Lesinurad

{{DrugProjectFormSinglePage |authorTag=Martin Nino [1] |genericName=Lesinurad |aOrAn=a |drugClass=URAT1 inhibitor |indicationType=treatment |indication=hyperuricemia associated with gout (in combination with a xanthine oxidase inhibitor) in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone |hasBlackBoxWarning=Yes |adverseReactions=headache, influenza, blood creatinine increased, and gastroesophageal reflux disease (≥2%) |blackBoxWarningTitle=RISK OF ACUTE RENAL FAILURE, MORE COMMON WHEN USED WITHOUT A XANTHINE OXIDASE INHIBITOR |blackBoxWarningBody= Acute renal failure has occurred with Lesinurad and was more common when Lesinurad was given alone. Lesinurad should be used in combination with a xanthine oxidase inhibitor. |fdaLIADAdult=======Indications====== Lesinurad is indicated in combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone.

• Limitations of Use

• Lesinurad is not recommended for the treatment of asymptomatic hyperuricemia.

• Lesinurad should not be used as monotherapy.

Dosage

• Recommended Dosing

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

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

Lesinurad 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 Lesinurad 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 Lesinurad at the same time as the morning dose of xanthine oxidase inhibitor. If treatment with the xanthine oxidase inhibitor is interrupted, Lesinurad should also be interrupted. Failure to follow these instructions may increase the risk of renal events.

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

• Patients with Renal Impairment

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

• Gout Flares

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

If a gout flare occurs during Lesinurad treatment, Lesinurad need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient. |offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Lesinurad in adult patients. |offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Lesinurad in adult patients. |fdaLIADPed=Safety and effectiveness in pediatric patients under 18 years of age have not been established. |offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Lesinurad in pediatric patients. |offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Lesinurad in pediatric patients. |contraindications=The use of Lesinurad 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.
• Tumor lysis syndrome or Lesch-Nyhan syndrome.

|warnings=:*Renal Events Treatment with Lesinurad 200 mg in combination with a xanthine oxidase inhibitor was associated with an increased incidence of serum creatinine elevations, most of which were reversible. Adverse reactions related to renal function have occurred after initiating Lesinurad. A higher incidence of serum creatinine elevations and renal-related adverse reactions, including serious adverse reactions of [acute renal failure], was observed with Lesinurad 400 mg, with the highest incidence as monotherapy. Lesinurad should not be used as monotherapy.

Lesinurad should not be initiated in patients with an eCLcr less than 45 mL/min. Renal function should be evaluated prior to initiation of Lesinurad and periodically thereafter, as clinically indicated. More frequent renal function monitoring is recommended in patients with an eCLcr less than 60 mL/min or with serum creatinine elevations 1.5 to 2 times the pre-treatment value. Lesinurad 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. Lesinurad should not be restarted without another explanation for the serum creatinine abnormalities.

• Cardiovascular Events

In clinical trials, major adverse cardiovascular events (defined as cardiovascular deaths, non-fatal myocardial infarctions, or non-fatal strokes) were observed with Lesinurad. A causal relationship with Lesinurad has not been established. |clinicalTrials=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 Lesinurad is 200 mg once daily in combination with a xanthine oxidase inhibitor.

In 3 randomized, placebo-controlled studies of Lesinurad 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 Lesinurad 200 mg, Lesinurad 400 mg, and placebo, respectively. The mean duration of treatment with Lesinurad 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

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, when used as monotherapy or in combination with a xanthine oxidase inhibitor.

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 Lesinurad 200 mg and Lesinurad 400 mg 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 a Xanthine Oxidase Inhibitor (XOI)

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ZURAMPIC: Lesinurad's Brand name

Renal-related adverse reactions, including blood creatinine increases and renal failure, and nephrolithiasis reported in patients receiving Lesinurad 200 mg, Lesinurad 400 mg and [placebo] in combination with a xanthine oxidase inhibitor are shown in Table 2. The incidence of reports of “blood creatinine increased” was higher with Lesinurad and was highest with Lesinurad 400 mg. Renal-related adverse reactions by baseline renal function category are shown in Table 3. Blood creatinine increased occurred more frequently in patients treated with Lesinurad 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 Lesinurad in Combination with a Xanthine Oxidase Inhibitor (XOI)

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ZURAMPIC: Lesinurad's Brand name

