This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Truberzi 75 mg film-coated tablets.

Truberzi 100 mg film-coated tablets.

2. Qualitative and quantitative composition

Truberzi 75 mg film-coated tablets

Each film-coated tablet contains 75 mg of eluxadoline.

Truberzi 100 mg film-coated tablets

Each film-coated tablet contains 100 mg of eluxadoline.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Truberzi 75 mg film-coated tablets

Modified capsule-shaped, pale yellow to light-tan film-coated tablet of approximately 7 mm x 17 mm, debossed with “FX75” on one side.

Truberzi 100 mg film-coated tablets

Modified capsule-shaped, pink-orange to peach film-coated tablet of approximately 8 mm x 19 mm, debossed with “FX100” on one side.

4. Clinical particulars
4.1 Therapeutic indications

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

4.2 Posology and method of administration

Posology

The treatment should be initiated and supervised by a physician experienced in diagnosis and management of gastrointestinal disorders.

The recommended dose is 200 mg daily (one 100 mg tablet, twice daily).

For patients who are unable to tolerate the 200 mg daily dose (one 100 mg tablet, twice daily), the dose can be lowered to 150 mg daily (one 75 mg tablet twice daily).

Elderly

In principle, general dose recommendations also apply to patients aged 65 years and above.

However, given the potential for increased sensitivity to experience undesirable effects, it may be considered to initiate eluxadoline treatment in a dosage of 150 mg daily (one 75 mg tablet twice daily). If this dosage is well tolerated, but not sufficiently effective, dosage may subsequently be increased to 200 mg daily (one 100 mg tablet twice daily). See section 4.4.

Patients with renal impairment

The safety and pharmacokinetics of eluxadoline in patients with renal impairment have not yet been established. With the renal route being a minor route of elimination for eluxadoline, no dose adjustment based on renal function may be necessary (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of eluxadoline in children aged 0 to18 years have not yet been established.

No data are available.

Benefits and risks of the treatment should be periodically assessed in the context of patient symptoms severity.

Method of administration

For oral use.

The tablets should be taken with food in the morning and in the evening (see section 5.2).

Patients should be instructed if they miss a dose (delay of 4 hours) to 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.

4.3 Contraindications

• Hypersensitivity to eluxadoline or to any of the excipients listed in section 6.1.

• Alcoholism, alcohol abuse, alcohol addiction or chronic or acute excessive alcohol use. These patients are at increased risk for acute pancreatitis (see section 4.4).

• Known or suspected biliary tree and/or pancreatic duct obstruction (e.g. gallstones, tumour, periampullary duodenal diverticulum) or sphincter of Oddi disease or dysfunction. These patients are at increased risk for sphincter of Oddi spasm (see section 4.4).

• Patients without a gallbladder (e.g. due to cholecystectomy or agenesis). These patients are also at increased risk for sphincter of Oddi spasm (see section 4.4).

• Patients on treatment with potent inhibitors of OATP1B1 (e.g. cyclosporine)

• A history of pancreatitis; or known or suspected structural diseases of the pancreas, including pancreatic duct obstruction. These patients are at increased risk for acute pancreatitis (see section 4.4).

• Hepatic impairment (Child-Pugh Class A-C). These patients are at risk for significantly increased plasma concentrations of eluxadoline (see sections 4.4 and 5.2).

• 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.

4.4 Special warnings and precautions for use

Sphincter of Oddi Spasm

Given the mu opioid receptor agonism of eluxadoline, there is a potential for increased risk of sphincter of Oddi spasm, resulting in pancreatitis or hepatic enzyme elevation associated with acute abdominal pain (eg, biliary-type pain) in patients taking eluxadoline, especially in patients without a gallbladder (see sections 4.3 and 4.8). Patients with known or suspected sphincter of Oddi disease or dysfunction and/or biliary tract or pancreatic disease, including a history of pancreatitis, and those who have had a cholecystectomy or are missing a gallbladder due to other reasons must not receive this medicinal product (see section 4.3).

