Diflucan (Fluconazole) With Zofran (Ondansetron)

There is potentially a serious interaction between Diflucan (fluconazole) and Zofran (ondansetron).


I took a fluconazole pill 150mg on Friday afternoon. However, I have GERD that comes with a lot of nausea and usually take Zofran for that. I know fluconazole and Zofran can have some serious side effects. When will I be able to take Zofran again?

Asked by Krodg On Jan 13, 2019

Answered by
Medical Content Reviewed By PharmacistAnswers Staff

On Jan 15, 2019
Drug Interaction Q Mark

You are correct that there is potentially a serious interaction between Diflucan (fluconazole) and Zofran (ondansetron). Both can cause QT prolongation, an abnormal heart rhythm. QT prolongation increases the risk of serious cardiac conditions, such  Torsades de pointes and ventricular fibrillation.

The prescribing information for both Diflucan and Zofran warn about QT prolongation. They recommend avoiding concomitant medications that are also associated with it. From the prescribing information for Zofran:

Avoid in patients with congenital long QT syndrome; monitor with electrocardiograms (ECGs) if concomitant electrolyte abnormalities, cardiac failure or arrhythmias, or use of other QT prolonging drugs.

Making this interaction potentially more serious is the fact that both Zofran and Diflucan are metabolized by the enzyme CYP3A4.

Although Diflucan is metabolized by CYP3A4, it is also a known inhibitor of the enzyme. Therefore, fluconazole can theoretically decrease the metabolism of Zofran, increasing drug concentrations and increase the risk of dose related side effects (such as QT prolongation).

The prescribing information for Diflucan states that it should not be used with other drugs that are metabolized by CYP3A4 and are known to cause QT prolongation:

Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4, such as cisapride, astemizole, erythromycin, pimozide, and quinidine are contraindicated in patients receiving fluconazole.

Zofran would fall right into this definition of drugs to be avoided.

The exact risk for QT prolongation with these drugs isn't well known, but extreme caution is certainly recommended if they are being used together.

Answer Summary

Both Diflucan (fluconazole) and Zofran (ondansetron) can cause QT prolongation, increasing the risk of serious arrhythmias. Additionally, Diflucan is an inhibitor of the metabolizing enzyme CYP3A4, and can increase Zofran concentrations.

How Long To Separate Doses

So, we've established that there is potentially a severe interaction between Diflucan and Zofran. In terms of how long to wait between doses for the interaction risk to subside, there isn't a definite recommendation. We can however, come up with a safe estimate based on the known metabolism of both drugs.

Diflucan First, Then Zofran

Diflucan stays in the body for a long time. It has a reported elimination half-life of 30 hours, but can range between 20 to 50 depending on the individual. The elimination half-life is the time it takes for the concentration of the drug to be reduced by 50%. In general, it takes around 5 half-lives for a drug to be considered completely metabolized and eliminated.

Using the average reported half-life of 30 hours, this equates to 150 hours, or a little over 6 days.

Whether or not Diflucan actually continues to inhibit CYP3A4 for 6 days (or more) from the last dose isn't well known.

Most studies suggest that Diflucan is only a moderate inhibitor of the enzyme, and the extent of inhibition is dose-dependent, meaning that higher doses are more likely to cause it. As such, the risk of Diflucan causing significant CYP3A4 inhibition after a few half-lives shouldn't be all that high.

Fortunately, the prescribing information for Diflucan provides some clarity and gives us a specific time frame for which potential drug interactions are a concern:

...there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole [Diflucan]. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole.

Diflucan causing CYP3A4 enzyme inhibition for 4-5 days is pretty close to our estimate of 6 days.

So, to avoid potential interactions, Zofran should not be given within 4 to 5 days of Diflucan. If your doctor recommends both together as the best course of therapy for you, caution and careful monitoring is advised.

Zofran First, Then Diflucan

Zofran has a considerably shorter half-life than Diflucan. It is reported to range from 3.1 to 5.8 hours. It should be essentially completely metabolized and eliminated in slightly more than 1 day.

Therefore, it would be prudent to wait 1 to 2 days before taking Diflucan after your last Zofran dose.

  • Elsevier ClinicalKey: Diflucan (Accessed 1/15/19)
  • Elsevier ClinicalKey: Zofran (Accessed 1/15/19)
  • Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. PubMed (Accessed 1/15/19)
  • Diflucan Prescribing Information (Accessed 1/15/19)
  • Zofran Prescribing Information (Accessed 1/15/19)
  • Pharmacokinetics 101. PubMed (Accessed 1/15/19)
  • Clinical Relevance of the Pharmacokinetic Interactions of Azole Antifungal Drugs with Other Coadministered Agents. Drug Metabolism and Disposition (Accessed 1/15/19)

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