FDA label cb69308c-9652-4f7d-ad7a-6e84f48b5809

WARNING: RISK OF ACUTE RENAL FAILURE Acute renal failure has occurred with lesinurad, one of the components of DUZALLO. [see Warning and Precautions (5.1) , Adverse Reactions (6.1) ] WARNING: RISK OF ACUTE RENAL FAILURE See full prescribing information for complete boxed warning Acute renal failure has occurred with lesinurad, one of the components of DUZALLO. ( 5.1 , 6.1 )

5 WARNINGS AND PRECAUTIONS Renal events : Adverse reactions related to renal function, including acute renal failure, have occurred after initiating lesinurad, one of the components of DUZALLO. A higher incidence has occurred at the 400 mg dose of lesinurad than at the 200 mg dose. Monitor renal function at initiation and during therapy with DUZALLO, particularly in patients with eCLcr below 60 mL/min, and evaluate for signs and symptoms of acute uric acid nephropathy. ( 5.1 ) Skin Rash and Hypersensitivity : DUZALLO, should be discontinued at the first appearance of skin rash or other signs that may indicate an allergic reaction, as allopurinol has been associated with severe hypersensitivity (some resulting in death). ( 5.2 ) Hepatotoxicity: Hepatotoxicity has been reported in patients on allopurinol. Inform patients of warning signs and symptoms of hepatotoxicity. If symptoms develop, liver function evaluation should be performed. ( 5.3 ) Cardiovascular events: Major adverse cardiovascular events were observed with lesinurad; a causal relationship has not been established. ( 5.4 ) Bone Marrow Suppression: Bone marrow depression affecting one or more cell lines has been reported with allopurinol. ( 5.5 ) 5.1 Renal Events Adverse reactions related to renal function, including acute renal failure, can occur after initiating DUZALLO. Treatment with lesinurad 200 mg in combination with allopurinol was associated with an increased incidence of serum creatinine elevations, most of which were reversible [see Adverse Reactions (6.1) ]. A higher incidence of serum creatinine elevations and renal-related adverse reactions, including serious adverse reactions of acute renal failure, were observed with lesinurad 400 mg in combination with allopurinol, with the highest incidence when lesinurad was given alone. DUZALLO treatment should be interrupted if serum creatinine is elevated to greater than 2 times the value when lesinurad treatment was initiated. 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. DUZALLO should not be restarted without another explanation for the serum creatinine abnormalities. DUZALLO should not be initiated in patients with an eCLcr less than 45 mL/min. Renal function should be evaluated prior to initiation of DUZALLO 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 value when lesinurad treatment was initiated. Some patients with pre-existing renal disease or poor urate clearance have shown a rise in BUN during administration of allopurinol. 5.2 Skin Rash and Hypersensitivity Skin rash is a frequently reported adverse event in patients taking allopurinol [see Adverse Reactions (6.2) ]. In some instances, a skin rash may be followed by more severe hypersensitivity reactions associated with exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia including Stevens-Johnson syndrome and toxic epidermal necrolysis. Associated vasculitis and tissue response may be manifested in various ways including hepatitis, renal impairment, seizures, and on rare occasions, death. The HLA-B*5801 allele is a genetic risk marker for severe skin reactions indicative of hypersensitivity to allopurinol. DUZALLO should be discontinued immediately at the first appearance of skin rash or other signs which may indicate an allergic reaction, and additional medical care should be provided as needed. Hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function receiving thiazide diuretics and DUZALLO concurrently. For this reason, in this clinical setting, such combinations should be administered with caution and patients should be observed closely. 5.3 Hepatotoxicity A few cases of reversible clinical hepatotoxicity have been reported in patients taking allopurinol, and in some patients, asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed. If anorexia, weight loss, or pruritus develops in patients on DUZALLO, evaluation of liver function should be performed. In patients with pre-existing liver disease, periodic liver function tests are recommended. 5.4 Cardiovascular Events In clinical trials with lesinurad and allopurinol, major adverse cardiovascular events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) were observed [see Adverse Reactions (6.1) ]. A causal relationship has not been established. 5.5 Bone Marrow Depression Bone marrow depression has been reported in patients receiving allopurinol, most of whom received concomitant drugs with the potential for causing this reaction. This has occurred as early as six weeks to as long as six years after the initiation of allopurinol therapy. Rarely a patient may develop varying degrees of bone marrow depression, affecting one or more cell lines, while receiving allopurinol alone. Patients taking allopurinol and mercaptopurine or azathioprine require a reduction in dose to approximately one-third to one-fourth of the usual dose of mercaptopurine or azathioprine. Subsequent adjustment of doses of mercaptopurine or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects. Patients should be closely monitored for therapeutic response and the appearance of toxicity [see Drug Interaction (7.2) ]. 5.6 Increase in Prothrombin Time It has been reported that allopurinol prolongs the half-life of dicumarol, a coumarin anticoagulant. The prothrombin time should be reassessed periodically in patients receiving coumarin anticoagulants (dicumarol, warfarin) concomitantly with DUZALLO [see Drug Interaction (7.2) ]. 5.7 Drowsiness Occasional occurrence of drowsiness was reported in patients taking allopurinol. Patients should be alerted to the need for due caution when engaging in activities where alertness is mandatory [see Patient Counseling Information (17) ].

