From the Guidelines
Fluoxetine (Prozac) has significant interactions with various medications, including monoamine oxidase inhibitors (MAOIs), serotonergic drugs, and drugs metabolized by the CYP2D6 liver enzyme pathway, which can increase the risk of serotonin syndrome, bleeding, and other adverse effects. When considering medication interactions with fluoxetine, it is essential to note that concomitant administration of any of the SSRIs, including fluoxetine, with any of the MAOIs is contraindicated because of increased risk of serotonin syndrome 1. Other significant interactions include:
- Increased risk of serotonin syndrome with serotonergic drugs such as St. John’s wort, L-tryptophan, and illicit drugs like ecstasy, methamphetamine, cocaine, and LSD 1
- Interactions with drugs metabolized by CYP2D6, which can lead to increased blood levels of these drugs and their side effects 1
- Potential interactions with drugs that prolong the QT interval, although citalopram is more commonly associated with this risk 1 It is crucial to inform healthcare providers about all medications, including over-the-counter drugs and supplements, before starting fluoxetine to minimize the risk of adverse interactions. Medical education, training, and experience are necessary to safely and effectively prescribe antidepressant medications like fluoxetine, and a conservative medication trial with careful monitoring of treatment response and potential interactions is recommended 1.
From the FDA Drug Label
Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued CNS active drugs — The risk of using Prozac in combination with other CNS active drugs has not been systematically evaluated. Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Concomitant use of Prozac and pimozide is contraindicated Benzodiazepines — The half–life of concurrently administered diazepam may be prolonged in some patients Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Tryptophan — Five patients receiving Prozac in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. Monoamine oxidase inhibitors — See CONTRAINDICATIONS Other drugs effective in the treatment of major depressive disorder — In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2– to 10–fold when fluoxetine has been administered in combination. Serotonergic drugs — Based on the mechanism of action of SNRIs and SSRIs, including Prozac, and the potential for serotonin syndrome, caution is advised when Prozac is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non–selective MAOI), lithium, tramadol, or St John’s Wort
The medications that interact with fluoxetine (Prozac) include:
- CYP2D6 substrates:
- Flecainide
- Propafenone
- Vinblastine
- Tricyclic antidepressants (TCAs)
- Antipsychotics:
- Haloperidol
- Clozapine
- Pimozide (contraindicated)
- Thioridazine (contraindicated)
- Anticonvulsants:
- Phenytoin
- Carbamazepine
- Benzodiazepines:
- Diazepam
- Alprazolam
- Lithium
- Tryptophan
- Monoamine oxidase inhibitors (contraindicated)
- Other antidepressants:
- Imipramine
- Desipramine
- Serotonergic drugs:
- Triptans
- Linezolid
- Tramadol
- St John’s Wort 2
From the Research
Medications that Interact with Fluoxetine (Prozac)
- Fluoxetine interacts with various medications, including:
- Monoamine oxidase inhibitors (MAOIs) 3, 4, 5, 6
- Tricyclic antidepressants, such as imipramine and desipramine 3, 5, 6
- Clozapine 3, 5
- Lithium 3
- Methadone 3, 5
- Carbamazepine 3, 5
- Phenytoin 3
- Oral anticoagulants 3
- Diuretics, which may increase the risk of hyponatraemia 3
- Alprazolam and midazolam, with interactions occurring on the level of CYP3A 5
- CYP2D6-dependent drugs, such as codeine, some antiarrhythmics, and beta-blockers 6
Mechanisms of Interaction
- Fluoxetine inhibits CYP2D6, which can lead to increased plasma concentrations of other drugs that are metabolized by this enzyme 5, 6
- Fluoxetine also inhibits CYP3A, which can lead to interactions with drugs such as alprazolam and midazolam 5
- The long elimination half-life of fluoxetine and its active metabolite norfluoxetine can lead to persistent interactions even after discontinuation of the drug 3, 6
Clinical Consequences of Interactions
- Interactions with fluoxetine can lead to serious clinical consequences, including:
- Serotonin syndrome, a potentially life-threatening condition characterized by neuromuscular and autonomic symptoms 3, 4
- Overdosing of the combined drug, which can lead to adverse effects such as increased risk of bleeding or seizures 3, 4
- Hyponatraemia, which can occur when fluoxetine is combined with diuretics 3