• Table 3: Incidence of Renal-Related Adverse Reactions by Baseline Renal Function Category in Placebo-Controlled Clinical Studies with Lesinurad in Combination with a Xanthine Oxidase Inhibitor (XOI)

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ZURAMPIC: Lesinurad's Brand name

Renal-related adverse reactions resulted in a similar discontinuation rate on Lesinurad 200 mg in combination with a xanthine oxidase inhibitor (1.2%) and a xanthine oxidase inhibitor alone (1%) and a higher rate on Lesinurad 400 mg in combination with a xanthine oxidase inhibitor (3.3%). Serious renal-related adverse reactions were reported in patients on Lesinurad 400 mg in combination with a xanthine oxidase inhibitor (1%) and a xanthine oxidase inhibitor alone (0.4%) and in no patients on Lesinurad 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 Lesinurad 200 mg and Lesinurad 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 Lesinurad 400 mg alone and in no patients receiving placebo. Serum creatinine elevations 1.5-fold or greater occurred in 24.3 % of patients receiving Lesinurad 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 Lesinurad. In the randomized controlled studies, the numbers of patients with adjudicated MACE events (incidences per 100 patient-years of exposure) were: 3 (0.71) for [placebo], 4 (0.96) for Lesinurad 200 mg, and 8 (1.94) for Lesinurad 400 mg when used in combination with a xanthine oxidase inhibitor. Incidence rate ratios for Lesinurad 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 Lesinurad 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 Lesinurad 200 mg-Treated Patients and at Least 1% Greater than Seen in Patients Receiving Placebo in Controlled Studies with Lesinurad in Combination with a Xanthine Oxidase Inhibitor (XOI)

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ZURAMPIC: Lesinurad's Brand name |drugInteractions=:*CYP2C9 Inhibitors, CYP2C9 Poor Metabolizers, and CYP2C9 Inducers Lesinurad exposure is increased when Lesinurad is co-administered with inhibitors of CYP2C9, and in CYP2C9 poor metabolizers. Lesinurad should be used with caution in patients taking moderate inhibitors of CYP2C9 (eg, fluconazole, amiodarone), and in CYP2C9 poor metabolizers.

Lesinurad exposure is decreased when Lesinurad is co-administered with moderate inducers of CYP2C9 (eg, rifampin, carbamazepine), which may decrease the therapeutic effect of Lesinurad.

• CYP3A Substrates

In interaction studies conducted in healthy subjects with Lesinurad and CYP3A substrates, Lesinurad reduced the plasma concentrations of sildenafil and amlodipine. 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 (eg, 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 (ie, valproic acid) may interfere with metabolism of Lesinurad. Lesinurad 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 Lesinurad is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking Lesinurad.

• Aspirin

Aspirin at doses higher than 325 mg per day may decrease the efficacy of Lesinurad in combination with allopurinol. Aspirin at doses of 325 mg or less per day (ie, for cardiovascular protection) does not decrease the efficacy of Lesinurad and can be coadministered with Lesinurad. |FDAPregCat=N |useInPregnancyFDA=:*Risk Summary

There are no available human data on use of Lesinurad in pregnant women to inform a drug-associated risk. 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 approximately 45 and 10 times, respectively, the exposure at the maximum recommended human dose (MRHD). No adverse developmental effects were observed in a pre- and postnatal development study with administration of Lesinurad to pregnant rats from organogenesis through lactation at a dose approximately 5 times the MRHD.

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.

• Data

• Animal Data

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 postnatal 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 dose oral dose of 100 mg/kg/day). In rats, plasma and milk concentrations of Lesinurad were approximately equal. |useInNursing=There is no information regarding the presence of Lesinurad in human milk, the effects on the breastfed infant, or the effects on milk production. Lesinurad is present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Lesinurad and any potential adverse effects on the breastfed infant from Lesinurad or from the underlying maternal condition. |useInPed=Safety and effectiveness in pediatric patients under 18 years of age have not been established. |useInGeri=No dose adjustment is necessary in elderly patients. In a pool of clinical safety and efficacy studies of Lesinurad 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. |useInRenalImpair=The pharmacokinetics (PK) of Lesinurad 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.

