Data from FDA - Curated by EPG Health - Last updated 29 August 2018

Indication(s)

1 INDICATIONS AND USAGE DUZALLO®, a combination of lesinurad, a uric acid transporter 1 (URAT1) inhibitor, and allopurinol, a xanthine oxidase inhibitor, is indicated for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a medically appropriate daily dose of allopurinol alone [see Clinical Studies (14) ]. DUZALLO, a combination of lesinurad, a URAT1 inhibitor, and allopurinol, a xanthine oxidase inhibitor, is indicated for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a medically appropriate daily dose of allopurinol alone. (1) Limitations of Use: DUZALLO is not recommended for the treatment of asymptomatic hyperuricemia. (1.1) 1.1 Limitations of Use DUZALLO is not recommended for the treatment of asymptomatic hyperuricemia.

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Advisory information

contraindications
4 CONTRAINDICATIONS The use of DUZALLO is contraindicated in the following conditions: Severe renal impairment (eCLcr less than 30 mL/min), end-stage renal disease, kidney transplant recipients, or patients on dialysis [see Use in Specific Populations (8.6) ]. Tumor lysis syndrome or Lesch-Nyhan syndrome [see Use in Specific Populations (8.8) ]. Known hypersensitivity to allopurinol, including previous occurrence of skin rash [see Warnings and Precautions (5.2) ]. Severe renal impairment, end-stage renal disease, kidney transplant recipients, or patients on dialysis (4, 8.6) Tumor lysis syndrome or Lesch-Nyhan syndrome (4) Known hypersensitivity to allopurinol, including previous occurrence of skin rash (5.2)
Adverse reactions
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 failureRenal 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 failureRenal 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

