Eluxadoline (Monograph)

Brand name: Viberzi
Drug class: GI Drugs, Miscellaneous
ATC class: A07DA06
VA class: GA208
Chemical name: 5-[[[(2S)-2-Amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(5-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy-benzoic acid
Molecular formula: C₃₂H₃₅N₅O₅
CAS number: 864821-90-9

Medically reviewed by Drugs.com on Nov 17, 2022. Written by ASHP.

Introduction

Mixed μ-opiate receptor agonist and δ-opiate receptor antagonist; has poor oral bioavailability and is used for its local effects at opiate receptors in the GI tract.

Uses for Eluxadoline

Irritable Bowel Syndrome

Management of irritable bowel syndrome (IBS) with diarrhea.

Responses (reduced abdominal pain and improved stool consistency) observed in both male and female patients.

Eluxadoline Dosage and Administration

Administration

Oral Administration

Administer twice daily with food.

Dosage

Adults

Irritable Bowel Syndrome with Diarrhea

Oral

100 mg twice daily.

75 mg twice daily in patients who cannot tolerate the 100-mg dosage or are receiving concomitant therapy with an organic anion transporter protein (OATP) 1B1 inhibitor. (See Drugs Affecting or Affected by OATPs under Interactions.)

Discontinue if severe constipation lasting >4 days develops.

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): 75 mg twice daily.

Severe hepatic impairment (Child-Pugh class C): Contraindicated. (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations. (See Geriatric Use under Cautions.)

Cautions for Eluxadoline

Contraindications

• No gallbladder (because of increased risk for pancreatitis and/or sphincter of Oddi spasm). (See Pancreatitis and also see Sphincter of Oddi Spasm under Cautions.)

• Known or suspected biliary duct obstruction or sphincter of Oddi disease or dysfunction (because of increased risk for sphincter of Oddi spasm).

• Alcoholism, alcohol abuse or addiction, consumption of >3 alcoholic beverages per day, or history of pancreatitis or structural pancreatic disease, including known or suspected pancreatic duct obstruction (because of increased risk for acute pancreatitis).

• Severe hepatic impairment (Child-Pugh class C) (because of increased eluxadoline exposure). (See Special Populations under Pharmacokinetics.)

• History of chronic or severe constipation or sequelae from constipation, or known or suspected mechanical GI obstruction (because of increased risk for severe complications of bowel obstruction).

Warnings/Precautions

Pancreatitis

Pancreatitis with or without sphincter of Oddi spasm, including cases resulting in hospitalization, reported, mainly in patients without a gallbladder. Fatal cases also reported in patients without a gallbladder.

FDA states clinicians should consider alternative treatment options prior to initiating eluxadoline therapy. Eluxadoline is contraindicated in patients without a gallbladder.

From May 2015 through February 2017, FDA received 120 reports of serious pancreatitis or death in patients receiving eluxadoline.

Serious pancreatitis generally has occurred within the first week of therapy; symptoms in some patients developed after 1 or 2 doses. Pancreatitis reported at dosages of either 75 or 100 mg twice daily.

Pancreatitis has developed in some patients who did not consume alcohol.

Risk of pancreatitis is increased in those who consume >3 alcoholic beverages per day. Evaluate patients' alcohol intake prior to initiation of drug. Patients should avoid chronic or acute excessive alcohol consumption while receiving eluxadoline.

Monitor patients for symptoms of pancreatitis (e.g., new or worsening abdominal pain that may radiate to the back or shoulder, with or without nausea and vomiting). (See Contraindications under Cautions and see Advice to Patients.)

Sphincter of Oddi Spasm

Risk of sphincter of Oddi spasm because of μ-opiate receptor agonist effects; spasm can result in pancreatitis or increases in hepatic enzyme concentrations associated with acute abdominal pain (e.g., biliary-type pain). (See Pancreatitis under Cautions.)

