Drug Interactions between fluoxetine / olanzapine and metoclopramide

CONTRAINDICATED: Coadministration of metoclopramide with phenothiazines, neuroleptics, or other antidopaminergic agents (e.g., tetrabenazine) may increase the frequency and severity of extrapyramidal reactions (i.e., acute dystonic reactions, tardive dyskinesia, akathisia, Parkinson-like symptoms) due to additive antidopaminergic effects. By itself, metoclopramide can cause acute dystonic reactions in approximately 0.2% of patients treated with the usual adult dosages of 30 to 40 mg/day. These reactions are typically seen during the first 24 to 48 hours of treatment, occur more frequently in pediatric and adult patients less than 30 years of age, and are increased with higher dosages. Symptoms may include involuntary movements of limbs, facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus, opisthotonus (tetanus-like reactions), and rarely, stridor and dyspnea due to laryngospasm. Dystonic reactions usually respond to treatment with anticholinergic agents such as diphenhydramine or benztropine. Tardive dyskinesia (TD) is a potentially irreversible and disfiguring disorder characterized most frequently by involuntary movements of the tongue, face, mouth, or jaw, and less frequently by involuntary movements of the trunk and/or extremities. Movements may be choreoathetotic in appearance. Although the risk of TD with metoclopramide has not been extensively studied, a prevalence of 20% has been reported in one study among patients treated for at least 12 weeks. The risk is increased in the elderly, women, and diabetic populations; however, it is not possible to predict which patients will develop TD. Both the risk of developing TD and the likelihood that TD will become irreversible increase with duration of treatment and total cumulative dose. There is no known effective treatment. In some patients, TD may remit, partially or completely, within several weeks to months after metoclopramide is withdrawn. Akathisia, or motor restlessness, consist of feelings of anxiety, agitation, jitteriness, and insomnia, as well as inability to sit still, pacing, and foot tapping. Symptoms may disappear spontaneously or respond to a reduction in dosage. Parkinsonian-like symptoms may include bradykinesia, tremor, cogwheel rigidity, and mask-like facies. These symptoms most commonly occur within the first 6 months of metoclopramide therapy and subside within 2 to 3 months following drug discontinuation.

MANAGEMENT: Due to the potential for increased risk of serious and potentially irreversible extrapyramidal reactions, metoclopramide should not be prescribed in combination with other antidopaminergic agents. In addition, metoclopramide should not be used for longer than 12 weeks except in rare cases where therapeutic benefit is anticipated to outweigh the risk of developing tardive dyskinesia.

MONITOR: Coadministration of metoclopramide with serotonin reuptake inhibitors has been associated with development of the serotonin syndrome and severe extrapyramidal reactions. The exact mechanism is unknown but may involve a pharmacodynamic interaction between serotonergic and antidopaminergic effects of the drugs. A pharmacokinetic interaction is also possible, since metoclopramide and most serotonin reuptake inhibitors are primarily or at least partially metabolized by the CYP450 2D6 isoenzyme. Theoretically, competitive and/or noncompetitive inhibition may lead to elevated plasma levels of one or both drugs, resulting in excessive central serotonergic and antidopaminergic effects. A pharmacokinetic study conducted in 24 young, healthy, nonsmoking volunteers found that administration of a single 20 mg dose of metoclopramide following pretreatment with fluoxetine (60 mg/day for 8 days) resulted in a 42% and 89% increase in metoclopramide peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to metoclopramide administered alone. In a published case report, a 72-year-old woman treated with sertraline and a 32-year-old woman treated with venlafaxine developed movement disorders and symptoms consistent with the serotonin syndrome shortly after single doses of metoclopramide. Both cases resolved following treatment with diazepam, and the patients resumed their sertraline and venlafaxine therapy without further incident. Serotonin syndrome 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.

MANAGEMENT: Caution is advised if metoclopramide is prescribed in combination with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Patients should be monitored for symptoms of the serotonin syndrome as well as development of extrapyramidal reactions such as involuntary twitching of the jaw and limbs, teeth clenching, severe jerking, trismus, and tongue and neck stiffness. If serotonin syndrome develops or is suspected during the course of therapy, all serotonergic agents should be discontinued immediately and supportive care rendered as necessary. Moderately ill patients may also benefit from the administration of a serotonin antagonist (e.g., cyproheptadine, chlorpromazine). Severe cases should be managed under consultation with a toxicologist and may require sedation, neuromuscular paralysis, intubation, and mechanical ventilation in addition to the other measures.

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.