Eluxadoline

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

Eluxadoline (Eluxadoline) works directly in your intestines to slow the movement of food during digestion. Eluxadoline also makes the nerves in your intestines less sensitive to stimulation.

Eluxadoline is used to treat irritable bowel syndrome when the main symptom is diarrhea.

Eluxadoline may also be used for purposes not listed in this medication guide.

The recommended dosage of Eluxadoline is 100 mg taken orally twice daily with food.

The recommended dosage of Eluxadoline is 75 mg taken orally twice daily with food in patients who:

• do not have a gallbladder.
• are unable to tolerate the 100 mg dose of Eluxadoline.
• are receiving concomitant OATP1B1 inhibitors.
• have mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

Discontinue Eluxadoline in patients who develop severe constipation for more than 4 days.

Instruct patients if they miss a dose, take the next dose at the regular time and not to take 2 doses at the same time to make up for a missed dose.

How supplied

Dosage Forms And Strengths

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

Storage And Handling

Eluxadoline is available as:

75 mg tablets: capsule-shaped tablets, coated in pale-yellow to light tan color, debossed with “FX75” on one side.

Bottle of 60: NDC 0456-5375-60

100 mg tablets: capsule-shaped tablets, coated in pink-orange to peach color, debossed with “FX100” on one side.

Bottle of 60: NDC 0456-5310-60

Store Eluxadoline tablets at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F).

Manufactured by: Patheon Pharmaceuticals, Inc, Cincinnati, OH 45237-1625 USA. Distributed by: Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, LLC Cincinnati, Ohio 45209 USA. Issued: May 2015

See also:
What is the most important information I should know about Eluxadoline?

Eluxadoline is contraindicated in patients with:

• Known or suspected biliary duct obstruction; or sphincter of Oddi disease or dysfunction. These patients are at increased risk for sphincter of Oddi spasm.
• Alcoholism, alcohol abuse or alcohol addiction, or in patients who drink more than 3 alcoholic beverages per day. These patients are at increased risk for acute pancreatitis.
• A history of pancreatitis; or structural diseases of the pancreas, including known or suspected pancreatic duct obstruction. These patients are at increased risk for acute pancreatitis.
• Severe hepatic impairment (Child-Pugh Class C). These patients are at risk for significantly increased plasma concentrations of Eluxadoline
• A history of chronic or severe constipation or sequelae from constipation, or known or suspected mechanical gastrointestinal obstruction. These patients may be at risk for severe complications of bowel obstruction.

Use: Labeled Indications

Irritable bowel syndrome with diarrhea: Treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults

See also:
What other drugs will affect Eluxadoline?

The metabolism of Eluxadoline by CYP pathways has not been clearly established. In addition, the potential of Eluxadoline to inhibit CYP3A4 in the gut has not been established.

Tables 2 and 3 include drugs which demonstrated a clinically important drug interaction with Eluxadoline or which potentially may result in clinically relevant interactions.

Table 2: Established and Other Potentially Clinically Relevant Interactions Affecting Eluxadoline

Table 3: Established and Other Potentially Clinically Relevant Interactions Affecting Drugs Co-Administered with Eluxadoline

Drug Abuse And Dependence

Controlled Substance

Pending

Abuse

In a drug discrimination study in monkeys, intravenous administration of Eluxadoline hydrochloride produced full generalization to the morphine cue. In a self-administration study in monkeys, Eluxadoline hydrochloride was self-administered to a degree that was less than that of heroin but greater than that of saline.

Adverse reactions of euphoria and feeling drunk were reported in clinical trials of IBS-D evaluating 75 mg and 100 mg doses of Eluxadoline. The rate of euphoria was 0% for 75 mg and 0.2% (2/1032) for 100 mg and the rate of feeling drunk was 0.1% (1/807) for 75 mg and 0.1% (1/1032) for 100 mg.

In contrast, in two human abuse potential studies conducted in recreational opioid-experienced individuals, supratherapeutic oral doses of Eluxadoline (300 mg and/or 1000 mg) and intranasal doses of Eluxadoline (100 mg and/or 200 mg) produced the adverse reaction of euphoria (at a rate ranging from 14% to 28%) that was greater than that of placebo (0% to 5%) but less than that of oxycodone (44% to 76%). In the two human abuse potential studies, supratherapeutic oral and intranasal doses of Eluxadoline produced small but significant increases on positive subjective measures such as Drug Liking and High compared to placebo. Supratherapeutic oral and intranasal doses of Eluxadoline also produced small but significant increases on negative subjective measures such as Drug Disliking and Dysphoria compared to placebo. In the same studies, oxycodone (30 mg and 60 mg oral, and 15 and 30 mg intranasal) produced significantly greater responses on positive and negative subjective measures than those produced by Eluxadoline and placebo.

Dependence

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

See also:
What are the possible side effects of Eluxadoline?

