Does Zurampic (lesinurad) cause side effects?

Zurampic (lesinurad) is a selective uric acid reabsorption inhibitor (SURI) that reduces uric acid levels in people who have too much uric acid in their blood (hyperuricemia) and have symptoms of gout

Uric acid is formed from the breakdown of certain chemicals (purines) in the body. Hyperuricemia occurs when the body produces more uric acid than it can eliminate. The uric acid forms crystals in joints (gouty arthritis) and tissues, causing inflammation and pain

Elevated blood uric acid levels also can cause kidney disease and kidney stones

Zurampic reduces uric acid levels by blocking the function of proteins in the kidney involved in reabsorbing uric acid from urine back into the bloodstream. Reducing reabsorption of uric acid reduces the levels of uric acid in the body. Zurampic is used in combination with another class of drugs called xanthine oxidase inhibitors

Common side effects of Zurampic include

Serious side effects of Zurampic include

Drug interactions of Zurampic include amiodarone and fluconazole reduce the breakdown of Zurampic in the liver, increasing blood levels of Zurampic.

Zurampic blood levels are decreased by drugs such as rifampin and carbamazepine, that increase its breakdown in the liver. 

Zurampic may reduce blood levels of sildenafil, amlodipine, and other drugs that are broken down by CYP3A4 liver enzymes

Aspirin doses higher than 325 mg per day may decrease the effect of Zurampic and allopurinol treatment. 

Zurampic may reduce the effect of hormonal contraceptives. 

Women should use additional methods of contraception when taking Zurampic. There are no adequate trials of Zurampic use in pregnant women. Zurampic should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 

It is unknown if Zurampic is excreted into breast milk. Consult your doctor before breastfeeding.

What are the important side effects of Zurampic (lesinurad)?

Common side effects of lesinurad include:

Possible serious side effects of lesinurad include:

Zurampic (lesinurad) side effects list for healthcare professionals

The following adverse reactions are also discussed in other sections:

  • Renal Events
  • Cardiovascular Events

Clinical Trials Experience

Because clinical trials 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 Zurampic is 200 mg once daily in combination with a xanthine oxidase inhibitor.

In 3 randomized, placebo-controlled studies of Zurampic 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 Zurampic 200 mg, Zurampic 400 mg, and placebo, respectively.

The mean duration of treatment with Zurampic 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 (eCLcr less than 90 mL/min) and 79% of patients had at least one co-morbid condition including

Renal Events

Zurampic 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 Zurampic 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 Zurampic 200 mg and Zurampic 400 mg resolved without treatment interruption (Table 1).

Table 1: Patients with Elevated Serum Creatinine Values in the Placebo-Controlled Clinical Studies with Zurampic in Combination with a Xanthine Oxidase Inhibitor (XOI)

[n (%)]Placebo +XOI (N=516)Zurampic 200 mg + XOI (N=511)Zurampic 400 mg + XOI (N=510)
Serum creatinine elevation 1.5 x to < 2.0 x baseline12 (2.3%)20 (3.9%)51 (10.0%)
  Resolution of serum creatinine elevations by end of study9/12 (75.0%)18/20 (90.0%)42/51 (82.4%)
Serum creatinine elevation ≥ 2.0 x baseline09 (1.8%)34 (6.7%)
  Resolution of serum creatinine elevations by end of studyN/A8/9 (88.9%)26/34 (76.5%)

Renal-related adverse reactions, including blood creatinine increases and renal failure, and nephrolithiasis reported in patients receiving Zurampic 200 mg, Zurampic 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 Zurampic and was highest with Zurampic 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 Zurampic 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 Zurampic in Combination with a Xanthine Oxidase Inhibitor (XOI)

[n (%)]Placebo + XOI (N=516)Zurampic 200 mg + XOI (N=511)Zurampic 400 mg + XOI (N=510)
Blood creatinine increased12 (2.3%)22 (4.3%)40 (7.8%)
Renal failure111 (2.1%)6 (1.2%)18 (3.5%)
Nephrolithiasis9 (1.7%)3 (0.6%)13 (2.5%)
1Renal failure includes the following adverse reactions: renal failure, renal impairment, renal failure chronic, renal failure acute, acute prerenal failure.

