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Fluconazole

Medically reviewed on Nov 15, 2018

Pronunciation

(floo KOE na zole)

Index Terms

  • Diflucan

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous:

Generic: 100 mg (50 mL [DSC]); 100 mg/50 mL in NaCl 0.9% (50 mL); 200 mg (100 mL); 200 mg/100 mL in NaCl 0.9% (100 mL); 400 mg (200 mL); 400 mg/200 mL in NaCl 0.9% (200 mL)

Solution, Intravenous [preservative free]:

Generic: 200 mg (100 mL); 200 mg/100 mL in NaCl 0.9% (100 mL); 400 mg (200 mL); 400 mg/200 mL in NaCl 0.9% (200 mL)

Suspension Reconstituted, Oral:

Diflucan: 10 mg/mL (35 mL); 40 mg/mL (35 mL) [orange flavor]

Generic: 10 mg/mL (35 mL); 40 mg/mL (35 mL)

Tablet, Oral:

Diflucan: 50 mg, 100 mg, 150 mg, 200 mg

Generic: 50 mg, 100 mg, 150 mg, 200 mg

Brand Names: U.S.

  • Diflucan

Pharmacologic Category

  • Antifungal Agent, Oral
  • Antifungal Agent, Parenteral

Pharmacology

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

Absorption

Oral: Well absorbed; food does not affect extent of absorption

Distribution

Vd: ~0.6 L/kg; 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: 50% to 90%; Inflamed meninges: ~80%

Excretion

Urine (80% as unchanged drug)

Time to Peak

Oral: 1 to 2 hours

Half-Life Elimination

Normal renal function: ~30 hours (range: 20 to 50 hours); Elderly: 46.2 hours; Neonates (gestational age 26 to 29 weeks): 73.6 to 46.6 hours (decreases with increasing postnatal age); Pediatric patients 9 months to 15 years: 19.5 to 25 hours

Protein Binding

Plasma: 11% to 12%

Special Populations: Renal Function Impairment

Pharmacokinetics are markedly affected; there is an inverse relationship between half-life and creatinine clearance.

Use: Labeled Indications

Treatment of candidiasis (esophageal, oropharyngeal, peritoneal, urinary tract, vaginal); systemic candida infections (eg, candidemia, disseminated candidiasis, and pneumonia); cryptococcal meningitis; antifungal prophylaxis in allogeneic hematopoietic cell transplant recipients

Off Label Uses

Blastomycosis

Data from a randomized, multicenter, open-label study comparing fluconazole 400 mg versus 800 mg suggests that the use of fluconazole at both of these doses is effective for the treatment of non-life-threatening blastomycosis [Pappas 1997].

Based on the IDSA clinical practice guidelines for the management of blastomycosis, fluconazole is an effective and recommended agent for consolidation treatment of CNS disease and an effective and recommended alternative agent for treatment of pulmonary disease.

Candida intertrigo

Data from case reports and a multicenter, randomized, double-blind, double-dummy trial supports the use of fluconazole for the treatment of candida intertrigo [Coldiron 1991], [Nozickova 1998], [Stengel 1994].

Candidiasis, empiric therapy (nonneutropenic patients in the ICU)

Based on the IDSA clinical practice guidelines for the management of candidiasis, fluconazole is an effective and recommended alternative agent for empiric therapy of suspected invasive candidiasis in nonneutropenic patients in the ICU. It should not be used for patients with previous azole exposure or those colonized with azole-resistant Candida spp.

Candidiasis, prophylaxis in high-risk ICU patients (in units with high incidence of invasive candidiasis)

Based on the IDSA clinical practice guidelines for the management of candidiasis, fluconazole may be considered for prophylaxis against invasive candidiasis in high-risk patients in adult ICUs with a high rate of invasive candidiasis (>5%).

Candidiasis, prophylaxis in hematologic malignancy patients

Data from an open-label, randomized trial support the use of fluconazole for the prevention of invasive fungal infection in patients with hematologic malignancy during neutropenia [Glasmacher 2006].

Based on the ASCO and the IDSA clinical practice guidelines for antimicrobial prophylaxis for adult patients with cancer related immunosuppression, fluconazole is recommended for prophylaxis for patients with hematologic malignancy who do not require mold-active prophylaxis.

Candidiasis, prophylaxis in solid organ transplant recipients

Based on the American Society of Health-System Pharmacists (ASHP), the IDSA, the Surgical Infection Society (SIS), and the Society of Healthcare Epidemiology of America (SHEA) guidelines for antimicrobial prophylaxis in surgery and the American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) guidelines for management of Candida infections in solid organ transplant, fluconazole is recommended for surgical prophylaxis (perioperative) in select solid organ transplant patients (eg, liver, pancreas, kidney, pancreas-kidney transplantation).

Coccidioidomycosis

Based on the IDSA clinical practice guidelines for the treatment of coccidioidomycosis and the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, fluconazole is an effective and recommended agent in the treatment of coccidioidomycosis as well as in the prophylaxis (initial or chronic suppressive therapy) of coccidioidomycosis in HIV-infected patients and solid organ transplant recipients undergoing transplantation in endemic areas and/or from infected donors.

Cryptococcal pneumonia

Based on the IDSA guidelines for management of cryptococcal disease, fluconazole is effective and recommended for the treatment of cryptococcal pneumonia.

Cryptococcus due to Cryptococcus gattii

Based on the IDSA guidelines for management of cryptococcal disease, fluconazole is effective and recommended for the following manifestations of C. gattii: consolidation and maintenance therapy of CNS infection, extensive pulmonary infection, or pulmonary infection in immunocompromised patients and initial therapy for limited pulmonary infection in immunocompetent patients.

Primary antifungal prophylaxis in pediatric oncology patients

The C17 Council guidelines for antifungal prophylaxis in pediatric cancer recommend the use of fluconazole for primary antifungal prophylaxis in pediatric oncology patients.

Tinea

Data from multiple noncomparative trials suggest that the use of fluconazole is effective for the treatment of tinea corporis or cruris tinea pedis [Kotogyan 1996], [Montero-Gei 1992], [Stary 1998]. In addition, data from one noncomparative trial suggest the use of fluconazole is effective for the treatment of tinea versicolor [Karakas 2005].

