Does Diflucan (fluconazole) cause side effects?

Diflucan (fluconazole) is an antifungal medication used to treat vaginal, oral, and esophageal fungal infections caused by Candida. 

It is used for treating uncomplicated, complicated, or recurrent vaginal Candida infections. Diflucan also may be effective in treating urinary tract infections (UTIs), peritonitis, pneumonia and disseminated infections caused by Candida. 

Diflucan is also used to treat cryptococcal meningitis, and prevention of Candida infections in patients treated with chemotherapy or radiation after bone marrow transplantation. Diflucan prevents growth of fungi by preventing production of the membranes that surround fungal cells.

Common side effects of Diflucan include

Serious side effects of Diflucan include

  • seizures,
  • reduced white blood cells,
  • reduced blood platelets,
  • toxic epidermal necrolysis,
  • liver dysfunction (jaundice, hepatitis),
  • abnormal heartbeats, and
  • Stevens-Johnson syndrome.

Rarely, serious allergic reactions, including angioedema (swelling of tissues), may also occur. 

Drug interactions of Diflucan include hydrochlorothiazide, which increases the blood concentration of Diflucan by 40%.

There are no adequate studies of Diflucan in pregnant women. There are reports of harmful effects to the fetus when high dose Diflucan was administered to pregnant women for a few months. Use of Diflucan during pregnancy is not recommended. 

Diflucan is secreted in breast milk at concentrations similar to the mother's blood level. However, Diflucan is used for treating neonates with fungal infections and for treating lactation associated Candida infections. Available evidence suggests that use of Diflucan during breastfeeding has little risk.

What are the important side effects of Diflucan (fluconazole)?

Common side effects of fluconazole include

Other important side effects include

Possible serious side effects include

  • seizures,
  • reduced number of white blood cells,
  • reduced number of blood platelets, and
  • toxic epidermal necrolysis.

Rarely, serious allergic reactions, including angioedema (swelling of tissues), may also occur. Liver dysfunction (jaundice, hepatitis) and abnormal heart beats have been associated with fluconazole. Stevens-Johnson syndrome has also been reported.

Diflucan (fluconazole) side effects list for healthcare professionals

  • Diflucan is generally well tolerated.
  • In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.

In Patients Receiving A Single Dose For Vaginal Candidiasis

  • During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with Diflucan, 150 mg single dose.
  • The overall incidence of side effects possibly related to Diflucan was 26%.
  • In 422 patients receiving active comparative agents, the incidence was 16%.
  • The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were
  • Other side effects reported with an incidence equal to or greater than 1% included
    • diarrhea (3%),
    • dyspepsia (1%),
    • dizziness (1%), and
    • taste perversion (1%).
  • Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience.

In Patients Receiving Multiple Doses For Other Infections

  • Sixteen percent of over 4000 patients treated with Diflucan (fluconazole) in clinical trials of 7 days or more experienced adverse events.
  •  Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities.
  • Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar.
  • The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%).
  • The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving Diflucan for 7 or more days in clinical trials:
    • nausea 3.7%,
    • headache 1.9%,
    • skin rash 1.8%,
    • vomiting 1.7%,
    • abdominal pain 1.7%, and
    • diarrhea 1.5%.
Hepato-Biliary
  • In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with Diflucan.
  • The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities.
  • Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications.
  • Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of Diflucan.
  • In two comparative trials evaluating the efficacy of Diflucan for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials.
  • These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic.
  • The incidence of abnormally elevated serum transaminases was greater in patients taking Diflucan concomitantly with one or more of the following medications:

Post-Marketing Experience

In addition, the following adverse events have occurred during post-marketing experience.

  • Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported.
  • Body as a Whole: Asthenia, fatigue, fever, malaise.
  • Cardiovascular: QT prolongation, torsade de pointes.
  • Central Nervous System: Seizures, dizziness.
  • Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia.
  • Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia.
  • Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting.
  • Other Senses: Taste perversion.
  • Musculoskeletal System: myalgia.
  • Nervous System: Insomnia, paresthesia, somnolence, tremor, vertigo.
  • Skin and Appendages: Acute generalized exanthematous pustulosis, drug eruption including fixed drug eruption, increased sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), alopecia.

