1.1 Limitations of Use

ZURAMPIC is not recommended for the treatment of asymptomatic hyperuricemia.

ZURAMPIC should not be used as monotherapy [see Warnings and Precautions (5.1)].

2.1 Recommended Dosing

ZURAMPIC tablets are for oral use and should be co-administered with a xanthine oxidase inhibitor, including allopurinol or febuxostat.

ZURAMPIC is recommended at 200 mg once daily. This is also the maximum daily dose. ZURAMPIC should be taken by mouth, in the morning with food and water.

ZURAMPIC may be added when target serum uric acid levels are not achieved on the medically appropriate dose of the xanthine oxidase inhibitor alone.

Use of ZURAMPIC is not recommended for patients taking daily doses of allopurinol less than 300 mg (or less than 200 mg in patients with estimated creatinine clearance (eCLcr) less than 60 mL/min). Take ZURAMPIC at the same time as the morning dose of xanthine oxidase inhibitor. If treatment with the xanthine oxidase inhibitor is interrupted, ZURAMPIC should also be interrupted. Failure to follow these instructions may increase the risk of renal events [see Warnings and Precautions (5.1)].

Patients should be instructed to stay well hydrated (e.g., 2 liters [68 oz] of liquid per day).

2.2 Patients with Renal Impairment

No dose adjustment is needed in patients with mild or moderate renal impairment (eCLcr of 45 mL/min or greater). ZURAMPIC should not be initiated in patients with an eCLcr less than 45 mL/min. Assessment of renal function is recommended prior to initiation of ZURAMPIC therapy and periodically thereafter [see Warnings and Precautions (5.1)]. More frequent renal function monitoring is recommended in patients with an eCLcr below 60 mL/min. ZURAMPIC should be discontinued when eCLcr is persistently less than 45 mL/min [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

2.3 Gout Flares

Gout flares may occur after initiation of urate lowering therapy, including ZURAMPIC, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Gout flare prophylaxis is recommended when starting ZURAMPIC, according to practice guidelines.

If a gout flare occurs during ZURAMPIC treatment, ZURAMPIC need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient [see Patient Counseling Information (17)].

5.1 Renal Events

Treatment with ZURAMPIC 200 mg in combination with a xanthine oxidase inhibitor was associated with an increased incidence of serum creatinine elevations, most of which were reversible [see Adverse Reactions (6)]. Adverse reactions related to renal function have occurred after initiating ZURAMPIC. A higher incidence of serum creatinine elevations and renal-related adverse reactions, including serious adverse reactions of acute renal failure, was observed with ZURAMPIC 400 mg, with the highest incidence as monotherapy. ZURAMPIC should not be used as monotherapy [see Limitation of Use (1.1)].

ZURAMPIC should not be initiated in patients with an eCLcr less than 45 mL/min. Renal function should be evaluated prior to initiation of ZURAMPIC and periodically thereafter, as clinically indicated. More frequent renal function monitoring is recommended in patients with an eCLcr less than 60 mL/min [see Renal Impairment (8.6)] or with serum creatinine elevations 1.5 to 2 times the pre-treatment value. ZURAMPIC treatment should be interrupted if serum creatinine is elevated to greater than 2 times the pre-treatment value. In patients who report symptoms that may indicate acute uric acid nephropathy including flank pain, nausea or vomiting, interrupt treatment and measure serum creatinine promptly. ZURAMPIC should not be restarted without another explanation for the serum creatinine abnormalities.

5.2 Cardiovascular Events

In clinical trials, major adverse cardiovascular events (defined as cardiovascular deaths, non-fatal myocardial infarctions, or non-fatal strokes) were observed with ZURAMPIC [see Adverse Reactions (6.1)]. A causal relationship with ZURAMPIC has not been established.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Although other doses have been studied, the recommended dose of ZURAMPIC is 200 mg once daily in combination with a xanthine oxidase inhibitor.

In 3 randomized, placebo-controlled studies of ZURAMPIC in combination with a xanthine oxidase inhibitor (Studies 1 and 2 were with allopurinol and Study 3 was with febuxostat) for up to 12 months, a total of 511, 510, and 516 patients were treated with ZURAMPIC 200 mg, ZURAMPIC 400 mg, and placebo, respectively. The median duration of treatment with ZURAMPIC was 11.2 months. The mean age of the population was 52 years (18-82), and 95% were males. At baseline, 62% of the patient population showed mild or moderate renal impairment (eCLcr less than 90 mL/min) and 79% of patients had at least one co-morbid condition including hypertension (65%), hyperlipidemia (45%), diabetes (17%), and kidney stones (12%).

