Febuxostat

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# Overview
Febuxostat is a xanthine oxidase (XO) inhibitor that is FDA approved for the {{{indicationType}}} of hyperuricemia in patients with gout.   Common adverse reactions include liver function abnormalities, nausea, arthralgia, and rash.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- For treatment of hyperuricemia in patients with gout, ULORIC is recommended at 40 mg or 80 mg once daily.
- The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a serum uric acid (sUA) less than 6 mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended.
- Gout Flares
- Gout flares may occur after initiation of ULORIC 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 ULORIC. Prophylactic therapy may be beneficial for up to six months.
- If a gout flare occurs during ULORIC treatment, ULORIC need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Febuxostat in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Febuxostat in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Febuxostat in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Febuxostat in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Febuxostat in pediatric patients.

# Contraindications
- ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine.

# Warnings

### Precautions
- Gout Flare
- After initiation of ULORIC, 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 ULORIC is initiated, concurrent prophylactic treatment with an NSAID or colchicine is recommended.
- 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 ULORIC (0.74 per 100 P-Y ) than allopurinol (0.60 per 100 P-Y ). A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of myocardial infarction (MI) and stroke.
- Hepatic Effects
- There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking ULORIC, 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 ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted.
- Obtain a liver test panel (serum alanine aminotransferase , aspartate aminotransferase , alkaline phosphatase, and total bilirubin) as a baseline before initiating ULORIC.
- 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), ULORIC treatment should be interrupted and investigation done to establish the probable cause. ULORIC 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 ULORIC. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with ULORIC can be used with caution.

# Adverse Reactions

## 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 ULORIC 40 mg or 80 mg daily in clinical studies. For ULORIC 40 mg, 559 patients were treated for 6 months. For ULORIC 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 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 ULORIC treatment groups and at least 0.5% greater than placebo.
- The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of ULORIC 40 mg, 1.2% of ULORIC 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 ULORIC-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 ULORIC. This list also includes adverse reactions (less than 1% of subjects) associated with organ systems from Warnings and Precautions.
Anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia.
Angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia.
Deafness, tinnitus, vertigo.
Vision blurred.
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.
Asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst.
Cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly.
Hypersensitivity.
Herpes zoster.
Contusion.
Anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased.
Arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia.
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.
Agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change.
Hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence.
Breast pain, erectile dysfunction, gynecomastia.
Bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection.
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.
Flushing, hot flush, hypertension, hypotension.
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.

## Postmarketing Experience
- Adverse reactions have been identified during postapproval use of ULORIC. 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.
Hepatic failure (some fatal), jaundice, serious cases of abnormal liver function test results, liver disorder.
Anaphylaxis, anaphylactic reaction.
Rhabdomyolysis.
Psychotic behavior including aggressive thoughts.
Tubulointerstitial nephritis.
Generalized rash, Stevens Johnson Syndrome, hypersensitivity skin reactions.

# Drug Interactions
- Xanthine Oxidase Substrate Drugs
- ULORIC is an XO inhibitor. Based on a drug interaction study in healthy subjects, febuxostat altered the metabolism of theophylline (a substrate of XO) in humans. Therefore, use with caution when coadministering ULORIC with theophylline.
- Drug interaction studies of ULORIC with other drugs that are metabolized by XO (e.g., mercaptopurine and azathioprine) have not been conducted. Inhibition of XO by ULORIC may cause increased plasma concentrations of these drugs leading to toxicity. ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine.
- Cytotoxic Chemotherapy Drugs
- Drug interaction studies of ULORIC with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of ULORIC during cytotoxic chemotherapy.
- In Vivo Drug Interaction Studies
- Based on drug interaction studies in healthy subjects, ULORIC does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine. Therefore, ULORIC may be used concomitantly with these medications.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. ULORIC 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/kg (40 and 51 times the human plasma exposure at 80 mg/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/kg (40 times the human plasma exposure at 80 mg/day) during organogenesis and through lactation period.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Febuxostat in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Febuxostat during labor and delivery.

### 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 ULORIC is administered to a nursing woman.

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

### Geriatic Use
- No dose adjustment is necessary in elderly patients. Of the total number of subjects in clinical studies of ULORIC, 16% were 65 and over, while 4% 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 ULORIC in geriatric subjects (65 years) were similar to those in younger subjects (18 to 40 years).