The efficacy and safety of Lesinurad were evaluated in studies that included gout patients with mild and moderate renal impairment. There were no clear differences in safety and effectiveness of Lesinurad in patients with mild renal impairment compared to patients with normal renal function and no dose adjustment is recommended.

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. The experience with Lesinurad in patients with an eCLcr less than 45 mL/min is limited and there was a trend toward lesser efficacy. Lesinurad 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. Lesinurad should be discontinued when eCLcr is persistently less than 45 mL/min.

The efficacy and safety of Lesinurad 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. Lesinurad is not expected to be effective in these patient populations. |useInHepaticImpair=No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh classes A and B). Lesinurad has not been studied in patients with severe hepatic impairment and is therefore not recommended. |othersTitle=Secondary Hyperuricemia |useInOthers=No studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); Lesinurad is contraindicated for use in tumor lysis syndrome or Lesch-Nyhan syndrome, where the rate of uric acid formation is greatly increased. |overdose=Lesinurad was studied in healthy subjects given single doses up to 1600 mg without evidence of dose-limiting toxicities. In case of overdose patients should be managed by symptomatic and supportive care including adequate hydration. |drugBox=|drugBox={{Drugbox2 | drug_name = | type = | IUPAC_name = 2-{[5-Bromo-4-(4-cyclopropyl-1-naphthyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid | image = les3.png | width = 180 | image2 = les4.png

| pronounce = | tradename = Zurampic | Drugs.com = zurampic | MedlinePlus = | pregnancy_AU = | pregnancy_AU_comment = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_AU_comment = | legal_CA = | legal_DE = | legal_NZ = | legal_UK = | legal_US = Rx-only | legal_UN = | legal_status = | routes_of_administration = Oral (tablets)

| bioavailability = ~100% | protein_bound = >98% | metabolism = Hepatic (CYP2C9) | metabolites = | onset = | elimination_half-life = ~5 hours | duration_of_action = | excretion = Urine (63%), feces (32%)

| CAS_number = 878672-00-5 | ATCvet = | ATC_prefix = M04 | ATC_suffix = AB05 | PubChem = 56928182 | ChEBI_Ref =  ^Y | ChEBI = 90929 | ChemSpiderID = 28527877 | KEGG = D09921 | DrugBank =

| C = 17 | H = 14 | Br = 1 | N = 3 | O = 2 | S = 1 | SMILES = c1ccc2c(c1)c(ccc2n3c(nnc3Br)SCC(=O)O)C4CC4 | StdInChI = 1S/C17H14BrN3O2S/c18-16-19-20-17(24-9-15(22)23)21(16)14-8-7-11(10-5-6-10)12-3-1-2-4-13(12)14/h1-4,7-8,10H,5-6,9H2,(H,22,23) | StdInChIKey = FGQFOYHRJSUHMR-UHFFFAOYSA-N }} |mechAction=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. |structure=Lesinurad is a URAT1 inhibitor. Lesinurad has the following chemical name: 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid. The molecular formula is C17H14BrN3O2S and the molecular weight is 404.28. The structural formula is:

This image is provided by the National Library of Medicine.

Lesinurad is available as blue film-coated tablets for oral administration containing 200 mg Lesinurad and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, hypromellose 2910, crospovidone, and magnesium stearate. Lesinurad tablets are coated with Opadry blue. |PD=:*Effects on Serum Uric Acid and Urinary Excretion of Uric Acid

In gout patients, Lesinurad lowered serum uric acid levels and increased renal clearance and fractional excretion of uric acid. Following single and multiple oral doses of Lesinurad to gout patients, dose-dependent decreases in serum uric acid levels and increases in urinary uric acid excretion were observed.

• Effect on Cardiac Repolarization

The effect of Lesinurad on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and gout patients. Lesinurad at doses up to 1600 mg did not demonstrate an effect on the QTc interval. |PK=Following oral administration of Lesinurad 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 Lesinurad from 5 to 1200 mg. Following multiple once daily dosing of Lesinurad, there was no evidence of time dependent changes in pharmacokinetics and dose proportionality was preserved.

• Absorption

The absolute bioavailability of Lesinurad is approximately 100%. Lesinurad is rapidly absorbed after oral administration. Following administration of a single dose of a Lesinurad tablet in either fed or fasted state, maximum plasma concentrations (Cmax) were attained within 1 to 4 hours. Cmax and AUC exposures of Lesinurad increased proportionally with single doses of Lesinurad from 5 to 1200 mg.

