Viberzi

1 INDICATIONS AND USAGE VIBERZI is indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D). VIBERZI is a mu-opioid receptor agonist, indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D). ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of VIBERZI is 100 mg taken orally twice daily with food. The recommended dosage of VIBERZI is 75 mg taken orally twice daily with food in patients: unable to tolerate the 100 mg dose of VIBERZI [see Adverse Reactions ( 6.1 ) ]. receiving concomitant OATP1B1 inhibitors [see Drug Interactions ( 7 )] . with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment [see Use in Specific Population s ( 8.6 ) ] . with moderate or severe renal impairment (eGFR less than 60 mL/min/1.73 m 2 ); and in patients with end stage renal disease (ESRD) not yet on dialysis (eGFR less than 15 mL/min/1.73 m 2 ) [see Use in Specific Populations ( 8.7 )]. Discontinue VIBERZI in patients who develop severe constipation [see Warnings and Precautions ( 5.4 )] . Instruct patients if they miss a dose, take the next dose at the regular time and not to take 2 doses at the same time to make up for a missed dose. 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: unable to tolerate the 100 mg dose. ( 2 , 6.1 ) receiving concomitant OATP1B1 inhibitors. ( 2 , 7 ) with mild or moderate hepatic impairment. ( 2 , 8.6 ) with moderate or severe renal impairment; and in patients with end stage renal disease not yet on dialysis. ( 2 , 8.7 ) Discontinue VIBERZI in patients who develop severe constipation. ( 2 ) If a dose is missed, take the next dose at the regular time; do not take 2 doses at once. ( 2 )

4 CONTRAINDICATIONS VIBERZI is contraindicated in patients: Without a gallbladder. These patients are at increased risk of developing serious adverse reactions of pancreatitis and/or sphincter of Oddi spasm [see Warnings and Precautions ( 5.1 , 5.2 )] With known or suspected biliary duct obstruction; or sphincter of Oddi disease or dysfunction. These patients are at increased risk for sphincter of Oddi spasm [see Warnings and Precautions ( 5.1 )]. With alcoholism, alcohol abuse or alcohol addiction, or in patients who drink more than 3 alcoholic beverages per day. These patients are at increased risk for acute pancreatitis [see Warnings and Precautions ( 5.1 )]. With a history of pancreatitis; or structural diseases of the pancreas, including known or suspected pancreatic duct obstruction. These patients are at increased risk for acute pancreatitis [see Warnings and Precautions ( 5.1 )] . With a known hypersensitivity reaction to VIBERZI [see Warnings and Precautions ( 5.3 )]. With severe hepatic impairment (Child-Pugh Class C). These patients are at risk for significantly increased plasma concentrations of eluxadoline [see Use in Specific Populations ( 8.6 )] With a history of chronic or severe constipation or sequelae from constipation, or known or suspected mechanical gastrointestinal obstruction. These patients may be at risk for severe complications of bowel obstruction [see Warnings and Precautions ( 5.4 )] . patients without a gallbladder ( 4 ) 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 ) patients with a known hypersensitivity reaction to VIBERZI ( 4 , 5.3 ) severe hepatic impairment (Child-Pugh Class C) ( 4 , 8.6 ) a history of chronic or severe constipation or sequelae from constipation, or known or suspected mechanical gastrointestinal obstruction ( 4 )

