Acute renal failure has occurred with lesinurad, one of the components of Duzallo.
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.
Note : Use of this combination product is not recommended in patients with an estimated CrCl <60 mL/minute who are receiving allopurinol <200 mg/day.
Prior to initiation: 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 renal function more frequently.
Estimated CrCl 30 to <45 mL/minute: Treatment should not be initiated; therapy may be less effective (based on limited experience).
Estimated CrCl <30 mL/minute: Use is contraindicated.
ESRD or patients on dialysis: Use is contraindicated.
During therapy: Renal impairment:
Estimated CrCl persistently <45 mL/minute: Discontinue treatment.
Serum creatinine elevated >2 times baseline: Interrupt therapy.
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.
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.
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]
No
Duzallo has been discontinued in the United States for >1 year.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209203s000lbl.pdf#page=27, must be dispensed with this medication.
Administer in the morning with food and water. Stay well hydrated (eg, 2 liters of liquid per day).
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.
See individual agents.
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 Asian descent (eg, Korean, Han Chinese, Thai) and African American patients (ACR [FitzGerald 2020]).
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 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.
Refer to individual components.
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
Aluminum Hydroxide: May decrease the serum concentration of Allopurinol. Management: Consider administering allopurinol 3 hours prior to aluminum hydroxide. Risk D: Consider therapy modification
Amoxicillin: Allopurinol may enhance the potential for allergic or hypersensitivity reactions to Amoxicillin. Risk C: Monitor therapy
Ampicillin: Allopurinol may enhance the potential for allergic or hypersensitivity reactions to Ampicillin. Risk C: Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: May enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Risk C: Monitor therapy
Aspirin: May diminish the therapeutic effect of Lesinurad. Risk C: 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. Risk D: Consider therapy modification
Bacampicillin: Allopurinol may enhance the potential for allergic or hypersensitivity reactions to Bacampicillin. Risk C: Monitor therapy
Bendamustine: Allopurinol may enhance the adverse/toxic effect of Bendamustine. Specifically, the risk of severe skin reactions may be enhanced. Risk C: Monitor therapy
CarBAMazepine: Allopurinol may increase the serum concentration of CarBAMazepine. 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
Cyclophosphamide: Allopurinol may increase the serum concentration of Cyclophosphamide. Risk C: Monitor therapy
CycloSPORINE (Systemic): Allopurinol may increase the serum concentration of CycloSPORINE (Systemic). 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
Didanosine: Allopurinol may increase the serum concentration of Didanosine. Risk X: Avoid combination
Doxofylline: Allopurinol may increase the serum concentration of Doxofylline. Risk C: Monitor therapy
Fluorouracil Products: Allopurinol may decrease serum concentrations of the active metabolite(s) of Fluorouracil Products. Risk X: Avoid combination
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
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. Risk C: 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). Risk C: 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. Risk D: Consider therapy modification
NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Risk C: 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. Risk X: Avoid combination
Rifapentine: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: 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. Risk D: Consider therapy modification
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
Theophylline Derivatives: Allopurinol may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Thiazide and Thiazide-Like Diuretics: May enhance the potential for allergic or hypersensitivity reactions to Allopurinol. 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
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. Risk D: Consider therapy modification
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.
Animal reproduction studies have not been conducted with this combination. See individual monographs for additional information.
Allopurinol and its active metabolite are present in breast milk. Excretion of lesinurad is not known. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. See individual monographs.
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.
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/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
Protein binding: Lesinurad: >98%, primarily to albumin
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
Bioavailability: Lesinurad: ~100%
Half-life elimination: Allopurinol: ~1 to 2 hours; Oxypurinol: ~26 hours; lesinurad: ~5 hours
Time to peak: Allopurinol: 1.5 hours; Oxypurinol: 4.5 hours
Excretion: Allopurinol: feces (~20%); lesinurad: urine (63%; ~30% as unchanged drug); feces (32%)
Altered kidney function: 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.
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.
Tablets (Duzallo Oral)
200-200 mg (per each): $14.84
200-300 mg (per each): $14.84
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