6 ADVERSE REACTIONS The following adverse reactions are also discussed in other sections: Renal Events [see Boxed Warning and Warnings and Precautions (5.1) ]. Skin Rash and Hypersensitivity [see Warnings and Precautions (5.2) ]. Hepatotoxicity [see Warnings and Precautions (5.3) ]. Cardiovascular Events [see Warnings and Precautions (5.4) ]. Bone Marrow Depression [see Warnings and Precautions (5.5) ]. Drowsiness [see Warnings and Precautions (5.7) ]. Most common adverse reactions in 12-month controlled clinical trials (occurring in greater than or equal to 2% of patients treated with lesinurad in combination with a xanthine oxidase inhibitor and more frequently than on xanthine oxidase inhibitor alone) were headache, influenza, blood creatinine increased, and gastroesophageal reflux disease. ( 6.1 ) The most frequently reported adverse reaction for allopurinol is skin rash. ( 6.2 ) 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. Lesinurad in Combination With Allopurinol In 2 randomized, placebo-controlled studies (Studies 1 and 2), a total of 405, 401, and 407 patients with gout were treated with lesinurad 200 mg, lesinurad 400 mg, or placebo, respectively, once daily in combination with allopurinol (200 mg to 900 mg daily) for up to 12 months. The majority of patients in these studies received allopurinol daily doses of 200 mg or 300 mg (average dose of allopurinol in the studies was 310 mg), corresponding to the allopurinol doses contained in DUZALLO. The median duration of treatment with lesinurad in combination with allopurinol was 11.2 months. The mean age of the population was 52 years (range 18-82), and 95% were males. At baseline, 61% of the patient population showed mild or moderate renal impairment (eCLcr less than 90 mL/min) and 81% of patients had at least one co-morbid condition including hypertension (66%), hyperlipidemia (46%), diabetes (17%), and kidney stones (12%). Renal Events Lesinurad 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 lesinurad 400 mg than in patients receiving 200 mg [see Warnings and Precautions (5.1) ]. The number of patients with serum creatinine elevations in the 12-month placebo-controlled trials in combination with allopurinol is shown in Table 1. Most of these elevations on lesinurad 200 mg in combination with allopurinol and lesinurad 400 mg in combination with allopurinol resolved without treatment interruption (Table 1). Table 1: Patients With Elevated Serum Creatinine Values in the Placebo-Controlled Clinical Studies With Lesinurad in Combination With Allopurinol [n (%)] Placebo + Allopurinol (N=407) Lesinurad 200 mg + Allopurinol (N=405) Lesinurad 400 mg + Allopurinol (N=401) Serum creatinine elevation 1.5 × to < 2.0 × baseline 9 (2.2%) 18 (4.4%) 44 (11.0%) Resolution of serum creatinine elevations by end of study 6/9 (66.7%) 16/18 (88.9%) 35/44 (79.5%) Serum creatinine elevation ≥ 2.0 × baseline 0 6 (1.5%) 28 (7.0%) Resolution of serum creatinine elevations by end of study N/A 6/6 (100.0%) 21/28 (75.0%) Renal-related adverse reactions, including blood creatinine increased and renal failure, and nephrolithiasis reported in patients receiving lesinurad 200 mg, lesinurad 400 mg, and placebo in combination with allopurinol are shown in Table 2 [see Warnings and Precautions (5.1) ]. The incidence of reports of "blood creatinine increased" was higher with lesinurad in combination with allopurinol and was highest with lesinurad 400 mg in combination with allopurinol. 