• Renal function should be evaluated prior to initiation of ZURAMPIC and periodically monitored thereafter as clinically indicated
ZURAMPIC recommendations for patients with renal impairment
Creatinine clearance Recommendation
<90 - ≥60 mL/min
  • ZURAMPIC can be added to an XOI in these patients
  • No dose adjustment is needed
<60 - ≥45 mL/min
  • ZURAMPIC can be added to an XOI in these patients
  • More frequent renal monitoring is recommended while patients are on ZURAMPIC
  • No dose adjustment is needed
<45 mL/min
  • ZURAMPIC should not be initiated
  • ZURAMPIC should be discontinued when eCLcr is persistently <45 mL/min
<30 mL/min ZURAMPIC is contraindicated.
Incidence of renal-related adverse reactions by baseline renal function category in placebo-controlled clinical studies with ZURAMPIC in combination with an XOI (allopurinol or febuxostat)
n (%) Placebo + XOI ZURAMPIC 200 mg + XOI
60 - <90 mL/min n=229 n=208
Blood creatinine increased 4 (1.7%) 8 (3.8%)
Renal failure* 4 (1.7%) 1 (0.5%)
30 - <60 mL/min n=101 n=101
Blood creatinine increased 6 (5.9%) 7 (6.9%)
Renal failure* 5 (5.0%) 2 (2.0%)

*Renal failure includes the following adverse reactions: renal failure, renal impairment, renal failure chronic, renal failure acute, acute prerenal failure.

  • There were limited data in patients with eCLcr ≤45 mL/min and a trend toward decreasing magnitudes of effect in this population
  • ZURAMPIC was contraindicated in patients with severe renal impairment (CLcr <30 mL/min), end-stage renal disease, kidney transplant recipients, or patients on dialysis

Clinical Trial Design1,2

CLEAR 1 (N=402: 201 in the ZURAMPIC 200 mg in combination with allopurinol group and 201 in the allopurinol-alone group) and CLEAR 2 (N=410: 204 in the ZURAMPIC 200 mg in combination with allopurinol group and 206 in the allopurinol-alone group) are phase III, randomized, double-blind, multicenter, placebo-controlled, clinical studies to evaluate the efficacy and safety of ZURAMPIC and allopurinol compared with allopurinol alone in adult subjects with hyperuricemia and gout. The primary endpoint for both studies was to determine the proportion of subjects with an sUA level that is <6.0 mg/dL by Month 6.

Two phase III, randomized, double-blind, multicenter, placebo-controlled clinical trials of ZURAMPIC in combination with allopurinol in adult patients with gout

ZURAMPIC Efficacy Study Design

Key inclusion criteria

  • Stable dose of allopurinol, 300 mg to 900 mg (200 mg for renal impairment) for at least 8 weeks prior to screening
  • sUA ≥6.5 mg/dL at screening and ≥6 mg/dL at Day 7 visit
  • Reported at least 2 gout flares in the prior 12 months

Key exclusion criteria

  • Experiencing an acute gout flare that has not resolved at least 7 days before baseline visit
  • Taking any other ULT approved for the treatment of gout besides allopurinol
  • Known hypersensitivity or allergy to allopurinol
  • Estimated creatinine clearance <30 mL/min

At baseline

  • 62% of patients across ZURAMPIC clinical trials had mild or moderate renal impairment
  • 12% of patients in the clinical trials had a history of kidney stones
  • 79% of patients had at least 1 comorbid condition, including hypertension (65%), hyperlipidemia (45%), and diabetes (17%)

ZURAMPIC causes an increase in renal UA excretion, which may lead to renal events including transient increases in serum creatinine, renal-related adverse reactions, and kidney stones. In patients treated with ZURAMPIC 400 mg in combination with an XOI (allopurinol or febuxostat), these renal events occurred more frequently compared with ZURAMPIC 200 mg in combination with an XOI or an XOI alone.

