Source: FDA, National Drug Code (US) Revision Year: 2021
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.
In healthy patients, 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.
The effect of ULORIC on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy patients and in patients with gout. ULORIC 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.
In healthy patients, maximum plasma concentrations (Cmax) and AUC of febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg (0.25 times the lowest recommended dosage) to 120 mg (1.5 times the maximum recommended dosage). There is no accumulation when therapeutic doses are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t1/2) of approximately 5 to 8 hours. Febuxostat pharmacokinetic parameters for patients with hyperuricemia and gout estimated by population pharmacokinetic analyses were similar to those estimated in healthy patients.
The absorption of radiolabeled febuxostat following oral dose administration was estimated to be at least 49% (based on total radioactivity recovered in urine). Maximum plasma concentrations of febuxostat occurred between 1 and 1.5 hours postdose. After multiple oral 40 mg and 80 mg once daily doses, Cmax is approximately 1.6 ± 0.6 mcg/mL (N=30), and 2.6 ± 1.7 mcg/mL (N=227), respectively. Absolute bioavailability of the febuxostat tablet has not been studied.
Following multiple 80 mg once daily doses with a high fat meal, there was a 49% decrease in Cmax and an 18% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed (58% fed vs 51% fasting). Thus, 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.
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.
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 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.
The Cmax and AUC of febuxostat and its metabolites following multiple oral doses of ULORIC in geriatric patients (≥65 years) were similar to those in younger patients (18 to 40 years). In addition, the percent decrease in serum uric acid concentration was similar between elderly and younger patients. No dose adjustment is necessary in geriatric patients [see Use in Specific Populations (8.5)].
In a dedicated phase I pharmacokinetics study, following multiple 80 mg doses of ULORIC in healthy patients with mild (Clcr 50 to 80 mL/min), moderate (Clcr 30 to 49 mL/min) or severe renal impairment (Clcr 10 to 29 mL/min), the Cmax of febuxostat did not change relative to patients with normal renal function (Clcr greater than 80 mL/min). AUC and half-life of febuxostat increased in patients with renal impairment in comparison to patients with normal renal function, but values were similar among three renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in patients with renal impairment compared to those with normal renal function. Mean Cmax and AUC values for three active metabolites increased up to two and four-fold, respectively. However, the percent decrease in serum uric acid concentration for patients with renal impairment was comparable to those with normal renal function (58% in normal renal function group and 55% in the severe renal function group).
Based on population pharmacokinetic analysis, following multiple 40 mg or 80 mg doses of ULORIC, 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.
ULORIC has not been studied in end stage renal impairment patients who are on dialysis.
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 patients with normal hepatic function. In addition, the percent decrease in serum uric acid concentration was comparable between different hepatic groups (62% in healthy group, 49% in mild hepatic impairment group, and 48% in moderate hepatic impairment group). No dose adjustment is necessary in patients with mild or moderate hepatic impairment. No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients [see Use in Specific Populations (8.7)].
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.
No specific pharmacokinetic study was conducted to investigate the effects of race.
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 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.
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.
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.
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:
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.
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.
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%).
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%).
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.
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 patients. INR and Factor VII activity were also not affected by the coadministration of ULORIC.
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).
Two year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of the urinary bladder was observed at 24 mg/kg (25 times the MRHD on an AUC basis and 18.75 mg/kg (12.5 times the MRHD on an AUC basis) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder.
Febuxostat showed a positive clastogenic 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 following genotoxicity assays: the in vitro Ames assay, in vitro chromosomal aberration assay in human peripheral lymphocytes, the L5178Y mouse lymphoma cell line assay, the in vivo mouse micronucleus assay, and the rat unscheduled DNA synthesis assay.
Fertility and reproductive performance were unaffected in male or female rats that received febuxostat at oral doses up to 48 mg/kg/day (approximately 31 and 40 times the MRHD on an AUC basis in males and females respectively).
A 12 month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg/kg (approximately 4 times the MRHD on an AUC basis). 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 31 and 40 times the MRHD on an AUC basis in males and females respectively).
