Lesinurad

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Lesinurad helps the kidneys remove uric acid from the body. Lesinurad is used together with other medicines that can cause the body to produce less uric acid.

Lesinurad is used as part of a combination of medicines to treat high levels of uric acid in your blood, also called hyperuricemia (HYE-per-URE-i-SEE-mee-a). High levels of uric acid can lead to a condition called gout.

Lesinurad should be used together with allopurinol (Zyloprim) or febuxostat (Uloric). Lesinurad should not be used alone.

Lesinurad may also be used for purposes not listed in this medication guide.

Lesinurad can cause kidney failure, especially if you take it without your other prescribed medications. Call your doctor right away if you urinate less than usual or not at all, if you have pain when urinating, swelling in your feet or ankles, or shortness of breath.

You should not use lesinurad if you are allergic to it, or if:

• you have severe kidney disease;
• you are on dialysis;
• you received a kidney transplant;
• you have Lesch-Nyhan syndrome (a genetic condition that increases uric acid levels in the blood); or
• you have tumor lysis syndrome (rapid breakdown of cancer cells).

To make sure lesinurad is safe for you, tell your doctor if you have:

• kidney disease;
• liver disease;
• heart disease; or
• a stomach disorder called gastroesophageal reflux disease (GERD).

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

Lesinurad can make birth control pills less effective. Ask your doctor about using a non hormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy.

Other forms of hormonal contraception (injections, implants, skin patches, vaginal rings, and certain intrauterine devices) may not be effective enough to prevent pregnancy during your treatment with lesinurad.

It is not known whether lesinurad passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Lesinurad is not approved for use by anyone younger than 18 years old.

Serious side effects have been reported with lesinurad including the following: 

• Heart problems. People who take lesinurad can have serious heart problems including heart attack and stroke.
• Kidney problems. Your doctor will monitor your kidney function before starting lesinurad and monitor during your treatment. 

Make sure to take lesinurad with xanthine oxidase inhibitor such as allopurinol or febuxostat. Lesinurad should not be taken alone. Taking lesinurad alone can hurt your kidneys. 

Make sure to remain hydrated and avoid becoming dehydrated. It is recommended you drink 2 liters (68 ounces) of fluid each day to stay hydrated. 

Do not take lesinurad if you:

• are allergic to lesinurad or to any of its ingredients (include for all meds)
• have severe kidney problems, received a kidney transplant or you are on dialysis
• have a fast breakdown of cancer cells that can lead to high uric acid (Tumor lysis syndrome)
• have a rare inherited condition that causes too much uric acid in the blood (Lesch Nyhan syndrome)

WARNING: RISK OF ACUTE RENAL FAILURE, MORE COMMON WHEN USED WITHOUT A XANTHINE OXIDASE INHIBITOR

Acute renal failure has occurred with Zurampic and was more common when Zurampic was given alone. Zurampic should be used in combination with a xanthine oxidase inhibitor.

Contraindications

• Patients with severe renal impairment (estimated Clcr <30 mL/minute) or end-stage renal disease, patients undergoing dialysis, renal transplant recipients, and patients with tumor lysis syndrome or Lesch-Nyhan syndrome.1

Warnings/Precautions

Warnings

Acute renal failure reported; more common when lesinurad administered as monotherapy.1 Use in combination with a xanthine oxidase inhibitor (e.g., allopurinol, febuxostat).1 (See Renal Effects under Cautions.)

Other Warnings/Precautions

Lesinurad increases renal excretion of uric acid, which can result in uric acid microcrystallization in the renal tubule or urinary system, potentially resulting in acute uric acid nephropathy or renal stones.1 5 10 Combined use with a xanthine oxidase inhibitor, which blocks uric acid production, reduces the amount of uric acid available for excretion and decreases the risk of adverse renal effects.4 9

Therapy with lesinurad 200 mg daily (maximum recommended dosage) in combination with a xanthine oxidase inhibitor associated with increased Scr (generally reversible), adverse renal-related effects, and renal stones.1 Higher incidence of increased Scr and adverse renal-related effects, including acute renal failure, reported with lesinurad 400 mg daily; highest incidence occurred with the 400-mg dosage given as monotherapy.1

Adverse renal effects reported in patients with normal or impaired renal function, but incidence is higher in patients with moderate renal impairment compared with those with mild renal impairment or normal baseline renal function.1

Do not use lesinurad as monotherapy; do not initiate in patients with estimated Clcr <45 mL/minute.1

Evaluate renal function prior to initiating therapy and periodically thereafter as clinically indicated.1 More frequent monitoring recommended in patients with estimated Clcr <60 mL/minute or with Scr elevations of 1.5–2 times the baseline value.1

Treatment interruption or discontinuance may be necessary in patients with adverse renal effects.1 (See Dosage under Dosage and Administration.)