Patients should be instructed to stop the treatment 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. Eluxadoline should not be restarted in patients who developed biliary duct obstruction or sphincter of Oddi spasm while taking eluxadoline (see section 4.3).

Pancreatitis

There is an increased risk of pancreatitis with or without sphincter of Oddi spasm (see section 4.3) in patients taking eluxadoline. Serious cases resulting in hospitalization and death, primarily in patients without a gallbladder have been reported. Truberzi is contraindicated in patients without a gallbladder and other conditions that increase the risk of developing pancreatitis (see section 4.3). Most of the reported cases of serious pancreatitis occurred within a week of starting treatment with eluxadoline and some patients developed symptoms even after one to two doses but cases of pancreatitis after longer duration of treatment have also been reported.

Patients should be informed of and monitored for signs and symptoms suggestive of pancreatitis e.g. abdominal pain, that may radiate to the back or shoulder, nausea and vomiting. Patients should be instructed to stop the medicinal product and seek medical attention if these symptoms develop while taking eluxadoline (see section 4.8).

All patients should be instructed not to use alcohol while on treatment with eluxadoline.

Constipation

There is a potential for increased risk of constipation when taking eluxadoline (see section 4.8). If patients develop severe constipation for a duration of more than 4 days, they should be instructed to stop the treatment and seek medical attention.

Risk of constipation with eluxadoline in patients with other IBS sub-types is unknown, but may be increased. Caution should be exercised when administering eluxadoline in IBS patients whose bowel habits vary over time.

Somnolence and sedation

There is a potential for increased risk of somnolence and sedation when taking eluxadoline (see section 4.8) 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 (see sections 4.7. and 4.8).

Drug dependence and potential for abuse

Based on the physical-chemical and biopharmaceutical properties (very low oral bioavailability), eluxadoline is expected to have minimal abuse or dependence liability.

Special populations

Elderly

Overall, there was an increased frequency of adverse events reported for patients aged 65 years or greater in the clinical studies. However, patients 65 years of age and older, treated with the 75 mg dose twice daily experienced a reduced rate of serious adverse events as well as adverse events leading to discontinuation compared to patients treated with 100 mg dose twice daily (see section 4.8). Therefore, the 75 mg dose twice daily can be considered for this population, but its benefit risk ratio should be periodically assessed in the context of their symptoms severity (see section 4.2).

Paediatric population

Eluxadoline should not be used in children and adolescents as it has not been studied in this population (see section 4.2).

Renal impairment

No data on the pharmacokinetics of eluxadoline in patients with renal impairment are available (see section 5.2). Due to minimal absorption and the negligible role for renal elimination, an influence of renal impairment on the plasma levels of eluxadoline is not expected.

Hepatic impairment

Eluxadoline must not be used in patients with a history of or known or suspected hepatic impairment (Child-Pugh Class A-C) (see section 4.3).

Effect of OATP1B1 transporter function variability on plasma levels

The plasma levels in patients with a genetic predisposition for poor function of OATP1B1 transporter are increased, and in these patients a higher rate of adverse events, especially with regard to gastrointestinal events, as well as CNS effects might be expected (see section 5.2).

Bile acid malabsorption

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.

4.5 Interaction with other medicinal products and other forms of interaction

Medicinal products that cause constipation

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

OATP1B1 inhibitors

Co-administration of OATP1B1 inhibitors (cyclosporine, gemfibrozil, antiretrovirals [atazanavir, lopinavir, ritonavir, saquinavir, tipranavir], rifampin) with eluxadoline may increase exposure to eluxadoline (see section 5.2). Eluxadoline should not be administered concomitantly with such medicinal products (see section 4.3).

OATP1B1 substrates

Eluxadoline increases the exposure of the co-administered OATP1B1 substrate; rosuvastatin (see section 5.2) 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 (valasartan, olmesaran).

CYP3A substrates

Eluxadoline may increase the exposure of co-administered medicinal products metabolised by Cytrochrome CYP3A4. Caution should be exercised when administering such products (e.g. midazolam, erythromycin, nifedipine), especially for those with a narrow therapeutic index (e.g. alfentanil, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus). The concentration of these co-administered medicinal products with a narrow therapeutic index or their other pharmacodynamic markers should be monitored when concomitant use with eluxadoline is initiated or discontinued.

