Fluoxetine with Clozapine Interaction Details

Brand Names Associated with Fluoxetine

Brand Names Associated with Clozapine

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 11, 2023

Interaction Effect

Increased cloZAPine exposure, an increased risk of cloZAPine-related adverse effects and an increased risk of QT interval prolongation

Interaction Summary

Avoid coadministration of cloZAPine with FLUoxetine. CloZAPine is a CYP2D6 substrate, FLUoxetine is strong CYP2D6 inhibitor, and both agents are associated with QT prolongation. Concurrent use may lead to increased cloZAPine exposure, increased risk of cloZAPine adverse events , and additive effects on QT interval, increasing risk for ventricular arrhythmias, including torsade de pointes . If coadministration is necessary, closely monitor patients for adverse reactions and consider a cloZAPine dose reduction if necessary. If coadministration is discontinued, monitor for reduced cloZAPine effectiveness and consider increasing the cloZAPine dose if indicated .Consider ECG assessment and periodic ECG monitoring if initiating treatment with FLUoxetine in patients with risk factors for QT interval prolongation and ventricular arrhythmia. Discontinue FLUoxetine and obtain a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia .

Severity

Major

Onset

Unspecified

Evidence

Theoretical

How To Manage Interaction

Coadministration of FLUoxetine with cloZAPine should be avoided as concurrent use may lead to an increased risk of QT interval prolongation and ventricular arrhythmias, including torsade de pointes. Additionally, coadministration may increase cloZAPine exposure and the risk of cloZAPine adverse events. If coadministration is necessary, closely monitor patients for adverse reactions and consider a cloZAPine dose reduction if necessary. If coadministration is discontinued, monitor for reduced cloZAPine effectiveness and consider increasing the cloZAPine dose if indicated .Consider ECG assessment and periodic ECG monitoring if initiating treatment with FLUoxetine in patients with risk factors for QT interval prolongation and ventricular arrhythmia. Discontinue FLUoxetine and obtain a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia .

Mechanism Of Interaction

Inhibition of CYP2D6-mediated metabolism of cloZAPine by FLUoxetine; additive QT interval prolongation

Literature Reports

A) While minor changes in the levels of cloZAPine and its metabolites were reported in patients with schizophrenia when PARoxetine was added to their steady-state cloZAPine treatment regimen (n=14), other clinical reports have described a less than 2-fold elevation in cloZAPine and metabolite concentrations with FLUoxetine, PARoxetine, and sertraline coadministration .

B) A 44-year-old man receiving FLUoxetine and cloZAPine was found dead in his yard. The dates of the prescriptions and the number of tablets that remained indicated that he had been taking his medications as prescribed. Autopsy results showed a high therapeutic FLUoxetine concentration (0.7 mcg/mL) and also a high therapeutic norFLUoxetine concentration (0.6 mcg/mL). FLUoxetine found in his gastric contents also indicated that the medication was being taken as directed. The cloZAPine blood concentration was in the lethal concentration range (4.9 mcg/mL), but the cloZAPine in the gastric contents suggested that the cloZAPine was being taken as prescribed and that the patient had not consumed a large overdose amount prior to his death. Other pathological findings included pulmonary edema, visceral vascular congestion, paralytic ileus, gastroenteritis, and eosinophilia, which are all consistent with cloZAPine toxicity. The combined central nervous system, respiratory, and cardiovascular depression caused by these 2 drugs was sufficient to result in the death of this patient, and his death was ruled to be a cloZAPine overdose due to a fatal drug interaction .

C) Ten institutionalized patients with schizophrenia stabilized on cloZAPine therapy for at least 1 month participated in a prospective study to evaluate the effect of FLUoxetine on cloZAPine pharmacokinetics. FLUoxetine 20 mg once daily was administered for 8 consecutive weeks. Mean plasma cloZAPine concentrations increased from 348 nanograms/milliliter (ng/mL) to 550 ng/mL (58%) at week 8. Plasma levels of norcloZAPine were also increased by 36% (from 280 ng/mL to 381 ng/mL). CloZAPine N-oxide levels rose from 89 ng/mL at baseline to 128 ng/mL, representing a 38% increase. However, these increases in cloZAPine and metabolite plasma concentrations were not associated with significant changes in efficacy or safety .

D) A study evaluated the serum concentrations of cloZAPine and norcloZAPine, the major metabolite, when given in combination with the SSRIs FLUoxetine, PARoxetine, and sertraline. Eighty outpatients receiving cloZAPine all had been diagnosed with schizophrenia or major affective disorder, and 40 of these patients were receiving an SSRI in combination with cloZAPine. Of these 40 patients, 14 were receiving FLUoxetine, 10 were receiving sertraline, and 16 were receiving PARoxetine therapy. Among the patients on SSRI therapy, serum concentrations of cloZAPine and norcloZAPine were 41.1% and 44.8% higher, respectively, than in matched patients who were not receiving an SSRI. The ratio of cloZAPine plus norcloZAPine concentration to dose was also 37.7% higher in patients receiving SSRIs, indicating cloZAPine impaired clearance. The differences among the 3 SSRIs were minor, and the study groups were too limited for an accurate statistical comparison among the individual SSRIs .

E) Subjects receiving concurrent cloZAPine and FLUoxetine had 76% higher serum cloZAPine concentrations and 61% higher metabolite concentrations on average compared with controls receiving only cloZAPine. The mean ratio of total drug level (cloZAPine plus metabolites) to dose was 60% higher and the mean ratio of concentrations to dose was 75% higher in patients receiving cloZAPine and FLUoxetine compared with concentrations in patients receiving cloZAPine alone .

F) Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of cloZAPine has been observed in patients receiving concomitant FLUoxetine .

Fluoxetine Overview

• Fluoxetine is used to treat depression, obsessive-compulsive disorder (bothersome thoughts that won't go away and the need to perform certain actions over and over), some eating disorders, and panic attacks (sudden, unexpected attacks of extreme fear and worry about these attacks). Fluoxetine is also used to relieve the symptoms of premenstrual dysphoric disorder, including mood swings, irritability, bloating, and breast tenderness. It is also used along with olanzapine (Zyprexa) to treat depression that did not respond to other medications and episodes of depression in people with bipolar I disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). Fluoxetine is in a class of medications called selective serotonin reuptake inhibitors (SSRIs). It works by increasing the amount of serotonin, a natural substance in the brain that helps maintain mental balance.

Clozapine Overview

• Clozapine is used to treat the symptoms of schizophrenia (a mental illness that causes disturbed or unusual thinking, loss of interest in life, and strong or inappropriate emotions) in people who have not been helped by other medications or who have tried to kill themselves and are likely to try to kill or harm themselves again. Clozapine is in a class of medications called atypical antipsychotics. It works by changing the activity of certain natural substances in the brain.

Return To Our Drug Interaction Homepage

Feedback, Question Or Comment About This Information?

Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.