Dosing

Dosing: Adult
The daily dose of fluconazole is the same for both oral and I.V. administration
Usual dosage range: 150 mg once or 200-800 mg/day; duration and dosage depends on severity of infection
Indication-specific dosing:
Candidiasis (Pappas, 2009):
Candidemia (neutropenic and non-neutropenic): Loading dose: 800 mg on first day, then 400 mg/day for 14 days after first negative blood culture and resolution of signs/symptoms; Note: Not recommended for neutropenic patients with recent azole exposure and critical illness
Chronic, disseminated: 400 mg/day until calcification or lesion resolution
CNS candidemia: 400-800 mg/day until CSF/radiological abnormalities resolved
Oropharyngeal: 100-200 mg/day for 7-14 days for uncomplicated, moderate-to-severe disease; chronic therapy of 100 mg 3 times weekly is recommended in immunocompromised patients with history of oropharyngeal candidiasis (OPC)
Osteoarticular: 400 mg/day for 6-12 months (osteomyelitis) or 6 weeks (septic arthritis)
Esophageal: 200-400 mg/day for 14-21 days
Prophylaxis:
Solid organ: 200-400 mg/day for 7-14 days
Neutropenic patients: 400 mg/day for duration of neutropenia
Urinary tract:
Fungus balls: 200-400 mg/day
Pyelonephritis: 200-400 mg/day for 2 weeks
Symptomatic cystitis: 200 mg/day for 2 weeks
Vaginal:
Uncomplicated: 150 mg as a single dose
Complicated: 150 mg every 72 hours for 3 doses
Recurrent: 150 mg daily for 10-14 days, followed by 150 mg once weekly for 6 months
Candidal intertrigo (unlabeled use; Coldiron, 1991; Nozickova, 1998; Stengel, 1994): 50 mg/day or 150 mg once weekly
Coccidioidomycosis (unlabeled use; Galgiani, 2005): 400-800 mg/day; doses of 800-1000 mg/day have been used for meningeal disease; usual duration of therapy ranges from 3-6 months for primary uncomplicated infections and up to 1 year for pulmonary (chronic and diffuse) infection
Endocarditis, prosthetic valve, early (unlabeled use; Pappas, 2009): 400-800 mg/day for 6 weeks after valve replacement (as step-down in stable, culture-negative patients); long-term suppression in absence of valve replacement: 400-800 mg/day
Endophthalmitis (Pappas, 2009): 400-800 mg/day for 4-6 weeks until examination indicates resolution
Meningitis, cryptococcal (Perfect, 2010):
Induction therapy: Typically consists of an amphotericin product and flucytosine for 2-6 weeks
Consolidation therapy: Fluconazole 400-800 mg/day for 8 weeks
Maintenance therapy: 200 mg/day for 6-12 months (post-transplant patients; non-HIV infected patients) or ≥1 year (HIV-infected patients may require lifelong therapy; CDC, 2009)
Pericarditis or myocarditis (Pappas, 2009): 400-800 mg/day
Pneumonia, cryptococcal (mild-to-moderate) (unlabeled use; Perfect, 2010): 400 mg/day for 6-12 months (HIV-infected patients may require lifelong therapy; CDC, 2009)

