Drug Interactions between eluxadoline and fluoxetine / olanzapine

MONITOR: It is uncertain whether olanzapine causes clinically significant prolongation of the QT interval. In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, including QT, QTcF (Fridericia-corrected), and PR intervals. In clinical trials, clinically meaningful QTc prolongations (QTcF >=500 msec at any time post-baseline in patients with baseline QTcF <500 msec) occurred in 0.1% to 1% of patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. Published studies have generally reported no significant effect of olanzapine on QTc interval, although both QTc prolongation and QTc shortening have also been reported. There have been a few isolated case reports of QT prolongation in patients receiving olanzapine. However, causality is difficult to establish due to confounding factors such as concomitant use of drugs that cause QT prolongation and underlying conditions that may predispose to QT prolongation (e.g., hypokalemia, congenital long QT syndrome, preexisting conduction abnormalities).

MANAGEMENT: Some authorities recommend caution when olanzapine is used with drugs that are known to cause QT prolongation. ECG monitoring may be advisable in some cases, such as in patients with a history of cardiac arrhythmias or congenital or family history of long QT syndrome. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

GENERALLY AVOID: The risk of constipation and serious constipation-related adverse reactions may be increased when eluxadoline is used with other drugs that are also associated with this adverse effect. In placebo-controlled studies, constipation occurred in 7% and 8% of patients receiving eluxadoline 75 mg twice daily and 100 mg twice daily, respectively. Approximately 50% of constipation events occurred within the first 2 weeks of treatment, while the majority occurred within the first 3 months. The rates of constipation were similar between eluxadoline and placebo beyond the first 3 months of therapy.

MANAGEMENT: Concomitant use of eluxadoline with other drugs that can cause constipation such as alosetron, anticholinergics, and opioids should generally be avoided. Loperamide may be used occasionally for acute management of severe diarrhea, but chronic use is not recommended, and it should be discontinued immediately if constipation occurs. Eluxadoline should also be discontinued if constipation occurs for more than 4 days.

It is not known to what extent eluxadoline may be metabolized by CYP450 isoenzymes and may interact with inhibitors of CYP450 isoenzymes. Some authorities have indicated that CYP450 has minimal involvement in the metabolism of eluxadoline. This suggests that alterations in the metabolism of eluxadoline by these isoenzymes are unlikely to have a clinically meaningful effect on the overall systemic exposure of eluxadoline. However, as a precautionary measure, it may be advisable to monitor patients for adverse effects such as sedation, nausea, vomiting, constipation, abdominal pain, liver enzyme elevations, and pancreatitis.