Drug Interactions between fluoxetine / olanzapine and Kao-Paverin

MONITOR: The use of higher than recommended dosages of loperamide (e.g., through abuse or misuse) has been associated with serious and potentially fatal cardiac adverse events, including syncope, cardiac arrest, and arrhythmia related to prolongation of the QT interval. Under such circumstances, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias such as torsade de pointes and sudden death. According to the FDA, the agency received reports of 48 cases of serious heart problems associated with use of loperamide from when it was first approved in 1976 through 2015. Thirty-one of these cases resulted in hospitalizations, and 10 patients died. The serious heart problems occurred mostly in patients who were using loperamide dosages that were much higher than recommended in an attempt to achieve euphoria, prevent opioid withdrawal, or treat diarrhea. In the most severe cases, individuals self-treated with dosages ranging from 70 to 1600 mg/day, or 4 to 100 times the recommended dosage. In other cases, patients were taking the recommended dosage, but with concomitant interacting drugs that caused an increase in loperamide levels. There have been additional cases of serious heart problems associated with loperamide use reported in the medical literature. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended if loperamide is used in combination with other drugs that can prolong the QT interval. Patients should be counseled to not exceed the recommended dosage and frequency or duration of use of loperamide, and 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. If loperamide-induced cardiotoxicity is suspected, promptly discontinue loperamide and initiate therapy to manage and prevent cardiac arrhythmias and adverse outcomes. Electrical pacing or cardioversion may be necessary if torsade de pointes persists despite pharmacotherapy. In many of the reported cases of loperamide-induced cardiotoxicity, standard antiarrhythmic drugs were ineffective, and electrical pacing or cardioversion was necessary.

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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.

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MONITOR: Coadministration with drugs that possess significant anticholinergic activity may potentiate the antimotility effect of loperamide. An isolated case report describes an incident of fatal gastroenteritis during concomitant treatment with clozapine and loperamide. A 36-year-old man who had been treated with clozapine 500 mg/day and was previously in good health died after taking a total of 6 mg of loperamide during an outbreak of intestinal disease in a Finnish hospital. The patient received no other medications. The authors theorized that the anticholinergic effect of clozapine in combination with the antimotility effect of loperamide may have led to toxic megacolon. However, causality has not been determined.

MANAGEMENT: Until further information is available, loperamide should be used with caution in combination with drugs that possess significant anticholinergic activity (e.g., antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; class IA antiarrhythmics especially disopyramide). Ambulatory patients should also be made aware of the possibility of additive CNS effects (e.g., drowsiness, dizziness, lightheadedness, confusion) and counseled to avoid activities requiring mental alertness until they know how these agents affect them.

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