Diflucan

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

NOTE: No dosage adjustments are required for single-dose therapy. For multiple-dose regimens, the following adjustments are suggested; further adjustments may be needed depending upon the clinical situation.[28674]
 
Adults [28674] [32569] [60686]
CrCl more than 50 mL/minute: No dosage adjustment needed.
CrCl 50 mL/minute or less: Administer usual loading dose, then reduce maintenance dose by 50%.
 
Infants, Children, and Adolescents [28674] [32569] [60686]
CrCl more than 50 mL/minute/1.73 m2: No dosage adjustment needed.
CrCl 10 to 50 mL/minute/1.73 m2: Administer usual loading dose, then reduce maintenance dose by 50%.
CrCl less than 10 mL/minute/1.73 m2: Administer usual loading dose, then reduce maintenance dose by 50% and administer every 48 hours.
 
Neonates† [53038]
Serum creatinine (SCr) less than 1.3 mg/dL: No dosage adjustment needed.
Serum creatinine (SCr) 1.3 mg/dL or more: Consider extending the dosage interval (e.g., every 48 to 72 hours) depending on the degree of renal impairment.
 
Intermittent hemodialysis
NOTE: A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%.[28674] [32569] [60686]
 
Adults and Pediatric patients (FDA-approved labeling)
Administer 100% of the usual daily dose after each dialysis session; on non-dialysis days, administer a reduced dose based on creatinine clearance. Further adjustments may be needed depending upon the clinical situation.[28674] [60686]
 
Adults (alternative)†
200 to 400 mg IV or PO every 48 to 72 hours or 100 to 200 mg IV or PO every 24 hours.[42303]
 
Pediatric patients (alternative)†
Administer usual loading dose, then reduce maintenance dose by 50% and administer every 48 hours (after dialysis).[32569]
 
Peritoneal dialysis†
Adults
Administer usual loading dose, then reduce maintenance dose by 50%.[32569]
 
Pediatric patients
Administer usual loading dose, then reduce maintenance dose by 50% and administer every 48 hours.[32569]
 
Continuous renal replacement therapy (CRRT)†
NOTE: Various CRRT modalities include continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), continuous venovenous hemodiafiltration (CVVHDF), continuous venovenous high-flux hemodialysis (CVVHFD), continuous arteriovenous hemofiltration (CAVH), continuous arteriovenous hemodialysis (CAVHD), and continuous arteriovenous hemodiafiltration (CAVHDF). Dosing should take into consideration patient-specific factors (e.g., intrinsic renal function), type of infection, the duration of renal replacement therapy, the effluent flow rate, and the replacement solution administered.[42303]
 
Adults
200 to 400 mg IV or PO every 24 hours has generally been suggested for CRRT.[32569] Specific recommendations for patients receiving CVVH, CVVHD, or CVVHD include the following:
CVVH: 400 to 800 mg IV or PO loading dose, then 200 to 400 mg IV or PO every 24 hours.[34038] [42303]
CVVHD or CVVHDF: 400 mg to 800 mg IV or PO every 24 hours. If the dialysate flow rate is 2 L/hour or more and/or if treating relatively resistant organisms, 800 mg IV or PO every 24 hours.[34038] [42303]
 
Pediatric patients
Pediatric recommendations are based on limited study data, mainly derived from adult patients, and extrapolation of CRRT clearance based on fluconazole pharmacokinetic parameters.
6 mg/kg/dose IV or PO every 24 hours has generally been suggested for CRRT.[32569] Specific recommendations for patients receiving CAVH/CVVH and CAVHD/CVVHD based on dialysate flow rate include the following:
Dialysate flow rate (ultrafiltration rate + dialysis inflow rate) less than 1,500 mL/m2/hour: Administer usual loading dose, then 3 to 12 mg/kg/dose IV or PO every 24 hours.
Dialysate flow rate (ultrafiltration rate + dialysis inflow rate) 1,500 mL/m2/hour or more: Administer usual loading dose, then 6 to 12 mg/kg/dose IV or PO every 24 hours.
 
Hybrid hemodialysis†
NOTE: Hybrid treatments include prolonged intermittent renal replacement therapy (PIRRT), sustained low-efficiency dialysis (SLED), slow extended daily dialysis/diafiltration (SLEDD-f), and extended daily dialysis (EDD). Dosing should take into consideration patient-specific factors (e.g., intrinsic renal function), the type of infection, the duration of renal replacement therapy, the ultrafiltration rate, the dialysis flow rate, and how often dialysis sessions occur.[65397]
 
Adults
800 mg IV loading dose, then 400 mg IV every 12 hours or pre- and post-PIRRT achieved at least a 90% probability of pharmacodynamic target attainment for C. albicans for an 8- to 10-hour PIRRT session. Dosing was studied using 4 different PIRRT setting simulations over 8 to 10 hours/day in a Monte Carlo simulation study using population pharmacokinetic data.[65424]
 
Pediatric patients
Fluconazole dosing data are not available in pediatric patients receiving hybrid hemodialysis. Based on adult data, dosage adjustments may be necessary.[65424]

