Fluconazole (Monograph)

Brand name: Diflucan
Drug class: Azoles
VA class: AM700
Chemical name: α-(2,4-Difluorophenyl)-α-(1H-1,2,4-triazole-1-ylmethyl)-1H-1,2,4-triazole-1-ethanol
CAS number: 86386-73-4

Medically reviewed by Drugs.com on Sep 25, 2023. Written by ASHP.

Introduction

Antifungal; azole (triazole derivative).¹ ⁵ ⁵¹ ⁶⁸ ⁸⁴ ¹²⁴

Uses for Fluconazole

Blastomycosis

Alternative for treatment of blastomycosis^{† [off-label]} caused by Blastomyces dermatitidis.²⁸⁶ ²⁸⁷ ²⁸⁸ ²⁸⁹ ²⁹⁰ ²⁹² ²⁹⁷ ⁴³⁶

Drugs of choice are IV amphotericin B and oral itraconazole;²⁸⁹ ²⁹⁰ ²⁹² ²⁹⁶ ³¹⁵ ³¹⁶ ⁴²⁴ ⁴³⁶ oral fluconazole is an alternative,⁴³⁶ ⁴²⁴ but may be less effective and should be used only when drugs of choice are contraindicated or cannot be used.⁴³⁶ ⁴²⁴

Do not use oral azoles for initial treatment of CNS blastomycosis.⁴²⁴ Treatment failures or relapses reported when an oral azole (e.g., ketoconazole) was used in treatment of cutaneous or pulmonary blastomycosis in patients who had asymptomatic or subclinical CNS involvement at the time of initial diagnosis.²⁹³ ²⁹⁴

Consult current IDSA clinical practice guidelines available at [Web] for additional information on management of blastomycosis.⁴²⁴

Candidemia and Disseminated Candida Infections

Treatment of candidemia,¹ ¹²⁴ ³²² ³²⁴ ³³¹ ³⁹⁴ ⁴¹⁰ ⁴¹¹ ⁴²⁵ ⁴³⁶ disseminated candidiasis (e.g., disseminated hepatosplenic infections),¹ ³³⁰ ³³³ ³³⁴ and other serious Candida infections, including urinary tract infections (cystitis, pyelonephritis, fungus balls),³⁷ ⁴⁹ ⁶¹ ⁶⁴ ⁹⁴ ⁴²⁵ ⁴³⁶ peritonitis,³⁶ ⁴⁷ ⁶¹ ⁶⁴ ⁶⁸ ⁹⁴ ⁴³⁶ meningitis,⁴⁰⁷ ⁴⁰⁹ ⁴²⁵ osteoarticular infections (osteomyelitis, septic arthritis),⁴⁰⁵ ⁴²⁵ intravascular infections (endocarditis, implantable cardiac device infections),⁴²⁵ pneumonia,¹ ³⁷ ⁶⁴ ⁹⁴ endophthalmitis,⁴²⁵ and neonatal candidiasis^{† [off-label]} (including CNS infections).²⁹² ⁴²⁵

A drug of choice for many Candida infections.³²⁶ ⁴²⁵ ⁴³⁶ However, fluconazole-resistant C. albicans are being isolated with increasing frequency from patients who received prior fluconazole therapy (especially HIV-infected patients), and some Candida infections (e.g., candidemia) are increasingly caused by strains intrinsically resistant to fluconazole (e.g., C. krusei) or likely to have resistance or reduced susceptibility to the drug (e.g., C. glabrata).²⁶⁷ ⁴²⁵

When choosing antifungals for treatment of candidemia or invasive Candida infections, take into consideration any history of recent exposure to azole or echinocandin antifungals or intolerance to antifungals, local and/or institutional epidemiologic data regarding prevalence of the various Candida strains and their patterns of resistance, severity of illness, relevant comorbidities, presence and duration of neutropenia or immunosuppression, and evidence of involvement of the CNS, cardiac valves, and/or visceral organs.⁴²⁵

For treatment of candidemia in nonneutropenic patients or for empiric treatment of suspected invasive candidiasis^{† [off-label]} in nonneutropenic patients in intensive care units (ICUs), IDSA recommends an IV echinocandin (anidulafungin, caspofungin, micafungin) for initial therapy;⁴²⁵ IV or oral fluconazole is an acceptable alternative for initial therapy in selected patients, including those who are not critically ill and unlikely to have infections caused by fluconazole-resistant Candida.⁴²⁵ IV amphotericin B recommended if echinocandin- and azole-resistant Candida suspected and is an alternative when echinocandins and fluconazole have been ineffective or cannot be used.⁴²⁵ Consider transition from the echinocandin to fluconazole (usually within 5–7 days) in clinically stable patients if strain susceptible to fluconazole (e.g., C. albicans) and initial treatment resulted in negative repeat blood cultures.⁴²⁵

For treatment of candidemia in neutropenic patients, IDSA recommends an IV echinocandin (anidulafungin, caspofungin, micafungin) or, alternatively, amphotericin B for initial therapy.⁴²⁵ Fluconazole is an alternative for initial therapy in those who are not critically ill and have had no prior exposure to azole antifungals;⁴²⁵ also can be used for step-down therapy in clinically stable patients who have fluconazole-susceptible isolates and negative repeat blood cultures.⁴²⁵

For treatment of disseminated candidiasis in neonates^{† [off-label]} (neonatal candidiasis), IV amphotericin B usually drug of choice.²⁹² ⁴²⁵ IDSA states fluconazole is a reasonable alternative in those who have not been receiving fluconazole prophylaxis;⁴²⁵ AAP states fluconazole can be considered for follow-up (step-down) therapy after initial response to IV amphotericin B.²⁹² Fluconazole also has been used for prophylaxis to reduce the incidence of invasive candidiasis in low birthweight neonates^{† [off-label]} at high risk.²⁹² ⁴²⁵ ⁴⁷¹ ⁴⁷² ⁴⁷³ ⁴⁷⁴ ⁴⁷⁵ (See Prevention of Candidiasis in Transplant Recipients, Cancer Patients, or Other Patients at High Risk under Uses.)

For treatment of CNS candidiasis, IDSA recommends initial treatment with IV amphotericin B (with or without oral flucytosine) and follow-up treatment with fluconazole.⁴²⁵

Antifungal treatment not recommended in patients with asymptomatic candiduria, unless there is high risk of disseminated candidiasis (e.g., neutropenic patients, low birthweight infants [<1.5 kg], patients who will undergo urologic manipulations).⁴²⁵ Fluconazole is the drug of choice for treatment of symptomatic candiduria (cystitis, pyelonephritis, fungus balls) caused by fluconazole-susceptible Candida;⁴²⁵ IV amphotericin B and/or flucytosine is recommended when fluconazole-resistant Candida (e.g., C. glabrata, C. krusei) are likely.⁴²⁵

For treatment of osteoarticular infections (e.g., osteomyelitis, septic arthritis) caused by Candida, IDSA recommends initial treatment with fluconazole or an IV echinocandin (anidulafungin, caspofungin, micafungin) and follow-up treatment with fluconazole.⁴²⁵ If septic arthritis involved a prosthetic device and the device cannot be removed, long-term suppressive or maintenance therapy (secondary prophylaxis)^† with fluconazole recommended if isolate is susceptible.⁴²⁵

