Important Drug Interactions for the Antidepressant Fluoxetine (PROZAC, SYMBYAX)

Patients taking the commonly prescribed antidepressant fluoxetine should be aware that it has clinically important and potentially dangerous interactions with many other prescription and over-the-counter medications.

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was initially approved by the Food and Drug Administration in 1987 under the brand name PROZAC for treatment of depression.[1] The drug was subsequently approved for obsessive compulsive disorder, panic disorder and bulimia nervosa.[2] Fluoxetine also is marketed as a combination product under the brand name SYMBYAX, which also contains the antipsychotic olanzapine, for treatment of acute depressive episodes associated with bipolar disorder and treatment-resistant depression.[3]

Public Citizen’s Health Research Group has designated SSRIs like fluoxetine as first-choice medications for major depression and the fluoxetine-olanzapine combination product as Do Not Use.

Increased risk of fatal heart-rhythm abnormalities[4],[5]

Fluoxetine can cause prolongation of the QT interval[6] — a change in the electrical activity of the heart that can lead to a fatal heart-rhythm disturbance called torsades de pointes, which can cause cardiac arrest and sudden death.

Numerous oral drugs, when used concomitantly (at the same time) with fluoxetine, further increase the risk of QT prolongation (see Table 1, below, for examples). Such drugs include certain medications for treating abnormal heart rhythms, Alzheimer’s disease, bacterial infections, HIV infection, muscle spasms, opioid-use disorder, pain and psychosis, among other diseases.

For several of these drugs, the risk of QT prolongation and potentially fatal abnormal heart rhythms is so high that they should not be taken concomitantly with fluoxetine.

Table 1: Examples of Oral Drugs That May Increase the Risk of Fatal Heart-Rhythm Abnormalities When Used Concomitantly With Fluoxetine

†Brand-name combination products were excluded.
*Designated as Limited Use by Worst Pills, Best Pills News
**Designated as Do Not Use by Worst Pills, Best Pills News

Other important drug interactions[7],[8]

Drugs that increase bleeding risk

Fluoxetine, like other SSRIs, may increase the risk of bleeding in the gastrointestinal tract and elsewhere. Concomitant use of fluoxetine with any of the following drugs increases this bleeding risk further (brand names for combination products excluded):

• aspirin (BAYER ASPIRIN, DURLAZA, ECOTRIN, VAZALORE)
• other nonsteroidal anti-inflammatory drugs, including ibuprofen (ADVIL, IBU-TAB, MIDOL LIQUID GELS, MOTRIN IB, TAB-PROFEN) and naproxen (ALEVE, ANAPROX DS, NAPRELAN, NAPROSYN)
• warfarin (COUMADIN, JANTOVEN)

Serotonin syndrome

Fluoxetine and other SRRIs rarely can cause serotonin syndrome, a potentially fatal condition characterized by agitation, confusion, hallucinations, rapid heartbeat, high blood pressure, high fever, shivering, sweating, nausea, vomiting, diarrhea and muscle rigidity. In severe cases, the syndrome can lead to seizures and coma.

The risk of serotonin syndrome increases when fluoxetine is taken concomitantly with other drugs that cause elevated serotonin levels in the body (see Table 2, below, for a list of examples). Such drugs include certain opioids, monoamine oxidase (MOA) inhibitors for depression, tricyclic antidepressants, and triptans for migraine headaches, among others. For the MOA inhibitors and the antibiotic linezolid (ZYVOX), the risk of serotonin syndrome is so great that they should never be taken concomitantly with fluoxetine.

Concomitant use of fluoxetine with the dietary supplement St. John’s wort also raises the risk of serotonin syndrome.

Table 2: Examples of Oral or Nasal Drugs That Increase the Risk of Serotonin Syndrome When Used Concomitantly With Fluoxetine

†Brand-name combination products were excluded.
*Designated as Limited Use by Worst Pills, Best Pills News
**Designated as Do Not Use by Worst Pills, Best Pills News

What You Can Do

If you need treatment with fluoxetine, review all your other medications with your doctor to assess for potentially significant drug interactions. If you are taking a medication that interacts with fluoxetine, you may need to stop or adjust the dosage of the interacting drug, or your doctor may advise you to take a different drug for your depression or other mental health disorder. Be aware that other drugs not listed in this article also may have dangerous interactions with fluoxetine.
 

References

[1] Wong DT, Perry KW, Bymaster FP. Case history: The discovery of fluoxetine hydrochloride (Prozac). Nat Rev Drug Discov. 2005;4(9):764-774.

[2] Eli Lilly and Company. Label: fluoxetine (PROZAC). October 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/018936s111lbl.pdf. Accessed December 6, 2021.

[3] Eli Lilly and Company. Label: olanzapine and fluoxetine (SYMBYAX). September 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021520s054lbl.pdf. Accessed December 6, 2021.

[4] Eli Lilly and Company. Label: fluoxetine (PROZAC). October 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/018936s111lbl.pdf. Accessed December 6, 2021.

[5] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Search term: “fluoxetine.” Accessed November 12, 2021.

[6] Eli Lilly and Company. Label: fluoxetine (PROZAC). October 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/018936s111lbl.pdf. Accessed November 12, 2021.

[7] Eli Lilly and Company. Label: fluoxetine (PROZAC). October 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/018936s111lbl.pdf. Accessed December 6, 2021.

[8] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Search term: “fluoxetine.” Accessed November 12, 2021.