CONTRAINDICATIONS / PRECAUTIONS
Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, females, fever, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)
Fluconazole should be administered cautiously in patients with potentially proarrhythmic conditions, including a history of torsade de pointes. Some azole antifungals, including fluconazole, have been associated with QT prolongation. During post-marketing surveillance, rare cases of QT prolongation and torsade de pointes have been reported with fluconazole use. These reports have included seriously ill patients with multiple confounding risk factors that may have been contributory, such as structural cardiac disease, electrolyte imbalance, and concomitant medications that could be associated with proarrhythmic conditions. Fluconazole is not likely to cause QT prolongation or torsade de pointes when administered at usual therapeutic dosages. Use fluconazole with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.
Hepatic disease
Fluconazole can be hepatotoxic and should be used with caution in patients with preexisting hepatic disease. The related azole, ketoconazole, also has been associated with hepatotoxicity. Liver-function tests should be monitored. If signs and symptoms of hepatotoxicity develop, fluconazole therapy should be stopped.
Renal failure, renal impairment
Approximately 60 to 80% of fluconazole is renally excreted. Dose reduction or extension of the dosing interval is indicated in patients with renal impairment or renal failure.
Pregnancy
Avoid the use of fluconazole during pregnancy except in patients with severe or potentially life-threatening fungal infections in whom fluconazole may be used if the potential benefit outweighs the possible risk to the fetus. No adequate and well-controlled studies have been conducted in pregnant women; however, a few case reports have described a pattern of distinct congenital anomalies in infants born to women exposed to high dose fluconazole (400 to 800 mg/day) during the first trimester.[28674] The features observed in fluconazole-exposed infants included brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. The nature of these birth defects suggests that the teratogenic effect may occur early in the first trimester.[26025] Additionally, retrospective epidemiological studies suggest a potential association between the use of low-dose fluconazole (i.e., 150 mg) and increased risk of birth defects and spontaneous abortions.[60495] [60789] Data from the National Birth Defects Prevention Study found an association between maternal exposure to low-dose fluconazole in the first trimester and both cleft lip with cleft palate and d-transposition of the great arteries. Of the 43,247 mothers analyzed, 44 case mothers and 6 control mothers were identified. The majority of cases (n =36/50; 72%) reported taking fluconazole for vaginal candidiasis and almost all (n = 49/50) reported taking fluconazole for a short duration. Six exposed infants had cleft lip with cleft palate, 4 had an atrial septal defect, and each of the following defects had 3 exposed cases: hypospadias, tetralogy of Fallot, d-transposition of the great arteries, and pulmonary valve stenosis. Fluconazole use was associated with a significant risk for cleft lip with cleft palate (OR 5.53; 95% CI, 1.68 to 18.24) and d-transposition of the great arteries (OR 7.56; 95% CI, 1.22 to 35.45). The increases for the other conditions were not statistically significant.[60789] A large population-based cohort study of U.S. Medicaid data found oral fluconazole use during the first trimester to be associated with musculoskeletal malformations but not with oral clefts or conotruncal malformations. This cohort included 1,969,954 pregnancies, with 37,650 pregnancies exposed to oral fluconazole and 82,090 exposed to topical azoles during the first trimester. The unadjusted relative risk for musculoskeletal malformations with fluconazole vs. unexposed pregnancies was 1.37 (95% CI, 1.19 to 1.58). When comparing oral fluconazole with topical azoles, the unadjusted relative risk for musculoskeletal malformations was 1.4 (95% CI, 1.17 to 1.67). A subanalysis found a 30% increase in risk for musculoskeletal malformations for cumulative fluconazole doses of 150 to 450 mg and an almost 2-fold increase in risk for cumulative doses more than 450 mg. Malformations were defined as deformities of the skull/face/jaw, feet, and/or spine.[65469] A nationwide Danish cohort study also found an association between maternal exposure to oral fluconazole, including doses used to treat vaginal candidiasis, during gestational weeks 7 through 22 and spontaneous abortions. Specifically, 147 spontaneous abortions were reported among 3,315 fluconazole-treated women, as compared to 563 spontaneous abortions among the 13,246 unexposed matched control pregnancies. Of these 147 spontaneous abortions, 132 were reported in pregnancies exposed to a fluconazole dose of 150 to 300 mg (n = 2,986 fluconazole-treated women). These data indicate a statistically significant increase in risk for spontaneous abortion with maternal exposure to fluconazole during gestational weeks 7 through 22 (HR, 1.48; 95% CI, 1.23 to 1.77).[60495] Topical antifungals, administered for a longer duration in persistent or recurrent infections, are recommended for the treatment of vaginal candidiasis during pregnancy.[60741] Guidelines for the prevention of opportunistic infections in HIV patients recommend that oral azole antifungals, including fluconazole, not be started during pregnancy and that these agents should be discontinued in HIV-positive women who become pregnant.[34362] If fluconazole is administered during pregnancy, or if a patient becomes pregnant while taking fluconazole, advise the patient of the potential hazard to the infant.[28674]
Breast-feeding
Use caution when fluconazole is administered to a breast-feeding woman.[28674] Previous American Academy of Pediatrics (AAP) recommendations considered fluconazole as usually compatible with breast-feeding.[27500] Fluconazole is distributed in human breast milk at concentrations similar to those in the plasma. A case report found breast milk to plasma ratios of 0.46, 0.85, 0.85, and 0.83 at 2, 5, 24, and 48 hours after a single 150 mg dose of fluconazole.[46093] Experts have estimated, based on limited data of concentrations in breast milk, that an exclusively breast-fed infant whose mother was receiving fluconazole 200 mg daily would receive a maximum dose of 0.6 mg/kg/day. This is equivalent to 60% of the recommended dose for thrush in newborns younger than 2 weeks of age and 20% of the recommended dose for older newborns and infants.[46094] Another study determined the daily infant fluconazole dose from breast milk (assuming mean milk consumption of 150 mL/kg/day) based on the mean peak milk concentration (2.61 mcg/mL [range: 1.57 to 3.65 mcg/mL] at 5.2 hours post-dose) to be 0.39 mg/kg/day, which is approximately 13% of the recommended pediatric dose for oropharyngeal candidiasis.[28674] Fluconazole has been used successfully to treat mastitis due to yeast resistant to other therapies in breast-feeding mothers.[46095] [46096]
Azole antifungals hypersensitivity
Fluconazole should be used with caution in patients with azole antifungals hypersensitivity. Fluconazole may have a cross sensitivity with other azole derivatives.
Neonates
Fluconazole is approved for all pediatric populations. The safety of fluconazole has been studied in children ages 1 day to 17 years; however, experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. Several studies have shown fluconazole to be effective in treating oropharyngeal candidiasis in children 6 months to 13 years. Fluconazole has also been shown effective in treating serious systemic fungal infections and for suppression of cryptococcal meningitis; there is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children. Pharmacokinetic studies in children have established dose proportionality between children and adults.
Geriatric
Controlled clinical trials of fluconazole did not include sufficient numbers of geriatric patients (65 years of age and older) to evaluate whether they respond differently from younger adults in each indication. Other reported clinical experience has not identified differences in responses between older adult and younger adult patients. Since fluconazole is primarily cleared renally and geriatric patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance. It may also be useful to monitor renal function. Systemic fluconazole can prolong the QT interval. Geriatric patients may be at increased risk for QT prolongation and for serious drug-drug interactions that may increase the risk QT prolongation risk or may increase the risk for other serious side effects. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, systemic azole antifungals should be used in the lowest possible dose for the shortest possible duration, particularly in patients receiving other medications known to interact with these medications. Increased monitoring may be required to identify and minimize the toxicity of warfarin, phenytoin, theophylline, or sulfonylureas when an azole antifungal is co-administered; other medications such as rifampin and cimetidine may decrease the therapeutic effect of the antifungal. Some drug-drug combinations may be contraindicated. OBRA guidelines caution that azole antifungals may cause hepatotoxicity, headaches, and GI distress.
Driving or operating machinery
Fluconazole may rarely cause dizziness or seizures. Patients should use caution when driving or operating machinery until they are aware of the effects of the drug.
Serious rash
Serious rash, including exfoliative skin disorders such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients receiving treatment with fluconazole. According to the manufacturer, fluconazole-associated dermatologic adverse events have resulted in fatal outcomes for patients with serious underlying diseases. Monitor drug recipients for development of rash. If a rash is observed on a patient being treated for a superficial fungal infection, and the rash is attributed to fluconazole, immediately discontinue use of the drug. However, if a rash develops on a patient being treated for a deep seated fungal infection, the patients should be closely monitored, and the drug discontinued if the lesion progresses.
Contraception requirements, reproductive risk
Fluconazole may be associated with reproductive risk. Discuss contraception requirements with the patient. Consider effective contraceptive measures for women of child-bearing potential who are receiving high dose fluconazole (i.e., 400 to 800 mg/day), and continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose.
DRUG INTERACTIONS
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) During concomitant administration with fluconazole, the clearance of zidovudine may be reduced. Although the clinical significance of this interaction has not been established, patients receiving fluconazole with zidovudine should be closely monitored for zidovudine-induced adverse effects, especially hematologic toxicity. Zidovudine dosage reduction may be considered.