For treatment of endocarditis (native or prosthetic valve) or implantable cardiac device infections caused by Candida, IDSA recommends initial treatment with IV amphotericin B (with or without flucytosine) or an IV echinocandin (anidulafungin, caspofungin, micafungin) and follow-up treatment with fluconazole.⁴²⁵ If isolate is susceptible, long-term suppressive or maintenance therapy (secondary prophylaxis)^† with fluconazole recommended to prevent recurrence in those with native valve endocarditis who cannot undergo valve replacement and in those with prosthetic valve endocarditis.⁴²⁵

For treatment of chorioretinitis (with or without vitritis) caused by Candida, IDSA recommends fluconazole or voriconazole when isolates are susceptible and amphotericin B (with or without oral flucytosine) when isolates are resistant to fluconazole and voriconazole;⁴²⁵ intravitreal amphotericin B or voriconazole may also be indicated.⁴²⁵

Consult current IDSA clinical practice guidelines available at [Web] for additional information on management of candidemia and disseminated candida infections.⁴²⁵

Oropharyngeal Candidiasis

Treatment of oropharyngeal candidiasis in immunocompromised adults with HIV infection, malignancy, or other serious underlying disease.³⁹ ⁴⁰ ⁴¹ ⁹² ⁹⁵ ¹²⁴ ³³⁵ ³³⁶ ³³⁷ ⁴⁰⁰ ⁴⁰² ⁴⁰⁴ ⁴⁰⁶ ⁴²⁵ ⁴²⁵ ⁴³⁶ ⁴⁴⁰ ⁴⁴¹ A drug of choice.³³⁷ ⁴²⁵ ⁴³⁶ ⁴⁴⁰ ⁴⁴¹

For mild oropharyngeal candidiasis, IDSA recommends topical treatment with clotrimazole lozenges or miconazole buccal tablets;⁴²⁵ nystatin (oral suspension or tablets) is an alternative.⁴²⁵ For moderate to severe oropharyngeal candidiasis, IDSA recommends oral fluconazole.⁴²⁵ For fluconazole-refractory oropharyngeal candidiasis, IDSA recommends itraconazole oral solution or posaconazole oral suspension;⁴²⁵ oral voriconazole or amphotericin B oral suspension (not commercially available in US) recommended as alternatives.⁴²⁵ Other alternatives for refractory oropharyngeal candidiasis are IV echinocandins (anidulafungin, caspofungin, micafungin) or IV amphotericin B.⁴²⁵

For HIV-infected adults and adolescents with oropharyngeal candidiasis, CDC, NIH, and IDSA recommend oral fluconazole as the preferred drug of choice for initial episodes;⁴⁴⁰ if topical therapy used (e.g., mild to moderate episodes), drugs of choice are clotrimazole lozenges or miconazole buccal tablets.⁴⁴⁰ Alternatives for systemic treatment are itraconazole oral solution or posaconazole oral suspension;⁴⁴⁰ nystatin oral suspension is an alternative for topical treatment.⁴⁴⁰ For fluconazole-refractory infections in HIV-infected adults and adolescents, posaconazole oral suspension is preferred;⁴⁴⁰ itraconazole oral solution is an alternative.⁴⁴⁰

Although routine long-term suppressive or maintenance therapy (secondary prophylaxis)^† to prevent relapse or recurrence not usually recommended in patients adequately treated for oropharyngeal candidiasis (including HIV-infected individuals), patients with frequent or severe recurrences of oropharyngeal candidiasis may benefit from secondary prophylaxis with oral fluconazole;⁴²⁵ ⁴⁴⁰ ⁴⁴¹ however, consider potential for development of azole resistance.⁴²⁵ ⁴⁴⁰ ⁴⁴¹

Consult current IDSA clinical practice guidelines available at [Web]⁴²⁵ and current CDC, NIH, and IDSA clinical practice guidelines for prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]⁴⁴⁰ ⁴⁴¹ for additional information on management of oropharyngeal candidiasis.

Esophageal Candidiasis

Treatment of esophageal candidiasis.¹ ⁴⁴ ¹⁷³ ⁴⁰¹ ⁴⁰³ ⁴⁰⁴ ⁴²⁵ ⁴³⁶ ⁴⁴⁰ ⁴⁴¹ A drug of choice.⁴²⁵ ⁴³⁶ ⁴⁴⁰ ⁴⁴¹

Esophageal candidiasis requires treatment with a systemic antifungal (not a topical antifungal).⁴²⁵ ⁴⁴⁰

IDSA recommends oral fluconazole as the preferred drug of choice for treatment of esophageal candidiasis;⁴²⁵ if oral therapy not tolerated, IV fluconazole or an IV echinocandin (anidulafungin, caspofungin, micafungin) recommended.⁴²⁵ For fluconazole-refractory esophageal candidiasis, IDSA recommends itraconazole oral solution or IV or oral voriconazole;⁴²⁵ alternatives are an IV echinocandin (anidulafungin, caspofungin, micafungin) or IV amphotericin B.⁴²⁵ IDSA states oral posaconazole (oral suspension or delayed-release tablets) is another possible alternative for treatment of fluconazole-refractory esophageal candidiasis.⁴²⁵

For HIV-infected adults and adolescents with esophageal candidiasis, CDC, NIH, and IDSA recommend oral or IV fluconazole or itraconazole oral solution.⁴⁴⁰ Alternatives include oral or IV voriconazole, an IV echinocandin (anidulafungin, caspofungin, micafungin), or IV amphotericin B.⁴⁴⁰ For refractory esophageal candidiasis, including fluconazole-refractory infections, in HIV-infected adults and adolescents, itraconazole oral solution or posaconazole oral suspension is recommended;⁴⁴⁰ alternatives are IV amphotericin B, an IV echinocandin (anidulafungin, caspofungin, micafungin), or oral or IV voriconazole.⁴⁴⁰

Although routine long-term suppressive or maintenance therapy (secondary prophylaxis)^† to prevent relapse or recurrence not usually recommended in patients adequately treated for oropharyngeal candidiasis (including HIV-infected individuals), patients with frequent or severe recurrences of esophageal candidiasis may benefit from secondary prophylaxis with oral fluconazole or posaconazole oral suspension;⁴²⁵ ⁴⁴⁰ ⁴⁴¹ however, consider potential for development of azole resistance.⁴²⁵ ⁴⁴⁰ ⁴⁴¹

Vulvovaginal Candidiasis

Treatment of uncomplicated vulvovaginal candidiasis or complicated vulvovaginal candidiasis^†.¹ ⁴⁵ ⁶⁶ ¹²⁹ ¹⁴⁷ ¹⁴⁸ ¹⁹⁷ ¹⁹⁸ ²⁰¹ ²⁰³ ²⁰⁴ ²⁰⁵ ²⁰⁶ ²⁰⁹ ²¹⁰ ³⁴⁴ ³⁹⁹ ⁴²⁵ ⁴³⁶ ⁴⁴⁰

For treatment of uncomplicated vulvovaginal candidiasis (mild to moderate, sporadic or infrequent, most likely caused by C. albicans, occurring in immunocompetent women) in nonpregnant women, CDC and others recommend a topical (intravaginal) azole antifungal (e.g., butoconazole, clotrimazole, miconazole, terconazole, tioconazole) given in appropriate single-dose or short-course (1–3 days) regimen or, alternatively, single-dose regimen of oral fluconazole.³⁴⁴ ³⁴⁸ ³⁴⁹ ³⁵⁰ ³⁵² ⁴²⁵ ⁴³⁶ ⁴⁴⁰ Single-dose oral fluconazole offers some advantages over topical agents⁴⁵ ⁴⁶ ⁵¹ ¹¹⁶ ¹⁹⁵ ¹⁹⁷ ¹⁹⁸ (e.g., ensures compliance, may reduce or eliminate concurrent rectal infections that can be source of reinfection).⁴⁵ ⁴⁶ ⁶⁶ ¹⁹⁵ ¹⁹⁶