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 lesinurad 400 mg in combination with allopurinol across baseline renal function categories (Table 3). Table 2: Incidence of Renal-Related Adverse Reactions and Nephrolithiasis in Placebo-Controlled Clinical Studies With Lesinurad in Combination With Allopurinol [n (%)] Placebo + Allopurinol (N=407) Lesinurad 200 mg + Allopurinol (N=405) Lesinurad 400 mg + Allopurinol (N=401) Blood creatinine increased 9 (2.2%) 15 (3.7%) 32 (8.0%) Renal failure Renal failure includes the following adverse reactions: renal failure, renal impairment, renal failure chronic, renal failure acute, acute prerenal failure. 7 (1.7%) 4 (1.0%) 14 (3.5%) Nephrolithiasis 5 (1.2%) 2 (0.5%) 9 (2.2%) Table 3: Incidence of Renal-Related Adverse Reactions by Baseline Renal Function Category in Placebo-Controlled Clinical Studies With Lesinurad in Combination With Allopurinol n (%) Placebo + Allopurinol Lesinurad 200 mg + Allopurinol Lesinurad 400 mg + Allopurinol ≥ 90 mL/min n=149 n=163 n=161 Blood creatinine increased 0 5 (3.1%) 6 (3.7%) Renal failure Renal failure includes the following adverse reactions: renal failure, renal impairment, renal failure chronic, renal failure acute, acute prerenal failure. 0 2 (1.2%) 6 (3.7%) ≥ 60 - < 90 mL/min n=176 n=167 n=168 Blood creatinine increased 3 (1.7%) 5 (3.0%) 17 (10.1%) Renal failure 4 (2.3%) 1 (0.6%) 6 (3.6%) ≥ 30 - < 60 mL/min n=78 n=73 n=70 Blood creatinine increased 6 (7.7%) 4 (5.5%) 8 (11.4%) Renal failure 3 (3.8%) 1 (1.4%) 2 (2.9%) Renal-related adverse reactions resulted in a similar discontinuation rate on lesinurad 200 mg in combination with allopurinol (1.0%) and allopurinol alone (1.0%) and a higher rate on lesinurad 400 mg in combination with allopurinol (3.2%). Serious renal-related adverse reactions were reported in patients on lesinurad 400 mg in combination with allopurinol (0.7%) and allopurinol alone (0.2%) and in no patients on lesinurad 200 mg in combination with allopurinol during the 12-month controlled period of the studies. Serious renal-related adverse reactions were reported with lesinurad 200 mg and lesinurad 400 mg in combination with allopurinol in the uncontrolled long-term extensions [see Warnings and Precautions (5.1) ]. 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 lesinurad in combination with allopurinol. In the randomized controlled studies, the numbers of patients with adjudicated MACE (incidences per 100 patient-years of exposure) were: 2 (0.60) for placebo, 2 (0.61) for lesinurad 200 mg, and 6 (1.85) for lesinurad 400 mg when used in combination with allopurinol. Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on lesinurad in combination with a xanthine oxidase inhibitor and at least 1% greater than that observed in patients on placebo with a xanthine oxidase inhibitor were identified in the lesinurad development program. The incidence of these adverse reactions in controlled studies with lesinurad 200 mg in combination with allopurinol is summarized in Table 4. Table 4: Incidence in Controlled Studies With Lesinurad in Combination With Allopurinol of Adverse Reactions Identified in the Lesinurad Development Program Adverse Reaction Placebo + Allopurinol (N=407) Lesinurad 200 mg + Allopurinol (N=405) Headache 3.2% 4.2% Influenza 2.9% 4.9% Gastroesophageal reflux disease 0.5% 3.2% 6.2 Postmarketing Experience Allopurinol The following adverse reactions have been identified during post-approval use of allopurinol. 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 to drug exposure. The most frequent adverse reaction to allopurinol is skin rash [see Warnings and Precautions (5.2) ]. Most Common Adverse Reactions Gastrointestinal disorders: diarrhea, nausea Investigations: blood alkaline phosphatase increased, aspartate aminotransferase increased, alanine aminotransferase increased Skin and subcutaneous tissue disorders: rash, rash maculo-papular Less Common (<1%) Adverse Reactions Blood and lymphatic system disorders: ecchymosis, thrombocytopenia, eosinophilia, leukocytosis, leukopenia Gastrointestinal