7.1 CYP2C9 Inhibitors, CYP2C9 Poor Metabolizers, and CYP2C9 Inducers

Lesinurad exposure is increased when ZURAMPIC is co-administered with inhibitors of CYP2C9, and in CYP2C9 poor metabolizers. ZURAMPIC should be used with caution in patients taking moderate inhibitors of CYP2C9 (e.g., fluconazole, amiodarone), and in CYP2C9 poor metabolizers [see Clinical Pharmacology (12.3)].

Lesinurad exposure is decreased when ZURAMPIC is co-administered with moderate inducers of CYP2C9 (e.g., rifampin, carbamazepine), which may decrease the therapeutic effect of ZURAMPIC [see Clinical Pharmacology (12.3)].

7.2 CYP3A Substrates

In interaction studies conducted in healthy subjects with ZURAMPIC and CYP3A substrates, lesinurad reduced the plasma concentrations of sildenafil and amlodipine [see Clinical Pharmacology (12.3)]. Although there was not a clinically significant interaction with atorvastatin, HMG-CoA reductase inhibitors that are sensitive CYP3A substrates may be affected. The possibility of reduced efficacy of concomitant drugs that are CYP3A substrates should be considered and their efficacy (e.g., blood pressure and cholesterol levels) should be monitored.

7.3 Epoxide Hydrolase Inhibitors

In vitro studies suggest that lesinurad is not an inhibitor of epoxide hydrolase; however, inhibitors of epoxide hydrolase (i.e., valproic acid) may interfere with metabolism of lesinurad. ZURAMPIC should not be administered with inhibitors of epoxide hydrolase.

7.4 Hormonal Contraceptives

Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when ZURAMPIC is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking ZURAMPIC.

7.5 Aspirin

Aspirin at doses higher than 325 mg per day may decrease the efficacy of ZURAMPIC in combination with allopurinol. Aspirin at doses of 325 mg or less per day (i.e., for cardiovascular protection) does not decrease the efficacy of ZURAMPIC and can be coadministered with ZURAMPIC.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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

8.5 Geriatric Use

No dose adjustment is necessary in elderly patients. In a pool of clinical safety and efficacy studies of ZURAMPIC in gout patients, 13% were 65 years and older and 2% were 75 years and older. No overall differences between lesinurad and placebo in safety and effectiveness were observed between these subjects and younger subjects but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

The pharmacokinetics (PK) of ZURAMPIC was evaluated in studies that included patients with mild (eCLcr 60 to less than 90 mL/min), moderate (eCLcr 30 to less than 60 mL/min), and severe renal impairment (eCLcr less than 30 mL/min). Lesinurad exposure (AUC) increased by 30%, 50-73%, and 113%, respectively, in subjects with mild, moderate, and severe renal impairment [see Clinical Pharmacology (12.3)].

The efficacy and safety of ZURAMPIC were evaluated in studies that included gout patients with mild and moderate renal impairment [see Adverse Reactions (6) and Clinical Studies (14)]. There were no clear differences in safety and effectiveness of ZURAMPIC in patients with mild renal impairment compared to patients with normal renal function and no dose adjustment is recommended [see Dosage and Administration (2.2) and Clinical Studies (14.5)].

Across all ZURAMPIC and placebo treatment groups, patients with moderate renal impairment had a higher occurrence of renal related adverse reactions compared to patients with mild renal impairment or normal renal function [see Adverse Reactions (6.1)]. The experience with ZURAMPIC in patients with an eCLcr less than 45 mL/min is limited and there was a trend toward lesser efficacy [see Clinical Studies (14.5)]. ZURAMPIC should not be initiated in patients with an eCLcr less than 45 mL/min. No dose adjustment is recommended in patients with an eCLcr 45 to less than 60 mL/min, however, more frequent renal function monitoring is recommended. ZURAMPIC should be discontinued when eCLcr is persistently less than 45 mL/min [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

The efficacy and safety of ZURAMPIC have not been evaluated in gout patients with severe renal impairment (eCLcr less than 30 mL/min), with end-stage renal disease, or receiving dialysis. ZURAMPIC is not expected to be effective in these patient populations [see Contraindications (4)].