For treatment of recurrent vulvovaginal candidiasis (usually defined as ≥4 episodes of symptomatic vulvovaginal candidiasis within a year), each individual episode caused by C. albicans may respond to a short-course regimen of intravaginal azole or oral fluconazole.³⁴⁴ To maintain clinical and mycologic control, some experts recommend a longer duration of initial therapy (e.g., 7–14 days of intravaginal azole antifungal or 3-dose regimen of oral fluconazole) to attempt mycologic remission before initiating a maintenance antifungal regimen.³⁴⁴ ⁴²⁵ Women with recurrent infections who are symptomatic and remain culture-positive despite maintenance antifungal therapy should be managed in consultation with a specialist.³⁴⁴

Vulvovaginal candidiasis frequently occurs during pregnancy.³⁴⁴ CDC states use topical (intravaginal) azole antifungals (not oral fluconazole) for treatment of vulvovaginal candidiasis during pregnancy.³⁴⁴ (See Pregnancy under Cautions.)

Consult current CDC guidelines available at [Web],³⁴⁴ current IDSA clinical practice guidelines available at [Web],⁴²⁵ and current CDC, NIH, and IDSA clinical practice guidelines on prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]⁴⁴⁰ for additional information on management of vulvovaginal candidiasis.

Coccidioidomycosis

Treatment and prevention of coccidioidomycosis^† caused by Coccidioides immitis or C. posadasii.⁵⁴ ⁹⁷ ¹¹⁵ ¹²⁵ ²²⁰ ²⁹² ²⁹⁸ ²⁹⁹ ³⁰⁰ ⁴²⁶ ⁴³⁶ ⁴⁴⁰ ⁴⁴¹ ⁴⁶⁴ ⁴⁶⁵ ⁴⁶⁶ A drug of choice.²⁹² ⁴²⁶ ⁴³⁶ ⁴⁴⁰ ⁴⁴¹ ⁴⁶⁴

Used for treatment of coccidioidal pulmonary infections, meningitis, and disseminated (extrapulmonary) infections involving soft tissue or bone and joint.⁵⁴ ⁹⁷ ¹¹⁵ ¹²⁵ ²²⁰ ²⁹² ²⁹⁸ ²⁹⁹ ³⁰⁰ ⁴²⁶ ⁴⁴⁰ ⁴⁴¹ ⁴⁶⁴ ⁴⁶⁵ ⁴⁶⁶

Antifungal treatment may not be necessary for mild, uncomplicated coccidioidal pneumonia since such infections may resolve spontaneously;²⁹² ⁴²⁶ treatment recommended for patients with more severe or rapidly progressing infections, those with chronic pulmonary or disseminated infections, and immunocompromised or debilitated individuals (e.g., HIV-infected individuals, organ transplant recipients, those receiving immunosuppressive therapy, those with diabetes or cardiopulmonary disease).²⁹² ⁴²⁶ ⁴⁴⁰ ⁴⁴¹

IDSA and others recommend an oral azole (fluconazole or itraconazole) for initial treatment of symptomatic pulmonary coccidioidomycosis and chronic fibrocavitary or disseminated (extrapulmonary) coccidioidomycosis.²⁹² ⁴²⁶ ⁴³⁶ ⁴⁴⁰ IV amphotericin B recommended as an alternative and is preferred for initial treatment of severely ill patients who have hypoxia or rapidly progressing disease, for immunocompromised individuals, or when azole antifungals have been ineffective or cannot be used (e.g., pregnant women).²⁹² ⁴²⁶ ⁴⁴⁰

For HIV-infected adults and adolescents with clinically mild coccidioidomycosis (e.g., focal pneumonia), CDC, NIH, and IDSA recommend oral fluconazole or oral itraconazole for initial treatment;⁴⁴⁰ although data are limited, oral voriconazole or posaconazole oral suspension are alternatives if there is no response to fluconazole or itraconazole.⁴⁴⁰

For HIV-infected adults and adolescents with diffuse pulmonary infections or extrathoracic disseminated coccidioidomycosis (nonmeningeal), CDC, NIH, and IDSA recommend initial therapy with IV amphotericin B followed by an oral azole (e.g., fluconazole).⁴⁴⁰ Alternatively, some experts recommend initial therapy with IV amphotericin B used in conjunction with an oral azole (e.g., fluconazole) followed by an oral azole alone.⁴⁴⁰

For treatment of diffuse pulmonary or disseminated coccidioidomycosis in HIV-infected infants and children, CDC, NIH, and IDSA recommend initial treatment with IV amphotericin B followed by oral fluconazole or oral itraconazole.⁴⁴¹ In those with severe disseminated disease, some experts recommend initial therapy with IV amphotericin B used in conjunction with an oral azole (e.g., fluconazole) followed by an oral azole alone.⁴⁴¹ Use of fluconazole or itraconazole alone may be sufficient for treatment of mild coccidioidomycosis in HIV-infected infants and children with only mild disease (e.g., focal pneumonia) and also can be considered an alternative for those with stable pulmonary or disseminated coccidioidomycosis (nonmeningeal).⁴⁴¹

For treatment of coccidioidal meningitis in HIV-infected adults, adolescents, and children and other individuals, fluconazole (with or without intrathecal amphotericin B) is considered the regimen of choice.²⁹² ⁴²⁶ ⁴⁴⁰ ⁴⁴¹ Consultation with an expert is recommended.²⁹² ⁴⁴⁰ ⁴⁴¹

In HIV-infected adults and adolescents who live in areas in the US where coccidioidomycosis is endemic (e.g., lower San Joaquin Valley in California, much of Arizona, southern regions of Utah, Nevada, and New Mexico, western Texas), CDC, NIH, and IDSA recommend annual serologic testing for the disease.⁴⁴⁰ Those with newly positive IgM or IgG serologic tests and CD4⁺ T-cell counts <250/mm³ should receive oral fluconazole for primary prophylaxis against coccidioidomycosis^† (preemptive antifungal therapy) since they are at increased risk of developing active coccidioidomycosis.⁴⁴⁰ Primary prophylaxis against coccidioidomycosis is not recommended in other HIV-infected adults or adolescents or in HIV-infected infants and children.⁴⁴⁰ ⁴⁴¹

HIV-infected adults, adolescents, or children who have been adequately treated for coccidioidomycosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse^†.⁴⁴⁰ ⁴⁴¹ CDC, NIH, and IDSA recommend oral fluconazole or oral itraconazole for secondary prophylaxis of coccidioidomycosis in HIV-infected individuals.⁴⁴⁰ ⁴⁴¹

Consult current IDSA clinical practice guidelines available at [Web]⁴²⁶ and current CDC, NIH, and IDSA clinical practice guidelines on prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]⁴⁴⁰ ⁴⁴¹ for additional information on management of coccidioidomycosis.

