FEBOREX

Febuxostat is a xanthine oxidase inhibitor.

The active ingredient in febuxostat tablets is 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, with a molecular weight of 316.38.

The molecular formula is

C 16 H 16 N 2 O 3 S. The chemical structure is: Febuxostat is a non-hygroscopic, white to off-white crystalline powder that is freely soluble in N,N-dimethylformamide; soluble in dimethylsulfoxide; sparingly soluble in ethanol; and practically insoluble in water.

The melting range is about 208ºC. Febuxostat tablets for oral use contain the active ingredient, febuxostat, and are available in two dosage strengths, 40 mg and 80 mg. Inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, iron oxide yellow, lactose monohydrate, macrogol, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, talc and titanium dioxide.

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.

Febuxostat tablets are not recommended for the treatment of asymptomatic hyperuricemia.

Febuxostat, a xanthine oxidase inhibitor, achieves its therapeutic effect by decreasing serum uric acid.

Febuxostat is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic concentrations. 12.2 Pharmacodynamics Effect on Uric Acid and Xanthine Concentrations In healthy patients, febuxostat resulted in a dose dependent decrease in 24-hour mean serum uric acid concentrations and an increase in 24-hour mean serum xanthine concentrations.

In addition, there was a decrease in the total daily urinary uric acid excretion.

Also, there was an increase in total daily urinary xanthine excretion.

Percent reduction in 24-hour mean serum uric acid concentrations was between 40% and 55% at the exposure levels of 40 mg and 80 mg daily doses.

The effect of febuxostat on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy patients and in patients with gout.

Febuxostat in doses up to 300 mg daily (3.75 times the maximum recommended daily dosage), at steady-state, did not demonstrate an effect on the QTc interval. 12.3 Pharmacokinetics In healthy patients, maximum plasma concentrations (C max ) 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 (t 1/2 ) of approximately 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.

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 and 1.5 hours postdose.

After multiple oral 40 mg and 80 mg once daily doses, C max 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 C max 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 C max and a 15% decrease in AUC∞.

As AUC rather than

C max was related to drug effect, change observed in AUC was not considered clinically significant.

Therefore, febuxostat may be taken without regard to antacid use.

The mean apparent steady state volume of distribution (V ss /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.

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.

Febuxostat is eliminated by both hepatic and renal pathways.

Following an 80 mg oral dose of 14 C-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 (t 1/2 ) of febuxostat was approximately to 8 hours.

Specific Populations Geriatric Patients The C max 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.

Patients with Renal Impairment In a dedicated phase I pharmacokinetics study, following multiple 80 mg doses of febuxostat in healthy patients with mild (Cl cr to 80 mL/min), moderate (Cl cr to 49 mL/min) or severe renal impairment (Cl cr to 29 mL/min), the C max of febuxostat did not change relative to patients with normal renal function (Cl cr 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 C max 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.

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 C max and AUC 24 (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.

Following multiple oral doses of febuxostat, the C max and AUC of febuxostat were 30% and 14% higher in females than in males, respectively.

However, weight-corrected C max 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.

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, and Theophylline Febuxostat is an XO inhibitor.

A drug-drug interaction study evaluating the effect of febuxostat upon the pharmacokinetics of theophylline (an XO substrate) in healthy patients showed that coadministration of febuxostat with theophylline resulted in an approximately 400-fold increase in the amount of 1-methylxanthine, one of the major metabolites of theophylline, excreted in the urine.

Since the long-term safety of exposure to 1-methylxanthine in humans is unknown, use with caution when coadministering febuxostat with theophylline.

A drug interaction study of febuxostat and azathioprine has been conducted.

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.

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.

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.

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. Theophylline No dose adjustment is necessary for theophylline when coadministered with febuxostat.

Administration of febuxostat (80 mg once daily) with theophylline resulted in an increase of 6% in C max and 6.5% in AUC of theophylline.

