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Lesinurad and Allopurinol

Medically reviewed by Drugs.com. Last updated on Aug 22, 2020.

Pronunciation

(le SIN ure ad & al oh PURE i nole)

Index Terms

  • Allopurinol and Lesinurad

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Duzallo: Lesinurad 200 mg and allopurinol 200 mg [DSC], Lesinurad 200 mg and allopurinol 300 mg [DSC]

Brand Names: U.S.

  • Duzallo [DSC]

Pharmacologic Category

  • Antigout Agent
  • Uric Acid Transporter 1 (URAT1) Inhibitor
  • Xanthine Oxidase Inhibitor

Pharmacology

Lesinurad/allopurinol: Lowers serum uric acid levels by increasing excretion and inhibiting production of uric acid.

Allopurinol: Allopurinol inhibits xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine to uric acid. Allopurinol is metabolized to oxypurinol which is also an inhibitor of xanthine oxidase; allopurinol acts on purine catabolism, reducing the production of uric acid without disrupting the biosynthesis of vital purines.

Lesinurad: 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

Allopurinol: ~90% from GI tract; lesinurad: rapid

Distribution

Lesinurad: Vdss: IV: ~20 L

Metabolism

Allopurinol: Rapidly oxidized, primarily to oxypurinol

Lesinurad: Metabolized oxidatively primarily via CYP2C9; plasma exposure to metabolites is minimal; metabolites are not known to contribute to activity

Excretion

Allopurinol: feces (~20%); lesinurad: urine (63%; ~30% as unchanged drug); feces (32%)

Time to Peak

Allopurinol: 1.5 hours; Oxypurinol: 4.5 hours

Half-Life Elimination

Allopurinol: ~1 to 2 hours; Oxypurinol: ~26 hours; lesinurad: ~5 hours

Protein Binding

Lesinurad: >98%, primarily to albumin

Special Populations: Renal Function Impairment

Lesinurad: Lesinurad exposure 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 following administration of a single dose.

Special Populations: Hepatic Function Impairment

Lesinurad: AUC was 7% and 33% higher in patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) impairment following administration of a single dose.

Use: Labeled Indications

Hyperuricemia associated with gout: Treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a medically appropriate daily dose of allopurinol alone.

Limitations of use: Not recommended for the treatment of asymptomatic hyperuricemia.

Contraindications

Hypersensitivity to allopurinol, including previous occurrence of skin rash, or any component of the formulation; severe renal impairment (CrCl <30 mL/minute), ESRD, kidney transplant recipients, dialysis; tumor lysis syndrome; Lesch-Nyhan syndrome

Note: While not an absolute contraindication, the American College of Rheumatology suggests avoiding the use of allopurinol in patients with the HLA-B*5801 genotype due to the increased risk of allopurinol hypersensitivity syndrome (AHS). The guidelines recommend HLA-B*5801 screening in patients with a high incidence of this genotype; this includes patients of Southeast Asian descent (eg, Korean, Han Chinese, Thai) and African American patients (ACR [FitzGerald 2020]).

Dosing: Adult

Note: Duzallo has been discontinued in the United States for >1 year.

Note: Use of this combination product is not recommended in patients taking allopurinol <300 mg/day (or <200 mg/day in patients with estimated CrCl <60 mL/minute). Gout flare prophylaxis is recommended in patients not currently receiving lesinurad. In clinical trials, colchicine or nonsteroidal anti-inflammatory drugs were given for gout flare prophylaxis during the first 5 months following lesinurad/allopurinol treatment initiation in patients not adequately controlled on allopurinol alone.

Hyperuricemia associated with gout: Oral: 1 tablet (lesinurad 200 mg/allopurinol 200 mg or lesinurad 200 mg/allopurinol 300 mg) once daily; maximum dose: Lesinurad 200 mg once daily; do not exceed one tablet per day.

Patients who have not achieved target serum uric acid on a medically appropriate dose of allopurinol >300 mg: Initiate therapy by using one tablet of lesinurad/allopurinol once daily in place of an equivalent portion of the total daily allopurinol dose. Duzallo dosage forms allow for either allopurinol 200 mg or 300 mg once daily.

Patients who have not achieved target serum uric acid on a medically appropriate dose of allopurinol 300 mg: Initiate therapy by using one tablet of lesinurad 200 mg/allopurinol 300 mg once daily in place of allopurinol 300 mg.

Patients who have not achieved target serum uric acid on a medically appropriate dose of allopurinol 200 mg: Initiate therapy by using one tablet of lesinurad 200 mg/allopurinol 200 mg once daily in place of allopurinol 200 mg.

