Ondansetron Drug Interactions: What You Need to Know Before Taking It

Ondansetron (brand name Zofran) is a safe and effective anti-nausea medication for most people. But like many drugs, it can interact with other medications in ways that increase side effects or reduce how well either drug works.

This guide explains the most important Ondansetron drug interactions, including which medications to avoid, which supplements to be cautious with, and exactly what to tell your doctor before starting treatment. For background on how the medication works, see our guide on Ondansetron's mechanism of action.

How Drug Interactions Work

Drug interactions happen in several ways:

• Additive effects — Two drugs cause the same side effect, making it worse (e.g., two drugs that both affect heart rhythm)
• Metabolic interference — One drug changes how your body processes another, raising or lowering its levels in your blood
• Receptor competition — Two drugs compete for the same target in your body, which can reduce the effectiveness of one or both

Ondansetron is primarily metabolized by liver enzymes CYP3A4 and CYP2D6, and it affects serotonin signaling and heart rhythm. These are the main pathways where interactions occur.

Major Drug Interactions

These interactions are the most serious and may require avoiding the combination entirely or close medical monitoring.

Apomorphine (Apokyn) — Contraindicated

Ondansetron should never be taken with Apomorphine, a medication used for Parkinson's disease. This combination can cause severe hypotension (dangerously low blood pressure) and loss of consciousness. This is the only absolute contraindication listed in Ondansetron's labeling.

Serotonergic Medications — Risk of Serotonin Syndrome

Taking Ondansetron with drugs that increase serotonin levels raises the risk of serotonin syndrome — a potentially life-threatening condition. Medications in this category include:

• SSRIs — Fluoxetine (Prozac), Sertraline (Zoloft), Escitalopram (Lexapro), Paroxetine (Paxil), Citalopram (Celexa)
• SNRIs — Venlafaxine (Effexor), Duloxetine (Cymbalta)
• Tramadol (Ultram) — Also a pain medication with serotonergic activity
• Fentanyl — An opioid pain medication
• Lithium — Used for bipolar disorder
• MAOIs — Phenelzine (Nardil), Tranylcypromine (Parnate), Selegiline (Emsam)

Symptoms of serotonin syndrome include agitation, rapid heartbeat, high fever, muscle twitching, and loss of coordination. Learn more about this and other risks in our side effects guide.

Important: Many people safely take Ondansetron with SSRIs under medical supervision. The risk exists but is relatively low at standard doses. Your doctor will weigh the benefits vs. risks.

QT-Prolonging Medications — Additive Cardiac Risk

Ondansetron can prolong the QT interval on an ECG, which in rare cases leads to dangerous heart rhythms. Taking it with other QT-prolonging drugs increases this risk:

• Amiodarone (Cordarone) — Heart rhythm medication
• Sotalol (Betapace) — Heart rhythm and blood pressure medication
• Haloperidol (Haldol) — Antipsychotic
• Methadone — Used for pain and opioid use disorder
• Certain antibiotics — Erythromycin, Moxifloxacin, Azithromycin (lower risk)
• Certain antifungals — Fluconazole

CYP3A4 Inducers — May Reduce Ondansetron Effectiveness

These medications speed up Ondansetron's breakdown in the liver, potentially making it less effective:

• Phenytoin (Dilantin) — Seizure medication
• Carbamazepine (Tegretol) — Seizure and mood medication
• Rifampin (Rifadin) — Antibiotic for tuberculosis

If you take any of these, your doctor may need to adjust your Ondansetron dose.

Moderate Drug Interactions

• Tramadol (Ultram) — Beyond the serotonin syndrome risk, Ondansetron may also reduce Tramadol's pain-relieving effectiveness. If you take Tramadol for pain, tell your doctor before starting Ondansetron.
• CYP3A4 inhibitors — Medications like Ketoconazole (Nizoral) and Erythromycin can slow Ondansetron's breakdown, potentially increasing its levels and side effects.

Supplements and Over-the-Counter Medications to Watch

While Ondansetron has fewer supplement interactions than many medications, a few deserve attention:

• St. John's Wort — This herbal supplement has serotonergic activity and can increase the risk of serotonin syndrome when combined with Ondansetron. It also induces CYP3A4 and may reduce Ondansetron levels.
• 5-HTP and L-Tryptophan — These supplements increase serotonin production and should be used cautiously with Ondansetron.
• Antihistamines (Benadryl, Dramamine) — Generally safe to combine with Ondansetron, but the combination may increase drowsiness. Your doctor may actually recommend using both together in some cases.

Food and Drink Interactions

Ondansetron has no significant food interactions. You can take it with or without meals.

A few notes:

• Alcohol — While there's no direct drug interaction, alcohol can worsen nausea and dizziness, which defeats the purpose of taking Ondansetron. Avoid alcohol if you're taking it for nausea.
• Grapefruit juice — Grapefruit inhibits CYP3A4 and could theoretically increase Ondansetron levels, but this interaction is not considered clinically significant at normal consumption levels.

What to Tell Your Doctor

Before starting Ondansetron, make sure your doctor knows about:

1. All prescription medications you take — especially antidepressants, heart medications, seizure drugs, and pain medications
2. Over-the-counter medications — including antihistamines and pain relievers
3. Supplements and herbal products — especially St. John's Wort, 5-HTP, and L-Tryptophan
4. Heart conditions — including long QT syndrome, arrhythmias, or a family history of heart rhythm problems
5. Liver problems — Ondansetron is processed by the liver, and dosing may need adjustment
6. Electrolyte issues — Low potassium or magnesium increases the risk of QT prolongation

Keep a current medication list and bring it to every appointment. This is the single most effective way to prevent drug interactions.

Final Thoughts

Ondansetron is a well-tolerated medication with a manageable list of drug interactions. The most important ones to know about are the contraindication with Apomorphine, the serotonin syndrome risk with SSRIs and similar drugs, and the cardiac risk with QT-prolonging medications.

The key takeaway: always share your complete medication list with your doctor and pharmacist. They can check for interactions and adjust your treatment plan if needed.

If you need help finding Ondansetron at a pharmacy near you, Medfinder can help you check stock in real time.