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Febuxostat Tablet

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING


1. DESCRIPTION

Febuxostat is a xanthine oxidase inhibitor. The active ingredient in febuxostat is 2-[3-cyano4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, with a molecular weight of 316.38. The empirical formula is C16H16N2O3S.

The chemical structure is:

Febuxostat is a non-hygroscopic, white crystalline powder that is freely soluble in dimethylformamide; soluble in dimethylsulfoxide; sparingly soluble in ethanol; slightly soluble in methanol and acetonitrile; and practically insoluble in water. The melting range is 205oC to 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 lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium croscarmellose, silicon dioxide and magnesium stearate. Febuxostat tablets are coated with Opadry II, green.

2. INDICATIONS AND USAGE

Febuxostat is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout.

Febuxostat is not recommended for the treatment of asymptomatic hyperuricemia.

3. DOSAGE AND ADMINISTRATION

3.1 Recommended Dose

For treatment of hyperuricemia in patients with gout, febuxostat is recommended at 40 mg or 80 mg once daily.

The recommended starting dose of febuxostat is 40 mg once daily. For patients who do not achieve a serum uric acid (sUA) less than 6 mg per dL after 2 weeks with 40 mg, febuxostat 80 mg is recommended.

Febuxostat can be taken without regard to food or antacid use.

3.2 Special Populations

No dose adjustment is necessary when administering febuxostat in patients with mild to moderate renal impairment [see Use in Specific Populations]. The recommended starting dose of febuxostat is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg, febuxostat 80 mg is recommended.

No dose adjustment is necessary in patients with mild to moderate hepatic impairment [see Use in Specific Populations].

3.3 Uric Acid Level

Testing for the target serum uric acid level of less than 6 mg per dL may be performed as early as 2 weeks after initiating febuxostat therapy.

3.4 Gout Flares

Gout flares may occur after initiation of febuxostat 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. Prophylactic therapy may be beneficial for up to six months.

If a gout flare occurs during febuxostat treatment, febuxostat need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient [see Warnings and Precautions].

4. CONTRAINDICATIONS

Febuxostat is contraindicated in patients being treated with azathioprine or mercaptopurine [see Drug Interactions].

5. MECHANISM OF ACTION

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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Febuxostat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Febuxostat was not teratogenic in rats and rabbits at oral doses up to 48 mg per kg (40 and 51 times the human plasma exposure at 80 mg per day for equal body surface area, respectively) during organogenesis. However, increased neonatal mortality and a reduction in the neonatal body weight gain were observed when pregnant rats were treated with oral doses up to 48 mg per kg (40 times the human plasma exposure at 80 mg per day) during organogenesis and through lactation period.

6.2 Nursing Mothers

Febuxostat is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when febuxostat is administered to a nursing woman.

6.3 Pediatric Use

Safety and effectiveness in pediatric patients under 18 years of age have not been established.

6.4 Geriatric Use

No dose adjustment is necessary in elderly patients. Of the total number of subjects in clinical studies of febuxostat, 16 percent were 65 and over, while 4 percent were 75 and over. Comparing subjects 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 Cmax and AUC24 of febuxostat following multiple oral doses of febuxostat in geriatric subjects (= 65 years) were similar to those in younger subjects (18-40 years).

6.5 Renal Impairment

No dose adjustment is necessary in patients with mild or moderate renal impairment (Clcr 30-89 mL per min). The recommended starting dose of febuxostat is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg, febuxostat 80 mg is recommended.

There are insufficient data in patients with severe renal impairment (Clcr less than 30 mL per min); therefore, caution should be exercised in these patients.

6.6 Hepatic Impairment

No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); therefore, caution should be exercised in these patients.

6.7 Secondary Hyperuricemia

No studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); febuxostat is not recommended for use in patients whom the rate of urate formation is greatly increased (e.g., malignant disease and its treatment, Lesch-Nyhan syndrome). The concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract.

7. WARNINGS AND PRECAUTIONS

7.1 Gout Flare

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].

7.2 Cardiovascular Events

In the randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with febuxostat [0.74 per 100 P-Y (95% CI 0.36-1.37)] than allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)] [see Adverse Reactions]. A causal relationship with febuxostat has not been established. Monitor for signs and symptoms of myocardial infarction (MI) and stroke.

7.3 Hepatic Effects

There have been postmarketing reports of fatal and non-fatal 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 [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.

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.

8. ADVERSE REACTIONS

8.1 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.

A total of 2757 subjects with hyperuricemia and gout were treated with febuxostat 40 mg or 80 mg daily in clinical studies. For febuxostat 40 mg, 559 patients were treated for ≥ 6 months. For febuxostat 80 mg, 1377 subjects were treated for ≥ 6 months, 674 patients were treated for ≥ 1 year and 515 patients were treated for ≥ 2 years.

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 Febuxostat-Treated Patients and at Least 0.5% Greater than Seen in Patients Receiving Placebo in Controlled Studies

* Of the subjects 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 allopurinol-treated subjects.

