What drugs cannot mix with Prozac?

October 10, 2025 •

4 min read

In 2023, fluoxetine (Prozac) was the eighteenth most commonly prescribed medication in the United States, with over 27 million prescriptions [1.10.1]. Understanding what drugs cannot mix with Prozac is vital for avoiding potentially life-threatening interactions.

Quick Summary

Fluoxetine (Prozac) can have dangerous interactions with several drug classes. Key medications to avoid or use with extreme caution include MAOIs, pimozide, thioridazine, blood thinners, NSAIDs, and other serotonergic drugs.

Key Points

MAOIs are a No-Go: Combining Prozac with Monoamine Oxidase Inhibitors (MAOIs) is strictly contraindicated and can cause fatal serotonin syndrome [1.3.2].
Heart Rhythm Risks: Taking Prozac with thioridazine or pimozide is forbidden due to a high risk of life-threatening heart rhythm problems (QT prolongation) [1.3.4].
Increased Bleeding: Prozac increases bleeding risk, a danger that is amplified when mixed with blood thinners like warfarin or common NSAIDs like ibuprofen and aspirin [1.5.1, 1.7.2].
Serotonin Syndrome Risk: Mixing Prozac with other antidepressants (SSRIs, SNRIs, TCAs), triptans, or St. John's Wort can lead to potentially serious serotonin syndrome [1.8.3].
CYP2D6 Enzyme Inhibition: Prozac blocks the CYP2D6 enzyme, causing levels of many other drugs (including certain antipsychotics and beta-blockers) to rise to potentially toxic levels [1.2.1].
Consult Professionals: Always give your doctor and pharmacist a full list of all your medications and supplements to prevent dangerous interactions [1.3.3].
Washout Periods are Critical: Specific waiting periods are required when switching between Prozac and MAOIs—at least 5 weeks after stopping Prozac before starting an MAOI [1.4.2].

Understanding Prozac and Its Mechanism

Prozac, the brand name for fluoxetine, is a selective serotonin reuptake inhibitor (SSRI) commonly prescribed for depression, obsessive-compulsive disorder (OCD), and other mental health conditions [1.3.3]. It works by increasing the levels of serotonin, a neurotransmitter in the brain, which helps improve mood [1.4.5]. A critical aspect of Prozac's safety profile involves how it is metabolized in the body. Fluoxetine is a potent inhibitor of a liver enzyme called cytochrome P450 2D6 (CYP2D6) [1.2.1, 1.9.3]. This enzyme is responsible for breaking down a wide range of other medications. By inhibiting CYP2D6, Prozac can cause other drugs to accumulate in the bloodstream, leading to increased risk of side effects, some of which can be severe or life-threatening [1.2.1].

Absolute Contraindications: Drugs You Must Not Take with Prozac

Certain medications are considered absolutely contraindicated with Prozac, meaning the combination should never be used due to the risk of severe, dangerous effects.

Monoamine Oxidase Inhibitors (MAOIs)

This is the most critical interaction. Combining Prozac with MAOIs can lead to a life-threatening condition called serotonin syndrome [1.4.3]. This occurs when there is an excessive amount of serotonin in the brain. Symptoms range from mild (agitation, sweating, fast heart rate) to severe (high fever, seizures, muscle rigidity, and unconsciousness) [1.3.4, 1.4.5].

Examples of MAOIs: Phenelzine (Nardil), isocarboxazid (Marplan), tranylcypromine (Parnate), selegiline (Emsam), and the antibiotic linezolid (Zyvox) [1.3.3, 1.4.2].
Required Washout Period: You must wait at least 14 days after stopping an MAOI before starting Prozac. Due to Prozac's long half-life, you must wait at least five weeks after stopping Prozac before starting an MAOI [1.2.2, 1.4.2].

Pimozide (Orap) and Thioridazine

Taking Prozac with the antipsychotic medications pimozide or thioridazine is strictly contraindicated [1.3.2, 1.3.5]. Prozac inhibits the enzymes that break down these drugs, causing their levels to rise dangerously in the body [1.3.2]. This significantly increases the risk of a serious heart problem called QT prolongation, an abnormality in the heart's electrical rhythm that can lead to life-threatening arrhythmias and sudden death [1.2.1, 1.3.4]. You must wait at least five weeks after stopping Prozac to take thioridazine [1.3.5].

Significant Interactions: Drugs to Use with Extreme Caution

Many other medications can interact with Prozac, requiring close monitoring by a healthcare provider, dose adjustments, or choosing an alternative medication.

Other Serotonergic Drugs

Combining Prozac with other drugs that increase serotonin levels also raises the risk of serotonin syndrome, although the risk is typically lower than with MAOIs [1.8.3].

Other Antidepressants: Tricyclic antidepressants (TCAs) like amitriptyline, other SSRIs like sertraline (Zoloft) and escitalopram (Lexapro), and SNRIs like duloxetine (Cymbalta) and venlafaxine (Effexor XR) [1.8.3, 1.8.5].
Triptans: Medications for migraines such as sumatriptan (Imitrex) and rizatriptan (Maxalt) [1.2.1, 1.6.1].
Opioid Pain Relievers: Tramadol and fentanyl have serotonergic activity [1.3.3, 1.8.4].
Herbal Supplements: St. John's Wort is a well-known supplement that increases serotonin and should be avoided [1.2.1, 1.3.1].