Patients currently on lesinurad in combination with allopurinol: Initiate therapy by using one tablet of lesinurad/allopurinol once daily in place of lesinurad and an equivalent portion of the daily allopurinol dose. Duzallo dosage forms allow for lesinurad 200 mg with either allopurinol 200 mg or 300 mg once daily.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Symptoms indicative of acute uric acid nephropathy (eg, flank pain, nausea, vomiting): Interrupt therapy and measure serum creatinine promptly; do not resume therapy if another cause of serum creatinine abnormalities is not identified.

Administration

Administer in the morning with food and water. Stay well hydrated (eg, 2 liters of liquid per day).

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Alpelisib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Monitor therapy

Aluminum Hydroxide: May decrease the serum concentration of Allopurinol. Management: Consider administering allopurinol 3 hours prior to aluminum hydroxide. Consider therapy modification

Amoxicillin: Allopurinol may enhance the potential for allergic or hypersensitivity reactions to Amoxicillin. Monitor therapy

Ampicillin: Allopurinol may enhance the potential for allergic or hypersensitivity reactions to Ampicillin. Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: May enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Monitor therapy

Aspirin: May diminish the therapeutic effect of Lesinurad. Monitor therapy

AzaTHIOprine: Allopurinol may increase serum concentrations of the active metabolite(s) of AzaTHIOprine. More specifically, allopurinol may increase mercaptopurine serum concentrations and promote formation of active thioguanine nucleotides. Management: Reduce azathioprine dose to one third to one quarter of the usual dose if used with allopurinol, and monitor closely for systemic toxicity. Further dose reduction or alternative therapies should be considered for patients with low or absent TPMT activity. Consider therapy modification

Bacampicillin: Allopurinol may enhance the potential for allergic or hypersensitivity reactions to Bacampicillin. Monitor therapy

Bendamustine: Allopurinol may enhance the adverse/toxic effect of Bendamustine. Specifically, the risk of severe skin reactions may be enhanced. Monitor therapy

Capecitabine: Allopurinol may decrease serum concentrations of the active metabolite(s) of Capecitabine. Avoid combination

CarBAMazepine: Allopurinol may increase the serum concentration of CarBAMazepine. Monitor therapy

CloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine. Monitor therapy

Cyclophosphamide: Allopurinol may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, bone marrow suppression. Monitor therapy

CycloSPORINE (Systemic): Allopurinol may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

CYP2C9 Inducers (Moderate): May decrease the serum concentration of Lesinurad. Monitor therapy

CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Lesinurad. Monitor therapy

Didanosine: Allopurinol may increase the serum concentration of Didanosine. Avoid combination

Doxofylline: Allopurinol may increase the serum concentration of Doxofylline. Monitor therapy

Estrogen Derivatives (Contraceptive): Lesinurad may decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use of an additional, nonhormonal contraceptive is recommended in patients being treated with lesinurad who desire effective contraception. Consider therapy modification

Loop Diuretics: May enhance the adverse/toxic effect of Allopurinol. Loop Diuretics may increase the serum concentration of Allopurinol. Specifically, Loop Diuretics may increase the concentration of Oxypurinol, an active metabolite of Allopurinol. Monitor therapy

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). Monitor therapy

Mercaptopurine: Allopurinol may increase the serum concentration of Mercaptopurine. Allopurinol may also promote formation of active thioguanine nucleotides. Management: Reduce the mercaptopurine dose to one third to one quarter of the usual dose if used with allopurinol, and monitor closely for systemic toxicity. Consider therapy modification

NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Monitor therapy

Pegloticase: Allopurinol may enhance the adverse/toxic effect of Pegloticase. Specifically, Allopurinol may blunt increases in serum urate that would signal an increased risk of anaphylaxis and infusion reactions. Avoid combination

Progestins (Contraceptive): Lesinurad may decrease the serum concentration of Progestins (Contraceptive). Management: Use of an additional, nonhormonal contraceptive is recommended in patients being treated with lesinurad who desire effective contraception. Consider therapy modification

Rifapentine: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Monitor therapy

Riluzole: Allopurinol may enhance the adverse/toxic effect of Riluzole. Specifically, the risk of hepatotoxicity may be increased. Management: Consider alternatives to allopurinol in patients receiving treatment with riluzole due to the potential for additive hepatotoxicity. Consider therapy modification

Selpercatinib: CYP3A4 Inducers (Weak) may decrease the serum concentration of Selpercatinib. Monitor therapy

Tacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease the serum concentration of Tacrolimus (Systemic). Monitor therapy

Tegafur: Allopurinol may diminish the therapeutic effect of Tegafur. Avoid combination

Theophylline Derivatives: Allopurinol may increase the serum concentration of Theophylline Derivatives. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Allopurinol. Specifically, Thiazide Diuretics may increase the concentration of Oxypurinol, an active metabolite of Allopurinol. 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. Consider therapy modification

Valproate Products: May increase the serum concentration of Lesinurad. Avoid combination

Vitamin K Antagonists (eg, warfarin): Allopurinol may enhance the anticoagulant effect of Vitamin K Antagonists. Management: Monitor for increased prothrombin times (PT)/therapeutic effects of oral anticoagulants if allopurinol is initiated/dose increased, or decreased effects if allopurinol is discontinued/dose decreased. Reductions in coumarin dosage will likely be needed. Consider therapy modification

Adverse Reactions

See individual agents.

