Eluxadoline

Eluxadoline increases the exposure of the co-administered OATP1B1 substrate; rosuvastatin by up to 40% of the total exposure which is usually not considered to be clinically relevant. The effect on other statins which are more sensitive OATP1B1 substrates (e.g. simvastatin and atorvastatin), however, may be more pronounced. Caution should therefore be exercised in patients receiving such medicinal products especially with high doses. Other substrates potentially affected include e.g. sartans (valsartan, olmesaran).

Co-administration of OATP1B1 inhibitors (cyclosporine, gemfibrozil, antiretrovirals [atazanavir, lopinavir, ritonavir, saquinavir, tipranavir], rifampin) with eluxadoline may increase exposure to eluxadoline. Eluxadoline should not be administered concomitantly with such medicinal products.

The use of eluxadoline with other medicinal products that may cause constipation (for example anticholinergics, opioids etc) should also be avoided.

Systemic exposure to medicinal products metabolised by CYP3A4 may be decreased when co-administered with Eluxadoline. Loss of efficacy can occur, especially when medicinal products with low dose and narrow therapeutic index (e.g. alfentanil, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), are co-administered with Eluxadoline.

Although no direct drug-drug interactions have been demonstrated, chronic use of loperamide with eluxadoline should be avoided as this may increase the risk of constipation.

There is a potential for increased risk of somnolence and sedation when taking eluxadoline in patients who may experience increased plasma levels, such as in patients with a genetic predisposition for poor function of OATP1B1 transporter. As patient’s genetic disposition may be unknown, it is recommended that patients be monitored for impaired mental or physical abilities needed to perform potentially hazardous activities such as driving a car or using machines.

A relevant proportion of patients diagnosed with IBS-D may be affected by bile-acid malabsorption as a potential reason for IBS-D symptoms. The safety and efficacy of eluxadoline in this subgroup of IBS-D patients has not been established.

There is limited amount of data from the use of eluxadoline in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of eluxadoline during pregnancy.

It is unknown whether eluxadoline is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of eluxadoline in milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from eluxadoline therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No human data on the effect of eluxadoline on fertility are available. In rats, there was no effect on mating, fertility and fecundity indices.

Eluxadoline has a minor influence on the ability to drive and use machines. Due to events of somnolence and sedation observed in clinical studies, caution should be exercised.

Summary of the safety profile

The most common adverse reactions (incidence of >5%) reported were constipation (7% and 8% of patients receiving 75 mg and 100 mg respectively), nausea (8% and 7% of patients receiving 75 mg and 100 mg respectively) and abdominal pain (6% and 7% of patients receiving 75 mg and 100 mg respectively). Serious adverse reactions of pancreatitis (0.2% and 0.3% of patients receiving 75 mg and 100 mg respectively) and sphincter of Oddi spasm (0.2% of patients receiving 75 mg and 0.8% of patients receiving 100 mg) may also occur.

List of adverse reactions

The following adverse reactions considered related to eluxadoline treatment from clinical trials and spontaneous reporting are presented according to the MedDRA System Organ Classification and frequency convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

Immune system disorders

Not known: Hypersensitivity⁶

Nervous system disorders

Common: Dizziness, Somnolence¹

Gastrointestinal disorders

Common: Constipation, Nausea, Abdominal pain2, Vomiting, Flatulence, Abdominal distention, Gastroesophageal reflux disease⁴

Uncommon: Sphincter of Oddi spasm³, Pancreatitis

Skin and subcutaneous tissue disorders

Common: Rash⁵

Investigations

Common: Increased ALT, Increased AST

¹ “Somnolence” term includes: somnolence and sedation.
² “Abdominal pain” term includes: abdominal pain, abdominal pain lower, and abdominal pain upper.
³ “Sphincter of Oddi spasm” term includes: manifestation as pancreatitis (terms include alcoholic pancreatitis, pancreatitis, and pancreatitis acute) and hepatic enzyme elevations with abdominal pain (terms include abdominal pain, abdominal pain upper, dyspepsia, and sphincter of Oddi dysfunction).
⁴ “Gastrooesophageal reflux disease” term includes gastrooesophageal reflux disease, dyspepsia and gastritis.
⁵ “Rash” term includes: dermatitis, dermatitis allergic, rash, rash generalized, rash macula-papular, rash papular, rash pruritic, urticaria, and idiopathic urticarial.
⁶ “Hypersensitivity” term includes: anaphylaxis, angioedema, (e.g. swollen face and/or throat), dyspnea, throat tightness and chest pain/tightness – spontaneously reported in the post-marketing period.

Description of selected adverse reactions

Constipation

Approximately 50% of constipation events occurred within the first 2 weeks of treatment. Rates of severe constipation were less than 1% in patients receiving 75 mg and 100 mg eluxadoline and there were no serious complications of constipation related to eluxadoline use in pivotal studies. 1% of patients receiving 75 mg and 2% of patients receiving 100 mg discontinued treatment or temporarily suspended dosing secondary to constipation, respectively, compared to <1% of patients treated with placebo. Patients should be instructed to stop the medicinal product and seek medical attention if they develop severe constipation.

Sphincter of Oddi spasm

In clinical studies, events of sphincter of Oddi spasm manifested as elevated hepatic enzymes associated with abdominal pain in 8 patients, pancreatitis in 1 patient and abdominal pain with lipase elevation less than 3 times the upper limit of normal in 1 patient. 80% (8/10) of sphincter of Oddi spasm events presented within the first week of treatment. All events resolved upon discontinuation of eluxadoline, with symptoms typically improved by the following day. All events of sphincter of Oddi spasm occurred in patients without a gallbladder. Therefore, eluxadoline is contraindicated in this population as well as in those with previous biliary tract problems. The occurrence of such events in patients with an intact biliary tract cannot be excluded.

Pancreatitis

Additional cases of pancreatitis not associated with sphincter of Oddi spasm were reported in clinical studies. Of the 5 cases reported, 3 were associated with excessive alcohol intake, 1 was associated with biliary sludge, and in one case the patient discontinued eluxadoline 2 weeks prior to the onset of symptoms.

All pancreatic events, whether or not associated with sphincter of Oddi spasm, were retrospectively evaluated as mild, indicating an absence of organ failure and local or systemic complications. All pancreatic events resolved with lipase normalization upon discontinuation of eluxadoline, with 80% (4/5) resolving within 1 week of treatment discontinuation.

Elderly

Of 1,795 IBS-D patients who were enrolled in clinical studies of eluxadoline and assigned to 75 mg or 100 mg twice daily, 139 (7.7%) were at least 65 years of age, while 15 (0.8%) were at least 75 years old.

There was an overall increased frequency of adverse events in the older population compared to patients <65 years which was comparable across all treatment groups, including placebo.

The frequency of serious adverse events, gastrointestinal events, and events leading to discontinuation tended to be lower for the 75 mg dose compared to the 100 mg dose. Therefore, in this population, the 75 mg dose twice daily can be used.