These changes were not considered statistically significant.

However, the study also showed an approximately 400-fold increase in the amount of 1-methylxanthine (one of the major theophylline metabolites) excreted in urine as a result of XO inhibition by febuxostat.

The safety of long-term exposure to 1-methylxanthine has not been evaluated.

This should be taken into consideration when deciding to coadminister febuxostat a.

The following serious adverse reactions are described elsewhere in the prescribing information: Cardiovascular Death Hepatic Effects Serious Skin Reactions Adverse reactions in ≥ 1% of patients treated with febuxostat are liver function abnormalities, nausea, arthralgia, and rash.

To report SUSPECTED ADVERSE

REACTIONS, contact Aurobindo Pharma USA, Inc.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 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 were treated for ≥2 years.

In three randomized, controlled clinical studies (Studies and 3), which were 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. * 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.

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% 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.

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.

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.

Disorders : anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia.

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

Ear and

Disorders : deafness, tinnitus, vertigo.

Disorders : vision blurred.

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.

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

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

Disorder: hypersensitivity.

Infections and Infestations: herpes zoster.

Complications: contusion.

Metabolism and

Disorders : anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased.

Disorders : arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia.

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

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

Renal and

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

Changes: breast pain, erectile dysfunction, gynecomastia.

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

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.

Disorders : flushing, hot flush, hypertension, hypotension.

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 post approval 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.

Disorders: agranulocytosis, eosinophilia.

Disorders: hepatic failure (some fatal), jaundice, serious cases of abnormal liver function test results, liver disorder.

Disorders: anaphylaxis, anaphylactic reaction.

Disorders: rhabdomyolysis.

Disorders: psychotic behavior including aggressive thoughts.

Disorders: tubulointerstitial nephritis.

Disorders: generalized rash, Stevens-Johnson syndrome, hypersensitivity skin reactions, erythema multiforme, drug reaction with eosinophilia and systemic symptoms, toxic epidermal necrolysis.

Febuxostat was studied in healthy patients in doses up to 300 mg daily for seven days without evidence of dose-limiting toxicities.

No overdose of febuxostat was reported in clinical studies.

Patients should be managed by symptomatic and supportive care should there be an overdose.

Febuxostat tablets are contraindicated in patients being treated with azathioprine or mercaptopurine.

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.

Patients with severe renal impairment

Limit the dosage to 40 mg once daily.

Flare prophylaxis is recommended upon initiation of febuxostat tablets.

Can be administered without regard to food or antacid use. 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.

Concurrent prophylactic treatment with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended. 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.

No dosage modification is necessary in patients with mild to moderate hepatic impairment. 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.

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.

Tablets 40 mg are light yellow to yellow color, biconvex round shaped film-coated tablets debossed with “FEB” on one side and “40” on the other side.

Bottle of 30’s NDC 59651-113-30 Bottle of 90’s NDC 59651-113-90 Bottle of 500’s NDC 59651-113-05 Febuxostat Tablets 80 mg are light yellow to yellow color, biconvex oval shaped film-coated tablets debossed with “FEB” on one side and “80” on the other side.

Bottle of 30’s NDC 59651-114-30 Bottle of 90’s NDC 59651-114-90 Bottle of 100’s NDC 59651-114-01 Bottle of 500’s NDC 59651-114-05 Store at 20° to 25°C (68° to 77°F) .

Protect from light.

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 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.

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 to 4% and to 20%, respectively.

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days 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 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.

Safety and effectiveness of febuxostat in pediatric patients have not been established.

No dose adjustment is necessary in elderly patients.

Of the total number of patients in Studies 1, 2, and 3 (clinical studies of febuxostat in the treatment of gout) , 16% were and over, while 4% were and over.

Comparing patients in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out.

The C max and

AUC of febuxostat following multiple oral doses of febuxostat in geriatric patients (≥65 years) were similar to those in younger patients (18 to 40 years) .