4.6 Fertility, pregnancy and lactation

Pregnancy

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 (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Truberzi during pregnancy.

Breast-feeding

It is unknown whether eluxadoline is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of eluxadoline in milk (for details see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Truberzi 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 (see section 5.3).

4.7 Effects on ability to drive and use machines

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 (see sections 4.4 and 4.5).

4.8 Undesirable effects

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.

Tabulated list of adverse reactions

Adverse reactions 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).

System organ class

Common

Uncommon

Nervous system disorders

Dizziness

Somnolence1

Gastrointestinal disorders

Constipation

Nausea

Abdominal pain2

Vomiting

Flatulence

Abdominal distention

Gastroesophageal reflux disease4

Sphincter of Oddi spasm3

Pancreatitis

Skin and subcutaneous tissue disorders

Rash5

Investigations

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.

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 for more than 4 days (see section 4.4).

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 Truberzi, 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 (see sections 4.2, 4.3 and 4.4). 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 (see section 4.4).

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. (see sections 4.2 and 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

Single supratherapeutic oral doses of eluxadoline up to 1,000 mg and single intranasal doses up to 200 mg were associated with a higher incidence of adverse events than a 100 mg single dose, especially gastrointestinal and central nervous system events. An overdose of eluxadoline may result in symptoms resulting from an exaggeration of the known pharmacodynamic effects of the medicinal product.

Management

In the event of acute overdose, the patient should be carefully observed and given standard supportive treatment as required. Gastric lavage or charcoal administration should be considered. Given eluxadoline's action at opioid receptors, administration of a narcotic mu opioid antagonist, such as naloxone, should be considered. Considering the short half-life of naloxone, repeated administration may be necessary. In the event of naloxone administration, subjects should be monitored closely for the return of overdose symptoms, which may indicate need for repeated naloxone injection.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: {not yet assigned}, ATC code: {not yet assigned}

Mechanism of action

Eluxadoline is a locally acting, mixed mu opioid receptor (μOR) agonist and delta opioid receptor (δOR) antagonist. Eluxadoline is also an agonist at the kappa opioid receptor (κOR). The binding affinities (Ki) of eluxadoline for human μOR and δOR are 1.8 nM and 430 nM, respectively. The binding affinity (Ki) of eluxadoline for human κOR has not been determined; however, the Ki for guinea pig cerebellum κOR is 55 nM. In animals, eluxadoline interacts with opioid receptors in the gut. Eluxadoline has demonstrated efficacy in normalizing GI transit and defecation in several models of stress induced or post GI inflammation-altered GI function in animals. Eluxadoline has very low oral bioavailability and exerts no detectable central nervous system (CNS)-mediated effects when administered orally to animals at effective doses. Eluxadoline also reverses hyperalgesic responses in an animal model of acute colitis-induced visceral pain.

Pharmacodynamic effects

Since bioavailability is limited, the pharmacodynamic activity of eluxadoline is based predominantly on local action within the GI tract. Supporting the lack of systemic pharmacodynamic effects are results from an oral abuse liability study in recreational opioid users that showed oral doses up to 1,000 mg did not produce significant pupillary constriction or significant drug liking. An abuse liability study with 100 mg and 200 mg intranasal doses of eluxadoline resulted in higher systemic concentrations of eluxadoline that produced changes in pupil diameter but were associated with drug disliking. In patients with IBS-D, no signal for central nervous system-mediated adverse events was identified. Taken together these results suggest that when using the medicinal product as directed at therapeutic doses patients will not experience significant central nervous system effects or adverse events consistent with a drug of abuse.

Clinical efficacy and safety

The efficacy and safety of eluxadoline in IBS-D patients was established in two randomized, multi-center, multi-national, double-blind, placebo-controlled studies (Studies 1 & 2). A total of 1,282 patients in Study 1 (IBS-3001) and 1,146 patients in Study 2 (IBS-3002) were enrolled and received treatment with Truberzi 75 mg, Truberzi 100 mg or placebo twice daily. Overall, patients had a mean age of 45 years (range 18-80 years with 10% at least 65 years of age or older), 66% female, 86% white, 12% black, and 27% Hispanic.

