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    Peripheral Mu Opioid Receptor Agonists for IBS-D

    DEA CLASS

    Rx, schedule IV

    DESCRIPTION

    Oral mu and kappa opioid receptor agonist and delta opioid receptor antagonist
    Indicated for use in adults to treat irritable bowel syndrome with diarrhea (IBS-D)
    Stop treatment if severe constipation lasting more than 4 days develops

    COMMON BRAND NAMES

    Viberzi

    HOW SUPPLIED

    Viberzi Oral Tab: 75mg, 100mg

    DOSAGE & INDICATIONS

    For the treatment of irritable bowel syndrome with diarrhea (IBS-D).
    Oral dosage
    Adults

    100 mg by mouth twice daily with food. Decrease the dosage to 75 mg by mouth twice daily with food in patients who are receiving concurrent treatment with an OATP1B1 inhibitor or who are unable to tolerate 100 mg dose. Discontinue treatment in patients who develop severe constipation.

    MAXIMUM DOSAGE

    Adults

    200 mg/day PO.

    Geriatric

    200 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild to moderate hepatic impairment (Child-Pugh Class A and B, score 9 or less): The recommended dose is 75 mg PO twice daily with food.
    Severe hepatic impairment (Child-Pugh Class C, score more than 9): Use is contraindicated.

    Renal Impairment

    eGFR 60 mL/minute/1.73 m2 or more: No dosage adjustment needed.
    eGFR less than 60 mL/minute/1.73 m2: The recommended dose is 75 mg PO twice daily with food.
    eGFR less than 15 mL/minute/1.73 m2 [includes those with end-stage renal disease (ESRD) not yet on dialysis]: 75 mg PO twice daily with food.

    ADMINISTRATION

    Oral Administration

    Administer the tablets with food.
    Missed dose: Skip the missed dose, and administer the next scheduled dose at the usual time.

    STORAGE

    Viberzi:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Serious hypersensitivity reactions or anaphylaxis

    Eluxadoline is contraindicated in patients who have demonstrated a hypersensitivity to eluxadoline or its ingredients. A risk of serious hypersensitivity reactions or anaphylaxis has been reported in patients receiving eluxadoline; some reports occurred after the first 1 or 2 doses. In postmarketing experience, serious hypersensitivity reactions (including anaphylaxis) have been reported during eluxadoline use. Hypersensitivity reactions have included angioedema, dyspnea, throat tightness, and chest pain/tightness. Instruct patients to immediately stop eluxadoline and seek medical attention if they experience symptoms suggestive of a hypersensitivity reaction.

    Constipation, fecal impaction, GI obstruction, GI perforation

    Administration of eluxadoline is contraindicated in patients with chronic or severe constipation and in patients with known or suspected mechanical GI obstruction. These patients may be at risk for severe complications of bowel obstruction. Constipation, sometimes requiring hospitalization, has been reported following eluxadoline administration. In postmarketing experience, severe cases with the development of intestinal obstruction, GI perforation, and fecal impaction, requiring intervention, have also been reported. Monitor all drug recipients closely for the development of constipation and discontinue treatment in patients who develop severe constipation. Avoid the use of eluxadoline with other drugs that may cause constipation.

    Alcoholism, ethanol ingestion, pancreatitis

    Treatment with eluxadoline is contraindicated in patients with a history of pancreatitis, structural disease of the pancreas including known or suspected pancreatic duct obstruction, in patients without a gallbladder, or alcoholism (e.g., alcohol addiction or abuse, or consumption of more than 3 alcoholic drinks per day) due to the increased risk of pancreatitis in patients in these risk groups. Pancreatitis, with or without sphincter of Oddi spasm, has been reported in patients taking eluxadoline, including serious cases resulting in hospitalization, primarily in patients without a gallbladder. Fatal cases have also been reported in patients without a gallbladder. Most of the reported cases of serious pancreatitis occurred within a week of starting treatment with eluxadoline and some developed symptoms after 1 to 2 doses. In patients with a gallbladder, evaluate a patient's alcohol intake prior to starting eluxadoline. Instruct patients to avoid chronic or acute excessive ethanol ingestion while taking eluxadoline. Monitor for new or worsening pain in the abdomen that may radiate to the back or shoulder, with or without nausea and vomiting. Instruct patients to immediately stop eluxadoline 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.