5 WARNINGS AND PRECAUTIONS Pancreatitis and Sphincter of Oddi Spasm : Monitor patients for new or worsening abdominal pain, with or without nausea and vomiting, or acute biliary pain with liver or pancreatic enzyme elevations; immediately discontinue VIBERZI and seek medical attention if symptoms develop. ( 5.1 , 5.2 ) Hypersensitivity Reactions, including anaphylaxis : Immediately discontinue VIBERZI and seek medical attention if symptoms develop. ( 4 , 5.3 ) Constipation: Instruct patients to stop VIBERZI and immediately contact their healthcare provider if they develop severe constipation. Avoid use with other drugs that may cause constipation ( 5.4 , 7 ) 5.1 Pancreatitis Pancreatitis, with or without sphincter of Oddi spasm [ see Warnings and Precautions ( 5.1 ) ] , has been reported in patients taking either the 75 mg or 100 mg dosage of VIBERZI, including serious cases resulting in hospitalization, primarily in patients without a gallbladder. Fatal cases have also been reported in patients without a gallbladder. VIBERZI is contraindicated in patients without a gallbladder [ see Contraindications ( 4 ) ] . Most of the reported cases of serious pancreatitis occurred within a week of starting treatment with VIBERZI and some developed symptoms after one to two doses. In patients with a gallbladder, evaluate a patient’s alcohol intake prior to starting VIBERZI. Instruct patients to avoid chronic or acute excessive alcohol use while taking VIBERZI. Monitor for new or worsening abdominal pain that may radiate to the back or shoulder, with or without nausea and vomiting. Instruct patients to immediately stop VIBERZI and seek medical attention if they experience symptoms suggestive of pancreatitis such as acute abdominal or epigastric pain radiating to the back or shoulder associated with elevations of pancreatic enzymes with or without nausea and vomiting [ see Contraindications ( 4 ) ] . 5.2 Sphincter of Oddi Spasm There is a risk of sphincter of Oddi spasm, resulting in pancreatitis or hepatic enzyme elevation associated with acute abdominal pain (e.g., biliary-type pain) in patients taking VIBERZI [ see Adverse Reactions ( 6.1 ) ] . Postmarketing serious adverse reactions of sphincter of Oddi spasm with or without pancreatitis resulting in hospitalization have been reported, primarily in patients without a gallbladder [ see Warnings and Precautions ( 5.1 ) ] . Most of the reported cases of serious sphincter of Oddi spasm occurred within a week of starting treatment with VIBERZI and some developed symptoms after one to two doses. VIBERZI is contraindicated in patients without a gallbladder [ see Contraindications ( 4 ) ] . Instruct patients to immediately stop VIBERZI and seek medical attention if they experience symptoms suggestive of sphincter of Oddi spasm such as acute worsening of abdominal pain, (e.g. acute epigastric or biliary [i.e., right upper quadrant] pain), that may radiate to the back or shoulder with or without nausea and vomiting, associated with elevations of pancreatic enzymes or liver transaminases. Do not restart VIBERZI in patients who developed biliary duct obstruction or sphincter of Oddi spasm while taking VIBERZI [ see Contraindications ( 4 ) ] . 5.3 Hypersensitivity Reactions In postmarketing experience, serious hypersensitivity reactions (including anaphylaxis) have been reported following VIBERZI administration. Some of these reactions occurred after the first one or two doses of VIBERZI [ see Adverse Reactions ( 6.2 )] . Instruct patients to immediately stop VIBERZI and seek medical attention if they experience symptoms suggestive of a hypersensitivity reaction [ see Contraindications ( 4 ) ] . 5.4 Constipation Constipation, sometimes requiring hospitalization, has been reported following VIBERZI administration. In postmarketing experience, severe cases with development of intestinal obstruction, intestinal perforation, and fecal impaction, requiring intervention, have also been reported. Instruct patients to stop VIBERZI and immediately contact their healthcare provider if they experience severe constipation. Avoid use with other drugs that may cause constipation [ see Adverse Reactions ( 6.1 ), Drug Interactions ( 7 ) ] .