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); coadministration of terfenadine in adult patients receiving multiple doses of 400 mg or higher or with CYP3A4 substrates which may lead to QTc prolongation (eg, astemizole, cisapride, erythromycin, pimozide, or quinidine)

Dosing: Adult

Indication-specific dosing:

Blastomycosis (off-label use):

CNS disease (follow-up therapy after initial response to a lipid formulation of amphotericin B): IV, Oral: 800 mg once daily for ≥12 months and until resolution of CSF abnormalities (IDSA [Chapman 2008])

Pulmonary disease (alternative agent if unable to tolerate itraconazole): IV, Oral: 400 to 800 mg once daily for 6 to 12 months (IDSA [Chapman 2008]; Pappas 1997)

Candidiasis, treatment:

Candidemia (neutropenic and nonneutropenic patients):

Initial therapy (alternative agent to echinocandins if no previous azole exposure, noncritically ill, and not at high risk of fluconazole-resistant isolate): IV, Oral: Loading dose of 800 mg (12 mg/kg) once on day 1, then 400 mg (6 mg/kg) once daily; if Candida glabrata (fluconazole-susceptible) isolated, transition to 800 mg (12 mg/kg) once daily (IDSA [Pappas 2016]).

Step-down therapy:

Isolates other than C. glabrata: Oral: 400 mg (6 mg/kg) once daily (IDSA [Pappas 2016])

Isolates of C. glabrata (fluconazole-susceptible): Oral: 800 mg (12 mg/kg) once daily (IDSA [Pappas 2016])

Duration: Continue for at least 14 days after first negative blood culture and resolution of signs/symptoms (longer duration required in patients with metastatic complications); step-down therapy to oral fluconazole is recommended only in clinically stable patients with negative repeat cultures and fluconazole-susceptible isolates (IDSA [Pappas 2016]; Kauffman 2018a)

Candidiasis, invasive (suspected; empiric therapy) and/or critically ill nonneutropenic patients in the ICU at risk of invasive infection with fever and unidentified etiology (alternative agent to echinocandins if no previous azole exposure and not known to be colonized with fluconazole-resistant isolates): IV, Oral: Loading dose of 800 mg (12 mg/kg) once on day 1, then 400 mg (6 mg/kg) once daily; treatment should continue for at least 14 days in patients with clinical improvement. Consider discontinuing after 4 to 5 days in patients with no clinical response and without signs of invasive candidiasis (IDSA [Pappas 2016]; Kauffman 2018a).

Cardiac device infection (eg, implantable cardiac defibrillator [ICD], pacemaker, ventricular assist device [VAD]): Step-down therapy: IV, Oral: 400 to 800 mg (6 to 12 mg/kg) once daily for 4 to 6 weeks after device removal (4 weeks for infections limited to generator pockets and at least 6 weeks for infections involving wires). Note: When VAD cannot be removed and as long as device remains in place, chronic suppressive therapy with fluconazole 400 to 800 mg (6 to 12 mg/kg) once daily should be used (IDSA [Pappas 2016]).

Chronic, disseminated (hepatosplenic) (fluconazole-susceptible isolates): Step-down therapy: Oral: 400 mg (6 mg/kg) once daily; continue fluconazole until lesion resolution (usually several months) (IDSA [Pappas 2016]).

CNS candidiasis: Step-down therapy: IV, Oral: 400 to 800 mg (6 to 12 mg/kg) once daily; continue fluconazole until signs/symptoms and CSF/radiological abnormalities have resolved (IDSA [Pappas 2016]; IDSA [Tunkel 2017])

Empyema (fluconazole-susceptible isolates): Limited data available; based on expert opinion. IV, Oral: Loading dose of 800 mg (12 mg/kg) once on day 1, then 400 mg (6 mg/kg) once daily for ≥2 weeks after chest tube removal or decortication (Kauffman 2018b)

Endocarditis, native or prosthetic valve: Step-down therapy: IV, Oral: 400 to 800 mg (6 to 12 mg/kg) once daily for at least 6 weeks after valve replacement surgery (longer durations recommended in patients with perivalvular abscesses or other complications) (IDSA [Pappas 2016]). Note: In patients who cannot undergo valve replacement surgery or with prosthetic valve endocarditis, long-term or chronic suppressive therapy with fluconazole 400 to 800 mg (6 to 12 mg/kg) once daily should be used (fluconazole-susceptible isolates) (IDSA [Pappas 2016]).

Endophthalmitis, endogenous (with or without vitritis) (fluconazole-susceptible isolates): IV, Oral: Loading dose of 800 mg (12 mg/kg) once on day 1, then 400 to 800 mg (6 to 12 mg/kg) once daily for at least 4 to 6 weeks until examination indicates resolution (longer duration may be needed for patients with vitreous involvement); for patients with vitritis or with macular involvement (with or without vitritis), an intravitreal injection with voriconazole or amphotericin B deoxycholate is also recommended (IDSA [Pappas 2016]; Kauffman 2018c)

Esophageal: IV, Oral: Loading dose of 400 mg (6 mg/kg) once on day 1, then 200 to 400 mg (3 to 6 mg/kg) once daily for 14 to 21 days; chronic suppressive therapy of 100 to 200 mg 3 times weekly may be used for recurrent infections (IDSA [Pappas 2016]; Kauffman 2018d)

Manufacturer's labeling: Dosing in the prescribing information may not reflect current clinical practice. IV, Oral: Loading dose of 200 mg on day 1, then 100 mg once daily

Intertrigo, refractory to topical therapy (off-label use): Limited data available to define optimal dose: IV, Oral: 50 to 100 mg once daily or 150 mg once weekly (Coldiron 1991; Nenoff 2015; Nozickova 1998; Stengel 1994); some experts prefer 100 to 200 mg once weekly for 4 weeks (Brodell 2018).

Intra-abdominal infections (alternative agent to echinocandins if no previous azole exposure, noncritically ill, and not at high risk of fluconazole-resistant isolate): IV, Oral: Loading dose of 800 mg (12 mg/kg) once on day 1, then 400 mg (6 mg/kg) once daily; duration of therapy determined by clinical response and source control. Step-down therapy (after patient has responded to initial therapy [eg, echinocandin] with fluconazole is recommended only in clinically stable patients with fluconazole-susceptible isolate (IDSA [Pappas 2016]; Kauffman 2018b).

Mediastinitis (fluconazole-susceptible isolates): IV, Oral: Loading dose of 800 mg (12 mg/kg) once on day 1, then 400 mg (6 mg/kg) once daily; therapy is most often prolonged and continued until resolution of clinical and laboratory signs of infection (if sternal involvement is present, therapy may extend to 6 months or longer) (Kauffman 2018b; Malani 2002).