In addition to the adverse reactions presented in Table 1, dizziness was reported in more than 1% of febuxostat-treated subjects although not at a rate more than 0.5% greater than placebo.

Less Common Adverse Reactions

In Phase 2 and 3 clinical studies the following adverse reactions occurred in less than 1% of subjects 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 subjects) 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.

Cardiovascular Safety

Cardiovascular events and deaths were adjudicated to one of the pre-defined endpoints from the Anti-Platelet Trialists' Collaborations (APTC) (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in the randomized controlled and long-term extension studies. In the Phase 3 randomized controlled studies, the incidences of adjudicated APTC events per 100 patient-years of exposure were: Placebo 0 (95% CI 0.00-6.16), febuxostat 40 mg 0 (95% CI 0.00-1.08), febuxostat 80 mg 1.09 (95% CI 0.44-2.24), and allopurinol 0.60 (95% CI 0.16-1.53).

In the long-term extension studies, the incidences of adjudicated APTC events were: febuxostat 80 mg 0.97 (95% CI 0.57-1.56), and allopurinol 0.58 (95% CI 0.02-3.24).

Overall, a higher rate of APTC events was observed in febuxostat than in allopurinol-treated patients. A causal relationship with febuxostat has not been established. Monitor for signs and symptoms of MI and stroke.

8.2 Postmarketing Experience

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.

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.

9. OVERDOSAGE

Febuxostat was studied in healthy subjects 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.

10. DRUG INTERACTIONS

10.1 Xanthine Oxidase Substrate Drugs

Febuxostat is an XO inhibitor. Drug interaction studies of febuxostat with drugs that are metabolized by XO (e.g., theophylline, mercaptopurine, azathioprine) have not been conducted. Inhibition of XO by febuxostat may cause increased plasma concentrations of these drugs leading to toxicity. Febuxostat is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline [see Contraindications].

10.2 Cytotoxic Chemotherapy Drugs

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

10.3 In Vivo Drug Interaction Studies

Based on drug interaction studies in healthy subjects, febuxostat does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine. Therefore, febuxostat may be used concomitantly with these medications.

11. PHARMACOKINETICS

In healthy subjects, maximum plasma concentrations (Cmax) and AUC of febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg to 120 mg. There is no accumulation when therapeutic doses are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t½) 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 subjects.

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 to 1.5 hours post-dose. After multiple oral 40 mg and 80 mg once daily doses, Cmax is approximately 1.6 ± 0.6 mcg per mL (N=30), and 2.6 ± 1.7 mcg per 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 1 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 (t½) of febuxostat was approximately 5 to 8 hours.

Special Populations

Pediatric Use: The pharmacokinetics of febuxostat in patients under the age of 18 years have not been studied.

Geriatric Use: The Cmax and AUC of febuxostat and its metabolites following multiple oral doses of febuxostat in geriatric subjects (≥ 65 years) were similar to those in younger subjects (18-40 years). In addition, the percent decrease in serum uric acid concentration was similar between elderly and younger subjects. No dose adjustment is necessary in geriatric patients [see Use in Specific Populations].

Renal Impairment: Following multiple 80 mg doses of febuxostat in healthy subjects with mild (Clcr 50-80 mL per min), moderate (Clcr 30-49 mL per min) or severe renal impairment (Clcr 10-29 mL per min), the Cmax of febuxostat did not change relative to subjects with normal renal function (Clcr greater than 80 mL per min). AUC and half-life of febuxostat increased in subjects with renal impairment in comparison to subjects 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 subjects with renal impairment compared to those with normal renal function. Mean Cmax and AUC values for 3 active metabolites increased up to 2- and 4-fold, respectively. However, the percent decrease in serum uric acid concentration for subjects 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).

No dose adjustment is necessary in patients with mild to moderate renal impairment [see Dosage and Administration and Use in Specific Populations]. The recommended starting dose of febuxostat is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg, febuxostat 80 mg is recommended. There is insufficient data in patients with severe renal impairment; caution should be exercised in those patients [see Use in Specific Populations].

Febuxostat has not been studied in end stage renal impairment patients who are on dialysis.

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 20-30% increase was observed for both Cmax and AUC24 (total and unbound) in hepatic impairment groups compared to subjects 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 subjects with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients [see Use in Specific Populations].

Gender: 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.

Race: No specific pharmacokinetic study was conducted to investigate the effects of race.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: ULORIC, by TAKEDA PHARMS.

b) Generic drugs: None.

2) How Supplied:

ULORIC 40 mg tablets are light green to green in color, round shaped, debossed with "TAP" on one side and "40" on the other side and supplied as:

ULORIC 80 mg tablets are light green to green in color, teardrop shaped, debossed with "TAP" on one side and "80" on the other side and supplied as:

3) Storage:

Store at 25°C (77°F); excursions permitted to 15°- 30°C (59°- 86°F) [See USP Controlled Room Temperature]. Protect from light.

Rx only

Rev 11/12