ALERT: U.S. Boxed Warning

Risk of acute renal failure:

Acute renal failure has occurred with lesinurad, one of the components of Duzallo.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Bone marrow suppression has been reported in patients receiving allopurinol, most of whom received concomitant medications with a potential for hematologic toxicity. The onset occurs between 6 weeks to 6 years after allopurinol initiation.

• Cardiovascular events: Major cardiac adverse events (cardiovascular deaths, non-fatal MI, or non-fatal strokes) were observed in clinical trials, although a causal relationship was not established.

• CNS effects: May occasionally cause drowsiness; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Gout flare: Following initiation of urate-lowering therapy, including lesinurad/allopurinol, gout may flare due to mobilization of urate from tissue deposits; gout flare prophylaxis (such as colchicine or an NSAID) is recommended when initiating treatment in patients not currently taking lesinurad. Lesinurad/allopurinol treatment may continue during gout flare and management of the flare.

• Hepatotoxicity: Cases of hepatotoxicity (reversible) have been reported with allopurinol. Asymptomatic elevations of serum alkaline phosphatase or serum transaminases have been observed. Monitor for signs/symptoms of hepatotoxicity; evaluate liver function if they occur. Periodic liver function tests are recommended in patients with preexisting hepatic impairment.

• Hypersensitivity: Allopurinol has been frequently associated with a skin rash. In some instances a skin rash may be followed by more severe hypersensitivity reactions, including exfoliation, fever, lymphadenopathy, arthralgia, eosinophilia, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Associated vasculitis and tissue response may be manifested as hepatitis, renal impairment, seizures, or death (rare). Use with caution in patients with renal impairment and taking concomitant thiazide diuretics; hypersensitivity reactions may be increased. Discontinue therapy at first sign of skin rash or other signs indicative of allergic reaction. HLA-B*5801 allele testing prior to initiation of therapy in patients at a higher risk for allopurinol hypersensitivity syndrome (patients of Southeast Asian descent [eg, Korean, Han Chinese, Thai] and African American patients) is recommended (ACR [FitzGerald 2020]).

• 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). If serum creatinine increases >2 times the baseline, interrupt treatment. If symptoms of acute uric acid nephropathy (eg, flank pain, nausea, vomiting) are reported, interrupt treatment and measure creatinine promptly; do not restart therapy without another explanation for serum creatinine abnormalities.

Disease-related concerns:

• Renal impairment: Evaluate renal function prior to treatment initiation and periodically thereafter. Evaluate more frequently in patients with estimated CrCl <60 mL/minute or with serum creatinine elevations 1.5 to 2 times the baseline level. Do not initiate in patients with estimated CrCl <45 mL/minute; discontinue therapy if estimated CrCl <45 mL/minute persistently (contraindicated with CrCl <30 mL/minute).

• 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 in CYP2C9 poor metabolizers and patients taking concomitant moderate CYP2C9 inhibitors.

Monitoring Parameters

CBC, 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); LFTs (periodically in patients with preexisting hepatic disease), renal function (BUN, serum creatinine or creatinine clearance [prior to initiation and periodically]; more frequently in patients with estimated CrCl <60 mL/minute or with serum creatinine elevations 1.5 to 2 times the baseline level), prothrombin time (periodically in patients receiving warfarin); consider HLA-B*5801 testing prior to initiation of therapy in patients at a higher risk for allopurinol hypersensitivity syndrome (see Contraindications) (ACR guidelines [Khanna 2012]). Monitor hydration status, for signs and symptoms of hypersensitivity, hepatotoxicity.

Reproductive Considerations

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.

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. See individual monographs for additional information.

Patient Education

What is this drug used for?

• It is used to lower uric acid in the blood.

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

• Diarrhea

• Fatigue

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Infection

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain

• Nausea

• Vomiting

• Lower back pain

• Side pain

• Painful urination

• Swollen glands

• Joint pain

• Seizures

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

More about allopurinol / lesinurad

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Other brands: Duzallo

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