Administration with a high-fat meal (800 to 1000 calories with 50% of calories being derived from fat content) decreases Lesinurad Cmax by up to 18% but does not alter AUC as compared with fasted state. In clinical trials, Lesinurad was administered with food.

• Distribution

Lesinurad is extensively bound to proteins in plasma (greater than 98%), mainly to albumin. Plasma protein binding of Lesinurad is not meaningfully altered in patients with renal or hepatic impairment. The mean steady state volume of distribution of Lesinurad was approximately 20 L following intravenous dosing of Lesinurad.

• Elimination

The elimination half-life (t½) of Lesinurad was approximately 5 hours. Lesinurad does not accumulate following multiple doses. The total body clearance is approximately 6 L/hr.

• Metabolism

Lesinurad undergoes oxidative metabolism mainly via the polymorphic cytochrome P450 CYP2C9 enzyme. Plasma exposure of metabolites is minimal (< 10% of unchanged Lesinurad). Metabolites are not known to contribute to the uric acid lowering effects of Lesinurad. A transient oxide metabolite is rapidly eliminated by microsomal epoxide hydrolase in the liver and not detected in [plasma].

Patients who are CYP2C9 poor metabolizers are deficient in CYP2C9 enzyme activity. A cross-study pharmacogenomic analysis assessed the association between CYP2C9 polymorphism and Lesinurad exposure in patients receiving single or multiple doses of Lesinurad at 200 mg, 400 mg or 600 mg. At the 400 mg dose, Lesinurad exposure was approximately 1.8-fold higher in CYP2C9 poor metabolizers (i.e., subjects with CYP2C9 *2/*2 [N=1], and *3/*3 [N=1] genotype) compared to CYP2C9 extensive metabolizers (i.e., CYP2C9 *1/*1 [N=41] genotype). Use with caution in CYP2C9 poor metabolizers, and in patients taking moderate inhibitors of CYP2C9.

• Excretion

Within 7 days following single dosing of radiolabeled Lesinurad, 63% of administered radioactive dose was recovered in urine and 32% of administered radioactive dose was recovered in feces. Most of the radioactivity recovered in urine (> 60% of dose) occurred in the first 24 hours. Unchanged Lesinurad in urine accounted for approximately 30% of the dose.

• Special Populations

• Renal Impairment

Two dedicated studies were performed to assess PK in renal impairment (classified using the Cockcroft-Gault formula) subjects. In both studies, Cmax was comparable in renal impairment subjects compared to healthy subjects.

Study 1 was a single-dose, open-label study evaluating the pharmacokinetics of Lesinurad 200 mg in subjects with mild (eCLcr 60 to less than 90 mL/min) and moderate renal impairment (eCLcr 30 to less than 60 mL/min) compared to healthy subjects. Compared to healthy subjects (N=6; eCLcr greater than or equal to 90 mL/min), plasma AUC of Lesinurad was increased by approximately 30% and 73% in subjects with mild (N=8) and moderate (N=10) renal impairment, respectively.

Study 2 was a single-dose, open-label study evaluating the pharmacokinetics of Lesinurad 400 mg in subjects with moderate and severe renal impairment (eCLcr less than 30 mL/min) compared to healthy subjects. Compared to healthy subjects (N=6), plasma AUC of Lesinurad was increased by approximately 50% and 113% in subjects with moderate (N=6) and severe (N=6) renal impairment, respectively.

• Hepatic Impairment

Following administration of a single dose of Lesinurad at 400 mg in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, Lesinurad Cmax was comparable and Lesinurad AUC was 7% and 33% higher, respectively, compared to individuals with normal [hepatic function]. There is no clinical experience in patients with severe (Child-Pugh class C) hepatic impairment.

• Effect of Age, Gender, Race and Ethnicity on Pharmacokinetics

Based on the population pharmacokinetic analysis, age, gender, race and ethnicity do not have a clinically meaningful effect on the pharmacokinetics of Lesinurad.

• Pediatric Use

Studies characterizing the pharmacokinetics of Lesinurad in pediatric patients have not been conducted.

• Drug-Drug Interactions

• Effects of Other Drugs on Lesinurad

Based on in vitro data, Lesinurad is a substrate for CYP2C9, OAT1 and OAT3; however, no clinical studies have been conducted with OAT1 and OAT3 inhibitors (eg, probenecid).