Oropharyngeal: IV, Oral: Loading dose of 200 mg once on day 1, then 100 to 200 mg once daily for 7 to 14 days; recommended for HIV-seronegative patients unresponsive to topical therapy and for HIV-seropositive patients with moderate to severe infection, recurrent infection, and/or at risk of developing esophageal candidiasis (CD4 count <100 cells/mm3); in patients with recurrent infection (to prevent subsequent recurrences), prophylactic therapy of 100 mg 3 times weekly or 100 mg once daily may be considered (IDSA [Pappas 2016]; Kauffman 2018d).

Osteoarticular (osteomyelitis or septic arthritis) (fluconazole-susceptible isolates): IV, Oral: 400 mg (6 mg/kg) once daily for 6 to 12 months for osteomyelitis or for septic arthritis, a total of 6 weeks (includes 2 weeks of initial treatment with a lipid formulation of amphotericin B or an echinocandin). In patients with fluconazole-susceptible isolates and septic arthritis involving a prosthetic device which cannot be removed, chronic suppressive therapy with fluconazole 400 mg once daily is recommended (IDSA [Pappas 2016]).

Pericarditis (initial or step-down therapy for fluconazole-susceptible isolates): IV, Oral: Loading dose of 800 mg (12 mg/kg) once on day 1, then 400 mg (6 mg/kg) once daily; therapy is most often prolonged and continued until resolution of clinical and laboratory signs of infection (Kauffman 2018b).

Peritonitis, associated with peritoneal dialysis: Note: Use for empiric treatment if no azole exposure or for directed therapy against fluconazole-susceptible isolates: Oral: 200 mg once daily for 2 to 4 weeks (Glickman 2018; Vas 2001; Wang 2000).

Thrombophlebitis, suppurative: IV, Oral: 400 to 800 mg (6 to 12 mg/kg) once daily for at least 2 weeks after candidemia has cleared (IDSA [Pappas 2016]).

Urinary tract infection (UTI):

Candiduria (asymptomatic):

Patients with neutropenia: Treat as if patient has candidemia (Georgiadou 2013; IDSA [Pappas 2016]).

Patients undergoing a urologic procedure: Oral: 400 mg (6 mg/kg) once daily several days before and after the procedure (IDSA [Pappas 2016]).

Cystitis (symptomatic): Oral: 200 mg (3 mg/kg) once daily for 2 weeks (IDSA [Pappas 2016])

Pyelonephritis: Oral: 200 to 400 mg once daily for 2 weeks (IDSA [Pappas 2016])

UTI associated with fungus balls: Oral: 200 to 400 mg (3 to 6 mg/kg) once daily; concomitant irrigation of amphotericin B deoxycholate via nephrostomy tubes, if present, is also recommended, along with surgical management (IDSA [Pappas 2016]).

Manufacturer's labeling: Doses in the prescribing information may not reflect current clinical practice. Urinary tract infection: Oral, IV: 50 to 100 mg once daily

Vaginal/Vulvovaginal:

Uncomplicated: Oral: 150 mg as a single dose (manufacturer's labeling)

Complicated or severe: Oral: 150 mg every 72 hours for 2 or 3 doses (CDC [Workowski 2015]; Pappas [IDSA 2016])

Recurrent: Oral: 150 mg once daily for 10 to 14 days, followed by 150 mg once weekly for 6 months (IDSA [Pappas 2016]) or 100 mg, 150 mg, or 200 mg every 72 hours for a total of 3 doses, then 100 mg, 150 mg, or 200 mg once weekly for 6 months (CDC [Workowski 2015]). Some experts recommend the use of 150 every 72 hours for a total of 3 doses, then 150 mg once weekly for 6 months (Sobel 2018).

Candidiasis, prophylaxis:

Prophylaxis:

Hematologic malignancy patients (who do not warrant mold-active prophylaxis) (off-label use): Oral: 400 mg once daily for at least the duration of neutropenia (ASCO/IDSA [Taplitz 2018]; Glasmacher 2006; Wingard 2018)

Hematopoietic cell transplant (HCT) recipients: Oral: 400 mg once daily. Patients anticipated to have severe neutropenia should start therapy several days prior to the anticipated onset; duration is at least until resolution of neutropenia and/or through day 75 in allogeneic HCT recipients (ASBMT [Tomblyn 2009]; ASCO/IDSA [Taplitz 2018]).

High-risk ICU patients (in units with high incidence of invasive candidiasis) (off-label use): Oral, IV: Loading dose of 800 mg (12 mg/kg) once on day 1, then 400 mg (6 mg/kg) once daily (IDSA [Pappas 2016])

Peritoneal dialysis associated infection (concurrently treated with antibiotics), prevention of secondary fungal infection: Oral: 200 mg every 48 hours (Restrepo 2010)

Solid organ transplant recipients (liver, pancreas, kidney, pancreas-kidney, or small bowel transplantation) at high-risk of invasive infection (off-label use): Oral, IV: 400 mg (6 mg/kg) given in the perioperative period and continued once daily in the postoperative period; time of initiation and duration varies with transplant type and operative protocol (ASHP/IDSA/SIS/SHEA [Bratzler 2013]; AST-IDCOP [Silveira 2013]; Fishman 2018; Winston 2002).

Coccidioidomycosis, treatment (off-label use):

Bone and/or joint infection: Initial or step-down therapy: Oral: 800 mg once daily for a minimum of 3 years; in some cases, lifetime treatment is needed; duration depends on severity and host immunocompetence (IDSA [Galgiani 2016]).

Meningitis: Oral: 400 to 1,200 mg once daily, depending on severity; continue indefinitely (high rate of relapse when dose is decreased or treatment is discontinued) (HHS [OI adult 2018]; IDSA [Galgiani 2016])

Pneumonia, primary infection: Note: Only for patients with severely debilitating illness or with extensive pulmonary involvement, concurrent diabetes, frailty due to age or comorbidities, or HIV (HHS [OI adult 2018]; IDSA [Galgiani 2016]):

Oral: Usual dose: 400 mg once daily; IDSA guidelines state that some experts recommend 800 mg once daily. Duration of therapy is 3 to 6 months for immunocompetent patients; patients with immunosuppression require a longer duration of therapy (sometimes indefinite) (HHS [adult OI 2018]; IDSA [Galgiani 2016]).

Pneumonia, symptomatic chronic cavitary and/or cavitary disease in immunocompromised patients: Oral: 400 mg once daily for ≥12 months. In patients with ruptured cavities, doses of ≥400 mg may be used; duration in these patients depends upon postoperative course (IDSA [Galgiani 2016]; Jaroszewski 2018).