Sphincter of Oddi spasm (with or without pancreatitis) resulting in hospitalization reported, mainly in patients without a gallbladder. Eluxadoline is contraindicated in patients without a gallbladder.

Spasm generally has occurred within the first week of therapy; symptoms in some patients developed after 1 or 2 doses.

Do not reinitiate in patients who develop biliary duct obstruction or sphincter of Oddi spasm while receiving the drug. (See Contraindications under Cautions.)

Dependence and Abuse

Subject to control as a schedule IV (C-IV) drug.

Low incidence of euphoria or feelings of drunkenness (0–0.2%) in clinical trials at recommended dosages. In abuse-potential studies, supratherapeutic doses produced small but significant subjective responses (e.g., drug liking or disliking, high, dysphoria) and rates of euphoria (14–28%) that were intermediate to those produced by placebo (0–5%) or oxycodone (44–76%), suggesting potential for psychological dependence.

In animal studies, discontinuance following chronic administration did not produce behavioral signs of withdrawal, but the drug appeared to be sufficiently self-rewarding to produce reinforcement.

Specific Populations

Pregnancy

No studies in pregnant women assessing eluxadoline-associated risks.

No evidence of teratogenicity or adverse developmental effects in animals.

Lactation

Not known whether distributed into human milk; distributed into milk in rats.

Consider benefits of breast-feeding and importance of the drug to the woman; also consider potential adverse effects on the breast-fed child from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No overall differences in efficacy or types of adverse effects relative to younger adults, but a higher proportion of geriatric patients experienced adverse effects, serious adverse effects, and adverse GI effects.

Hepatic Impairment

Exposure to eluxadoline is increased in patients with hepatic impairment. (See Special Populations under Pharmacokinetics.)

Reduce dosage in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); monitor patients with any degree of hepatic impairment for impairment of mental or physical abilities needed to perform potentially hazardous activities (e.g., driving, operating machinery) and for other eluxadoline-related adverse effects. (See Hepatic Impairment under Dosage and Administration.)

Contraindicated in patients with severe hepatic impairment; safety not established.

Common Adverse Effects

Constipation, nausea, abdominal pain, upper respiratory tract infection, vomiting, nasopharyngitis, abdominal distention, bronchitis, dizziness, flatulence, rash, increased ALT concentrations, fatigue, viral gastroenteritis.

Interactions for Eluxadoline

Metabolism via CYP pathways; potential to inhibit CYP3A4 in the gut not established.

Did not induce CYP 1A2, 2C9, 2C19, or 3A4 or inhibit CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 3A4 in vitro at clinically relevant systemic concentrations. Slightly inhibited CYP2E1, but clinically meaningful pharmacokinetic interactions unlikely. In vitro studies not adequate to establish the potential for eluxadoline to inhibit CYP3A4 in the gut.

In vitro studies suggest eluxadoline is a substrate for organic anion transporter (OAT) 3, organic anion transport protein (OATP) 1B1, bile salt export pump (BSEP), and multidrug resistance protein (MRP) 2, but is not a substrate for organic cation transporter (OCT) 1 or 2, OAT1, OATP1B3, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP).

Clinically meaningful pharmacokinetic interactions via inhibition of OCT1, OCT2, OAT1, OAT3, OATP1B3, BSEP, and MRP2 by eluxadoline unlikely based on in vitro studies. In vitro studies not adequate to establish the potential for eluxadoline to inhibit P-gp in the gut.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potent CYP inhibitors: Metabolic pathways of eluxadoline not fully established; potential exists for increase in eluxadoline exposure. As a precautionary measure, monitor patients for impairment of mental or physical abilities required to perform potentially hazardous tasks (e.g., driving, operating machinery) and for other eluxadoline-related adverse effects.

CYP3A substrates: Potential for eluxadoline to inhibit CYP3A4 in the gut not established; potential exists for increase in exposure to CYP3A substrates. In patients receiving a CYP3A substrate with narrow therapeutic index, monitor plasma concentrations or pharmacodynamic effects of the substrate drug when eluxadoline is initiated or discontinued.

