Clinical Pharmacology Update: Duzallo

The FDA has approved Duzallo (lesinurad and allopurinol; Ironwood Pharmaceuticals, Inc) for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid (sUA) levels with a medically appropriate daily dose of allopurinol alone. The approval carries the limitation that the medication is not recommended for the treatment of asymptomatic hyperuricemia.¹

Pharmacology and Pharmacokinetics

Lesinurad is a uric acid reabsorption inhibitor. It lowers sUA levels by increasing renal excretion of uric acid. Allopurinol, a xanthine oxidase inhibitor, exerts its effect by reducing the production of uric acid.^1,2

Dosage and Administration

The dose of Duzallo is one 200-mg lesinurad/300-mg allopurinol tablet by mouth once daily in the morning, taken with food and water. In patients with decreased renal function, the dose is reduced to one 200-mg lesinurad/200-mg allopurinol tablet daily. No more than 1 tablet should be taken per day, because each contains the maximum daily dose of lesinurad. Duzallo should not be taken with another formulation of lesinurad, such as Zurampic.

Patients using less than 300 mg of allopurinol daily or patients with decreased renal function using less than 200 mg daily should not take Duzallo. Treatment with Duzallo replaces an equivalent portion of the total daily allopurinol dose, which should be maintained when Duzallo is initiated.

Renal function should be assessed prior to beginning treatment with Duzallo. Treatment should not be initiated if the estimated creatinine clearance (eCLcr) is less than 45 ml/min, and the medication should be discontinued if the eCLcr persistently falls below 45 ml/min. Patients should stay well hydrated while using Duzallo, aiming for of 2 liters of fluid per day.¹

Clinical Trials

Although Duzallo has not been studied in phase 3 clinical trials, bioequivalence of the medication to its individual components was demonstrated, and this combination was then evaluated for efficacy in 2 phase 3 clinical studies. Both were 12-month, multicenter, randomized, double-blind, placebo-controlled studies in adult patients with hyperuricemia and gout. The results showed that in patients who did not achieve target sUA levels on allopurinol monotherapy, the combination of lesinurad and allopurinol was superior to allopurinol alone in lowering sUA to less than 6 mg/dL at month 6. The combination also was found to reduce the mean sUA level to <6 mg/dL by month 1 and maintain that level through month 12.^1,2

Contraindications, Warnings, and Precautions

Treatment with Duzallo is contraindicated in patients with severe renal impairment, end-stage renal disease, a history of kidney transplant, dialysis, tumor lysis syndrome, Lesch-Nyhan syndrome, or a known hypersensitivity to allopurinol, including skin rash. Renal function should be monitored at initiation of and throughout treatment, particularly in patients with an eCLcr below 60 mL/min. Duzallo should be discontinued immediately if a rash or an allergic reaction occurs. Hepatotoxicity has been reported in patients using allopurinol. Duzallo should not be used in patients with severe hepatic impairment. Liver function evaluation should be performed if signs and symptoms of liver toxicity develop. Major cardiovascular events have been observed during treatment with lesinurad. However, a causal relationship has not been established. Bone marrow depression has been reported in patients taking allopurinol.

Dose reductions of mercaptopurine or azathioprine are required when either agent is used concurrently with Duzallo. Caution and extra monitoring are advised when Duzallo is used concomitantly with coumarin anticoagulants, moderate cytochrome P450 2C9 isozyme (CYP2C9) inhibitors, or cytochrome P450 3A isozyme (CYP3A) substrates. The most commonly reported adverse reactions are gastroesophageal reflux disease, headache, increased blood creatinine, and influenza.¹

Monica Holmberg, PharmD, BCPS, earned her PharmD at the University of Connecticut in Storrs and completed an ambulatory care residency at the Phoenix VA Healthcare System in Arizona. Her practice has also included pediatrics and inpatient mental health. She lives in Phoenix.

References

• Duzallo [prescribing information]. Cambridge, MA: Ironwood Pharmaceuticals, Inc; 2017. irwdpi.com/duzallo/DuzalloPIandMedguide2017.pdf#page=1. Accessed December 22, 2017.
• Ironwood Pharmaceuticals announces FDA approval of Duzallo (lesinurad and allopurinol) for the treatment of hyperuricemia in patients with uncontrolled gout [press release]. Cambridge, MA: Ironwood Pharmaceuticals, Inc; August 21, 2017. news.ironwoodpharma.com/phoenix.zhtml?c=228069&p=irol- newsArticle&ID=2294774. Accessed December 22, 2017.