All patients met Rome III criteria for IBS and were required to meet the following criteria:

• an average of worst abdominal pain (WAP) scores in the past 24 hours of >3.0 on a 0 to 10 scale over the week prior to randomization.

• an average daily stool consistency score (BSS) of ≥5.5 and at least 5 days with a BSS score ≥5 on a 1 to 7 scale over the week prior to randomization.

• an average global symptom score >2.0 on a 0-4 scale (0 corresponds to no symptoms, 1 corresponds to mild symptoms, 2 corresponds to moderate symptoms, 3 corresponds to severe symptoms and 4 corresponds to very severe symptoms) over the week prior to randomization

The study designs were identical through the first 26 weeks. Study1 (IBS-3001) continued double-blinded for an additional 26 weeks for long-term safety (total of 52 weeks of treatment), followed by a 2-week follow-up. Study 2 (IBS-3002) included a 4-week single-blinded, placebo-withdrawal period upon completion of the 26-week treatment period.

Efficacy of eluxadoline was assessed using an overall responder analyses as defined by the simultaneous improvement in the daily WAP score by ≥30% as compared to the baseline weekly average AND a reduction in the BSS to <5 on at least 50% of the days within a time interval. Improvements in global symptoms of IBS were assessed based on an adequate relief response endpoint defined as achieving adequate relief of IBS symptoms on at least 50% of weeks and on a global symptom response endpoint defined by a daily rating of global symptoms of none or mild on at least 50% of days. Results for endpoints were based on electronic daily diary entries by patients.

The efficacy results for ≥50% of responder days (primary composite endpoint) over 6 months are shown in Table 2. In both studies, the proportion of patients who were composite responders to Truberzi 100 mg twice daily was statistically significantly higher than placebo. The proportion of patients who were adequate relief responders was statistically significantly higher than placebo for Truberzi 100 mg twice daily over 6 month interval in both studies. The proportion of patients who were global symptom responders was statistically significantly higher than placebo for Truberzi 100 mg twice daily over 6 month interval in Study 2 and numerically higher than placebo in Study 1. There were no efficacy differences according to gender.

Table 2: Efficacy Results in Randomized Clinical Studies

Study 1 (IBS 3001)

Study 2 (IBS 3002)

Truberzi

100 mg

n=426

Truberzi

75 mg

n=427

Placebo

n=427

Truberzi

100 mg

n=382

Truberzi

75 mg

n=381

Placebo n=382

Composite Response

Responder rates

P values

 

29%

<0.001

 

23%

0.112

 

19%

 

33%

<0.001

 

30%

0.001

 

20%

Abdominal Pain Response

Responder rates

P values

 

47%

0.355

 

45%

0.852

 

43%

 

50%

0.148

 

48%

0.448

 

45%

BSS <5 Response

Responder rates

P values

 

34%

0.001

 

28%

0.186

 

24%

 

40%

<0.001

 

34%

<0.001

 

24%

Adequate Relief Response

Responder rates

P values

 

49.5%

0.005

 

45.7%

0.097

 

40.0%

 

53.7%

0.006

 

52.8%

0.013

 

43.7%

Global Symptom Response

Responder rates

P values

 

34.7%

0.063

 

35.1%

0.048

 

28.8%

 

43.2%

0.012

 

45.1%

0.002

 

34.3%

For the daily composite response, eluxadoline began to separate from placebo shortly after initiating treatment with a maximal effect seen at 4-6 weeks that was maintained throughout the course of treatment. Additionally, the proportion of patients who were composite responders to eluxadoline at each 4-week interval for months 1 through 6 was higher than placebo for both doses in both Phase 3 studies demonstrating that efficacy is maintained with continuous eluxadoline treatment.

