Drug Interactions between fluoxetine / olanzapine and isocarboxazid

CONTRAINDICATED: Concomitant use of selective serotonin reuptake inhibitors (SSRIs) with monoamine oxidase inhibitors (MAOIs) or agents that possess MAOI activity may increase the risk of a potentially life-threatening condition called serotonin syndrome, which is believed to result from the hyperstimulation of postsynaptic 5-HT (serotonin) receptors. Postsynaptic 5-HT1A and 5-HT2A are usually implicated, but it is likely that no single receptor is solely responsible in leading to serotonin syndrome. Cases of serious reactions have been reported in patients receiving an SSRI in combination with a non-selective, irreversible MAOI as well as in patients who recently discontinued treatment with an SSRI and then started treatment with a MAOI. The development of serotonin syndrome was identified in some of these cases. On the other hand, there are limited studies demonstrating the potential safety of specific dosages of certain MAOIs in combination with certain SSRIs at specific dosages. A small study in patients with mild to moderate Parkinson's disease (n=8) on selegiline (5 mg to 10 mg/day) and in one case selegiline (10 mg/day) with levodopa (375 mg/day) were started on citalopram (20 mg/day) for major depression. Patients were observed for 8 weeks and generally tolerated the combination well. One patient increased the citalopram dose to 40 mg/day without approval from the investigators and experienced nausea and abdominal discomfort, which resolved when the dose of citalopram was reduced to 20 mg. In a separate study, healthy subjects (n=18) changed from moclobemide (300 mg on day 1) to fluoxetine (40 mg for 7 days followed by 20 mg daily). On day 16 of the study patients received fluoxetine (20 mg) with either placebo or moclobemide (ascending doses from 100 mg to 600 mg for 8 days). On day 24, all patients received moclobemide (300 mg). There were no differences in adverse reactions reported between the 2 groups. Clinical data are not available for every SSRI with every MAOI.

MANAGEMENT: In general, SSRIs should not be used concurrently with MAOIs or other agents that possess MAOI activity and when switching from one to the other at least 4 to 5 half-lives of the agent being discontinued should elapse before starting the new agent. The product labeling for most SSRIs advises a separation of at least 14 days between the discontinuation of MAOI therapy and the initiation of an SSRI, and vice versa. However, due to the long half-life of fluoxetine and its active metabolite, norfluoxetine, a washout period of at least 5 weeks is recommended when switching from fluoxetine to a MAOI. Similarly, a washout period of 3 weeks is recommended when switching from vortioxetine to a MAOI. Some authorities have noted that selegiline doses of up to 10 mg/day have been safely coadministered with low doses of citalopram. Shorter washout periods have been used when transitioning between moclobemide and SSRIs; however, the transition must be done cautiously, with consideration of the pharmacology and dosing requirements of each agent. As serotonin syndrome is a very serious and potentially life-threatening adverse effect, the labeling for each agent involved in the interaction should be reviewed as well as any relevant guidelines that may apply. Patients should be instructed to seek immediate medical attention if they develop any signs or symptoms of serotonin syndrome, including 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.

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.