WARNING: RISK OF ACUTE RENAL FAILURE, MORE COMMON WHEN USED WITHOUT A XANTHINE OXIDASE INHIBITOR Acute renal failure has occurred with ZURAMPIC and was more common when ZURAMPIC was given alone. ZURAMPIC should be used in combination with a xanthine oxidase inhibitor [ see Limitations of Use (1.1) , Warnings and Precautions (5.1) , Adverse Reactions (6.1) ]. WARNING: RISK OF ACUTE RENAL FAILURE, MORE COMMON WHEN USED WITHOUT A XANTHINE OXIDASE INHIBITOR See full prescribing information for complete boxed warning. Acute renal failure has occurred with ZURAMPIC and was more common when ZURAMPIC was given alone. ZURAMPIC should be used in combination with a xanthine oxidase inhibitor. ( 1.1 , 5.1 , 6.1 )
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warnings and cautions
5 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, and evaluate for signs and symptoms of acute uric acid nephropathy. ( 5.1 ) Cardiovascular events: Major adverse cardiovascular events were observed with ZURAMPIC; a causal relationship has not been established. ( 5.2 ) 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 ADVERSE REACTIONS The following adverse reactions are also discussed in other sections: Renal Events [ see Warnings and Precautions (5.1) ] Cardiovascular Events [ see Warnings and Precautions (5.2) ] Most common adverse reactions in 12-month controlled clinical trials (occurring in greater than or equal to 2% of patients treated with ZURAMPIC in combination with a xanthine oxidase inhibitor and more frequently than on a xanthine oxidase inhibitor alone) were headache, influenza, blood creatinine increased, and gastroesophageal reflux disease. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ironwood Pharmaceuticals, Inc. at 1-844-374-4793 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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%). Renal Events ZURAMPIC causes an increase in renal uric acid excretion, which may lead to renal events including transient increases in serum creatinine, renal-related adverse reactions, and kidney stones. These renal events occurred more frequently in patients receiving ZURAMPIC 400 mg, when used as monotherapy or in combination with a xanthine oxidase inhibitor [ see Warnings and Precautions (5.1) ]. The number of patients with serum creatinine elevations in the 12-month placebo-controlled trials in combination with a xanthine oxidase inhibitor are shown in Table 1. Most of these elevations on ZURAMPIC 200 mg and ZURAMPIC 400 mg resolved without treatment interruption (Table 1). Table 1: Patients with Elevated Serum Creatinine Values in the Placebo-Controlled Clinical Studies with ZURAMPIC in Combination with a Xanthine Oxidase Inhibitor (XOI) [n (%)] Placebo+XOI (N=516) ZURAMPIC 200 mg + XOI (N=511) ZURAMPIC 400 mg + XOI (N=510) Serum creatinine elevation 1.5 × to < 2.0 × baseline 12 (2.3%) 20 (3.9%) 51 (10.0%) Resolution of serum creatinine elevations by end of study 9/12 (75.0%) 18/20 (90.0%) 42/51 (82.4%) Serum creatinine elevation ≥ 2.0 × baseline 0 9 (1.8%) 34 (6.7%) Resolution of serum creatinine elevations by end of study N/A 8/9 (88.9%) 26/34 (76.5%) Renal-related adverse reactions, including blood creatinine increases and renal failure, and nephrolithiasis reported in patients receiving ZURAMPIC 200 mg, ZURAMPIC 400 mg and placebo in combination with a xanthine oxidase inhibitor are shown in Table 2 [ see Warnings and Precautions (5.1) ]. The incidence of reports of "blood creatinine increased" was higher with ZURAMPIC and was highest with ZURAMPIC 400 mg. Renal-related adverse reactions by baseline renal function category are shown in Table 3 [ see Warnings and Precautions (5.1) ]. Blood creatinine increased occurred more frequently in patients treated with ZURAMPIC in combination with a xanthine oxidase inhibitor across baseline renal function categories (Table 3). Table 2: Incidence of Renal-Related Adverse Reactions and Nephrolithiasis in Placebo-Controlled Clinical Studies with ZURAMPIC in Combination with a Xanthine Oxidase Inhibitor (XOI) [n (%)] Placebo + XOI (N=516) ZURAMPIC 200 mg + XOI (N=511) ZURAMPIC 400 mg + XOI (N=510) Blood creatinine increased 12 (2.3%) 22 (4.3%) 40 (7.8%) Renal failure Renal failure includes the following adverse reactions: renal failure, renal impairment, renal failure chronic, renal failure acute, acute prerenal failure. 