Interaction Between Diflucan And Norco

In our latest question and answer, our pharmacist discusses the drug interaction between Diflucan and Norco.


Can you explain the possible drug interactions between Diflucan and Norco?

Asked by Ann On Feb 02, 2023

Answered by
Medical Content Reviewed By HelloPharmacist Staff

Published Feb 02, 2023
Last updated Feb 02, 2023

Key points

  • Fluconazole inhibits a prominent metabolizing enzyme, CYP3A4, which is partially responsible for hydrocodone metabolism.
  • Combining fluconazole and hydrocodone can result in increased blood concentrations of hydrocodone, increasing the risk of side effects.


Sure, I'd be happy to describe in detail the interaction between Diflucan (fluconazole) and Norco (hydrocodone; acetaminophen).

Fluconazole is an antifungal drug and is known to inhibit an important enzyme known as CYP3A4.

CYP3A4 is an enzyme that plays an important role in the metabolism of many drugs, including hydrocodone.

When a CYP3A4 inhibitor such as fluconazole is taken, it can reduce the activity of CYP3A4, resulting in an increase in the levels of drugs that are normally metabolized by this enzyme. This can cause an accumulation of these drugs in the blood, leading to an increase in their concentration. In the case of hydrocodone, this could lead to an increased risk of side effects and adverse reactions, such as increased drowsiness or sedation. In serious cases, respiratory depression could occur.

Now, I couldn't find any studies that specifically looked at fluconazole and hydrocodone, but there are plenty of published studies that have evaluated other known CYP3A4 inhibitors with hydrocodone and they have shown hydrocodone concentrations being increased when taken with them.

Additionally, there are several case studies I found where severe toxicity was reported when hydrocodone was given with a CYP3A4 inhibitor.

There are several hydrocodone products that contain warnings about CYP3A4 inhibition in their labeling.

For example, the package insert for Zohydro ER, a hydrocodone product, carries a prominent warning that using hydrocodone and any CYP3A4 inhibitor together may result in a rise in the levels of hydrocodone in the blood. This elevation in hydrocodone levels could lead to prolonged adverse effects and even potentially fatal respiratory depression.

It recommends that if it's necessary to take a CYP3A4 inhibitor and hydrocodone together, patients should be closely monitored for drowsiness and breathing difficulties, and their hydrocodone dose may need to be adjusted until the desired effects are achieved. 

Other Thoughts From The Pharmacist

This interaction, according to most of the 'online interaction checkers' you'll find, will list this as a moderate interaction.

This is because fluconazole, while a known CYP3A4 inhibitor, isn't necessarily the strongest CYP3A4 inhibitor out there and subsequent changes in drug concentrations tend to be on the lower, less significant end, overall. Others drugs, like clarithromycin, cause far more severe interactions. Also, CYP3A4 isn't the only enzyme that metabolizes hydrocodone. Others, like CYP2D6, do as well.

However, if you happened to also be taking a CYP2D6 inhibitor, this interaction would be in the more severe category.

All in all, it's important to know about this interaction as you may experience more side effects than usual if you combine fluconazole and hydrocodone-containing products.

A good rule of thumb, if you need both drugs, is to start on a low dose of hydrocodone and see how you respond. Of course, make sure you're doctor knows about all your medications as well so you can be appropriately monitored.

Final Words

I hope this helped!

Thanks for reaching out!


  • Fatal hydrocodone overdose in a child: pharmacogenetics and drug interactions, PubMed
  • Drug-Drug Interactions Between the Anti-Hepatitis C Virus 3D Regimen of Ombitasvir, Paritaprevir/Ritonavir, and Dasabuvir and Eight Commonly Used Medications in Healthy Volunteers, PubMed
  • Zohydro Prescribing Information, AccessFDA
  • Hydrocodone Monograph, PubChem

About the Pharmacist

Dr. Brian Staiger, PharmD

Dr. Brian has been practicing pharmacy for over 13 years and has wide-ranging experiences in many different areas of the profession. From retail, clinical, program development, and administrative responsibilities, he's your knowledgeable and go-to source for all your pharmacy and medication-related questions! Dr. Brian Staiger also has herbalist training and educational certificates in the field of medical ethnobotany. Feel free to send him an email at! You can also connect with Dr. Brian Staiger on LinkedIn.

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