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Eluxadoline

Class: GI Drugs, Miscellaneous
VA Class: 0000
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
Brands: Viberzi

Introduction

Mixed μ-opiate receptor agonist and δ-opiate receptor antagonist;1 2 3 4 5 6 has poor oral bioavailability and is used for its local effects at opiate receptors in the GI tract.2 3 4 6 8

Uses for Eluxadoline

Irritable Bowel Syndrome

Management of irritable bowel syndrome (IBS) with diarrhea.1 4 8

Responses (reduced abdominal pain and improved stool consistency) observed in both male and female patients.1 8

Eluxadoline Dosage and Administration

Administration

Oral Administration

Administer twice daily with food.1

Dosage

Adults

Irritable Bowel Syndrome with Diarrhea
Oral

100 mg twice daily.1

75 mg twice daily in patients who cannot tolerate the 100-mg dosage, do not have a gallbladder, or are receiving concomitant therapy with an organic anion transporter protein (OATP) 1B1 inhibitor.1 (See Sphincter of Oddi Spasm and Associated Pancreatitis under Cautions and also see Drugs Affecting or Affected by OATPs under Interactions.)

Discontinue if severe constipation lasting >4 days develops.1

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): 75 mg twice daily.1

Severe hepatic impairment (Child-Pugh class C): Contraindicated.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations.1

Geriatric Patients

No specific dosage recommendations.1 (See Geriatric Use under Cautions.)

Cautions for Eluxadoline

Contraindications

  • Known or suspected biliary duct obstruction or sphincter of Oddi disease or dysfunction (because of increased risk for sphincter of Oddi spasm).1 (See Sphincter of Oddi Spasm and Associated Pancreatitis under Cautions.)

  • 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).1 (See Pancreatitis Not Associated with Sphincter of Oddi Spasm under Cautions.)

  • Severe hepatic impairment (Child-Pugh class C) (because of increased eluxadoline exposure).1 (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).1

Warnings/Precautions

Sphincter of Oddi Spasm and Associated Pancreatitis

Potential for 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).1

Sphincter of Oddi spasm occurred in <1% of patients receiving eluxadoline in clinical studies.1 Spasm generally occurred within the first week of therapy and resolved upon drug discontinuance, with symptoms typically improved by the following day.1

Patients without a gallbladder are at an increased risk.1 Consider alternative therapies prior to initiating eluxadoline in patients without a gallbladder, and evaluate benefits and risks in the context of the patient's symptom severity.1 If decision is made to initiate eluxadoline, reduce dosage and monitor for signs and symptoms of sphincter of Oddi spasm (e.g., elevated hepatic aminotransferase concentrations associated with abdominal pain or pancreatitis), especially during the first few weeks of therapy.1 (See Dosage under Dosage and Administration and see Advice to Patients.)

Do not reinitiate in patients who develop biliary duct obstruction or sphincter of Oddi spasm while receiving the drug.1 (See Contraindications under Cautions.)

Pancreatitis Not Associated with Sphincter of Oddi Spasm

Possible increased risk of pancreatitis not associated with sphincter of Oddi spasm.1 Reported cases have resolved following drug discontinuance.1

Patients should avoid chronic or acute excessive alcohol consumption while receiving eluxadoline.1

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).1 (See Contraindications under Cautions and see Advice to Patients.)

Dependence and Abuse

Subject to control as a schedule IV (C-IV) drug.1

Low incidence of euphoria or feelings of drunkenness (0–0.2%) in clinical trials at recommended dosages.1 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.1

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.1

Specific Populations

Pregnancy

No studies in pregnant women assessing eluxadoline-associated risks.1

No evidence of teratogenicity or adverse developmental effects in animals.1

Lactation

Not known whether distributed into human milk; distributed into milk in rats.1

Consider benefits of breast-feeding and importance of the drug to the woman;1 also consider potential adverse effects on the breast-fed child from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

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.1

Hepatic Impairment

Exposure to eluxadoline is increased in patients with hepatic impairment.1 (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.1 (See Hepatic Impairment under Dosage and Administration.)

