NDC 61874-100 Viberzi

Eluxadoline

NDC Product Code 61874-100

NDC CODE: 61874-100

Proprietary Name: Viberzi What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Eluxadoline What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This medication is used to treat a certain stomach/abdominal disorder (irritable bowel syndrome with diarrhea, or IBS-D). It works by slowing down the motion in your gut. This effect helps lessen symptoms such as belly pain and diarrhea.

Product Characteristics

Color(s):
YELLOW (C48330 - YELLOW)
PINK (C48328 - PINK)
Shape: CAPSULE (C48336)
Size(s):
17 MM
19 MM
Imprint(s):
FX75
FX100
Score: 1

NDC Code Structure

NDC 61874-100-60

Package Description: 60 CARTON in 1 BOTTLE > 1 BLISTER PACK in 1 CARTON (61874-100-08) > 8 TABLET, FILM COATED in 1 BLISTER PACK

NDC Product Information

Viberzi with NDC 61874-100 is a a human prescription drug product labeled by Allergan, Inc.. The generic name of Viberzi is eluxadoline. The product's dosage form is tablet, film coated and is administered via oral form.

Labeler Name: Allergan, Inc.

Dosage Form: Tablet, Film Coated - A solid dosage form that contains medicinal substances with or without suitable diluents and is coated with a thin layer of a water-insoluble or water-soluble polymer.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

DEA Schedule: Schedule IV (CIV) Substances What is the Drug Enforcement Administration (DEA) CIV Schedule?
The controlled substances in the CIV schedule have an abuse potential and dependence liability less than those listed in CIII and have an accepted medical use in the United States.

Viberzi Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • ELUXADOLINE 100 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • CROSPOVIDONE (UNII: 2S7830E561)
  • MANNITOL (UNII: 3OWL53L36A)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)
  • TALC (UNII: 7SEV7J4R1U)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • CROSPOVIDONE (UNII: 2S7830E561)
  • MANNITOL (UNII: 3OWL53L36A)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)
  • TALC (UNII: 7SEV7J4R1U)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • mu-Opioid Receptor Agonist - [EPC] (Established Pharmacologic Class)
  • Opioid mu-Receptor Agonists - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Allergan, Inc.
Labeler Code: 61874
FDA Application Number: NDA206940 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 10-01-2015 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Information for Patients

Eluxadoline

Eluxadoline is pronounced as (el" ux ad' oh leen)

Why is eluxadoline medication prescribed?
Eluxadoline is used to treat irritable bowel syndrome with diarrhea (IBS-D; a condition that causes stomach pain, cramping, or loose or watery stools) in adults. Eluxadol...
[Read More]

* Please review the disclaimer below.

Viberzi Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1       Indications And Usage

VIBERZI is indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D).

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 who:are unable to tolerate the 100 mg dose of VIBERZI [see Adverse Reactions (6.1)]. are receiving concomitant OATP1B1 inhibitors [see Drug Interactions (7)].have mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment [see Use in Specific Population (8.6), Clinical Pharmacology (12.3)].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.

3       Dosage Forms And Strengths

  • 75 mg tablets: capsule-shaped tablets are coated in pale-yellow to light tan color debossed with “FX75” on one side. Each tablet contains 75 mg eluxadoline. 100 mg tablets: capsule-shaped tablets are coated in pink-orange to peach color debossed with “FX100” on one side. Each tablet contains 100 mg eluxadoline.

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)].

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)].

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)]

6.1       Clinical Trials 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.PancreatitisCases 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. Sphincter of Oddi SpasmIn 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 painAmong 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 painOf 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 ReactionsTable 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 PatientsAdverse ReactionsVIBERZI100 mg twice daily (N= 1032)%VIBERZI75 mg twice daily(N=807)%Placebo(N=975)%Constipation872Nausea785Abdominal Pain**764Upper Respiratory Tract Infection534Vomiting441Nasopharyngitis343Abdominal Distention332Bronchitis332Dizziness332Flatulence332Rash***332Increased ALT321Fatigue232Viral gastroenteritis132* 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 urticariaConstipation 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 DiscontinuationEight 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 ReactionsAdverse reactions that were reported in ≤ 2% of VIBERZI-treated patients are listed below by body system. Gastrointestinal: gastroesophageal reflux diseaseGeneral Disorders and administration site conditions: feeling drunkInvestigations: increased ASTNervous system: sedation, somnolencePsychiatric disorders: euphoric moodRespiratory: 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)].

