13/15.  VIBERZI- (Eluxadoline)- (May 2015)-

These highlights do not include all the information needed to use VIBERZI safely and effectively. See full prescribing information for VIBERZI. VIBERZI (eluxadoline) tablets, for oral use, C-X Initial U.S. Approval: 2015 ---------------------INDICATIONS AND USAGE------------------------ VIBERZI is a mu-opioid receptor agonist, indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D). (1) ------------------DOSAGE AND ADMINISTRATION------------------ • The recommended dosage in adults is 100 mg twice daily taken with food. (2) • The recommended dosage is 75 mg twice daily taken with food in patients who: o do not have a gallbladder (2, 5.1) o are unable to tolerate the 100 mg dose (2, 6.1) o are receiving concomitant OATP1B1 inhibitors (2, 7) o have mild or moderate hepatic impairment (2, 8.6) • Discontinue VIBERZI in patients who develop severe constipation for more than 4 days (2) • If a dose is missed, take the next dose at the regular time; do not take 2 doses at once (2) ----------------DOSAGE FORMS AND STRENGTHS----------------- 75 mg and 100 mg tablets (3) --------------------------CONTRAINDICATIONS------------------------ Patients with: • known or suspected biliary duct obstruction, or sphincter of Oddi disease or dysfunction (4)

• alcoholism, alcohol abuse, alcohol addiction, or drink more than 3 alcoholic beverages/day (4) • a history of pancreatitis; structural diseases of the pancreas, including known or suspected pancreatic duct obstruction (4) • severe hepatic impairment (Child-Pugh Class C) (4, 8.6) • severe constipation or sequelae from constipation, or known or suspected mechanical gastrointestinal obstruction (4) -------------------WARNINGS AND PRECAUTIONS------------------ • Sphincter of Oddi Spasm and Pancreatitis: Monitor patients without a gallbladder for new or worsening abdominal pain, with or without nausea and vomiting, or acute biliary pain with liver or pancreatic enzyme elevations; discontinue VIBERZI and seek medical attention if symptoms develop. (5.1, 5.2) -------------------------ADVERSE REACTIONS-------------------------- Most common adverse reactions (>5%) are constipation, nausea and abdominal pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Forest Pharmaceuticals, Inc., at 1- 800- 678-1605 or FDA at 1 800-FDA-1088 or www.fda.gov/medwatch. -------------------------DRUG INTERACTIONS-------------------------- See full prescribing inform

CLINICAL PHARMACOLOGY

12.1 Mechanism of Action Eluxadoline is a mu-opioid receptor agonist; eluxadoline is also a delta opioid receptor antagonist and a kappa opioid receptor agonist.

12.3 Pharmacokinetics Following oral administration of 100 mg VIBERZI in healthy subjects, the Cmax of eluxadoline was approximately 2 to 4 ng/mL and AUC was 12 to 22 ng.h/mL.

erived from fat content decreased the Cmax of eluxadoline by 50% and AUC by 60%.

Distribution Plasma protein binding of eluxadoline was 81%. Page 12 of 18 Reference ID: 3766744 Elimination The mean plasma elimination half-life of eluxadoline ranged from 3.7 hours to 6 hour

Metabolism

Metabolism of eluxadoline is not clearly established [see Drug Interactions (7)]. There is evidence that glucuronidation can occur to form an acyl glucuronide metabolite. Excretion Following a single oral dose of 300 mg [14C] eluxadoline in healthy male subjects, 82.2% of the total radioactivity was recovered in feces within 336 hours and less than 1% was recovered in urine within 192 hours.

tSpecific Populations

Hepatic   Impairment -

Following a single oral 100–mg dose in subjects with varying degrees of liver impairment and healthy subjects, mean eluxadoline plasma exposure was 6-fold, 4-fold, and 16-fold higher in mild, moderate, and severe hepatically impaired subjects (Child Pugh Class A, B, C), respectively, compared to the subjects with normal liver function [see Dosage and Administration (2), Contraindications (4), Use in Specific Populations (8.6)].

Drug Interactions -

In Vitro Assessment of Drug Interactions In vitro studies indicate that eluxadoline is neither an inducer of CYP1A2, CYP2C9, CYP2C19, and CYP3A4, nor an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant systemic concentrations. Although CYP2E1 was slightly inhibited by eluxadoline (IC50 of approximately 20 micromolar [11 mcg/mL]), clinically meaningful interactions are unlikely.

Oral Contraceptives Coadministration of multiple doses of 100 mg VIBERZI with multiple dose administration of an oral contraceptive (norethindrone 0.5 mg/ethinyl estradiol 0.035 mg) does not change the exposure of either drug.

USE IN SPECIFIC POPULATIONS

Pregnancy Risk Summary

There are no studies with VIBERZI in pregnant women that inform any drug-associated risks. The background risk of major birth defects and miscarriage for the indicated population is unknown.

However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. In animal reproduction studies, oral and subcutaneous administration of eluxadoline to rats and rabbits during organogenesis at doses approximately 51 and 115 times the human exposure after a single oral dose of 100 mg, respectively, demonstrated no teratogenic effects. In a pre- and postnatal development study in rats, no adverse effects were observed in offspring with oral administration of eluxadoline at doses approximately 10 times the human exposure [see Data].

. 8.2 Lactation Risk Summary No data are available regarding the presence of eluxadoline in human milk, the effects of eluxadoline on the breastfed infant, or the effects of eluxadoline on milk production. However, eluxadoline is present in rat milk [see

Use in Specific Populations (8.1) ]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VIBERZI and any potential adverse effects on the breastfed infant from VIBERZI or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Juvenile Toxicology Data Eluxadoline was orally administered to juvenile rats at 500, 750, and 1500 mg/kg/day (about 16, 54 and 30 times, respectively, the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) for 4 weeks.

Hepatic Impairment Plasma concentrations of eluxadoline increase in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. Page 9 of 18 Reference ID: 3766744 VIBERZI is contraindicated in patients with severe hepatic impairment (Child-

 eluxadoline-related adverse reactions [see Adverse Reactions (6.1)]. 9 9.1 Pending 9.2

DRUG ABUSE AND DEPENDENCE Controlled Substance Abuse In a drug discrimination study in monkeys, intravenous administration of eluxadoline hydrochloride produced full generalization to the morphine cue. In a self-administration study in monkeys, eluxadoline hydrochloride was self-administered to a degree that was less than that of heroin but greater than that of saline