A serum uric acid level of less than 6 mg/dL is the goal of antihyperuricemic 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 (ClinicalTrials.gov identifier NCT00430248) 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 (ClinicalTrials.gov identifier NCT00174915) 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 (ClinicalTrials.gov identifier NCT00102440), a one year study, randomized patients to: ULORIC 80 mg daily, ULORIC 120 mg daily, or allopurinol 300 mg daily. Patients who completed Study 2 and Study 3 were eligible to enroll in a Phase 3 long-term extension study in which patients received treatment with ULORIC for over three years.
In all three studies, patients received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis. In Study 1 the duration of prophylaxis was six months; in Study 2 and Study 3 the duration of prophylaxis was eight weeks.
The efficacy of 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. Patients who completed this study were eligible to enroll in a long-term extension study in which patients 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 patients enrolled in the studies.
Table 2. Patient Demographics and Baseline Characteristics in Study 1, Study 2, and Study 3:
| Male | 95% | |
| Race: | Caucasian | 80% |
| African American | 10% | |
| Ethnicity: Hispanic or Latino | 7% | |
| Alcohol User | 67% | |
| Mild to Moderate Renal Insufficiency (percent with estimated Clcr less than 90 mL/min) | 59% | |
| History of Hypertension | 49% | |
| History of Hyperlipidemia | 38% | |
| BMI ≥30 kg/m2 | 63% | |
| Mean BMI | 33 kg/m2 | |
| Baseline sUA ≥10 mg/dL | 36% | |
| Mean baseline sUA | 9.7 mg/dL | |
| Experienced a gout flare in previous year | 85% | |
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).
Table 3. Proportion of Patients with Serum Uric Acid Levels less than 6 mg/dL at Final Visit:
| Difference in Proportion (95% CI) | ||||||
|---|---|---|---|---|---|---|
| Study* | ULORIC 40 mg daily | ULORIC 80 mg daily | allopurinol | Placebo | ULORIC 40 mg vs allopurinol | ULORIC 80 mg vs allopurinol |
| Study 1 (6 months) (N=2268) | 45% | 67% | 42% | 3% (-2%, 8%) | 25% (20%, 30%) | |
| Study 2 (6 months) (N=643) | 72% | 39% | 1% | 33% (26%, 42%) | ||
| Study 3 (12 months) (N=491) | 74% | 36% | 38% (30%, 46%) | |||
* Randomization was balanced between treatment groups, except in Study 2 in which twice as many patients were randomized to each of the active treatment groups compared to placebo.
In 76% of 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 patients with higher baseline serum urate levels (≥10 mg/dL) and/or tophi achieved the goal of lowering serum uric acid to less than 6 mg/dL at the final visit; however, a higher proportion achieved a serum uric acid less than 6 mg/dL with 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 subgroup of patients are shown in Table 4.
Table 4. Proportion of Patients with Serum Uric Acid Levels less than 6 mg/dL in Patients with Mild or Moderate Renal Impairment at Final Visit:
| Difference in Proportion (95% CI) | ||||
|---|---|---|---|---|
| ULORIC 40 mg daily (N=479) | ULORIC 80 mg daily (N=503) | allopurinol?footnote? 300 mg daily (N=501) | ULORIC 40 mg vs allopurinol | ULORIC 80 mg vs allopurinol |
| 50% | 72% | 42% | 7% (1%, 14%) | 29% (23%, 35%) |
* Allopurinol patients (n=145) with estimated Clcr ≥30 mL/min and Clcr ≤59 mL/min were dosed at 200 mg daily.
A randomized, double-blind, allopurinol-controlled CV outcomes study (CARES) was conducted to evaluate the CV risk of ULORIC. The study compared the risk of MACE between patients treated with ULORIC (N=3098) and allopurinol-treated patients (N=3092). The primary endpoint was the time to first occurrence of a MACE defined as the composite of CV death, nonfatal MI, nonfatal stroke, or unstable angina with urgent coronary revascularization. The study was designed to exclude a prespecified risk margin of 1.3 for the hazard ratio of MACE. An independent committee conducted a blinded evaluation of serious CV adverse events according to predefined criteria (adjudication) for determination of MACE. The study was event driven and patients were followed until a sufficient number of primary outcome events accrued. The median on-study follow-up time was 2.6 years.