Contraindicated in patients with severe hepatic impairment; safety not established.1

Common Adverse Effects

Constipation,1 nausea,1 abdominal pain,1 upper respiratory tract infection,1 vomiting,1 nasopharyngitis,1 abdominal distention,1 bronchitis,1 dizziness,1 flatulence,1 rash,1 increased ALT concentrations,1 fatigue,1 viral gastroenteritis.1

Interactions for Eluxadoline

Metabolism via CYP pathways; potential to inhibit CYP3A4 in the gut not established.1

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.1 Slightly inhibited CYP2E1, but clinically meaningful pharmacokinetic interactions unlikely.1 In vitro studies not adequate to establish the potential for eluxadoline to inhibit CYP3A4 in the gut.1

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).1

Clinically meaningful pharmacokinetic interactions via inhibition of OCT1, OCT2, OAT1, OAT3, OATP1B3, BSEP, and MRP2 by eluxadoline unlikely based on in vitro studies.1 In vitro studies not adequate to establish the potential for eluxadoline to inhibit P-gp in the gut.1

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.1 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.1

CYP3A substrates: Potential for eluxadoline to inhibit CYP3A4 in the gut not established; potential exists for increase in exposure to CYP3A substrates.1 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.1

Drugs Affecting or Affected by OATPs

OATP1B1 inhibitors: Increased eluxadoline exposure.1 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.1

OATP1B1 substrates: Potential increase in exposure to the OATP1B1 substrate.1

BCRP Substrates

Potential increase in exposure to the BCRP substrate.1

Constipating Drugs

Increased risk of constipation-related adverse effects, including serious adverse effects.1 Avoid concomitant use; however, loperamide may be used occasionally.1 (See Specific Drugs under Interactions.)

Specific Drugs

Drug

Interaction

Comments

Alfentanil

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased alfentanil exposure1

Monitor for changes in alfentanil concentration or effect when eluxadoline is initiated or discontinued1

Alosetron

Increased risk of constipation-related adverse effects, including serious adverse effects1

Avoid concomitant use1

Anticholinergics

Increased risk of constipation-related adverse effects, including serious adverse effects1

Avoid concomitant use1

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

Possible increased eluxadoline exposure1

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 effects1

Bupropion

Eluxadoline metabolism not fully known; potential exists for increased eluxadoline exposure1

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 effects1

Ciprofloxacin

Eluxadoline metabolism not fully known; potential exists for increased eluxadoline exposure1

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 effects1

Clarithromycin

Eluxadoline metabolism not fully known; potential exists for increased eluxadoline exposure1

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 effects1

Cyclosporine

Peak plasma concentration and AUC of eluxadoline increased by 6.2- and 4.4-fold, respectively1 2

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased cyclosporine exposure1

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 effects1

Monitor for changes in cyclosporine concentration or effect when eluxadoline is initiated or discontinued1

Eltrombopag

Possible increased eluxadoline exposure1

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 effects1

Ergot alkaloids (dihydroergotamine, ergotamine)

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased exposure to the ergot alkaloid1

Monitor for changes in concentration or effect of the ergot alkaloid when eluxadoline is initiated or discontinued1

Fentanyl

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased fentanyl exposure1

Monitor for changes in fentanyl concentration or effect when eluxadoline is initiated or discontinued1

Fluconazole

Eluxadoline metabolism not fully known; potential exists for increased eluxadoline exposure1

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 effects1

Gemfibrozil

Possible increased eluxadoline exposure1

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 effects1

Loperamide

Increased risk of constipation-related adverse effects, including serious adverse effects1

May use loperamide occasionally for acute management of severe diarrhea, but avoid chronic use; discontinue loperamide immediately if constipation occurs1

Opiates

Increased risk of constipation-related adverse effects, including serious adverse effects1

Avoid concomitant use1

Oral contraceptives

Oral contraceptive containing ethinyl estradiol and norethindrone: No substantial change in exposure to the oral contraceptive components or eluxadoline1 7

Paroxetine

Eluxadoline metabolism not fully known; potential exists for increased eluxadoline exposure1

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 effects1

Pimozide

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased pimozide exposure1

Monitor for changes in pimozide concentration or effect when eluxadoline is initiated or discontinued1

Probenecid

Increased peak plasma concentration and AUC of eluxadoline; not expected to be clinically meaningful1 2

Quinidine

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased quinidine exposure1

Monitor for changes in quinidine concentration or effect when eluxadoline is initiated or discontinued1