Table 3: Incidence of Renal-Related Adverse Reactions by Baseline Renal Function Category in Placebo-Controlled Clinical Studies with Zurampic in Combination with a Xanthine Oxidase Inhibitor (XOI)

n (%)Placebo + XOIZurampic 200 mg + XOIZurampic 400 mg + XOI
≥ 90 mL/minn=180n=200n=203
  Blood creatinine increased1 (0.6%)6 (3.0%)12 (5.9%)
  Renal failure103 (1.5%)7 (3.4%)
≥ 60 - < 90 mL/minn=229n=208n=213
  Blood creatinine increased4 (1.7%)8 (3.8%)21 (9.9%)
  Renal failure14 (1.7%)1 (0.5%)7 (3.3%)
≥ 30 - < 60 mL/minn=101n=101n=92
  Blood creatinine increased6 (5.9%)7 (6.9%)10 (10.9%)
  Renal failure15 (5.0%)2 (2.0%)4 (4.3%)
1 Renal failure includes the following adverse reactions: renal failure, renal impairment, renal failure chronic, renal failure acute, acute prerenal failure.

Renal-related adverse reactions resulted in a similar discontinuation rate on Zurampic 200 mg in combination with a xanthine oxidase inhibitor (1.2%) and a xanthine oxidase inhibitor alone (1%) and a higher rate on Zurampic 400 mg in combination with a xanthine oxidase inhibitor (3.3%).

Serious renal-related adverse reactions were reported in patients on Zurampic 400 mg in combination with a xanthine oxidase inhibitor (1%) and a xanthine oxidase inhibitor alone (0.4%) and in no patients on Zurampic 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 Zurampic 200 mg and Zurampic 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 Zurampic 400 mg alone and in no patients receiving placebo. Serum creatinine elevations 1.5-fold or greater occurred in 24.3 % of patients receiving Zurampic 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 Zurampic.

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 Zurampic 200 mg, and 8 (1.94) for Zurampic 400 mg when used in combination with a xanthine oxidase inhibitor.

Incidence rate ratios for Zurampic 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 Zurampic 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 Zurampic 200 mg-Treated Patients and at Least 1% Greater than Seen in Patients Receiving Placebo in Controlled Studies with Zurampic in Combination with a Xanthine Oxidase Inhibitor (XOI)

Adverse ReactionPlacebo + XOI (N=516)Zurampic 200 mg + XOI (N=511)
Headache4.1%5.3%
Influenza2.7%5.1%
Gastroesophageal reflux disease0.8%2.7%

What drugs interact with Zurampic (lesinurad)?

CYP2C9 Inhibitors, CYP2C9 Poor Metabolizers, And CYP2C9 Inducers

  • Lesinurad exposure is increased when Zurampic is co-administered with inhibitors of CYP2C9, and in CYP2C9 poor metabolizers.
  • Zurampic 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 Zurampic is co-administered with moderate inducers of CYP2C9 (eg, rifampin, carbamazepine), which may decrease the therapeutic effect of Zurampic.

CYP3A Substrates

  • In interaction studies conducted in healthy subjects with Zurampic 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.

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.

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.

Summary

Zurampic (lesinurad) is a selective uric acid reabsorption inhibitor (SURI) that reduces uric acid levels in people who have too much uric acid in their blood (hyperuricemia) and have symptoms of gout. Common side effects of Zurampic include headache, influenza, and gastroesophageal reflux disease (GERD). There are no adequate trials of Zurampic use in pregnant women. It is unknown if Zurampic is excreted into breast milk.

Treatment & Diagnosis

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Medically Reviewed on 9/28/2020
References
FDA Prescribing Information

Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.
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