Therapy/Monitor Closely.levonorgestrel intrauterineSerious - Use Alternative (1)lesinurad decreases effects of levonorgestrel intrauterine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use additional methods of nonhormonal contraception. Do not rely on hormonal contraception alone when taking lesinurad.levonorgestrel oralSerious - Use Alternative (1)lesinurad decreases effects of levonorgestrel oral by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use additional methods of nonhormonal contraception. Do not rely on hormonal contraception alone when taking lesinurad.levonorgestrel oral/ethinylestradiol/ferrous bisglycinateMonitor Closely (1)lesinurad will decrease the level or effect of levonorgestrel oral/ethinylestradiol/ferrous bisglycinate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. The efficacy of hormonal contraceptives may be reduced. Use an alternative method of contraception or a backup method when enzyme inducers are used with combined hormonal contraceptives (CHCs), and continue backup contraception for 28 days after discontinuing enzyme inducer to ensure contraceptive reliability.medroxyprogesteroneSerious - Use Alternative (1)lesinurad decreases effects of medroxyprogesterone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use additional methods of nonhormonal contraception. Do not rely on hormonal contraception alone when taking lesinurad.mefenamic acidMonitor Closely (1)mefenamic acid will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.nicardipineMonitor Closely (1)nicardipine will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.nitisinoneMonitor Closely (1)nitisinone will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Nitisinone inhibits CYP2C9. Caution if CYP2C9 substrate coadministered, particularly those with a narrow therapeutic index.norethindroneSerious - Use Alternative (1)lesinurad decreases effects of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use additional methods of nonhormonal contraception. Do not rely on hormonal contraception alone when taking lesinurad.pacritinibSerious - Use Alternative (1)lesinurad will decrease the level or effect of pacritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.phenobarbitalMonitor Closely (1)phenobarbital will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.phenytoinMonitor Closely (1)phenytoin will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.piroxicamMonitor Closely (1)piroxicam will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.primidoneMonitor Closely (1)primidone will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.rifampinMonitor Closely (1)rifampin will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.rifapentineMonitor Closely (1)rifapentine will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.rucaparibMonitor Closely (1)rucaparib will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP2C9 substrates, if clinically indicated.secobarbitalMonitor Closely (1)secobarbital will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.sildenafilMonitor Closely (1)lesinurad decreases levels of sildenafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.sparsentanMonitor Closely (1)sparsentan will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Sparsentan (a CYP2C9 inducer) decreases exposure of CYP2C9 substrates and reduces efficacy related to these substrates. sulfadiazineMonitor Closely (1)sulfadiazine will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.sulfamethoxazoleMonitor Closely (1)sulfamethoxazole will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.tazemetostatMonitor Closely (1)lesinurad will decrease the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.tolbutamideMonitor Closely (1)tolbutamide will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.ubrogepantMonitor Closely (1)lesinurad will decrease the level or effect of ubrogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Dose adjustment is recommended with concomitant use of ubrogepant and moderate and weak CYP3A4 inducers. (see Dosage Modifications)valproic acidSerious - Use Alternative (1)valproic acid, lesinurad. Other (see comment). Avoid or Use Alternate Drug. Comment: Avoid coadministration with inhibitors of epoxide hydrolase (valproic acid) which may interfere with metabolism of lesinurad.voriconazoleMonitor Closely (1)voriconazole will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely. 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 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 inhibitorContraindications 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 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 conditionPregnancy 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. 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) 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) No images available for this drug. No images available for this drug.A Patient Handout is not currently available for this monograph.Print