disorders: vomiting, abdominal pain, gastritis, dyspepsia General disorders and administration site conditions: pyrexia Hepatobiliary disorders: hepatitis (including hepatic necrosis and granulomatous hepatitis), hepatomegaly, hyperbilirubinemia, cholestatic jaundice Musculoskeletal and connective tissue disorders: myopathy, arthralgia Nervous system disorders: headache, peripheral neuropathy, neuritis, paresthesia, somnolence, ageusia (taste loss) Renal and urinary disorders: renal failure, azotemia Respiratory, thoracic and mediastinal disorders: epistaxis Skin and subcutaneous tissue disorders: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, leukocytoclastic vasculitis, purpura, bullous dermatitis, exfoliative dermatitis, eczema, pruritus, urticaria, alopecia, onycholysis, lichen planus Vascular disorders: vasculitis necrotizing, vasculitis Other Uncommon (<1%) Adverse Events Blood and lymphatic system disorders: aplastic anemia, agranulocytosis, pancytopenia, anemia, hemolytic anemia, reticulocytosis, lymphadenopathy, lymphocytosis Cardiac disorders: pericarditis, bradycardia Endocrine disorders: hypercalcemia, gynecomastia Eye disorders: cataract, retinitis, iritis, conjunctivitis, amblyopia Gastrointestinal disorders: hemorrhagic pancreatitis, gastrointestinal hemorrhage, stomatitis, salivary gland enlargement, tongue edema General disorders and administration site conditions: malaise, asthenia, hyperhidrosis Infections and infestations: pharyngitis, rhinitis Investigations: prothrombin level decreased Metabolism and nutrition disorders: hyperlipidemia, decreased appetite Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: optic neuritis, confusional state, dizziness, vertigo, peroneal nerve palsy, amnesia, tinnitus, insomnia Psychiatric disorders: libido decreased, depression, erectile dysfunction Renal and urinary disorders: nephritis, hematuria, albuminuria Reproductive system and breast disorders: infertility male Respiratory, thoracic and mediastinal disorders: bronchospasm, asthma Skin and subcutaneous tissue disorders: furuncle, face edema, skin edema Vascular disorders: peripheral vascular disorder, thrombophlebitis, vasodilatation

<table width="90%"> <caption>Table 1: Patients With Elevated Serum Creatinine Values in the Placebo-Controlled Clinical Studies With Lesinurad in Combination With Allopurinol</caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr> <th styleCode="Lrule Rrule" align="center">[n (%)]</th> <th styleCode="Rrule">Placebo + Allopurinol (N=407)</th> <th styleCode="Rrule">Lesinurad 200 mg + Allopurinol (N=405)</th> <th styleCode="Rrule">Lesinurad 400 mg + Allopurinol (N=401)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Serum creatinine elevation 1.5 &#xD7; to &lt; 2.0 &#xD7; baseline</td> <td styleCode="Rrule">9 (2.2%)</td> <td styleCode="Rrule">18 (4.4%)</td> <td styleCode="Rrule">44 (11.0%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Resolution of serum creatinine elevations by end of study</td> <td styleCode="Rrule">6/9 (66.7%)</td> <td styleCode="Rrule">16/18 (88.9%)</td> <td styleCode="Rrule">35/44 (79.5%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Serum creatinine elevation &#x2265; 2.0 &#xD7; baseline</td> <td styleCode="Rrule">0</td> <td styleCode="Rrule">6 (1.5%)</td> <td styleCode="Rrule">28 (7.0%)</td> </tr> <tr> <td styleCode="Lrule Rrule"> Resolution of serum creatinine elevations by end of study</td> <td styleCode="Rrule">N/A</td> <td styleCode="Rrule">6/6 (100.0%)</td> <td styleCode="Rrule">21/28 (75.0%)</td> </tr> </tbody> </table>

