Monoamine Oxidase Inhibitors (MAOIs) (e.g., tranylcypromine, isocarboxazid, phenelzine and selegeline): Concomitant use of fluoxetine and MAO inhibitors is contraindicated.
There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation leading to delirium and coma) in patients receiving fluoxetine in combination with a MAOI, and in patients who have recently discontinued fluoxetine and are then started on a MAOI. There have also been reports that this may lead to a condition resembling neuroleptic malignant syndrome. Thus, fluoxetine should not be used in combination with a MAOI, or within a minimum of 14 days of discontinuing therapy with a MAOI. A wash-out period should be observed when switching to or from MAOIs (see also Dosage & Administration).
Thioridazine: Fluoxetine inhibits the CYP2D6 enzyme system thereby increasing plasma levels of thioridazine. This interaction is clinically significant particularly for poor metabolizers because they are at greater risk of experiencing dose-related adverse effects associated with thioridazine. Thioridazine has been known to cause prolongation of the QTc interval, which is linked to serious ventricular arrhythmias (such as torsades de pointes-type arrhythmias) and sudden death. This risk is increased with fluoxetine-induced inhibition of thioridazine metabolism.
Thioridazine should not be administered with fluoxetine or within a minimum of five weeks after fluoxetine has been discontinued because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine.
Drugs metabolized by CYP 2D6 [antidepressants (e.g., TCAs); antipsychotics (e.g., phenothiazines and most atypicals); antiarrhythmics (e.g., propafenone, flecainide and others)]: Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer.
Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants, antipsychotics, and antiarrhythmics should be approached with caution.
If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered.
Serotonergic Drugs (e.g., linezolid, tramadol, or St. John's Wort): Coadministration of other serotonergic drugs and fluoxetine may precipitate serotonin syndrome.
Tryptophan: Coadministration of fluoxetine and tryptophan causes adverse reactions such as agitation, restlessness, and gastrointestinal distress.
Triptans: Coadministration of triptans and fluoxetine may precipitate serotonin syndrome. If concomitant treatment of fluoxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
Drugs highly bound to plasma proteins (e.g., warfarin and digoxin): Since fluoxetine is tightly bound to plasma proteins, administration of fluoxetine to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Also, adverse effects may result from displacement of protein bound fluoxetine by other tightly bound drugs.
Drugs that interfere with hemostasis (e.g., NSAIDs, aspirin, warfarin): There is an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin should be carefully monitored when fluoxetine is initiated or discontinued.
Drugs metabolized by CYP3A4 (e.g., ketoconazole, astemizole, midazolam): In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine.
In vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor or the metabolism of several substrates for this enzyme, including astemizole, cisapride and midazolam. These data indicate that fluoxetine's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.
CNS-active drugs: Caution is advised if the concomitant use of fluoxetine and these drugs is required. Consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status.
TCAs (e.g., imipramine, desipramine): Combining TCAs with fluoxetine may lead to a significant increase in the concentrations of the former. Dose adjustment and temporary plasma level monitoring is necessary when administering these drugs with fluoxetine or when these are to be initiated following recent discontinuation of fluoxetine.
Anticonvulsants (e.g., phenytoin, carbamazepine): Fluoxetine may increase plasma levels of anticonvulsants to an extent that clinical anticonvulsant toxicity may occur.
Antipsychotics (e.g., haloperidol, clozapine, olanzapine, pimozide): Fluoxetine has been shown to increase blood levels of haloperidol and clozapine. Coadministration of pimozide and fluoxetine may potentially lead to drug interactions and QTc prolongation; concurrent administration of these drugs is contraindicated.
Fluoxetine causes a small increase in the maximum concentration of olanzapine and a small decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and thus dose modification is not routinely recommended.
Benzodiazepines (e.g., diazepam, alprazolam): Fluoxetine may prolong the half-life of diazepam in some patients.
Plasma concentrations of alprazolam have been shown to increase when coadministered with fluoxetine.
Lithium: Fluoxetine may increase lithium levels, which may result in toxicity and serotogenic effects. It is necessary to monitor lithium levels when this drug is to be administered concurrently.
Other Interaction: Electroconvulsive Therapy (ECT): There have been rare reports that patients receiving ECT together with fluoxetine experienced prolonged seizures.