Drug Interactions between fluoxetine / olanzapine and ziprasidone

CONTRAINDICATED: Ziprasidone can cause dose-related prolongation of the QT 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 placebo-controlled trials in adults, oral ziprasidone increased the QTc interval by approximately 10 msec at the highest recommended daily dosage of 160 mg compared to placebo. In a study comparing the QT prolonging effect of several antipsychotic drugs at the maximum plasma concentration following administration alone in patient volunteers, the mean increase in QTc (QT interval corrected for heart rate) from baseline for ziprasidone ranged from approximately 9 to 14 msec greater than for four of the comparator drugs (haloperidol, olanzapine, quetiapine, and risperidone), but was approximately 14 msec less than the prolongation observed for thioridazine. In another study evaluating the QT prolonging effect of intramuscular ziprasidone versus intramuscular haloperidol (control) at the maximum plasma concentration following administration in patient volunteers, the mean increase in QTc from baseline for ziprasidone (20 mg and 30 mg doses given 4 hours apart) was 4.6 msec after the first injection and 12.8 msec after the second injection, which at 30 mg is 1.5 times the highest recommended dose. The mean increase in QTc from baseline for haloperidol (7.5 mg and 10 mg doses given 4 hours apart) was 6.0 msec following the first injection and 14.7 msec following the second injection. No patients had a QTc interval exceeding 500 msec. 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).

MONITOR CLOSELY: Central nervous system depressant or toxic effects may be additively or synergistically increased in patients taking ziprasidone with certain other drugs (such as other CNS-active agents or efavirenz) that cause these effects, especially in elderly or debilitated patients.

MANAGEMENT: Coadministration of ziprasidone with other drugs that can prolong the QT interval is considered contraindicated. Additionally, patients treated with any medication that can cause CNS toxicity symptoms should be advised to seek prompt medical attention if they experience symptoms. Patients should be advised to avoid driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until they know how the medications affect them.

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: Agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; disopyramide) may have additive effects when used in combination. Excessive parasympatholytic effects may result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures. Central nervous system-depressant effects may also be additively or synergistically increased when these agents are combined, especially in elderly or debilitated patients. Use of neuroleptics in combination with other neuroleptics or anticholinergic agents may increase the risk of tardive dyskinesia. In addition, some neuroleptics and tricyclic antidepressants may cause prolongation of the QT interval and theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Caution is advised when agents with anticholinergic properties are combined, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication such as abdominal pain, fever, heat intolerance, blurred vision, confusion, and/or hallucinations. Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A reduction in anticholinergic dosages may be necessary if excessive adverse effects develop.