Drug Interactions between fluoxetine / olanzapine and Procot

MONITOR: Coadministration with fluoxetine may increase the plasma concentrations of certain neuroleptic agents and potentiate the risk of extrapyramidal adverse effects. The proposed mechanism is inhibition of CYP450 2D6 metabolism by fluoxetine and its active metabolite, norfluoxetine. In 10 psychiatric patients stabilized on risperidone therapy (4 to 6 mg/day), the addition of fluoxetine (20 mg/day) led to a mean 4-fold increase in plasma risperidone concentrations and a 75% increase in levels of active moiety (i.e. sum of the concentrations of risperidone and its active 9-hydroxy metabolite). One patient developed severe akathisia and two developed Parkinsonian symptoms within the first two weeks. In contrast, mean plasma concentrations of haloperidol were elevated by just 20% following the addition of fluoxetine (20 mg/day for 7 to 10 days) in eight psychotic patients stabilized on haloperidol, and extrapyramidal side effects did not increase appreciably. However, haloperidol has been implicated clinically in various case reports, as has the phenothiazine fluphenazine. Some believe that a pharmacodynamic interaction may be partially responsible, as fluoxetine alone has been associated with extrapyramidal symptoms, possibly due to serotonergic inhibition of nigrostriatal dopaminergic pathways.

MANAGEMENT: Caution is recommended if fluoxetine is prescribed with phenothiazines or other neuroleptic agents that are thought to be metabolized by CYP450 2D6. Plasma neuroleptic levels and pharmacologic effects should be closely monitored and the dosage(s) adjusted accordingly, particularly following initiation or discontinuation of fluoxetine in patients who are stabilized on their neuroleptic regimen. Patients should be advised to contact their physician if they develop extrapyramidal symptoms such as tremor, shuffling gait, drooling, a mask-like face, tongue stiffness, muscle spasms or rigidity, and involuntary movements. Due to the long half-life of fluoxetine and norfluoxetine, the risk of an interaction may exist for an extended period (up to several weeks) after discontinuation of fluoxetine.

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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: 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.

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