Dosing: Pediatric
The daily dose of fluconazole is the same for oral and I.V. administration
Usual dosage range: Children: Loading dose: 6-12 mg/kg; maintenance: 3-12 mg/kg/day; duration and dosage depends on severity of infection
Indication-specific dosing:
Candidiasis:
Oropharyngeal:
Manufacturer’s recommendation: Loading dose: 6 mg/kg; maintenance: 3 mg/kg/day once daily for 2 weeks
HIV-exposed/-positive: 3-6 mg/kg/day once daily (maximum: 400 mg/day) (CDC, 2009)
Esophageal:
Manufacturer’s recommendation: Loading dose: 6 mg/kg; maintenance: 3-12 mg/kg/day once daily for 21 days and at least 2 weeks following resolution of symptoms
HIV-exposed/-positive: Loading dose: 6 mg/kg once on day 1; maintenance: 3-6 mg/kg/day once daily (maximum: 400 mg/day) (CDC, 2009)
Relapse suppression (HIV-exposed/-positive): 3-6 mg/kg/day once daily (maximum: 200 mg/day) (CDC, 2009)
Invasive disease (independent of HIV status): 5-6 mg/kg every 12 hours for 28 days (maximum: 600 mg/day) (CDC, 2009)
Coccidioidomycosis (CDC, 2009):
Meningeal and disseminated disease (HIV-exposed/-positive): 5-6 mg/kg/dose every 12 hours (maximum: 800 mg/day)
Relapse suppression (HIV-exposed/-positive): 6 mg/kg/day once daily (maximum: 400 mg/day)
Histoplasmosis, relapse suppression (HIV-exposed/-positive): 3-6 mg/kg/day once daily (maximum: 200 mg/day) (CDC, 2009)
Cryptococcal disease (CDC, 2009):
Meningitis (consolidation): Loading dose: 12 mg/kg once on day 1; maintenance: 6-12 mg/kg/day once daily for a minimum of 8 weeks (maximum: 800 mg/day)
Disseminated (non-CNS) or severe pulmonary disease: Loading dose: 12 mg/kg once on day 1; maintenance: 6-12 mg/kg/day once daily (maximum: 600 mg/day)
Relapse suppression (HIV-exposed/-positive): 6 mg/kg/day once daily (maximum: 200 mg/day)

Dosing: Geriatric
Refer to adult dosing.

Dosing: Renal Impairment
No adjustment for vaginal candidiasis single-dose therapy
For multiple dosing, administer usual load then adjust daily doses as follows:
Clcr ≤50 mL/minute (no dialysis): Administer 50% of recommended dose or administer every 48 hours.
Intermittent hemodialysis (IHD): Dialyzable (50%): May administer 100% of daily dose (according to indication) after each dialysis session. Alternatively, doses of 200-400 mg every 48-72 hours or 100- 200 mg every 24 hours have been recommended (Heintz, 2009). Note: Dosing dependent on the assumption of 3 times/week, complete IHD sessions.
Continuous renal replacement therapy (CRRT) (Heintz, 2009; Trotman, 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1-2 L/hour and minimal residual renal function) and should not supersede clinical judgment:
CVVH: Loading dose of 400-800 mg followed by 200-400 mg every 24 hours
CVVHD/CVVHDF: Loading dose of 400-800 mg followed by 400-800 mg every 24 hours (CVVHD or CVVHDF) or 800 mg every 24 hours (CVVHDF)
Note: Higher maintenance doses of 400 mg every 24 hours (CVVH), 800 mg every 24 hours (CVVHD), and 500-600 mg every 12 hours (CVVHDF) may be considered when treating resistant organisms and/or when employing combined ultrafiltration and dialysis flow rates of ≥2 L/hour for CVVHD/CVVHDF (Heintz, 2009; Trotman, 2005).

Use

Treatment of candidiasis (vaginal, oropharyngeal, esophageal, urinary tract infections, peritonitis, pneumonia, and systemic infections); cryptococcal meningitis; antifungal prophylaxis in allogeneic bone marrow transplant recipients
Use - Unlabeled/Investigational
Cryptococcal pneumonia; candidal intertrigo

Adverse Reactions

Frequency not always defined.
Cardiovascular: Angioedema, pallor, QT prolongation (rare, case reports), torsade de pointes(rare, case reports)
Central nervous system: Headache (2% to 13%), dizziness (1%), seizure
Dermatologic: Rash (2%), alopecia, toxic epidermal necrolysis, Stevens-Johnson syndrome
Endocrine & metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia
Gastrointestinal: Nausea (2% to 7%), abdominal pain (2% to 6%), vomiting (2% to 5%), diarrhea (2% to 3%), dyspepsia (1%), taste perversion (1%)
Hematologic: Agranulocytosis, leukopenia, neutropenia, thrombocytopenia
Hepatic: Alkaline phosphatase increased, ALT increased, AST increased, cholestasis, hepatic failure (rare), hepatitis, jaundice
Respiratory: Dyspnea
Miscellaneous: Anaphylactic reactions (rare)