Soft tissue infection (not associated with bone infection): Oral: 400 mg once daily; IDSA guidelines state that some experts use up to 800 mg once daily; duration is for a minimum of 6 to 12 months (IDSA [Galgiani 2016])

Coccidioidomycosis, prophylaxis (off-label use):

HIV-infected patients (HHS [OI adult 2018]): Oral:

Primary prophylaxis is not recommended; yearly or twice-yearly serologic testing should be performed in patients living in endemic areas. Patients with a CD4 count <250 cells/mm3 who have a new positive serologic test result should receive fluconazole 400 mg once daily until CD4 count is ≥250 cells/mm3 and antiretroviral therapy has fully suppressed HIV replication.

Solid organ transplant recipients:

Seronegative patients in endemic areas (regardless of clinical history of coccidioidomycosis): Oral: 200 mg once daily for 6 to 12 months (Ampel 2018; IDSA [Galgiani 2016])

Seropositive patients in endemic areas: Oral: 400 mg once daily for 6 to 12 months (IDSA [Galgiani 2016])

Donor with isolated pulmonary infection and seropositive or culture positive or seropositive donor without identified focus of infection:

Lung recipient: Oral: 400 mg once daily continued lifelong (AST-IDCOP [Singh 2012])

Non-lung recipient: Oral: 400 mg once daily for 1 year, then consider 200 mg once daily for an indefinite duration (AST-IDCOP [Singh 2012])

Donor with isolated pulmonary infection and seronegative and culture negative:

Lung recipient: Oral: 400 mg once daily continued lifelong (AST-IDCOP [Singh 2012])

Non-lung recipient: Oral: 400 mg once daily for 3 to 6 months, then consider 200 mg once daily or stop and observe (AST-IDCOP [Singh 2012])

Donor with extrapulmonary infection: All recipients: Oral: 400 mg once daily continued lifelong (AST-IDCOP [Singh 2012])

Cryptococcosis, meningitis:

HIV-infected:

Induction (alternative regimens or when resources are limited): Oral:

Alternative regimens:

If flucytosine is not available or cannot be tolerated: 800 mg once daily with concomitant amphotericin B (lipid formulation preferred) for at least 2 weeks followed by consolidation therapy (IDSA [Perfect 2010]); or

If amphotericin B is not available or cannot be tolerated: 800 to 1,200 mg once daily with concomitant flucytosine for 6 weeks followed by consolidation therapy (IDSA [Perfect 2010]; Molloy 2018; Nussbaum 2010); or

If flucytosine and amphotericin B unavailable or cannot be tolerated: 1,200 to 2,000 mg once daily as monotherapy for 10 to 12 weeks (IDSA [Perfect 2010]).

Resource-limited settings:

Following 1 week of amphotericin B deoxycholate and flucytosine (preferred regimen), as a 2-week induction regimen with flucytosine, or when flucytosine is unavailable in combination with amphotericin B deoxycholate: 1,200 mg once daily; duration depends on induction regimen (Cox 2018a; WHO 2018).

Note: Induction therapy should be continued beyond above durations if clinical improvement is not yet observed and/or if CSF cultures remain positive (Cox 2018a).

Consolidation: Oral:

Following induction with a preferred regimen of amphotericin B and flucytosine: Fluconazole 400 mg once daily for at least 8 weeks (HHS [OI adult 2018]; IDSA [Perfect 2010]); or

Following induction therapy with an alternative regimen of fluconazole and amphotericin B: Fluconazole 800 mg once daily for at least 8 weeks (Cox 2018a; IDSA [Perfect 2010]).

Maintenance (suppression): Oral: 200 mg once daily for at least 12 months; may discontinue if completed induction, consolidation, and at least 12 months of maintenance therapy, patient remains asymptomatic from cryptococcal infection, and CD4 count ≥100 cells/mm3 for ≥3 months and HIV RNA suppressed in response to effective ART (HHS [OI adult 2018]; IDSA [Perfect 2010]).

HIV-uninfected:

Induction (alternative regimens): Oral:

If amphotericin B is not available or cannot be tolerated: 800 to 1,200 mg once daily with concomitant flucytosine for 2 to 10 weeks (duration depends on severity and response to therapy) (Cox 2018b); or

If flucytosine is not available or cannot be tolerated: 800 mg once daily with concomitant amphotericin B for 2 weeks (Cox 2018b); or

If amphotericin B and flucytosine not available or cannot be tolerated: 800 to 1,200 mg once daily as monotherapy for ≥10 weeks (Cox 2018b)

Consolidation: Oral: 400 to 800 mg once daily for 8 weeks (800 mg once daily preferred for patients who receive only 2-week induction course) (AST-IDCOP [Baddley 2013]; Cox 2018b; IDSA [Perfect 2010])

Maintenance (suppression): Oral: 200 to 400 mg once daily for 6 to 12 months (AST-IDCOP [Baddley 2013]; IDSA [Perfect 2010]) (a longer duration may be warranted for patients on high-dose steroids, receipt of biologics [eg, alemtuzumab], or if there is radiographic evidence of cryptococcoma [Cox 2018b])

Cryptococcosis, pulmonary and extra-pulmonary infection (non-CNS) (off-label use):

Pulmonary infection: Mild to moderate symptoms (if severe pneumonia, treat like CNS infection): Immunocompetent or immunosuppressed patients without evidence of pulmonary infiltrates or disseminated infection: Oral: 400 mg (6 mg/kg) once daily for 6 to 12 months (Cox 2018c; IDSA [Perfect 2010]) (a duration of 12 months [or longer for chronic suppressive therapy] is preferred in HIV-infected patients) (HHS [OI adult 2018]).

Extrapulmonary infection: Immunocompetent patients with a single-site of infection without evidence of CNS disease (ie, nonmeningeal) and fungemia: Oral: 400 mg (6 mg/kg) once daily for 6 to 12 months (Cox 2018c; IDSA [Perfect 2010]).

Cryptococcosis due to C. gattii (off-label use): Note: Recommendations based predominantly from extrapolation of studies involving treatment of Cryptococcus neoformans.

CNS disease, meningoencephalitis and/or cerebral cryptococcomas (immunocompetent or immunosuppressed patients):

Consolidation therapy (following induction therapy with appropriate antifungal agents): Oral: 400 mg once daily for 8 weeks (meningoencephalitis) or 400 to 800 mg once daily for 6 to 18 months (cerebral cryptococcomas) (IDSA [Perfect 2010])

Maintenance therapy: Oral: 200 mg once daily for 6 to 12 months to sufficiently eradicate the infection; however, total duration of therapy should be dependent upon clinical and mycologic response (IDSA [Perfect 2010]). Some experts extend duration beyond 12 months (median duration in one trial: 18 months) (Chen 2013). Note: For HIV-infected patients, a minimum duration of 1 year is required; timing of discontinuation dependent on patient-specific factors (eg, viral load, CD4 count) (HHS [OI adult 2018]).

