Drug Interactions between pimozide and Symbyax

CONTRAINDICATED: Coadministration with fluoxetine may significantly increase the plasma concentrations of pimozide. The proposed mechanism is fluoxetine inhibition of the metabolism of pimozide via CYP450 2D6 and 3A4. Although the interaction has not been formally studied with fluoxetine, data exist for paroxetine, a drug with similar CYP450 inhibition characteristics. In a controlled study of healthy volunteers, pretreatment with immediate-release paroxetine (titrated up to 60 mg/day) increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of pimozide (2 mg single oral dose) by an average of 62% and 151%, respectively, compared to administration of pimozide alone. The use of pimozide has been associated with dose-related prolongation of the QT interval, thus elevated plasma levels of the drug may potentiate the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes as well as cardiac arrest and sudden death. In addition, case reports suggest that concurrent administration of fluoxetine and pimozide may be associated with mental status changes and adverse cardiovascular effects. The mechanism of interaction has not been determined but may involve additive pharmacodynamic effects and/or fluoxetine inhibition of pimozide metabolism. In one case report, a young woman receiving pimozide for obsessive delusional thoughts became stuporous and complained of inability to think clearly following the addition of fluoxetine. She also had hypersalivation while receiving the combination. In another case, an elderly patient treated with pimozide developed severe bradycardia approximately one week after the addition of fluoxetine. Decreases in pulse also occurred during titration of the pimozide dose, but they were more significant with the combination of fluoxetine and pimozide. In other reports, use of selective serotonin reuptake inhibitors in combination with neuroleptics or other agents with antidopaminergic effect have resulted in increased extrapyramidal symptoms.

MANAGEMENT: Given the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and fluoxetine is considered contraindicated. Due to the long half-life of fluoxetine and its metabolite norfluoxetine, the risk of an interaction may exist for an extended period (up to several weeks) after discontinuation of fluoxetine.

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.