    Abdominal pain, biliary obstruction, cholecystectomy, gallbladder disease

    Treatment with eluxadoline is contraindicated in patients without a gallbladder (i.e., patients who have had a cholecystectomy), known or suspected biliary obstruction, or sphincter of Oddi dysfunction. These patients are at increased risk for serious events related to sphincter of Oddi spasm and/or pancreatitis. Use with caution in other patients who have known gallbladder disease. Eluxadoline is an opiate receptor agonist, and as such, may increase the tone of the biliary tract resulting in spasms (especially in the sphincter of Oddi) and increased biliary tract pressure. Spasms in the sphincter of Oddi may cause pancreatitis or acute abdominal pain associated with elevated hepatic enzymes. 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 eluxadoline. 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. Most of the reported cases of serious sphincter of Oddi spasm occurred within 1 week of starting treatment and some developed symptoms after 1 to 2 doses. Instruct patients to immediately stop eluxadoline 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 eluxadoline in patients who developed biliary duct obstruction or sphincter of Oddi spasm while taking eluxadoline.

    Driving or operating machinery, hepatic disease

    Administration of eluxadoline to patients with severe hepatic disease (Child-Pugh class C) is contraindicated, as drug exposures (AUC) are increased 16-fold. In patients with mild to moderate hepatic impairment (Child-Pugh class A and B), the AUCs are increased by 4 and 6-fold, respectively; thus, a dose reduction is recommended for these patients. Monitor patients with any degree of hepatic impairment for impaired mental or physical abilities needed to perform potentially hazardous activities such as driving or operating machinery and for other eluxadoline-related adverse reactions.

    Renal failure, renal impairment

    A dosage adjustment is required in patients with moderate or severe renal impairment. The reduction is also recommended for patients with end-stage renal disease (ESRD, renal failure) not yet receiving dialysis. In clinical trials, these patients had increased exposure of eluxadoline.

    Substance abuse

    Administer eluxadoline cautiously to patient with a history of substance abuse. The drug is a mixed opioid agonist/antagonist, and therefore, has the potential to be abused. In two abuse potential studies, opioid experienced individuals administered supratherapeutic oral doses (300 mg and 1000 mg) and intranasal doses (100 mg and 200 mg) reported feelings of euphoria at a rate of 14 to 28%. This was greater than placebo (0 to 5%) but less than oxycodone (44 to 76%).

    Pregnancy

    There are no studies with eluxadoline during human pregnancy that inform any drug-associated risks. In animal studies, no teratogenic effects were observed in rats or rabbits administered oral and subcutaneous doses approximately 51 and 115 times the human exposure, respectively. 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.

    Breast-feeding

    No data are available regarding the presence of eluxadoline in human milk, the effects of eluxadoline on the breast-fed infant, or the effects of eluxadoline on milk production. However, eluxadoline is present in rat milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition in the mother.

    Geriatric

    Use caution when using eluxadoline in the elderly. No overall differences in effectiveness were observed between geriatric patients and younger adult patients during clinical trials and the types of side effects observed were similar in the groups. 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%).

    ADVERSE REACTIONS

    Severe

    bronchospasm / Rapid / 3.0-3.0
    constipation / Delayed / 0-1.0
    pancreatitis / Delayed / 0.3-0.3
    GI perforation / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    impaired cognition / Early / 0-2.0
    euphoria / Early / 0-2.0
    wheezing / Rapid / 0-2.0
    elevated hepatic enzymes / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    dyspnea / Early / Incidence not known
    respiratory depression / Rapid / Incidence not known

