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.
Hyperuricemia associated with gout: Oral: 200 mg once daily (in combination with a xanthine oxidase inhibitor, including allopurinol or febuxostat); maximum dose: 200 mg once daily. Note: If treatment with the xanthine oxidase inhibitor therapy is interrupted, lesinurad should also be withheld.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Preexisting renal impairment:
Estimated CrCl ≥60 mL/minute: No dosage adjustment necessary.
Estimated CrCl 45 to <60 mL/minute: No dosage adjustment is necessary; monitor more frequently.
Estimated CrCl 30 to <45 mL/minute: Treatment may be less effective (based on limited experience) and should not be initiated.
Estimated CrCl <30 mL/minute: Use is contraindicated.
End-stage renal disease (ESRD) or patients on dialysis: Use is contraindicated.
Renal toxicity during treatment: Estimated CrCl persistently <45 mL/minute: Discontinue treatment.
Mild to moderate impairment (Child-Pugh class A and B): No dosage adjustment necessary.
Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Zurampic: 200 mg [DSC]
No
An FDA-approved patient medication guide, which is available with the product information and at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207988lbl.pdf#page=17, must be dispensed with this medication.
Oral: Administer in the morning with food and water. Administer at the same time in the morning as the dose of xanthine oxidase inhibitor. Advise patients to stay well hydrated (eg 2 L of fluids/day).
Hyperuricemia associated with gout: 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.
Limitations of use: Lesinurad is not recommended for the treatment of asymptomatic hyperuricemia. Lesinurad should not be used as monotherapy.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Incidence reported in combination with a xanthine oxidase inhibitor.
1% to 10%:
Central nervous system: Headache (5%)
Gastrointestinal: Gastroesophageal reflux disease (3%)
Infection: Influenza (5%)
Renal: Increased serum creatinine (≤6%; 1.5 x to <2.0 x baseline: 4%; ≥2.0 x baseline: 2%; most elevations were transient and resolved without therapy interruption), renal failure (2%)
Frequency not defined:
Cardiovascular: Cerebrovascular accident, myocardial infarction
Renal: Acute renal failure
<1%, postmarketing, and/or case reports: Nephrolithiasis
Severe renal impairment (CrCl <30 mL/minute), end-stage renal disease (ESRD), dialysis, kidney transplant recipients, tumor lysis syndrome, or Lesch-Nyhan syndrome
Concerns related to adverse effects:
• Cardiovascular events: Major cardiac adverse events (cardiovascular deaths, non-fatal MI, or non-fatal strokes) were observed in clinical trials, although a causal relationship with lesinurad was not established.
• Gout flare: Following initiation of uric acid lowering therapy, gout may flare due to mobilization of urate from tissue deposits; gout flare prophylaxis is recommended when initiating lesinurad treatment. Lesinurad treatment may continue during gout flare and management of the flare.
• Nephrotoxicity: Lesinurad, when used concurrently with a xanthine oxidase inhibitor, is associated with an increased incidence of serum creatinine elevations (generally reversible). [US Boxed Warning]: Acute renal failure has occurred with lesinurad and was more common when lesinurad was given alone. Renal failure (acute and chronic) and nephrolithiasis have also been reported (when used in combination with a xanthine oxidase inhibitor). The incidence of renal-related adverse events was also higher with lesinurad dosed at 400 mg (which is higher than the approved dose).
Disease-related concerns:
• Renal impairment: Evaluate renal function prior to treatment initiation and periodically, as clinically indicated, thereafter (more frequently in patients with estimated CrCl <60 mL/minute or with serum creatinine elevations 1.5 to 2 times the baseline level). Lesinurad should not be initiated in patients with estimated CrCl <45 mL/minute and is contraindicated with estimated CrCl <30 mL/minute. Lesinurad is not expected to be effective in patients with estimated CrCl <30 mL/minute, end-stage renal disease (ESRD), and/or on dialysis. Interrupt treatment if serum creatinine is elevated to >2 times baseline level. Interrupt treatment and measure serum creatinine if symptoms indicative of acute uric acid nephropathy (including flank pain, nausea, or vomiting) occur; do not restart without determining the cause of the serum creatinine abnormality.
• Secondary hyperuricemia: Lesinurad has not been studied in patients with secondary hyperuricemia (including organ transplant recipients); use is contraindicated in patients with tumor lysis syndrome or Lesch-Nyhan syndrome, where the uric acid formation rate is greatly increased.