7       Drug Interactions

The metabolism of eluxadoline by CYP pathways has not been clearly established.  In addition, the potential of eluxadoline to inhibit CYP3A4 in the gut has not been established. 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 VIBERZIOATP1B1 InhibitorsClinical 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 Strong CYP Inhibitors*Clinical Impact:Potential for increased exposure to eluxadoline [see Clinical Pharmacology (12.3)]Intervention: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:ciprofloxacin, (CYP1A2), gemfibrozil (CYP2C8), fluconazole, (CYP2C19), clarithromycin (CYP3A4), paroxetine and bupropion, (CYP2D6)Drugs that Cause ConstipationClinical 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*As a precautionary measure due to incomplete information on the metabolism of eluxadolineTable 3:
     
Established and Other Potentially Clinically Relevant Interactions Affecting Drugs Co-Administered with VIBERZIOATP1B1 and BCRP SubstrateClinical 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).CYP3A Substrates with Narrow Therapeutic IndexClinical Impact:Potential for increased exposure of co-administered drug [see Clinical Pharmacology (12.3)]Intervention:Monitor drug concentrations or other pharmacodynamic markers of drug effect when concomitant use with eluxadoline is initiated or discontinued.Examples:alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus

8.1       Pregnancy

Risk SummaryThere 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].DataAnimal DataEluxadoline 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.

8.2       Lactation

Risk SummaryNo 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 DataEluxadoline 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. There were no adverse physiologic effects related to eluxadoline. Based on these results, the NOAEL for male and female juvenile rats was 1500 mg/kg/day (about 30 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg).

8.5       Geriatric Use

Of 1795 IBS-D patients in clinical trials of VIBERZI who received 75 mg or 100 mg twice daily, 139 (7.7%) were at least 65 years of age, while 15 (0.8%) were at least 75 years old. No overall differences in effectiveness were observed between these patients and younger patients. There were no overall differences in the types of adverse reactions observed between elderly and younger patients; however, a higher proportion of elderly patients than younger patients experienced adverse reactions (66% vs 59%), serious adverse reactions (9% vs 4%), and gastrointestinal adverse reactions (39% vs 28%).

8.6       Hepatic Impairment

Plasma concentrations of eluxadoline increase in patients with hepatic impairment [see Clinical Pharmacology (12.3)].  VIBERZI is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) as plasma concentrations of eluxadoline increase significantly (16-fold) and there is no information to support the safety of VIBERZI in these patients.  In patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, plasma concentrations of eluxadoline increase to a lesser extent (6- and 4-fold, respectively). Administer VIBERZI at a reduced dose of 75 mg twice daily to these patients [see Dosage and Administration (2)]. Monitor patients with any degree of hepatic impairment 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)].

9.1       Controlled Substance

Eluxadoline is listed in Schedule IV of the Controlled Substances Act.

9.2       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. Adverse reactions of euphoria and feeling drunk were reported in clinical trials of IBS-D evaluating 75 mg and 100 mg doses of VIBERZI. The rate of euphoria was 0% for 75 mg and 0.2% (2/1032) for 100 mg and the rate of feeling drunk was 0.1% (1/807) for 75 mg and 0.1% (1/1032) for 100 mg. In contrast, in two human abuse potential studies conducted in recreational opioid-experienced individuals, supratherapeutic oral doses of VIBERZI (300 mg and/or 1000 mg) and intranasal doses of VIBERZI (100 mg and/or 200 mg) produced the adverse reaction of euphoria (at a rate ranging from 14% to 28%) that was greater than that of placebo (0% to 5%) but less than that of oxycodone (44% to 76%).  In the two human abuse potential studies, supratherapeutic oral and intranasal doses of VIBERZI produced small but significant increases on positive subjective measures such as Drug Liking and High compared to placebo.  Supratherapeutic oral and intranasal doses of VIBERZI also produced small but significant increases on negative subjective measures such as Drug Disliking and Dysphoria compared to placebo.  In the same studies, oxycodone (30 mg and 60 mg oral, and 15 and 30 mg intranasal) produced significantly greater responses on positive and negative subjective measures than those produced by eluxadoline and placebo.

9.3       Dependence

In studies with monkeys and rats in which eluxadoline and eluxadoline hydrochloride were chronically administered, discontinuation of the drug did not lead to behavioral signs of withdrawal, a measure of physical dependence.  However, the ability of eluxadoline hydrochloride in monkeys to induce self-administration suggests that the drug is sufficiently rewarding to produce reinforcement.  In two human abuse potential studies with VIBERZI conducted in recreational opioid-experienced individuals, euphoria was reported at a rate of 14% to 28%.  These data suggest that eluxadoline may produce psychological dependence.

