PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Instruct patients to: • stop VIBERZI and seek medical attention if unusual or severe abdominal pain develops, especially if they do not have a gallbladder [see Warnings and Precautions (5.1)]. • avoid chronic or acute excessive alcohol use while taking VIBERZI [see Warnings and Precautions (5.2)]. • take one tablet twice daily with food. • if they miss a dose, take the next dose at the regular time. Do not take 2 doses at the same time to make up for a missed dose. • call their healthcare provider if they are unable to tolerate VIBERZI • discontinue VIBERZI and call their health care provider if they experience constipation lasting more than 4 days • not take alosetron with VIBERZI or not take loperamide on a chronic basis with VIBERZI due to the potential for constipation. Loperamide may occasionally be used with VIBERZI for acute management of severe diarrhea, but must be discontinued if constipation develops. Also, instruct patients to avoid taking VIBERZI with other medications that may cause constipation (for example opioids, anticholinergics, etc.). Page 17 of 18 Reference ID: 3766744 Manufactured by: Patheon Pharmaceuticals, Inc Cincinnati, OH 45237-1625 USA Distributed by: Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, LLC Cincinnati, Ohio 45209 USA © 2015 Actavis. All rights

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. The binding affinities (Ki) of eluxadoline for the human mu and delta opioid receptors are 1.8 nM and 430 nM, respectively. The binding affinity (Ki) of eluxadoline for the human kappa opioid receptor has not been determined; however, the Ki for guinea pig cerebellum kappa opioid receptor is 55 nM. In animals, eluxadoline interacts with opioid receptors in the gut. 12.2 Pharmacodynamics Cardiac Electrophysiology At a dose 10 times the maximum recommended dose (100 mg), VIBERZI does not prolong the QT interval to any clinically relevant extent. 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. Eluxadoline has approximately linear pharmacokinetics with no accumulation upon repeated twice daily dosing. The variability of eluxadoline pharmacokinetic parameters ranges from 51% to 98%. Absorption Absolute bioavailability of eluxadoline has not been determined. The median Tmax value was 1.5 hours (range: 1 to 8 hours) under fed conditions and 2 hours (range: 0.5 to 6 hours) under fasting conditions. The administration of VIBERZI with a high fat meal that contained approximately 800 to 1000 total calories, with 50% of calories being derived 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 hours. 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. Specific 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. The in vitro studies were not adequate to establish the potential for eluxadoline to inhibit CYP3A4 in the gut [see Drug Interactions (7)]. In vitro studies suggest that eluxadoline is a substrate for OAT3, OATP1B1, BSEP and MRP2, but not for OCT1, OCT2, OAT1, OATP1B3, P-gp and BCRP. Based on the in vitro studies, clinically meaningful interaction via inhibition of OCT1, OCT2, OAT1, OAT3, OATP1B3, BSEP and MRP2 by eluxadoline is unlikely. However, the in vitro studies were not adequate to establish the potential for eluxadoline to inhibit P-gp in the gut. In Vivo Assessment of Drug Interactions The following drug interactions were studied in healthy subjects: Page 13 of 18 Reference ID: 3766744 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 dru