11 (2.1%) 6 (1.2%) 18 (3.5%) Nephrolithiasis 9 (1.7%) 3 (0.6%) 13 (2.5%) Table 3: Incidence of Renal-Related Adverse Reactions by Baseline Renal Function Category in Placebo-Controlled Clinical Studies with ZURAMPIC in Combination with a Xanthine Oxidase Inhibitor (XOI) n (%) Placebo + XOI ZURAMPIC 200 mg + XOI ZURAMPIC 400 mg + XOI ≥ 90 mL/min n=180 n=200 n=203 Blood creatinine increased 1 (0.6%) 6 (3.0%) 12 (5.9%) Renal failure Renal failure includes the following adverse reactions: renal failure, renal impairment, renal failure chronic, renal failure acute, acute prerenal failure. 0 3 (1.5%) 7 (3.4%) ≥ 60 - < 90 mL/min n=229 n=208 n=213 Blood creatinine increased 4 (1.7%) 8 (3.8%) 21 (9.9%) Renal failure 4 (1.7%) 1 (0.5%) 7 (3.3%) ≥ 30 - < 60 mL/min n=101 n=101 n=92 Blood creatinine increased 6 (5.9%) 7 (6.9%) 10 (10.9%) Renal failure 5 (5.0%) 2 (2.0%) 4 (4.3%) Renal-related adverse reactions resulted in a similar discontinuation rate on ZURAMPIC 200 mg in combination with a xanthine oxidase inhibitor (1.2%) and a xanthine oxidase inhibitor alone (1%) and a higher rate on ZURAMPIC 400 mg in combination with a xanthine oxidase inhibitor (3.3%). Serious renal-related adverse reactions were reported in patients on ZURAMPIC 400 mg in combination with a xanthine oxidase inhibitor (1%) and a xanthine oxidase inhibitor alone (0.4%) and in no patients on ZURAMPIC 200 mg in combination with a xanthine oxidase inhibitor 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. Monotherapy : In a 6-month double-blind, placebo-controlled monotherapy study, renal failure (9.3%), blood creatinine increased (8.4%), and nephrolithiasis (0.9%) were reported in patients receiving ZURAMPIC 400 mg alone and in no patients receiving placebo [ see Warnings and Precautions (5.1) and Dosage and Administration (2.1) ]. Serum creatinine elevations 1.5-fold or greater occurred in 24.3 % of patients receiving ZURAMPIC 400 mg and in no patients receiving placebo. Cardiovascular Safety Cardiovascular events and deaths were adjudicated as Major Adverse Cardiovascular Events (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in the Phase 3 randomized controlled studies of ZURAMPIC. In the randomized controlled studies, the numbers of patients with adjudicated MACE (incidences per 100 patient-years of exposure) were: 3 (0.71) for placebo, 4 (0.96) for ZURAMPIC 200 mg, and 8 (1.94) for ZURAMPIC 400 mg when used in combination with a xanthine oxidase inhibitor. Incidence rate ratios for ZURAMPIC 200 mg and 400 mg compared with placebo were 1.36 (95% CI: 0.23, 9.25) and 2.71 (95% CI: 0.66, 16.00), respectively. Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on ZURAMPIC 200 mg in combination with a xanthine oxidase inhibitor and at least 1% greater than that observed in patients on placebo with a xanthine oxidase inhibitor are summarized in Table 4. Table 4: Adverse Reactions Occurring in ≥ 2% of ZURAMPIC 200 mg-Treated Patients and at Least 1% Greater than Seen in Patients Receiving Placebo in Controlled Studies with ZURAMPIC in Combination with a Xanthine Oxidase Inhibitor (XOI) Adverse Reaction Placebo + XOI (N=516) ZURAMPIC 200 mg + XOI (N=511) Headache 4.1% 5.3% Influenza 2.7% 5.1% Gastroesophageal reflux disease 0.8% 2.7%