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.
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. When administered concurrently with fluconazole, the systemic exposure of abrocitinib was increased by approximately 4.8-fold, and the combined exposure of abrocitinib and its active metabolites was increased by 2.5-fold. Abrocitinib is a substrate of CYP2C9 and CYP2C19; fluconazole is a moderate CYP2C9 and strong CYP2C19 inducer.
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; 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; Pyrilamine: (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; Ibuprofen: (Moderate) Fluconazole is an inhibitor of CYP2C9, 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 mcg x hour/mL. In contrast, the mean systemic exposure was 122 +/- 32 mcg x hour/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.
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.
Adagrasib: (Contraindicated) Avoid concomitant use of adagrasib and fluconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Coadministration of fluconazole with medications metabolized via CYP3A that are known to prolong the QT interval is contraindicated per the manufacturer of fluconazole. If concomitant use is necessary, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Adagrasib is a CYP3A substrate, fluconazole is a moderate CYP3A inhibitor, and both medications have been associated with QT interval prolongation. No clinically significant differences in adagrasib pharmacokinetics adagrasib are predicted with moderate CYP3A inhibitors.
Albuterol; Budesonide: (Moderate) Avoid coadministration of oral budesonide with fluconazole due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
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; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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 lipid complex (ABLC): (Moderate) In vitro and in vivo animal studies of the combination of amphotericin B and imidazoles suggest that imidazole antifungal agents may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.
Amphotericin B liposomal (LAmB): (Moderate) In vitro and in vivo animal studies of the combination of amphotericin B and imidazoles suggest that imidazole antifungal agents may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.
Amphotericin B: (Moderate) In vitro and in vivo animal studies of the combination of amphotericin B and imidazoles suggest that imidazole antifungal agents may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.
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) Concomitant use of fluconazole and apomorphine 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.
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 regarding concomitant use 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 CYP3A substrates, such as aripiprazole, is contraindicated in patients receiving fluconazole. The manufacturers of aripiprazole products do not contraindicate use of fluconazole, but do recommend dosage reductions in patients who are also receiving a CYP2D6 inhibitor. Specific dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Aripiprazole is a CYP3A and CYP2D6 substrate, fluconazole is a moderate CYP3A inhibitor, and both medications have been associated with QT prolongation.
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; 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; 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.
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.
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.
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.
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) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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.
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) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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%.
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.
Budesonide: (Moderate) Avoid coadministration of oral budesonide with fluconazole due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide with fluconazole due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of oral budesonide with fluconazole due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
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.
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.
Butalbital; Aspirin; 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) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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%.
Capivasertib: (Major) Reduce the dose of capivasertib to 320 mg PO twice daily for 4 days followed by 3 days off if coadministration with fluconazole is necessary; monitor for adverse reactions. Concomitant use may increase capivasertib exposure which may increase the risk for capivasertib-related adverse effects. Capivasertib is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor is predicted to increase the overall exposure of capivasertib by up to 1.5-fold.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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) Monitor carbamazepine concentrations closely during coadministration of fluconazole; carbamazepine dose adjustments may be needed. Concomitant use may increase carbamazepine concentrations. Carbamazepine is a CYP3A substrate and fluconazole is a CYP3A inhibitor.
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) Concomitant use of chloroquine 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.
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; 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; Ibuprofen; Pseudoephedrine: (Moderate) Fluconazole is an inhibitor of CYP2C9, 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 mcg x hour/mL. In contrast, the mean systemic exposure was 122 +/- 32 mcg x hour/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.
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: (Minor) Fluconazole 100 mg was administered as a single oral dose alone and 2 hours after a single dose of cimetidine 400 mg to healthy volunteers (n = 6); after administration of cimetidine, there was a mean decrease in fluconazole AUC of 13% and Cmax decreased by 19%. However, the administration of cimetidine 600 to 900 mg IV over 4 hours (from 1 hour before to 3 hours after a single oral dose of fluconazole 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in healthy volunteers (n = 24).
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: (Moderate) Concomitant use of clofazimine 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.
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) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with fluconazole; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A substrate and fluconazole is a moderate CYP3A 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 inhibit or 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) Avoid concomitant use of colchicine and fluconazole due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Concomitant use increased colchicine overall exposure by 1.4-fold.
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.
Daridorexant: (Major) Limit the daridorexant dose to 25 mg if coadministered with fluconazole. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
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.
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.
Degarelix: (Moderate) Concomitant use of fluconazole and androgen deprivation therapy (i.e., degarelix) 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.
Desflurane: (Major) Concomitant use of fluconazole and halogenated anesthetics 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.
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.
Dexmedetomidine: (Moderate) Concomitant use of dexmedetomidine 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.
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) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with fluconazole is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 and CYP3A substrate and fluconazole is a CYP2C19 and CYP3A inhibitor.
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) Monitor for diclofenac toxicity if coadministered with fluconazole; a diclofenac dosage adjustment may be necessary. Concurrent use may increase diclofenac exposure. Diclofenac is a CYP2C9 substrate and fluconazole is a CYP2C9 inhibitor.
Diclofenac; Misoprostol: (Moderate) Monitor for diclofenac toxicity if coadministered with fluconazole; a diclofenac dosage adjustment may be necessary. Concurrent use may increase diclofenac exposure. Diclofenac is a CYP2C9 substrate and fluconazole is a CYP2C9 inhibitor.
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.
Dihydroergotamine: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of fluconazole is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and fluconazole is a moderate CYP3A inhibitor.
Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with fluconazole is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Diphenhydramine; Ibuprofen: (Moderate) Fluconazole is an inhibitor of CYP2C9, 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 mcg x hour/mL. In contrast, the mean systemic exposure was 122 +/- 32 mcg x hour/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) Concomitant use of fluconazole and dolasetron 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.
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) Concomitant use of fluconazole and donepezil 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.
Donepezil; Memantine: (Moderate) Concomitant use of fluconazole and donepezil 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.
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 if coadministration of fluconazole with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
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) Concomitant use of fluconazole and efavirenz 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.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Concomitant use of fluconazole and efavirenz 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.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Concomitant use of fluconazole and efavirenz 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.
Elacestrant: (Major) Avoid concomitant use of elacestrant and fluconazole due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Concomitant use with fluconazole increased elacestrant overall exposure by 2.3-fold.
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. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A, and fluconazole is a moderate CYP3A inhibitor. Coadministration of other moderate CYP3A inhibitors increased the eletriptan AUC by 2 to 4-fold.
Elexacaftor; tezacaftor; ivacaftor: (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. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to every other day in the morning when coadministered with fluconazole; omit the ivacaftor evening dose and administer in the morning every other day alternating with elexacaftor; tezacaftor; ivacaftor (i.e., recommended dose of elexacaftor; tezacaftor; ivacaftor on day 1 in the morning and recommended dose of ivacaftor on day 2 in the morning). Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; fluconazole is a moderate CYP3A inhibitor. Coadministration increased ivacaftor exposure by 2.9-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2.1-fold, respectively.
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; 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; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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) Fluconazole use in contraindicated with other medications that may prolong the QT interval and are metabolized via CYP3A, such as encorafenib. Avoid concomitant use of encorafenib and fluconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase encorafenib exposure and the risk for other encorafenib-related adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Encorafenib is a CYP3A substrate, fluconazole is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Entrectinib: (Major) Avoid concomitant use of entrectinib with fluconazole due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, fluconazole is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of a moderate CYP3A inhibitor is predicted to increase the overall exposure 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) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of fluconazole is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and fluconazole is a moderate CYP3A inhibitor.
Ergot alkaloids: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of fluconazole is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and fluconazole is a moderate CYP3A inhibitor.
Ergotamine: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of fluconazole is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and fluconazole is a moderate CYP3A inhibitor.
Ergotamine; 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. (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of fluconazole is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and fluconazole is a moderate CYP3A inhibitor.
Eribulin: (Major) Concomitant use of eribulin 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.
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.
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: (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.
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.
Etrasimod: (Major) Avoid concomitant use of etrasimod and fluconazole due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Etrasimod is a CYP2C9 and CYP3A substrate and fluconazole is a moderate CYP2C9 and moderate CYP3A inhibitor. Concomitant use with a moderate CYP2C9 and moderate CYP3A inhibitor increased etrasimod overall exposure by 84%. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
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.
Fedratinib: (Moderate) Closely monitor for an increase in fedratinib-related adverse effects if coadministered with fluconazole. Coadministration may increase fedratinib exposure. Fedratinib is a CYP3A and CYP2C19 substrate; fluconazole is an inhibitor of both CYP3A and CYP2C19. Coadministration is predicted to increase fedratinib exposure by approximately 1.5-fold at steady-state.