Contraindications

Hypersensitivity to fluconazole or any component of the formulation (cross-reaction with other azole antifungal agents may occur, but has not been established; use caution); concomitant administration with cisapride or terfenadine

Warnings / Precautions Drug

Concerns related to adverse effects:
• Skin reactions: Rare exfoliative skin disorders have been observed; monitor closely if rash develops and discontinue if lesions progress.
Disease-related concerns:
• Arrhythmias: The manufacturer reports rare cases of QTc prolongation and torsade de pointes associated with fluconazole use and advises caution in patients with concomitant medications or conditions which are arrhythmogenic. However, given the limited number of cases and the presence of multiple confounding variables, the likelihood that fluconazole causes conduction abnormalities appears remote.
• Hepatic impairment: Serious (and rarely fatal) hepatic toxicity (eg, hepatitis, cholestasis, fulminant failure) has been observed with azole therapy. Use with caution in patients with pre-existing hepatic impairment; monitor liver function closely and dosage adjustment may be warranted; discontinue if symptoms consistent with liver disease develop.
• Renal impairment: Use with caution in patients with renal impairment.
Metabolism/Transport Effects
Inhibits CYP1A2 (weak), 2C9 (strong), 2C19 (strong), 3A4 (moderate)

Interactions

Alfentanil: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Alfentanil. Risk D: Consider therapy modification
Alfentanil: Fluconazole may decrease the metabolism of Alfentanil. Risk D: Consider therapy modification
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Amphotericin B: Antifungal Agents (Azole Derivatives, Systemic) may diminish the therapeutic effect of Amphotericin B. Risk C: Monitor therapy
Aprepitant: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Aprepitant. Risk C: Monitor therapy
Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Benzodiazepines (metabolized by oxidation): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Benzodiazepines (metabolized by oxidation). Management: The following combinations are specifically contraindicated: itraconazole with alprazolam, estazolam, oral midazolam, or triazolam; ketoconazole with alprazolam, estazolam, or triazolam. Consider initial dose reductions of other benzodiazepines. Exceptions: Quazepam. Risk D: Consider therapy modification
Benzodiazepines (metabolized by oxidation): Fluconazole may decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification
Bosentan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Bosentan. Risk C: Monitor therapy
Budesonide (Systemic, Oral Inhalation): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic, Oral Inhalation). Management: Consider reducing the oral budesonide dose when used together with a CYP3A4 inhibitor. This interaction is likely less severe with orally inhaled budesonide. Monitor patients closely for signs/symptoms of corticosteroid excess. Risk D: Consider therapy modification
BusPIRone: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of BusPIRone. Risk D: Consider therapy modification
Busulfan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Busulfan. Risk C: Monitor therapy
Calcium Channel Blockers: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Calcium Channel Blockers. Exceptions: Clevidipine. Risk D: Consider therapy modification
Calcium Channel Blockers: Fluconazole may decrease the metabolism of Calcium Channel Blockers. Exceptions: Clevidipine. Risk C: Monitor therapy
CarBAMazepine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of CarBAMazepine. Risk C: Monitor therapy
CarBAMazepine: Fluconazole may decrease the metabolism of CarBAMazepine. Risk C: Monitor therapy
Carvedilol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Risk C: Monitor therapy
Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Cilostazol: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Cilostazol. Risk D: Consider therapy modification
Cinacalcet: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Cinacalcet. Risk C: Monitor therapy
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin (Systemic): May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Cisapride: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Cisapride. Risk X: Avoid combination
Citalopram: Fluconazole may increase the serum concentration of Citalopram. Risk C: Monitor therapy
Clopidogrel: CYP2C19 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk X: Avoid combination
Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Risk D: Consider therapy modification
Conivaptan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Conivaptan. Risk X: Avoid combination
Corticosteroids (Systemic): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Corticosteroids (Systemic). Risk C: Monitor therapy
Corticosteroids (Systemic): Fluconazole may decrease the metabolism of Corticosteroids (Systemic). Risk C: Monitor therapy
CycloSPORINE: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of CycloSPORINE. Risk D: Consider therapy modification
CycloSPORINE: Fluconazole may increase the serum concentration of CycloSPORINE. Risk C: Monitor therapy
CycloSPORINE (Systemic): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of CycloSPORINE (Systemic). Risk D: Consider therapy modification
CycloSPORINE (Systemic): Fluconazole may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP2C19 Substrates: CYP2C19 Inhibitors (Strong) may decrease the metabolism of CYP2C19 Substrates. Risk D: Consider therapy modification
CYP2C9 Substrates (High risk): CYP2C9 Inhibitors (Strong) may decrease the metabolism of CYP2C9 Substrates (High risk). Risk D: Consider therapy modification
CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Diclofenac: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Diclofenac. Risk C: Monitor therapy
Didanosine: May decrease the absorption of Antifungal Agents (Azole Derivatives, Systemic). Enteric coated didanosine capsules are not expected to affect these antifungals. Risk D: Consider therapy modification
DOCEtaxel: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of DOCEtaxel. Risk D: Consider therapy modification
Dofetilide: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Dofetilide. Risk X: Avoid combination
Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination
Eletriptan: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Eletriptan. Risk D: Consider therapy modification
Eletriptan: Fluconazole may decrease the metabolism of Eletriptan. Risk C: Monitor therapy
Eplerenone: Fluconazole may increase the serum concentration of Eplerenone. Management: Reduce the starting dose of eplerenone to 25 mg/day; monitor patients closely for increased eplerenone effects. Risk D: Consider therapy modification
Erlotinib: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Erlotinib. Risk C: Monitor therapy
Eszopiclone: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Eszopiclone. Risk C: Monitor therapy
Etravirine: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Etravirine. Etravirine may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). This would be anticipated with itraconazole or ketoconazole. Etravirine may increase the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). This would be anticipated with voriconazole. Management: Monitor for increased effects/toxicity of etravirine. Antifungal dose adjustment may be needed for ketoconazole, itraconazole, or posaconazole but specific dosing guidelines are lacking. Risk D: Consider therapy modification
Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Risk D: Consider therapy modification
FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients extra closely for several days following initiation of the combination, and fentanyl dosage reductions should be made as appropriate. Risk D: Consider therapy modification
Fosaprepitant: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Fosaprepitant. Specifically, concentrations of aprepitant are likely to be increased. Risk C: Monitor therapy
Fosphenytoin: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Risk D: Consider therapy modification
Fosphenytoin: Fluconazole may increase the serum concentration of Fosphenytoin. Risk D: Consider therapy modification
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
Gefitinib: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Gefitinib. Risk C: Monitor therapy
Grapefruit Juice: May increase the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). This specifically applies to oral antifungal administration, and the interaction may be different depending on specific dosage form being used. Risk C: Monitor therapy
HMG-CoA Reductase Inhibitors: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of HMG-CoA Reductase Inhibitors. Management: Consider use of HMG-CoA reductase inhibitors posing the least rhabdomyolysis risk (e.g. fluva- or pravastatin), and monitor for signs/symptoms of rhabdomyolysis. Do not use keto- or itraconazole with lova- or simvastatin, or posaconazole with simvastatin. Exceptions: Fluvastatin; Pitavastatin; Rosuvastatin. Risk D: Consider therapy modification
HMG-CoA Reductase Inhibitors: Fluconazole may decrease the metabolism of HMG-CoA Reductase Inhibitors. Exceptions: Pitavastatin; Pravastatin; Rosuvastatin. Risk D: Consider therapy modification
Imatinib: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Imatinib. Risk C: Monitor therapy
Irbesartan: Fluconazole may decrease the metabolism of Irbesartan. Risk C: Monitor therapy
Irinotecan: Antifungal Agents (Azole Derivatives, Systemic) may enhance the adverse/toxic effect of Irinotecan. Risk D: Consider therapy modification
Losartan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Losartan. Risk C: Monitor therapy
Losartan: Fluconazole may decrease the metabolism of Losartan. Risk C: Monitor therapy
Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Risk D: Consider therapy modification
Macrolide Antibiotics: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Macrolide Antibiotics. Macrolide Antibiotics may decrease the metabolism of Antifungal Agents (Azole Derivatives, Systemic). Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin (Systemic); Spiramycin. Risk D: Consider therapy modification
Methadone: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Methadone. Risk C: Monitor therapy
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Phenytoin: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Risk D: Consider therapy modification
Phenytoin: Fluconazole may increase the serum concentration of Phenytoin. Risk D: Consider therapy modification
Phosphodiesterase 5 Inhibitors: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Phosphodiesterase 5 Inhibitors. Risk D: Consider therapy modification
Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Risk C: Monitor therapy
Pimozide: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Pimozide. Risk X: Avoid combination
Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination
Protease Inhibitors: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Protease Inhibitors. Protease Inhibitors may increase the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Management: Limit indinavir adult dose to 600 mg every 8 hours with itraconazole or ketoconazole. With ritonavir, limit ketoconazole adult dose to 200 mg/day. Limit fluconazole, itraconazole, and ketoconazole to 200 mg (adult dose) with tipranavir/ritonavir. Risk D: Consider therapy modification