Abarelix: (Major) Separately both fluconazole and abarelix have been associated with QT prolongation. If fluconazole and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation and torsade de pointes.
Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with fluconazole is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
Abrocitinib: (Major) Avoid coadministration of abrocitinib with fluconazole as the combined exposure of abrocitinib and its 2 active metabolites may be increased, which may increase the risk for adverse reactions. Abrocitinib is a substrate of CYP2C19 and CYP2C9; fluconazole is a strong inhibitor of CYP2C19 and a moderate CYP2C9 inhibitor.
Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with fluconazole. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined.
Acetaminophen; Caffeine: (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with fluconazole may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fluconazole is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined.
Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined.
Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with fluconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluconazole is a moderate inhibitor of CYP3A4.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If fluconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. If fluconazole is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like fluconazole can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If fluconazole is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Acetohexamide: (Moderate) Fluconazole should be used cautiously with oral sulfonylureas because blood glucose response may be altered in diabetic patients. In some cases, dosage adjustment of the sulfonylurea may be necessary.
Alfentanil: (Moderate) Fluconazole may decrease the systemic clearance of alfentanil. Prolonged duration of opiate action, increased sedation, respiratory depression or other opiate side effects may occur. Close monitoring of patients is warranted.
Alfuzosin: (Contraindicated) Due to the risk of life-threatening arrhythmias such as torsade de pointes (TdP), coadministration of fluconazole with drugs that both prolong the QT interval and are CYP3A4 substrates, such as alfuzosin, is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of TdP. Additonally, fluconazole is an inhibitor of CYP3A4. Coadministration may result in elevated plasma concentrations of alfuzosin, causing an increased risk for adverse events, such as QT prolongation.
Aliskiren; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fluconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Hydrochlorothiazide may decrease the renal clearance of fluconazole. Coadministration of fluconazole 100 mg PO and hydrochlorothiazide 50 mg PO for 10 days in normal volunteers (n=13) resulted in a significant increase in fluconazole AUC and Cmax compared to fluconazole given alone. There was a mean +/- SD increase in fluconazole AUC and Cmax of 45 +/- 31% and 43 +/- 31%, respectively. These changes are attributed to a mean +/- SD reduction in fluconazole renal clearance of 30% +/- 12%. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fluconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Hydrochlorothiazide may decrease the renal clearance of fluconazole. Coadministration of fluconazole 100 mg PO and hydrochlorothiazide 50 mg PO for 10 days in normal volunteers (n=13) resulted in a significant increase in fluconazole AUC and Cmax compared to fluconazole given alone. There was a mean +/- SD increase in fluconazole AUC and Cmax of 45 +/- 31% and 43 +/- 31%, respectively. These changes are attributed to a mean +/- SD reduction in fluconazole renal clearance of 30% +/- 12%.
Alprazolam: (Major) Avoid coadministration of alprazolam and fluconazole due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with fluconazole, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased alprazolam exposure by 1.6- to 1.98-fold.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Hydrochlorothiazide may decrease the renal clearance of fluconazole. Coadministration of fluconazole 100 mg PO and hydrochlorothiazide 50 mg PO for 10 days in normal volunteers (n=13) resulted in a significant increase in fluconazole AUC and Cmax compared to fluconazole given alone. There was a mean +/- SD increase in fluconazole AUC and Cmax of 45 +/- 31% and 43 +/- 31%, respectively. These changes are attributed to a mean +/- SD reduction in fluconazole renal clearance of 30% +/- 12%.
Amiodarone: (Contraindicated) Avoid concomitant use of amiodarone and fluconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase amiodarone exposure and the risk for other amiodarone-related adverse effects; amiodarone is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with fluconazole. Amisulpride causes dose- and concentration- dependent QT prolongation. Fluconazole has been associated with QT prolongation and rare cases of TdP.
Amitriptyline: (Minor) Fluconazole should be administered together with TCAs with caution. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, fluconazole has been reported to increase the effects of amitriptyline, likely via inhibition of the hepatic microsomal CYP2C19 or CYP3A4 isoenzymes. In at least one case, the interaction resulted in an increased incidence of TCA-related side effects, like dizziness and syncope. Monitor for an increased response to amitriptyline if fluconazole is coadministered.
Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fluconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fluconazole is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a CYP3A substrate; fluconazole is a CYP3A inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fluconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fluconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Celecoxib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fluconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure. (Moderate) The dose of celecoxib may need to be reduced in patients receiving fluconazole. Fluconazole significantly inhibits the metabolism of celecoxib via CYP2C9. Fluconazole at 200 mg per day resulted in a two-fold increase in celecoxib plasma concentration after a single 200 mg dose of celecoxib.
Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fluconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fluconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Hydrochlorothiazide may decrease the renal clearance of fluconazole. Coadministration of fluconazole 100 mg PO and hydrochlorothiazide 50 mg PO for 10 days in normal volunteers (n=13) resulted in a significant increase in fluconazole AUC and Cmax compared to fluconazole given alone. There was a mean +/- SD increase in fluconazole AUC and Cmax of 45 +/- 31% and 43 +/- 31%, respectively. These changes are attributed to a mean +/- SD reduction in fluconazole renal clearance of 30% +/- 12%. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fluconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amobarbital: (Minor) Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of fluconazole. Be alert for lack of efficacy of fluconazole in concurrent use.
Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) Coadministration is contraindicated. Fluconazole has been associated with QT prolongation and clarithromycin has been specifically established to have a causal association with QT prolongation and torsade de pointes (TdP). Additionally, fluconazole is an inhibitor of CYP3A4 and clarithromycin is a known inhibitor and substrate of CYP3A4. In healthy volunteers, the coadministration of clarithromycin (500 mg orally twice daily) with fluconazole (200 mg once daily) led to increases in clarithromycin mean steady-state Cmin (33%) and AUC (18%); however, mean steady-state concentrations of 14-OH clarithromycin were not affected. The changes appeared to be of minor consequence in healthy subjects. The potential for a more significant interaction between fluconazole and clarithromycin might exist at higher dosages of either drug; caution is advised in such circumstances but should not normally alter therapy. Fluconazole is usually considered a less potent inhibitor of CYP3A4 than other azole-family systemic antifungal agents (e.g., ketoconazole, itraconazole), especially at dosages of < 200 mg/day. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4.
Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Theoretically, azole antifungals could interfere with the action of amphotericin B by depleting polyene binding sites. Whenever possible, azole antifungals should not be coadministered with amphotericin B until more data are available.
Amphotericin B lipid complex (ABLC): (Moderate) Theoretically, azole antifungals could interfere with the action of amphotericin B by depleting polyene binding sites. Whenever possible, azole antifungals should not be coadministered with amphotericin B until more data are available.
Amphotericin B liposomal (LAmB): (Moderate) Theoretically, azole antifungals could interfere with the action of amphotericin B by depleting polyene binding sites. Whenever possible, azole antifungals should not be coadministered with amphotericin B until more data are available.
Amphotericin B: (Moderate) Theoretically, azole antifungals could interfere with the action of amphotericin B by depleting polyene binding sites. Whenever possible, azole antifungals should not be coadministered with amphotericin B until more data are available.
Amprenavir: (Moderate) Fluconazole inhibits CYP3A4 and is expected to increase amprenavir plasma concentrations, a CYP3A4 substrate .
Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include fluconazole.
Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with fluconazole since concurrent use may increase the risk of QT prolongation. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of fluconazole with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant. After administration, fosaprepitant is rapidly converted to aprepitant. Fluconazole is a moderate CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur.
Aripiprazole: (Contraindicated) Avoid use of aripiprazole with fluconazole unless the benefit outweighs the risk of QT prolongation or other side effects. Conflicting recommendations are available from the manufacturers of the drugs. According to the manufacturer of fluconazole, coadministration of drugs known to prolong the QT interval and which are CYP3A4 substrates, such as aripiprazole, is contraindicated in patients receiving fluconazole. Metabolism of aripiprazole occurs mainly through CYP3A4 and CYP2D6. Both fluconazole and aripiprazole have been associated with QT prolongation. The manufacturers of aripiprazole products do not contraindicate use of fluconazole, but do recommend dosage adjustments of oral aripiprazole when used with CYP3A4 inhibitors such as fluconazole. Manufacturers of aripiprazole injections recommend adjustments when a potent CYP3A4 inhibitor will be used for more than 14 days. See the manufacturer prescribing information for detailed recommendations.
Armodafinil: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as fluconazole are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
Arsenic Trioxide: (Major) Concurrent use of arsenic trioxide and fluconazole should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If possible, fluconazole should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. TdP and complete atrioventricular block have been reported. Fluconazole has also been associated with QT prolongation and rare cases of TdP.
Artemether; Lumefantrine: (Contraindicated) Concomitant administration of fluconazole and lumefantrine is contraindicated. Fluconazole has been associated with QT prolongation and is contraindicated for use with other drugs that both prolong the QT interval and are CYP3A4 substrates, such as lumefantrine. Coadministration of fluconazole with lumefantrine may result in elevated plasma concentrations of lumefantrine, causing an increased risk for adverse events, such as QT prolongation. (Contraindicated) The concomitant administration of fluconazole and artemether is contraindicated. Fluconazole has been associated with QT prolongation and is contraindicated for use with other drugs that both prolong the QT interval and are CYP3A4 substrates, such as artemether. Coadministration of fluconazole with artemether may result in elevated plasma concentrations of artemether as well.