    Mild

    nausea / Early / 7.0-8.0
    abdominal pain / Early / 6.0-7.0
    infection / Delayed / 3.0-5.0
    vomiting / Early / 4.0-4.0
    pharyngitis / Delayed / 3.0-4.0
    flatulence / Early / 3.0-3.0
    fatigue / Early / 3.0-3.0
    dizziness / Early / 3.0-3.0
    rash / Early / 3.0-3.0
    gastroesophageal reflux / Delayed / 0-2.0
    drowsiness / Early / 0-2.0
    maculopapular rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as dihydrocodeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together. Additionally, concomitant use of dihydrocodeine with eluxadoline may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of eluxadoline could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If eluxadoline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Eluxadoline is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Codeine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as codeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Acetaminophen; Hydrocodone: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of eluxadoline is necessary. If eluxadoline is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like eluxadoline can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If eluxadoline is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Acetaminophen; Propoxyphene: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as propoxyphene. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Alfentanil: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as alfentanil. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Alosetron: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as alosetron. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Consider a reduction of the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with clarithromycin. Coadministration may increase exposure of eluxadoline. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is an OATP1B1 substrate and clarithromycin is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
    Anticholinergics: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as codeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as dihydrocodeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together. Additionally, concomitant use of dihydrocodeine with eluxadoline may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of eluxadoline could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If eluxadoline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Eluxadoline is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as codeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of eluxadoline is necessary. If eluxadoline is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like eluxadoline can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If eluxadoline is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Atazanavir: (Major) When administered concurrently with atazanavir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); atazanavir is an OATP1B1 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Atazanavir; Cobicistat: (Major) When administered concurrently with atazanavir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); atazanavir is an OATP1B1 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. (Major) When administered concurrently with cobicistat, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); cobicistat is an OATP1B1/1B3 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Atogepant: (Major) Limit the dose of atogepant to 10 or 30 mg PO once daily if coadministered with eluxadoline. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of OATP1B1 and OATP1B3 and eluxadoline is an OATP inhibitor. Coadministration with an OATP inhibitor resulted in a 2.85-fold increase in atogepant exposure and a 2.23-fold increase in atogepant peak concentration.
    Atropine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Atropine; Difenoxin: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Atropine; Edrophonium: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Belladonna; Opium: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days. (Major) Avoid use of eluxadoline with medications that may cause constipation, such as opium. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with eluxadoline may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of eluxadoline in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If eluxadoline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Eluxadoline is a weak inhibitor of CYP3A4.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Benztropine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking eluxadoline. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a BCRP substrate and eluxadoline is a BCRP inhibitor. Coadministration with another BCRP inhibitor increased berotralstat exposure by 69%.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Budesonide; Glycopyrrolate; Formoterol: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as codeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Ceritinib: (Moderate) Monitor for an increase in eluxadoline-related adverse reactions including impaired mental or physical abilities if coadministration with ceritinib is necessary. The metabolism of eluxadoline by CYP pathways has not been clearly established, but strong CYP inhibitors such as ceritinib have the potential to increase eluxadoline exposure.
    Chlordiazepoxide; Clidinium: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Chlorpheniramine; Codeine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as codeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as dihydrocodeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together. Additionally, concomitant use of dihydrocodeine with eluxadoline may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of eluxadoline could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If eluxadoline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Eluxadoline is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as dihydrocodeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together. Additionally, concomitant use of dihydrocodeine with eluxadoline may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of eluxadoline could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If eluxadoline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Eluxadoline is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Chlorpheniramine; Hydrocodone: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Clarithromycin: (Major) Consider a reduction of the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with clarithromycin. Coadministration may increase exposure of eluxadoline. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is an OATP1B1 substrate and clarithromycin is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
