OVERDOSAGE
SYMBYAX
During premarketing clinical studies of the olanzapine/fluoxetine combination, overdose of both fluoxetine and olanzapine were reported in five study subjects. Four of the five subjects experienced loss of consciousness (3) or coma (1). No fatalities occurred.
Since the market introduction of olanzapine in October 1996, adverse event cases involving combination use of fluoxetine and olanzapine have been reported to Eli Lilly and Company. An overdose of combination therapy is defined as confirmed or suspected ingestion of a dose of olanzapine 20 mg or greater in combination with a dose of fluoxetine 80 mg or greater. As of 1 February 2002, 12 cases of combination therapy overdose were reported, most of which involved additional substances. Adverse events associated with these reports included somnolence; impaired consciousness (coma, lethargy); impaired neurologic function (ataxia, confusion, convulsions, dysarthria); arrhythmias; and fatality. Fatalities have been confounded by exposure to additional substances including alcohol, thioridazine, oxycodone, and propoxyphene.
Olanzapine
In postmarketing reports of overdose with olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Among less commonly reported symptoms were the following potentially medically serious events: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia as well as a patient that experienced sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. Eli Lilly and Company has received reports of fatality in association with overdose of olanzapine alone. In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2 g of oral olanzapine.
Fluoxetine
Worldwide exposure to fluoxetine is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine, alone or with other drugs, reported from this population, there were 195 deaths.
Among 633 adult patients who overdosed on fluoxetine alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdose, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non–fatal overdose were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established.
Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the 6 fatalities was a 9–year–old boy who had a history of OCD, Tourette’s Syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed–drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams, which was non–lethal.
Other important adverse events reported with fluoxetine overdose (single or multiple drugs) included coma, delirium, ECG abnormalities (such as QT–interval prolongation and ventricular tachycardia, including torsades de pointes–type arrhythmias), hypotension, mania, neuroleptic malignant syndrome–like events, pyrexia, stupor, and syncope.
Management of Overdose
In managing overdose, the possibility of multiple drug involvement should be considered. In case of acute overdose, establish and maintain an airway and ensure adequate ventilation, which may include intubation. Induction of emesis is not recommended as the possibility of obtundation, seizures, or dystonic reactions of the head and neck following overdose may create a risk for aspiration. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
A specific precaution involves patients who are taking or have recently taken SYMBYAX and may have ingested excessive quantities of a TCA (tricyclic antidepressant). In such cases, accumulation of the parent TCA and/or an active metabolite may increase the possibility of serious sequelae and extend the time needed for close medical observation.
Due to the large volume of distribution of olanzapine and fluoxetine, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidote for either fluoxetine or olanzapine overdose is known. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. Do not use epinephrine, dopamine, or other sympathomimetics with β–agonist activity, since beta stimulation may worsen hypotension in the setting of olanzapine–induced alpha blockade.
The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).
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