Proton Pump Inhibitors: Fluconazole may increase the serum concentration of Proton Pump Inhibitors. Risk C: Monitor therapy
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
QUEtiapine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
QuiNIDine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of QuiNIDine. Management: Itraconazole, voriconazole, and posaconazole are specifically contraindicated with quinidine. Use of quinidine with any azole antifungal may require quinidine dose adjustment and should be done with caution and close monitoring. Risk X: Avoid combination
QuiNIDine: Fluconazole may decrease the metabolism of QuiNIDine. Risk C: Monitor therapy
QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Ramelteon: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Ramelteon. Risk C: Monitor therapy
Ramelteon: Fluconazole may decrease the metabolism of Ramelteon. Risk C: Monitor therapy
Ranolazine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Ranolazine. Risk X: Avoid combination
Repaglinide: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Repaglinide. Management: Concurrent use of an azole antifungal with both repaglinide and gemfibrozil should be avoided. Risk C: Monitor therapy
Rifamycin Derivatives: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Rifamycin Derivatives. Only rifabutin appears to be affected. Rifamycin Derivatives may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Risk D: Consider therapy modification
Rifamycin Derivatives: May increase the metabolism of Fluconazole. Fluconazole may decrease the metabolism of Rifamycin Derivatives. This appears only affect rifabutin. Risk C: Monitor therapy
Saccharomyces boulardii: Antifungal Agents may diminish the therapeutic effect of Saccharomyces boulardii. Risk D: Consider therapy modification
Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Risk C: Monitor therapy
Saxagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Saxagliptin. Risk C: Monitor therapy
Sirolimus: Fluconazole may increase the serum concentration of Sirolimus. Management: Sirolimus dose adjustments will likely be needed when starting/stopping any azole antifungal. Clinical data suggest sirolimus (adult) dose reductions of 50-90% will be needed when starting an azole antifungal, but specific guidelines are lacking. Risk D: Consider therapy modification
Solifenacin: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Solifenacin. Risk D: Consider therapy modification
Sucralfate: May decrease the absorption of Antifungal Agents (Azole Derivatives, Systemic). Risk C: Monitor therapy
Sulfonylureas: Fluconazole may increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
SUNItinib: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of SUNItinib. Risk D: Consider therapy modification
Tacrolimus: Fluconazole may decrease the metabolism of Tacrolimus. Management: Monitor tacrolimus concentrations closely and adjust dose as necessary when concomitantly administered with fluconazole. Reduced doses of fluconazole will likely be required. Risk D: Consider therapy modification
Tacrolimus (Systemic): Fluconazole may decrease the metabolism of Tacrolimus (Systemic). Management: Monitor tacrolimus concentrations closely and adjust dose as necessary when concomitantly administered with fluconazole. Reduced doses of fluconazole will likely be required. Risk D: Consider therapy modification
Tacrolimus (Topical): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Tacrolimus (Topical). Risk C: Monitor therapy
Tacrolimus (Topical): Fluconazole may decrease the metabolism of Tacrolimus (Topical). Risk C: Monitor therapy
Temsirolimus: Fluconazole may increase serum concentrations of the active metabolite(s) of Temsirolimus. Management: Consider temsirolimus dose reductions or alternatives to fluconazole. Monitor sirolimus concentrations in all patients receiving fluconazole or any systemic azole antifungal. Risk D: Consider therapy modification
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Tolterodine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Tolterodine. This is likely only of concern in CYP2D6-deficient patients (ie, "poor metabolizers") Risk D: Consider therapy modification
Tolterodine: Fluconazole may decrease the metabolism of Tolterodine. This is likely only of concern in CYP2D6-deficient patients (ie, "poor metabolizers") Risk C: Monitor therapy
Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Risk X: Avoid combination
Toremifene: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Toremifene. The risk for potentially dangerous arrhythmias may be increased. Risk X: Avoid combination
Vandetanib: QTc-Prolonging Agents may enhance the arrhythmogenic effect of Vandetanib. Risk X: Avoid combination
Vemurafenib: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Vemurafenib. Risk X: Avoid combination
Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Fluconazole may increase the serum concentration of Vitamin K Antagonists. Risk D: Consider therapy modification
Voriconazole: Fluconazole may increase the serum concentration of Voriconazole. Risk X: Avoid combination
Zidovudine: Fluconazole may decrease the metabolism of Zidovudine. Risk C: Monitor therapy
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
Ziprasidone: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Ziprasidone. Risk C: Monitor therapy
Zolpidem: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Zolpidem. Management: Consider using a lower starting dose of zolpidem in patients receiving systemic azole antifungals. Monitor patients closely for increased magnitude and/or duration of zolpidem effects when using this combination. Risk D: Consider therapy modification

