Fluconazole interactions to avoid

Drug interactions | Food interactions | Other interactions | Avoiding interactions | When to see a doctor

Fluconazole, also known as the brand name of this medication, Diflucan, is a type of antifungal medication that treats certain yeast infections. These conditions can range from oral thrush to vaginal candidiasis to systemic Candida infections to cryptococcal meningitis. Many possible interactions occur because fluconazole is a CYP3A4 inhibitor. Fluconazole can also prolong the QTc interval, which may result in heart arrhythmias. Those with a family history of certain heart problems may need to avoid Fluconazole.

Caution or avoidance should take place if taking fluconazole with the following medicines: 

• Certain immunosuppressants
• Blood thinning medications 
• Corticosteroids 
• Fluoroquinolone
• Macrolide antibiotics
• Antipsychotic medications
• Narcotic pain relievers 
• Statins
• Other azole antifungal medicine
• Heart medications used to manage medical conditions associated with irregular heartbeats 

It’s important to be aware of fluconazole interactions as other drugs and foods can cause serious side effects and serious medical problems requiring immediate medical attention. 

Consult a healthcare professional or a pharmacist for medical advice before initiating fluconazole to review potential drug interactions and determine the best treatment if alternatives are necessary. 

Related: Fluconazole side effects and how to avoid them

Fluconazole drug interactions

The most serious medications that fluconazole interferes with include:

• Certain antiarrhythmics 
• Antifungal medicines
• Fluoroquinolone and 
• Macrolide antibiotics
• Anti-rejection medications 
• Corticosteroids 
• Statins
• Analgesics
• Blood thinning medications. 

Fluconazole can inhibit the metabolism of different medicines from the body by inhibiting the enzyme CYP3A4. CYP3A4 inhibitors are a class of medications that inhibit the activity of a common subtype of an enzyme (cytochrome P450) involved in the metabolism of many medications into inactive forms that the body goes on to eliminate. Inhibition of CYP3A4 can result in increased blood concentrations of other medications that require metabolism through this same route. Serious medical problems may result depending on the concomitant medication whose metabolism is inhibited. Fluconazole can also impact cardiac conduction, resulting in QT prolongation. When taken with other medications with QTc-prolonging potential, the additive effects can be deadly. 

QTc prolonging agents

Fluconazole may enhance the QTc-prolonging effect of other QTc-prolonging medications with a single dose, which can result in life-threatening heart rhythm patterns like torsades de pointes. The QT interval is the part of an electrocardiogram (EKG) report that represents the time it takes the heart to contract and recover. Long QT syndromes can be inherited and are the result of an issue with the heart’s electrical conduction such that it takes longer than normal to recharge between heartbeats, which is due to an issue with ion channels or the flow of ions (sodium, calcium, potassium, and chloride) in and out of heart muscle cells to produce electrical activity, resulting in an irregular heartbeat. Medications can cause acquired long QT syndrome. 

Prolonging the QT interval increases the risk of irregular heartbeats, such as ventricular tachycardias, which can result in cardiac arrest and sudden death due to the heart’s inability to pump blood throughout the body effectively. 

The class of drugs that can independently prolong the QTc interval are listed below. 

Antiarrhythmic medications, including:

• Class IA antiarrhythmics, including:
  • Disopyramide
  • Procainamide
  • Quinidine
• Class III antiarrhythmics, including:
  • Amiodarone
  • Dofetilide
  • Dronaderone
  • Ibutilide
  • Sotalol
• Miscellaneous antiarrhythmics, including:
  • Digoxin

Fluoroquinolone antibiotics, including:

• Ciprofloxacin
• Delafloxacin
• Levofloxacin
• Moxifloxacin

Macrolide antibiotics, including:

• Azithromycin
• Clarithromycin
• Erythromycin

Azole antifungals, including:

• Ketoconazole
• Isavuconazole
• Posaconazole
• Itraconazole
• Voriconazole

Antipsychotics, including:

• Pimozide
• Ziprasidone

In addition to possible additive QTc prolongation, the CYP3A4 inhibition of fluconazole may also increase the serum concentration of these medications that are dependent on metabolism by this route. This further exacerbates the risk of arrhythmias. Alternatives to these combinations should be considered whenever possible. Additional risk factors, including older adults, female gender, low levels of potassium or magnesium, and a medical history of heart problems, increase the risk of QTc prolongation. 

