Dosing & Uses
Dosage Form & Strengths
April 2019: Manufacturer announced product to be discontinued
tablet
- 200mg
Hyperuricemia
Indicated in combination with a xanthine oxidase inhibitor for hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone
200 mg PO qDay in combination with a xanthine oxidase inhibitor (ie, allopurinol or febuxostat)
Not to exceed 200 mg/day
Also see Administration section
Dosage Modifications
Renal impairment
- CrCl ≥45 mL/min: No dosage adjustment required
- CrCl <45 mL/min: Do not initiate lesinurad
- Discontinue lesinurad if estimated CrCl is persistently <45 mL/min
Dosing Considerations
Assess renal function prior to initiation of therapy and periodically thereafter; monitor more frequently for estimated CrCl <60 mL/min
Not recommended for the treatment of asymptomatic hyperuricemia
Do not use as monotherapy; failure to take lesinurad with a xanthine oxidase inhibitor may increase the risk of renal adverse reactions
Gout flares
- Gout flares may occur after initiation of urate-lowering therapy, including lesinurad, because of 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 treatment, lesinurad need not be discontinued
- The gout flare should be managed concurrently, as appropriate for the individual patient
<18 years: Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
1-10%
Headache (5.3%)
Influenza (5.1%)
GERD (2.7%)
Renal failure (1.2%)
Serum creatinine
- Increased creatinine (4.3%)
- Elevation 1.5 to <2 x baseline (3.9%)
- Elevation ≥2 x baseline (1.8%)
- Nearly 90% resolved by end of study
<1%
Nephrolithiasis
Warnings
Black Box Warnings
Acute renal failure has occurred and was more common when lesinurad was given alone
Should be used in combination with a xanthine oxidase inhibitor
Contraindications
Severe renal impairment (estimated CrCl <30 mL/min), end-stage renal disease, kidney transplant recipients, or patients on dialysis
Tumor lysis syndrome or Lesch-Nyhan syndrome
Cautions
Adverse effects related to renal function have occurred after initiating lesinurad; incidence was higher with doses exceeding 200 mg/day, with the highest incidence occurring with monotherapy use; monitor renal function at initiation and during therapy, particularly in patients with estimated CrCl <60 mL/min, and evaluate for signs and symptoms of acute uric acid nephropathy
Major adverse cardiovascular events were observed during clinical trials (defined as cardiovascular deaths, nonfatal myocardial infarctions, or nonfatal strokes); a causal relationship has not been established
Drug interaction overview
- Lesinurad is a CYP2C9 substrate and its exposure is increased when coadministered with CYP2C9 inhibitors and in CYP2C9 poor metabolizers, while its exposure is decreased when coadministered with CYP2C9 inducers
- Lesinurad is a weak inducer of CYP3A and has no relevant effect on any other CYP enzyme for induction or inhibition; caution with sensitive CYP3A substrates
- 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; should not be administered with epoxide hydrolase inhibitors
- Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when lesinurad is coadministered; use additional methods of nonhormonal contraception
- Doses of aspirin >325 mg/day may decrease lesinurad efficacy
- 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
- 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
Pregnancy
Pregnancy
There are no available human data on use in pregnant women to inform a drug-associated risk
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 approximately 45 and 10 times, respectively, the exposure at the maximum recommended human dose (MRHD)
- No adverse developmental effects were observed in a prenatal and postnatal development study with administration of lesinurad to pregnant rats from organogenesis through lactation at a dose approximately 5 times the MRHD
Lactation
Unknown if distributed in human breast milk It is present in the milk of rats
Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition
Pregnancy Categories
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Pharmacology
Mechanism of Action
Selective uric acid reabsorption inhibitor (SURI); it acts by inhibiting the urate transporter, URAT1, which is responsible for the majority of the renal reabsorption of uric acid
It also inhibits organic anion transporter 4 (OAT4), a uric acid transporter associated with diuretic-induced hyperuricemia
Absorption
Absolute bioavailability: ~100%
Peak plasma time: 1-4 hr
Peak plasma concentration: 6 mcg/mL
AUC: 30 mcg·hr/mL
Distribution
Protein bound: >98% (mainly albumin)
Vd: 20 L
Metabolism
Undergoes oxidative metabolism mainly via CYP2C9
Elimination
Half-life: ~5 hr
Total body clearance: 6 L/hr
Excretion: 63% urine (30% of this as unchanged drug); 32% feces
Pharmacogenomics
Lesinurad is a CYP2C9 substrate
Increased systemic exposure may be observed with slow metabolizers of CYP2C9
Exposure was ~1.8-fold higher in CYP2C9 poor metabolizers (ie, subjects with CYP2C9 *2/*2 [N=1], and *3/*3 [N=1] genotype) compared with CYP2C9 extensive metabolizers (ie, CYP2C9 *1/*1 [N=41] genotype)
Administration
Oral Administration
Coadminister with a xanthine oxidase inhibitor
Not recommended for patients taking allopurinol <300 mg/day (or <200 mg/day if estimated CrCl <60 mL/min)
Take 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
Patients should be instructed to stay well hydrated (eg, 2 liters [68 oz] of liquid per day)
Failure to follow these instructions may increase the risk of renal events
Storage
Store at 20-25°C (68-77°F); excursions permitted from 15-30°C (59-86°F)