Treatment with eluxadoline also resulted in significant improvements in patients whose IBS-D symptoms were not adequately controlled with use of loperamide prior to enrolment.

When the threshold for abdominal pain response was increased to ≥40% or ≥50% improvement from baseline in daily worst abdominal pain, the proportion of abdominal pain responders was 6%-7% higher for eluxadoline 100 mg twice daily compared to placebo which was statistically significant (P ≤ 0.009) for the pooled (Study 1 and Study 2) data. Patients receiving eluxadoline also reported significant reductions in bowel movement frequency and abdominal bloating compared to placebo as demonstrated by changes from baseline in daily bowel movements and bloating score at Weeks 12 and 26. Patients receiving eluxadoline reported significant increases in urgency-free days both for ≥50% urgency-free days as well as ≥75% urgency free days. Also, eluxadoline significantly improves patients quality of life as demonstrated by change from baseline score in the IBS-QOL questionnaire at weeks 12 and 26.

During the 4 week single-blind withdrawal period in Study 2 (IBS-3002), no evidence of rebound diarrhoea or abdominal pain was demonstrated.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of clinical studies with Truberzi in one or more subsets of the paediatric population in IBS-D (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Eluxadoline's systemic exposure following oral administration is low and is consistent with its local action in the GI tract. The active substance has linear pharmacokinetics with no accumulation upon repeated twice daily dosing. Mean plasma elimination half-life is 5 hours with high inter-subject variability. Eluxadoline is primarily cleared as such via the biliary system with the kidney playing a minimal role in elimination. Eluxadoline is not an inducer/inhibitor of major CYP enzymes, however, eluxadoline has some potential for the metabolism based inactivation of CYP3A4. It is a substrate and an inhibitor of the hepatic uptake transporter OATP1B1; and a substrate for the hepatic efflux transporter MRP2. Hepatic impairment or coadministration with cysclosporine results in significant increases in plasma concentrations of eluxadoline.

Absorption

The absolute bioavailability of eluxadoline has not been determined but is estimated to be low due to limited absorption and first pass effects. The absorption of eluxadoline was rapid under fasting conditions, with a median Tmax value of 2 hours. The administration of eluxadoline with a high fat meal significantly decreased both Cmax (50%) and AUC (60%) without any effect on Tmax. Upon administration of multiple oral doses twice daily, there was no accumulation of active substance.

Distribution

In a population pharmacokinetic analysis, the estimated apparent volume of distribution of eluxadoline was 27,100 L. In healthy subjects, eluxadoline was moderately (81%) bound to plasma proteins.

Biotransformation

Eluxadoline is primarily excreted in the feces, either as unabsorbed active substance or via the biliary system with the kidney playing a minimal role in elimination.

In vitro studies demonstrated that eluxadoline was stable in human hepatocytes, liver and intestinal microsomes, and that the only minor and inactive metabolite of eluxadoline detected was the acyl glucuronide metabolite (M11) formed through glucuronidation of the methoxybenzoic acid moiety. Following a 1,000 mg oral dose in healthy male volunteers, M11 was detected in urine but not in systemic circulation.

Eluxadoline exists predominantly as the (S,S)-diastereomer (>99%) and undergoes little or no chiral conversion in vivo.

Eluxadoline has a low potential for drug-drug interactions based on limited in vitro CYP inhibition/induction and given that eluxadoline is not a substrate for CYPs at clinically meaningful concentrations.

OATP1B1 inhibitors

Eluxadoline is a substrate of the hepatic uptake transporter OATP1B1. Co-administration of eluxadoline with cyclosporine (an OATP1B1 inhibitor) increased eluxadoline exposure by approximately 5-fold (see sections 4.3 and 4.5).

MRP2 inhibitors

Eluxadoline is a substrate of the hepatic efflux transporter MRP2. Co-administration of eluxadoline with probenecid (MRP2 inhibitor) resulted in approximately 1.4-fold increase in exposure to eluxadoline. No dose adjustment is necessary.

