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Lesinurad

Class: Uricosuric Agents
Chemical Name: 2-[[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-1,2,4-triazol-3-yl]sulfanyl]acetic acid
Molecular Formula: C17H14BrN3O2S
CAS Number: 878672-00-5
Brands: Zurampic

Warning(s)

Warning: Risk of Acute Renal Failure, More Common When Used Without a Xanthine Oxidase Inhibitor1

See full prescribing information for complete boxed warning. 1

  • Acute renal failure has occurred with lesinurad and was more common when lesinurad was given alone.1

  • Lesinurad should be used in combination with a xanthine oxidase inhibitor.1

Introduction

Lesinurad is an antigout agent.

Uses for Lesinurad

Lesinurad has the following uses:

Lesinurad is a uric acid transporter 1 (URAT1) inhibitor 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. 1

Lesinurad has the following limitations of use:

Lesinurad is not recommended for the treatment of asymptomatic hyperuricemia.1

Lesinurad should not be used as monotherapy.1

Lesinurad Dosage and Administration

General

Lesinurad is available in the following dosage form(s) and strength(s):

Tablet: 200 mg. 1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Lesinurad is recommended at 200 mg once daily in combination with a xanthine oxidase inhibitor, including allopurinol or febuxostat. The maximum daily dose of lesinurad is 200 mg. 1

  • Failure to take lesinurad with a xanthine oxidase inhibitor may increase the risk of renal adverse reactions. 1

  • Lesinurad tablets should be taken in the morning with food and water. 1

  • Patients should be instructed to stay well hydrated. 1

  • Assess renal function before initiating lesinurad. Do not initiate lesinurad if estimated creatinine clearance (eCLcr) is below 45 mL/min. 1

  • Discontinue lesinurad if eCLcr persistently falls below 45 mL/min. 1

Cautions for Lesinurad

Contraindications

  • Severe renal impairment, end stage renal disease, kidney transplant recipients, or patients on dialysis. 1

  • Tumor lysis syndrome or Lesch-Nyhan syndrome. 1

Warnings/Precautions

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.1

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.1

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.1

Specific Populations

Pregnancy

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.1

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.1

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.1

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 100mg/kg/day). In rats, plasma and milk concentrations of lesinurad were approximately equal.1

Lactation

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.1

Pediatric Use

Safety and effectiveness in pediatric patients under 18 years of age have not been established.1

Geriatric Use

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.1

Renal Impairment

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. 1

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. 1

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.1

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. 1

Hepatic Impairment

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.1

Secondary Hyperuricemia

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.1

Common Adverse Effects

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 a xanthine oxidase inhibitor alone) were headache, influenza, blood creatinine increased, and gastroesophageal reflux disease.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Moderate Cytochrome P-450 2C9 (CYP2C9) Inhibitors: Use with caution. 1

  • Sensitive CYP3A Substrates: Monitor for efficacy of the CYP3A substrate. 1

Actions

Mechanism Of Action

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, 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.1

Advice to Patients

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).1

Administration

Advise patients: 1

To take lesinurad in the morning with food and water at the same time as a xanthine oxidase inhibitor, allopurinol, or febuxostat. 1

Not to take lesinurad alone and to discontinue lesinurad if treatment with the xanthine oxidase inhibitor medication is discontinued.1

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.1

To stay well hydrated (e.g., 2 liters [68 oz] of liquid per day).1

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.1

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.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Lesinurad

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, Film Coated

200 mg

Zurampic

AstraZeneca Pharmaceuticals LP

AHFS Drug Information. © Copyright 2016, Selected Revisions November 17, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. AstraZeneca Pharmaceuticals LP. ZURAMPIC (lesinurad) ORAL prescribing information. 2016 Jan.

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