Major adverse cardiovascular events (i.e., cardiovascular death, nonfatal MI, nonfatal stroke) reported in clinical studies; causal relationship not established.1

Specific Populations

Data not available regarding use in pregnant women.1 Animal studies revealed no evidence of teratogenicity, embryofetal toxicity, or adverse developmental effects.1

Not known whether lesinurad is distributed into human milk or has any effects on breast-fed infants or on milk production.1 Distributed into milk in rats in concentrations approximately equivalent to plasma concentrations.1

Consider the benefits of breast-feeding along with the importance of the drug to the woman and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1

Safety and efficacy in pediatric patients <18 years of age not established.1

No overall differences in safety and efficacy observed between geriatric patients and younger adults.1 However, possibility of greater sensitivity of some older patients cannot be ruled out.1

Mild or moderate hepatic impairment does not substantially alter lesinurad pharmacokinetics.1 4

Not studied in patients with severe hepatic impairment and not recommended in this population.1

AUC is increased in patients with renal impairment.1 (See Special Populations under Pharmacokinetics: Absorption.)

In clinical studies of combination lesinurad and xanthine oxidase inhibitor therapy, 62% of patients had mild or moderate renal impairment.1 No clear differences in safety and efficacy in patients with mild renal impairment (estimated Clcr 60 to <90 mL/minute) compared with those with normal renal function.1 Patients with moderate renal impairment (estimated Clcr 30 to <60 mL/minute) had higher incidence of adverse renal effects compared with those with mild renal impairment or normal renal function.1 (See Renal Effects under Cautions.) Trend toward lesser efficacy observed in patients with estimated Clcr <45 mL/minute (only limited experience in this population).1

Efficacy and safety not established in those with severe renal impairment (estimated Clcr <30 mL/minute) or end-stage renal disease, or in those undergoing dialysis; not expected to be effective in these patients.1 Contraindicated in these patients and in renal transplant recipients.1

Assess renal function before initiating lesinurad and periodically thereafter as clinically appropriate; more frequent monitoring recommended in patients with estimated Clcr <60 mL/minute or with increases in Scr to 1.5–2 times the baseline value.1 Do not initiate in patients with estimated Clcr <45 mL/minute; discontinue lesinurad if estimated Clcr is persistently <45 mL/minute.1

Use with caution in patients who are poor CYP2C9 metabolizers; lesinurad exposure may be increased.1 (See Special Populations under Pharmacokinetics: Absorption.)

Common Adverse Effects

Headache,1 10 influenza,1 increased Scr,1 10 GERD.1

Storage

Oral

20–25°C (may be exposed to 15–30°C).1 Protect from light.1

• Reduces serum uric acid concentrations via inhibition of URAT1 and OAT4, 2 apical transporter proteins in the OAT family6 involved in renal reabsorption of uric acid.1 8 URAT1 accounts for majority of reabsorption of filtered uric acid from renal tubular lumen;1 OAT4 is associated with diuretic-induced hyperuricemia.1 8

• Does not inhibit glucose transporter 9 (GLUT9), a uric acid reabsorption transporter located on the basolateral membrane of the proximal tubule cell.1 5 8

• More selective than probenecid, which inhibits URAT1, OAT4, and other OAT family members (OAT1 and OAT3) in the clinical setting.2 8

• Increases renal clearance and fractional excretion of uric acid and lowers serum uric acid concentrations in a dose-dependent manner in patients with gout.1 Combined use with a xanthine oxidase inhibitor, which blocks uric acid production, reduces amount of uric acid available for excretion and decreases risk of adverse renal effects.4 9

It is very important that your doctor check your progress at regular visits to make sure lesinurad is working properly. Blood and urine tests may be needed to check for unwanted effects.

lesinurad may cause kidney problems. Tell your doctor right away if you have decreased urine output, depression, dizziness, a headache, lethargy, muscle twitching, nausea, rapid weight gain, seizures, swelling of the face, ankles, or hands, or unusual tiredness or weakness after taking lesinurad.

