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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, 2023. 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

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.

Drug Interactions

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

Drug

Interaction

Comments

Alfentanil

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased alfentanil exposure

Monitor for changes in alfentanil concentration or effect when eluxadoline is initiated or discontinued

Alosetron

Increased risk of constipation-related adverse effects, including serious adverse effects

Avoid concomitant use

Anticholinergics

Increased risk of constipation-related adverse effects, including serious adverse effects

Avoid concomitant use

Antiretrovirals that inhibit OATP1B1 (e.g., atazanavir, lopinavir, ritonavir, saquinavir, tipranavir)

Possible increased eluxadoline exposure

Reduce eluxadoline dosage to 75 mg twice daily; monitor 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

Bupropion

Eluxadoline metabolism not fully known; potential exists for increased eluxadoline exposure

Monitor 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

Ciprofloxacin

Eluxadoline metabolism not fully known; potential exists for increased eluxadoline exposure

Monitor 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

Clarithromycin

Eluxadoline metabolism not fully known; potential exists for increased eluxadoline exposure

Monitor 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

Cyclosporine

Peak plasma concentration and AUC of eluxadoline increased by 6.2- and 4.4-fold, respectively

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased cyclosporine exposure

Reduce eluxadoline dosage to 75 mg twice daily; monitor 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

Monitor for changes in cyclosporine concentration or effect when eluxadoline is initiated or discontinued

Eltrombopag

Possible increased eluxadoline exposure

Reduce eluxadoline dosage to 75 mg twice daily; monitor 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

Ergot alkaloids (dihydroergotamine, ergotamine)

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased exposure to the ergot alkaloid

Monitor for changes in concentration or effect of the ergot alkaloid when eluxadoline is initiated or discontinued

Fentanyl

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased fentanyl exposure

Monitor for changes in fentanyl concentration or effect when eluxadoline is initiated or discontinued

Fluconazole

Eluxadoline metabolism not fully known; potential exists for increased eluxadoline exposure

Monitor 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

Gemfibrozil

Possible increased eluxadoline exposure

Reduce eluxadoline dosage to 75 mg twice daily; monitor 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

Loperamide

Increased risk of constipation-related adverse effects, including serious adverse effects

May use loperamide occasionally for acute management of severe diarrhea, but avoid chronic use; discontinue loperamide immediately if constipation occurs

Opiates

Increased risk of constipation-related adverse effects, including serious adverse effects

Avoid concomitant use

Oral contraceptives

Oral contraceptive containing ethinyl estradiol and norethindrone: No substantial change in exposure to the oral contraceptive components or eluxadoline

Paroxetine

Eluxadoline metabolism not fully known; potential exists for increased eluxadoline exposure

Monitor 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

Pimozide

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased pimozide exposure

Monitor for changes in pimozide concentration or effect when eluxadoline is initiated or discontinued

Probenecid

Increased peak plasma concentration and AUC of eluxadoline; not expected to be clinically meaningful

Quinidine

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased quinidine exposure

Monitor for changes in quinidine concentration or effect when eluxadoline is initiated or discontinued

Rifampin

Possible increased eluxadoline exposure

Reduce eluxadoline dosage to 75 mg twice daily; monitor 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

Rosuvastatin

Increased peak plasma concentration and AUC of rosuvastatin by 18 and 40%, respectively; similar effects on N-desmethyl rosuvastatin (active major metabolite)

Possible increased risk of myopathy or rhabdomyolysis

Use lowest effective dosage of rosuvastatin

Sirolimus

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased sirolimus exposure

Monitor for changes in sirolimus concentration or effect when eluxadoline is initiated or discontinued

Tacrolimus

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased tacrolimus exposure

Monitor for changes in tacrolimus concentration or effect when eluxadoline is initiated or discontinued

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

Advice to Patients

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.

Eluxadoline

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

75 mg

Viberzi (C-IV)

Allergan

100 mg

Viberzi (C-IV)

Allergan

AHFS DI Essentials™. © Copyright 2024, Selected Revisions November 27, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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