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.
Fexinidazole: (Major) Concomitant use of fexinidazole 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. Additionally, monitor for decreased fexinidazole efficacy if coadministration is necessary. Concomitant use may limit conversion of fexinidazole to its active metabolites. Fexinidazole is converted to its active metabolites via CYP3A and fluconazole is a moderate CYP3A inhibitor.
Finasteride; Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with fluconazole is necessary. Tadalafil is a CYP3A4 substrate and fluconazole is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
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) Concomitant use of fluconazole and fingolimod 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.
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.
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.
Fluvastatin: (Major) Avoid coadministration of fluvastatin extended release (ER) and fluconazole. Limit the fluvastatin immediate release (IR) dose to 20 mg twice daily and monitor for signs of myopathy and rhabdomyolysis if concomitant use with fluconazole is necessary. Concomitant use may increase fluvastatin expos ure and the risk for fluvastatin-related adverse effects. Fluvastatin is a CYP2C9 substrate and fluconazole is a CYP2C9 inhibitor. Concomitant use with fluconazole increased fluvastatin exposure by 84%.
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: (Major) Advise patients to avoid cannabis use during fluconazole treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoid delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A and CYP2C9 substrates and fluconazole is a moderate CYP3A and CYP2C9 inhibitor.
Fosamprenavir: (Moderate) Monitor for increased fosamprenavir toxicity if coadministered with fluconazole. Concurrent use may increase the plasma concentrations of fosamprenavir. Fosamprenavir is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Foscarnet: (Major) Concomitant use of foscarnet 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.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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) Monitor phenytoin concentrations during concomitant therapy with fosphenytoin and fluconazole due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. The incidence of abnormally elevated serum transaminases was higher in patients taking fluconazole concomitantly with phenytoin. A mean increase of 88% in phenytoin serum AUC has been seen in some healthy volunteers taking both fluconazole and phenytoin. Fosphenytoin is a CYP2C9 and CYP2C19 substrate and fluconazole is a CYP2C9 and CYP2C19 inhibitor.
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) Concomitant use of fluconazole and gemifloxacin 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.
Gemtuzumab Ozogamicin: (Moderate) Concomitant use of fluconazole and gemtuzumab ozogamicin 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.
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) Monitor for an increase in glimepiride-related adverse reactions, such as hypoglycemia, if coadministration with fluconazole is necessary. Concomitant use resulted in a more than 100% increase in glimepiride AUC in healthy volunteers. Glimepiride is a CYP2C9 substrate; fluconazole is a moderate CYP2C9 inhibitor.
Glipizide: (Moderate) Monitor for an increase in glipizide-related adverse reactions, such as hypoglycemia, if coadministration with fluconazole is necessary. Concomitant use has resulted in significant increases in the AUCs (roughly 49% or more) and Cmax (roughly 20%) of glipizide in healthy volunteers. In some cases, dosage adjustment of the sulfonylurea may be necessary. Glipizide is a CYP2C9 substrate; fluconazole is a moderate CYP2C9 inhibitor.
Glipizide; Metformin: (Moderate) Monitor for an increase in glipizide-related adverse reactions, such as hypoglycemia, if coadministration with fluconazole is necessary. Concomitant use has resulted in significant increases in the AUCs (roughly 49% or more) and Cmax (roughly 20%) of glipizide in healthy volunteers. In some cases, dosage adjustment of the sulfonylurea may be necessary. Glipizide is a CYP2C9 substrate; fluconazole is a moderate CYP2C9 inhibitor.
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) Concomitant use of fluconazole and androgen deprivation therapy (i.e., goserelin) 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.
Granisetron: (Moderate) Concomitant use of fluconazole and granisetron 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.
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.
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.
Halogenated Anesthetics: (Major) Concomitant use of fluconazole and halogenated anesthetics 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.
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.
Histrelin: (Moderate) Concomitant use of fluconazole and androgen deprivation therapy (i.e., histrelin) 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.
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 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.
Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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%.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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%.
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.
Hydrocodone; Ibuprofen: (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. (Moderate) Fluconazole is an inhibitor of CYP2C9, 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 mcg x hour/mL. In contrast, the mean systemic exposure was 122 +/- 32 mcg x hour/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.
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.
Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine 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.
Hydroxyzine: (Moderate) Concomitant use of hydroxyzine 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.
Ibrutinib: (Major) If ibrutinib is coadministered with fluconazole, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if fluconazole is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Ibuprofen: (Moderate) Fluconazole is an inhibitor of CYP2C9, 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 mcg x hour/mL. In contrast, the mean systemic exposure was 122 +/- 32 mcg x hour/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.
Ibuprofen; Famotidine: (Moderate) Fluconazole is an inhibitor of CYP2C9, 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 mcg x hour/mL. In contrast, the mean systemic exposure was 122 +/- 32 mcg x hour/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.
Ibuprofen; 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. (Moderate) Fluconazole is an inhibitor of CYP2C9, 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 mcg x hour/mL. In contrast, the mean systemic exposure was 122 +/- 32 mcg x hour/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.
Ibuprofen; Pseudoephedrine: (Moderate) Fluconazole is an inhibitor of CYP2C9, 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 mcg x hour/mL. In contrast, the mean systemic exposure was 122 +/- 32 mcg x hour/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.
Ibutilide: (Major) Use caution during concurrent use of ibutilide and fluconazole. Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. Fluconazole has also been associated with QT prolongation and rare cases of TdP.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with fluconazole is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Fluconazole is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Contraindicated) The concurrent use of fluconazole and iloperidone is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Fluconazole inhibits CYP3A4, an isoenzyme partially responsible for the metabolism of iloperidone. These drugs used in combination may result in elevated iloperidone plasma concentrations, causing an increased risk for iloperidone-related adverse events, such as QT prolongation. Additionally, fluconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; do not use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as iloperidone.
Imatinib: (Moderate) Fluconazole may inhibit the metabolism of imatinib, STI-571 via cytochrome P450 3A4. Increased imatinib serum levels and toxicity may result with concurrent use of fluconazole. Close monitor patients for any signs of toxicity.
Imipramine: (Major) 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). Fluconazole has been reported to increase the effects of certain TCAs, perhaps through inhibition of the hepatic microsomal CYP2C19 or CYP3A4 isoenzymes and may result in an increased incidence of TCA-related side effects, like dizziness and syncope. Imipramine may be affected by this potential interaction due to the drug's metabolic pathways, but specific data are lacking.
Indinavir: (Moderate) Due to effects on cytochrome P450 3A4, the combination of indinavir and fluconazole may result in changes in concentrations of one or both of the agents.
Infigratinib: (Major) Avoid concomitant use of infigratinib and fluconazole. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with fluconazole due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Fluconazole has been associated with QT prolongation and rare cases of TdP.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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%.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with fluconazole may result in increased serum concentrations of isavuconazonium. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of the hepatic isoenzyme CYP3A4; fluconazole is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoflurane: (Major) Concomitant use of fluconazole and halogenated anesthetics 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.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin is a potent enzyme inducer and can increase the metabolism of fluconazole. Administration of fluconazole 200 mg PO after 15 days of rifampin 600 mg PO daily to 8 healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in fluconazole apparent oral clearance. The AUC was reduced by about 23% and the apparent oral clearance was increased by about 32%. Fluconazole half-life decreased from approximately 33 hours to approximately 27 hours. The dose of fluconazole may need to be increased in patients also receiving rifampin to assure adequate fluconazole plasma concentrations. Although available data are inconclusive, rifabutin may be less likely than rifampin to interact with fluconazole in this manner.
Isoniazid, INH; Rifampin: (Moderate) Rifampin is a potent enzyme inducer and can increase the metabolism of fluconazole. Administration of fluconazole 200 mg PO after 15 days of rifampin 600 mg PO daily to 8 healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in fluconazole apparent oral clearance. The AUC was reduced by about 23% and the apparent oral clearance was increased by about 32%. Fluconazole half-life decreased from approximately 33 hours to approximately 27 hours. The dose of fluconazole may need to be increased in patients also receiving rifampin to assure adequate fluconazole plasma concentrations. Although available data are inconclusive, rifabutin may be less likely than rifampin to interact with fluconazole in this manner.
Isradipine: (Moderate) Fluconazole may decrease the clearance of calcium-channel blockers, including isradipine, via inhibition of CYP3A4 metabolism. Monitor blood pressure closely during concurrent use of these medications.
Itraconazole: (Major) Typically fluconazole and itraconazole would not be used in combination due to similar mechanisms of action and indications for use (duplicate therapies). Fluconazole may inhibit the CYP3A4 metabolism of itraconazole, resulting in increased itraconazole serum concentrations. Furthermore, all systemic azole antifungal agents have been associated with prolongation of the QT interval. Coadministration would increase the risk of QT prolongation.
Ivabradine: (Major) Avoid coadministration of ivabradine and fluconazole as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; fluconazole inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
Ivacaftor: (Major) If fluconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with fluconazole due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Fluconazole is a moderate CYP3A4 inhibitor that has also been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration with fluconazole is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of fluconazole with ivosidenib are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control. Additive QT prolongation may also occur.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of fluconazole is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Lacosamide: (Moderate) Use caution during concurrent use of lacosamide and fluconazole, particularly in patients with renal or hepatic impairment. Patients with renal or hepatic impairment may have significantly increased exposure to lacosamide if coadministered with fluconazole. Dosage reduction of lacosamide may be necessary in this population. Lacosamide is a CYP3A4, CYP2C9, CYP2C19 substrate; fluconazole is a potent inhibitor of CYP2C19 and a moderate inhibitor of CYP3A4 and CYP2C9.
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.
Lansoprazole; Amoxicillin; 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.
Lapatinib: (Contraindicated) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as lapatinib, is contraindicated according to the manufacturer of fluconazole. The manufacturer of lapatinib recommends avoidance of concurrent use if possible, but if unavoidable, decrease the dose of lapatinib to 500 mg PO once daily while monitoring ECGs and electrolytes. Correct any electrolyte abnormalities prior to treatment. If fluconazole is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Fluconazole is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and torsade de pointes. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold.
Larotrectinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with fluconazole is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration with fluconazole is predicted to increase larotrectinib exposure by 2.7-fold.
Lefamulin: (Major) Avoid coadministration of lefamulin with fluconazole as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Fluconazole is a moderate CYP3A4 that has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Lemborexant: (Major) Avoid coadministration of lemborexant and fluconazole as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. In a drug interaction study, fluconazole increased the lemborexant AUC by up to 4.5-fold.
Lenvatinib: (Major) Concomitant use of lenvatinib 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.
Lesinurad: (Moderate) Use lesinurad and fluconazole together with caution; fluconazole may increase the systemic exposure of lesinurad. Fluconazole is a moderate inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate. The enzyme-inhibiting effect of fluconazole persists 4 to 5 days after discontinuation of fluconazole treatment due to its long half-life.
Lesinurad; Allopurinol: (Moderate) Use lesinurad and fluconazole together with caution; fluconazole may increase the systemic exposure of lesinurad. Fluconazole is a moderate inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate. The enzyme-inhibiting effect of fluconazole persists 4 to 5 days after discontinuation of fluconazole treatment due to its long half-life.
Leuprolide: (Moderate) Concomitant use of fluconazole and androgen deprivation therapy (i.e., leuprolide) 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.
Leuprolide; Norethindrone: (Moderate) Concomitant use of fluconazole and androgen deprivation therapy (i.e., leuprolide) 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.
Levamlodipine: (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.
Levofloxacin: (Moderate) Concomitant use of levofloxacin 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.
Levonorgestrel; 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.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (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.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (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.
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.
Lidocaine; Epinephrine: (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.
Lidocaine; Prilocaine: (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.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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%.
Lithium: (Moderate) Concomitant use of fluconazole and lithium 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.
Lofexidine: (Major) Concomitant use of lofexidine 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.
Lomitapide: (Contraindicated) Concomitant use of fluconazole and lomitapide is contraindicated. If treatment with fluconazole is unavoidable, lomitapide should be stopped during the course of treatment. Fluconazole is a moderate CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor. Although concomitant use of moderate CYP3A4 inhibitors with lomitapide has not been studied, a significant increase in lomitapide exposure is likely during concurrent use.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and fluconazole is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and a CYP2C9 substrate; fluconazole is a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor.
Loperamide: (Contraindicated) Avoid concomitant use of loperamide and fluconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Loperamide; Simethicone: (Contraindicated) Avoid concomitant use of loperamide and fluconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with fluconazole due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Based on metabolic profiles, clinically significant pharmacokinetic drug interactions are not expected. (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.
Lorlatinib: (Major) Avoid concomitant use of lorlatinib and fluconazole due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. If concomitant use is necessary, reduce the starting dose of lorlatinib to 75 mg PO once daily. Lorlatinib is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Concomitant use with fluconazole 200 mg once daily is predicted to increase the steady-state AUC of lorlatinib by 59%.
Losartan: (Moderate) Closely monitor blood pressure during coadministration of losartan and fluconazole; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; fluconazole is a moderate CYP2C9 inhibitor. Coadministration with fluconazole in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure during coadministration of losartan and fluconazole; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; fluconazole is a moderate CYP2C9 inhibitor. Coadministration with fluconazole in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%. (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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%.
Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fluconazole is necessary. Concomitant use may increase lovastatin exposure. Lovastatin is a sensitive substrate of CYP3A and fluconazole is a moderate CYP3A inhibitor.
Lumacaftor; Ivacaftor: (Major) If fluconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold.
Lumateperone: (Major) Reduce the dose of lumateperone to 21 mg once daily if concomitant use of fluconazole is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased lumateperone exposure by approximately 2-fold.
Lurasidone: (Major) Fluconazole is a moderate inhibitor of CYP3A4 and has the potential for interactions with substrates of CYP3A4 such as lurasidone. Concurrent use of these medications may lead to an increased risk of lurasidone-related adverse reactions. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and fluconazole due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. If concomitant use is unavoidable, consider reducing the dose of lurbinectedin if clinically indicated. Lurbinectedin is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as fluconazole. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Macitentan: (Major) Avoid coadministration of macitentan with fluconazole due to the potential for increases in macitentan exposure and adverse effects. Macitentan is a CYP3A4 and CYP2C9 substrate and fluconazole is a dual moderate CYP3A4 and CYP2C9 inhibitor. Concomitant use is predicted to increase macitentan exposure approximately 4-fold.
Maprotiline: (Moderate) Concomitant use of fluconazole and maprotiline 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.
Maraviroc: (Moderate) Use caution if coadministration of maraviroc with fluconazole is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A substrate and fluconazole is a CYP3A4 inhibitor. Monitor for an increase in adverse effects with concomitant use.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with fluconazole due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure. Mavacamten is a CYP2C19 and CYP3A substrate and fluconazole is a strong CYP2C19 inhibitor and a moderate CYP3A inhibitor. The impact that a CYP3A inhibitor may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a moderate CYP3A inhibitor increased mavacamten overall exposure by 15% in CYP2C19 normal and intermediate metabolizers; concomitant use in poor metabolizers is predicted to increase mavacamten exposure by up to 55%.
Mefenamic Acid: (Moderate) Mefenamic acid is a substrate for CYP450 2C9. Inhibitors of the 2C9 isoenzyme, such as fluconazole, may lead to increased serum concentrations of mefenamic acid. If coadministered, monitor for NSAID related side effects, such as fluid retention or GI irritation, or renal dysfunction; adjust the mefenamic acid dose, if needed.
Mefloquine: (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 mefloquine, 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 mefloquine, causing an increased risk for adverse events such as QT prolongation.
Meglitinides: (Moderate) Fluconazole should be used cautiously with oral hypoglycemic agents (i.e., nateglinide, repaglinide) because blood glucose response may be altered in patients with diabetes. However, concurrent fluconazole and nateglinide use did not significantly affect blood glucose concentrations despite an increase in the nateglinide AUC by 48% and an increase in the nateglinide half-life from 1.6 to 1.9 hours. The increases in systemic exposure and half-life of nateglinide may be due to fluconazole's inhibition of CYP2C9, which has been shown to participate in nateglinide's metabolism in vitro. Blood glucose concentrations should be monitored during fluconazole treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary.
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.
Metformin; Repaglinide: (Moderate) Fluconazole should be used cautiously with oral hypoglycemic agents (i.e., nateglinide, repaglinide) because blood glucose response may be altered in patients with diabetes. However, concurrent fluconazole and nateglinide use did not significantly affect blood glucose concentrations despite an increase in the nateglinide AUC by 48% and an increase in the nateglinide half-life from 1.6 to 1.9 hours. The increases in systemic exposure and half-life of nateglinide may be due to fluconazole's inhibition of CYP2C9, which has been shown to participate in nateglinide's metabolism in vitro. Blood glucose concentrations should be monitored during fluconazole treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary.
Methadone: (Major) Administer fluconazole and methadone concomitantly with caution. Both fluconazole and methadone are associated with QT prolongation and torsade de pointes (TdP). Additionally, fluconazole is a CYP3A4, CYP2C19, and CYP2C9 inhibitor and methadone is a CYP3A4, CYP2C19, and CYP2C9 substrate; therefore, increased concentrations of methadone may occur which may result in prolonged duration of action, increased sedation, respiratory depression, QT prolongation, or other side effect. The manufacturer of fluconazole states dosage adjustments of methadone may be necessary during concomitant therapy with fluconazole.
Methohexital: (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.
Methylergonovine: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of fluconazole is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and fluconazole is a moderate CYP3A inhibitor.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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%.
Metronidazole: (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.
Midazolam: (Moderate) Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway can potentiate the clinical effects of midazolam. Interactions of this type are most pronounced with oral midazolam. However, the pharmacokinetics of IV midazolam may also be affected to a lesser extent.
Midostaurin: (Contraindicated) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as midostaurin, is contraindicated. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. During post-marketing surveillance, rare cases of QT prolongation and torsade de pointes have been reported with fluconazole use.
Mifepristone: (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 f luconazole include mifepristone.
Mirtazapine: (Moderate) Concomitant use of fluconazole and mirtazapine 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.
Mitapivat: (Moderate) Do not exceed mitapivat 20 mg PO twice daily during coadministration with fluconazole and monitor hemoglobin and for adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Fluconazole increased mitapivat overall and peak exposure by approximately 2.6-fold and 1.6-fold, respectively, after mitapivat 5, 20, or 50 mg twice daily.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and fluconazole; reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently if use is necessary. Concomitant use increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase mobocertinib exposure and the risk for mobocertinib-related adverse reactions. Mobocertinib is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%.
Modafinil: (Moderate) Modafinil is significantly metabolized by the CYP3A4 hepatic microsomal enzyme system. Azole antifungals, such as fluconazole, are significant inhibitors of this isoenzyme and may reduce the clearance of modafinil.
Moxifloxacin: (Major) Concomitant use of fluconazole and moxifloxacin 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.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with fluconazole. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor.
Naloxegol: (Major) Avoid concomitant administration of naloxegol and fluconazole due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with fluconazole is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of fluconazole. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Naproxen; 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.
Nateglinide: (Moderate) Fluconazole should be used cautiously with oral hypoglycemic agents (i.e., nateglinide, repaglinide) because blood glucose response may be altered in patients with diabetes. However, concurrent fluconazole and nateglinide use did not significantly affect blood glucose concentrations despite an increase in the nateglinide AUC by 48% and an increase in the nateglinide half-life from 1.6 to 1.9 hours. The increases in systemic exposure and half-life of nateglinide may be due to fluconazole's inhibition of CYP2C9, which has been shown to participate in nateglinide's metabolism in vitro. Blood glucose concentrations should be monitored during fluconazole treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary.
Neratinib: (Major) Avoid concomitant use of fluconazole with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a CYP3A4 inhibitor, such as fluconazole, can increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Nevirapine: (Moderate) Monitor for an increase in nevirapine-related adverse reactions if coadministration with fluconazole is necessary. Nevirapine is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Coadministration with fluconazole increased nevirapine exposure by 100%.
