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.
Hepatobiliary Disorders: hepatic failure (some fatal), jaundice, serious cases of abnormal liver function test results, liver disorder.
Immune System Disorders: anaphylaxis, anaphylactic reaction.
Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis.
Psychiatric Disorders: psychotic behavior including aggressive thoughts.
Renal and Urinary Disorders: tubulointerstitial nephritis.
Skin and Subcutaneous Tissue Disorders: generalized rash, Stevens Johnson Syndrome, hypersensitivity skin reactions.
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 [see Clinical Pharmacology (12.3)]. 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 [see Clinical Pharmacology (12.3)]. ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine [see Contraindications (4)].
Drug interaction studies of ULORIC with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of ULORIC during cytotoxic chemotherapy.
Based on drug interaction studies in healthy subjects, ULORIC does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine [see Clinical Pharmacology (12.3)]. Therefore, ULORIC may be used concomitantly with these medications.
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.
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.
Safety and effectiveness in pediatric patients under 18 years of age have not been established.
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) [see Clinical Pharmacology (12.3)].
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 [see Clinical Pharmacology (12.3)].
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 [see Clinical Pharmacology (12.3)].
No studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); ULORIC 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.
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. Patients should be managed by symptomatic and supportive care should there be an overdose.
ULORIC (febuxostat) is a xanthine oxidase inhibitor. The active ingredient in ULORIC is 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, with a molecular weight of 316.38. The empirical formula is C16 H16 N2 O3 S.
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 205°C to 208°C.
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.
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.
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.
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 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 (t1/2 ) of febuxostat was approximately 5 to 8 hours.
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 [see Use in Specific Populations (8.5)].
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 [see Dosage and Administration (2) and Use in Specific Populations (8.6)]. 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 [see Use in Specific Populations (8.6)].
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 [see Use in Specific Populations (8.7)].
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.
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 [see Contraindications (4) and Drug Interactions (7)].
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 [a xanthine oxidase inhibitor] 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).
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