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION The recommended dose of DUZALLO is one 200 mg lesinurad/300 mg allopurinol tablet per day (or one 200 mg lesinurad/200 mg allopurinol tablet per day for patients with renal impairment (45 - < 60 mL/min eCLcr) on a medically appropriate dose of 200 mg allopurinol (2.2)). Use one tablet of DUZALLO in place of an equivalent portion of the total daily allopurinol dose. The total daily dose of allopurinol should be maintained at the time of initiating DUZALLO. (2.1) One tablet of DUZALLO contains the maximum daily lesinurad dose (200 mg). (2.1) Do not take more than 1 tablet of DUZALLO per day. (2.1) Do not combine DUZALLO with ZURAMPIC® (lesinurad). (2.1) Use of DUZALLO is not recommended for patients taking daily doses of allopurinol less than 300 mg (or less than 200 mg in patients with moderate renal impairment). (2.1) DUZALLO tablets should be taken in the morning with food and water. (2.1) Patients should be instructed to stay well hydrated. (2.1) Assess renal function before initiating DUZALLO. Do not initiate DUZALLO if eCLcr is below 45 mL/min. (2.2) Discontinue DUZALLO if eCLcr persistently falls below 45 mL/min. (2.2) 2.1 Recommended Dosing DUZALLO tablets are for oral use. DUZALLO should be taken once daily by mouth, in the morning with food and water. Patients should be instructed to stay well hydrated (e.g., 2 liters of liquid per day). One tablet of DUZALLO contains the maximum daily lesinurad dose (200 mg). Do not take more than 1 tablet of DUZALLO per day. Do not combine DUZALLO with ZURAMPIC® (lesinurad). Use of DUZALLO 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). Use one tablet of DUZALLO in place of an equivalent portion of the total daily allopurinol dose. The total daily dose of allopurinol should be maintained at the time of initiating DUZALLO. For patients who have not achieved target serum uric acid on a medically appropriate dose of allopurinol > 300 mg, DUZALLO may be initiated by using one tablet of DUZALLO in place of an equivalent portion of the total daily allopurinol dose. For patients who have not achieved target serum uric acid on a medically appropriate dose of allopurinol of 300 mg, DUZALLO may be initiated by using one tablet of DUZALLO 200 mg lesinurad /300 mg allopurinol daily in place of 300 mg of allopurinol. For patients who have not achieved target serum uric acid on a medically appropriate dose of allopurinol of 200 mg, DUZALLO may be initiated by using one tablet of DUZALLO 200 mg lesinurad /200 mg allopurinol daily in place of 200 mg of allopurinol. For patients currently on ZURAMPIC (lesinurad) in combination with allopurinol, DUZALLO may be initiated by using one tablet of DUZALLO in place of ZURAMPIC (lesinurad) and an equivalent portion of the daily allopurinol dose. 2.2 Patients With Renal Impairment Patients with decreased renal function require lower doses of allopurinol than those with normal renal function. No dose adjustment is needed for lesinurad in patients with mild or moderate renal impairment (eCLcr of 45 mL/min or greater). Assessment of renal function is recommended prior to initiation of DUZALLO and periodically thereafter [see Warnings and Precautions (5.1) ]. DUZALLO should not be initiated in patients with an eCLcr less than 45 mL/min. DUZALLO 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) ]. More frequent renal function monitoring is recommended in patients with an eCLcr below 60 mL/min. 2.3 Gout Flares Gout flares may occur after initiation of urate-lowering therapy, including DUZALLO, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. For patients not currently taking lesinurad, gout flare prophylaxis is recommended when starting DUZALLO, according to practice guidelines. If a gout flare occurs during DUZALLO treatment, DUZALLO need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient [see Patient Counseling Information (17) ].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Renal impairment: Not recommended for patients with eCLcr below 45 mL/min. (2.2, 5.1, 8.6) Hepatic impairment: Not recommended for patients with severe hepatic impairment. (8.7) 8.1 Pregnancy Risk Summary There are no available human data on use of DUZALLO or lesinurad in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Limited published data on allopurinol use in pregnant women do not demonstrate a clear pattern or increase in frequency of adverse development outcomes. Animal reproductive toxicity studies have not been conducted with DUZALLO; however, studies were conducted with its individual components [see Animal Data]. No teratogenicity or effects on fetal development were observed in embryo-fetal development studies with oral administration of lesinurad to pregnant rats and rabbits during organogenesis at doses that produced maternal exposures up to 45 and 10 times, respectively, the exposure at the maximum recommended human dose (MRHD). No teratogenic or fetotoxic effects were observed in embryo-fetal development studies with orally administered allopurinol to pregnant rats and rabbits during organogenesis at doses approximately 6 times the MRHD in both species. However, intraperitoneal administration of allopurinol to pregnant mice on gestation days 10 or 13, during the period of organogenesis, produced fetal deaths and teratogenic effects at doses 0.8 times the MRHD and higher. No adverse developmental effects were observed in a pre- and post-natal development study with oral administration of lesinurad to pregnant rats from organogenesis through lactation at a dose approximately 5 times the MRHD. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Animal Data Lesinurad In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-17, lesinurad was not teratogenic and did not affect fetal development or survival at exposures up to approximately 45 times the MRHD (on an AUC basis at maternal oral doses up to 300 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 7-20, lesinurad was not teratogenic and did not affect fetal development at exposures up to approximately 10 times the MRHD (on an AUC basis at maternal oral doses up to 75 mg/kg/day). Severe maternal toxicity, including mortality, was observed in rats and rabbits at exposures equal to or greater than approximately 45 and 4 times the MRHD (on an AUC basis at maternal oral doses of 300 mg/kg/day in rats and 25 mg/kg/day and higher in rabbits) respectively. In a pre- and post-natal development study in pregnant female rats dosed from gestation day 7 through lactation day 20, lesinurad had no effects on delivery or growth and development of offspring at a dose approximately 5 times the MRHD (on a mg/m2 basis at a maternal oral dose of 100 mg/kg/day). In rats, plasma and milk concentrations of lesinurad were approximately equal. Allopurinol In embryo-fetal development studies with pregnant rats or rabbits, allopurinol administered during the period of organogenesis (gestation days 8 – 16) was not teratogenic or fetotoxic in either species at doses up to approximately 6 times the MRHD (on a mg/m2 basis at maternal oral doses up to 200 mg/kg/day in rats and 100 mg/kg/day in rabbits). However, in an embryo-fetal development study with pregnant mice, single intraperitoneal doses of allopurinol on gestation days 10 or 13 produced significant increases in fetal deaths and teratogenic effects, including external and skeletal malformations, at 0.8 times the MRHD and higher (on a mg/m2 basis at maternal intraperitoneal doses of 50 or 100 mg/kg). It is uncertain whether the findings in mice represented a fetal effect or an effect secondary to maternal toxicity. Allopurinol crossed the placental barrier following oral administration to pregnant pigs and was detected in fetal plasma. 8.2 Lactation Risk Summary There is no information regarding the presence of DUZALLO or lesinurad in human milk, the effects on the breastfed infant, or the effects on milk production. Lesinurad was present in the milk of rats [see Use in Specific Populations (8.1) ]. Based on information from a single case report, allopurinol and its active metabolite, oxypurinol, were detected in the milk of a mother at five weeks postpartum. There was no report of effects of allopurinol on the breastfed infant or on milk production. The effect of allopurinol on the nursing infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DUZALLO and any potential adverse effects on the breastfed infant from DUZALLO or from the underlying maternal condition. 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 lesinurad in combination with allopurinol in gout patients, 12% were 65 years and older and 2% were 75 years and older. No overall differences between lesinurad in combination with allopurinol and allopurinol alone in safety and effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment The efficacy and safety of lesinurad in combination with allopurinol were evaluated in studies that included gout patients with mild and moderate renal impairment [see Adverse Reactions (6.1) and Clinical Studies (14) ]. There were no clear differences in safety and effectiveness of lesinurad in combination with allopurinol in patients with mild renal impairment compared to patients with normal renal function. No lesinurad dose adjustment is recommended [see Dosage and Administration (2.2) , and Clinical Studies (14.3) ]. Across all lesinurad 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 lesinurad in combination with allopurinol in patients with an eCLcr less than 45 mL/min is limited and there was a trend toward lesser efficacy [see Clinical Studies (14.3) ]. DUZALLO should not be initiated in patients with an eCLcr less than 45 mL/min. No lesinurad dose adjustment is recommended in patients with an eCLcr 45 to less than 60 mL/min, however, more frequent renal function monitoring is recommended. DUZALLO 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 DUZALLO 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. DUZALLO is not expected to be effective in these patient populations [see Contraindications (4) ]. Lesinurad The pharmacokinetics (PK) of lesinurad were 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) ]. Allopurinol Allopurinol and its metabolites are excreted via the kidney. Impairment of renal function may lead to retention of the drug and its metabolites with consequent prolongation of action. In patients with severely impaired renal function or decreased urate clearance, the half-life of oxypurinol in the plasma is greatly prolonged. Patients with reduced renal function require lower doses of allopurinol than those with normal renal function [see Clinical Pharmacology (12.3) ]. 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) ]. Neither DUZALLO nor its individual components have been studied in patients with severe hepatic impairment; DUZALLO is therefore not recommended in these patients [see Warnings and Precautions (5.3) ]. 8.8 Secondary Hyperuricemia No studies with DUZALLO have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); DUZALLO 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) ].