Clinical trials characterizing risks of the combination are limited, but there is substantial evidence regarding the individual drugs causing QTc prolongation or torsades de pointes (TdP). Combined use of drugs that prolong QTc interval raises the concern for further increased risk of serious toxicities, with at least one study demonstrating that the use of an additional QT-prolonging drug is the most common risk factor among patients with QTc prolongation. The magnitude of the risk is also dependent upon the specific drugs and doses used.

Doctors should closely monitor the QTc interval prolongation if concomitant use is necessary. Symptoms of QTc interval prolongation could include the sensation of heart palpitations and a sensation of severe dizziness and fainting. Unfortunately, more serious effects could occur from QTc interval prolongation, including seizure-like activity or sudden cardiac arrest. 

To prevent this, consider alternatives to fluconazole. The selection of alternatives to fluconazole is heavily dependent upon the infection being managed. Topical antifungals with minimal systemic absorption may be considered for vulvovaginal candidiasis, whereas echinocandins (only available intravenously) could be considered for more serious infections like systemic candidiasis. 

Immunosuppressants

Immunosuppressants like cyclosporine, tacrolimus, and sirolimus are medications used in multiple conditions, such as aplastic anemia, bone marrow transplant recipients, graft-versus-host disease, psoriasis, and others. Fluconazole inhibits the metabolism of these agents, increasing their serum concentrations, which can have serious side effects. Increased cyclosporine exposure can result in side effects like kidney failure and liver damage. Due to the interaction with cyclosporine, the general recommendation is to conduct blood tests to monitor for increased cyclosporine concentrations when combined with fluconazole. The dose of cyclosporine could then be modified, likely decreased, to maintain goal levels. Similarly, when a patient is on the combination and fluconazole is discontinued, cyclosporine levels should be monitored closely for the need to increase the dose without this ongoing interaction. 

Fluconazole can also increase the blood levels of tacrolimus and sirolimus by inhibiting CYP3A4. Coadministration with tacrolimus and fluconazole doses of more than 100 mg per day will require a dose reduction of tacrolimus and sirolimus by up to 75% to maintain safe blood levels of these immunosuppressants. Supratherapeutic serum concentrations of tacrolimus and sirolimus can also result in serious side effects like renal injury, infections, and secondary malignancies like skin cancer.

Corticosteroids

Fluconazole, as a moderate CYP3A4 inhibitor, can decrease the metabolism of corticosteroids and, therefore, increase their blood levels and an individual’s overall exposure if taken concomitantly. This interaction can increase the risk of adverse corticosteroid effects, and a healthcare provider should employ increased monitoring of such side effects in any person receiving this combination. Side effects to monitor increased mood changes, insomnia, high blood sugars, and increased blood pressure. 

Corticosteroids dependent on CYP3A4 metabolism include:

• Dexamethasone
• Methylprednisolone 
• Prednisolone 
• Prednisone

Analgesics

Certain pain medications can interact with fluconazole through the same mechanisms already discussed—CYPA3A4 inhibition or additive QTc-prolonging potential. Fentanyl is one such pain medication that interacts with fluconazole via inhibition of CYP3A4-mediated fentanyl metabolism. Fentanyl doses should be reduced in the setting of a concomitant CYP3A4 inhibitor until the effects of the combination are known to maintain constant levels of fentanyl in the body. Symptoms of excess fentanyl levels include respiratory depression and excess sedation. Likewise, suppose someone is using both fentanyl and fluconazole. In that case, close observation is necessary for signs of withdrawal upon discontinuing fluconazole, and there might be a need to adjust the fentanyl dosage. 

Methadone is another pain medication that may increase the risk of QT prolongation with QT-prolonging CYP3A4 inhibitors like fluconazole. The product labeling for methadone strongly advises exploring alternative options instead of using a combination of these two medications. If no alternatives exist, a doctor should educate the individual to monitor for symptoms of increased methadone toxicities, including respiratory depression. 

Anticoagulants

Warfarin, a Vitamin K Antagonist, is a blood thinning medication used in cardiac conditions like atrial fibrillation (afib) and in managing acute venous thromboembolism (VTE), otherwise known as blood clots. The use of warfarin comes with a risk of bleeding, which is why regularly performed monitoring of the international normalized ratio (INR) with goal ranges established based on indication should be performed. Many medications and changes in diet can interact with warfarin, causing changes to a person’s INR, which is a measure of how long it takes blood to clot (e.g., the higher the INR, the longer it will take for clotting to occur, meaning the more at risk of a significant bleed). 

