A closer look at new FDA actions: Uloric

Ms. Domenici and Dr. Patel are both pharmacists at Brigham and Women's Hospital, Boston, Massachusetts. Ms. Viscusi is a 5th-year pharmacy student at Massachusetts College of Pharmacy in Boston.

Takeda Pharmaceuticals' Uloric

On February 14, 2009, the FDA announced the approval of Takeda Pharmaceutical Company's Uloric (febuxostat) for the chronic management of hyperuricemia in patients with gout.¹ Uloric is not recommended for treatment of asymptomatic hyperuricemia.²

Clinical Pharmacology

Uloric exerts its effect by inhibiting the enzyme xanthine oxidase.² Xanthine oxidase is responsible for breaking down hypoxanthine, a purine base, into xanthine, and then further into uric acid.¹ Through the inhibition of xanthine oxidase, uric acid production is prevented, thus lowering serum uric acid (sUA) levels in patients with elevated levels. At therapeutic concentrations, Uloric is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis.²

Pharmacokinetics

Uloric has once-daily dosing and has approximately 49% bioavailability, without regard to food. Uloric has a mean terminal elimination half-life of approximately 5 to 8 hours, and is 99% bound to plasma protein.

Uloric is metabolized extensively in the liver, where it is metabolized by conjugation using uridine diphosphate glucuronosyltransferase enzymes and CYP450 enzymes. Uloric produces acyl glucuronide and oxidative metabolites which account for the major metabolites found in the urine and feces. Excretion occurs in the kidneys and liver, accounting for 49% renal excretion and 45% hepatic excretion.³

Dose adjustments are not required for mild-to-moderate renal or hepatic impairment. Patients with severe renal or hepatic impairment should use caution when taking Uloric, however, due to insufficient data. No dose adjustments are needed for elderly patients.²

Clinical Trials

A phase 2, randomized, double-blind, placebo-controlled trial was conducted in 153 patients (aged 23-80 years) who received Uloric (40 mg, 80 mg, 120 mg) or placebo once daily for 28 days and colchicine prophylaxis for 14 days prior to and 14 days after randomization.

The primary end point was the proportion of subjects with sUA levels <6.0 mg/dL on day 28. The targeted sUA level was attained on day 28 in 56% of those taking 40 mg, 76% taking 80 mg, and 94% taking 120 mg of Uloric and in none of those taking placebo.

The mean sUA reduction from baseline to day 28 was 37% in the 40-mg, 44% in the 80-mg, and 59% in the 120-mg Uloric groups, and was 2% in the placebo group. Gout flares occurred with similar frequency in the placebo (37%) and 40-mg Uloric (35%) groups, and with increased frequency in the higher dosage Uloric groups (43% taking 80 mg; 55% taking 120 mg). During colchicine prophylaxis, gout flares occurred less frequently (8%-13%).⁴

Contraindications

Uloric is contraindicated in patients taking mercaptopurine, azathiopurine, and theophylline.3 Concurrent use will cause increased plasma concentrations of these medications resulting in severe toxicity. Uloric has been found to be teratogenic to the fetus in pregnancy, and thus should be avoided in pregnant patients (pregnancy category C). Although no human data exist of Uloric being excreted in breast milk, nursing mothers should use caution while using the medication.³

Precautions

Gout flares may occur during initiation of Uloric, but patients should not discontinue Uloric, as this may aggravate the flare. Prophylaxis therapy with nonsteriodal anti-inflammatory drugs or colchicine may be beneficial for up to 6 months. Cardiovascular thromboembolic events occurred at a higher rate than allopurinol in clinical trials, and thus patients should be monitored for signs and symptoms of myocardial infarction and stroke. Liver function tests should be given periodically in patients taking Uloric due to an increased incidence of liver transaminases.² Serum urate levels less than 6 mg/dL after 2 weeks of treatment require an increase in doseof Uloric.³