8.7 Hepatic Impairment

No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh classes A and B) [see Clinical Pharmacology (12.3)]. Lesinurad has not been studied in patients with severe hepatic impairment and is therefore not recommended.

8.8 Secondary Hyperuricemia

No studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); ZURAMPIC is contraindicated for use in tumor lysis syndrome or Lesch-Nyhan syndrome, where the rate of uric acid formation is greatly increased [see Contraindications (4)].

12.1 Mechanism of Action

Lesinurad reduces serum uric acid levels by inhibiting the function of transporter proteins involved in uric acid reabsorption in the kidney. Lesinurad inhibited the function of two apical transporters responsible for uric acid reabsorption, uric acid transporter 1 (URAT1) and organic anion transporter 4 (OAT4), with IC50 values of 7.3 and 3.7 µM, respectively. URAT1 is responsible for the majority of the reabsorption of filtered uric acid from the renal tubular lumen. OAT4 is a uric acid transporter associated with diuretic-induced hyperuricemia. Lesinurad does not interact with the uric acid reabsorption transporter SLC2A9 (Glut9), located on the basolateral membrane of the proximal tubule cell.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Following oral administration of ZURAMPIC 200 mg in healthy subjects, the mean (% CV) Cmax and AUC for lesinurad were 6 µg/mL (31%) and 30 µg∙hr/mL (44%), respectively. Cmax and AUC exposures of lesinurad increased proportionally with single doses of ZURAMPIC from 5 to 1200 mg. Following multiple once daily dosing of ZURAMPIC, there was no evidence of time dependent changes in pharmacokinetics and dose proportionality was preserved.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of lesinurad was evaluated in Sprague-Dawley rats and TgRasH2 mice. No evidence of tumorigenicity was observed in male or female rats that received lesinurad for 91 to 100 weeks at oral doses up to 200 mg/kg/day (approximately 35 times the MRHD on an AUC basis). No evidence of tumorigenicity was observed in TgRasH2 mice that received lesinurad for 26 weeks at oral doses up to 125 and 250 mg/kg/day in male and female mice, respectively.

Lesinurad tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo rat bone marrow micronucleus assay.

Fertility and reproductive performance were unaffected in male or female rats that received lesinurad at oral doses up to 300 mg/kg/day (approximately 15 times the MRHD on a mg/m2 basis).

14.1 Overview of Clinical Studies of ZURAMPIC

The efficacy of ZURAMPIC 200 mg and 400 mg once daily was studied in 3 multicenter, randomized, double-blind, placebo-controlled clinical studies in adult patients with hyperuricemia and gout in combination with a xanthine oxidase inhibitor, allopurinol or febuxostat. All studies were of 12 months duration and patients received prophylaxis for gout flares with colchicine or non-steroidal anti-inflammatory drugs (NSAIDs) during the first 5 months of ZURAMPIC treatment.

Although other doses have been studied, the recommended dose of ZURAMPIC is 200 mg once daily in combination with a xanthine oxidase inhibitor.

14.2 Add-on to Allopurinol in Inadequate Responders

Study 1 and Study 2 enrolled patients with gout who were on a stable dose of allopurinol of at least 300 mg (or 200 mg for moderate renal impairment) that had a serum uric acid > 6.5 mg/dL and reported at least 2 gout flares in the prior 12 months. Mean years since gout diagnosis were 12 years. More than half of the patients (61%) had mild or moderate renal impairment and 19% of the patients had tophi. Patients continued their allopurinol dose and were randomized 1:1:1 to receive ZURAMPIC 200 mg, ZURAMPIC 400 mg, or placebo once daily. The average dose of allopurinol in the studies was 310 mg (range: 200-900 mg).

As shown in Table 5, ZURAMPIC 200 mg in combination with allopurinol was superior to allopurinol alone in lowering serum uric acid to less than 6 mg/dL at Month 6.

The estimated effect of ZURAMPIC 200 mg on serum uric acid in the subgroup of patients taking thiazide diuretics at baseline was similar to the estimated effect in the overall population. The estimated effect was also similar in the subgroup of patients taking low dose aspirin at baseline.

