Drug Interactions between apomorphine 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.

MONITOR: Apomorphine may cause modest dose-related prolongation of the QTc interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In addition, some of these agents (e.g., phenothiazines, tricyclic antidepressants) may cause additive sedative and hypotensive effects with apomorphine. In a thorough QT study where apomorphine exposures were comparable to those of the recommended subcutaneous dosage (6 mg), apomorphine was found to prolong the QTcF interval by 10 msec, with the 90% upper confidence interval reaching 16 msec. The study also established a significant exposure-response relationship between apomorphine concentration and QTcF. Torsade de pointes has not been reported with apomorphine alone at recommended doses. 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 apomorphine is used in combination with other drugs that can prolong the QT interval. Doses of subcutaneous apomorphine above 6 mg are not recommended. 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. If taking drugs that also cause CNS or orthostatic effects (e.g., psychotropic drugs like tricyclic antidepressants, phenothiazines, and neuroleptics), patients should be made aware of the possibility of additive effects with apomorphine and counseled to avoid activities requiring mental alertness until they know how these agents affect them.

GENERALLY AVOID: Coadministration with dopamine antagonists (e.g., neuroleptic agents, metoclopramide) or other drugs that interfere with central amine mechanisms may decrease the effectiveness of apomorphine, which is a dopaminergic agent. In addition, some of these agents as well as apomorphine have been associated with sedation, hypotension, and QT interval prolongation. Additive pharmacodynamic effects may occur when used in combination. Excessive prolongation of the QT interval can increase the risk of ventricular arrhythmias including torsade de pointes and sudden death in susceptible patients. Apomorphine doses greater than 6 mg have been associated with minimal increases of the QT interval. The average QTc prolongation was 1 msec at 6 mg and 7 msec at 8 mg. Two patients experienced large increases of more than 60 msec with 2 mg and 6 mg doses. Torsade de pointes has not been reported with apomorphine alone at recommended doses. 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: The use of apomorphine in combination with dopamine antagonists should generally be avoided unless the potential benefits outweigh the risks. The UK product labeling recommends considering a gradual reduction of apomorphine dosage when this is administered by minipump and/or syringe-driver. Monitoring for altered efficacy of apomorphine and increased side effects such as sedation or hypotension is recommended if concomitant use is required. 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. Also, they should avoid activities requiring mental alertness until they know how these agents affect them. Patients who experience increased episodes of falling asleep during normal daily activities should avoid driving and other potentially hazardous activities until they have been evaluated by their physician.