Asenapine: (Contraindicated) Due to the risk of life-threatening arrhythmias such as torsade de pointes (TdP), coadministration of fluconazole with drugs that both prolong the QT interval and are CYP3A4 substrates, such as asenapine, is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of TdP. Additonally, fluconazole is an inhibitor of CYP3A4. Coadministration may result in elevated plasma concentrations of asenapine, causing an increased risk for adverse events such as QT prolongation.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined. (Minor) Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of fluconazole. Be alert for lack of efficacy of fluconazole in concurrent use.
Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with fluconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluconazole is a moderate inhibitor of CYP3A4. (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined. (Minor) Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of fluconazole. Be alert for lack of efficacy of fluconazole in concurrent use.
Aspirin, ASA; Caffeine: (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined.
Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with fluconazole may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fluconazole is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with fluconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluconazole is a moderate inhibitor of CYP3A4.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. If fluconazole is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like fluconazole can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If fluconazole is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with fluconazole as there is a potential for elevated cobicistat concentrations. Fluconazole is a CYP3A4 inhibitor, while cobicistat is a substrate of CYP3A4.
Atomoxetine: (Moderate) Concomitant use of atomoxetine and fluconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fluconazole is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a CYP3A substrate; fluconazole is a CYP3A inhibitor.
Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fluconazole is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a CYP3A substrate; fluconazole is a CYP3A inhibitor.
Avanafil: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving fluconazole. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Avapritinib: (Major) Avoid coadministration of avapritinib with fluconazole due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with fluconazole is predicted to increase the AUC of avapritinib by 210% at steady-state.
Avatrombopag: (Major) In patients with chronic immune thrombocytopenia (ITP), reduce the starting dose of avatrombopag to 20 mg PO 3 times weekly when used concomitantly with fluconazole. In patients starting fluconazole while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inhibitors such as fluconazole increase avatrombopag exposure, increasing the risk of avatrombopag toxicity.
Azelastine; Fluticasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Azithromycin: (Major) Concomitant use of azithromycin and fluconazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Barbiturates: (Minor) Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of fluconazole. Be alert for lack of efficacy of fluconazole in concurrent use.
Beclomethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Bedaquiline: (Major) Caution is advised when administering bedaquiline concurrently with fluconazole due to the risk for increased bedaquiline concentrations and a potential for QT prolongation. Fluconazole may inhibit the CYP3A4 metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval and torsade de pointes (TdP). Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Fluconazole should be used cautiously in patients taking certain ergot alkaloids. Fluconazole may reduce the metabolism of ergot alkaloids via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids. (Minor) Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of fluconazole. Be alert for lack of efficacy of fluconazole in concurrent use.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of fluconazole with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and fluconazole is a CYP2C19 inhibitor.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Hydrochlorothiazide may decrease the renal clearance of fluconazole. Coadministration of fluconazole 100 mg PO and hydrochlorothiazide 50 mg PO for 10 days in normal volunteers (n=13) resulted in a significant increase in fluconazole AUC and Cmax compared to fluconazole given alone. There was a mean +/- SD increase in fluconazole AUC and Cmax of 45 +/- 31% and 43 +/- 31%, respectively. These changes are attributed to a mean +/- SD reduction in fluconazole renal clearance of 30% +/- 12%.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with fluconazole may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of fluconazole in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Fluconazole is an inhibitor of CYP3A4.
Betamethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and fluconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and fluconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Hydrochlorothiazide may decrease the renal clearance of fluconazole. Coadministration of fluconazole 100 mg PO and hydrochlorothiazide 50 mg PO for 10 days in normal volunteers (n=13) resulted in a significant increase in fluconazole AUC and Cmax compared to fluconazole given alone. There was a mean +/- SD increase in fluconazole AUC and Cmax of 45 +/- 31% and 43 +/- 31%, respectively. These changes are attributed to a mean +/- SD reduction in fluconazole renal clearance of 30% +/- 12%.
Boceprevir: (Moderate) Close clinical monitoring is advised when administering fluconazole with boceprevir due to an increased potential for boceprevir-related adverse events. If fluconazole dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of fluconazole and boceprevir. Fluconazole is an inhibitor of the hepatic isoenzyme CYP3A4; boceprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of boceprevir may be elevated.
Bortezomib: (Minor) Fluconazole inhibits CYP3A4 and may increase the exposure to bortezomib and increase the risk for toxicity; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with fluconazole is not known.
Bosentan: (Major) Coadministration of fluconazole with bosentan is not recommended due to the potential for large increases in bosentan exposure. Fluconazole is a CYP3A4 and CYP2C9 inhibitor; bosentan is metabolized by both CYP3A4 and CYP2C9.
Bosutinib: (Major) Avoid concomitant use of bosutinib and fluconazole; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Brigatinib: (Major) Avoid coadministration of brigatinib with fluconazole if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of fluconazole, resume the brigatinib dose that was tolerated prior to initiation of fluconazole. Brigatinib is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of fluconazole. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; fluconazole is a moderate inhibitor of CYP3A4. Administration of bromocriptine with a moderate inhibitor of CYP3A4 increased the bromocriptine mean AUC and Cmax by 3.7-fold and 4.6-fold, respectively.
Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If fluconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If fluconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Budesonide: (Moderate) Avoid coadministration of oral budesonide and fluconazole due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and fluconazole due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of oral budesonide and fluconazole due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine; Epinephrine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and fluconazole may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; fluconazole inhibits CYP3A4. (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with fluconazole is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and fluconazole is a moderate CYP2C9 inhibitor. (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Buprenorphine: (Contraindicated) Avoid concomitant use of fluconazole and buprenorphine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when fluconazole is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping fluconazole, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If fluconazole is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and fluconazole is a CYP3A inhibitor.
Buprenorphine; Naloxone: (Contraindicated) Avoid concomitant use of fluconazole and buprenorphine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when fluconazole is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping fluconazole, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If fluconazole is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and fluconazole is a CYP3A inhibitor.
Butabarbital: (Minor) Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of fluconazole. Be alert for lack of efficacy of fluconazole in concurrent use.
Butalbital; Acetaminophen: (Minor) Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of fluconazole. Be alert for lack of efficacy of fluconazole in concurrent use.
Butalbital; Acetaminophen; Caffeine: (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined. (Minor) Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of fluconazole. Be alert for lack of efficacy of fluconazole in concurrent use.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with fluconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluconazole is a moderate inhibitor of CYP3A4. (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined. (Minor) Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of fluconazole. Be alert for lack of efficacy of fluconazole in concurrent use.
Cabotegravir; Rilpivirine: (Contraindicated) Concurrent use of fluconazole and rilpivirine is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Fluconazole is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of rilpivirine. These drugs used in combination may result in elevated rilpivirine plasma concentrations, causing an increased risk for adverse events, such as QT prolongation. Additionally, fluconazole has been associated with prolongation of the QT interval; do not use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as rilpivirine.
Caffeine: (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined.
Caffeine; Sodium Benzoate: (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Hydrochlorothiazide may decrease the renal clearance of fluconazole. Coadministration of fluconazole 100 mg PO and hydrochlorothiazide 50 mg PO for 10 days in normal volunteers (n=13) resulted in a significant increase in fluconazole AUC and Cmax compared to fluconazole given alone. There was a mean +/- SD increase in fluconazole AUC and Cmax of 45 +/- 31% and 43 +/- 31%, respectively. These changes are attributed to a mean +/- SD reduction in fluconazole renal clearance of 30% +/- 12%.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Hydrochlorothiazide may decrease the renal clearance of fluconazole. Coadministration of fluconazole 100 mg PO and hydrochlorothiazide 50 mg PO for 10 days in normal volunteers (n=13) resulted in a significant increase in fluconazole AUC and Cmax compared to fluconazole given alone. There was a mean +/- SD increase in fluconazole AUC and Cmax of 45 +/- 31% and 43 +/- 31%, respectively. These changes are attributed to a mean +/- SD reduction in fluconazole renal clearance of 30% +/- 12%.
Carbamazepine: (Moderate) Carbamazepine is metabolized by the hepatic isoenzyme CYP3A4. Fluconazole inhibits CYP3A4 and may decrease carbamazepine metabolism and increase carbamazepine plasma concentrations.
Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If fluconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If fluconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Carvedilol: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of carvedilol with fluconazole is necessary. Carvedilol is a CYP2C9 substrate and fluconazole is a CYP2C9 inhibitor. Concomitant use may enhance the beta-blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction.
Celecoxib: (Moderate) The dose of celecoxib may need to be reduced in patients receiving fluconazole. Fluconazole significantly inhibits the metabolism of celecoxib via CYP2C9. Fluconazole at 200 mg per day resulted in a two-fold increase in celecoxib plasma concentration after a single 200 mg dose of celecoxib.
Celecoxib; Tramadol: (Moderate) The dose of celecoxib may need to be reduced in patients receiving fluconazole. Fluconazole significantly inhibits the metabolism of celecoxib via CYP2C9. Fluconazole at 200 mg per day resulted in a two-fold increase in celecoxib plasma concentration after a single 200 mg dose of celecoxib.