Pulmonary infection:

Immunocompetent patients with a single, small cryptococcoma without evidence of extrapulmonary involvement: Oral: 400 mg once daily for 6 to 12 months (IDSA [Perfect 2010])

Immunocompromised or immunocompetent patients with large and/or multiple cryptococcomas: Consolidation and maintenance therapy (following induction therapy with appropriate antifungal agents): Oral: 400 mg once daily for 8 weeks for consolidation therapy, followed by 200 mg once daily for 4 to 18 months for maintenance therapy (Chen 2018; IDSA [Perfect 2010])

Tinea:

Tinea corporis or cruris: Oral: 150 to 200 mg once weekly for 2 to 4 weeks (Goldstein 2018; Kotogyan 1996; Montero-Gei 1992; Stary 1998)

Tinea pedis: Oral: 150 mg once weekly for 2 to 6 weeks (Gupta 2008; Kotogyan 1996; Montero-Gei 1992)

Tinea versicolor: Oral: 300 mg once weekly for 2 weeks (Karakas 2005)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

The daily dose of fluconazole is the same for oral and IV administration

Usual dosage range: Oral, IV: Loading dose: 6 to 12 mg/kg/dose; maintenance: 3 to 12 mg/kg/dose once daily; duration and dosage depend on location and severity of infection

Indication-specific dosing:

Candidiasis: Oral, IV:

Esophageal:

Manufacturer’s recommendation: Loading dose: 6 mg/kg/dose; maintenance: 3-12 mg/kg/dose once daily for 21 days and for at least 2 weeks following resolution of symptoms (maximum: 600 mg/day)

HIV-exposed/-infected: Loading dose: 6 mg/kg/dose once on day 1; maintenance: 3 to 6 mg/kg/dose once daily for 4 to 21 days (maximum: 400 mg/day) (CDC 2009)

Relapse suppression (HIV-exposed/-infected): 3 to 6 mg/kg/dose once daily (maximum: 200 mg/day) (CDC 2009)

Invasive disease (alternative therapy): 5 to 6 mg/kg/dose every 12 hours for ≥28 days (maximum: 600 mg/day) (CDC 2009)

Oropharyngeal:

Manufacturer’s recommendation: Loading dose: 6 mg/kg/dose; maintenance: 3 mg/kg/dose once daily for ≥2 weeks (maximum: 600 mg/day)

HIV-exposed/-infected: 3 to 6 mg/kg/dose once daily for 7 to 14 days (maximum: 400 mg/day) (CDC 2009)

Surgical (perioperative) prophylaxis in high-risk patients undergoing liver, pancreas, kidney, or pancreas-kidney transplantation (off-label use): IV: 6 mg/kg given in the perioperative period and continued in the postoperative period for ≤28 days (maximum dose 400 mg). Time of initiation and duration varies with transplant type and operative protocol (Bratzler 2013).

Coccidioidomycosis: Oral, IV:

Children: Meningeal infection, or in a stable patient with diffuse pulmonary or disseminated disease (HIV-exposed/-infected):

Treatment: 5 to 6 mg/kg/dose twice daily (maximum daily dose: 800 mg/day) (CDC 2009) followed by chronic suppressive therapy (see below)

Relapse suppression: 6 mg/kg/dose once daily (maximum daily dose: 400 mg/day) (CDC 2009)

Adolescents: Treatment, primary prophylaxis, or chronic suppressive therapy (secondary prophylaxis): Refer to adult dosing.

Cryptococcosis: Oral, IV:

Meningitis: Manufacturer's labeling: 12 mg/kg/dose for 1 dose, then 6 to 12 mg/kg/day for 10-12 weeks following negative CSF culture

HIV-exposed/-infected:

CNS disease (alternative therapy in patients intolerant of amphotericin B):

Children:

Induction: 12 mg/kg/dose for 1 dose, then 6 to 12 mg/kg/day (maximum: 800 mg/day) for ≥2 weeks (in combination with flucytosine) (CDC 2009)

Consolidation: 10 to 12 mg/kg/day for 8 weeks (Perfect 2010) or 12 mg/kg/dose for 1 dose, then 6 to 12 mg/kg/day (maximum: 800 mg/day) for 8 weeks (CDC 2009)

Maintenance (suppression): 6 mg/kg/day (maximum: 200 mg/day) (CDC 2009; Perfect 2010)

Adolescents: Refer to adult dosing.

Non-CNS disease, disseminated (including severe pulmonary disease) (alternative therapy; off-label use): Induction: 12 mg/kg/dose for 1 dose, then 6 to 12 mg/kg/day (maximum: 600 mg/day) (CDC 2009)

Non-CNS disease, localized (including isolated pulmonary disease) (off-label use): 12 mg/kg/dose for 1 dose, then 6 to 12 mg/kg/day (maximum: 600 mg/day). Note: Duration depends upon infection site and severity (CDC 2009). For patients with pulmonary disease (not delineated by severity), the IDSA recommends a duration of 6 to 12 months (Perfect 2010).

Primary antifungal prophylaxis in pediatric oncology patients (guideline recommendations; Science 2014): Oral, IV:

Allogeneic hematopoietic stem cell transplant (HSCT): Infants ≥1 month, Children, and Adolescents <19 years: 6 to 12 mg/kg/day (maximum: 400 mg/day), begin at the start of conditioning; continue until engraftment

Allogeneic HSCT with grades 2 to 4 acute graft-versus-host-disease (GVHD) or chronic extensive GVHD: Begin with GVHD diagnosis, continue until GVHD resolves:

Infants ≥1 month and Children <13 years: 6 to 12 mg/kg/day (maximum: 400 mg/day)

Adolescents ≥13 years (where posaconazole is contraindicated): 6 to 12 mg/kg/day (maximum: 400 mg/day)

Autologous HSCT with neutropenia anticipated >7 days: Infants ≥1 month, Children, and Adolescents <19 years: 6 to 12 mg/kg/day (maximum: 400 mg/day), begin at the start of conditioning; continue until engraftment

Acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS): Infants ≥1 month, Children, and Adolescents <19 years: 6 to 12 mg/kg/day (maximum: 400 mg/day) during chemotherapy associated neutropenia; alternative antifungals may be suggested for children ≥13 years in centers with a high local incidence of mold infections or if fluconazole is not available

Dosing: Renal Impairment

Manufacturer's labeling: Note: Renal function estimated using the Cockcroft-Gault formula

No adjustment for vaginal candidiasis single-dose therapy

For multiple dosing in adults, administer loading dose of 50 to 400 mg, then adjust daily doses as follows (dosage reduction in children should parallel adult recommendations):

CrCl >50 mL/minute: No dosage adjustment necessary

CrCl ≤50 mL/minute (no dialysis): Reduce dose by 50%

End-stage renal disease on intermittent hemodialysis (IHD):

Manufacturer's labeling: 100% of daily dose (according to indication) after each dialysis session; on nondialysis days, patient should receive a reduced dose according to their CrCl.