Patients with elevated serum creatinine values in the placebo-controlled clinical studies with ZURAMPIC in combination with an XOI
Placebo + XOI(N=516) ZURAMPIC 200 mg + XOI(N=511)
Serum creatinine elevation 1.5 x to < 2.0 x baseline 12 (2.3%) 20 (3.9%)
Resolution of serum creatinine elevations by end of study 9/12 (75.0%) 18/20 (90.0%)
Serum creatinine elevation ≥ 2.0 x baseline 0 9 (1.8%)
Resolution of serum creatinine elevations by end of study N/A 8/9 (88.9%)
Incidence of renal-related adverse reactions and nephrolithiasis in placebo-controlled clinical studies with ZURAMPIC in combination with an XOI
Placebo + XOI(N=516) ZURAMPIC 200 mg + XOI(N=511)
Blood creatinine increased 2.3% 4.3%
Renal failure* 2.1% 1.2%
Nephrolithiasis (kidney stones) 1.7% 0.6%

*Renal failure includes the following adverse reactions: renal failure, renal impairment, renal failure chronic, renal failure acute, acute prerenal failure.

  • Renal-related adverse reactions resulted in a similar discontinuation rate on ZURAMPIC 200 mg in combination with an XOI (1.2%) and an XOI alone (1%), and a higher rate on ZURAMPIC 400 mg in combination with an XOI (3.3%)
  • Serious renal-related adverse reactions were reported in patients on ZURAMPIC 400 mg in combination with an XOI (1%) and an XOI alone (0.4%), and in no patients on ZURAMPIC 200 mg in combination with an XOI during the 12-month controlled period of the studies
  • Serious renal-related adverse reactions were reported with ZURAMPIC 200 mg and ZURAMPIC 400 mg in the uncontrolled long-term extensions

Data in patients with renal impairment

The efficacy and safety of ZURAMPIC were evaluated in studies that included gout patients with mild and moderate renal impairment. 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. There was limited data in patients to eCLcr less than 45 mL/min and there was a trend toward decreasing magnitudes of effect with decreasing renal function.

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.

Clinical Trial Design1,2

CLEAR 1 (N=402: 201 in the ZURAMPIC 200 mg in combination with allopurinol group and 201 in the allopurinol-alone group) and CLEAR 2 (N=410: 204 in the ZURAMPIC 200 mg in combination with allopurinol group and 206 in the allopurinol-alone group) are phase III, randomized, double-blind, multicenter, placebo-controlled, clinical studies to evaluate the efficacy and safety of ZURAMPIC and allopurinol compared with allopurinol alone in adult subjects with hyperuricemia and gout. The primary endpoint for both studies was to determine the proportion of subjects with an sUA level that is <6.0 mg/dL by Month 6.

Two phase III, randomized, double-blind, multicenter, placebo-controlled clinical trials of ZURAMPIC in combination with allopurinol in adult patients with gout

ZURAMPIC Efficacy Study Design

Key inclusion criteria

  • Stable dose of allopurinol, 300 mg to 900 mg (200 mg for renal impairment) for at least 8 weeks prior to screening
  • sUA ≥6.5 mg/dL at screening and ≥6 mg/dL at Day 7 visit
  • Reported at least 2 gout flares in the prior 12 months

Key exclusion criteria

  • Experiencing an acute gout flare that has not resolved at least 7 days before baseline visit
  • Taking any other ULT approved for the treatment of gout besides allopurinol
  • Known hypersensitivity or allergy to allopurinol
  • Estimated creatinine clearance <30 mL/min

At baseline

  • 62% of patients across ZURAMPIC clinical trials had mild or moderate renal impairment
  • 12% of patients in the clinical trials had a history of kidney stones
  • 79% of patients had at least 1 comorbid condition, including hypertension (65%), hyperlipidemia (45%), and diabetes (17%)

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

 

Limitations of Use for ZURAMPIC:

  • ZURAMPIC is not recommended for the treatment of asymptomatic hyperuricemia
  • ZURAMPIC should not be used as monotherapy

IMPORTANT SAFETY INFORMATION ABOUT ZURAMPIC

WARNING: RISK OF ACUTE RENAL FAILURE, MORE COMMON WHEN USED WITHOUT A XANTHINE OXIDASE INHIBITOR (XOI)

