat (N=3098) and allopurinol-treated patients (N=3092). The primary endpoint was the time to first occurrence of a 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. An independent committee conducted a blinded evaluation of serious CV adverse events according to predefined criteria (adjudication) for determination of MACE. The study was event driven and patients were followed until a sufficient number of primary outcome events accrued. The median on-study follow-up time was 2.6 years. Patients randomized to febuxostat initially received 40 mg once daily which was increased to 80 mg once daily, if their sUA was 6mg/dL at Week 2. For patients randomized to allopurinol, those who had normal renal function or mild renal impairment (estimated creatinine clearance (eClcr) 60 to <90 mL/minute) initially received 300 mg once daily with 100 mg/day dose increments monthly until either sUA <6mg/dL or an allopurinol dosage of 600 mg once daily was achieved; those who had moderate renal impairment (eClcr 30 to <60 mL/minute) initially received 200 mg once daily with 100 mg/day dose increments monthly until either a sUA <6 mg/dL or an allopurinol dosage of 400 mg once daily was achieved. The mean age of the population was 65 years (range: 44 to 93 years). Most patients were male (84%) and Caucasian (69%). Patients had a diagnosis of gout for approximately 12 years, a mean baseline sUA of 8.7 mg/dL, and 90% had experienced at least one gout flare in the past year. CV history included MI (39%), hospitalization for unstable angina (28%), cardiac revascularization (37%), and stroke (14%). The most prevalent comorbid conditions were hypertension (92%), hyperlipidemia (87%), diabetes mellitus (55%), diabetes mellitus with micro-or macrovascular disease (39%), and renal impairment [92% with an eClcr 30 to 89 mL/minute]. The use of CV disease medication was balanced across treatment groups. Baseline CV disease medications included: ACE inhibitors or ARBs (70%), lipid modifying agents (74%), aspirin (62%), beta-blockers (59%), calcium channel blockers (26%), and nonaspirin antiplatelet medications (31%). Table 5 shows the study results for the primary MACE composite endpoint and its individual components. For the composite primary endpoint, the febuxostat group was non-inferior compared with the allopurinol group. The rates of nonfatal MI, stroke, and unstable angina with urgent coronary revascularization were similar. There was a higher rate of CV deaths in patients treated with febuxostat (134 CV deaths; 1.5 per 100 PY) than in allopurinol-treated patients (100 CV deaths; 1.1 per 100 PY). 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%). The biological plausibility of CV death associated with febuxostat is unclear. All-cause mortality was higher in the febuxostat group (243 deaths [7.8%]; 2.6 per 100 PY) than the allopurinol group (199 deaths [6.4%]; 2.2 per 100 PY) [Hazard Ratio: 1.22, 95% CI: 1.01, 1.47], due to a higher rate of CV deaths. Table 5: Patients with MACE in CARES (Cardiovascular Outcomes Study in Patients with Gout Febuxostat N=3098 Allopurinol N=3092 Hazard Ratio Number of Patients with Event (%) Rate per 100 PY* Number of Patients with Event (%) Rate per 100 PY* 95% CI Composite of primary endpoint MACE 335 (10.8) 3.8 321 (10.4) 3.7 1.03 (0.89, 1.21) Cardiovascular Death 134 (4.3) 1.5 100 (3.2) 1.1 1.34 (1.03, 1.73) Nonfatal MI 111 (3.6) 1.2 118 (3.8) 1.3 0.93 (0.72, 1.21) Nonfatal stroke 71 (2.3) 0.8 70 (2.3) 0.8 1.01 (0.73, 1.41) Unstable angina with urgent coronary revascularization 49 (1.6) 0.5 56 (1.8) 0.6 0.86 (0.59, 1.26) * Patient Years (PY)

Dispense with Medication Guide available at: www.macleodspharma.com/usa Febuxostat(feb ux' oh stat) (febuxostat) tablets, for oral use Read the Medication Guide that comes with Febuxostat tablet before you start taking it and each time you get a refill. There may be new information. The Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information that I should know about febuxostat tablet? Febuxostat tablet may cause serious side effects, including: Heart -related deaths. Call your doctor or get emergency medical help right away if you have any of the following symptoms, especially if they are new, worse, or worry you: chest pain shortness of breath or trouble breathing dizziness, fainting or feeling lightheaded rapid or irregular heartbeat numbness or weakness on one side of your body slurring of speech sudden blurry vision or sudden severe headache What is febuxostat tablet? Febuxostat tablet is a prescription medicine called a xanthine oxidase (XO) inhibitor used