    Cobicistat: (Major) When administered concurrently with cobicistat, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); cobicistat is an OATP1B1/1B3 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Codeine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as codeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Codeine; Guaifenesin: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as codeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Codeine; Guaifenesin; Pseudoephedrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as codeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as codeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Codeine; Promethazine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as codeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Cyclosporine: (Major) When administered concurrently with cyclosporine, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); cyclosporine is an OATP inhibitor. Use of these drugs together results in a 4.4-fold increase in exposure (AUC) and a 6.2-fold increase in maximum plasma concentration of eluxadoline. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Daclatasvir: (Major) Consider a reduction in the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with daclatasvir. Coadministration may increase exposure of eluxadoline. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is an OATP1B1 substrate and daclatasvir is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
    Darolutamide: (Major) Reduce the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with darolutamide. Coadministration may increase exposure of eluxadoline. Eluxadoline is an OATP1B1 substrate and darolutamide is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
    Darunavir; Cobicistat: (Major) When administered concurrently with cobicistat, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); cobicistat is an OATP1B1/1B3 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) When administered concurrently with cobicistat, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); cobicistat is an OATP1B1/1B3 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) When administered concurrently with paritaprevir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for adverse effects. Both eluxadoline and paritaprevir are substrates and inhibitors of the organic anion-transporting peptide (OATP1B1). In addition, eluxadoline may inhibit the breast cancer resistance protein (BCRP); paritaprevir is a substrate of this transporter. This specific interaction has not been evaluated; however, administration of eluxadoline with another OATP and BCRP substrate (rosuvastatin) resulted in an increase in the exposure (AUC) and maximum plasma concentration (Cmax) of rosuvastatin by 40% and 18%, respectively. In another study, coadministration of eluxadoline with an OATP inhibitor (cyclosporine) resulted in elevated AUC and Cmax of eluxadoline by 4.4- and 6.2-fold, respectively. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. (Major) When administered concurrently with ritonavir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); ritonavir is an OATP1B1 inhibitor.
    Dicyclomine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as dihydrocodeine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together. Additionally, concomitant use of dihydrocodeine with eluxadoline may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of eluxadoline could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If eluxadoline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Eluxadoline is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Diphenoxylate; Atropine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Elagolix: (Contraindicated) Concomitant use of elagolix and organic anion transporting polypeptide (OATP) 1B1 inhibitors such as eluxadoline is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of OATP1B1. Eluxadoline inhibits OATP1B1. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density.
    Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Concomitant use of elagolix and organic anion transporting polypeptide (OATP) 1B1 inhibitors such as eluxadoline is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of OATP1B1. Eluxadoline inhibits OATP1B1. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for eluxadoline-related adverse reactions (i.e., decreased mental and physical acuity) during coadministration of elexacaftor; tezacaftor; ivacaftor as concurrent use may increase exposure of eluxadoline. Eluxadoline is a substrate for the transporter OATP1B1; elexacaftor; tezacaftor; ivacaftor may inhibit uptake of OATP1B1.
    Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of eluxadoline and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of eluxadoline and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily. Eluxadoline is a weak CYP3A4 inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration with CYP3A4 inhibitors, such as eluxadoline, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
    Eltrombopag: (Major) When administered concurrently with eltrombopag, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); eltrombopag is an in vitro inhibitor of OATP1B1. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) When administered concurrently with cobicistat, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); cobicistat is an OATP1B1/1B3 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) When administered concurrently with cobicistat, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); cobicistat is an OATP1B1/1B3 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Enasidenib: (Major) Reduce the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with enasidenib. Coadministration may increase exposure of eluxadoline. Eluxadoline is an OATP1B1 substrate and enasidenib is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
    Erythromycin: (Major) Consider reduction of the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with erythromycin. Coadministration may increase exposure of eluxadoline. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is an OATP1B1 substrate and erythromycin is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
    Erythromycin; Sulfisoxazole: (Major) Consider reduction of the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with erythromycin. Coadministration may increase exposure of eluxadoline. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is an OATP1B1 substrate and erythromycin is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
    Fentanyl: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as fentanyl. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Flavoxate: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Gemfibrozil: (Major) When administered concurrently with gemfibrozil, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); gemfibrozil is an OATP1B1/2B1 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Glecaprevir; Pibrentasvir: (Major) Reduce the dose of eluxadoline to 75 mg PO twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with glecaprevir. Advise patients against driving or operating machinery until the combined effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); glecaprevir is an OATP1B1/1B3 inhibitor. This specific interaction has not been evaluated; however, administration of eluxadoline with another OATP inhibitor resulted in elevated exposure (AUC) and maximum plasma concentration of eluxadoline by 4.4- and 6.2-fold, respectively. (Major) Reduce the dose of eluxadoline to 75 mg PO twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with pibrentasvir. Advise patients against driving or operating machinery until the combined effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); pibrentasvir is an OATP1B1/1B3 inhibitor. This specific interaction has not been evaluated; however, administration of eluxadoline with another OATP inhibitor resulted in elevated exposure (AUC) and maximum plasma concentration of eluxadoline by 4.4- and 6.2-fold, respectively.