Blood Thinners and NSAIDs

Prozac can increase the risk of bleeding [1.2.3]. This risk is compounded when taken with other medications that thin the blood.

Anticoagulants (Blood Thinners): Warfarin (Coumadin), apixaban (Eliquis), and rivaroxaban (Xarelto) [1.2.1, 1.7.2]. The combination with warfarin is particularly risky, as fluoxetine can enhance its effects, requiring close monitoring of blood tests (INR) [1.7.2, 1.7.3].
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Over-the-counter pain relievers like ibuprofen (Advil, Motrin), naproxen (Aleve), and aspirin increase the risk of gastrointestinal bleeding when combined with Prozac [1.3.1, 1.5.1, 1.5.4].

Drugs Affecting Heart Rhythm

As Prozac itself can cause QT prolongation, combining it with other drugs that have the same effect increases the risk of dangerous arrhythmias [1.2.1].

Certain Antipsychotics: Ziprasidone (Geodon), haloperidol (Haldol) [1.2.1, 1.3.2].
Antiarrhythmics: Amiodarone (Pacerone), quinidine [1.3.1, 1.4.2].
Certain Antibiotics: Ciprofloxacin (Cipro), azithromycin (Zithromax) [1.3.2].

Other Notable Interactions

Benzodiazepines: Prozac can increase the plasma concentration of drugs like alprazolam (Xanax) and diazepam (Valium), leading to increased sedation [1.3.1].
Anticonvulsants: Levels of phenytoin and carbamazepine can be increased by Prozac, requiring monitoring [1.3.1].
Alcohol: While not a direct drug-drug interaction, alcohol can worsen side effects like drowsiness and impaired judgment and may negatively affect the underlying condition being treated [1.3.3].

Comparison of Major Interacting Drug Classes


Drug Class	Examples	Potential Major Risk(s)	Management Recommendation
MAOIs	Phenelzine, Selegiline, Linezolid	Serotonin Syndrome (Life-threatening)	Strictly Contraindicated. Requires a 2 to 5-week washout period [1.4.2].
Certain Antipsychotics	Pimozide, Thioridazine	QT Prolongation, Fatal Arrhythmias	Strictly Contraindicated [1.3.2].
Blood Thinners	Warfarin, Apixaban, Clopidogrel	Increased risk of serious bleeding	Use with extreme caution. Requires close monitoring and possible dose adjustments [1.7.2, 1.7.3].
NSAIDs	Ibuprofen, Naproxen, Aspirin	Increased risk of gastrointestinal bleeding	Use with caution, especially long-term. Monitor for signs of bleeding [1.5.2, 1.5.4].
Other Antidepressants (SSRIs, SNRIs, TCAs)	Sertraline, Duloxetine, Amitriptyline	Serotonin Syndrome	Use with caution. Provider may lower doses and monitor for symptoms [1.8.5].
Triptans	Sumatriptan, Rizatriptan	Serotonin Syndrome	Use with caution. Monitor for symptoms, especially when starting or increasing a dose [1.6.3].

Conclusion: Always Consult Your Healthcare Provider

The list of potential drug interactions with Prozac is extensive. Many interactions stem from its effects on serotonin levels and its inhibition of the CYP2D6 liver enzyme [1.2.1, 1.3.1]. Because of these complex mechanisms, it is absolutely essential to provide your doctor and pharmacist with a complete list of all medications you take, including prescriptions, over-the-counter drugs, and herbal supplements. Never start or stop any medication without first consulting your healthcare provider, as they can help you navigate these risks safely and effectively.

For more authoritative information on medication interactions, you can visit the U.S. Food and Drug Administration (FDA) website.FDA Drug Information Resources

Frequently Asked Questions

You should use caution. Combining Prozac with NSAIDs like ibuprofen increases the risk of stomach and intestinal bleeding. While short-term use might be acceptable for some, you should consult your doctor first, especially if you are elderly or have a history of ulcers [1.5.3, 1.5.4].

Mixing Prozac and an MAOI can cause a life-threatening condition called serotonin syndrome. It leads to dangerously high levels of serotonin, causing symptoms like high fever, severe muscle rigidity, seizures, and can result in a coma or death. This combination is absolutely contraindicated [1.3.4, 1.4.5].

Due to fluoxetine's long duration in the body, you must wait at least five weeks after stopping Prozac before you can safely begin taking an MAOI [1.2.2, 1.4.2].

It is generally advised to avoid alcohol. While not a direct chemical interaction, alcohol can worsen Prozac's side effects like drowsiness and impaired concentration. It may also negatively impact the depression or anxiety being treated [1.3.3].

This combination should be used with caution. Both medications increase serotonin levels, which can raise the risk of serotonin syndrome. Your doctor may determine the benefit outweighs the risk but will likely monitor you closely for symptoms like confusion, rapid heart rate, or muscle twitching [1.6.1, 1.6.3].

Prozac blocks the liver enzymes needed to clear thioridazine and pimozide from your body. This causes their levels to become dangerously high, leading to a significant risk of a fatal heart rhythm abnormality known as QT prolongation [1.3.2, 1.3.4].

Yes, Prozac can interact with other SSRIs like Zoloft (sertraline) and SNRIs like Cymbalta (duloxetine). Taking them together increases the risk of serotonin syndrome. If co-prescribed, your doctor will likely use lower doses and monitor you carefully [1.8.3, 1.8.5].