Interactions

7 DRUG INTERACTIONS No drug interactions studies were conducted with DUZALLO. However, as DUZALLO contains lesinurad and allopurinol, any interactions that have been identified with these agents individually may occur with DUZALLO. The following interactions have been noted with the individual components of DUZALLO. Mercaptopurine or Azathioprine: Reduce mercaptopurine or azathioprine dose to approximately one-third to one-fourth of the usual dose and closely monitor for therapeutic response and the appearance of toxicity. (5.5, 7.2) Coumarin Anticoagulants: Carefully monitor prothrombin time. (5.6, 7.2) Moderate Cytochrome P450 2C9 (CYP2C9) Inhibitors: Use DUZALLO with caution. (7.1) CYP3A Substrates: Monitor for efficacy of the CYP3A substrate. (7.1) 7.1 Drug Interactions With Lesinurad CYP2C9 Inhibitors, CYP2C9 Poor Metabolizers, and CYP2C9 Inducers Co-administration of lesinurad with inhibitors of CYP2C9, and administration of lesinurad to CYP2C9 poor metabolizers, resulted in increased lesinurad exposure. DUZALLO 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 lesinurad is co-administered with moderate inducers of CYP2C9 (e.g., rifampin, carbamazepine), which may decrease the therapeutic effect of DUZALLO [see Clinical Pharmacology (12.3) ]. CYP3A Substrates In interaction studies conducted in healthy subjects with lesinurad 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 by co-administration with DUZALLO. 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. 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. DUZALLO should not be administered with inhibitors of epoxide hydrolase. Hormonal Contraceptives Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when DUZALLO is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking DUZALLO. Aspirin Aspirin at doses higher than 325 mg per day may decrease the efficacy of DUZALLO. Aspirin at doses of 325 mg or less per day (i.e., for cardiovascular protection) does not decrease the efficacy of DUZALLO and can be co-administered with DUZALLO. 7.2 Drug Interactions With Allopurinol Immunosuppressants/Cytotoxics Mercaptopurine and azathioprine Azathioprine is metabolized to mercaptopurine which is inactivated by the action of xanthine oxidase. Since allopurinol is an inhibitor of xanthine oxidase, the activity of azathioprine and mercaptopurine is prolonged. Therefore, during concomitant administration with DUZALLO, the dose of mercaptopurine or azathioprine will require reduction to approximately one-third to one-fourth of the usual dose, and should be closely monitored for therapeutic response and the appearance of toxicity. Subsequent adjustment of doses of mercaptopurine or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects [see Warnings & Precautions (5.5) and Clinical Pharmacology (12.3) ]. Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechloroethamine Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease (except leukemia), in the presence of allopurinol. However, in a well-controlled study of patients with lymphoma on combination therapy, allopurinol did not increase the marrow toxicity of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine, and/or mechlorethamine [see Warnings and Precautions (5.5) ]. Cyclosporine Rare reports indicate that cyclosporine levels may be increased during concomitant treatment with allopurinol. Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should be considered when cyclosporine and DUZALLO are coadministered. Dicumarol There have been reports of prolonged half-life of dicumarol, a coumarin anticoagulant, when coadministered with allopurinol; therefore, patients receiving DUZALLO in addition to dicumarol must be carefully monitored [see Warnings & Precautions (5.6) ]. Thiazide diuretics The concomitant use of allopurinol and thiazide diuretics may contribute to the enhancement of allopurinol toxicity in some patients. Although a causal mechanism and a cause-and-effect relationship have not been established, current evidence suggests that renal function should be monitored in patients on thiazide diuretics and allopurinol even in the absence of renal failure, and dosage levels should be even more conservatively adjusted in those patients on such combined therapy if diminished renal function is detected [see Warnings and Precautions (5.2) ]. Ampicillin/Amoxicillin An increase in the frequency of skin rash has been reported among patients receiving amoxicillin or ampicillin concurrently with allopurinol compared to patients who are not receiving both drugs. The cause of the association has not been established. [see Warnings and Precautions (5.2) ]. Chlorpropamide Plasma half-life of chlorpropamide may be prolonged by allopurinol, since allopurinol and chlorpropamide may compete for excretion in the renal tubule. The risk of hypoglycemia secondary to this mechanism may be increased if allopurinol and chlorpropamide are given concomitantly in the presence of renal insufficiency.

More information

Category Value
Authorisation number NDA209203
Agency product number 63CZ7GJN5I
Orphan designation No
Product NDC 70785-021,70785-022
Date Last Revised 03-11-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1944786
Storage and handling 16.2 Storage and Handling 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].
Marketing authorisation holder Ironwood Pharmaceuticals, Inc.
Warnings 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)