Are concentrations of 5095 and 4393 nmol/L of fluoxetine and norfluoxetine, respectively, toxic?/nA
Fråga: Are concentrations of 5095 and 4393 nmol/L of fluoxetine and norfluoxetine, respectively, toxic?
A 30-year-old man began treatment with fluoxetine 100 mg daily due to bulimia. Three months later the dose of fluoxetine was increased to 120 mg daily due to lack of effect. Drug measurement made five months later revealed plasma levels of fluoxetine and norfluoxetine of 5095 and 4393 nmol/L, respectively.
Molecular weights of fluoxetine and norfluoxetine are 345.8 and 331.8, respectively.
Sammanfattning: Fluoxetine is a drug with a wide margin of safety. The risk of mortality after acute overdose appears to be small; of 633 reported cases of fluoxetine overdose, 5 percent died while around half of the cases remained asymptomatic even with doses 75 times above commonly used doses. The largest reported non-fatal dose was eight grams. Some patients tolerate concentrations above 3000 nmol/L of fluoxetine. The concentrations of fluoxetine and norfluoxetine in the present case fall on the upper range of reported blood concentrations of fluoxetine in patients who took overdoses of the drug. It is likely that some patients remain asymptomatic even with this high level, but the concentration should be regarded toxic. Moreover, the long-term effect of chronic supraconcentrations of fluoxetine remains unknown.
Svar: Fluoxetine has a time-dependant pharmacokinetics, in the sense that there is a significant increase in the half-life of the drug during repeated dosing (1). It´s half-life is one to three days after acute administration and four to six days after chronic administration. This is probably due to inhibition of cytochrome P450 2D6 fluoxetine. The long elimination half-lives of fluoxetine and its major metabolite, norfluoxetine (four to 16 days) has the effect that, even when dosing is stopped, the compounds persist in the body for weeks. This is of potential clinical significance when drug discontinuation is required in cases of fluoxetine overdosing. After 30 days of dosing at 40 mg per day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/ml (263-873 nmol/L) and norfluoxetine in the range of 72 to 258 ng/ml (208-746) have been observed (1).
In a recent report, Barby and Roose (2) reviewed the published information on the safety of overdose of fluoxetine. The authors identified four studies and six case reports. The studies included 366 patients of which 137 ingested fluoxetine alone. Of those patients who took fluoxetine alone, 48 patients experienced no symptoms. The largest ingested dose among asymptomatic patients in this group was 1500 mg (75 times the common daily dose of 20 mg). The most frequent symptoms among those who ingested fluoxetine alone were tachycardia, and lethargy or drowsiness. Infrequent symptoms included QT-prolongation, tremor, nausea, and vomiting. The potential for serious toxicity was higher in patients who ingested fluoxetine together with alcohol or other drugs. Symptoms experienced by these patients included cardiac arrhythmias, seizures, respiratory arrest and chronic dystonic reactions. Few studies reported the plasma concentrations of fluoxetine and norfluoxetine.
In a multicentre study involving the American Association of Poison Control Centres (AAPCC), Borys et al (3), identified 234 cases of acute fluoxetine toxicity. Plasma levels of fluoxetine were obtained in 22 patients; twelve patients ingested fluoxetine alone. The amount of fluoxetine ingested by this later group ranged from 280 to 1260 mg, while plasma levels of fluoxetine ranged from 232 to 1390 ng/ml (671-4020 nmol/L). Ten blood samples were obtained at six hours and two samples were obtained at four hours after ingestion. A 28-year-old patient had the highest levels of fluoxetine and complained of headache, insomnia, and confusion. Another patient who had fluoxetine concentrations of 1092 ng/ml (3158 nmol/L) six hours after drug ingestion showed however no symptoms. Plasma levels of fluoxetine were also determined in ten patients who ingested fluoxetine in combination with other drugs (alcohol, ASA, diphenyhydramine, pseudoephedrine, thioridazine, amitriptline, nortriptline and lithium). The amount of fluoxetine ingested ranged from 300 to 1000 mg, while plasma levels of fluoxetine and norfluoxetine ranged from 13 to 1044 ng/ml (38-3019 nmol/L) and 89 to 1287 ng/ml (268-3879 nmol/L) respectively. A 27-year-old female who had the highest dose/concentration developed tremor, ataxia, lethargy, and seizures after drug ingestion. Her 6-hour blood levels of fluoxetine and norfluoxetine were 912 ng/ml (2637 nmol/L) and 152 ng/ml (458 nmol/L), respectively. She was treated with ipecac, activated charcoal, cathartic, and aggressive supportive care.
In another report, Graudins et al (4) describe a 33-year-old male patient who presented with lethargy and cardiac conduction delays and self-limiting seizures 16-hours after ingestion of unknown doses of fluoxetine. A comprehensive toxicology screen (time not reported) showed serum concentrations of fluoxetine and norfluoxetine of 901 ng/ml (2606 nmol/L) and 451 ng/ml (458 nmol/L), respectively as well as acetaminophen concentration of 174 mg/L. The patient recovered. In another report (5) a 58-year-old woman with a history of suicide attempts was found dead at home. Postmortum blood levels of fluoxetine and norfluoxetine were 6000 ng/ml (17351 nmol/L) and 5000 ng/ml (15069 nmol/L), respectively. In another case report, a 28-year-old woman died after ingesting an unknown amount of fluoxetine and ethanol. Postmortum heart blood levels of ethanol of 48 nmol/L were measured as well as concentrations of 800 ng/ml (2313 nmol/L) and 650 ng/ml (1959 nmol/L) of fluoxetine and norfluoxetine, respectively. Time of drug ingestion in relation to death is unknown.
In an updated literature search including the database Medline, we found two further reports of fluoxetine overdosage. Details are missing in both cases. One report (6) describes a 9-year-old boy with attention-deficit hyperactivity disorder who was treated with a combination of methylphenidate, clonidine, and fluoxetine. The patient experienced over a period of 10-months, signs and symptoms marked by bouts of gastrointestinal distress, low-grade fever, in-coordination and generalised seizures. He subsequently died. At autopsy toxic concentrations of fluoxetine were found (the actual concentration not given); no other drugs could be identified. The patient was found to be a poor metaboliser of CYP2D6. The second report (7) describes a 54-year-old woman with psychiatric problems since the age of 20. She died after intake of unknown amounts of fluoxetine. Autopsy revealed concentrations of fluoxetine of 10 ug per g of blood. No other drugs could be identified.
The worldwide exposure to fluoxetine is estimated to over 38 million patients up to 1999 (1). These include 1578 cases of overdose involving fluoxetine, alone or in combination with other drugs. Among adult cases who took only fluoxetine were 633. Thirty-four resulted in a fatal (5 percent), 378 completely recovered, and 15 patients experienced sequelae. The remaining 206 had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. Blood levels of fluoxetine are not reported. The largest known ingestion of fluoxetine was eight grams in a patient who took fluoxetine alone and who subsequently recovered. Among paediatric patients (three months to 17 years), there were 156 cases of overdosage. The number of children that ingested fluoxetine alone is unknown. Six patients died, 127 completely recovered, one patient experienced renal failure, and 22 had an unknown outcome. The largest ingested dose was three grams, which was non-lethal. Blood levels of fluoxetine were not reported in any of the cases.
In animals, the oral median lethal doses in rats and mice are 452 and 248 mg/kg, respectively (more than 200 times the highest recommend human daily dose of 80 mg) (8). 1 Prozac Product/Prescribing Information, Eli Lilly (on line)