As shown in Figure 3, reduction in average serum uric acid levels to < 6 mg/dL was noted for ZURAMPIC 200 mg in combination with allopurinol at the Month 1 visit and was maintained throughout the 12-month study.

Figure 3: Mean Serum Uric Acid Levels Over Time in Pooled Clinical Studies with ZURAMPIC in Combination with Allopurinol (Study 1 and Study 2)

14.3 Combination with Febuxostat in Tophaceous Gout

Study 3 enrolled gout patients with measurable tophi. Patients received febuxostat 80 mg once daily for 3 weeks and then were randomized 1:1:1 to once daily doses of ZURAMPIC 200 mg, ZURAMPIC 400 mg, or placebo in combination with febuxostat. A total of 66% of patients had mild or moderate renal impairment. Fifty percent of patients did not reach target serum uric acid < 5.0 mg/dL at Baseline after 3 weeks of febuxostat treatment.

As shown in Table 6, there was not statistical evidence of a difference in the proportion of patients treated with ZURAMPIC 200 mg in combination with febuxostat achieving a serum uric acid < 5 mg/dL by Month 6, compared with patients receiving febuxostat alone. However, the average decrease in serum uric acid with ZURAMPIC 200 mg in Study 3 was similar to that seen in Study 1 and Study 2 (see Figure 3 and Figure 4).

As shown in Figure 4, reduction in average serum uric acid levels to < 5 mg/dL was noted for ZURAMPIC 200 mg in combination with febuxostat at the Month 1 visit and was maintained throughout the 12-month study.

Figure 4: Mean Serum Uric Acid Levels Over Time in a Study with ZURAMPIC in Combination with Febuxostat in Tophaceous Gout (Study 3)

14.4 Gout Flares and Tophus Outcomes

In each of the three pivotal studies of ZURAMPIC in combination with a xanthine oxidase inhibitor, the rates of gout flare requiring treatment from the end of Month 6 to the end of Month 12 were not statistically different between ZURAMPIC 200 mg in combination with allopurinol or febuxostat compared with allopurinol or febuxostat alone. In Study 3, the proportion of patients who experienced a complete resolution of ≥ 1 target tophus was not statistically different between ZURAMPIC 200 mg in combination with febuxostat compared with febuxostat alone.

14.5 Use in Patients with Renal Impairment

The estimated differences between ZURAMPIC and placebo in the proportions of patients achieving target serum uric acid levels in the renal impairment subgroups were largely consistent with the results in the overall population in the three studies. However, there were limited data in patients with eCLcr less than 45 mL/min and there was a trend toward decreasing magnitudes of effect with decreasing renal function: in patients with eCLcr less than 45 mL/min, the estimated difference between ZURAMPIC 200 mg and placebo in the proportion achieving serum uric acid < 6.0 mg/dL at Month 6 was 10% (95% CI: -17, 37), as compared with 27% (95% CI: 9, 45) in the 45 to less than 60 mL/min subgroup and 30% (95% CI: 23, 37) in the 60 mL/min or greater subgroup, based on integrated data from Study 1 and Study 2.

16.1 How Supplied

ZURAMPIC Tablets, 200 mg are blue in color, oval shaped, debossed with "LES200" and are supplied as follows:

16.2 Storage and Handling

Protect from light. Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Administration

Advise patients:

• To take ZURAMPIC in the morning with food and water at the same time as a xanthine oxidase inhibitor, allopurinol, or febuxostat.
• Not to take ZURAMPIC alone and to discontinue ZURAMPIC if treatment with the xanthine oxidase inhibitor medication is discontinued.
• Not to take a missed dose of ZURAMPIC later in the day, to wait to take ZURAMPIC on the next day, and not to double the dose.
• To stay well hydrated (e.g., 2 liters [68 oz] of liquid per day).

Renal Events

Inform patients that renal events including transient increases in blood creatinine level and acute renal failure have occurred in some patients who take ZURAMPIC. Advise patients that periodic monitoring of blood creatinine levels are recommended [see Warnings and Precautions (5.1)].

Gout Flares

Inform patients that gout flares may occur after initiation of ZURAMPIC and of the importance of taking gout flare prophylaxis medication to help prevent gout flares. Advise patients not to discontinue ZURAMPIC if a gout flare occurs during treatment [see Dosage and Administration (2.3)].