Drug Interactions between fluoxetine / olanzapine and rasagiline

GENERALLY AVOID: By inhibiting serotonin metabolism, monoamine oxidase inhibitors (MAOIs) may potentiate the pharmacologic activity of selective serotonin reuptake inhibitors (SSRIs) and increase the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucinations, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea. The extent to which rasagiline, a selective MAO-B inhibitor, may interact with SSRIs is unknown. In rasagiline clinical trials, concomitant use of fluoxetine or fluvoxamine was prohibited, although the use of some antidepressants, including citalopram (20 mg/daily), sertraline (100 mg/daily) and paroxetine (30 mg/daily), was allowed. A total of 141 rasagiline-treated patients were exposed to SSRIs in these trials. However, the exposure, both in dosage and number of subjects, was not adequate to rule out the possibility of a potential interaction. In the postmarketing period, non-fatal cases of serotonin syndrome have been reported in patients receiving rasagiline in combination with antidepressants.

MANAGEMENT: In general, SSRIs should not be used concurrently with MAOIs or other agents that possess MAOI activity. At least 14 days should elapse between discontinuation of MAOI therapy and initiation of treatment with SSRIs, and vice versa. Due to the long half-life of fluoxetine and its active metabolite, norfluoxetine, a washout period of 5 weeks minimum is recommended when switching from fluoxetine to an MAOI. Similarly, a washout period of 3 weeks is recommended when switching from vortioxetine to an MAOI.

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: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.