Rifampin

Possible increased eluxadoline exposure1

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 effects1

Rosuvastatin

Increased peak plasma concentration and AUC of rosuvastatin by 18 and 40%, respectively; similar effects on N-desmethyl rosuvastatin (active major metabolite) 1

Possible increased risk of myopathy or rhabdomyolysis1

Use lowest effective dosage of rosuvastatin1

Sirolimus

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased sirolimus exposure1

Monitor for changes in sirolimus concentration or effect when eluxadoline is initiated or discontinued1

Tacrolimus

Not known whether eluxadoline inhibits CYP in gut; potential exists for increased tacrolimus exposure1

Monitor for changes in tacrolimus concentration or effect when eluxadoline is initiated or discontinued1

Eluxadoline Pharmacokinetics

Absorption

Bioavailability

Poorly absorbed after oral administration; some data suggest moderate hepatic first-pass extraction occurs.2 8 Absolute oral bioavailability not established.1

Exhibits substantial interpatient variability in pharmacokinetic parameters.1 7

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.1

Exhibits approximately linear pharmacokinetics with no evidence of accumulation with twice-daily dosing.1 7

Food

High-fat meal decreases peak plasma concentration and AUC by 50 and 60%, respectively.1 7

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.1

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

81%.1

Elimination

Metabolism

Not fully established; an acyl glucuronide metabolite has been detected in urine.1 7

Elimination Route

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

Half-life

3.7–6 hours.1 7

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Mixed μ-opiate receptor agonist and δ-opiate receptor antagonist.1 2 3 4 5 6 Also exhibits agonist activity at κ-opiate receptor, but binding affinity for this receptor in humans not determined.1

  • Has poor oral bioavailability and is used for its local effects at opiate receptors in the GI tract.2 3 4 6 8

  • In animals, interacts with opiate receptors in the gut,1 5 reduces contractility in intestinal tissue, and inhibits neurogenically mediated secretion in vitro;4 5 normalizes GI transit and reduces fecal output in animal models of altered GI function.3 4 5 6 9

Advice to Patients

  • Advise patients to read the manufacturer's medication guide before beginning treatment and each time the prescription is refilled.1

  • Advise patients without a gallbladder that they are at increased risk for sphincter of Oddi spasm.1 Advise all patients, but especially those without a gallbladder, to 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.1

  • Advise patients to inform their clinician if they cannot tolerate eluxadoline.1

  • Advise patients to inform their clinician if constipation occurs and lasts >4 days.1

  • 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.1 Advise patients to discontinue loperamide if constipation develops.1 Advise patients to avoid concomitant use of other drugs that may cause constipation (e.g., opiates, anticholinergics).1

  • Advise patients to avoid chronic or acute excessive alcohol consumption while taking eluxadoline.1

  • 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.1

  • Advise patients with hepatic impairment not to drive, operate machinery, or perform other potentially hazardous activities until they know how eluxadoline affects them.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (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.1

Eluxadoline

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

75 mg

Viberzi (C-IV)

Actavis

100 mg

Viberzi (C-IV)

Actavis

AHFS DI Essentials. © Copyright 2016, Selected Revisions March 23, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Actavis Pharma, Inc. Viberzi (eluxadoline) tablets prescribing information. Parsippany, NJ; 2015 May.

2. Davenport JM, Covington P, Bonifacio L et al. Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline. J Clin Pharmacol. 2015; 55:534-42. [PubMed 25491493]

3. Fujita W, Gomes I, Dove LS et al. Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers. Biochem Pharmacol. 2014; 92:448-56. [PubMed 25261794]

4. Dove LS, Lembo A, Randall CW et al. Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a phase 2 study. Gastroenterology. 2013; 145:329-38.e1. [PubMed 23583433]

5. Garnock-Jones KP. Eluxadoline: First Global Approval. Drugs. 2015; 75:1305-10. [PubMed 26149369]

6. Hornby PJ. Drug discovery approaches to irritable bowel syndrome. Expert Opin Drug Discov. 2015; 10:809-24. [PubMed 26193876]

7. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206940Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website.

8. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206940Orig1s000: Medical review(s). From FDA website.

9. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206940Orig1s000: Pharmacology review(s). From FDA website.

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