Heart or blood vessel problems may occur with lesinurad. Tell your doctor if you have chest pain or discomfort, confusion, nausea or vomiting, pain or discomfort in the arms, jaw, back, or neck, sweating, trouble speaking, or slow speech, or are unable to move your arms, legs, or facial muscles.

Birth control pills, patches, and injections may not work as well while you are using lesinurad. Use another form of birth control together with your birth control pills to keep from getting pregnant. Check with your doctor if you have any questions.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take in the morning.
• Take with food.
• Take with a full glass of water.
• Take lesinurad at the same time as the drug you take it with. Do not take this medicine by itself. Tell your doctor if you stop taking the other drug for any reason.
• Drink lots of noncaffeine liquids every day unless told to drink less liquid by your doctor.

What do I do if I miss a dose?

• Skip the missed dose and go back to your normal time.
• Do not take more than 1 dose of lesinurad in the same day.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Flu-like signs.
• Heartburn.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

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.

Refer to adult dosing.

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.

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 every 2 to 5 weeks during uric acid lowering therapy titration then every 6 months (Khanna 2012).

Adverse events were not observed in animal reproduction studies.

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.

Commonly reported side effects of lesinurad include: increased serum creatinine. Other side effects include: acute renal failure. See below for a comprehensive list of adverse effects.

Applies to lesinurad: oral tablet

General

The more common side effects include increased serum creatinine, headache, influenza, and gastroesophageal reflux disease.[Ref]

Renal

When used at labeled doses in combination with a xanthine oxidase inhibitor (XOI), serum creatinine increases of 1.5 to less than 2 times or 2 times or greater from baseline occurred in 3.9% (n=20/511) and 1.8% (n=9/511) of patients, respectively. Increased serum creatinine levels resolved in most patients (up to 90%) without treatment interruption. Based on baseline renal function, serum creatinine increases occurred in 3%, 3.8%, and 6.9% of patients with normal (CrCl greater than 90 mL/min), mild (CrCl 60 to less than 90 mL/min), or moderate (CrCl greater than 30 to less than 60 mL/min) renal impairment.

Use at higher than approved doses with or without an XOI resulted in increased serum creatinine levels. Consistently, patients receiving 400 mg daily as monotherapy experienced a higher incidence of renal failure. Nephrolithiasis occurred more frequently in patients receiving 400 mg daily in combination with an XOI (2.5%) compared to labeled doses in combination with an XOI (0.6%).[Ref]

Common (1% to 10%): Increased serum creatinine, renal failure
Uncommon (0.1% to 1%): Nephrolithiasis[Ref]

Nervous system

Common (1% to 10%): Headache[Ref]

Immunologic

Common (1% to 10%): Influenza[Ref]

Gastrointestinal

Common (1% to 10%): Gastroesophageal reflux disease[Ref]

Cardiovascular

Frequency not reported: Cardiovascular death, non-fatal myocardial infarction, non-fatal stroke[Ref]

Incidence rate ratios for major adverse cardiac events compared to placebo were 1.36 (95% CI: 0.23, 9.25) in 200 mg and 2.71 (95% CI: 0.66, 16) in 400 mg.[Ref]

Some side effects of lesinurad may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Safety has not been established during pregnancy. US FDA pregnancy category: Not assigned. Risk Summary: No available human data on use of this drug in pregnant women to inform a drug-related risk. Comments: In female patients using hormonal contraceptives to prevent pregnancy, concomitant use with this drug may decrease contraceptive reliability; use of adequate methods of non-hormonal contraception should be discussed.

Studies in rabbits and rats have failed to reveal evidence of teratogenicity, effect on fetal development, or survival at doses of 10 times the maximum recommended human dose (MRHD) and 45 times MRHD, respectively; however, maternal toxicity was observed. There are no controlled data in human pregnancy. US FDA pregnancy category Not assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion about the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.