Patients randomized to ULORIC initially received 40 mg once daily which was increased to 80 mg once daily, if their sUA was ≥6mg/dL at Week 2. For patients randomized to allopurinol, those who had normal renal function or mild renal impairment (estimated creatinine clearance (eClcr) ≥60 to ˂90 mL/minute) initially received 300 mg once daily with 100 mg/day dose increments monthly until either sUA ˂6mg/dL or an allopurinol dosage of 600 mg once daily was achieved; those who had moderate renal impairment (eClcr ≥30 to ˂60 mL/minute) initially received 200 mg once daily with 100 mg/day dose increments monthly until either a sUA ˂6 mg/dL or an allopurinol dosage of 400 mg once daily was achieved.
The mean age of the population was 65 years (range: 44 to 93 years). Most patients were male (84%) and Caucasian (69%). Patients had a diagnosis of gout for approximately 12 years, a mean baseline sUA of 8.7 mg/dL, and 90% had experienced at least one gout flare in the past year. CV history included MI (39%), hospitalization for unstable angina (28%), cardiac revascularization (37%), and stroke (14%). The most prevalent comorbid conditions were hypertension (92%), hyperlipidemia (87%), diabetes mellitus (55%), diabetes mellitus with micro- or macrovascular disease (39%), and renal impairment [92% with an eClcr 30 to 89 mL/minute]. The use of CV disease medication was balanced across treatment groups. Baseline CV disease medications included: ACE inhibitors or ARBs (70%), lipid modifying agents (74%), aspirin (62%), beta-blockers (59%), calcium channel blockers (26%), and nonaspirin antiplatelet medications (31%).
Table 5 shows the study results for the primary MACE composite endpoint and its individual components. For the composite primary endpoint, the ULORIC group was non-inferior compared with the allopurinol group. The rates of nonfatal MI, stroke, and unstable angina with urgent coronary revascularization were similar. There was a higher rate of CV deaths in patients treated with ULORIC (134 CV deaths; 1.5 per 100 PY) than in allopurinol-treated patients (100 CV deaths; 1.1 per 100 PY). Sudden cardiac death was the most common cause of adjudicated CV deaths in the ULORIC group (83 of 3,098; 2.7%) as compared to the allopurinol group (56 of 3,092; 1.8%). The biological plausibility of CV death associated with ULORIC is unclear.
All-cause mortality was higher in the ULORIC group (243 deaths [7.8%]; 2.6 per 100 PY) than the allopurinol group (199 deaths [6.4%]; 2.2 per 100 PY) [Hazard Ratio: 1.22, 95% CI: 1.01, 1.47], due to a higher rate of CV deaths.
Table 5. Patients with MACE in CARES (Cardiovascular Outcomes Study in Patients with Gout):
| ULORIC N=3098 | Allopurinol N=3092 | Hazard Ratio | |||
|---|---|---|---|---|---|
| Number of Patients with Event (%) | Rate per 100 PY* | Number of Patients with Event (%) | Rate per 100 PY* | 95% CI | |
| Composite of primary endpoint MACE | 335 (10.8) | 3.8 | 321 (10.4) | 3.7 | 1.03 (0.89, 1.21) |
| Cardiovascular Death | 134 (4.3) | 1.5 | 100 (3.2) | 1.1 | 1.34 (1.03, 1.73) |
| Nonfatal MI | 111 (3.6) | 1.2 | 118 (3.8) | 1.3 | 0.93 (0.72, 1.21) |
| Nonfatal stroke | 71 (2.3) | 0.8 | 70 (2.3) | 0.8 | 1.01 (0.73, 1.41) |
| Unstable angina with urgent coronary revascularization | 49 (1.6) | 0.5 | 56 (1.8) | 0.6 | 0.86 (0.59, 1.26) |
* Patient Years (PY)
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