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December 22, 2015
The U.S. Food and Drug Administration approved Zurampic-lesinurad to treat high levels of uric acid in the blood (hyperuricemia) associated with gout, when used in combination with a xanthine oxidase inhibitor (XOI), a type of drug approved to reduce the production of uric acid in the body.
ZURAMPIC (lesinurad) is a URAT1 inhibitor.
Lesinurad has the following chemical name: 2-((5-bromo-4-(4 cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid. The molecular formula is C17H14BrN3O2S and the molecular weight is 404.28. The structural formula is:
Mechanism of Action
- Lesinurad reduces serum uric acid levels by inhibiting the function of transporter proteins involved in uric acid reabsorption in the kidney.
- Lesinurad inhibited the function of two apical transporters responsible for uric acid reabsorption, uric acid transporter 1 (URAT1) and organic anion transporter 4 (OAT4), with IC50 values of 7.3 and 3.7 µM, respectively.
- URAT1 is responsible for the majority of the reabsorption of filtered uric acid from the renal tubular lumen.
- OAT4 is a uric acid transporter associated with diuretic-induced hyperuricemia.
- Lesinurad does not interact with the uric acid reabsorption transporter SLC2A9 (Glut9), located on the basolateral membrane of the proximal tubule cell.
Effects on Serum Uric Acid and Urinary Excretion of Uric Acid :
- In gout patients, ZURAMPIC lowered serum uric acid levels and increased renal clearance and fractional excretion of uric acid.
- Following single and multiple oral doses of ZURAMPIC to gout patients, dose-dependent decreases in serum uric acid levels and increases in urinary uric acid excretion were observed.
Safety & Efficacy
The safety and efficacy for Zurampic were evaluated in three randomized, placebo-controlled studies in combination with a XOI involving 1,537 participants for up to 12 months.
Participants treated with Zurampic in combination with a XOI experienced reduced serum uric acid levels compared to placebo.
INDICATIONS AND USAGE
ZURAMPIC is a URAT1 inhibitor indicated in combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone.
Limitations of Use:
- ZURAMPIC is not recommended for the treatment of asymptomatic hyperuricemia.
- ZURAMPIC should not be used as monotherapy.
DOSAGE AND ADMINISTRATION
- Recommended Dosing ZURAMPIC tablets are for oral use and should be co-administered with a xanthine oxidase inhibitor, including allopurinol or febuxostat.
- ZURAMPIC is recommended at 200 mg once daily. This is also the maximum daily dose.
- ZURAMPIC should be taken by mouth, in the morning with food and water.
- ZURAMPIC may be added when target serum uric acid levels are not achieved on the medically appropriate dose of the xanthine oxidase inhibitor alone.
- Use of ZURAMPIC is not recommended for patients taking daily doses of allopurinol less than 300 mg (or less than 200 mg in patients with estimated creatinine clearance (eCLcr) less than 60 mL/min).
- Take ZURAMPIC at the same time as the morning dose of xanthine oxidase inhibitor. If treatment with the xanthine oxidase inhibitor is interrupted, ZURAMPIC should also be interrupted. Failure to follow these instructions may increase the risk of renal events.
- Gout flares may occur after initiation of urate lowering therapy, including ZURAMPIC, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits.
- Gout flare prophylaxis is recommended when starting ZURAMPIC, according to practice guidelines.
- If a gout flare occurs during ZURAMPIC treatment, ZURAMPIC need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient.
The use of ZURAMPIC is contraindicated in the following conditions:
- Severe renal impairment (eCLcr less than 30 mL/min), end stage renal disease, kidney transplant recipients, or patients on dialysis [see Use in Specific Populations.
- Tumor lysis syndrome or Lesch-Nyhan syndrome.
WARNINGS AND PRECAUTIONS
Adverse reactions related to renal function have occurred after initiating ZURAMPIC. A higher incidence was observed at the 400 mg dose, with the highest incidence occurring with monotherapy use.
Monitor renal function at initiation and during therapy with ZURAMPIC, particularly in patients with eCLcr below 60 mL/min, and evaluate for signs and symptoms of acute uric acid nephropathy.
Major adverse cardiovascular events were observed with ZURAMPIC; a causal relationship has not been established.
Most common adverse reactions in 12-month controlled clinical trials (occurring in greater than or equal to 2% of patients treated with ZURAMPIC in combination with a xanthine oxidase inhibitor and more frequently than on a xanthine oxidase inhibitor alone) were headache, influenza, blood creatinine increased, and gastroesophageal reflux disease.
Zurampic has a boxed warning that provides important safety information for health care professionals, including the risk for acute kidney (renal) failure, which is more common when used without an XOI and with higher than approved doses of Zurampic.
The FDA is also requiring a postmarketing study to further evaluate the renal and cardiovascular safety of Zurampic.
Zurampic is manufactured by AstraZeneca Pharmaceuticals LP, based in Wilmington, Delaware.
Image: AstraZeneca Pharmaceuticals LP