DRUG INTERACTIONS -(summary)

 Moderate Cytochrome P450 2C9 (CYP2C9) Inhibitors: Use with caution.

Sensitive CYP3A Substrates: M

45/15 PRODUCT DETAILS 

Drug Name-                ZURAMPIC

Active Ingredient-      Lesirurad

 Approved date         12/22/2015                                                                                       

FDA approved use-  To treat high blood uric acid levels associated with gout                                     

HIGHLIGHTS OF PRESCRIBING INFORMATION -

These highlights do not include all the information needed to use ZURAMPIC safely and effectively.

See full prescribing information for ZURAMPIC. ZURAMPIC® (lesinurad) tablets, for oral use

Initial U.S. Approval: 2015

WARNING:

RISK OF ACUTE RENAL FAILURE, MORE COMMON WHEN USED WITHOUT A XANTHINE OXIDASE INHIBITOR See full prescribing information for complete boxed warning.  Acute renal failure has occurred with ZURAMPIC and was more common when ZURAMPIC was given alone.                                                                                    ZURAMPIC should be used in combination with a xanthine oxidase inhibitor.

 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.

(1) Limitations of Use:  ZURAMPIC is not recommended for the treatment of asymptomatic hyperuricemia. (1.1) ? ZURAMPIC should not be used as monotherapy.

DOSAGE AND ADMINISTRATION-

 ZURAMPIC is recommended at 200 mg once daily in combination with a xanthine oxidase inhibitor, including allopurinol or febuxostat. The maximum daily dose of ZURAMPIC is 200 mg.

Failure to take ZURAMPIC with a xanthine oxidase inhibitor may increase the risk of renal adverse reactions.

 ZURAMPIC tablets should be taken in the morning with food and water.

 Patients should be instructed to stay well hydrated.

 Assess renal function before initiating ZURAMPIC. Do not initiate ZURAMPIC if eCLcr is below 45 mL/min.

 Discontinue ZURAMPIC if eCLcr persistently falls below 45 mL/min. 

 ADVERSE REACTIONS-

 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.

DOSAGE FORMS AND STRENGTHS ------------------- Tablet: 200 mg. (3) ---------------------

--------- CONTRAINDICATIONS ---------------------------- ? Severe renal impairment, end stage renal disease, kidney transplant recipients, or patients on dialysis. (4, 8.6) ? Tumor lysis syndrome or Lesch-Nyhan syndrome.

(4) ----------------------- WARNINGS AND PRECAUTIONS --------------------- ? Renal events: 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. (5.1) ? Cardiovascular events: Major adverse cardiovascular events were observed with ZURAMPIC; a causal relationship has not been established.

(5.2) ------------------------------ ADVERSE REACTIONS ---------------------------- 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. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

------------------------------ DRUG INTERACTIONS ---------------------------- ? Moderate Cytochrome P450 2C9 (CYP2C9) Inhibitors: Use with caution. (7.1) ? Sensitive CYP3A Substrates: M

DOSAGE AND ADMINISTRATION-

 ZURAMPIC is recommended at 200 mg once daily in combination with a xanthine oxidase inhibitor, including allopurinol or febuxostat. The maximum daily dose of ZURAMPIC is 200 mg.

Failure to take ZURAMPIC with a xanthine oxidase inhibitor may increase the risk of renal adverse reactions.

 ZURAMPIC tablets should be taken in the morning with food and water.

 Patients should be instructed to stay well hydrated.

 Assess renal function before initiating ZURAMPIC. Do not initiate ZURAMPIC if eCLcr is below 45 mL/min.

Discontinue ZURAMPIC if eCLcr persistently falls below 45 mL/min. 

 DOSAGE FORMS AND STRENGTHS -

 Tablet: 200 mg. 

 PATIENT COUNSELING INFORMATION -

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Administration

Advise patients:  To take ZURAMPIC in the morning with food and water at the same time as a xanthine oxidase inhibitor, allopurinol, or febuxostat

Not to take ZURAMPIC alone and to discontinue ZURAMPIC if treatment with the xanthine oxidase inhibitor medication is discontinued.