Cryptococcosis

Treatment of meningitis caused by Cryptococcus neoformans.¹ ²⁸ ²⁹ ³⁰ ³¹ ³² ³³ ⁹³ ¹¹⁸ ²⁹² ³⁰³ ³⁰⁴ ³⁰⁵ ³⁰⁶ ³¹⁰ ³¹¹ ⁴²⁷ ⁴³⁶ ⁴⁴⁰ ⁴⁴¹ Also used for treatment of pulmonary cryptococcosis^†, cryptococcemia^†, and disseminated cryptococcal infections^†.⁵⁷ ¹³⁵ ¹³⁶ ³⁰⁹ ⁴²⁷

For treatment of cryptococcal meningitis in HIV-infected adults, adolescents, and children, CDC, NIH, IDSA, and others state that the preferred regimen is initial (induction) therapy with IV amphotericin B given in conjunction with oral flucytosine for at least 2 weeks until there is evidence of clinical improvement and negative CSF culture after repeat lumbar puncture, then follow-up (consolidation) therapy with oral fluconazole administered for at least 8 weeks.²⁹² ⁴²⁷ ⁴³⁶ ⁴⁴⁰ ⁴⁴¹

Alternative regimens for treatment of cryptococcal meningitis in HIV-infected adults, adolescents, and children who cannot receive the preferred regimen are induction and consolidation therapy with IV amphotericin B alone;⁴²⁷ ⁴⁴¹ induction therapy with IV amphotericin B given in conjunction with oral fluconazole, then consolidation therapy with oral fluconazole;⁴²⁷ ⁴⁴⁰ ⁴⁴¹ induction and consolidation therapy with oral or IV fluconazole used in conjunction with oral flucytosine, then consolidation therapy with oral fluconazole;⁴²⁷ ⁴⁴⁰ ⁴⁴¹ or induction and consolidation therapy with oral fluconazole alone.⁴²⁷ ⁴⁴⁰ ⁴⁴¹ These alternative regimens may be less effective and are recommended only in patients who cannot tolerate or have not responded to the preferred regimen.⁴²⁷ ⁴⁴⁰ ⁴⁴¹

For treatment of cryptococcal CNS infections in organ transplant recipients, IDSA recommends induction therapy with IV amphotericin B given in conjunction with oral flucytosine for at least 2 weeks, then consolidation therapy with oral fluconazole given for 8 weeks.⁴²⁷ If induction regimen does not include flucytosine, continue for at least 4–6 weeks.⁴²⁷ For organ transplant recipients with mild to moderate pulmonary cryptococcosis (without diffuse pulmonary infiltrates) or with other mild to moderate cryptococcal infections not involving the CNS, IDSA recommends fluconazole given for 6–12 months.⁴²⁷

In adults and children who do not have HIV infection and are not transplant recipients, the preferred regimen for treatment of cryptococcal meningitis is induction therapy with IV amphotericin B given in conjunction with oral flucytosine for at least 4 weeks (a 2-week induction period can be considered in those who are immunocompetent, are without uncontrolled underlying disease, and are at low risk for therapeutic failure), then consolidation therapy with oral fluconazole administered for an additional 8 weeks or longer.⁴²⁷ IDSA states that data are insufficient to date to recommend fluconazole used alone or in conjunction with flucytosine for induction therapy in non-HIV-infected individuals.⁴²⁷

For treatment of mild to moderate pulmonary cryptococcosis (nonmeningeal) in immunocompetent or immunosuppressed adults or children, IDSA states that the regimen of choice is oral fluconazole given for 6–12 months.⁴²⁷ A regimen of oral fluconazole given for 6–12 months also can be considered for treatment of nonmeningeal, nonpulmonary cryptococcosis in immunocompetent individuals if the infection occurs at a single site and fungemia is not present.⁴²⁷ Severe pulmonary infections, cryptococcemia, and disseminated infections in immunocompetent or immunosuppressed individuals should be treated using regimens recommended for cryptococcal meningitis.⁴²⁷

HIV-infected adults, adolescents, and children who have been adequately treated for cryptococcal meningitis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse^†.⁴²⁷ ⁴⁴⁰ ⁴⁴¹ CDC, NIH, and IDSA recommend oral fluconazole as the drug of choice for secondary prophylaxis of cryptococcosis in HIV-infected individuals;⁴²⁷ ⁴⁴⁰ ⁴⁴¹ although oral itraconazole suggested as an alternative in those who cannot tolerate fluconazole, it may be less effective than fluconazole.⁴²⁷ ⁴⁴⁰ ⁴⁴¹ IV amphotericin B can be used for secondary prophylaxis if necessary in individuals who cannot receive azole antifungals, but is less effective and not generally recommended.⁴²⁷

Long-term suppressive or maintenance therapy (secondary prophylaxis)^† with oral fluconazole also recommended in non-HIV-infected adults and children who have been adequately treated for cryptococcal meningitis, including organ transplant recipients who have been adequately treated for CNS cryptococcosis.⁴²⁷

Although data are limited, IDSA states that recommendations for treatment of CNS, pulmonary, or disseminated infections caused by Cryptococcus gattii and recommendations for secondary prophylaxis of C. gattii infections are the same as recommendations for C. neoformans infections.⁴²⁷ Consider that there is some in vitro evidence that fluconazole may be less active against C. gattii than some other azole antifungals (e.g., itraconazole, posaconazole, voriconazole).⁴⁴⁹ ⁴⁵⁰ (See Actions and Spectrum.)

Consult current IDSA clinical practice guidelines available at [Web]⁴²⁷ and current CDC, NIH, and IDSA clinical practice guidelines on prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]⁴⁴⁰ ⁴⁴¹ for additional information on management of cryptococcosis.

Histoplasmosis

Alternative for treatment of histoplasmosis^† caused by Histoplasma capsulatum.³¹² ³¹³ ³¹⁵ ³¹⁶ ⁴²⁸ ⁴³⁶ ⁴⁴⁰ ⁴⁴¹

IDSA and others recommend IV amphotericin B or oral itraconazole for treatment of histoplasmosis.²⁹² ³¹⁵ ³¹⁶ ⁴²⁸ ⁴³⁶ ⁴⁴⁰ ⁴⁴¹ IV amphotericin B preferred for initial treatment of severe, life-threatening histoplasmosis, especially in immunocompromised patients.⁴²⁸ ⁴³⁶ ⁴⁴⁰ Other azole antifungals (fluconazole, ketoconazole, posaconazole, voriconazole) considered second-line alternatives to itraconazole.³¹⁵ ³¹⁶ ⁴²⁸ ⁴³⁶ ⁴⁴⁰

Consult current IDSA clinical practice guidelines available at [Web]⁴²⁸ and current CDC, NIH, and IDSA clinical practice guidelines on prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]⁴⁴⁰ ⁴⁴¹ for additional information on management of histoplasmosis.