<table width="90%"> <caption>Table 2: Incidence of Renal-Related Adverse Reactions and Nephrolithiasis in Placebo-Controlled Clinical Studies With Lesinurad in Combination With Allopurinol</caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr> <th styleCode="Lrule Rrule" align="center">[n (%)]</th> <th styleCode="Rrule">Placebo + Allopurinol (N=407)</th> <th styleCode="Rrule">Lesinurad 200 mg + Allopurinol (N=405)</th> <th styleCode="Rrule">Lesinurad 400 mg + Allopurinol (N=401)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Blood creatinine increased</td> <td styleCode="Rrule">9 (2.2%)</td> <td styleCode="Rrule">15 (3.7%)</td> <td styleCode="Rrule">32 (8.0%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Renal failure<footnote>Renal failure includes the following adverse reactions: renal failure, renal impairment, renal failure chronic, renal failure acute, acute prerenal failure.</footnote> </td> <td styleCode="Rrule">7 (1.7%)</td> <td styleCode="Rrule">4 (1.0%)</td> <td styleCode="Rrule">14 (3.5%)</td> </tr> <tr> <td styleCode="Lrule Rrule">Nephrolithiasis</td> <td styleCode="Rrule">5 (1.2%)</td> <td styleCode="Rrule">2 (0.5%)</td> <td styleCode="Rrule">9 (2.2%)</td> </tr> </tbody> </table>

<table width="90%"> <caption>Table 3: Incidence of Renal-Related Adverse Reactions by Baseline Renal Function Category in Placebo-Controlled Clinical Studies With Lesinurad in Combination With Allopurinol</caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr styleCode="Botrule"> <th styleCode="Lrule Rrule" align="center">n (%)</th> <th styleCode="Rrule">Placebo + Allopurinol</th> <th styleCode="Rrule">Lesinurad 200 mg + Allopurinol</th> <th styleCode="Rrule">Lesinurad 400 mg + Allopurinol</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <th styleCode="Lrule Rrule"> <content styleCode="bold">&#x2265; 90 mL/min</content> </th> <th styleCode="Rrule"> <content styleCode="bold">n=149</content> </th> <th styleCode="Rrule"> <content styleCode="bold">n=163</content> </th> <th styleCode="Rrule"> <content styleCode="bold">n=161</content> </th> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Blood creatinine increased</td> <td styleCode="Rrule">0</td> <td styleCode="Rrule">5 (3.1%)</td> <td styleCode="Rrule">6 (3.7%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Renal failure<footnote ID="t3f1">Renal failure includes the following adverse reactions: renal failure, renal impairment, renal failure chronic, renal failure acute, acute prerenal failure.</footnote> </td> <td styleCode="Rrule">0</td> <td styleCode="Rrule">2 (1.2%)</td> <td styleCode="Rrule">6 (3.7%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">&#x2265; 60 - &lt; 90 mL/min</content> </td> <td styleCode="Rrule"> <content styleCode="bold">n=176</content> </td> <td styleCode="Rrule"> <content styleCode="bold">n=167</content> </td> <td styleCode="Rrule"> <content styleCode="bold">n=168</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Blood creatinine increased</td> <td styleCode="Rrule">3 (1.7%)</td> <td styleCode="Rrule">5 (3.0%)</td> <td styleCode="Rrule">17 (10.1%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Renal failure<footnoteRef IDREF="t3f1"/> </td> <td styleCode="Rrule">4 (2.3%)</td> <td styleCode="Rrule">1 (0.6%)</td> <td styleCode="Rrule">6 (3.6%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">&#x2265; 30 - &lt; 60 mL/min</content> </td> <td styleCode="Rrule"> <content styleCode="bold">n=78</content> </td> <td styleCode="Rrule"> <content styleCode="bold">n=73</content> </td> <td styleCode="Rrule"> <content styleCode="bold">n=70</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Blood creatinine increased</td> <td styleCode="Rrule">6 (7.7%)</td> <td styleCode="Rrule">4 (5.5%)</td> <td styleCode="Rrule">8 (11.4%)</td> </tr> <tr> <td styleCode="Lrule Rrule"> Renal failure<footnoteRef IDREF="t3f1"/> </td> <td styleCode="Rrule">3 (3.8%)</td> <td styleCode="Rrule">1 (1.4%)</td> <td styleCode="Rrule">2 (2.9%)</td> </tr> </tbody> </table>