Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Allergan Pharmaceuticals International Limited, Clonshaugh Business & Technology Park, Dublin 17, D17 E400, Ireland
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.
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).
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 a week of starting treatment with eluxadoline and some developed symptoms after one to two doses. Truberzi is contraindicated in patients without a gallbladder. Patients with known or suspected sphincter of Oddi disease or dysfunction and/or biliary tract or pancreatic disease, including a history of pancreatitis, must not receive Truberzi (see section 4.3).
Patients should be instructed to stop the treatment immediately 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. Truberzi should not be restarted in patients who developed biliary duct obstruction or sphincter of Oddi spasm while taking Truberzi (see section 4.3).
Eluxadoline may cause constipation. Avoid use with other drugs that may cause constipation (see section 4.5). If patients develop severe constipation, they should be instructed to stop Truberzi 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.
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).
Based on the physical-chemical and biopharmaceutical properties (very low oral bioavailability), eluxadoline is expected to have minimal abuse or dependence liability.
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).
Eluxadoline should not be used in children and adolescents as it has not been studied in this population (see section 4.2).
In participants with end stage renal disease (ESRD) not yet on dialysis, exposure of eluxadoline was significantly increased compared with matched, healthy participants with normal renal function. However, such an increase is unlikely to be of clinical significance (see section 5.2).
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).
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).
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.
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.
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).
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 (valsartan, olmesaran).
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.
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.
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.
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).
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).
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.
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).
Not known: Hypersensitivity6
Common: Dizziness, Somnolence1
Common: Constipation, Nausea, Abdominal pain2, Vomiting, Flatulence, Abdominal distention, Gastroesophageal reflux disease4
Uncommon: Sphincter of Oddi spasm3, Pancreatitis
Common: Rash5
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.
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 (see section 4.4).
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.
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).
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 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
Not applicable.
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