Ceritinib: (Contraindicated) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as ceritinib, is contraindicated. Fluconazole has been associated with QT prolongation and concentration-dependent QT prolongation has been reported with ceritinib.
Chlordiazepoxide; Amitriptyline: (Minor) Fluconazole should be administered together with TCAs with caution. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, fluconazole has been reported to increase the effects of amitriptyline, likely via inhibition of the hepatic microsomal CYP2C19 or CYP3A4 isoenzymes. In at least one case, the interaction resulted in an increased incidence of TCA-related side effects, like dizziness and syncope. Monitor for an increased response to amitriptyline if fluconazole is coadministered.
Chloroquine: (Major) Avoid coadministration of chloroquine with fluconazole due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Fluconazole has been associated with QT prolongation and rare cases of TdP.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with fluconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluconazole is a moderate inhibitor of CYP3A4.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with fluconazole may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fluconazole is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with fluconazole may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fluconazole is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If fluconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If fluconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If fluconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If fluconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Fluconazole is an inhibitor of cytochrome P450 isoenzyme 2C9, which is the isoenzyme responsible for the metabolism of ibuprofen. Thus, increased plasma concentrations of ibuprofen are possible. If fluconazole is administered concurrently with ibuprofen, monitor for NSAID-related side-effects such as fluid retention, GI irritation, or renal dysfunction and adjust the ibuprofen dose, if needed. Among 12 healthy males, the mean systemic exposure of S-(+)-ibuprofen after a single dose of 400 mg of racemic ibuprofen was 67.4 +/- 16.2 mcghr/ml. In contrast, the mean systemic exposure was 122 +/- 32 mcghr/ml when ibuprofen was given 1 hour after the second fluconazole dose; fluconazole 400 mg was given on day 1 and 200 mg was given on day 2. In addition to increased systemic exposure, the maximum concentration and half-life of S-(+)-ibuprofen were all statistically significantly greater in the presence of fluconazole. Increased S-(+)-ibuprofen concentrations leads to increased inhibition of both COX-1 and COX-2, and impaired ibuprofen metabolism due to mutations in the CYP2C9 gene increases the risk of acute gastrointestinal bleeding.
Chlorpromazine: (Major) Concurrent use of chlorpromazine and fluconazole should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Fluconazole has been associated with QT prolongation and rare cases of TdP. Phenothiazines have also been associated with a risk of QT prolongation and/or TdP. This risk is generally higher at elevated drugs concentrations of phenothiazines. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine.
Chlorpropamide: (Moderate) Fluconazole should be used cautiously with oral sulfonylureas because blood glucose response may be altered in diabetic patients. In some cases, dosage adjustment of the sulfonylurea may be necessary.
Ciclesonide: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Cilostazol: (Major) Decrease cilostazol dose to one half of the recommended dosage when coadministered with fluconazole. Coadministration may increase cilostazol serum concentrations and increase the risk for adverse reactions. Cilostazol is extensively metabolized by hepatic isoenzyme CYP3A4; fluconazole is a moderate inhibitor of CYP3A4.
Cimetidine: (Moderate) It is not clear that cimetidine interacts with fluconazole in any clinically significant way. Significant decreases in the AUC and Cmax of fluconazole were noted following administration of fluconazole 50 mg PO given two hours after a single dose of cimetidine 400 mg PO to six healthy male volunteers. However, fluconazole pharmacokinetics and bioavailability were not affected when fluconazole 200 mg PO as a single dose was given with cimetidine 600 mg to 900 mg IV over a 4-hour period in healthy male volunteers. Cimetidine, due to inhibition of hepaticCYP P450 enzyme system, may also inhibit the metabolism of the systemic azole antifungal agents, but a clinically important interaction has not been established.
Cinacalcet: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include fluconazole. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
Ciprofloxacin: (Moderate) Concomitant use of ciprofloxacin and fluconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Cisapride: (Contraindicated) Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP). Because of the potential for TdP, use of cisapride with fluconazole is contraindicated.
Citalopram: (Contraindicated) Due to the risk of life-threatening arrhythmias such as torsade de pointes (TdP), coadministration of fluconazole with drugs that both prolong the QT interval and are CYP3A4 substrates, such as citalopram, is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of TdP. Additonally, fluconazole is an inhibitor of CYP3A4. Coadministration may result in elevated plasma concentrations of citalopram, causing an increased risk for adverse events such as QT prolongation.
Clarithromycin: (Contraindicated) Coadministration is contraindicated. Fluconazole has been associated with QT prolongation and clarithromycin has been specifically established to have a causal association with QT prolongation and torsade de pointes (TdP). Additionally, fluconazole is an inhibitor of CYP3A4 and clarithromycin is a known inhibitor and substrate of CYP3A4. In healthy volunteers, the coadministration of clarithromycin (500 mg orally twice daily) with fluconazole (200 mg once daily) led to increases in clarithromycin mean steady-state Cmin (33%) and AUC (18%); however, mean steady-state concentrations of 14-OH clarithromycin were not affected. The changes appeared to be of minor consequence in healthy subjects. The potential for a more significant interaction between fluconazole and clarithromycin might exist at higher dosages of either drug; caution is advised in such circumstances but should not normally alter therapy. Fluconazole is usually considered a less potent inhibitor of CYP3A4 than other azole-family systemic antifungal agents (e.g., ketoconazole, itraconazole), especially at dosages of < 200 mg/day. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4.
Clobazam: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of fluconazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and fluconazole is a potent inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with fluconazole. QT prolongation and torsade de pointes (TdP) have been reported in patients receiving clofazimine in combination with QT prolonging medications. Fluconazole has been associated with QT prolongation and rare cases of TdP.
Clomipramine: (Minor) Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP). Tricyclic antidepressants have been associated with a possible risk of QT prolongation. Fluconazole should be administered together with TCAs with caution.
Clonazepam: (Moderate) Use fluconazole cautiously and carefully monitor patients receiving concurrent clonazepam due to impaired metabolism of clonazepam leading to exaggerated concentrations and adverse effects, such as CNS and/or respiratory depression. Clonazepam in a CYP3A4 substrate. Fluconazole is a CYP3A4 inhibitor.
Clopidogrel: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of fluconazole. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; fluconazole is a potent CYP2C19 inhibitor.
Clozapine: (Contraindicated) Due to the risk of life-threatening arrhythmias such as torsade de pointes (TdP), coadministration of fluconazole with drugs that both prolong the QT interval and are CYP3A4 substrates, like clozapine, is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of TdP. Additonally, fluconazole is an inhibitor of CYP3A4. Coadministration may result in elevated plasma concentrations of clozapine, causing an increased risk for adverse events such as QT prolongation.
Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with fluconazole as there is a potential for elevated cobicistat concentrations. Fluconazole is a CYP3A4 inhibitor, while cobicistat is a substrate of CYP3A4.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with chronic fluconazole therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of fluconazole is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of fluconazole, resume cobimetinib at the previous dose. Use an alternative to fluconazole in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a CYP3A substrate in vitro, and fluconazole is a moderate inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Codeine: (Moderate) Concomitant use of codeine with fluconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluconazole is a moderate inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with fluconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluconazole is a moderate inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with fluconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluconazole is a moderate inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with fluconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluconazole is a moderate inhibitor of CYP3A4. (Moderate) Concomitant use of promethazine and fluconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with fluconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluconazole is a moderate inhibitor of CYP3A4. (Moderate) Concomitant use of promethazine and fluconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and fluconazole unless the use of both agents is imperative. Fluconazole can inhibit colchicine's metabolism via CYP3A4, resulting in increased colchicine exposure. If coadministration cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken fluconazole in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg twice daily or 0.6 mg once daily or if the original dose is 0.6 mg once daily, decrease the dose to 0.3 mg once daily; for treatment of gout flares, give 1.2 mg as a single dose and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed 1.2 mg/day.
Corticosteroids: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Cortisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Crizotinib: (Contraindicated) The concurrent use of fluconazole with crizotinib is contraindicated due to the risk of QT prolongation; increased crizotinib exposure may also occur. Both fluconazole and crizotinib have been associated with QT prolongation; fluconazole has also been associated with rare cases of torsade de pointes (TdP). Additionally, fluconazole is a moderate inhibitor of CYP3A4 and crizotinib is a CYP3A4 substrate. Fluconazole is contraindicated for coadministration with drugs that are associated with QT prolongation and are also CYP3A4 substrates.
Cyclosporine: (Major) Fluconazole inhibits the CYP3A4 metabolism of cyclosporine, resulting in significant increases in cyclosporine plasma concentrations. If these drugs are used together, monitor serum creatinine and cyclosporine concentrations, and adjust cyclosporine dosage accordingly. Renal transplant patients stabilized on cyclosporine for at least 6 months and on a stable cyclosporine dose for at least 6 weeks received fluconazole 200 mg PO daily for 14 days. Cyclosporine AUC, Cmax, Cmin were increased by 92%, 60%, and 157%, respectively. In addition, the apparent cyclosporine clearance decreased by 45%.
Daclatasvir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with fluconazole, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
Darifenacin: (Moderate) Fluconazole, an inhibitor of CYP3A4, may decrease the metabolism of darifenacin and increase serum concentrations. Patients should be monitored for increased anticholinergic effects if these drugs are used concomitantly; dosage adjustments of darifenacin may be necessary.