### Gender
There is no FDA guidance on the use of Febuxostat with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Febuxostat with respect to specific racial populations.

### Renal Impairment
- No dose adjustment is necessary in patients with mild or moderate renal impairment (Clcr 30 to 89 mL/min). The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended.
- There are insufficient data in patients with severe renal impairment (Clcr less than 30 mL/min); therefore, caution should be exercised in these patients.

### 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.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Febuxostat in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Febuxostat in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
There is limited information regarding Monitoring of Febuxostat in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Febuxostat in the drug label.

# Overdosage

## Acute Overdose

### Signs and Symptoms
- ULORIC was studied in healthy subjects in doses up to 300 mg daily for seven days without evidence of dose-limiting toxicities. No overdose of ULORIC was reported in clinical studies.

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

## Chronic Overdose
There is limited information regarding Chronic Overdose of Febuxostat in the drug label.

# Pharmacology

## Mechanism of Action
- ULORIC, a xanthine oxidase inhibitor, achieves its therapeutic effect by decreasing serum uric acid. ULORIC is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic concentrations.

## Structure
- ULORIC (febuxostat) is a xanthine oxidase inhibitor. The active ingredient in ULORIC is 2--4-methylthiazole-5-carboxylic acid, with a molecular weight of 316.38. The empirical formula is C16H16N2O3S.
- 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 205C to 208C.
- ULORIC 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. ULORIC tablets are coated with Opadry II, green.

## Pharmacodynamics
- Effect on Uric Acid and Xanthine Concentrations: In healthy subjects, ULORIC 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.
- Effect on Cardiac Repolarization: The effect of ULORIC on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and in patients with gout. ULORIC in doses up to 300 mg daily, at steady-state, did not demonstrate an effect on the QTc interval.

## 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 (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 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 and 1.5 hours post-dose. 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, ULORIC 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 ULORIC 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, ULORIC 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.
- Special Populations
- Pediatric Use: The pharmacokinetics of ULORIC 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 ULORIC in geriatric subjects (65 years) were similar to those in younger subjects (18 to 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.
- Renal Impairment
- Following multiple 80 mg doses of ULORIC in healthy subjects 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 subjects with normal renal function (Clcr greater than 80 mL/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 three 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. The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended. There is insufficient data in patients with severe renal impairment; caution should be exercised in those patients.
- ULORIC has not been studied in end stage renal impairment patients who are on dialysis.
- Hepatic Impairment: Following multiple 80 mg doses of ULORIC 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 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.
- Gender: Following multiple oral doses of ULORIC, 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.
- Drug-Drug Interactions
- Effect of ULORIC 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 ULORIC upon the pharmacokinetics of theophylline (an XO substrate) in healthy subjects 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.
- Drug interaction studies of ULORIC with other drugs that are metabolized by XO (e.g., mercaptopurine and azathioprine) have not been conducted. Inhibition of XO by ULORIC may cause increased plasma concentrations of these drugs leading to toxicity. ULORIC 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. Although ULORIC drug interaction studies with azathioprine and mercaptopurine have not been conducted, concomitant administration of allopurinol  with azathioprine or mercaptopurine has been reported to substantially increase plasma concentrations of these drugs. Because ULORIC is a xanthine oxidase inhibitor, it could inhibit the XO-mediated metabolism of azathioprine and mercaptopurine leading to increased plasma concentrations of azathioprine or 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 ULORIC and drugs metabolized by these CYP enzymes are unlikely.
- Effect of Other Drugs on ULORIC
- Febuxostat is metabolized by conjugation and oxidation via multiple metabolizing enzymes. The relative contribution of each enzyme isoform is not clear. Drug interactions between ULORIC and a drug that inhibits or induces one particular enzyme isoform is in general not expected.
- In Vivo Drug Interaction Studies
- Theophylline: No dose adjustment is necessary for theophylline when coadministered with ULORIC. Administration of ULORIC (80 mg once daily) with theophylline resulted in an increase of 6% in Cmax 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 ULORIC. The safety of long-term exposure to 1-methylxanthine has not been evaluated. This should be taken into consideration when deciding to coadminister ULORIC and theophylline.
- Colchicine: No dose adjustment is necessary for either ULORIC or colchicine when the two drugs are coadministered. Administration of ULORIC (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 ULORIC (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 ULORIC or naproxen when the two drugs are coadministered. Administration of ULORIC (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 ULORIC or indomethacin when these two drugs are coadministered. Administration of ULORIC (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 ULORIC when coadministered with hydrochlorothiazide. Administration of ULORIC (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 ULORIC. Administration of ULORIC (80 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. INR and Factor VII activity were also not affected by the coadministration of ULORIC.
- Desipramine: Coadministration of drugs that are CYP2D6 substrates (such as desipramine) with ULORIC are not expected to require dose adjustment. Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro and in vivo. Administration of ULORIC (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).