    Glycopyrrolate: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Glycopyrrolate; Formoterol: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Guaifenesin; Hydrocodone: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Homatropine; Hydrocodone: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days. (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Hydrocodone: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Hydrocodone; Ibuprofen: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Hydrocodone; Phenylephrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Hydrocodone; Pseudoephedrine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Hydromorphone: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydromorphone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Hyoscyamine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of eluxadoline is necessary. If eluxadoline is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like eluxadoline can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If eluxadoline is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Indacaterol; Glycopyrrolate: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) When administered concurrently with rifampin, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); rifampin is an inhibitor of OATP. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Isoniazid, INH; Rifampin: (Major) When administered concurrently with rifampin, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); rifampin is an inhibitor of OATP. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Consider a reduction of the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with clarithromycin. Coadministration may increase exposure of eluxadoline. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is an OATP1B1 substrate and clarithromycin is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
    Leflunomide: (Major) Reduce the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with leflunomide. Coadministration may increase exposure of eluxadoline. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is an OATP1B1 substrate and leflunomide is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
    Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with eluxadoline as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; eluxadoline is reported to be a weak CYP3A4 inhibitor, but clinically relevant drug-drug interactions with eluxadoline are not certain. Coadministration with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
    Letermovir: (Moderate) Concurrent administration of eluxadoline and letermovir may increase the plasma concentration of both drugs. In patients receiving both letermovir and cyclosporine, administer eluxadoline at a dose of 75 mg twice daily, because cyclosporine increases the inhibitory potential of letermovir. If these drugs are given together, closely monitor for adverse events including impaired mental or physical abilities, tachycardia, atrial fibrillation, and gastrointestinal events. Both eluxadoline and letermovir are substrates and inhibitors of the organic anion-transporting polypeptide (OATP1B1).
    Levorphanol: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as levorphanol. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Loperamide: (Moderate) When possible, avoid use of eluxadoline with medications that may cause constipation. According to the manufacturer, short term administration of loperamide (for the managment of severe diarrhea) may be considered in patients receiving eluxadonline; however, loperamide must be immediately discontinued if constipation occurs. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Loperamide; Simethicone: (Moderate) When possible, avoid use of eluxadoline with medications that may cause constipation. According to the manufacturer, short term administration of loperamide (for the managment of severe diarrhea) may be considered in patients receiving eluxadonline; however, loperamide must be immediately discontinued if constipation occurs. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Lopinavir; Ritonavir: (Major) When administered concurrently with lopinavir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); lopinavir is an OATP1B1 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. (Major) When administered concurrently with ritonavir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); ritonavir is an OATP1B1 inhibitor.
    Mepenzolate: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Meperidine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as meperidine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Meperidine; Promethazine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as meperidine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Methadone: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as methadone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Methscopolamine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Midostaurin: (Major) Reduce the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with midostaurin. Coadministration may increase exposure of eluxadoline. Eluxadoline is an OATP1B1 substrate and midostaurin is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
    Morphine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as morphine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Morphine; Naltrexone: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as morphine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Nirmatrelvir; Ritonavir: (Major) When administered concurrently with ritonavir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); ritonavir is an OATP1B1 inhibitor.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with eluxadoline due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and eluxadoline is a weak CYP3A4 inhibitor.
    Obeticholic Acid: (Major) When administered concurrently with obeticholic acid, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); obeticholic acid is an in vitro inhibitor of OATP1B1 and 1B3. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) When administered concurrently with paritaprevir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for adverse effects. Both eluxadoline and paritaprevir are substrates and inhibitors of the organic anion-transporting peptide (OATP1B1). In addition, eluxadoline may inhibit the breast cancer resistance protein (BCRP); paritaprevir is a substrate of this transporter. This specific interaction has not been evaluated; however, administration of eluxadoline with another OATP and BCRP substrate (rosuvastatin) resulted in an increase in the exposure (AUC) and maximum plasma concentration (Cmax) of rosuvastatin by 40% and 18%, respectively. In another study, coadministration of eluxadoline with an OATP inhibitor (cyclosporine) resulted in elevated AUC and Cmax of eluxadoline by 4.4- and 6.2-fold, respectively. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. (Major) When administered concurrently with ritonavir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); ritonavir is an OATP1B1 inhibitor.