Adverse Reactions In Children

  • The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults.
  • In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with Diflucan at doses up to 15 mg/kg/day for up to 1,616 days.
  • Thirteen percent of children experienced treatment-related adverse events.
  • The most commonly reported events were
    • vomiting (5%),
    • abdominal pain (3%),
    • nausea (2%), and
    • diarrhea (2%).
  • Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities.
  • The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase.

Percentage of Patients With Treatment-Related Side Effects

  Fluconazole
(N=577)
Comparative Agents
(N=451)
With any side effect 13.0 9.3
Vomiting 5.4 5.1
Abdominal pain 2.8 1.6
Nausea 2.3 1.6
Diarrhea 2.1 2.2

What drugs interact with Diflucan (fluconazole)?

  • Fluconazole is a moderate CYP2C9 and CYP3A4 inhibitor. Fluconazole is also a strong inhibitor of CYP2C19.
  • Patients treated with Diflucan, who are also concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4, should be monitored for adverse reactions associated with the concomitantly administered drugs.
  • In addition to the observed /documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 coadministered with fluconazole.
  • Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored.
  • The enzyme inhibiting effect of fluconazole persists 4 to 5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole.
  • Clinically or potentially significant drug interactions between Diflucan and the following agents/classes have been observed and are described in greater detail below:

Alfentanil

  • A study observed a reduction in clearance and distribution volume as well as prolongation of t½ of alfentanil following concomitant treatment with fluconazole.
  • A possible mechanism of action is fluconazole’s inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.

Amiodarone

  • Concomitant administration of fluconazole with amiodarone may increase QT prolongation.
  • Caution must be exercised if the concomitant use of fluconazole and amiodarone is necessary, notably with high-dose fluconazole (800 mg).

Amitriptyline, Nortriptyline

  • Fluconazole increases the effect of amitriptyline and nortriptyline. 5-Nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after 1 week.
  • Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.

Amphotericin B

  • Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with Candida albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus.
  • The clinical significance of results obtained in these studies is unknown.

Astemizole

  • Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole.
  • Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes.
  • Coadministration of fluconazole and astemizole is contraindicated.

Azithromycin

  • An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin.
  • There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Calcium Channel Blockers

  • Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil, and felodipine) are metabolized by CYP3A4.
  • Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists.
  • Frequent monitoring for adverse events is recommended.

Carbamazepine

  • Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed.
  • There is a risk of developing carbamazepine toxicity.
  • Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect.

Celecoxib

  • During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the celecoxib Cmax and AUC increased by 68% and 134%, respectively.
  • Half of the celecoxib dose may be necessary when combined with fluconazole.

Cisapride

  • There have been reports of cardiac events, including torsade de pointes, in patients to whom fluconazole and cisapride were coadministered.
  • A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval.
  • The combined use of fluconazole with cisapride is contraindicated.

Coumarin-Type Anticoagulants

  • Prothrombin time may be increased in patients receiving concomitant Diflucan and coumarin-type anticoagulants.
  • In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin.
  • Careful monitoring of prothrombin time in patients receiving Diflucan and coumarin-type anticoagulants is recommended.
  • Dose adjustment of warfarin may be necessary.

Cyclophosphamide

  • Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine.
  • The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.

Cyclosporine

  • Diflucan significantly increases cyclosporine levels in renal transplant patients with or without renal impairment.
  • Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving Diflucan and cyclosporine.
  • This combination may be used by reducing the dosage of cyclosporine depending on cyclosporine concentration.

Fentanyl

  • One fatal case of possible fentanyl-fluconazole interaction was reported.
  • The author judged that the patient died from fentanyl intoxication.
  • Furthermore, in a randomized crossover study with 12 healthy volunteers, it was shown that fluconazole delayed the elimination of fentanyl significantly.
  • Elevated fentanyl concentration may lead to respiratory depression.

Halofantrine

  • Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.

HMG-CoA Reductase Inhibitors

  • The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin.
  • If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored.
  • HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.

Hydrochlorothiazide

  • In a pharmacokinetic interaction study, coadministration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%.
  • An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics.

Losartan

  • Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan.
  • Patients should have their blood pressure monitored continuously.

Methadone

  • Fluconazole may enhance the serum concentration of methadone.
  • Dosage adjustment of methadone may be necessary.