Darunavir: (Moderate) Caution is warranted when darunavir is administered with fluconazole as there is a potential for elevated concentrations of darunavir. Fluconazole is a CYP3A4 inhibitor, while darunavir is a CYP3A4 substrate.
Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with fluconazole as there is a potential for elevated cobicistat concentrations. Fluconazole is a CYP3A4 inhibitor, while cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with fluconazole as there is a potential for elevated concentrations of darunavir. Fluconazole is a CYP3A4 inhibitor, while darunavir is a CYP3A4 substrate.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with fluconazole as there is a potential for elevated cobicistat concentrations. Fluconazole is a CYP3A4 inhibitor, while cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with fluconazole as there is a potential for elevated concentrations of darunavir. Fluconazole is a CYP3A4 inhibitor, while darunavir is a CYP3A4 substrate.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concurrent administration of fluconazole with dasabuvir; ombitasvir; paritaprevir; ritonavir due to an increased risk of QT prolongation. Although therapy with dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QTc interval to a clinical relevant extent in healthy subjects, ritonavir has been associated with concentration-dependent QT prolongation in other trials. Concurrent use of fluconazole with other agents known to prolong the QT interval and which are metabolized by CYP3A4 is contraindicated. Fluconazole is an inhibitor of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are metabolized by this enzyme. (Moderate) Caution is warranted with the use of fluconazole and ritonavir as ritonavir serum concentrations may be increased resulting in increased treatment-related adverse effects. Fluconazole is a moderate CYP3A4 inhibitor, while ritonavir is a substrate of CYP3A4.
Dasatinib: (Contraindicated) Coadministration of fluconazole and dasatinib is contraindicated due to the potential for QT prolongation. Fluconazole has been associated with QT prolongation and is contraindicated for use with other drugs that both prolong the QT interval and are CYP3A4 substrates, such as dasatinib. Coadministration of fluconazole with dasatinib may result in elevated plasma concentrations of dasatinib, causing an increased risk for adverse events, such as QT prolongation.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with fluconazole. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; fluconazole is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold. (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving fluconazole as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Desflurane: (Major) Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with fluconazole include the halogenated anesthetics Halogenated anesthetics can prolong the QT interval and have been associated with QT prolongation and rare cases of torsades de pointes (TdP).
Desipramine: (Minor) Fluconazole should be administered together with TCAs with caution. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, fluconazole inhibits CYP2C19 and CYP3A4; both CYP2C19 and CYP3A4 are partially involved in the metabolism of TCAs. Fluconazole has been reported to increase the effects of amitriptyline. In at least one case, the interaction resulted in an increased incidence of TCA-related side effects, such as dizziness and syncope. In another case, QT-prolongation and TdP occurred. Desipramine may be affected by this potential interaction, but specific data are lacking.
Desogestrel; Ethinyl Estradiol: (Minor) CYP3A4 inhibitors such as fluconazole may increase plasma hormone concentrations of ethinyl estradiol. Fluconazole tablets, administered concomitantly with oral contraceptives containing ethinyl estradiol have resulted in an overall mean increase in ethinyl estradiol compared to placebo. However, in some patients there are decreases up to 47% of ethinyl estradiol concentrations. The available data indicate that the decreases in some individual ethinyl estradiol AUC values with fluconazole treatment are likely due to random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol, there is no evidence that fluconazole is a net inducer of ethinyl estradiol metabolism. The clinical significance of these effects is unknown.
Deutetrabenazine: (Moderate) Use fluconazole with caution in combination with deutetrabenazine. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexamethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Dextromethorphan; Quinidine: (Contraindicated) The concomitant administration of fluconazole and quinidine is contraindicated. Fluconazole has been associated with QT prolongation and is contraindicated for use with other drugs that both prolong the QT interval and are CYP3A4 substrates, such as quinidine. Coadministration of fluconazole with quinidine may result in elevated plasma concentrations of quinidine, causing an increased risk for adverse events, such as QT prolongation.
Diazepam: (Moderate) Fluconazole could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, such as diazepam. Coadminister these drugs with caution.
Dichlorphenamide: (Moderate) Use dichlorphenamide and fluconazole together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including antifungals. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dichlorphenamide dose or discontinuing dichlorphenamide therapy.
Diclofenac: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as fluconazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
Diclofenac; Misoprostol: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as fluconazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
Dienogest; Estradiol valerate: (Minor) As fluconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives. (Minor) Estradiol valerate and dienogest are both substrates of CYP3A4. Certain azole antifungals, including fluconazole, itraconazole, ketonconazole, miconazole (systemic formulation only), posaconazole, and voriconazole, are CYP3A4 inhibitors and therefore may inhibit the metabolism of dienogest; estradiol valerate, possibly leading to increased serum concentrations. In a pharmacokinetic study evaluating the effect of ketoconazole on dienogest and estradiol, co-administration with ketoconazole increased the AUC at steady-state for dienogest and estradiol by 2.86 and 1.57-fold, respectively. There was also a 1.94 and 1.65-fold increase of Cmax at steady-state for dienogest and estradiol when co-administered with ketoconazole.
Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with fluconazole may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of fluconazole could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fluconazole is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Dihydroergotamine: (Major) Fluconazole should be used cautiously in patients taking certain ergot alkaloids. Fluconazole may reduce the metabolism of ergot alkaloids via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
Diltiazem: (Moderate) Fluconazole may decrease the clearance of calcium-channel blockers, including diltiazem, via inhibition of CYP3A4 metabolism.
Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If fluconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Diphenhydramine; Ibuprofen: (Moderate) Fluconazole is an inhibitor of cytochrome P450 isoenzyme 2C9, which is the isoenzyme responsible for the metabolism of ibuprofen. Thus, increased plasma concentrations of ibuprofen are possible. If fluconazole is administered concurrently with ibuprofen, monitor for NSAID-related side-effects such as fluid retention, GI irritation, or renal dysfunction and adjust the ibuprofen dose, if needed. Among 12 healthy males, the mean systemic exposure of S-(+)-ibuprofen after a single dose of 400 mg of racemic ibuprofen was 67.4 +/- 16.2 mcghr/ml. In contrast, the mean systemic exposure was 122 +/- 32 mcghr/ml when ibuprofen was given 1 hour after the second fluconazole dose; fluconazole 400 mg was given on day 1 and 200 mg was given on day 2. In addition to increased systemic exposure, the maximum concentration and half-life of S-(+)-ibuprofen were all statistically significantly greater in the presence of fluconazole. Increased S-(+)-ibuprofen concentrations leads to increased inhibition of both COX-1 and COX-2, and impaired ibuprofen metabolism due to mutations in the CYP2C9 gene increases the risk of acute gastrointestinal bleeding.
Disopyramide: (Contraindicated) The concomitant administration of fluconazole and disopyramide is contraindicated. Fluconazole has been associated with QT prolongation and is contraindicated for use with other drugs that both prolong the QT interval and are CYP3A4 substrates, such as disopyramide. Coadministration of fluconazole with disopyramide may result in elevated plasma concentrations of disopyramide, causing an increased risk for adverse events, such as QT prolongation.
Docetaxel: (Minor) Docetaxel is metabolized by cytochrome P450 3A enzymes. Drugs that inhibit the CYP3A enzymes, such as fluconazole, can significantly reduce the metabolism of docetaxel. Use docetaxel cautiously when administered concurrently with inhibitors of CYP3A enzymes.
Dofetilide: (Contraindicated) Coadministration of dofetilide and fluconazole is contraindicated as concurrent use may increase the risk of QT prolongation and torsade de pointes (TdP). Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Fluconazole has been associated with QT prolongation and rare cases of TdP. Additionally, fluconazole is also an inhibitor of CYP3A4, which could increase dofetilide exposure, further increasing the risk of cardiac events.
Dolasetron: (Moderate) Administer dolasetron with caution in combination with fluconazole as concurrent use may increase the risk of QT prolongation. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir; Rilpivirine: (Contraindicated) Concurrent use of fluconazole and rilpivirine is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Fluconazole is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of rilpivirine. These drugs used in combination may result in elevated rilpivirine plasma concentrations, causing an increased risk for adverse events, such as QT prolongation. Additionally, fluconazole has been associated with prolongation of the QT interval; do not use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as rilpivirine.
Donepezil: (Moderate) Use donepezil with caution in combination with fluconazole as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Fluconazole has been associated with QT prolongation and rare cases of TdP.
Donepezil; Memantine: (Moderate) Use donepezil with caution in combination with fluconazole as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Fluconazole has been associated with QT prolongation and rare cases of TdP.
Doxepin: (Minor) Use fluconazole and tricyclic antidepressants (TCAs) with caution. Fluconazole is associated with QT prolongation. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, fluconazole inhibits CYP2C19, CYP2C9, and CYP3A4; these enzymes are involved in the metabolism of some TCAs. Doxepin is primarily metabolized by CYP2C19 and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9. In at least one case, a TCA interaction resulted in an increased incidence of TCA-related side effects, such as dizziness and syncope. In another case involving amitriptyline, QT-prolongation and torsade de pointes occurred. Concurrent administration of doxepin and fluconazole may result in increased doxepin plasma concentrations and subsequent adverse reactions.
Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as fluconazole, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
Doxorubicin Liposomal: (Major) Avoid coadministration of fluconazole with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Fluconazole is a moderate CYP3A4 inhibitor, and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of fluconazole with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Fluconazole is a moderate CYP3A4 inhibitor, and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with fluconazole is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Concomitant use may result in elevated plasma concentrations of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; fluconazole is a moderate inhibitor of both enzymes.
Dronedarone: (Contraindicated) Concurrent use of dronedarone and fluconazole is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Contraindicated) Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP). The concurrent use of fluconazole and other drugs that prolong the QT and are CYP3A4 substrates is contraindicated due to the risk of life-threatening arrhythmias such as TdP. Coadministration of fluconazole with drugs that are CYP3A4 substrates may result in an elevated plasma concentration of the interacting drug, causing an increased risk for adverse events, such as QT prolongation. Drugs that prolong QT and are substrates for CYP3A4 that are contraindicated with fluconazole include droperidol.
Drospirenone; Estradiol: (Minor) As fluconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Drospirenone; Ethinyl Estradiol: (Minor) CYP3A4 inhibitors such as fluconazole may increase plasma hormone concentrations of ethinyl estradiol. Fluconazole tablets, administered concomitantly with oral contraceptives containing ethinyl estradiol have resulted in an overall mean increase in ethinyl estradiol compared to placebo. However, in some patients there are decreases up to 47% of ethinyl estradiol concentrations. The available data indicate that the decreases in some individual ethinyl estradiol AUC values with fluconazole treatment are likely due to random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol, there is no evidence that fluconazole is a net inducer of ethinyl estradiol metabolism. The clinical significance of these effects is unknown.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) CYP3A4 inhibitors such as fluconazole may increase plasma hormone concentrations of ethinyl estradiol. Fluconazole tablets, administered concomitantly with oral contraceptives containing ethinyl estradiol have resulted in an overall mean increase in ethinyl estradiol compared to placebo. However, in some patients there are decreases up to 47% of ethinyl estradiol concentrations. The available data indicate that the decreases in some individual ethinyl estradiol AUC values with fluconazole treatment are likely due to random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol, there is no evidence that fluconazole is a net inducer of ethinyl estradiol metabolism. The clinical significance of these effects is unknown.
Dutasteride: (Moderate) Dutasteride is metabolized by the CYP3A4/5 hepatic enzyme. The clearance of dutasteride may be reduced when co-administered with CYP3A4 inhibitors including fluconazole.
Dutasteride; Tamsulosin: (Moderate) Dutasteride is metabolized by the CYP3A4/5 hepatic enzyme. The clearance of dutasteride may be reduced when co-administered with CYP3A4 inhibitors including fluconazole. (Moderate) Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as fluconazole. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
Duvelisib: (Moderate) Monitor for increased toxicity of duvelisib if coadministered with fluconazole. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; fluconazole is a moderate CYP3A inhibitor.
Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with flucanazole as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Efavirenz; Emtricitabine; Tenofovir: (Moderate) Consider alternatives to efavirenz when coadministering with flucanazole as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with flucanazole as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Elagolix; Estradiol; Norethindrone acetate: (Minor) As fluconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with fluconazole may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Fluconazole is a moderate inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with fluconazole. Coadministration of fluconazole increase the eletriptan AUC by 2-fold in a drug interaction study. Eletriptan is a substrate for CYP3A4, and fluconazole is a moderate CYP3A4 inhibitor.
Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the elexacaftor; tezacaftor; ivacaftor dosing schedule when coadministered with fluconazole; coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 2 elexacaftor; tezacaftor; ivacaftor combination tablets every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., elexacaftor/tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive substrate); fluconazole is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2-fold, respectively. (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with fluconazole; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); fluconazole is a moderate CYP3A inhibitor. Coadministration of fluconazole increased ivacaftor exposure 3-fold. Simulation suggests fluconazole may increase tezacaftor exposure 2-fold. (Major) If fluconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold.
Eliglustat: (Contraindicated) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of fluconazole and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EMs), coadministration of fluconazole and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both fluconazole and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Both eliglustat and fluconazole can independently prolong the QT interval, and coadministration increases this risk. Fluconazole is a moderate CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors, such as fluconazole, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A. Although fluconazole's product labeling states that coadministration of other drugs that prolong the QT interval and are metabolized by CYP3A4 is contraindicated, the specific interaction between fluconazole and eliglustat was studied during clinical trials and supports eliglustat dosage reduction in EMs instead of contraindication.Physiology-based pharmacokinetic (PBPK) models suggest that fluconazole may increase the Cmax and AUC of eliglustat 2.8- and 3.2-fold, respectively, in EMs and 2.5- and 2.9-fold, respectively, in IMs. PBPK suggests fluconazole may increase the Cmax and AUC of eliglustat 2.4- and 3-fold, respectively, when administered with eliglustat 84 mg PO once daily in PMs. In addition, PBPK modeling suggests concomitant use of eliglustat (84 mg PO twice daily) with a moderate 2D6 inhibitor and fluconazole (moderate 3A4 inhibitor) may increase the Cmax and AUC of eliglustat 10.2- and 13.6-fold, respectively, in EMs and 4.2- and 5-fold, respectively, in IMs.
Elvitegravir: (Moderate) Caution is warranted when elvitegravir is administered with fluconazole as there is a potential for elevated elvitegravir concentrations. Fluconazole is a CYP3A4 and CYP2D6 inhibitor, while elvitegravir is a substrate of CYP3A4.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with fluconazole as there is a potential for elevated cobicistat concentrations. Fluconazole is a CYP3A4 inhibitor, while cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when elvitegravir is administered with fluconazole as there is a potential for elevated elvitegravir concentrations. Fluconazole is a CYP3A4 and CYP2D6 inhibitor, while elvitegravir is a substrate of CYP3A4.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with fluconazole as there is a potential for elevated cobicistat concentrations. Fluconazole is a CYP3A4 inhibitor, while cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when elvitegravir is administered with fluconazole as there is a potential for elevated elvitegravir concentrations. Fluconazole is a CYP3A4 and CYP2D6 inhibitor, while elvitegravir is a substrate of CYP3A4.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Contraindicated) Concurrent use of fluconazole and rilpivirine is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Fluconazole is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of rilpivirine. These drugs used in combination may result in elevated rilpivirine plasma concentrations, causing an increased risk for adverse events, such as QT prolongation. Additionally, fluconazole has been associated with prolongation of the QT interval; do not use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as rilpivirine.
Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Contraindicated) Concurrent use of fluconazole and rilpivirine is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Fluconazole is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of rilpivirine. These drugs used in combination may result in elevated rilpivirine plasma concentrations, causing an increased risk for adverse events, such as QT prolongation. Additionally, fluconazole has been associated with prolongation of the QT interval; do not use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as rilpivirine.
Enalapril; Felodipine: (Moderate) Fluconazole may decrease the clearance of calcium-channel blockers, including felodipine, via inhibition of CYP3A4 metabolism. Monitor blood pressure closely during concurrent use of these medications.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Hydrochlorothiazide may decrease the renal clearance of fluconazole. Coadministration of fluconazole 100 mg PO and hydrochlorothiazide 50 mg PO for 10 days in normal volunteers (n=13) resulted in a significant increase in fluconazole AUC and Cmax compared to fluconazole given alone. There was a mean +/- SD increase in fluconazole AUC and Cmax of 45 +/- 31% and 43 +/- 31%, respectively. These changes are attributed to a mean +/- SD reduction in fluconazole renal clearance of 30% +/- 12%.
Encorafenib: (Contraindicated) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as encorafenib, is contraindicated. Fluconazole has been associated with QT prolongation.
Enflurane: (Major) Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with fluconazole include the halogenated anesthetics Halogenated anesthetics can prolong the QT interval and have been associated with QT prolongation and rare cases of torsades de pointes (TdP).
Entrectinib: (Major) Avoid coadministration of entrectinib with fluconazole due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If fluconazole is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of fluconazole. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; fluconazole is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Fluconazole is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Hydrochlorothiazide may decrease the renal clearance of fluconazole. Coadministration of fluconazole 100 mg PO and hydrochlorothiazide 50 mg PO for 10 days in normal volunteers (n=13) resulted in a significant increase in fluconazole AUC and Cmax compared to fluconazole given alone. There was a mean +/- SD increase in fluconazole AUC and Cmax of 45 +/- 31% and 43 +/- 31%, respectively. These changes are attributed to a mean +/- SD reduction in fluconazole renal clearance of 30% +/- 12%.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and fluconazole due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If fluconazole is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP2C9 substrate and fluconazole is a moderate CYP2C9 inhibitor. The mean ratios for the Cmax and AUC of erdafitinib were 121% and 148%, respectively, when coadministered with fluconazole.
Ergoloid Mesylates: (Major) Fluconazole should be used cautiously in patients taking certain ergot alkaloids. Fluconazole may reduce the metabolism of ergot alkaloids via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
Ergonovine: (Major) Fluconazole should be used cautiously in patients taking certain ergot alkaloids. Fluconazole may reduce the metabolism of ergot alkaloids via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
Ergot alkaloids: (Major) Fluconazole should be used cautiously in patients taking certain ergot alkaloids. Fluconazole may reduce the metabolism of ergot alkaloids via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
Ergotamine: (Major) Fluconazole should be used cautiously in patients taking certain ergot alkaloids. Fluconazole may reduce the metabolism of ergot alkaloids via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
Ergotamine; Caffeine: (Major) Fluconazole should be used cautiously in patients taking certain ergot alkaloids. Fluconazole may reduce the metabolism of ergot alkaloids via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids. (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined.