  • Acute renal failure has occurred with ZURAMPIC and was more common when ZURAMPIC was given alone
  • ZURAMPIC should be used in combination with an XOI

Contraindications:

  • Severe renal impairment (eCLcr less than 30 mL/min), end-stage renal disease, kidney transplant recipients, or patients on dialysis
  • Tumor lysis syndrome or Lesch-Nyhan syndrome

Warnings and Precautions:

  • Renal events: Adverse reactions related to renal function have occurred after initiating ZURAMPIC. A higher incidence was observed at the 400-mg dose, with the highest incidence occurring with monotherapy use. Monitor renal function at initiation and during therapy with ZURAMPIC, particularly in patients with eCLcr below 60 mL/min or with serum creatinine elevations 1.5 to 2 times the pre-treatment value, and evaluate for signs and symptoms of acute uric acid nephropathy. Interrupt treatment with ZURAMPIC if serum creatinine is elevated to greater than 2 times the pre-treatment value or if there are symptoms that may indicate acute uric acid nephropathy. ZURAMPIC should not be restarted without another explanation for the serum creatinine abnormalities. ZURAMPIC should not be initiated in patients with an eCLcr less than 45 mL/min
  • 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. A causal relationship has not been established.

Adverse Reactions:

  • Most common adverse reactions with ZURAMPIC (in combination with an XOI and more frequently than on an XOI alone) were headache, influenza, blood creatinine increased, and gastroesophageal reflux disease

Indication and Limitations of Use for ZURAMPIC:

ZURAMPIC is a URAT1 inhibitor indicated in combination with an XOI for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with an XOI alone.

  • ZURAMPIC is not recommended for the treatment of asymptomatic hyperuricemia
  • ZURAMPIC should not be used as monotherapy

Please see full Prescribing Information, including Boxed WARNING and Medication Guide.

Open/Close

Limitations of Use for ZURAMPIC:

  • ZURAMPIC is not recommended for the treatment of asymptomatic hyperuricemia
  • ZURAMPIC should not be used as monotherapy

IMPORTANT SAFETY INFORMATION ABOUT ZURAMPIC

WARNING: RISK OF ACUTE RENAL FAILURE, MORE COMMON WHEN USED WITHOUT A XANTHINE OXIDASE INHIBITOR (XOI)

  • Acute renal failure has occurred with ZURAMPIC and was more common when ZURAMPIC was given alone
  • ZURAMPIC should be used in combination with an XOI

Contraindications:

  • Severe renal impairment (eCLcr less than 30 mL/min), end-stage renal disease, kidney transplant recipients, or patients on dialysis
  • Tumor lysis syndrome or Lesch-Nyhan syndrome

Warnings and Precautions:

  • Renal events: Adverse reactions related to renal function have occurred after initiating ZURAMPIC. A higher incidence was observed at the 400-mg dose, with the highest incidence occurring with monotherapy use. Monitor renal function at initiation and during therapy with ZURAMPIC, particularly in patients with eCLcr below 60 mL/min or with serum creatinine elevations 1.5 to 2 times the pre-treatment value, and evaluate for signs and symptoms of acute uric acid nephropathy. Interrupt treatment with ZURAMPIC if serum creatinine is elevated to greater than 2 times the pre-treatment value or if there are symptoms that may indicate acute uric acid nephropathy. ZURAMPIC should not be restarted without another explanation for the serum creatinine abnormalities. ZURAMPIC should not be initiated in patients with an eCLcr less than 45 mL/min
  • 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. A causal relationship has not been established.

Adverse Reactions:

  • Most common adverse reactions with ZURAMPIC (in combination with an XOI and more frequently than on an XOI alone) were headache, influenza, blood creatinine increased, and gastroesophageal reflux disease

Indication and Limitations of Use for ZURAMPIC:

ZURAMPIC is a URAT1 inhibitor indicated in combination with an XOI for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with an XOI alone.

  • ZURAMPIC is not recommended for the treatment of asymptomatic hyperuricemia
  • ZURAMPIC should not be used as monotherapy

Please see full Prescribing Information, including Boxed WARNING and Medication Guide.

CLOSE