ould be discontinued when eCLcr is persistently less than 45 mL/min [see DOSAGE AND ADMINISTRATION (2.2) and WARNINGS AND PRECAUTIONS (5.1)].
The efficacy and safety of ZURAMPIC have not been eva luated in gout patients with severe renal impairment (eCLcr less than 30 mL/min), with end-stage renal disease, or receiving dialysis. ZURAMPIC is not expected to be effective in these patient populations [see CONTRAINDICATIONS (4)].
8.7 Hepatic Impairment
No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh classes A and B) [see CLINICAL PHARMACOLOGY (12.3)]. Lesinurad has not been studied in patients with severe hepatic impairment and is therefore not recommended.
8.8 Secondary Hyperuricemia
No studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); ZURAMPIC is contraindicated for use in tumor lysis syndrome or Lesch-Nyhan syndrome, where the rate of uric acid formation is greatly increased [see CONTRAINDICATIONS (4)].
10 OVERDOSAGE
ZURAMPIC was studied in healthy subjects given single doses up to 1600 mg without evidence of dose-limiting toxicities. In case of overdose patients should be managed by symptomatic and supportive care including adequate hydration.
11 DESCRIPTION
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:
chemical structure
ZURAMPIC is available as blue film-coated tablets for oral administration containing 200 mg lesinurad and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, hypromellose 2910, crospovidone, and magnesium stearate. ZURAMPIC tablets are coated with Opadry blue.
12 CLINICAL PHARMACOLOGY
12.1 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.
12.2 Pharmacodynamics
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.
Effect on Cardiac Repolarization
The effect of ZURAMPIC on cardiac repolarization as assessed by the QTc interval was eva luated in normal healthy subjects and gout patients. ZURAMPIC at doses up to 1600 mg did not demonstrate an effect on the QTc interval.
12.3 Pharmacokinetics
Following oral administration of ZURAMPIC 200 mg in healthy subjects, the mean (% CV) Cmax and AUC for lesinurad were 6 µg/mL (31%) and 30 & |