Drugs Affecting or Affected by OATPs

OATP1B1 inhibitors: Increased eluxadoline exposure. Reduce eluxadoline dosage to 75 mg twice daily; monitor patients for impairment of mental or physical abilities required to perform potentially hazardous tasks (e.g., driving, operating machinery) and for other eluxadoline-related adverse effects.

OATP1B1 substrates: Potential increase in exposure to the OATP1B1 substrate.

BCRP Substrates

Potential increase in exposure to the BCRP substrate.

Constipating Drugs

Increased risk of constipation-related adverse effects, including serious adverse effects. Avoid concomitant use; however, loperamide may be used occasionally. (See Specific Drugs under Interactions.)

Specific Drugs

Eluxadoline Pharmacokinetics

Absorption

Bioavailability

Poorly absorbed after oral administration; some data suggest moderate hepatic first-pass extraction occurs. Absolute oral bioavailability not established.

Exhibits substantial interpatient variability in pharmacokinetic parameters.

Median time to peak plasma concentration is 1.5 (range: 1–8) or 2 (range: 0.5–6) hours under fed or fasting conditions, respectively, following a single oral 100-mg dose in healthy individuals.

Exhibits approximately linear pharmacokinetics with no evidence of accumulation with twice-daily dosing.

Food

High-fat meal decreases peak plasma concentration and AUC by 50 and 60%, respectively.

Special Populations

Hepatic impairment: Plasma concentrations increased by 6-, 4-, and 16-fold in patients with mild, moderate, or severe (Child-Pugh class A, B, or C) hepatic impairment, respectively.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

81%.

Elimination

Metabolism

Not fully established; an acyl glucuronide metabolite has been detected in urine.

Elimination Route

Excreted principally in feces (approximately 82%); <1% excreted in urine.

Half-life

3.7–6 hours.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

• Mixed μ-opiate receptor agonist and δ-opiate receptor antagonist. Also exhibits agonist activity at κ-opiate receptor, but binding affinity for this receptor in humans not determined.

• Has poor oral bioavailability and is used for its local effects at opiate receptors in the GI tract.

• In animals, interacts with opiate receptors in the gut, reduces contractility in intestinal tissue, and inhibits neurogenically mediated secretion in vitro; normalizes GI transit and reduces fecal output in animal models of altered GI function.

Advice to Patients

• Advise patients to read the manufacturer's medication guide before beginning treatment and each time the prescription is refilled.

• Importance of patients informing clinician prior to initiating eluxadoline therapy if they do not have a gallbladder or have a history of pancreatic or gallbladder disease.

• Advise all patients to immediately discontinue the drug and seek medical attention if symptoms of sphincter of Oddi spasm or pancreatitis (e.g., unusual or severe abdominal, epigastric, or biliary pain that may radiate to the back or shoulder, with or without nausea and vomiting) develop.

• Advise patients to inform their clinician if they cannot tolerate eluxadoline.

• Advise patients to inform their clinician if constipation occurs and lasts >4 days.

• Advise patients receiving eluxadoline not to use alosetron concomitantly and not to use loperamide on a chronic basis due to the potential for constipation; however, loperamide may be used occasionally for acute management of severe diarrhea. Advise patients to discontinue loperamide if constipation develops. Advise patients to avoid concomitant use of other drugs that may cause constipation (e.g., opiates, anticholinergics).

• Advise patients to avoid chronic or acute excessive alcohol consumption while taking eluxadoline; consuming >3 alcoholic beverages per day increases the risk of developing pancreatitis.

• Advise patients that if a dose of eluxadoline is missed, to resume therapy with the next scheduled dose and to not double the dose to make up for the missed dose.

• Advise patients with hepatic impairment not to drive, operate machinery, or perform other potentially hazardous activities until they know how eluxadoline affects them.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.

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Frequently asked questions

• How does Viberzi work?

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