Alternate recommendations: Doses of 200 to 400 mg every 48 to 72 hours or 100 to 200 mg every 24 hours have been recommended. Note: Dosing dependent on the assumption of 3 times/week, complete IHD sessions (Heintz 2009).

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 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment:

CVVH: Loading dose of 400 to 800 mg followed by 200 to 400 mg every 24 hours

CVVHD/CVVHDF: Loading dose of 400 to 800 mg followed by 400 to 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 to 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).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Administration

IV: Do not use if cloudy or precipitated. Infuse over ~1 to 2 hours; do not exceed 200 mg/hour.

Oral: May be administered without regard to meals.

Storage

Tablet: Store at <30°C (86°F).

Powder for oral suspension: Store dry powder at <30°C (86°F). Following reconstitution, store at 5°C to 30°C (41°F to 86°F). Discard unused portion after 2 weeks. Do not freeze.

Injection: Store injection in glass at 5°C to 30°C (41°F to 86°F). Store injection in plastic flexible containers with overwrap at 20°C to 25°C (68°F to 77°F). Do not freeze. Do not unwrap unit until ready for use.

Drug Interactions

Abemaciclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Abemaciclib. Monitor therapy

Acalabrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Acalabrutinib. Management: Reduce acalabrutinib dose to 100 mg once daily with concurrent use of a moderate CYP3A4 inhibitor. Monitor patient closely for both acalabrutinib response and evidence of adverse effects with any concurrent use. Consider therapy modification

Alfentanil: Fluconazole may increase the serum concentration of Alfentanil. Management: Monitor for increased anesthetic and respiratory depressant effects if alfentanil is combined with fluconazole. Consider using lower initial doses of alfentanil or an alternative anesthetic. Consider therapy modification

Amiodarone: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Amiodarone. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Amiodarone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Amitriptyline: May enhance the QTc-prolonging effect of Fluconazole. Fluconazole may increase the serum concentration of Amitriptyline. Monitor therapy

AmLODIPine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of AmLODIPine. Monitor therapy

Amphotericin B: Antifungal Agents (Azole Derivatives, Systemic) may diminish the therapeutic effect of Amphotericin B. Monitor therapy

Apixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban. Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Astemizole: Fluconazole may enhance the QTc-prolonging effect of Astemizole. Fluconazole may increase the serum concentration of Astemizole. Avoid combination

Asunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir. Avoid combination

AtorvaSTATin: Fluconazole may increase the serum concentration of AtorvaSTATin. Monitor therapy

Avanafil: Fluconazole may increase the serum concentration of Avanafil. Management: Limit avanafil to a maximum dose of 50 mg per 24-hour period in any patient who is also receiving a moderate inhibitor of CYP3A4 such as fluconazole. Consider therapy modification

Avatrombopag: Fluconazole may increase the serum concentration of Avatrombopag. Monitor therapy

Benzhydrocodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Benzhydrocodone. Specifically, the concentration of hydrocodone may be increased. Monitor therapy

Blonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin. Monitor therapy

Bosentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosentan: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib. Avoid combination

Brexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations. Consider therapy modification

Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Avoid combination

Budesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Busulfan: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Busulfan. Isavuconazonium considerations are addressed in separate monographs. Monitor therapy

Calcium Channel Blockers: Fluconazole may increase the serum concentration of Calcium Channel Blockers. Exceptions: Clevidipine. Monitor therapy

Cannabidiol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabidiol. Monitor therapy

Cannabidiol: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Cannabidiol. Monitor therapy

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

CarBAMazepine: Fluconazole may increase the serum concentration of CarBAMazepine. Monitor therapy

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4. Consider therapy modification

Cilostazol: CYP2C19 Inhibitors may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

Citalopram: Fluconazole may enhance the QTc-prolonging effect of Citalopram. Fluconazole may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with fluconazole, which is a strong CYP2C19 inhibitor. Consider therapy modification

Clopidogrel: CYP2C19 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a strong CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination

Codeine: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Codeine. Monitor therapy

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. See full monograph for details. Use extra caution in patients with impaired renal and/or hepatic function. Consider therapy modification

Crizotinib: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Crizotinib. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Crizotinib. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

CycloSPORINE (Systemic): Fluconazole may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

CYP2C19 Substrates (High risk with Inhibitors): CYP2C19 Inhibitors (Strong) may decrease the metabolism of CYP2C19 Substrates (High risk with Inhibitors). Consider therapy modification

CYP2C9 Substrates (High risk with Inhibitors): CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Substrates (High risk with Inhibitors): CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Exceptions: Alitretinoin (Systemic); Praziquantel; Trabectedin; Vinorelbine. Monitor therapy

Dabigatran Etexilate: Fluconazole may enhance the anticoagulant effect of Dabigatran Etexilate. Monitor therapy

Dapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg per day when used together with a moderate inhibitor of CYP3A4. Consider therapy modification

Deflazacort: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Deflazacort. Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor. Consider therapy modification

Diclofenac (Systemic): CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Diclofenac (Systemic). Management: Consider using a reduced dose of diclofenac when used together with moderate CYP2C9 inhibitors. Arthrotec (diclofenac and misoprostol) prescribing information recommends a maximum dose of 50 mg twice daily. Consider therapy modification

Didanosine: May decrease the absorption of Antifungal Agents (Azole Derivatives, Systemic). Enteric coated didanosine capsules are not expected to affect these antifungals. Consider therapy modification

Domperidone: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Domperidone. Avoid combination

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Dronedarone: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Dronedarone. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Dronedarone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided. Consider therapy modification

Eliglustat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Encorafenib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Encorafenib. Management: Avoid concomitant use of encorafenib and moderate CYP3A4 inhibitors whenever possible. If concomitant administration is unavoidable, decrease the encorafenib dose to one-half of the encorafenib dose used prior to initiation of the CYP3A4 inhibitor. Consider therapy modification