Non-Steroidal Anti-Inflammatory Drugs

  • The Cmax and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone.
  • Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.
  • Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other non-steroidal anti-inflammatory drugs (NSAIDs) that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac).
  • Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.

Olaparib

  • Moderate inhibitors of CYP3A4 such as fluconazole increase olaparib plasma concentrations; concomitant use is not recommended. If the combination cannot be avoided, reduce the dose of olaparib as instructed in the Lynparza (Olaparib) Prescribing Information.

Oral Contraceptives

  • Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole.
  • There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively.
  • Thus, multiple-dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.

Oral Hypoglycemics

  • Clinically significant hypoglycemia may be precipitated by the use of Diflucan with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined Diflucan and glyburide use.
  • Diflucan reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents.
  • When Diflucan is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary.

Phenytoin

  • Diflucan increases the plasma concentrations of phenytoin.
  • Careful monitoring of phenytoin concentrations in patients receiving Diflucan and phenytoin is recommended.

Pimozide

  • Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism.
  • Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes.
  • Coadministration of fluconazole and pimozide is contraindicated.

Prednisone

  • There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a 3 month therapy with fluconazole was discontinued.
  • The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone.
  • Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.

Quinidine

  • Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism.
  • Use of quinidine has been associated with QT prolongation and rare occurrences of torsade de pointes.
  • Coadministration of fluconazole and quinidine is contraindicated.

Rifabutin

  • There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%.
  • There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered.
  • Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored.

Rifampin

  • Rifampin enhances the metabolism of concurrently administered Diflucan.
  • Depending on clinical circumstances, consideration should be given to increasing the dose of Diflucan when it is administered with rifampin.

Saquinavir

  • Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by approximately 55%, and decreases the clearance of saquinavir by approximately 50% due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein.
  • Dosage adjustment of saquinavir may be necessary.

Short-Acting Benzodiazepines

  • Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects.
  • This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously.
  • If short-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored.

Sirolimus

  • Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein.
  • This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements.

Tacrolimus

  • Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines.
  • No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously.
  • Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.

Terfenadine

  • Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed.
  • One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval.
  • Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that Diflucan taken in doses of 400 mg/day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
  • The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated.
  • The coadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored.

Theophylline

  • Diflucan increases the serum concentrations of theophylline.
  • Careful monitoring of serum theophylline concentrations in patients receiving Diflucan and theophylline is recommended.

Tofacitinib

  • Systemic exposure to tofacitinib is increased when tofacitinib is coadministered with fluconazole.
  • Reduce the dose of tofacitinib when given concomitantly with fluconazole (i.e., from 5 mg twice daily to 5 mg once daily as instructed in the Xeljanz [tofacitinib] label).

Triazolam

  • Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20% to 32%, and increases t½ by 25% to 50 % due to the inhibition of metabolism of triazolam.
  • Dosage adjustments of triazolam may be necessary.

Vinca Alkaloids

  • Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.

Vitamin A

  • Based on a case report in one patient receiving combination therapy with all-transretinoid acid (an acid form of vitamin A) and fluconazole, central nervous system (CNS) related undesirable effects have developed in the form of pseudotumor cerebri, which disappeared after discontinuation of fluconazole treatment.
  • This combination may be used but the incidence of CNS related undesirable effects should be borne in mind.

Voriconazole

  • Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is recommended; especially, if voriconazole is started within 24 h after the last dose of fluconazole.

Zidovudine

  • Fluconazole increases the Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an approximately 45% decrease in oral zidovudine clearance.
  • The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole.
  • Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.
  • Dosage reduction of zidovudine may be considered.
  • Physicians should be aware that interaction studies with medications other than those listed in the prescribing information have not been conducted, but such interactions may occur.

Summary

Diflucan (fluconazole) is an antifungal medication used to treat vaginal, oral, and esophageal fungal infections caused by Candida. Common side effects of Diflucan include headache, nausea, abdominal pain, diarrhea, indigestion/heartburn, dizziness, reduced blood levels of potassium, rash, and taste disturbance. Use of Diflucan during pregnancy is not recommended. Available evidence suggests that use of Diflucan during breastfeeding has little risk.

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Medically Reviewed on 2/5/2021
References
FDA Prescribing Information

Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.