7 DRUG INTERACTIONS Tables 2 and 3 include drugs which demonstrated a clinically important drug interaction with VIBERZI or which potentially may result in clinically relevant interactions. Table 2: Established and Other Potentially Clinically Relevant Interactions Affecting VIBERZI OATP1B1 Inhibitors Clinical Impact: Increased exposure to eluxadoline when coadministered with cyclosporine [ see Clinical Pharmacology ( 12.3 ) ] Intervention: Administer VIBERZI at a dose of 75 mg twice daily [see Dosage and Administration ( 2 )] and monitor patients for impaired mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery and for other eluxadoline-related adverse reactions [see Adverse Reactions ( 6.1 )] . Examples: cyclosporine, gemfibrozil, antiretrovirals (atazanavir, lopinavir, ritonavir, saquinavir, tipranavir), rifampin, eltrombopag Drugs that Cause Constipation Clinical Impact: Increased risk for constipation related adverse reactions and potential for constipation related serious adverse reactions Intervention: Avoid use with other drugs that may cause constipation (see below); loperamide may be used occasionally for acute management of severe diarrhea but avoid chronic use. Discontinue loperamide immediately if constipation occurs. Examples: alosetron, anticholinergics, opioids Table 3: Established and Other Potentially Clinically Relevant Interactions Affecting Drugs Co-Administered with VIBERZI OATP1B1 and BCRP Substrate Clinical Impact: VIBERZI may increase the exposure of co-administered OATP1B1 and BCRP substrates. Increased exposure to rosuvastatin when co-administered with VIBERZI with a potential for increased risk of myopathy/rhabdomyolysis [ see Clinical Pharmacology ( 12.3 ) ] Intervention: Use the lowest effective dose of rosuvastatin (see prescribing information of rosuvastatin for additional information on recommended dosing). See full prescribing information for clinically relevant interactions. ( 7 )

6 ADVERSE REACTIONS The following adverse reactions described below and elsewhere in the labeling include: Pancreatitis [see Warnings and Precautions ( 5.1 )] Sphincter of Oddi Spasm [ see Warnings and Precautions ( 5.2 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 )] Constipation [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (>5%) are constipation, nausea and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1- 800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial s Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Over 1700 patients with IBS-D have been treated with 75 or 100 mg of VIBERZI twice daily in controlled trials. Exposures from placebo-controlled clinical trials in adult patients with IBS-D included 1391 exposed for 3 months, 1001 exposed for 6 months and 488 exposed for one year. Demographic characteristics were comparable between the treatment groups [see Clinical Studies ( 14 )] . Data described below represent pooled data compared to placebo across the randomized trials. Pancreatitis Cases of pancreatitis, not associated with sphincter of Oddi spasm, were reported in 2/807 (0.2%) of patients receiving 75 mg and 3/1032 (0.3%) of patients receiving 100 mg VIBERZI twice daily in clinical trials. Of these 5 cases, 3 were associated with excessive alcohol intake, one was associated with biliary sludge, and in one case the patient discontinued VIBERZI 2 weeks prior to the onset of symptoms. All pancreatic events resolved with lipase normalization upon discontinuation of VIBERZI, with 80% (4/5) resolving within 1 week of treatment discontinuation. The case of sphincter of Oddi spasm-induced pancreatitis resolved within 24 hours of discontinuation. Sp h incter of Oddi Spasm In clinical trials, sphincter of Oddi spasm occurred in 0.2% (2/807) of patients receiving 75 mg and 0.8% (8/1032) of patients receiving 100 mg VIBERZI twice daily. Among patients receiving 75 mg, 1/807 (0.1%) patient experienced a sphincter of Oddi spasm presenting with abdominal pain but with lipase elevation less than 3 times the upper limit of normal (ULN) and 1/ 807 (0.1%) patient experienced a sphincter of Oddi spasm manifested as elevated hepatic enzymes associated with abdominal pain Among patients receiving 100 mg, 1/1032 (0.1%) patient experienced a sphincter of Oddi spasm manifested as pancreatitis and 7/1032 (0.7%) patients experienced sphincter of Oddi spasm manifested as elevated hepatic enzymes associated with abdominal pain Of those patients who experienced a sphincter of Oddi spasm, 80% (8/10) reported their first onset of symptoms within the first week of treatment. The case of sphincter of Oddi spasm-induced pancreatitis occurred within minutes of taking the first dose of VIBERZI. No cases of sphincter of Oddi spasm occurred greater than 1 month after treatment onset. All events resolved upon discontinuation of VIBERZI, with symptoms typically improved by the following day. Common Adverse Reactions Table 1 provides the incidence of common adverse reactions reported in > 2% of IBS-D patients in either VIBERZI treatment group and at an incidence greater than in the placebo group. Table 1: Common* Adverse Reactions in the Placebo-Controlled Studies in IBS-D Patients Adverse Reactions VIBERZI 100 mg twice daily (N= 1032) % VIBERZI 75 mg twice daily (N=807) % Placebo (N=975) % Constipation 8 7 2 Nausea 7 8 5 Abdominal Pain** 7 6 4 Upper Respiratory Tract Infection 5 3 4 Vomiting 4 4 1 Nasopharyngitis 3 4 3 Abdominal Distention 3 3 2 Bronchitis 3 3 2 Dizziness 3 3 2 Flatulence 3 3 2 Rash*** 3 3 2 Increased ALT 3 2 1 Fatigue 2 3 2 Viral gastroenteritis 1 3 2 * Reported in > 2% of VIBERZI-treated patients at either dose and at an incidence greater than in placebo-treated patients ** " Abdominal Pain" term includes: abdominal pain, abdominal pain lower, and abdominal pain upper *** " Rash" term includes: dermatitis, dermatitis allergic, rash, rash erythematous, rash generalized, rash maculo-papular, rash papular, rash pruritic, urticaria, and idiopathic urticaria Constipation was the most commonly reported adverse reaction in VIBERZI-treated patients in these trials. Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving 75 mg and 100 mg VIBERZI. Similar rates of constipation occurred between the active and placebo arms beyond 3 months of treatment. Adverse Reactions Leading to Discontinuation Eight percent of patients treated with 75 mg, 8% of patients treated with 100 mg VIBERZI and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the VIBERZI treatment groups, the most common reasons for discontinuation due to adverse reactions were constipation (1% for 75 mg and 2% for 100 mg) and abdominal pain (1% for both 75 mg and 100 mg). In comparison, less than 1% of patients in the placebo group withdrew due to constipation or abdominal pain. Less Common Adverse Reactions Adverse reactions that were reported in ≤ 2% of VIBERZI-treated patients are listed below by body system. Gastrointestinal : gastroesophageal reflux disease General Disorders and administration site conditions : feeling drunk Investigations: increased AST Nervous system : sedation, somnolence Psychiatric disorders : euphoric mood Respiratory : asthma, bronchospasm, respiratory failure, wheezing 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of VIBERZI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity : anaphylaxis, angioedema (e.g. swollen face and throat), dyspnea, throat tightness, and chest pain/tightness [see Warnings and Precautions ( 5.3 )] .

8.1 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 ) . Data Animal Data Eluxadoline administered as combined oral (1000 mg/kg/day) and subcutaneous (5 mg/kg/day) doses during the period of organogenesis to rats and rabbits (exposures about 51 and 115 times, respectively, the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) did not cause any adverse effects on embryofetal development. A pre- and postnatal development study in rats showed no evidence of any adverse effect on pre- and postnatal development at oral doses of eluxadoline up to 1000 mg/kg/day (with exposures about 10 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg). In the same study, eluxadoline was detected in the milk of lactating rats administered oral doses of 100, 300 and 1000 mg/kg/day (with exposures about 1.8, 3 and 10 times, respectively, the human AUC of 24 ng.h/mL after a single oral dose of 100 mg). Milk samples were collected from six lactating females per group on lactation day 12. Mean concentrations of eluxadoline in the milk of lactating rats on lactation day 12 were 2.78, 5.49 and 44.02 ng/mL at 100, 300 and 1000 mg/kg/day, respectively.