New drug approved for gout maintenance therapy

Kathryn WheelerOn December 22, 2015, FDA approved lesinurad (Zurampic; AstraZeneca Pharmaceuticals) for the treatment of gout-associated hyperuricemia in patients taking a xanthine oxidase inhibitor who have not attained desired levels of serum uric acid while on a xanthine oxidase inhibitor alone. Lesinurad is not intended as monotherapy for gout or for treatment of asymptomatic hyperuricemia.

Lesinurad lowers serum uric acid levels by inhibiting its resorption by the urate transporter, URAT 1, in the kidney. Lesinurad carries a boxed warning citing acute renal failure, which has occurred more commonly when used as monotherapy.

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Efficacy

Lesinurad was approved based on the results of three randomized, placebo-controlled trials of participants on a xanthine oxidase inhibitor for treatment of gout and hyperuricemia. Studies assessed daily doses of 200 mg and 400 mg in combination with either allopurinol or febuxostat over a period of 12 months. During the initial five months of all trials, participants received colchicine or a nonsteroidal anti-inflammatory drug as prophylactic therapy against flares of gout.

Trials 1 and 2 included participants with serum uric acid levels >6.5mg/dL, on a stable dose of allopurinol (minimum dose of 300 mg or 200 mg in patients with moderate renal dysfunction) and two or more gouty flares within the previous 12 months. Participants received lesinurad 200 mg, 400 mg, or placebo. Participants taking lesinurad plus allopurinol achieved serum uric acid level <6 mg/dL by the end of the study. This participant group was able to achieve target serum levels by week 4 of therapy and maintain such levels throughout the 12 months of the study.

A third study included participants with gout and measurable tophi. Participants received febuxostat 80 mg once daily for three weeks, then lesinurad 200 mg, 400 mg, or placebo was added. By week three, half of participants had not achieved a serum uric acid level <5 mg/dL on febuxostat alone. By week 24 there was no statistical difference in achievement of uric acid levels <5 mg/dL among the proportion of participants taking lesinurad 200 mg plus febusoxtat and those taking febuxostat alone.

No difference in the proportion of participants experiencing resolution of at least one tophus was demonstrated among study arms. None of the trials demonstrated a decrease in flares between any participant groups during months 6 and 12 of the studies.

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Safety

The most common adverse effects encountered in trials and occurring with greater frequency than with use of a xanthine oxidase inhibitor alone include headache, gastroesophageal reflux, increase in serum creatinine, and influenza.

Acute renal failure has occurred in association with lesinurad use and more commonly when used as monotherapy. In trials, a higher incidence of adverse renal events was observed with the higher dose studied.

An increase in major cardiovascular events has been observed among users of lesinurad. No causal relationship has been identified. However, the FDA has required post-marketing study to further evaluate safety regarding renal and cardiovascular adverse effects.

Dosage

Lesinurad is approved as a 200 mg daily dose in combination with a xanthine oxidase inhibitor. It is not recommended for patients with a creatinine clearance <45 mL/min. Increased monitoring of renal function is recommended for patients with a creatinine clearance between 45 and 60 mL/min.

Lesinurad is not recommended in patients with severe liver impairment. Lesinurad has not been studied in patients with secondary hyperuricemia and is contraindicated for use in patients with tumor lysis syndrome or Lesch-Nyhan syndrome.

Lesinurad should be used with caution in patients who are poor CYP2C9 metabolizers or who are taking moderate CYP2C9 inducers, as this may increase exposure to lesinurad.

Increased exposure to substrates of CYP3A4 may occur with lesinurad co-administration. Increased monitoring may be necessary.

The effectiveness of hormonal contraceptives is jeopardized with coadministration of lesinurad. Use of alternative methods of contraception is recommended.

Kathryn Wheeleris associate clinical professor, Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, Conn.