Sporotrichosis

Alternative for treatment of lymphocutaneous and cutaneous sporotrichosis^† caused by Sporothrix schenckii.²⁹² ⁴²⁹ ⁴³⁶

IV amphotericin B is the drug of choice for initial treatment of severe, life-threatening sporotrichosis and whenever sporotrichosis is disseminated or has CNS involvement.²⁹² ⁴²⁹ ⁴³⁶ Oral itraconazole is the drug of choice for treatment of cutaneous, lymphocutaneous, or mild pulmonary or osteoarticular sporotrichosis and for follow-up treatment of severe infections after a response has been obtained with IV amphotericin B.²⁹² ⁴²⁹ ⁴³⁶

Although fluconazole can be used as an alternative for treatment of cutaneous and lymphocutaneous sporotrichosis,⁴²⁹ ⁴³⁶ it may be less effective than itraconazole²⁹² ⁴²⁹ and should be used only if patient cannot tolerate itraconazole or other alternatives (oral terbinafine, oral potassium iodide, local hyperthermia).⁴²⁹

Do not use for treatment of pulmonary, osteoarticular, or meningeal sporotrichosis.⁴²⁹

Consult current IDSA clinical practice guidelines available at [Web] for additional information on management of sporotrichosis.⁴²⁹

Dermatophytoses

Treatment of certain dermatophytoses^† (e.g., tinea capitis,²⁹² ³⁷⁵ ³⁷⁶ ³⁷⁷ ³⁷⁹ ⁴⁵⁴ ⁴⁷⁷ ⁴⁷⁸ tinea corporis,²⁹² ³⁷³ ³⁷⁴ ³⁷⁸ ⁴⁷⁸ tinea cruris,³⁷³ ³⁷⁴ ³⁷⁸ ⁴⁷⁸ tinea pedis²⁹² ³⁷⁴ ⁴³⁶ ⁴⁷⁸ ) caused by Epidermophyton, Microsporum, or Trichophyton.

Tinea corporis and tinea cruris generally can be effectively treated using a topical antifungal; an oral antifungal may be necessary if the disease is extensive, dermatophyte folliculitis is present, the infection does not respond to topical therapy, or the patient is immunocompromised or has a coexisting disease.²⁹² ³⁸⁰ ³⁸¹ ³⁸² ³⁸³ ³⁸⁴ ³⁸⁶ ⁴⁷⁸ Tinea capitis and tinea barbae generally are treated using an oral antifungal.²⁹² ³⁷² ³⁸¹ ³⁸³ ³⁸⁵ ³⁸⁷ ⁴⁷⁸

While topical antifungals usually are effective for treatment of uncomplicated tinea manuum and tinea pedis,²⁹² ³⁸¹ ³⁸² ³⁸⁴ ³⁸⁶ ⁴¹⁹ ⁴⁷⁸ an oral antifungal usually is necessary for treatment of severe, chronic, or recalcitrant tinea pedis and for treatment of chronic moccasin-type (dry-type) tinea pedis.³⁸¹ ³⁸³ ³⁸⁴ ³⁸⁶ ⁴¹⁹ ⁴⁷⁸

Onychomycosis

Treatment of onychomycosis of toenails^† or fingernails.¹⁴⁰ ¹⁷⁶ ³⁸³ ⁴¹⁷ ⁴²⁰ ⁴²¹ ⁴³⁶ ⁴⁵⁵ ⁴⁵⁸ ⁴⁷⁶ ⁴⁷⁹ ⁴⁹⁹ ⁵⁰⁰

Onychomycosis generally treated using an oral antifungal (e.g., terbinafine, itraconazole, fluconazole) and adjunctive physical modalities (nail trimming, aggressive debridement, nail avulsion) with or without a topical antifungal.³⁸³ ⁴³⁶ ⁴⁵⁵ ⁴⁵⁶ ⁴⁵⁷ ⁴⁵⁸ ⁴⁷⁷ ⁴⁷⁸ ⁴⁹⁹ ⁵⁰⁰

Oral fluconazole may be less effective than oral terbinafine or oral itraconazole.¹⁴⁰ ¹⁷⁶ ⁴²⁰ ⁴²¹ ⁴⁵⁵ ⁴⁷⁷ ⁴⁷⁹ ⁵⁰⁰

Pityriasis (Tinea) Versicolor

Treatment of pityriasis (tinea) versicolor^† caused by Malassezia furfur (Pityrosporum orbiculare or P. ovale).²⁹² ⁴⁵⁹ ⁴⁶⁰ ⁴⁶¹ ⁴⁶² ⁴⁷⁷ ⁴⁷⁸

Pityriasis (tinea) versicolor generally can be treated topically with an azole antifungal (e.g., clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole), an allylamine antifungal (e.g., naftifine, terbinafine), ciclopirox olamine, or certain other topical therapies (e.g., selenium sulfide 2.5%).²⁹² ⁴⁵⁹ ⁴⁶³ An oral antifungal (e.g., fluconazole, itraconazole, ketoconazole) may be indicated, with or without a topical agent, in patients who have extensive or severe infections or who fail to respond to or have frequent relapses with topical therapy.⁴⁵⁹ ⁴⁶⁰ ⁴⁶³ ⁴⁷⁷ ⁴⁷⁸

Prevention of Candidiasis in Transplant Recipients, Cancer Patients, or Other Patients at High Risk

Prevention of Candida infections in patients at high risk, including those undergoing bone marrow transplantation (BMT), hematopoietic stem cell transplantation (HSCT)^†, or solid organ transplantation^† and neutropenic patients undergoing chemotherapy and radiation therapy^†.¹ ¹¹⁰ ¹²⁴ ¹⁵⁷ ¹⁵⁸ ¹⁵⁹ ¹⁶⁰ ¹⁶¹ ¹⁷⁹ ¹⁸⁴ ¹⁸⁶ ¹⁸⁸ ¹⁸⁹ ³⁴⁰ ³⁴¹ ³⁴² ⁴²² ⁴²⁵ ⁴³⁶ ⁴⁵² Also used to prevent Candida infections in high-risk patients undergoing urologic procedures^†⁴²⁵ and for prevention of invasive candidiasis in high-risk patients in intensive care units (ICUs)^†⁴²⁵ and in low birthweight neonates^† at high risk.²⁹² ⁴²⁵ ⁴⁷¹ ⁴⁷² ⁴⁷³ ⁴⁷⁴ ⁴⁷⁵

For primary prophylaxis to prevent Candida infections in neutropenic patients when risk of invasive candida infection is substantial (e.g., allogeneic HSCT recipients, patients with acute leukemia undergoing intensive remission-induction or salvage-induction chemotherapy), IDSA recommends an azole antifungal (fluconazole, itraconazole, posaconazole, voriconazole) or IV echinocandin (caspofungin or micafungin).⁴²² If primary prophylaxis is used to prevent invasive candida infection in high-risk adults in ICUs, IDSA recommends fluconazole as drug of choice and IV echinocandins (anidulafungin, caspofungin, micafungin) as alternatives.⁴²⁵

Has been used for prophylaxis of invasive candidiasis in low birthweight neonates^† at high risk.²⁹² ⁴²⁵ ⁴⁷¹ ⁴⁷² ⁴⁷³ ⁴⁷⁴ ⁴⁷⁵ Although such prophylaxis is controversial since there are concerns about emergence of resistant fungi or increased colonization with fluconazole-resistant Candida,²⁹² ⁴⁷¹ ⁴⁷² there is some evidence that fluconazole prophylaxis can prevent colonization and reduce the incidence of invasive candidiasis.²⁹² ⁴⁷¹ ⁴⁷² ⁴⁷³ ⁴⁷⁴ ⁴⁷⁵ IDSA and AAP state that use of fluconazole prophylaxis can be considered for very low birthweight neonates (<1 kg) in nurseries that have high rates of neonatal invasive candidiasis.²⁹² ⁴²⁵

Consult current IDSA clinical practice guidelines available at [Web]⁴²² ⁴²⁵ for additional information on prevention of fungal infections in immunocompromised patients.

