Fluoxetine drug interactions

List of drug interactions
Drugs metabolized by CYP2D6 Drugs metabolized by CYP3A4 CNS active drugs Anticonvulsants Benzodiazepines Tryptophan Monoamine oxidase inhibitors Sumatriptan Potential effects of coadministration of drugs tightly bound to plasma proteins Drugs that interfere with hemostasis (NSAIDs, aspirin, warfarin, etc.) Warfarin Electroconvulsive therapy (ECT) Carcinogenicity Mutagenicity

Drugs metabolized by CYP2D6
Approximately 7% of the normal population has a genetic defect that leads to reduced levels of activity of the cytochrome P450 isoenzyme 2D6. Such individuals have been referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and TCAs. Many drugs, such as most drugs effective in the treatment of major depressive disorder, including fluoxetine and other selective uptake inhibitors of serotonin, are metabolized by this isoenzyme; thus, both the pharmacokinetic properties and relative proportion of metabolites are altered in poor metabolizers. However, for fluoxetine and its metabolite, the sum of the plasma concentrations of the 4 active enantiomers is comparable between poor and extensive metabolizers. Fluoxetine, like other agents that are metabolized by CYP2D6, inhibits the activity of this isoenzyme, and thus may make normal metabolizers resemble poor metabolizers. 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. Thus, his/her dosing requirements resemble those of poor metabolizers. 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. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, 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. Return to top

Drugs metabolized by CYP3A4
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 addition, 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 of 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. Return to top

CNS active drugs
The risk of using Fluoxetine in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of Fluoxetine and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status. Return to top

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. Return to top

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. A single case report has suggested possible additive effects of pimozide and fluoxetine leading to bradycardia. For thioridazine. Return to top

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. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly. Return to top

Tryptophan
Five patients receiving Fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. Return to top

Monoamine oxidase inhibitors
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. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued. Return to top

Sumatriptan
There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, or citalopram) is clinically warranted, appropriate observation of the patient is advised. Return to top

Potential effects of coadministration of drugs tightly bound to plasma proteins
Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs. Return to top

Drugs that interfere with hemostasis (NSAIDs, aspirin, warfarin, etc.)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated 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 potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with fluoxetine. Return to top

Warfarin
Altered anticoagulant effects, including increased bleeding, have been reported when fluoxetine is coadministered with warfarin. Patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped. Return to top

Electroconvulsive therapy (ECT)
There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. Carcinogenesis, Mutagenesis, Impairment of Fertility There is no evidence of carcinogenicity, mutagenicity, or impairment of fertility with Fluoxetine. Return to top

Carcinogenicity
The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis], produced no evidence of carcinogenicity. Return to top

Mutagenicity
Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. Return to top