10       Overdosage

No reports of overdosage with VIBERZI have been reported.In the event of acute overdose, the stomach should be emptied and adequate hydration maintained. The patient should be carefully observed and given standard supportive treatment as required. Given eluxadoline’s action at opioid receptors, administration of a narcotic mu-opioid antagonist, such as naloxone, should be considered. Considering the short half-life of naloxone, repeated administration may be necessary. In the event of naloxone administration, subjects should be monitored closely for the return of overdose symptoms, which may indicate need for repeated naloxone injection.

11       Description

The active ingredient in VIBERZI is eluxadoline, a mu-opioid receptor agonist. The full chemical name is 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid.Eluxadoline has a molecular weight of 569.65 and a molecular formula of C32H35N5O5. The chemical structure of eluxadoline is:VIBERZI is available as 75 mg and 100 mg tablets for oral administration. In addition to the active ingredient, eluxadoline, each tablet contains the following inactive ingredients: silicified microcrystalline cellulose, colloidal silica, crospovidone, mannitol, magnesium stearate, and Opadry II (partially hydrolyzed polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, and iron oxide red).

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%. AbsorptionAbsolute bioavailability of eluxadoline has not been determined. Effect of FoodThe 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 [see Dosage and Administration (2)]. 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%.DistributionPlasma protein binding of eluxadoline was 81%.EliminationThe mean plasma elimination half-life of eluxadoline ranged from 3.7 hours to 6 hours. MetabolismMetabolism of eluxadoline is not clearly established [see Drug Interactions (7)]. There is evidence that glucuronidation can occur to form an acyl glucuronide metabolite.ExcretionFollowing 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 PopulationsPatients with Hepatic ImpairmentFollowing 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 Interaction StudiesIn Vitro Assessment of Drug InteractionsIn 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 InteractionsThe following drug interactions were studied in healthy subjects:Oral ContraceptivesCoadministration 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.CyclosporineCoadministration of a single dose of 100 mg VIBERZI with a single dose of 600 mg cyclosporine resulted in 4.4-fold and 6.2-fold increase in AUC and Cmax of eluxadoline, respectively, compared to administration of VIBERZI alone [see Drug Interactions (7)].ProbenecidCoadministration of a single dose of 100 mg VIBERZI with a single dose of 500 mg probenecid resulted in a 35% and 31% increase in eluxadoline AUC and Cmax, respectively, compared to administration of VIBERZI alone. This change in eluxadoline exposures is not expected to be clinically meaningful.RosuvastatinCoadministration of multiple doses of 100 mg VIBERZI twice daily with a single dose 20 mg rosuvastatin resulted in an increase in the AUC (40%) and Cmax (18%) of rosuvastatin compared to administration of rosuvastatin alone. Similar results were observed with the active, major metabolite, n-desmethyl rosuvastatin [see Drug Interactions (7)].

13.1       Carcinogenesis, Mutagenesis, Impairment Of Fertility

CarcinogenesisTwo-year oral carcinogenicity studies have been conducted with eluxadoline in CD-1 mice at doses up to 1500 mg/kg/day (about 14 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) and in Sprague Dawley rats at oral doses up to 1500 mg/kg/day (about 36 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg). Oral administration of eluxadoline for 104 weeks did not produce tumors in mice and rats.MutagenesisEluxadoline was negative in the Ames test, chromosome aberration test in human lymphocytes, in the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test and in the in vivo rat bone marrow micronucleus test.Impairment of FertilityEluxadoline at oral doses up to 1000 mg/kg/day (about 10 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