Nicardipine: (Moderate) Fluconazole may decrease the clearance of calcium-channel blockers, including nicardipine, via inhibition of CYP3A4 metabolism.
NIFEdipine: (Moderate) Fluconazole may decrease the clearance of calcium-channel blockers, including nifedipine, via inhibition of CYP3A4 metabolism. Consider initiating nifedipine therapy with the lowest available dose if coadminstered with fluconazole. Monitor blood pressure closely during concurrent use of these medications.
Nilotinib: (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 nilotinib, 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 nilotinib, causing an increased risk for adverse events such as QT prolongation.
Nimodipine: (Moderate) Fluconazole may decrease the clearance of calcium-channel blockers, including nimodipine, via inhibition of CYP3A4 metabolism. Monitor blood pressure closely during concurrent use of these medications.
Nirmatrelvir; Ritonavir: (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.
Nirogacestat: (Major) Avoid concomitant use of nirogacestat and fluconazole due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Concomitant use is predicted to increase nirogacestat overall exposure by 3.18-fold.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with fluconazole due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and fluconazole is a CYP3A4 inhibitor.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (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.
Norethindrone; 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.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (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.
Norgestimate; 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.
Nortriptyline: (Major) Use fluconazole and tricyclic antidepressants (TCAs) together 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 and CYP3A4. Both CYP2C19 and CYP3A4 may be 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 torsade de pointes occurred. Nortriptyline may be affected by this potential interaction, but specific data are lacking.
Ofloxacin: (Moderate) Concomitant use of ofloxacin 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.
Olanzapine: (Moderate) Concomitant use of fluconazole and olanzapine 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.
Olanzapine; 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. (Moderate) Concomitant use of fluconazole and olanzapine 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.
Olanzapine; Samidorphan: (Moderate) Concomitant use of fluconazole and olanzapine 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.
Olaparib: (Major) Avoid coadministration of olaparib with fluconazole due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 150 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after fluconazole is discontinued. Olaparib is a CYP3A substrate and fluconazole is a moderate CYP3A4 inhibitor. Coadministration with fluconazole is predicted to increase the olaparib Cmax by 14% and the AUC by 121%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and fluconazole is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and fluconazole may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If fluconazole is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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%.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and fluconazole. If concomitant use is necessary, decrease omaveloxolone dose to 100 mg once daily; additional dosage reductions may be necessary. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased omaveloxolone overall exposure by 1.25-fold.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Monitor for rifabutin-associated adverse effects with concomitant fluconazole use. Reduce the rifabutin dose or discontinue rifabutin if toxicity is suspected. Carefully monitor for uveitis when rifabutin is given concomitantly with fluconazole. If uveitis is suspected, refer the patient to an ophthalmologist, and if considered necessary, discontinue rifabutin. Coadministration of fluconazole increased the rifabutin AUC by 82% and Cmax by 88%.
Ondansetron: (Contraindicated) Concomitant administration of fluconazole and drugs that both prolong the QT interval and are CYP3A4 substrates is contraindicated according to the FDA-approved product labeling. The exact risk for QT prolongation when fluconazole and ondansetron are administered together has not been clearly defined. If ondansetron and fluconazole are administered together, extreme caution and careful monitoring is advised, especially if higher doses are used or if other drugs that may affect CYP1A2 or CYP2D6 are also given. Fluconazole is a CYP3A4 inhibitor. Ondansetron is metabolized by CYP3A, CYP1A2, and CYP2D6. In vivo microsomal inhibition data has suggested that no single isoenzyme dominates ondansetron's metabolism thereby making clinically significant interactions due to inhibition of a single isoenzyme unlikely; however, since the publication of this data, ondansetron has been found to produce concentration-dependent QT prolongation. It is not clear what degree of enzyme inhibition or increased concentration is required to increase the risk of QT prolongation. Inhibition of CYP3A isoenzymes is likely to increase with higher fluconazole doses (>= 200 mg/day in adults).
Osilodrostat: (Moderate) Concomitant use of fluconazole and osilodrostat 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.
Osimertinib: (Major) Concomitant use of osimertinib 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.
Ospemifene: (Major) Do not use fluconazole concomitantly with ospemifene. Fluconazole (a CYP3A4, CYP2C9, and CYP2C19 inhibitor) increases the systemic exposure of ospemifene by 2.7-fold and may increase the risk of ospemifene-related adverse reactions.
Oxaliplatin: (Major) Concomitant use of oxaliplatin 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.
Oxybutynin: (Moderate) Monitor for oxybutynin-related adverse reactions if coadministration with fluconazole is necessary. Oxybutynin is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Concomitant use with moderate CYP3A inhibitors may alter the mean pharmacokinetic parameters of oxybutynin, although the clinical relevance of these potential interactions is unknown.
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.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking fluconazole due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Fluconazole has been associated with QT prolongation and rare cases of TdP.
Paclitaxel: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. The metabolism of paclitaxel may be inhibited by drugs that inhibit these enzymes, including fluconazole. Closely monitor patients for toxicity when administering paclitaxel with fluconazole.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with fluconazole is contraindicated due to an increased risk for QT/QTc prolongation and torsade de pointes (TdP). Increased pacritinib exposure may also occur which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and fluconazole is a mosderate CYP3A inhibitor.
Paliperidone: (Contraindicated) The concurrent use of fluconazole and paliperidone is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Fluconazole is an inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of paliperidone. These drugs used in combination may result in elevated paliperidone plasma concentrations, causing an increased risk for paliperidone-related adverse events, such as QT prolongation. Additionally, fluconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as paliperidone.
Palovarotene: (Major) Avoid concomitant use of palovarotene and fluconazole due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. If concomitant use is necessary, decrease the palovarotene dose by half. Palovarotene is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased palovarotene overall exposure by 2.5-fold.
Panobinostat: (Contraindicated) Because of the potential for QT prolongation and torsade de pointes, the concomitant use of fluconazole and panobinostat is contraindicated. Fluconazole is a CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial.
Paricalcitol: (Moderate) Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as fluconazole. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
Pasireotide: (Moderate) Concomitant use of fluconazole and pasireotide 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.
Pazopanib: (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 pazopanib, 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 pazopanib, causing an increased risk for adverse events such as QT prolongation.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and fluconazole due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If fluconazole is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of fluconazole. Pemigatinib is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%.
Pentamidine: (Major) Intravenous pentamidine has been associated with QT prolongation and should be used with caution in combination with fluconazole. Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP).
Pentobarbital: (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.
Perindopril; 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.
Perphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering fluconazole with perphenazine. Fluconazole has been associated with QT prolongation and rare cases of TdP. Perphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Perphenazine; Amitriptyline: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering fluconazole with perphenazine. Fluconazole has been associated with QT prolongation and rare cases of TdP. Perphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation. (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.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and fluconazole due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If fluconazole is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of fluconazole. Pexidartinib is a CYP3A substrate; fluconazole is a moderate CYP3A inhibitor. Coadministration of fluconazole is predicted to increase the pexidartinib overall exposure by 67%.
Phenobarbital: (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.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (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.
Phenytoin: (Moderate) Monitor phenytoin concentrations during concomitant therapy with fluconazole due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. The incidence of abnormally elevated serum transaminases was higher in patients taking fluconazole concomitantly with phenytoin. A mean increase of 88% in phenytoin serum AUC has been seen in some healthy volunteers taking both fluconazole and phenytoin. Phenytoin is a CYP2C9 and CYP2C19 substrate and fluconazole is a CYP2C9 and CYP2C19 inhibitor.
Pimavanserin: (Contraindicated) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are CYP3A4 substrates is contraindicated. Fluconazole has been associated with QT prolongation; pimavanserin has been associated with QT prolongation and is primarily metabolized by CYP3A4/3A5.
Pimozide: (Contraindicated) Concurrent use of fluconazole and pimozide is contraindicated. Fluconazole has been associated with QT prolongation and pimozide has been specifically established to have a causal association with QT prolongation and torsade de pointes (TdP). Additionaly, fluconazole inhibits CYP3A4 and concomitant use of pimozide with CYP3A4 inhibitors is contraindicated; rare cases of QT prolongation, ventricular arrhythmia and sudden death have occured during coadministration of pimozide with CYP3A4 inhibitor.
Pioglitazone; Glimepiride: (Moderate) Monitor for an increase in glimepiride-related adverse reactions, such as hypoglycemia, if coadministration with fluconazole is necessary. Concomitant use resulted in a more than 100% increase in glimepiride AUC in healthy volunteers. Glimepiride is a CYP2C9 substrate; fluconazole is a moderate CYP2C9 inhibitor.
Pitolisant: (Major) Concomitant use of pitolisant 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.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking fluconazole due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Fluconazole has been associated with QT prolongation and rare cases of TdP.
Posaconazole: (Major) Concomitant use of posaconazole 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.
Pralsetinib: (Major) Avoid concomitant use of fluconazole with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration is predicted to increase the overall exposure of pralsetinib by 71%.
Primaquine: (Moderate) Concomitant use of fluconazole and primaquine 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.
Primidone: (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.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and fluconazole due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Concomitant use increased colchicine overall exposure by 1.4-fold.
Procainamide: (Major) Concomitant use of procainamide 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.
Prochlorperazine: (Minor) Use fluconazole with caution in combination with prochlorperazine 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). Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Progesterone: (Minor) The metabolism of progesterone may be inhibited by fluconazole, an inhibitor of cytochrome P450 3A4 hepatic enzymes.
Promethazine: (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.
Promethazine; Dextromethorphan: (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.
Promethazine; Phenylephrine: (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.
Propafenone: (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 propafenone, 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 propafenone, causing an increased risk for adverse events such as QT prolongation.
Protriptyline: (Minor) Use fluconazole and tricyclic antidepressants (TCAs) together 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 and CYP3A4. Both CYP2C19 and CYP3A4 may be 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 torsade de pointes occurred. Protriptyline may be affected by this potential interaction, but specific data are lacking.
Quazepam: (Moderate) CYP3A4 inhibitors, such as fluconazole, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity.