Fluconazole Dosage and Administration

Administration

Administer orally or by IV infusion.¹

Since absorption from the GI tract is rapid and almost complete,¹ ² ⁵¹ ⁶¹ ⁶⁷ ⁶⁸ IV route generally is reserved for patients who do not tolerate or are unable to take the drug orally.¹¹⁶ ¹¹⁷

Oral Administration

Administer orally without regard to meals.¹

Reconstitution

Reconstitute powder for oral suspension at time of dispensing by adding 24 mL of distilled or purified water to container containing 0.35 or 1.4 g of the drug to provide a suspension containing 50 or 200 mg/5 mL, respectively.¹ Shake bottle vigorously to suspend the powder.¹

Shake suspension well just prior to administration of each dose.¹

IV Infusion

For solution and drug compatibility information, see Compatibility under Stability.

Fluconazole solutions may be administered by IV infusion without further dilution.¹

Fluconazole solutions in plastic containers should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration from the secondary container is complete.¹

Rate of Administration

IV infusions should be administered at a rate ≤200 mg/hour.¹

Dosage

Oral and IV dosage are identical.¹

Use of loading dose that is twice the daily dosage generally is recommended on the first day of treatment; this results in fluconazole plasma concentrations on the second day of treatment that are close to steady-state concentrations.¹

Pediatric Patients

General Pediatric Dosage

Treatment of Fungal Infections

Oral or IV

3–12 mg/kg once daily.¹ ²⁹²

Dosage of 3, 6, or 12 mg/kg daily in pediatric patients is equivalent to dosage of 100, 200, or 400 mg daily, respectively, in adults.¹

Premature neonates (gestational age 26–29 weeks): Based on available pharmacokinetic data, manufacturer recommends that the usual pediatric dosage be given once every 72 hours during the first 2 weeks of life; after 2 weeks of age, give usual pediatric dosage once daily.¹

Candida Infections

Treatment of Disseminated or Invasive Candida Infections

Oral or IV

6–12 mg/kg daily.¹ ²⁹²

Meningitis or septicemia in neonates and infants ≤3 months of age^†: 5–6 mg/kg once daily has been used.³⁹⁴ ⁴⁰⁹ ⁴¹⁰ An initial loading dose of 10 mg/kg followed by 5 mg/kg once daily has been used for Candida septicemia.³⁹² ³⁹⁴

Treatment of Neonatal Candidiasis†

Oral or IV

12 mg/kg daily for at least 3 weeks has been recommended by IDSA and AAP as an alternative to IV amphotericin B.²⁹² ⁴²⁵

Treatment of Oropharyngeal Candidiasis

Oral or IV

6 mg/kg on the first day, then 3 mg/kg once daily.¹ ²⁹² To decrease likelihood of relapse, manufacturer states treatment usually should be continued for at least 2 weeks.¹

HIV-infected infants and children: 6–12 mg/kg (up to 400 mg) once daily for 7–14 days.⁴⁴¹

HIV-infected adolescents: 100 mg once daily for 7–14 days.⁴⁴⁰

Treatment of Esophageal Candidiasis

Oral or IV

6 mg/kg on the first day, then 3 mg/kg once daily.¹ ²⁹² Dosage may be increased up to 12 mg/kg daily if necessary, based on response and condition of the patient.¹ Manufacturer states treatment usually should be continued for at least 3 weeks and for at least 2 weeks after symptoms resolve.¹

HIV-infected infants and children: 6–12 mg/kg (up to 600 mg) once daily for at least 3 weeks and for at least 2 weeks after symptoms resolve.⁴⁴¹

HIV-infected adolescents: 100 mg (up to 400 mg) daily for 14–21 days.⁴⁴⁰

Prevention of Recurrence (Secondary Prophylaxis) of Oropharyngeal or Esophageal Candidiasis†

Oral

HIV-infected infants and children with frequent or severe recurrences: 3–6 mg/kg (up to 200 mg) once daily.⁴⁴¹

HIV-infected adolescents with frequent or severe recurrences of oropharyngeal candidiasis: 100 mg once daily or 3 times weekly.⁴⁴⁰

HIV-infected adolescents with frequent or severe recurrences of esophageal candidiasis: 100–200 mg once daily.⁴⁴⁰

HIV-infected infants and children: Consider discontinuing secondary prophylaxis against oropharyngeal or esophageal candidiasis if CD4⁺ T-cell count or percentage increases to CDC immunologic category 2 or 1.⁴⁴¹

HIV-infected adolescents: Consider discontinuing secondary prophylaxis against oropharyngeal or esophageal candidiasis if CD4⁺ T-cell count increases to >200/mm³ in response to antiretroviral therapy.⁴⁴⁰

Coccidioidomycosis†

Treatment of Coccidioidomycosis (Nonmeningeal)†

Oral or IV

HIV-infected infants and children with mild to moderate coccidioidomycosis (e.g., focal pneumonia): 6–12 mg/kg (up to 400 mg) once daily.⁴⁴¹

HIV-infected infants and children with diffuse pulmonary or disseminated coccidioidomycosis (nonmeningeal) who cannot receive amphotericin B: 12 mg/kg (up to 800 mg) once daily.⁴⁴¹

HIV-infected adolescents with mild coccidioidomycosis (e.g., focal pneumonia): 400 mg once daily.⁴⁴⁰

HIV-infected adolescents with severe coccidioidomycosis (e.g., diffuse pulmonary infection): 400 mg once daily.⁴⁴⁰ Usually used in conjunction with IV amphotericin B or as follow-up after an initial regimen of IV amphotericin B.⁴⁴⁰

Treatment of Coccidioidal Meningitis†

Oral or IV

HIV-infected infants and children: 12 mg (up to 800 mg) once daily.⁴⁴¹

HIV-infected adolescents: 400–800 mg daily.⁴⁴⁰

Consultation with an expert experienced in treating coccidioidal meningitis is recommended.²⁹²

Primary Prophylaxis to Prevent First Episode of Coccidioidomycosis†

Oral

HIV-infected adolescents living in areas endemic for coccidioidomycosis who have newly positive IgM or IgG serologic test and CD4⁺ T-cell count <250/mm³: 400 mg once daily.⁴⁴⁰

Prevention of Recurrence (Secondary Prophylaxis) of Coccidioidomycosis†

Oral

HIV-infected infants and children: 6 mg/kg (up to 400 mg) once daily.⁴⁴¹

HIV-infected adolescents: 400 mg once daily.⁴⁴⁰

Initiate secondary prophylaxis after primary infection has been adequately treated.⁴⁴⁰ ⁴⁴¹

HIV-infected infants and children: Continue life-long, secondary prophylaxis against coccidioidomycosis, regardless of antiretroviral therapy or immune reconstitution.⁴⁴¹

HIV-infected adolescents who were treated for focal coccidioidal pneumonia and are receiving antiretroviral therapy: Consider discontinuing secondary prophylaxis against coccidioidomycosis after 12 months if CD4⁺ T-cell count ≥250/mm³, but continue monitoring for recurrence (e.g., serial chest radiographs, coccidioidal serology).⁴⁴⁰

HIV-infected adolescents who were treated for diffuse pulmonary or disseminated coccidioidomycosis or coccidioidal meningitis: Life-long secondary prophylaxis against coccidioidomycosis usually required.⁴⁴⁰

Cryptococcosis

Treatment of Cryptococcal Meningitis

Oral or IV

Manufacturer recommends 12 mg/kg on the first day, then 6 mg/kg once daily.¹ Dosage may be increased to 12 mg/kg daily if necessary based on condition of the patient and response to the drug.¹ Continue for 10–12 weeks after CSF cultures are negative.¹