to lower blood uric acid levels in adult patients with gout when allopurinol has not worked well enough or when allopurinol is not right for you. Febuxostat tablet is not for use in people who do not have symptoms of high blood uric acid levels. It is not known if febuxostat tablet is safe and effective in children. Who should not take febuxostat tablet? Do not take febuxostat tablet if you: take azathioprine (Azasan, Imuran) take mercaptopurine (Purinethol, Purixan) What should I tell my doctor before taking febuxostat tablet? Before taking febuxostat tablet tell your doctor about all of your medical conditions, including if you: have taken allopurinol and what happened to you while you were taking it. have a history of heart disease or stroke. have liver or kidney problems. are pregnant or plan to become pregnant. It is not known if febuxostat tablet will harm your unborn baby. Talk with your doctor if you are pregnant or plan to become pregnant. are breastfeeding or plan to breastfeed. It is not known if febuxostat tablet passes into your breast milk. You and your doctor should decide if you should take febuxostat tablet while breastfeeding. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Febuxostat tablet may affect the way other medicines work, and other medicines may affect how febuxostat tablet works. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I take febuxostat tablet? Take febuxostat tablet exactly as your doctor tells you to take it. Febuxostat tablet can be taken with or without food. Febuxostat tablet can be taken with antacids. Your gout may get worse (flare) when you start taking febuxostat tablet. Do not stop taking febuxostat tablet because you have a flare. Your doctor may do certain tests while you take febuxostat tablet. What are the possible side effects of febuxostat tablet? febuxostat tablet may cause serious side effects, including: Heart problems. See What is the most important information I should know about febuxostat tablet? Gout Flares. Gout flares can happen when you start taking febuxostat tablet. Your doctor may give you other medicines to help prevent your gout flares. Liver problems. Liver problems can happen in people who take febuxostat tablet. Your doctor may do blood tests to check how well your liver is working before and during your treatment with febuxostat tablet. Tell your doctor if you get any of the following signs or symptoms of liver problems: fatigue loss of appetite for several days or longer pain, aching, or tenderness on the right side of your stomach-area dark or "tea-colored" urine your skin or the white part of your eyes turns yellow (jaundice) Severe skin and allergic reactions. Serious skin and allergic reactions that may affect different parts of the body such as your liver, kidneys, heart or lungs, can happen in people who take febuxostat tablet. Call your doctor right away or get emergency medical help if you have any of the following symptoms: rash red and painful skin severe skin blisters peeling skin sores around the lips, eyes or mouth swollen face, lips, mouth, tongue or throat flu-like symptoms The most common side effects of febuxostat tablet include: abnormal liver function tests nausea joint pain rash These are not all of the possible side effects of febuxostat tablet. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store febuxostat tablet? Store febuxostat tablet at room temperature. Keep febuxostat tablet out of the light. Keep febuxostat tablet and all medicines out of the reach of children. General information about the safe and effective use of febuxostat tablet. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use febuxostat tablet for a condition for which it was not prescribed. Do not give febuxostat tablet to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about febuxostat tablet that is written for health professionals. What are the ingredients in febuxostat tablet? Active ingredient: febuxostat Inactive ingredients: colloidal silicon dioxide, FD&C red #40/ allura red AC aluminum lake, FD&C yellow #5/tartrazine aluminum lake, FD&C Blue # 1/Brilliant Blue FCF Aluminum Lake, hydroxypropyl cellulose, lactose monohydrate, macrogol, microcrystalline cellulose, Polyvinyl alcohol-part hydrolyzed, magnesium stearate, sodium croscarmellose, talc, titanium dioxide. Manufactured for: Macleods Pharma USA, Inc. Princeton, NJ 08540 Manufactured by: Macleods Pharmaceuticals Ltd. Daman (U.T.), INDIA All other trademarks are the property of their respective owners. This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: September 2023