Quetiapine: (Contraindicated) Concurrent use of fluconazole and quetiapine 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 quetiapine. These drugs used in combination may result in elevated quetiapine plasma concentrations, causing an increased risk for quetiapine-related 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 quetiapine.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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%.
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.
Quinine: (Contraindicated) Concurrent use of fluconazole and quinine is contraindicated due to the risk of life-threatening arrhythmias such as torsade de pointes (TdP). Both fluconazole and quinine have been associated with QT prolongation and rare cases of TdP. In addition, fluconazole is an inhibitor of CYP3A4 and quinine is a CYP3A4 substrate. Coadministration may result in an elevated quinine plasma concentrations, causing an increased risk for adverse events, such as QT prolongation.
Quizartinib: (Major) Concomitant use of quizartinib 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.
Ramelteon: (Moderate) The AUC and Cmax of ramelteon after a single 16 mg dose was increased by approximately 150% when administered with fluconazole (a CYP2C9 inhibitor). Ramelteon should be administered with caution in subjects taking CYP2C9 inhibitors such as fluconazole. The patient should be monitored closely for toxicity from ramelteon.
Ranolazine: (Major) Limit the dose of ranolazine to 500 mg twice daily if administered with fluconazole as increased ranolazine exposure may occur; concurrent use may also increase the risk of QT prolongation. Ranolazine is a CYP3A4 substrate that is associated with dose- and plasma concentration-related increases in the QTc interval. Fluconazole is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Plasma levels of ranolazine were increased 50% to 130% when administered with moderate CYP3A4 inhibitors in drug interaction studies.
Red Yeast Rice: (Contraindicated) The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if lovastatin is administered concomitantly with CYP3A4 inhibitors, such as fluconazole. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity and certain products (i.e., pre-2005 Cholestin formulations) contain lovastatin, red yeast rice should not be used in combination with fluconazole.
Relugolix: (Moderate) Concomitant use of fluconazole and androgen deprivation therapy (i.e., relugolix) 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.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Concomitant use of fluconazole and androgen deprivation therapy (i.e., relugolix) 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. (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.
Repaglinide: (Moderate) Fluconazole should be used cautiously with oral hypoglycemic agents (i.e., nateglinide, repaglinide) because blood glucose response may be altered in patients with diabetes. However, concurrent fluconazole and nateglinide use did not significantly affect blood glucose concentrations despite an increase in the nateglinide AUC by 48% and an increase in the nateglinide half-life from 1.6 to 1.9 hours. The increases in systemic exposure and half-life of nateglinide may be due to fluconazole's inhibition of CYP2C9, which has been shown to participate in nateglinide's metabolism in vitro. Blood glucose concentrations should be monitored during fluconazole treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with fluconazole due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Repotrectinib is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Ribociclib: (Contraindicated) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are CYP3A4 substrates, such as ribociclib, is contraindicated. Fluconazole has been associated with QT prolongation. Additionally, the systemic exposure of ribociclib may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; fluconazole also prolongs the QT interval. Concomitant use may increase the risk for QT prolongation. Ribociclib is also extensively metabolized by CYP3A4 and fluconazole is a moderate CYP3A4 inhibitor.
Ribociclib; Letrozole: (Contraindicated) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are CYP3A4 substrates, such as ribociclib, is contraindicated. Fluconazole has been associated with QT prolongation. Additionally, the systemic exposure of ribociclib may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; fluconazole also prolongs the QT interval. Concomitant use may increase the risk for QT prolongation. Ribociclib is also extensively metabolized by CYP3A4 and fluconazole is a moderate CYP3A4 inhibitor.
Rifabutin: (Moderate) Monitor for rifabutin-associated adverse effects with concomitant fluconazole use. Reduce the rifabutin dose or discontinue rifabutin if toxicity is suspected. Carefully monitor for uveitis when rifabutin is given concomitantly with fluconazole. If uveitis is suspected, refer the patient to an ophthalmologist, and if considered necessary, discontinue rifabutin. Coadministration of fluconazole increased the rifabutin AUC by 82% and Cmax by 88%.
Rifampin: (Moderate) Rifampin is a potent enzyme inducer and can increase the metabolism of fluconazole. Administration of fluconazole 200 mg PO after 15 days of rifampin 600 mg PO daily to 8 healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in fluconazole apparent oral clearance. The AUC was reduced by about 23% and the apparent oral clearance was increased by about 32%. Fluconazole half-life decreased from approximately 33 hours to approximately 27 hours. The dose of fluconazole may need to be increased in patients also receiving rifampin to assure adequate fluconazole plasma concentrations. Although available data are inconclusive, rifabutin may be less likely than rifampin to interact with fluconazole in this manner.
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.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with fluconazole; concurrent use may increase rimegepant exposure. Rimegepant is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor.
Risperidone: (Moderate) Concomitant use of fluconazole and risperidone 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.
Ritonavir: (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.
Romidepsin: (Contraindicated) Concurrent use of fluconazole and romidepsin is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Fluconazole inhibits CYP3A4, an isoenzyme responsible for the metabolism of romidepsin. These drugs used in combination may result in elevated romidepsin plasma concentrations, causing an increased risk for romidepsin-related adverse events, such as QT prolongation. Additionally, fluconazole has been associated with prolongation of the QT interval as well as rare cases of TdP.
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.
Ruxolitinib: (Major) Avoid concomitant use of ruxolitinib with fluconazole doses greater than 200 mg/day; increased exposure and toxicity may occur. Modify the ruxolitinib dosage as follows in patients receiving fluconazole doses of 200 mg/day or less. In patients with graft-versus-host disease (GVHD), reduce the initial ruxolitinib dosage to 5 mg PO once daily in patients with acute GVHD and 5 mg twice daily in patients with chronic GVHD. In myelofibrosis (MF) patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3; in polycythemia vera (PV) patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of fluconazole in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily; alternatively, ruxolitinib therapy may be interrupted for the duration of fluconazole use. Ruxolitinib is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Coadministration with fluconazole 100 to 400 mg PO once daily increased steady-state ruxolitinib overall exposure by approximately 100% to 300%.
Saccharomyces boulardii: (Major) Because Saccharomyces boulardii is an active yeast, it would be expected to be inactivated by any antifungals. The manufacturer does not recommend taking in conjunction with any antifungal agents. Patients should avoid use of this probiotic yeast until the fungal or yeast infection is completely treated.
Saquinavir: (Contraindicated) Although the manufacturer of fluconazole provides dose adjustment recommendations for saquinavir when the two drugs are coadministered, the manufacturer of saquinavir contraindicates this drug combination. According to the manufacturer of saquinavir, saquinavir is contraindicated with drugs that prolong the QT interval and increase saquinavir concentrations. Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by approximately 55%, and decreases clearance of saquinavir by approximately 50%.
Secobarbital: (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.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Coadministration of segesterone, a CYP3A4 substrate and a moderate CYP3A4 inhibitor, such as fluconazole may increase the serum concentration of segesterone. (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.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and fluconazole due to the risk of additive QT prolongation and increased selpercatinib exposure resulting in increased treatment-related adverse effects. If coadministration is unavoidable, reduce the dose of selpercatinib to 80 mg PO twice daily if original dose was 120 mg twice daily, and to 120 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If fluconazole is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of fluconazole. Selpercatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation and fluconazole is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration with fluconazole is predicted to increase selpercatinib exposure by 60% to 99%.
Selumetinib: (Major) Avoid coadministration of selumetinib and fluconazole due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If fluconazole is discontinued, resume the original selumetinib dose after 3 elimination half-lives of fluconazole. Selumetinib is a CYP3A4 and CYP2C19 substrate and fluconazole is a moderate CYP3A4 and strong CYP2C19 inhibitor. Coadministration with fluconazole increased selumetinib exposure by 53%.
Sertraline: (Moderate) Concomitant use of fluconazole and sertraline 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. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Concomitant use of fluconazole and halogenated anesthetics 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.
Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with fluconazole is necessary; consider a starting dose of 25 mg of sildenafil when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration with a moderate CYP3A4 inhibitor increased the Cmax and AUC of sildenafil by 160% and 182%, respectively. Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A4 inhibitors will be less for sildenafil injection than those observed after oral sildenafil administration.
Silodosin: (Moderate) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4. In theory, drugs that inhibit CYP3A4 such as fluconazole may cause significant increases in silodosin plasma concentrations. KMD-3213G, the primary metabolite of silodosin, is formed from direct conjugation of silodosin by UDP-glucuronosyltransferase 2B7 (UBT2B7). In theory, coadministration of silodosin with UBT2B7 inhibitors such as fluconazole may increase silodosin plasma concentrations.
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.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving fluconazole due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes. Additionally, increased exposure to siponimod is also possible. Siponimod is a CYP2C9 and CYP3A4 substrate; fluconazole is a moderate CYP2C9/CYP3A4 dual inhibitor. Coadministration with fluconazole led to a 2-fold increase in the exposure of siponimod in CYP2C9*1/*1 healthy volunteers. Across different CYP2C9 genotypes, fluconazole led to a 2- to4-fold increase in the exposure of siponimod, according to in silico evaluation.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of fluconazole. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate 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.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with fluconazole. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Fluconazole is a CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with fluconazole. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Fluconazole is a CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
Solifenacin: (Contraindicated) Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP). The concurrent use of fluconazole, a moderate 3A4 inhibitor, and other drugs that prolong the QT interval and are CYP3A4 substrates, like solifenacin, is contraindicated due to the risk of TdP. Solifenacin is not usually contraindicated with moderate 3A4 inhibitors but because fluconazole is contraindicated with 3A4 substrates that prolong QT, these drugs should not be coadministered. Coadministration of fluconazole and solifenacin may result in an increased plasma concentration of solifenacin, causing an increased risk for adverse events, such as QT prolongation. It is not clear if single-dose fluconazole for vaginal candidiasis presents a lower risk for QT prolongation than other, multi-dose fluconazole regimens. Consider the risk vs. benefit of use of fluconazole versus alternative agents for the patients condition, particularly for vaginal yeast infection.
Sonidegib: (Major) Avoi d the concomitant use of sonidegib and fluconazole; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. If concomitant use cannot be avoided, administer fluconazole for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Sonidegib is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Sorafenib: (Major) Concomitant use of sorafenib 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.
Sotalol: (Major) Concomitant use of sotalol 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.
