Lesinurad
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2]
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Black Box Warning
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RISK OF ACUTE RENAL FAILURE, MORE COMMON WHEN USED WITHOUT A XANTHINE OXIDASE INHIBITOR
See full prescribing information for complete Boxed Warning.
- [Acute renal failure] has occurred with Lesinurad and was more common when Lesinurad was given alone.
- Lesinurad should be used in combination with a xanthine oxidase inhibitor.
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Overview
Lesinurad is a URAT1 inhibitor that is FDA approved for the treatment of [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. There is a Black Box Warning for this drug as shown here. Common adverse reactions include [headache], [influenza], blood [creatinine] increased, and [gastroesophageal reflux disease] (≥2%).
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lesinurad in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lesinurad in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients under 18 years of age have not been established.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lesinurad in pediatric patients.
Non–Guideline-Supported Use
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] (e[CLcr] less than 30 mL/min), [end stage renal disease], [kidney transplant] recipients, or patients on [dialysis].
- [Tumor lysis syndrome] or [Lesch-Nyhan syndrome].
Warnings
|
RISK OF ACUTE RENAL FAILURE, MORE COMMON WHEN USED WITHOUT A XANTHINE OXIDASE INHIBITOR
See full prescribing information for complete Boxed Warning.
- [Acute renal failure] has occurred with Lesinurad and was more common when Lesinurad was given alone.
- Lesinurad should be used in combination with a xanthine oxidase inhibitor.
|
- 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 e[CLcr] 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 trial]s, major adverse cardiovascular events (defined as cardiovascular deaths, non-fatal [myocardial infarction]s, or non-fatal [stroke]s) were observed with Lesinurad. A causal relationship with Lesinurad has not been established.
Adverse Reactions
Clinical Trials Experience
Because [clinical trial]s 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] (e[CLcr] 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)
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)
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)
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)
ZURAMPIC: Lesinurad's Brand name
Postmarketing Experience
There is limited information regarding Lesinurad Postmarketing Experience in the drug label.
Drug Interactions
- [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. ZURAMPIC should not be administered with inhibitors of epoxide hydrolase.
7.4 Hormonal Contraceptives Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when ZURAMPIC is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking ZURAMPIC.
7.5 Aspirin Aspirin at doses higher than 325 mg per day may decrease the efficacy of ZURAMPIC in combination with allopurinol. Aspirin at doses of 325 mg or less per day (ie, for cardiovascular protection) does not decrease the efficacy of ZURAMPIC and can be coadministered with ZURAMPIC.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Lesinurad in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lesinurad in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Lesinurad during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Lesinurad in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Lesinurad in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Lesinurad in geriatric settings.
Gender
There is no FDA guidance on the use of Lesinurad with respect to specific gender populations.
Race
There is no FDA guidance on the use of Lesinurad with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Lesinurad in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Lesinurad in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lesinurad in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Lesinurad in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Lesinurad Administration in the drug label.
Monitoring
There is limited information regarding Lesinurad Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Lesinurad and IV administrations.
Overdosage
There is limited information regarding Lesinurad overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Lesinurad Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Lesinurad Mechanism of Action in the drug label.
Structure
There is limited information regarding Lesinurad Structure in the drug label.
Pharmacodynamics
There is limited information regarding Lesinurad Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Lesinurad Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Lesinurad Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Lesinurad Clinical Studies in the drug label.
How Supplied
There is limited information regarding Lesinurad How Supplied in the drug label.
Storage
There is limited information regarding Lesinurad Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Lesinurad Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Lesinurad interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Lesinurad Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Lesinurad Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.