## Nonclinical Toxicology
- Carcinogenesis: Two-year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of urinary bladder was observed at 24 mg/kg (25 times the human plasma exposure at maximum recommended human dose of 80 mg/day) and 18.75 mg/kg (12.5 times the human plasma exposure at 80 mg/day) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder.
- Mutagenesis: Febuxostat showed a positive mutagenic response in a chromosomal aberration assay in a Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. Febuxostat was negative in the in vitro Ames assay and chromosomal aberration test in human peripheral lymphocytes, and L5178Y mouse lymphoma cell line, and in vivo tests in mouse micronucleus, rat unscheduled DNA synthesis and rat bone marrow cells.
- Impairment of Fertility: Febuxostat at oral doses up to 48 mg/kg/day (approximately 35 times the human plasma exposure at 80 mg/day) had no effect on fertility and reproductive performance of male and female rats.
- A 12-month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg/kg (approximately four times the human plasma exposure at 80 mg/day). A similar effect of calculus formation was noted in rats in a six-month study due to deposition of xanthine crystals at 48 mg/kg (approximately 35 times the human plasma exposure at 80 mg/day).

# Clinical Studies
- A serum uric acid level of less than 6 mg/dL is the goal of anti-hyperuricemic therapy and has been established as appropriate for the treatment of gout.
- The efficacy of ULORIC 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 randomized patients to: ULORIC 40 mg daily, ULORIC 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 randomized patients to: placebo, ULORIC 80 mg daily, ULORIC 120 mg daily, ULORIC 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, a 1-year study, randomized patients to: ULORIC 80 mg daily, ULORIC 120 mg daily, or allopurinol 300 mg daily. Subjects who completed Study 2 and Study 3 were eligible to enroll in a phase 3 long-term extension study in which subjects received treatment with ULORIC for over three years.
- In all three studies, subjects 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 ULORIC was also evaluated in a four week dose ranging study which randomized patients to: placebo, ULORIC 40 mg daily, ULORIC 80 mg daily, or ULORIC 120 mg daily. Subjects who completed this study were eligible to enroll in a long-term extension study in which subjects received treatment with ULORIC for up to five years.
- Patients in these studies were representative of the patient population for which ULORIC use is intended. Table 2 summarizes the demographics and baseline characteristics for the subjects enrolled in the studies.
- Serum Uric Acid Level less than 6 mg/dL at Final Visit: ULORIC 80 mg was superior to allopurinol in lowering serum uric acid to less than 6 mg/dL at the final visit. ULORIC 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).
- In 76% of ULORIC 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 subjects 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 ULORIC 80 mg than with ULORIC 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 sub-group of patients are shown in Table 4.

# How Supplied
- ULORIC 40 mg tablets are light green to green in color, round, 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:
- Protect from light. Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F).

## Storage
There is limited information regarding Febuxostat Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- General Information
- Patients should be advised of the potential benefits and risks of ULORIC. Patients should be informed about the potential for gout flares, elevated liver enzymes and adverse cardiovascular events after initiation of ULORIC therapy.
- Concomitant prophylaxis with an NSAID or colchicine for gout flares should be considered.
- Patients should be instructed to inform their healthcare professional if they develop a rash, chest pain, shortness of breath or neurologic symptoms suggesting a stroke. Patients should be instructed to inform their healthcare professional of any other medications they are currently taking with ULORIC, including over-the-counter medications.

# Precautions with Alcohol
- Alcohol-Febuxostat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- ULORIC

# Look-Alike Drug Names
There is limited information regarding Febuxostat Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price