Sparsentan: (Moderate) Monitor for an increase in sparsentan-related adverse effects if concomitant use with fluconazole is necessary. Concomitant use may increase sparsentan exposure. Sparsentan is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sparsentan overall exposure by 70%.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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%.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if fluconazole must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. If fluconazole is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a moderate CYP3A4 inhibitor like fluconazole can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If fluconazole is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sunitinib: (Contraindicated) FDA-approved labeling for fluconazole contraindicates use with CYP3A4 substrates that prolong the QT interval such as sunitinib. If alternative therapy is not available and concurrent use cannot be avoided, closely monitor for evidence of QT prolongation. Fluconazole is a moderate CYP3A4 inhibitor that has been associated with QT prolongation. Sunitinib is a CYP3A4 substrate that can prolong the QT interval. Coadministration of sunitinib with a strong CYP3A4 inhibitor increased the combined AUC of sunitinib and active metabolite by 51% in healthy subjects. The effect of moderate CYP3A4 inhibitors like fluconazole has not been studied.
Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with fluconazole. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased the suvorexant AUC by 2-fold.
Tacrolimus: (Contraindicated) Concurrent use of fluconazole and tacrolimus is contraindicated. Both drugs can cause QT/QTc prolongation and their use together increases the risk of life-threatening arrhythmias such as torsade de pointes (TdP). Additionally, concomitant use may increase tacrolimus exposure and the risk for tacrolimus-related adverse effects. If concomitant use is unavoidable, monitor tacrolimus serum concentrations more frequently and reduce the dose of tacrolimus if needed. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Tacrolimus is a CYP3A substrate, and fluconazole is a moderate CYP3A inhibitor.
Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with fluconazole is necessary. Tadalafil is a CYP3A4 substrate and fluconazole is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Tamoxifen: (Moderate) Concomitant use of tamoxifen 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.
Tamsulosin: (Moderate) Use caution if coadministration of fluconazole with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and fluconazole. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as fluconazole, may increase exposure to tasimelteon with the potential for adverse reactions.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with fluconazole as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. If concomitant use is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If fluconazole is discontinued, wait at least 3 half-lives of fluconazole before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Coadministration of fluconazole increased tazemetostat exposure by 3.1-fold.
Telavancin: (Moderate) Concomitant use of fluconazole and telavancin 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.
Telmisartan; 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.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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%.
Terbinafine: (Moderate) Caution is advised when using terbinafine concurrently with fluconazole. The Cmax and AUC of terbinafine is increased by 52% and 69%, respectively, when administered with a single 100 mg dose of fluconazole. Predictions about this interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9, CYP2C19, and CYP3A4; fluconazole is an inhibitor of these enzymes. Taking these drugs together may increase the risk for terbinafine related adverse effects. However, in vitro studies suggest that use of terbinafine in combination with fluconazole may have synergistic activity against certain fungal species, including Candida sp. Clinical study is needed to elucidate the potential utility of terbinafine combinations with other antifungal agents.
Tetrabenazine: (Major) Concomitant use of tetrabenazine 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.
Tezacaftor; Ivacaftor: (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. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold.
Theophylline, Aminophylline: (Moderate) Fluconazole may increase the serum concentrations of aminophylline. Serum aminophylline concentrations should be monitored closely if fluconazole is added. (Moderate) Fluconazole may increase the serum concentrations of theophylline. Serum theophylline concentrations should be monitored closely if fluconazole is added.
Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Thioridazine is considered contraindicated for use along with fluconazole which, when combined with thioridazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension.
Tipranavir: (Moderate) Tipranavir concentrations are increased when coadministered with fluconazole; however, no dose adjustments are required if fluconazole dose is less than 200 mg PO daily. Fluconazole doses greater than 200 mg per day are not recommended to be given with tipranavir.
Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with fluconazole chronically (beyond 1 dosage). In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with fluconazole. Fluconazole is a strong CYP2C19 and moderate CYP3A4 inhibitor; tofacitinib is a CYP3A4/CYP2C19 substrate. Coadministration with fluconazole increased tofacitinib exposure by 1.75-fold.
Tolterodine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering fluconazole with tolterodine. Fluconazole is associated with QT prolongation and rare cases of TdP. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess who are poor CYP2D6 metabolizers, patients receiving CYP3A4 inhibitors, such as fluconazole, should not receive > 2 mg/day of tolterodine. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed.
Tolvaptan: (Major) Avoid coadministration of fluconazole when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with fluconazole. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of fluconazole. Tolvaptan is a sensitive CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration of fluconazole increased the tolvaptan AUC by 200%.
Toremifene: (Contraindicated) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as toremifene, is contraindicated. Fluconazole has been associated with QT prolongation. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
Torsemide: (Moderate) Monitor the diuretic effect and blood pressure if torsemide and fluconazole are administered together. The torsemide dose may need to be reduced. Concomitant use of torsemide and fluconazole can decrease torsemide clearance and increase torsemide plasma concentrations. Torsemide is a substrate of CYP2C9; fluconazole inhibits CYP2C9.
Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with fluconazole. Coadministration may increase the exposure of verapamil. Verapamil is a substrate of CYP3A and fluconazole is a moderate CYP3A inhibitor.
Trazodone: (Contraindicated) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are CYP3A4 substrates, such as trazodone, is contraindicated. Fluconazole has been associated with QT prolongation; QT prolongation and torsade de pointes (TdP) have been observed during trazodone treatment. Additionally, fluconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as trazodone.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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%.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with fluconazole and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20 to 32%, and increases triazolam half-life by 25 to 50% due to the inhibition of metabolism of triazolam.
Triclabendazole: (Moderate) Concomitant use of triclabendazole 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.
Trifluoperazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering fluconazole with trifluoperazine. Fluconazole has been associated with QT prolongation and rare cases of TdP. Trifluoperazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Trimipramine: (Minor) Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Tricyclic antidepressants (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). Fluconazole should be administered together with TCAs with caution. In addition, fluconazole inhibits CYP2C19 and CYP3A4, enzymes that are partially involved in the metabolism of TCAs. Fluconazole has been reported to increase the effects of TCAs such as 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 torsades de pointes occurred. Trimipramine may be affected by this potential interaction, but specific data are lacking. Monitor for an increased response to trimipramine if fluconazole is coadministered.
Triptorelin: (Moderate) Concomitant use of fluconazole and androgen deprivation therapy (i.e., triptorelin) 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.
Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with fluconazole. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for fluconazole-related adverse events during concomitant hydrochlorothiazide use. 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%.
Vandetanib: (Major) Concomitant use of vandetanib 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.
Vardenafil: (Contraindicated) Avoid concomitant use of vardenafil and fluconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase vardenafil exposure, further increasing the risk of adverse effects. If concomitant use of fluconazole and vardenafil oral tablets is required, the maximum single dose is 5 mg every 24 hours. Do not use vardenafil orally disintegrating tablets with fluconazole. Vardenafil is primarily metabolized by CYP3A and fluconazole is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the AUC of vardenafil by 4-fold.
Vemurafenib: (Contraindicated) Concurrent use of fluconazole and vemurafenib 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 vemurafenib. These drugs used in combination may result in elevated vemurafenib plasma concentrations, causing an increased risk for vemurafenib-related 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 vemurafenib.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with fluconazole due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of fluconazole. Venetoclax is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor.
Venlafaxine: (Moderate) Concomitant use of fluconazole and venlafaxine 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.
Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with fluconazole. Coadministration may increase the exposure of verapamil. Verapamil is a substrate of CYP3A and fluconazole is a moderate CYP3A inhibitor.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with fluconazole is necessary. Vinblastine is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Enhanced vinblastine toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
Vincristine Liposomal: (Minor) Concomitant use of vincristine and fluconazole may increase the risk for vincristine-related adverse effects such as neurotoxicity. The data supporting the risk of adverse effects associated with this combination is limited to retrospective observational studies and results have been inconsistent. Some data suggest that short courses of low-dose, prophylactic fluconazole may be used safely. Vincristine is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Vincristine: (Minor) Concomitant use of vincristine and fluconazole may increase the risk for vincristine-related adverse effects such as neurotoxicity. The data supporting the risk of adverse effects associated with this combination is limited to retrospective observational studies and results have been inconsistent. Some data suggest that short courses of low-dose, prophylactic fluconazole may be used safely. Vincristine is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with fluconazole is necessary. Vinorelbine is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor.
Voclosporin: (Contraindicated) Concomitant use of voclosporin and fluconazole is contraindicated due to the risk for QT prolongation. Voclosporin exposure and the risk for voclosporin-related adverse effects may also be increased. If concomitant use is necessary, reduce the voclosporin dosage to 15.8 mg PO in the morning and 7.9 mg PO in the evening. Voclosporin is a sensitive CYP3A4 substrate that is associated with QT prolongation with supratherapeutic doses. Fluconazole is a moderate CYP3A4 inhibitor that has been associated with QT prolongation. Coadministration with moderate CYP3A4 inhibitors is predicted to increase voclosporin exposure by 3-fold.
Vonoprazan; Amoxicillin; 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.
Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and fluconazole. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with fluconazole, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
Voriconazole: (Contraindicated) Avoid concomitant use of fluconazole and voriconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Monitor for voriconazole-related adverse events, especially, if voriconazole is started within 24 hours after the last dose of fluconazole. Concomitant use increased voriconazole exposure by an average of 79% and may also increase the risk for other voriconazole-related adverse effects; reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this effect. Voriconazole is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Vorinostat: (Moderate) Concomitant use of fluconacole and vorinostat 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.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with fluconazole is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fluconazole is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. Fluconazole is also a moderate CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with fluconazole. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of fluconazole, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 177% to 284% when coadministered with fluconazole.
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.
Ziprasidone: (Contraindicated) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as ziprasidone, is considered contraindicated. Fluconazole is associated with QT prolongation and is a CYP3A4 inhibitor. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.