HIV-infected infants and children: Induction therapy with IV amphotericin B and oral flucytosine given for at least 2 weeks, then consolidation therapy with oral or IV fluconazole 12 mg/kg on first day, then 10–12 mg/kg (up to 800 mg) once daily for at least 8 weeks.⁴⁴¹

HIV-infected infants and children who cannot receive amphotericin B: Induction therapy with oral or IV fluconazole 12 mg/kg on first day, then 10–12 mg/kg (up to 800 mg) once daily given in conjunction with oral flucytosine (25 mg/kg 4 times daily) for at least 2 weeks, then consolidation therapy with oral or IV fluconazole 10–12 mg/kg (up to 800 mg) once daily for at least 8 weeks.⁴⁴¹

HIV-infected adolescents: Induction therapy with IV amphotericin B and oral flucytosine given for at least 2 weeks, then consolidation therapy with oral or IV fluconazole 400 mg (6 mg/kg) daily given for at least 8 weeks.⁴⁴⁰

HIV-infected adolescents who cannot receive flucytosine: Induction therapy with IV amphotericin B and oral or IV fluconazole 400 mg daily given for at least 2 weeks, then consolidation therapy with fluconazole 400 mg daily given for at least 8 weeks.⁴⁴⁰

HIV-infected adolescents who cannot receive amphotericin B: Induction therapy with oral or IV fluconazole 400–800 mg daily and oral flucytosine given for at least 4–6 weeks, then consolidation therapy with oral fluconazole 400 mg daily given for at least 8 weeks.⁴⁴⁰

Treatment of Cryptococcal Infections (Nonmeningeal)†

Oral or IV

HIV-infected infants and children with localized cryptococcosis without CNS involvement (e.g., isolated pulmonary disease): 12 mg/kg on first day, then 6–12 mg/kg (up to 600 mg) once daily.⁴²⁷ ⁴⁴¹

HIV-infected infants and children with disseminated or severe pulmonary cryptococcosis without CNS involvement who cannot receive amphotericin B: 12 mg/kg on first day, then 6–12 mg/kg (up to 600 mg) once daily.⁴⁴¹

Duration of treatment depends on clinical response and site and severity of infection.⁴⁴¹ A duration of 6–12 months has been recommended.⁴²⁷

Prevention of Recurrence (Secondary Prophylaxis) of Cryptococcosis†

Oral

HIV-infected infants and children: 6 mg/kg (up to 200 mg) once daily.⁴²⁷ ⁴⁴¹

HIV-infected adolescents: 200 mg once daily.⁴⁴⁰

Initiate secondary prophylaxis after primary infection has been adequately treated and continue for at least 1 year.⁴⁴⁰ ⁴⁴¹

HIV-infected infants and children: Consider discontinuing secondary prophylaxis against cryptococcosis in those ≥6 years of age who are asymptomatic for cryptococcosis, have received such prophylaxis for ≥1 year, are receiving antiretroviral therapy, have had undetectable or low plasma HIV RNA levels for ≥3 months, and have CD4⁺ T-cell counts ≥100/mm³.⁴⁴¹ Reinitiate secondary prophylaxis against cryptococcosis if CD4⁺ T-cell count decreases to <100/mm³.⁴⁴¹

HIV-infected adolescents: Consider discontinuing secondary prophylaxis against cryptococcosis in those who are asymptomatic for cryptococcosis, have received such prophylaxis for ≥1 year, are receiving antiretroviral therapy, have had undetectable or low plasma HIV RNA levels for ≥3 months, and have CD4⁺ T-cell counts ≥100/mm³.⁴⁴⁰ Reinitiate secondary prophylaxis against cryptococcosis if CD4⁺ T-cell count decreases to <100/mm³.⁴⁴⁰

Histoplasmosis

Treatment of Less Severe Histoplasmosis†

Oral

HIV-infected infants and children: 3–6 mg/kg (up to 200 mg) once daily for acute primary pulmonary histoplasmosis.⁴⁴¹

HIV-infected adolescents: 800 mg daily.⁴⁴⁰

Prevention of Recurrence (Secondary Prophylaxis) of Histoplasmosis†

Oral

HIV-infected infants and children: 3–6 mg/kg (up to 200 mg) once daily for at least 1 year.⁴⁴¹

HIV-infected adolescents: 400 mg daily.⁴⁴⁰

Consider discontinuing secondary prophylaxis against histoplasmosis in HIV-infected infants, children, or adolescents who have received such prophylaxis for ≥1 year, have negative fungal blood cultures and serum histoplasma antigen levels <2 ng/mL, have been receiving antiretroviral therapy for ≥6 months, and have CD4⁺ T-cell percentage >15% (CD4⁺ T-cell counts ≥150/mm³ in those ≥6 years of age).⁴⁴⁰ ⁴⁴¹

Reinitiate secondary prophylaxis against histoplasmosis if parameters for discontinuing such prophylaxis are not met.⁴⁴⁰ ⁴⁴¹

Dermatophytoses†

Tinea Capitis†

Oral

3–6 mg/kg daily for 2–6 weeks has been effective in children 1.5–16 years of age.³⁷⁵ ³⁷⁷ ³⁷⁹ AAP recommends 6 mg/kg daily for 3–6 weeks.²⁹²

Tinea Corporis† or Tinea Cruris†

Oral

Some clinicians recommend 150 mg once weekly for 2–6 weeks.⁴⁷⁶

Tinea Manuum† or Tinea Pedis†

Oral

Some clinicians recommend 150 mg once weekly for 4–6 weeks.⁴⁷⁶

Onychomycosis†

Oral

Some clinicians recommend 3–6 mg/kg once weekly for 12–16 weeks for fingernail infections or 3–6 mg/kg once weekly for 18–26 weeks for toenail infections.⁴⁵⁸ Others recommend 150 mg once weekly for 4–6 months for fingernail infections or 150 mg once weekly for 9–12 months for toenail infections.⁴⁷⁶

Prevention of Candidiasis in Transplant Recipients, Cancer Patients, or Other Patients at High Risk

Hematopoietic Stem Cell Transplant (HSCT) Recipients†

Oral or IV

Children 6 months to 13 years of age: 3–6 mg/kg daily (maximum 600 mg daily).⁴⁵²

Adolescents >13 years of age: 400 mg once daily.⁴⁵²

Initiate prophylaxis on the day of HSCT transplantation (i.e., day 0) and continue until engraftment occurs (i.e., approximately 30 days after HSCT) or until 7 days after neutrophil count is >1000/mm³.⁴⁵²

Low Birthweight Neonates†

Oral or IV

Various dosage regimens have been used for prophylaxis to reduce the incidence of invasive candidiasis in low birthweight neonates^† at high risk.⁴²⁵ ⁴⁷¹ ⁴⁷² ⁴⁷³ ⁴⁷⁴ ⁴⁷⁵ If such prophylaxis is used, monitor for antifungal resistance, toxicity, and neurodevelopmental outcomes.⁴²⁵

IDSA states that a dosage of 3 or 6 mg/kg twice weekly reduces the rate of invasive candidiasis in premature neonates in nurseries with a high incidence of Candida infections.⁴²⁵

Low birthweight neonates (<1 kg) at high risk: AAP recommends an initial dose of 3 mg/kg IV during first 48–72 hours after birth, followed by 3 mg/kg IV twice weekly for 4–6 weeks or until IV access no longer required for care.²⁹²

Adults

Blastomycosis†

Treatment of Blastomycosis†

Oral

Mild to moderate pulmonary or mild to moderate disseminated blastomycosis (without CNS involvement): 400–800 mg daily.⁴²⁴