14       Clinical Studies

  • The efficacy and safety of VIBERZI in IBS-D patients was established in two randomized, multi-center, multi-national, double-blind, placebo-controlled trials (Studies 1 and 2). A total of 1281 patients in Study 1 and 1145 patients in Study 2 received treatment with VIBERZI 75 mg, VIBERZI 100 mg or placebo twice daily [overall, patients had a mean age of 45 years (range 18 to 80 years with 10% at least 65 years of age or older), 66% female, 86% white, 11% black, and 27% Hispanic].All patients met Rome III criteria for IBS-D (loose [mushy] or watery stools ≥25% and hard or lumpy stools <25% of bowel movements) and were required to meet both of the following criteria:an average of worst abdominal pain scores in the past 24 hours of >3.0 on a 0 to 10 scale over the week prior to randomization.an average daily stool consistency score (Bristol Stool Scale or BSS) of ≥5.5 and at least 5 days with a BSS score ≥5 on a 1 to 7 scale over the week prior to randomization.Pertinent exclusion criteria included: prior pancreatitis, alcohol abuse, cholecystitis prior 6 months, sphincter of Oddi dysfunction, inflammatory bowel disease, intestinal obstruction, gastrointestinal infection or diverticulitis within prior 3 months, lipase greater than 2 xULN, ALT or AST greater than 3 xULN.Study 1 and Study 2 included identical 26-week double-blind, placebo-controlled treatment periods. Study 1 continued double-blinded for an additional 26 weeks for long-term safety (total of 52 weeks of treatment), followed by a 2-week follow-up. Study 2 included a 4-week single-blinded, placebo-withdrawal period upon completion of the 26-week treatment period. During the double-blind treatment phase and the single-blinded placebo withdrawal phase, patients were allowed to take loperamide rescue medication for the acute treatment of uncontrolled diarrhea, but were not allowed to take any other antidiarrheal, antispasmodic agent or rifaximin for their diarrhea. Additionally, patients were allowed to take aspirin-containing medications or nonsteroidal anti-inflammatory drugs, but no narcotic or opioid containing agents.Efficacy of VIBERZI was assessed in both trials using an overall composite responder primary endpoint. The primary endpoint was defined by the simultaneous improvement in the daily worst abdominal pain score by ≥30% as compared to the baseline weekly average AND a reduction in the BSS to <5 on at least 50% of the days within a 12-week time interval. Improvement in daily worst abdominal pain in the absence of a concurrent bowel movement was also considered a response day. Results for endpoints were based on electronic daily diary entries by patients.The proportion of composite responders over 12 weeks is shown in Table 4. In both trials, the proportion of patients who were composite responders to VIBERZI was statistically significantly higher than placebo for both doses. The proportion of patients who were composite responders to VIBERZI was similar for male and female patients in both trials.Table 4:
  • Efficacy Results in Randomized Clinical TrialsStudy 1Study 2 VIBERZI 100mg twice dailyn=426VIBERZI 75mgtwice dailyn=427PBOn=427VIBERZI100mgtwice dailyn=382VIBERZI75mgtwice dailyn=381PBO n=382Composite1 Response over 12 weeksResponder rates25%24%17%30%29%16%Treatment difference8%27%413%313%395% CI (%)(2.6, 13.5)(1.4, 12.2)(7.5, 19.2)(6.8, 18.5)Composite Response over 26 weeksResponder rates29%23%19%33%30%20%Treatment difference10%4%13%10%95% CI (%)(4.7, 16.1)(-1.0, 9.9)(6.4, 18.8)(4.2, 16.4)Abdominal Pain Response Improved ≥30% over 12 weeksResponder rates43%42%40%51%48%45%Treatment difference4%3%6%3%95% CI (%)(-3.0, 10.2)(-3.8, 9.4)(-1.3, 12.8)(-4.3, 9.8)BSS <5 Response over 12 weeksResponder rates34%30%22%36%37%21%Treatment difference12%8%15%16%95% CI (%)(6.3, 18.2)(2.1, 13.8)(8.4, 21.0)(9.7, 22.4)1Composite= Simultaneous improvement of Worst Abdominal Pain (WAP) by ≥30% and Bristol Stool Score (BSS) < 5 on the same day for ≥ 50% of days over the interval2 P<0.013 P<0.0014 P<0.05Additionally, the proportion of patients who were composite responders to VIBERZI at each 4-week interval was numerically higher than placebo for both doses as early as month 1 through month 6 demonstrating that efficacy is maintained throughout the course of treatment.During the 4 week single-blind withdrawal period in Study 2, no evidence of worsening of diarrhea or abdominal pain compared to baseline was demonstrated at either dose.

16       How Supplied/Storage And Handling

  • VIBERZI is available as: 75 mg tablets: capsule-shaped tablets, coated in pale-yellow to light tan color, debossed with “FX75” on one side. Bottle of 60: NDC 61874-075-60100 mg tablets: capsule-shaped tablets, coated in pink-orange to peach color, debossed with “FX100” on one side. Bottle of 60: NDC 61874-100-60Store VIBERZI tablets at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

17       Patient Counseling Information

  • Advise the patient to read the FDA-approved patient labeling (Medication Guide).Instruct patients to:stop VIBERZI immediately and seek medical attention if unusual or severe abdominal pain that may radiate to the back or shoulder with or without nausea and vomiting, develops [see Warnings and Precautions (5.1, 5.2)].avoid chronic or acute excessive alcohol use while taking VIBERZI [see Warnings and Precautions (5.1)]. stop VIBERZI immediately and seek medical attention if symptoms of a hypersensitivity reaction develop [see Warnings and Precautions (5.3)].stop VIBERZI and immediately call their health care provider if they experience severe constipation [see Dosage and Administration (2), Warnings and Precautions (5.4)].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 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.) [see Drug Interactions (7)].Distributed by:Allergan USA, Inc. Madison, NJ 07940© 2018 Allergan. All rights reserved.

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