Eribulin: (Major) Eribulin has been associated with QT prolongation. If eribulin and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with eribulin include fluconazole.
Erythromycin: (Major) Concomitant use of fluconazole and erythromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Erythromycin; Sulfisoxazole: (Major) Concomitant use of fluconazole and erythromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Escitalopram: (Moderate) Concomitant use of fluconazole and escitalopram may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Esomeprazole: (Minor) Fluconazole may inhibit the CYP2C19 isoenzyme, leading to increased plasma levels of drugs that are substrates for the CYP2C19 isoenzyme, such as esomeprazole.
Estazolam: (Moderate) In vitro studies with human liver microsomes indicate that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is mediated by CYP3A. In theory, CYP3A4 inhibitors, such as fluconazole, may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity. The manufacturer suggests that estazolam be used only with caution and consideration of appropriate dosage reduction during coadministration.
Estradiol Cypionate; Medroxyprogesterone: (Minor) As fluconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol: (Minor) As fluconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Levonorgestrel: (Minor) As fluconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Norethindrone: (Minor) As fluconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Norgestimate: (Minor) As fluconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Progesterone: (Minor) As fluconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives. (Minor) The metabolism of progesterone may be inhibited by fluconazole, an inhibitor of cytochrome P450 3A4 hepatic enzymes.
Eszopiclone: (Moderate) A pharmacokinetic study of ketoconazole coadministered with eszopiclone resulted in an a 2.2-fold increase in eszopiclone AUC. Although fluconazole inhibits CYP3A4 to a lesser extent than ketoconazole, a clinically relevant interaction is possible, and dose adjustments of eszopiclone may be necessary. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day psychomotor or memory impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
Ethinyl Estradiol: (Minor) CYP3A4 inhibitors such as fluconazole may increase plasma hormone concentrations of ethinyl estradiol. Fluconazole tablets, administered concomitantly with oral contraceptives containing ethinyl estradiol have resulted in an overall mean increase in ethinyl estradiol compared to placebo. However, in some patients there are decreases up to 47% of ethinyl estradiol concentrations. The available data indicate that the decreases in some individual ethinyl estradiol AUC values with fluconazole treatment are likely due to random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol, there is no evidence that fluconazole is a net inducer of ethinyl estradiol metabolism. The clinical significance of these effects is unknown.
Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) CYP3A4 inhibitors such as fluconazole may increase plasma hormone concentrations of ethinyl estradiol. Fluconazole tablets, administered concomitantly with oral contraceptives containing ethinyl estradiol have resulted in an overall mean increase in ethinyl estradiol compared to placebo. However, in some patients there are decreases up to 47% of ethinyl estradiol concentrations. The available data indicate that the decreases in some individual ethinyl estradiol AUC values with fluconazole treatment are likely due to random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol, there is no evidence that fluconazole is a net inducer of ethinyl estradiol metabolism. The clinical significance of these effects is unknown.
Ethinyl Estradiol; Norelgestromin: (Minor) CYP3A4 inhibitors such as fluconazole may increase plasma hormone concentrations of ethinyl estradiol. Fluconazole tablets, administered concomitantly with oral contraceptives containing ethinyl estradiol have resulted in an overall mean increase in ethinyl estradiol compared to placebo. However, in some patients there are decreases up to 47% of ethinyl estradiol concentrations. The available data indicate that the decreases in some individual ethinyl estradiol AUC values with fluconazole treatment are likely due to random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol, there is no evidence that fluconazole is a net inducer of ethinyl estradiol metabolism. The clinical significance of these effects is unknown.
Ethinyl Estradiol; Norethindrone Acetate: (Minor) CYP3A4 inhibitors such as fluconazole may increase plasma hormone concentrations of ethinyl estradiol. Fluconazole tablets, administered concomitantly with oral contraceptives containing ethinyl estradiol have resulted in an overall mean increase in ethinyl estradiol compared to placebo. However, in some patients there are decreases up to 47% of ethinyl estradiol concentrations. The available data indicate that the decreases in some individual ethinyl estradiol AUC values with fluconazole treatment are likely due to random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol, there is no evidence that fluconazole is a net inducer of ethinyl estradiol metabolism. The clinical significance of these effects is unknown.
Ethinyl Estradiol; Norgestrel: (Minor) CYP3A4 inhibitors such as fluconazole may increase plasma hormone concentrations of ethinyl estradiol. Fluconazole tablets, administered concomitantly with oral contraceptives containing ethinyl estradiol have resulted in an overall mean increase in ethinyl estradiol compared to placebo. However, in some patients there are decreases up to 47% of ethinyl estradiol concentrations. The available data indicate that the decreases in some individual ethinyl estradiol AUC values with fluconazole treatment are likely due to random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol, there is no evidence that fluconazole is a net inducer of ethinyl estradiol metabolism. The clinical significance of these effects is unknown.
Ethosuximide: (Moderate) Fluconazole may inhibit the CYP3A4 metabolism of ethosuximide. This interaction may or may not be clinically significant, since ethosuximide serum concentrations are not well correlated to drug efficacy or side effects.
Ethotoin: (Major) Fluconazole can decrease the metabolism of phenytoin. A mean increase of 88% in phenytoin serum AUC has been seen in some normal male volunteers taking both fluconazole and phenytoin. Concentrations of phenytoin should be carefully monitored if fluconazole is added. A similar interaction would be expected with ethotoin.
Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) CYP3A4 inhibitors such as fluconazole may increase plasma hormone concentrations of ethinyl estradiol. Fluconazole tablets, administered concomitantly with oral contraceptives containing ethinyl estradiol have resulted in an overall mean increase in ethinyl estradiol compared to placebo. However, in some patients there are decreases up to 47% of ethinyl estradiol concentrations. The available data indicate that the decreases in some individual ethinyl estradiol AUC values with fluconazole treatment are likely due to random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol, there is no evidence that fluconazole is a net inducer of ethinyl estradiol metabolism. The clinical significance of these effects is unknown.
Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as fluconazole may increase the serum concentration of etonogestrel.
Etonogestrel; Ethinyl Estradiol: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as fluconazole may increase the serum concentration of etonogestrel. (Minor) CYP3A4 inhibitors such as fluconazole may increase plasma hormone concentrations of ethinyl estradiol. Fluconazole tablets, administered concomitantly with oral contraceptives containing ethinyl estradiol have resulted in an overall mean increase in ethinyl estradiol compared to placebo. However, in some patients there are decreases up to 47% of ethinyl estradiol concentrations. The available data indicate that the decreases in some individual ethinyl estradiol AUC values with fluconazole treatment are likely due to random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol, there is no evidence that fluconazole is a net inducer of ethinyl estradiol metabolism. The clinical significance of these effects is unknown.
Etravirine: (Moderate) Although the manufacturer of etravirine does not recommend a dosage change for either fluconazole or etravirine when these drugs are coadministered, caution and careful monitoring is recommended. Coadministration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited. Fluconazole is a moderate CYP2C9 inhibitor and etravirine is a CYP2C9 substrate.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with fluconazole is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Fluconazole is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fluconazole is necessary. Concomitant use my increase simvastatin exposure. Simvastatin is a sensitive CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Ezogabine: (Moderate) Use fluconazole with caution in combination with ezogabine as concurrent use may increase the risk of QT prolongation. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Ezogabine has been associated with QT prolongation.
Famotidine; Ibuprofen: (Moderate) Fluconazole is an inhibitor of cytochrome P450 isoenzyme 2C9, which is the isoenzyme responsible for the metabolism of ibuprofen. Thus, increased plasma concentrations of ibuprofen are possible. If fluconazole is administered concurrently with ibuprofen, monitor for NSAID-related side-effects such as fluid retention, GI irritation, or renal dysfunction and adjust the ibuprofen dose, if needed. Among 12 healthy males, the mean systemic exposure of S-(+)-ibuprofen after a single dose of 400 mg of racemic ibuprofen was 67.4 +/- 16.2 mcghr/ml. In contrast, the mean systemic exposure was 122 +/- 32 mcghr/ml when ibuprofen was given 1 hour after the second fluconazole dose; fluconazole 400 mg was given on day 1 and 200 mg was given on day 2. In addition to increased systemic exposure, the maximum concentration and half-life of S-(+)-ibuprofen were all statistically significantly greater in the presence of fluconazole. Increased S-(+)-ibuprofen concentrations leads to increased inhibition of both COX-1 and COX-2, and impaired ibuprofen metabolism due to mutations in the CYP2C9 gene increases the risk of acute gastrointestinal bleeding.
Fedratinib: (Major) Avoid coadministration of fedratinib with fluconazole as concurrent use may increase fedratinib exposure. Fedratinib is a substrate of both CYP3A4 and CYP2C19; fluconazole is an inhibitor of both CYP3A4 and CYP2C19. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated.
