Drug Interactions between fenfluramine and Reglan

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.

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