 Not to take a missed dose of ZURAMPIC later in the day, to wait to take ZURAMPIC on the next day, and not to double the dose

 To stay well hydrated (eg, 2 liters [68 oz] of liquid per day). Renal Events Inform patients that renal events including transient increases in blood creatinine level and acute renal failure have occurred in some patients who take ZURAMPIC.

Advise patients that periodic monitoring of blood creatinine levels are recommended. 

Gout Flares Inform patients that gout flares may occur after initiation of ZURAMPIC and of the importance of taking gout flare prophylaxis medication to help prevent gout flares.

Advise patients not to discontinue ZURAMPIC if a gout flare occurs during treatment

Manufactured for: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 By: AstraZeneca AB, S-151 85 Sodertalje, Sweden Product of Ireland ZURAMPIC is a trademark of the AstraZeneca group of companies. © AstraZeneca 2015

CLINICAL PHARMACOLOGY

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.

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.

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 µg•hr/mL (44%), respectively.

Cmax and AUC exposures of lesinurad increased proportionally with single doses of ZURAMPIC from 5 to 1200 mg. Following multiple once daily dosing of ZURAMPIC, there was no evidence of time dependent changes in pharmacokinetics and dose proportionality was preserved.

Absorption -                                                                                                                   The absolute bioavailability of lesinurad is approximately 100%. Lesinurad is rapidly absorbed after oral administration.

Following administration of a single dose of a ZURAMPIC tablet in either fed or fasted state, maximum plasma concentrations (Cmax) were attained within 1 to 4 hours.

Distribution-                                                                                                              Lesinurad is extensively bound to proteins in plasma (greater than 98%), mainly to albumin.

Plasma protein binding of lesinurad is not meaningfully altered in patients with renal or hepatic impairment.

Elimination-                                                                                                                    The elimination half-life (t½) of lesinurad was approximately 5 hours. ZURAMPIC does not accumulate following multiple doses. The total bodyclearance is approximately 6 L/hr.

Metabolism Lesinurad undergoes oxidative metabolism mainly via the polymorphic cytochrome P450 CYP2C9 enzyme.

Metabolites are not known to contribute to the uric acid lowering effects of ZURAMPIC. A transient oxide metabolite is rapidly eliminated by microsomal epoxide hydrolase in the liver and not detected in plasma.

 Excretion-                                                                                                                          Within 7 days following single dosing of radiolabeled lesinurad, 63% of administered radioactive dose was recovered in urine and 32% of administered radioactive dose was recovered in feces.

Hepatic Impairment-                                                                                                      Following administration of a single dose of ZURAMPIC at 400 mg in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, lesinurad Cmax was comparable and lesinurad AUC was 7% and 33% higher, respectively, compared to individuals with normal hepatic function.

Effect of Age, Gender, Race and Ethnicity on Pharmacokinetics -                              Based on the population pharmacokinetic analysis, age, gender, race and ethnicity do not have a clinically meaningful effect on the pharmacokinetics of lesinurad

Pediatric Use-                                                                                                                   Studies characterizing the pharmacokinetics of lesinurad in pediatric patients have not been conducted. Drug-Drug Interactions Effects of Other Drugs on Lesinurad

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary There are no available human data on use of ZURAMPIC in pregnant women to inform a drug-associated risk

.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data

2. Lactation Risk Summary-                                                                                             There is no information regarding the presence of ZURAMPIC in human milk, the effects on the breastfed infant, or the effects on milk production.

3.Pediatric Use-                                                                                                                  Safety and effectiveness in pediatric patients under 18 years of age have not been established.

4. Geriatric Use -                                                                                                             No dose adjustment is necessary in elderly patients. In a pool of clinical safety and efficacy studies of ZURAMPIC in gout patients, 13% were 65 years and older and 2% were 75 years and older.

5. Renal Impairment-                                                                                                      The pharmacokinetics (PK) of ZURAMPIC was evaluated in studies that included patients with mild (eCLcr 60 to less than 90 mL/min), moderate (eCLcr 30 to less than 60 mL/min), and severe renal impairment (eCLcr less than 30 mL/min).

6.Hepatic Impairment -                                                                                                    No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh classes A and B)

7.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 

 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.