OATP1B1 substrates

Eluxadoline is an inhibitor of the hepatic uptake transporter OATP1B1. Co-administration of eluxadoline with rosuvastatin (an OATP1B1 substrate) resulted in an up to 1.4-fold increase in exposure of rosuvastatin and the major active metabolite, n-desmethyl rosuvastatin compared to administration of rosuvastatin alone. No dose adjustment is necessary for co-administered OATP1B1 substrates. However, caution should be exercised in patients receiving high doses of OATP1B1 substrates (see section 4.5).

In vitro assessment of drug interactions

In vitro studies indicate that eluxadoline is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, nor an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2C8 and CYP2D6 at clinically relevant concentrations. CYP2E1 was slightly inhibited (50% inhibitory concentration [IC50] of approximately 20 µM [11 µg/mL]), although this is not expected to result in any clinically meaningful interactions. In vitro studies in liver microsomes showed that eluxadoline is not an inhibitor of CYP3A4 at clinically relevant concentrations, but in intestinal microsomes, eluxadoline inhibited CYP3A4 with a Ki of 450 µM (256 µg/mL). Potentially high (up to 700 µM) eluxadoline concentrations in gut may affect the pharmacokinetic of concomitantly administered CYP3A4 substrates (see section 4.5).

In vitro studies indicated that eluxadoline is a substrate and an inhibitor of the hepatic uptake transporter OATP1B1; a substrate for the hepatic efflux transporter MRP2 and is not a substrate or inhibitor of the P-gp and BCRP transporters.

Elimination

Following a single oral dose of 300 mg [14C] eluxadoline in healthy male subjects, 82.2% of the total [14C] eluxadoline was recovered in faeces in 336 hours and less than 1% was recovered in urine in 192 hours.

Specific populations

Age and gender

Given eluxadoline's local action in the GI tract, low Foral and lack of metabolism, prospective clinical studies regarding differences in age, body mass index (BMI), ethnicity, and gender were deemed unnecessary. Pharmacokinetic data for healthy volunteers pooled across Phase 1 studies (using the 100 mg single oral dose) and analyzed for potential differences based on sex, age, race, and BMI demonstrated no significant differences.

Renal Impairment

Eluxadoline has not been specifically studied in patients who have renal impairment. Given the low estimated oral bioavailability (Foral 1.34%) of eluxadoline and limited renal elimination, renal impairment is not expected to affect clearance of eluxadoline.

Hepatic impairment

The apparent clearance of eluxadoline is markedly reduced and half-life increases in hepatic-impaired patients (see sections 4.3 and 4.4). Following single oral 100 mg dose in subjects with varying degrees of liver impairment and healthy subjects, eluxadoline plasma levels were on average 6-fold, 4-fold, and 16-fold elevated in mild, moderate, and severe hepatic impaired subjects (Child Pugh Class A, B, C), respectively, while half-life increased 3-5 fold (see sections 4.3 and 4.4).

OATP1B1 poor function haplotypes

The plasma levels in patients with a genetic predisposition for poor function of OATP1B1 transporter are increased and in these patients a higher rate of adverse events, especially with regard to gastrointestinal events, as well as CNS effects might be expected (see section 4.4).

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development. In rat, eluxadoline was excreted into milk in an approximately dose proportional manner with maximal concentrations less than plasma concentrations.

6. Pharmaceutical particulars
6.1 List of excipients

Silicified microcrystalline cellulose (E460);

Colloidal anhydrous silica (E551);

Crospovidone, type B (E1202);

Mannitol (E421);

Magnesium stearate (E572);

Polyvinyl alcohol (E1203);

Titanium dioxide (E171);

Macrogol 3350 (E1521);

Talc (E553b);

Iron oxide yellow (E172);

Iron oxide red (E172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PCTFE/PVC/Al-blister containing 14 film-coated tablets. Pack sizes of 28, 56 and a multipack containing 168 (3 packs of 56) film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Allergan Pharmaceuticals International Limited

Clonshaugh Industrial Estate

Coolock

Dublin 17

Ireland

8. Marketing authorisation number(s)

EU/1/16/1126/001-006

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 19 September 2016

10. Date of revision of the text

12/2017

Version 3

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.