    Oxybutynin: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of eluxadoline is necessary. If eluxadoline is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like eluxadoline can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If eluxadoline is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Oxymorphone: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as oxymorphone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Pramlintide: (Major) Due to its effects on gastric emptying, pramlintide should not be considered for patients taking medications that alter gastrointestinal motility (e.g., slow GI motility, such as eluxadoline). Consider alternative diabetic treatments. Patients using these medications have not been studied in pramlintide clinical trials. Severe constipation, which could result in bowel blockage, is a potential concern.
    Probenecid: (Minor) Systemic exposure (AUC) and maximum plasma concentration of eluxadoline are increased by 35% and 31%, respectively, when administered concurrently with probenecid. According to the manufacturer, the increase in exposure is not expected to be clinically meaningful; no dosage adjustments are required during coadministration with probenecid.
    Probenecid; Colchicine: (Minor) Systemic exposure (AUC) and maximum plasma concentration of eluxadoline are increased by 35% and 31%, respectively, when administered concurrently with probenecid. According to the manufacturer, the increase in exposure is not expected to be clinically meaningful; no dosage adjustments are required during coadministration with probenecid.
    Propantheline: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Propoxyphene: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as propoxyphene. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Remifentanil: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as remifentanil. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Ribociclib: (Moderate) Monitor for an increase in eluxadoline-related adverse reactions including impaired mental or physical abilities if coadministration with ribociclib is necessary. The metabolism of eluxadoline by CYP pathways has not been clearly established, but strong CYP inhibitors such as ribociclib have the potential to increase eluxadoline exposure.
    Ribociclib; Letrozole: (Moderate) Monitor for an increase in eluxadoline-related adverse reactions including impaired mental or physical abilities if coadministration with ribociclib is necessary. The metabolism of eluxadoline by CYP pathways has not been clearly established, but strong CYP inhibitors such as ribociclib have the potential to increase eluxadoline exposure.
    Rifampin: (Major) When administered concurrently with rifampin, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); rifampin is an inhibitor of OATP. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Ritonavir: (Major) When administered concurrently with ritonavir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); ritonavir is an OATP1B1 inhibitor.
    Rosuvastatin: (Moderate) Close monitoring for adverse effects, such as rhabdomyolysis and myopathy, is advised when eluxadoline is administered concurrently with rosuvastatin. Eluxadoline is an inhibitor of the organic anion-transporting peptide (OATP1B1) and the breast cancer resistance protein (BCRP); rosuvastatin is a substrate of both transporters. Use of these drugs together results in a 40% increase in the exposure (AUC) and a 18% increase in the maximum plasma concentration (Cmax) of rosuvastatin. Administer the lowest effect rosuvastatin dose and monitor for adverse effects.
    Rosuvastatin; Ezetimibe: (Moderate) Close monitoring for adverse effects, such as rhabdomyolysis and myopathy, is advised when eluxadoline is administered concurrently with rosuvastatin. Eluxadoline is an inhibitor of the organic anion-transporting peptide (OATP1B1) and the breast cancer resistance protein (BCRP); rosuvastatin is a substrate of both transporters. Use of these drugs together results in a 40% increase in the exposure (AUC) and a 18% increase in the maximum plasma concentration (Cmax) of rosuvastatin. Administer the lowest effect rosuvastatin dose and monitor for adverse effects.
    Saquinavir: (Major) When administered concurrently with saquinavir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); saquinavir is an OATP1B1 inhibitor.
    Scopolamine: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Simeprevir: (Major) When administered concurrently with simeprevir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); simeprevir is an OATP inhibitor and in vitro substrate. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Sofosbuvir; Velpatasvir: (Major) When administered concurrently with velpatasvir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); velpatasvir is an OATP1B1 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) When administered concurrently with velpatasvir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); velpatasvir is an OATP1B1 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. (Major) When administered concurrently with voxilaprevir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); voxilaprevir is an OATP1B1 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if eluxadoline must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of eluxadoline is necessary. If eluxadoline is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like eluxadoline can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If eluxadoline is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Telithromycin: (Major) When administered concurrently with telithromycin, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); telithromycin is an in vitro inhibitor of OATP1B1/1B3. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Teriflunomide: (Major) When administered concurrently with teriflunomide, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); teriflunomide is an in vitro inhibitor of OATP.
    Tipranavir: (Major) When administered concurrently with tipranavir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); tipranavir is an OATP1B1 inhibitor.
    Trihexyphenidyl: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Voclosporin: (Major) Reduce the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects including decreased mental and physical acuity if coadministered with voclosporin. Coadministration may increase exposure of eluxadoline. Eluxadoline is an OATP1B1 substrate and voclosporin is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no studies with eluxadoline during human pregnancy that inform any drug-associated risks. In animal studies, no teratogenic effects were observed in rats or rabbits administered oral and subcutaneous doses approximately 51 and 115 times the human exposure, respectively. 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.