Felodipine: (Moderate) Fluconazole may decrease the clearance of calcium-channel blockers, including felodipine, via inhibition of CYP3A4 metabolism. Monitor blood pressure closely during concurrent use of these medications.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. If fluconazole is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If fluconazole is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or fluconazole; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased overall exposure to finerenone by 248%.
Fingolimod: (Moderate) Use fluconazole with caution in combination with fingolimod as concurrent use may increase the risk of QT prolongation. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking fluconazole. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Major) Concomitant use of flecainide and fluconazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as fluconazole, is contraindicated. Moderate CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a moderate CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate CYP3A4 inhibitor following flibanserin use, start the moderate CYP3A4 inhibitor at least 2 days after the last dose of flibanserin. In a pharmacokinetic drug interaction study of 100 mg flibanserin and 200 mg fluconazole, hypotension or syncope requiring placement supine with legs elevated occurred in 20% of subjects treated with concomitant flibanserin and fluconazole compared to no similar reactions in subjects treated with flibanserin alone or fluconazole alone. One of the subjects experiencing hypotension became unresponsive with a blood pressure of 64/41 mm Hg and required transportation to the hospital emergency department where she required intravenous saline. Due to these adverse reactions, the study was stopped. In this study, the concomitant use of flibanserin and fluconazole increased flibanserin exposure 7-fold. It should be noted that in addition to being a moderate CYP3A4 inhibitor, fluconazole is a potent inhibitor of CYP2C19, a minor metabolic pathway of flibanserin.
Fludrocortisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Flunisolide: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Fluoxetine: (Moderate) Concomitant use of fluconazole and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Fluphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering fluconazole with fluphenazine. Fluconazole has been associated with QT prolongation and rare cases of TdP. Fluphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Flurazepam: (Moderate) Fluconazole could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, such as flurazepam. Coadminister these drugs with caution.
Flurbiprofen: (Moderate) Fluconazole significantly inhibits the metabolism of flurbiprofen via CYP2C9. Increased adverse effects of flurbiprofen may occur, especially if the two drugs are used concurrently over several days.
Fluticasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Fluticasone; Salmeterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Fluticasone; Vilanterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Fluvastatin: (Major) Coadministration of fluconazole and fluvastatin increases fluvastatin exposure, therefore increasing the risk of myopathy and rhabdomyolysis. If used together, limit fluvastatin to 20 mg PO twice daily in adult patients. Fluconazole is an inhibitor of CYP2C9 and fluvastatin is a major CYP2C9 substrate.
Fluvoxamine: (Minor) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluconazole and fluvoxamine. Fluconazole has been associated with QT prolongation and rare cases of TdP. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with fluconazole. Fluconazole is an inhibitor of CYP2C9 and CYP3A4, two isoenzymes responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with fluconazole the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
Formoterol; Mometasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
Fosamprenavir: (Minor) Fluconazole inhibits CYP3A4 and is expected to increase amprenavir plasma concentrations when coadministered with fosamprenavir.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as fluconazole. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Fluconazole has also been associated with QT prolongation and rare cases of TdP. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Hydrochlorothiazide may decrease the renal clearance of fluconazole. Coadministration of fluconazole 100 mg PO and hydrochlorothiazide 50 mg PO for 10 days in normal volunteers (n=13) resulted in a significant increase in fluconazole AUC and Cmax compared to fluconazole given alone. There was a mean +/- SD increase in fluconazole AUC and Cmax of 45 +/- 31% and 43 +/- 31%, respectively. These changes are attributed to a mean +/- SD reduction in fluconazole renal clearance of 30% +/- 12%.
Fosphenytoin: (Moderate) Fluconazole can decrease the metabolism of phenytoin. A mean increase of 88% in phenytoin serum AUC has been seen in some normal male volunteers taking both fluconazole and phenytoin. Concentrations of phenytoin should be carefully monitored if fluconazole is added. A similar interaction would be expected with fosphenytoin.
Fostemsavir: (Contraindicated) Avoid concomitant use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as fostemsavir. Closely monitor electrolytes and ECG if concomitant use is necessary. Fluconazole has been associated with QT prolongation and is a moderate CYP 3A4 inhibitor. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, 4 times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gemifloxacin: (Moderate) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering fluconazole with gemifloxacin. Fluconazole has been associated with QT prolongation and rare cases of TdP. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and fluconazole together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Fluconazole has been associated with QT prolongation and rare cases of TdP.
Gilteritinib: (Contraindicated) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as gilteritinib, is contraindicated. Both drugs have been associated with QT prolongation.
Glasdegib: (Contraindicated) Coadministration of glasdegib with fluconazole is contraindicated due to the potential for QT prolongation. Glasdegib is a CYP3A4 substrate that may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Fluconazole is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Glimepiride: (Moderate) Fluconazole should be used cautiously with glimepiride. The combination of fluconazole and glimepiride has resulted in a > 100% increase in glimepiride AUC in healthy volunteers; blood glucose response may be altered in diabetic patients. Inhibition of CYP2C9 by fluconazole is the suspected mechanism of this interaction.
Glimepiride; Rosiglitazone: (Moderate) Fluconazole is an inhibitor of CYP3A4 and CYP2C9. Because rosiglitazone is a substrate of CYP2C9, concomitant use with fluconazole may increase plasma concentrations of rosiglitazone. Patients should be monitored for changes in glycemic control if rosiglitazone is coadministered with fluconazole. (Moderate) Fluconazole should be used cautiously with glimepiride. The combination of fluconazole and glimepiride has resulted in a > 100% increase in glimepiride AUC in healthy volunteers; blood glucose response may be altered in diabetic patients. Inhibition of CYP2C9 by fluconazole is the suspected mechanism of this interaction.
Glipizide: (Moderate) A potential interaction between fluconazole and glipizide may lead to hypoglycemia that can sometimes be severe. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of glipizide by fluconazole. For example, the combination of fluconazole and glipizide has resulted in significant increases in the AUCs (roughly 49% or more) and Cmax (roughly 20%) of glipizide in healthy volunteers; however, individual patients may have greater or lesser changes in these pharmacokinetic parameters. Blood glucose concentrations should be monitored during concomitant treatment with these systemic azole antifungals; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations.
Glipizide; Metformin: (Moderate) A potential interaction between fluconazole and glipizide may lead to hypoglycemia that can sometimes be severe. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of glipizide by fluconazole. For example, the combination of fluconazole and glipizide has resulted in significant increases in the AUCs (roughly 49% or more) and Cmax (roughly 20%) of glipizide in healthy volunteers; however, individual patients may have greater or lesser changes in these pharmacokinetic parameters. Blood glucose concentrations should be monitored during concomitant treatment with these systemic azole antifungals; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations.
Glyburide: (Moderate) A potential interaction between fluconazole and glyburide, leading to hypoglycemia, sometimes severe, has been reported. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of oral hypoglycemics by azole antifungals. For example, the combination of fluconazole and glyburide has resulted in significant increases in the AUCs (roughly 44% or more) and Cmax (roughly 20%) of glyburide in healthy volunteers; however, individual patients may have greater or lesser changes in these pharmacokinetic parameters. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations.
Glyburide; Metformin: (Moderate) A potential interaction between fluconazole and glyburide, leading to hypoglycemia, sometimes severe, has been reported. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of oral hypoglycemics by azole antifungals. For example, the combination of fluconazole and glyburide has resulted in significant increases in the AUCs (roughly 44% or more) and Cmax (roughly 20%) of glyburide in healthy volunteers; however, individual patients may have greater or lesser changes in these pharmacokinetic parameters. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations.
Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving fluconazole as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Fluconazole has also been associated with QT prolongation as well as rare cases of torsade de pointes (TdP).
Granisetron: (Moderate) Use fluconazole with caution in combination with granisetron as concurrent use may increase the risk of QT prolongation. Granisetron has been associated with QT prolongation. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Green Tea: (Moderate) Some, but not all, green tea products contain caffeine. Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If fluconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If fluconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Guanfacine: (Major) Fluconazole may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon fluconazole discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and fluconazole is a moderate CYP3A4 inhibitor.
Halofantrine: (Moderate) Drugs which significantly inhibit cytochrome CYP3A4, such as fluconazole, may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity. If concurrent use of halofantrine and a CYP3A4 inhibitor is warranted, it would be prudent to use caution and monitor the ECG periodically.
Halogenated Anesthetics: (Major) Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with fluconazole include the halogenated anesthetics Halogenated anesthetics can prolong the QT interval and have been associated with QT prolongation and rare cases of torsades de pointes (TdP).
Haloperidol: (Contraindicated) FDA-approved labeling for fluconazole contraindicates use with CYP3A4 substrates that prolong the QT interval such as haloperidol. If alternative therapy is not available and concurrent use cannot be avoided, closely monitor for evidence of QT prolongation; a haloperidol dose reduction may be necessary. Fluconazole is a moderate CYP3A4 inhibitor that has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with CYP3A4 inhibitors.
Halothane: (Major) Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with fluconazole include the halogenated anesthetics Halogenated anesthetics can prolong the QT interval and have been associated with QT prolongation and rare cases of torsades de pointes (TdP).
Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving fluconazole as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Fluconazole has also been associated with QT prolongation as well as rare cases of torsade de pointes (TdP).
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6