When a person is on a combination of warfarin and fluconazole, close monitoring of the effect on the INR is recommended, with a gradual reduction in the warfarin dose when fluconazole is initiated. The mechanism of this interaction is due to fluconazole inhibition of CYP3A4 and another isoenzyme known as CYP2C9, which are primarily responsible for warfarin metabolism. 

Other anticoagulants that depend on CYP3A4 for their metabolism and thus interact with fluconazole, resulting in increased levels of these blood thinners, include apixaban (Eliquis) and rivaroxaban (Xarelto). A doctor should monitor patients on one of these agents with fluconazole for increased bleeding. If patients have decreased kidney function, it is best to avoid the combination entirely. Doctors or other health care providers should provide education about the need to immediately report any signs or symptoms of possible bleeding and seek medical help. 

Statins

Azole antifungals can increase the plasma concentrations of statins that metabolize CYP3A4, including atorvastatin, lovastatin, and simvastatin. Concomitant administration with an azole such as fluconazole can result in myopathy or rhabdomyolysis. Management of fluconazole interactions with this group of medications includes reducing the statin dose while receiving the azole antifungal or switching the statin to one not as associated with CYP interactions, such as pravastatin. 

Fluconazole food interactions

The presence or absence of food in the gastrointestinal tract can impact exposure to azole antifungals when dosing. Voriconazole is best absorbed on an empty stomach, while posaconazole exposure is optimized with a fatty meal or nutritional supplement. Fluconazole absorption is fortunately not affected by food.

Fluconazole and grapefruit 

Grapefruit juice may increase the amount of a drug available in the body by decreasing the way the body breaks down or metabolizes the medication. Grapefruit interacts with many prescription drugs, and when consumed with fluconazole, it can further increase the risk of drug interactions. Grapefruit juice inhibits CYP3A4, so the inhibition may be additive when taken concomitantly with fluconazole. If fluconazole and grapefruit juice are consumed with another medication that requires metabolism to an inactive form via CYP3A4, its blood levels and potential side effects could increase. Without definitive research to show that grapefruit juice is safe, limiting or avoiding grapefruit juice when taking fluconazole minimally to ensure a consistent intake is important, especially if receiving other medications metabolized by CYP3A4. 

Other fluconazole interactions

Fluconazole is metabolized almost exclusively by the liver, so consumption of other medications or substances requiring hepatic metabolism can be problematic, and individuals should be monitored closely for the development of liver injury. Fluconazole should also be used cautiously in certain patient populations, as outlined below. 

Fluconazole and alcohol 

There is no contraindication to consuming alcoholic drinks while taking fluconazole. However, the combination may strain the liver as both fluconazole and alcohol are hepatically metabolized and can, therefore, strain the liver. Alcohol consumption while receiving fluconazole should be in moderation. 

Fluconazole and pregnancy or breastfeeding

Fluconazole should be avoided in women at a minimum during the first trimester of pregnancy because of the risk of side effects to the unborn baby. There remains some concern about spontaneous abortion when pregnant women consume fluconazole up to week 22 of gestation. Women and their healthcare providers should carefully weigh the risks and benefits of fluconazole during pregnancy. Similarly, healthcare providers should exercise caution when administering fluconazole to breastfeeding mothers, as the drug is present in breast milk. Breastfeeding women prescribed fluconazole should openly communicate the risks and benefits, or possible alternatives, with their medical provider. 

Fluconazole and special patient populations

Older adult patients should use azole antifungals like fluconazole cautiously, ensuring they employ the appropriate dose based on their kidney function, which often diminishes in older age. Similarly, fluconazole should be dose-adjusted and monitored in individuals with kidney or serious liver disease. Apart from the heightened risk of drug accumulation caused by organ function changes, the situation can be worsened by interactions between drugs, leading to severe side effects. There is no restriction on fluconazole use in children. 

How to minimize fluconazole interactions

Always carry a complete list of medications, including those that are non-prescription, on your person. Any time you’re receiving medical advice with new therapy recommendations, provide this list so that your doctor can perform a thorough review and drug information assessment to minimize the risk of drug interactions. Whenever initiating a new medication and new signs or symptoms arise, it’s best to review them with your healthcare professional for any potential risks with this medicine. 

When to talk to a healthcare provider about fluconazole interactions

This article is not a complete list of fluconazole interactions or possible side effects. Be mindful of the risk of side effects and direct drug interactions, which may occur when taking fluconazole in combination with other prescription and over-the-counter medications or supplements. 

Directly communicate with a healthcare professional when needing fluconazole, including a single dose for vaginal yeast infections. Communication ensures a thorough review of interactions, including medications, diet, and conditions, for an effective monitoring plan.