lesinurad (Discontinued)

Brand and Other Names:Zurampic (DSC)
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Dosing & Uses

AdultPediatric

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

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Interactions

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            Contraindicated (0)

              Serious - Use Alternative (10)

              • aspirin

                aspirin decreases effects of lesinurad by unspecified interaction mechanism. Avoid or Use Alternate Drug. Aspirin at doses >325 mg/day may decrease lesinurad efficacy. Aspirin doses 325 mg/day or less (ie, for cardiovascular event prophylaxis) does not decrease lesinurad efficacy and can be coadministered.

              • dienogest/estradiol valerate

                lesinurad decreases effects of dienogest/estradiol valerate 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.

              • ethinylestradiol

                lesinurad decreases effects of ethinylestradiol 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.

              • etonogestrel

                lesinurad decreases effects of etonogestrel 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.

              • ivosidenib

                ivosidenib will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP2C9 substrates with ivosidenib or replace with alternate therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

              • levonorgestrel intrauterine

                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 oral

                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.

              • medroxyprogesterone

                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.

              • norethindrone

                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.

              • valproic acid

                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.

              Monitor Closely (38)

              • alpelisib

                alpelisib will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • amiodarone

                amiodarone will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • amlodipine

                lesinurad decreases levels of amlodipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • apalutamide

                apalutamide will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Coadministration of apalutamide, a weak CYP2C9 inducer, with drugs that are CYP2C9 substrates can result in lower exposure to these medications. Evaluate for loss of therapeutic effect if medication must be coadministered.

              • atogepant

                lesinurad will decrease the level or effect of atogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • bosentan

                bosentan will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • cannabidiol

                cannabidiol will increase the level or effect of lesinurad by decreasing metabolism. Modify Therapy/Monitor Closely. Cannabidiol may potentially inhibit CYP2C9 activity. Consider reducing the dose when concomitantly using CYP2C9 substrates.

              • capecitabine

                capecitabine will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • carbamazepine

                carbamazepine will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • fluconazole

                fluconazole will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • fluorouracil

                fluorouracil will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • flurbiprofen

                flurbiprofen will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • fosphenytoin

                fosphenytoin will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • gemfibrozil

                gemfibrozil will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • ibuprofen

                ibuprofen will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • ibuprofen IV

                ibuprofen IV will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • indomethacin

                indomethacin will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • isavuconazonium sulfate

                lesinurad will decrease the level or effect of isavuconazonium sulfate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • ketoconazole

                ketoconazole will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • levonorgestrel oral/ethinylestradiol/ferrous bisglycinate

                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.

              • mefenamic acid

                mefenamic acid will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • nicardipine

                nicardipine will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • nitisinone

                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.

              • phenobarbital

                phenobarbital will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • phenytoin

                phenytoin will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • piroxicam

                piroxicam will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • primidone

                primidone will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • rifampin

                rifampin will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • rifapentine

                rifapentine will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • rucaparib

                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.

              • secobarbital

                secobarbital will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • sildenafil

                lesinurad decreases levels of sildenafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • sulfadiazine

                sulfadiazine will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • sulfamethoxazole

                sulfamethoxazole will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • tazemetostat

                lesinurad will decrease the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • tolbutamide

                tolbutamide will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              • ubrogepant

                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)

              • voriconazole

                voriconazole will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

              Minor (0)

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                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

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                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
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                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.

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                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)

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                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)

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                A Patient Handout is not currently available for this monograph.
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                Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.