    No data are available regarding the presence of eluxadoline in human milk, the effects of eluxadoline on the breast-fed infant, or the effects of eluxadoline on milk production. However, eluxadoline is present in rat milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition in the mother.

    MECHANISM OF ACTION

    Eluxadoline is an agonist of the mu and kappa opioid receptors and an antagonist of the delta opioid receptor. The binding affinities (Ki) to human mu and delta opioid receptors are 1.8 nM and 430 nM, respectively. The Ki for human kappa opioid receptors has not been determined. When opioid receptors agonists, such as eluxadoline, interact with receptors located in the gastrointestinal tract, secretions from the stomach, pancreas, and biliary tract are decreased. The combination of effects of opiate agonists on the GI tract results in constipation and delayed digestion.

    PHARMACOKINETICS

    Eluxadoline is administered via the oral route. Following systemic absorption, the drug is 81% bound to human plasma proteins. The pathway by which the drug is metabolized has not been established; however, evidence suggests it may undergo glucuronidation resulting in an acyl glucuronide metabolite. The mean plasma elimination half-life ranges from 3.7 hours to 6 hours. Excretion occurs primarily through the feces, with 82.2% of an administered dose recovered within 336 hours; less than 1% is recovered in the urine after 192 hours.
     
    Affected cytochrome P450 isoenzymes and transporters: Bile salt export pump (BSEP), multidrug resistance-associated protein (MRP2), organic anion transporter (OAT3), organic anion-transporting polyprotein (OATP1B1)
    In vitro studies indicate that eluxadoline is neither an inducer of CYP1A2, CYP2C9, CYP2C19, and CYP3A4, nor an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, and CYP2D6 at clinically relevant systemic concentrations. Although CYP2E1 was slightly inhibited by eluxadoline, clinically meaningful interactions are unlikely. Despite mechanism-based inhibition of CYP3A4 in vitro, eluxadoline did not have a clinically meaningful drug-drug interaction with the CYP3A4 substrate midazolam. In vitro studies suggest eluxadoline is a substrate for the transporters OAT3, OATP1B1, BSEP, and MRP2, but not for OCT1, OCT2, OAT1, OATP1B3, P-gp and BCRP. Based on in vitro studies, clinically meaningful interaction via inhibition of OCT1, OCT2, OAT2, OAT3, OATP1B3, BSEP and MRP2 by eluxadoline is unlikely. Cytochrome P450 and UGT pathways have minimal involvement in the metabolism of eluxadoline. It is unlikely that metabolism of eluxadoline by these enzymes has a clinically meaningful impact on systemic exposure.

    Oral Route

    Following oral administration, eluxadoline displays linear pharmacokinetics with no accumulation resulting from repeated twice daily dosing. However, the pharmacokinetic parameters of eluxadoline are variable. In a study of health volunteers administered 100 mg doses, the maximum plasma concentration (Cmax) ranged from 2 to 4 ng/mL, exposures (AUC) ranged from 12 to 22 ng x h/mL. The time to reach maximum plasma concentrations (Tmax) is also variable. Under fed conditions, the median Tmax was 1.5 hours (range: 1 to 8 hours). When given with food, the median Tmax was 2 hours (range: 0.5 to 6 hours). Administering eluxadoline with a high-fat meal (800 to 1000 calories, 50% from fat) decreases the Cmax by 50% and the AUC by 60%. The absolute bioavailability has not been determined.