Figure 1 shows the effect of co-administered drugs on the pharmacokinetics of Lesinurad.

• Figure 1: Effect of Co-administered Drugs on the Pharmacokinetics of Lesinurad

This image is provided by the National Library of Medicine.

• Effects of Lesinurad on Other Drugs

Lesinurad is a weak inducer of CYP3A and has no relevant effect on any other CYP enzyme for induction (CYP1A2, CYP2C8, CYP2C9, CYP2B6, or CYP2C19) or inhibition (CYP1A2, CYP2B6, CYP2D6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4).

Based on in vitro studies, Lesinurad is an inhibitor of OATP1B1, OCT1, OAT1, and OAT3; however, Lesinurad is not an in vivo inhibitor of these transporters. In vivo drug interaction studies indicate that Lesinurad does not decrease the renal clearance of furosemide (substrate of OAT1/3), or affect the exposure of atorvastatin (substrate of OATP1B1) or metformin (substrate of OCT1). Based on in vitro studies, Lesinurad has no relevant effect on P-glycoprotein.

Figure 2 shows the effect of Lesinurad on co-administered drugs.

• Figure 2: Effect of Lesinurad on the Pharmacokinetics of Co-administered Drugs

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|nonClinToxic=======[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). |clinicalStudies=======Overview of Clinical Studies of Lesinurad====== The efficacy of Lesinurad 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 Lesinurad treatment.

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

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 Lesinurad 200 mg, Lesinurad 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, Lesinurad 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.

• Table 5: Proportion of Patients Achieving Target Serum Uric Acid Levels (< 6 mg/dL) in Two Studies of Lesinurad in Combination with Allopurinol

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ZURAMPIC: Lesinurad's Brand name

The estimated effect of Lesinurad 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 Lesinurad 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 Lesinurad in Combination with Allopurinol (Study 1 and Study 2)

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ZURAMPIC: Lesinurad's Brand name

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 Lesinurad 200 mg, Lesinurad 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 Lesinurad 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 Lesinurad 200 mg in Study 3 was similar to that seen in Study 1 and Study 2 (see Figure 3 and Figure 4).

• Table 6: Proportion of Patients Achieving Target Serum Uric Acid Levels (< 5 mg/dL) in a Study with Lesinurad in Combination with Febuxostat in Tophaceous Gout

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ZURAMPIC: Lesinurad's Brand name

As shown in Figure 4, reduction in average serum uric acid levels to < 5 mg/dL was noted for Lesinurad 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 Lesinurad in Combination with Febuxostat in Tophaceous Gout (Study 3)

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ZURAMPIC: Lesinurad's Brand name

Gout Flares and Tophus Outcomes

In each of the three pivotal studies of Lesinurad 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 Lesinurad 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 Lesinurad 200 mg in combination with febuxostat compared with febuxostat alone.

Use in Patients with Renal Impairment

The estimated differences between Lesinurad and placebo in the proportions of patients achieving target serum uric 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 Lesinurad 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. |howSupplied=Lesinurad Tablets, 200 mg are blue in color, oval shaped, debossed with “LES200” and are supplied as follows:

• 0310-1475-05 Bottle of 5 tablets
• 0310-1475-30 Bottle of 30 tablets
• 0310-1475-90 Bottle of 90 tablets

|storage=Protect from light. Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F).

|packLabel=

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|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling.

• Administration

Advise patients:

• To take Lesinurad in the morning with food and water at the same time as a xanthine oxidase inhibitor, allopurinol, or febuxostat.
• Not to take Lesinurad alone and to discontinue Lesinurad if treatment with the xanthine oxidase inhibitor medication is discontinued.
• Not to take a missed dose of Lesinurad later in the day, to wait to take Lesinurad on the next day, and not to double the dose.
• To stay well hydrated (eg, 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 Lesinurad. Advise patients that periodic monitoring of blood creatinine levels are recommended.

• Gout Flares

Inform patients that gout flares may occur after initiation of Lesinurad and of the importance of taking gout flare [prophylaxis] medication to help prevent gout flares. Advise patients not to discontinue Lesinurad if a gout flare occurs during treatment.

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|alcohol=Alcohol-Lesinurad interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. |brandNames=ZURAMPIC© }}