Diflucan/Fluconazole Oral Pwd F/Recon: 1mL, 10mg, 40mg
Diflucan/Fluconazole Oral Tab: 50mg, 100mg, 150mg, 200mg
Diflucan/Fluconazole/Fluconazole, Dextrose Intravenous Inj Sol: 1mL, 2mg, 100mL, 200mg, 200mL, 400mg, 200-5%, 400-5%

400 mg/day PO/IV is FDA-approved; however, up to 1,200 mg/day PO/IV has been used off-label.

400 mg/day PO/IV is FDA-approved; however, up to 1,200 mg/day PO/IV has been used off-label.

12 mg/kg/day (Max: 600 mg/day) PO/IV is FDA-approved; however, up to 1,200 mg/day PO/IV has been used off-label.

12 mg/kg/day (Max: 600 mg/day) PO/IV is FDA-approved; however, up to 800 mg/day PO/IV has been used off-label.

6 to 12 months: 12 mg/kg/day PO/IV.
1 to 5 months: Safety and efficacy have not been established; however, up to 12 mg/kg/day PO/IV has been used off-label.

Safety and efficacy have not been established; however, 25 mg/kg PO/IV loading dose, then up to 12 mg/kg/day PO/IV has been used off-label.

Fluconazole is a fungistatic antifungal agent with concentration-independent activity. Like other azole antifungals, fluconazole exerts its effect by altering the fungal cell membrane. Fluconazole inhibits ergosterol synthesis by interacting with 14-alpha demethylase, a cytochrome P450 enzyme that is needed to convert lanosterol to ergosterol, an essential component of the membrane. Inhibition of ergosterol synthesis results in increased cellular permeability causing leakage of cellular contents. Fluconazole does not appear to have the same activity on human cholesterol synthesis. Other antifungal effects of azole compounds have been proposed and include inhibition of endogenous respiration, interaction with membrane phospholipids, and inhibition of the transformation of yeasts to mycelial forms. Other mechanisms may involve inhibition of purine uptake and impairment of triglyceride and/or phospholipid biosynthesis.
 
The Clinical and Laboratory Standards Institute (CLSI) defines minimum inhibitory concentrations (MICs) for C. albicans, C. parapsilosis, and C. tropicalis as susceptible at 2 mcg/mL or less, susceptible dose-dependent (SDD) at 4 mcg/mL, and resistant at 8 mcg/mL or more. For C. glabrata, isolates are defined as SDD at 32 mcg/mL or less and resistant at 64 mcg/mL or more. C. krusei is considered intrinsically resistant to fluconazole.
 
The emergence of fungal organisms resistant to fluconazole, especially Candida species, is problematic. Increased frequency of non-Candida albicans species as causes of fungemia has been correlated in epidemiologic studies with the increased use of fluconazole both for prophylaxis and treatment. These non-Candida albicans species are often more resistant to fluconazole. Data indicate the annual incidence of fluconazole-resistant oropharyngeal candidiasis in persons with AIDS is roughly 5%. Consider susceptibility testing of invasive C. albicans isolates for persons with persistent candidemia or progressive disseminated candidiasis, despite fluconazole therapy, and on non-Candida albicans isolates (e.g., C. glabrata, C. tropicalis, or C. parapsilosis) from persons with candidemia or invasive disease.

Fluconazole is administered orally and intravenously. The pharmacokinetics of both IV and oral fluconazole are similar. Peak serum concentrations and AUC increase in proportion to the dose. Steady-state fluconazole plasma concentrations are achieved within 5 to 10 days at doses within the adult dosage range of 50 to 400 mg/day, and within 2 days when a loading dose of twice the usual daily dosage is given on the first day of therapy. Fluconazole is widely distributed into body tissues and fluids; the apparent volume of distribution approximates that of total body water. Saliva, sputum, nail, blister, and vaginal tissue concentrations are approximately equal to plasma concentrations. Urine and skin concentrations are approximately 10 times that of plasma concentrations. High concentrations also can be achieved in the cornea, aqueous humor, and vitreous body after IV administration. Fluconazole distributes well into the CSF, and achieves CSF concentrations that are 50% to 90% of plasma concentrations, regardless of the degree of meningeal inflammation. Plasma protein binding is low and ranges from 11% to 12%.[28674] [52683]
 
Fluconazole does not appear to undergo first-pass metabolism. Elimination is mainly renal; about 65% to 80% of a dose is excreted in the urine unchanged and 11% as metabolites. Plasma elimination half-life in adults with normal renal function is approximately 30 hours (range: 20 to 50 hours), which is shorter than the half-life in neonates and longer than the half-life in children. Small amounts of fluconazole are excreted in the feces.[28674] [53005]
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, CYP2C19, CYP3A4, UGT2B7
Fluconazole potently inhibits CYP2C19 and moderately inhibits CYP2C9 and CYP3A4. The extent of CYP3A4 inhibition is less than with ketoconazole or itraconazole.[28674] [29036] [34447] In vitro studies have also shown fluconazole to be a concentration-dependent inhibitor of uridine diphosphoglucuronosyltransferase UGT2B7.[60255] [60256]

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]

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]