Pregnancy

C (single dose for vaginal candidiasis) / D (all other indications)
Pregnancy Implications
When used in high doses, fluconazole is teratogenic in animal studies. Following exposure during the first trimester, case reports have noted similar malformations in humans when used in higher doses (400 mg/day) over extended periods of time. Use of lower doses (150 mg as a single dose) does not suggest an increase risk to the fetus.

Lactation

Enters breast milk/not recommended (AAP rates “compatible”; AAP 2001 update pending)
Breast-Feeding Considerations
Fluconazole is found in breast milk at concentration similar to plasma.

Mechanism of Action

Interferes with fungal cytochrome P450 activity (lanosterol 14-α-demethylase), decreasing ergosterol synthesis (principal sterol in fungal cell membrane) and inhibiting cell membrane formation

Pharmacodynamics / Kinetics

Distribution: Widely throughout body with good penetration into CSF, eye, peritoneal fluid, sputum, skin, and urine
Relative diffusion blood into CSF: Adequate with or without inflammation (exceeds usual MICs)
CSF:blood level ratio: Normal meninges: 70% to 80%; Inflamed meninges: >70% to 80%
Protein binding, plasma: 11% to 12%
Bioavailability: Oral: >90%
Half-life elimination: Normal renal function: ~30 hours
Time to peak, serum: Oral: 1-2 hours
Excretion: Urine (80% as unchanged drug)