Special populations:
• CYP2C9 poor metabolizers: Lesinurad exposure is ~1.8 fold higher in CYP2C9 poor metabolizers; use with caution.
Other warnings/precautions:
• Appropriate use: [US Boxed Warning]: Lesinurad should only be used in combination with a xanthine oxidase inhibitor; do not use as monotherapy. Lesinurad should be added when target serum uric acid levels are not achieved with a medically appropriate dose of single-agent xanthine oxidase inhibitor therapy. Lesinurad use is not recommended in patients taking allopurinol daily doses <300 mg (or <200 mg in patients with estimated CrCl <60 mL/minute).
Substrate of CYP2C9 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP3A4 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alpelisib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy
Aspirin: May diminish the therapeutic effect of Lesinurad. Risk C: Monitor therapy
CarBAMazepine: May decrease the serum concentration of Lesinurad. Lesinurad may decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy
CloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine. Risk C: Monitor therapy
CYP2C9 Inducers (Moderate): May decrease the serum concentration of Lesinurad. Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Lesinurad. Risk C: Monitor therapy
Hormonal Contraceptives: CYP3A4 Inducers (Weak) may decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a weak CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification
Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy
NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Risk C: Monitor therapy
Rifapentine: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy
Selpercatinib: CYP3A4 Inducers (Weak) may decrease the serum concentration of Selpercatinib. Risk C: Monitor therapy
Sirolimus (Conventional): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Sirolimus (Protein Bound): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Protein Bound). Risk C: Monitor therapy
Tacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Ubrogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a weak CYP3A4 inducer. Risk D: Consider therapy modification
Valproate Products: May increase the serum concentration of Lesinurad. Risk X: Avoid combination
All forms of hormonal contraceptives (eg, oral, injectable, topical) may be less effective during therapy with lesinurad. Additional methods of contraception are recommended during therapy.
Adverse events were not observed in animal reproduction studies.
It is not known if lesinurad is excreted in breast milk. According to the manufacturer, the decision to breastfeed during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.
Serum creatinine and estimated CrCl prior to treatment initiation and periodically, as clinically indicated, thereafter (more frequently in patients with estimated CrCl <60 mL/minute or with serum creatinine elevations 1.5 to 2 times the baseline level). Serum uric acid levels after every dose titration until desired level is achieved, then every 6 months (symptomatic patients) or every 12 months (all patients on urate-lowering therapy, regardless of symptoms) (FitzGerald 2018).
Uric acid, serum:
Adults:
Normal values:
Males: 3.4 to 7 mg/dL or slightly more
Females: 2.4 to 6 mg/dL or slightly more
Goal during therapy: <6 mg/dL; <5 mg/dL in patients with severe gout (eg, tophi, frequent attacks, chronic arthropathy) (EULAR [Richette 2017]). Levels <3 mg/dL are not recommended long-term (EULAR [Richette 2017]).
Note: Serum uric acid values >7 mg/dL do not necessarily represent clinical gout; the American College of Rheumatology (ACR) clinical practice guidelines recommend against initiating pharmacologic management of asymptomatic hyperuricemia (ACR [FitzGerald 2020]).
Lesinurad inhibits the function of transporter proteins involved in renal uric acid reabsorption (uric acid transporter 1 [URAT1] and organic anion transporter 4 [OAT4]), and lowers serum uric acid levels and increases renal clearance and fractional excretion of uric acid in patients with gout.
Absorption: Rapid
Distribution: Extensive. Vdss: ~20 L
Protein binding: >98%; primarily to albumin
Metabolism: Metabolized oxidatively primarily via CYP2C9; plasma exposure to metabolites is minimal; metabolites are not known to contribute to activity
Bioavailability: ~100%
Half-life elimination: ~5 hours
Time to peak: Within 1 to 4 hours
Excretion: Urine (63%; ~30% as unchanged drug); feces (32%)
Altered kidney function: Lesinurad exposure is increased by 30% in patients with estimated CrCl 60 to <90 mL/minute, 50% to 73% in patients with estimated CrCl 30 to <60 mL/minute, and 113% in patients with estimated CrCl <30 mL/minute; when compared with patients with normal renal function.
Hepatic function impairment: In patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B), following administration of a single 400 mg dose, the AUC was 7% and 33% higher, respectively, when compared with patients with normal hepatic function.
Tablets (Zurampic Oral)
200 mg (per each): $14.84
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