Encorafenib: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Encorafenib. Management: Avoid using moderate CYP3A4 inhibitors together with encorafenib if possible. If the combination must be used, reduce the encorafenib dose by 50% (to one-half of the prior dose). Consider therapy modification

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. Consider therapy modification

Erythromycin (Systemic): Fluconazole may enhance the QTc-prolonging effect of Erythromycin (Systemic). Fluconazole may increase the serum concentration of Erythromycin (Systemic). Avoid combination

Estrogen Derivatives: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Estrogen Derivatives. Monitor therapy

Etravirine: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Etravirine. Applicable Isavuconazonium considerations are addressed in separate monographs. 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. Consider therapy modification

Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for most indications. See full monograph or prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Avoid combination

Fluvastatin: Fluconazole may increase the serum concentration of Fluvastatin. Management: Limit fluvastatin maximum adult dose to 20 mg twice daily, and monitor for toxic effects of fluvastatin (e.g., myalgia, rhabdomyolysis, liver function test abnormalities), during concomitant treatment. Consider therapy modification

Fosphenytoin: Fluconazole may increase the serum concentration of Fosphenytoin. Consider therapy modification

GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification

Haloperidol: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

HYDROcodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone. Monitor therapy

Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: When treating B-cell malignancies, decrease ibrutinib to 280 mg daily when combined with moderate CYP3A4 inhibitors. When treating graft versus host disease, monitor patients closely and reduce the ibrutinib dose as needed based on adverse reactions. Consider therapy modification

Ifosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib. Monitor therapy

Ivabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full monograph content for specific age- and weight-based recommendations. No dose adjustment is needed when using ivacaftor/lumacaftor with a moderate CYP3A4 inhibitor. Consider therapy modification

Ivosidenib: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ivosidenib. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Lesinurad: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Lesinurad. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide. Avoid combination

Lornoxicam: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Lornoxicam. Monitor therapy

Losartan: Fluconazole may decrease the serum concentration of Losartan. Specifically, fluconazole may decrease the serum concentration of E3174, the more potent active metabolite of losartan. Monitor therapy

Lovastatin: Fluconazole may increase the serum concentration of Lovastatin. Monitor therapy

Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: Lurasidone US labeling recommends reducing lurasidone dose by half with a moderate CYP3A4 inhibitor. Some non-US labeling recommends initiating lurasidone at 20 mg/day and limiting dose to 40 mg/day; avoid concurrent use of grapefruit products. Consider therapy modification

Manidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Manidipine. Monitor therapy

Methadone: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Mirodenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil. Monitor therapy

Mizolastine: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Mizolastine. Avoid combination

Naldemedine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naldemedine. Monitor therapy

Nalfurafine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nalfurafine. Monitor therapy

Nalmefene: Fluconazole may increase the serum concentration of Nalmefene. Monitor therapy

Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Avoid combination

Nateglinide: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Nateglinide. Monitor therapy

Neratinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Neratinib. Avoid combination

Nevirapine: Fluconazole may increase the serum concentration of Nevirapine. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine. Monitor therapy

Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Consider therapy modification

Ondansetron: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Ospemifene: Fluconazole may increase the serum concentration of Ospemifene. Avoid combination

OxyCODONE: CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Monitor therapy

Parecoxib: Fluconazole may increase the serum concentration of Parecoxib. Management: Use the lowest possible dose of parecoxib in patients who are taking fluconazole. Consider therapy modification

Pentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Phenytoin: Fluconazole may increase the serum concentration of Phenytoin. Consider therapy modification

Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide. Avoid combination

Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination

PredniSONE: Fluconazole may increase the serum concentration of PredniSONE. Monitor therapy

Proton Pump Inhibitors: Fluconazole may increase the serum concentration of Proton Pump Inhibitors. Monitor therapy

QT-prolonging Antidepressants (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Exceptions: Citalopram. Monitor therapy

QT-prolonging Antipsychotics (Moderate Risk): QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Pimozide. Monitor therapy

QT-prolonging Class IA Antiarrhythmics (Highest Risk): Fluconazole may enhance the QTc-prolonging effect of QT-prolonging Class IA Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: QuiNIDine. Consider therapy modification

QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Class III Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Dronedarone. Consider therapy modification

QT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Ivosidenib. Consider therapy modification

QT-prolonging Kinase Inhibitors (Moderate Risk): QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Moderate Risk). Exceptions: Encorafenib. Monitor therapy

QT-prolonging Miscellaneous Agents (Highest Risk): May enhance the QTc-prolonging effect of Fluconazole. Fluconazole may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Astemizole; Terfenadine. Consider therapy modification

QT-prolonging Miscellaneous Agents (Moderate Risk): QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Domperidone. Monitor therapy

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): Fluconazole may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Crizotinib; Erythromycin (Systemic). Monitor therapy

QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): Fluconazole may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Voriconazole. Monitor therapy

QuiNIDine: Fluconazole may enhance the QTc-prolonging effect of QuiNIDine. Fluconazole may increase the serum concentration of QuiNIDine. Avoid combination

Ramelteon: Fluconazole may increase the serum concentration of Ramelteon. Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Consider therapy modification

Red Yeast Rice: Fluconazole may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin and related compounds found in Red Yeast Rice may be increased. 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). Management: Avoid these combinations when possible. Voriconazole and isavuconazonium are considered contraindicated. Consider therapy modification

Rupatadine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rupatadine. Monitor therapy

Ruxolitinib: Fluconazole may increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification

Saccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii. Avoid combination

Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Monitor therapy

SAXagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin. Monitor therapy

Sildenafil: Fluconazole may increase the serum concentration of Sildenafil. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir. Avoid combination

Simvastatin: Fluconazole may increase the serum concentration of Simvastatin. 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. Consider therapy modification

Solifenacin: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Solifenacin. Applicable Isavuconazonium considerations are addressed in separate monographs. Management: The manufacturer recommends not exceeding 5 mg daily of solifenacin during concomitant therapy with ketoconazole, or other potent CYP3A4 enzyme inhibitors. Consider therapy modification

Sonidegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib. Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible. When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions). Consider therapy modification

Sulfonylureas: Fluconazole may increase the serum concentration of Sulfonylureas. Management: Seek alternatives when possible. If used together, monitor closely for increased effects of sulfonylureas if fluconazole is initiated/dose increased, or decreased effects if fluconazole is discontinued/dose decreased. Consider therapy modification

SUNItinib: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of SUNItinib. Applicable Isavuconazonium considerations are addressed in separate monographs. Management: Consider a reduced dose of sunitinib (minimum of 37.5 mg daily) during concomitant use. Concurrent use with itraconazole is not recommended per itraconazole labeling. Consider therapy modification

Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Consider therapy modification

Tacrolimus (Systemic): Fluconazole may increase the serum concentration of Tacrolimus (Systemic). Management: Monitor tacrolimus concentrations closely and adjust oral tacrolimus dose as necessary when concomitantly administered with fluconazole. Reduced doses of tacrolimus will likely be required. Consider therapy modification

Tadalafil: Fluconazole may increase the serum concentration of Tadalafil. Monitor therapy

Tamsulosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin. Monitor therapy

Telithromycin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Telithromycin. 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. Consider therapy modification

Terfenadine: Fluconazole may enhance the QTc-prolonging effect of Terfenadine. Fluconazole may increase the serum concentration of Terfenadine. Management: Concomitant use of fluconazole at doses of 400 mg/day or greater and terfenadine is contraindicated and should be avoided. If lower doses of fluconazole and terfenadine are combined, monitor patients for QT-prolongation. Consider therapy modification

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Tetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol and Cannabidiol. Specifically, concentrations of tetrahydrocannabinol may be increased. Monitor therapy

Tezacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tezacaftor. Management: When combined with moderate CYP3A4 inhibitors, tezacaftor/ivacaftor (100 mg/150 mg) should be given in the morning, every other day. Ivacaftor (150 mg) alone should be given in the evening, every other day, on alternate days from tezacaftor/ivacaftor. Consider therapy modification

Theophylline Derivatives: Fluconazole may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor. Monitor therapy

Tipranavir: Fluconazole may increase the serum concentration of Tipranavir. Management: Limit fluconazole adult maximum dose to 200 mg/day in patients treated with tipranavir. Consider therapy modification

Tofacitinib: Fluconazole may increase the serum concentration of Tofacitinib. Management: Tofacitinib dose reductions are recommended when combined with fluconazole. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full monograph for details. Consider therapy modification

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Management: Jynarque dose requires adjustment when used with a moderate CYP3A4 inhibitor. See labeling or full interaction monograph for specific recommendations. Use of Samsca with moderate CYP3A4 ihibitors should generally be avoided. Consider therapy modification

Torsemide: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Torsemide. Monitor therapy

Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Monitor therapy

Udenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Udenafil. Monitor therapy

Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination

Vardenafil: Fluconazole may increase the serum concentration of Vardenafil. Management: Limit vardenafil doses to a maximum of 5 mg per 24-hour period in patients receiving concurrent therapy with a moderate CYP3A4 inhibitor such as fluconazole. Consider therapy modification

Venetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Monitor therapy

VinCRIStine: Fluconazole may increase the serum concentration of VinCRIStine. Monitor therapy

Vindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Fluconazole may increase the serum concentration of Vitamin K Antagonists. Consider therapy modification

Voriconazole: Fluconazole may enhance the QTc-prolonging effect of Voriconazole. Fluconazole may increase the serum concentration of Voriconazole. Avoid combination

Zidovudine: Fluconazole may decrease the metabolism of Zidovudine. Monitor therapy

Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Zuclopenthixol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol. Monitor therapy

Adverse Reactions

Frequency not always defined.

Central nervous system: Headache (2% to 13%), dizziness (1%)

Dermatologic: Skin rash (2%)

Gastrointestinal: Nausea (2% to 7%), abdominal pain (2% to 6%), vomiting (2% to 5%), diarrhea (2% to 3%), dysgeusia (1%), dyspepsia (1%)

Hepatic: Hepatitis, increased serum alkaline phosphatase, increased serum ALT, increased serum AST, jaundice

<1%, postmarketing, and/or case reports: Acute generalized exanthematous pustulosis, agranulocytosis, alopecia, anaphylaxis, angioedema, cholestasis, diaphoresis, drowsiness, fatigue, fever, fixed drug eruption, hepatic failure, hypercholesterolemia, hypertriglyceridemia, hypokalemia, insomnia, leukopenia, malaise, myalgia, neutropenia, paresthesia, prolonged Q-T interval on ECG, seizure, Stevens-Johnson syndrome, thrombocytopenia, torsades de pointes, toxic epidermal necrolysis, tremor, vertigo, weakness, xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• Arrhythmias: Cases of QTc prolongation and torsade de pointes associated with fluconazole use have been reported (usually high dose or in combination with agents known to prolong the QT interval); use caution in patients with concomitant medications or conditions which are arrhythmogenic.

• CNS effects: May occasionally cause dizziness or seizures; use caution driving or operating machinery.

• Hepatotoxicity: Serious (and sometimes fatal) hepatic toxicity (eg, hepatitis, cholestasis, fulminant hepatic failure) has been observed. Monitor patients who develop abnormal liver function tests for the development of more severe hepatic injury; discontinue fluconazole if signs and symptoms consistent with liver disease develop.

• Hypersensitivity reactions: Anaphylaxis has been reported rarely; use with caution in patients with hypersensitivity to other azoles.

• Skin reactions: Rare exfoliative skin disorders have been observed; fatal outcomes have been reported in patients with serious concomitant diseases. Monitor patients with deep seated fungal infections closely for rash development and discontinue if lesions progress. In patients with superficial fungal infections who develop a rash attributable to fluconazole, treatment should also be discontinued.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with preexisting hepatic impairment; monitor liver function closely and discontinue if symptoms consistent with liver disease develop.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be necessary.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP 1997; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

• Sucrose: Oral suspension contains sucrose; avoid use in patients with fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency.

Monitoring Parameters

Periodic liver function tests (AST, ALT, alkaline phosphatase) and renal function tests, potassium

Pregnancy Considerations

Following exposure during the first trimester, malformations have been noted in humans when fluconazole was used in higher doses (≥400 mg/day) over extended periods of time (eg, for the duration of pregnancy or intermittently throughout pregnancy). Abnormalities reported include brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. Use of lower doses (150 mg as a single dose) suggest increased risks to the fetus, however, additional study is needed.

Use of oral fluconazole for vaginal candidiasis is not recommended in pregnant women (HHS [OI adult 2017]; Workowski [CDC 2015]). Most azole antifungals, including fluconazole, are recommended to be avoided during the first trimester of pregnancy (IDSA [Pappas 2016]).

The manufacturer recommends females of childbearing potential taking higher doses (≥400 mg/day) use effective contraception during therapy and for ~1 week after the final fluconazole dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, nausea, vomiting, dizziness, abdominal pain, or change in taste. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), tachycardia, abnormal heartbeat, passing out, or severe skin irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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