The following adverse reactions described below and elsewhere in the labeling include:

• Sphincter of Oddi Spasm
• Pancreatitis

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Over 1700 patients with IBS-D have been treated with 75 or 100 mg of Eluxadoline twice daily in controlled trials. Exposures from placebo-controlled clinical trials in adult patients with IBS-D included 1391 exposed for 3 months, 1001 exposed for 6 months and 488 exposed for one year.

Demographic characteristics were comparable between the treatment groups. Data described below represent pooled data compared to placebo across the randomized trials.

Sphincter of Oddi Spasm

In clinical trials, sphincter of Oddi spasm occurred in 0.2% (2/807) of patients receiving 75 mg and 0.8% (8/1032) of patients receiving 100 mg Eluxadoline twice daily.

• Among patients receiving 75 mg, 1/807 (0.1%) patient experienced a sphincter of Oddi spasm presenting with abdominal pain but with lipase elevation less than 3 times the upper limit of normal (ULN) and 1/ 807 (0.1%) patient experienced a sphincter of Oddi spasm manifested as elevated hepatic enzymes associated with abdominal pain
• Among patients receiving 100 mg, 1/1032 (0.1%) patient experienced a sphincter of Oddi spasm manifested as pancreatitis and 7/1032 (0.7%) patients experienced sphincter of Oddi spasm manifested as elevated hepatic enzymes associated with abdominal pain

In patients without a gallbladder, 2/165 (1.2%) and 8/184 (4.3%) of patients receiving 75 mg and 100 mg, respectively, experienced a sphincter of Oddi spasm vs 0/1317 (0%) in patients with a gallbladder who had received either 75 mg or 100 mg treatment.

Of those patients who experienced a sphincter of Oddi spasm, 80% (8/10) reported their first onset of symptoms within the first week of treatment. The case of sphincter of Oddi spasminduced pancreatitis occurred within minutes of taking the first dose of Eluxadoline. No cases of sphincter of Oddi spasm occurred greater than 1 month after treatment onset. All events resolved upon discontinuation of Eluxadoline, with symptoms typically improved by the following day.

Pancreatitis

Additional cases of pancreatitis, not associated with sphincter of Oddi spasm, were reported in 2/807 (0.2%) of patients receiving 75 mg and 3/1032 (0.3%) of patients receiving 100 mg Eluxadoline twice daily in clinical trials. Of these 5 cases, 3 were associated with excessive alcohol intake, one was associated with biliary sludge, and in one case the patient discontinued Eluxadoline 2 weeks prior to the onset of symptoms. All pancreatic events resolved with lipase normalization upon discontinuation of Eluxadoline, with 80% (4/5) resolving within 1 week of treatment discontinuation. The case of sphincter of Oddi spasm-induced pancreatitis resolved within 24 hours of discontinuation.

Common Adverse Reactions

Table 1 provides the incidence of common adverse reactions reported in > 2% of IBS-D patients in either Eluxadoline treatment group and at an incidence greater than in the placebo group.

Table 1: Common* Adverse Reactions in the Placebo-Controlled Studies in IBS-D Patients

Constipation was the most commonly reported adverse reaction in Eluxadoline-treated patients in these trials. Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving 75 mg and 100 mg Eluxadoline. Similar rates of constipation occurred between the active and placebo arms beyond 3 months of treatment.

Adverse Reactions Leading to Discontinuation

Eight percent of patients treated with 75 mg, 8% of patients treated with 100 mg Eluxadoline and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the Eluxadoline treatment groups, the most common reasons for discontinuation due to adverse reactions were constipation (1% for 75 mg and 2% for 100 mg) and abdominal pain (1% for both 75 mg and 100 mg). In comparison, less than 1% of patients in the placebo group withdrew due to constipation or abdominal pain.

Less Common Adverse Reactions

Adverse reactions that were reported in ≤ 2% of Eluxadoline-treated patients are listed below by body system.

Gastrointestinal: gastroesophageal reflux disease

General Disorders and administration site conditions: feeling drunk

Investigations: increased AST

Nervous system: sedation, somnolence

Psychiatric disorders: euphoric mood

Respiratory: asthma, bronchospasm, respiratory failure, wheezing

Eluxadoline is a mixed mu-opioid receptor agonist, kappa-opioid receptor agonist, and a-delta opioid receptor antagonist indicated for use in diarrhea-predominant irritable bowel syndrome (IBS-D). The mu-, kappa-, and delta-opioid receptors mediate endogenous and exogenous opioid response in the central nervous system and peripherally in the gastrointestinal system. Agonism of peripheral mu-opioid receptors results in reduced colonic motility, while antagonism of central delta-opioid receptors results in improved analgesia, making Eluxadoline usable for the symptoms of both pain and diarrhea characteristic of IBS-D. Marketed under the tradename Eluxadoline (FDA), Eluxadoline is an antimotility agent that decreases bowel contractions, inhibits colonic transit, and reduces fluid/ion secretion resulting in improved symptoms of abdominal pain and reductions in the Bristol Stool Scale.