Drug Interaction Report

MONITOR: Coadministration with fluoxetine may increase the plasma concentrations of certain neuroleptic agents and potentiate the risk of extrapyramidal adverse effects. The proposed mechanism is inhibition of CYP450 2D6 metabolism by fluoxetine and its active metabolite, norfluoxetine. In 10 psychiatric patients stabilized on risperidone therapy (4 to 6 mg/day), the addition of fluoxetine (20 mg/day) led to a mean 4-fold increase in plasma risperidone concentrations and a 75% increase in levels of active moiety (i.e. sum of the concentrations of risperidone and its active 9-hydroxy metabolite). One patient developed severe akathisia and two developed Parkinsonian symptoms within the first two weeks. In contrast, mean plasma concentrations of haloperidol were elevated by just 20% following the addition of fluoxetine (20 mg/day for 7 to 10 days) in eight psychotic patients stabilized on haloperidol, and extrapyramidal side effects did not increase appreciably. However, haloperidol has been implicated clinically in various case reports, as has the phenothiazine fluphenazine. Some believe that a pharmacodynamic interaction may be partially responsible, as fluoxetine alone has been associated with extrapyramidal symptoms, possibly due to serotonergic inhibition of nigrostriatal dopaminergic pathways.

MANAGEMENT: Caution is recommended if fluoxetine is prescribed with phenothiazines or other neuroleptic agents that are thought to be metabolized by CYP450 2D6. Plasma neuroleptic levels and pharmacologic effects should be closely monitored and the dosage(s) adjusted accordingly, particularly following initiation or discontinuation of fluoxetine in patients who are stabilized on their neuroleptic regimen. Patients should be advised to contact their physician if they develop extrapyramidal symptoms such as tremor, shuffling gait, drooling, a mask-like face, tongue stiffness, muscle spasms or rigidity, and involuntary movements. Due to the long half-life of fluoxetine and norfluoxetine, the risk of an interaction may exist for an extended period (up to several weeks) after discontinuation of fluoxetine.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete 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.

GENERALLY AVOID: Concurrent use of ethanol and phenothiazines may result in additive CNS depression and psychomotor impairment. Also, ethanol may precipitate dystonic reactions in patients who are taking phenothiazines. The two drugs probably act on different sites in the brain, although the exact mechanism of the interaction is not known.

MANAGEMENT: Patients should be advised to avoid alcohol during phenothiazine therapy.