CNS blastomycosis: Initial regimen of IV amphotericin B given for 4–6 weeks, followed by fluconazole 800 mg daily for at least 12 months and until CSF abnormalities resolve.⁴²⁴

Candida Infections

Treatment of Disseminated or Invasive Candida Infections

Oral or IV

Candidemia, disseminated candidiasis, or pneumonia: Manufacturer states that 400 mg daily has been used.¹

Urinary tract infections or peritonitis: Manufacturer states that 50–200 mg daily has been used.¹

Candidemia in nonneutropenic or neutropenic adults: Loading dose of 800 mg (12 mg/kg) on first day, then 400 mg (6 mg/kg) daily continued for 2 weeks after documented clearance of Candida from the bloodstream, resolution of candidemia symptoms, and resolution of neutropenia.⁴²⁵

Chronic disseminated candidiasis (hepatosplenic) in clinically stable patients: 400 mg (6 mg/kg) daily.⁴²⁵ Severely ill patients should receive IV amphotericin B initially for several weeks, then fluconazole 400 mg (6 mg/kg) daily.⁴²⁵ Continue antifungal treatment until lesions resolve (usually several months);⁴²⁵ continue through periods of immunosuppression.⁴²⁵

CNS candidiasis: Initial regimen of IV amphotericin B (with or without oral flucytosine) given for several weeks, then follow-up therapy with fluconazole 400–800 mg (6–12 mg/kg) daily.⁴²⁵ Continue antifungal treatment until signs and symptoms, CSF abnormalities, and radiologic abnormalities resolve.⁴²⁵

Treatment of Candida Urinary Tract Infections

Oral or IV

Symptomatic cystitis caused by fluconazole-susceptible Candida: 200 mg (3 mg/kg) daily for 2 weeks.⁴²⁵

Pyelonephritis caused by fluconazole-susceptible Candida: 200–400 mg (3–6 mg/kg) daily for 2 weeks.⁴²⁵

Treatment of Candida Osteoarticular Infections

Oral or IV

Osteomyelitis: 400 mg (6 mg/kg) daily for 6–12 months.⁴²⁵

Septic arthritis: 400 mg (6 mg/kg) daily for 6 weeks.⁴²⁵

Secondary prophylaxis for prevention of recurrence if septic arthritis involved a prosthetic device that cannot be removed: 400 mg (6 mg/kg) daily.⁴²⁵

Treatment of Candida Intravascular Infections

Oral or IV

Endocarditis (native or prosthetic valve) or implantable cardiac device: Initial regimen of IV amphotericin B (with or without oral flucytosine), then follow-up therapy with fluconazole 400–800 mg (6–12 mg/kg) daily.⁴²⁵ Continue antifungal treatment for at least 6 weeks after valve replacement.⁴²⁵

Secondary prophylaxis for prevention of recurrence in those with native valve endocarditis who cannot undergo valve replacement or in those with prosthetic valve endocarditis: 400–800 mg (6–12 mg/kg) daily.⁴²⁵

Treatment of Candida Endophthalmitis

Oral or IV

Chorioretinitis (with or without vitritis): Loading dose of 800 mg (12 mg/kg) on first day, then 400–800 mg (6–12 mg/kg) daily for at least 4–6 weeks.⁴²⁵ Intravitreal amphotericin B or voriconazole may also be indicated if there is macular involvement.⁴²⁵

Treatment of Oropharyngeal Candidiasis

Oral or IV

200 mg on first day, then 100 or 200 mg once daily.¹ ⁶⁴ ⁶⁸ ¹¹⁸ ⁴³⁶ To decrease likelihood of relapse, manufacturer states treatment usually should be continued for at least 2 weeks.¹

Moderate or severe oropharyngeal candidiasis: IDSA recommends 100–200 mg daily for 7–14 days.⁴²⁵

HIV-infected adults: 100 mg daily for 7–14 days.⁴⁴⁰

Treatment of Esophageal Candidiasis

Oral or IV

200 mg on first day, then 100 or 200 mg once daily.¹ ⁶⁴ ⁶⁸ ¹¹⁸ ⁴³⁶ Up to 400 mg once daily may be used depending on the patient’s response.¹ Manufacturer states treatment usually should be continued for at least 3 weeks and for at least 2 weeks after symptoms resolve.¹

IDSA recommends 200–400 mg (3–6 mg/kg) daily for 14–21 days.⁴²⁵

HIV-infected adults: 100 mg (up to 400 mg) daily for 14–21 days.⁴⁴⁰

Prevention of Recurrence (Secondary Prophylaxis) of Oropharyngeal or Esophageal Candidiasis†

Oral

HIV-infected adults with frequent or severe recurrences of oropharyngeal candidiasis: 100 mg once daily or 3 times weekly.⁴⁴⁰

HIV-infected adults with frequent or severe recurrences of esophageal candidiasis: 100–200 mg daily.⁴⁴⁰

Consider discontinuing secondary prophylaxis against oropharyngeal or esophageal candidiasis in HIV-infected adults if CD4⁺ T-cell count increases to >200/mm³ in response to antiretroviral therapy.⁴⁴⁰

Treatment of Vulvovaginal Candidiasis

Oral

Uncomplicated infections in nonpregnant women: Single 150-mg dose.¹ ³⁴⁴ ⁴²⁵ ⁴³⁶

Recurrent vulvovaginal candidiasis^† caused by C. albicans in nonpregnant women: CDC recommends 100, 150, or 200 mg given every 3 days for 3 doses (i.e., days 1, 4, and 7) to achieve mycologic remission,³⁴⁴ then maintenance regimen of 100, 150, or 200 mg once weekly for 6 months to prevent recurrence.³⁴⁴ IDSA recommends maintenance regimen of 150 mg once weekly for 6 months.⁴²⁵

Severe vulvovaginal candidiasis^† (extensive vulvar erythema, edema, excoriation, and fissure formation) in nonpregnant women: CDC recommends 2-dose regimen (two 150-mg doses given 72 hours [3 days] apart).³⁴⁴ IDSA recommends 150 mg once every 72 hours for a total of 2 or 3 doses.⁴²⁵

HIV-infected nonpregnant women with uncomplicated or severe or recurrent vulvovaginal candidiasis^†: Use same regimens recommended for nonpregnant women without HIV infection.⁴⁴⁰

Coccidioidomycosis†

Treatment of Coccidioidomycosis (Nonmeningeal)†

Oral or IV

400–800 mg daily.⁴²⁶ ⁴³⁶

Diffuse pneumonia or disseminated infections: Usually used in conjunction with IV amphotericin B or as follow-up after an initial regimen of IV amphotericin B.⁴²⁶ Duration of treatment usually 3–6 months for uncomplicated pneumonia;⁴²⁶ total duration of treatment usually at least 1 year for diffuse pneumonia and chronic progressive fibrocavitary pneumonia.⁴²⁶

HIV-infected adults with mild coccidioidomycosis (e.g., focal pneumonia): 400 mg once daily.⁴⁴⁰

HIV-infected adults with severe coccidioidomycosis (e.g., diffuse pulmonary infection): 400 mg once daily.⁴⁴⁰ Usually used as follow-up after an initial regimen of IV amphotericin B or in conjunction with IV amphotericin B.⁴⁴⁰

Treatment of Coccidioidal Meningitis†

Oral or IV

HIV-infected adults or other adults: 400–800 mg daily.²⁹⁸ ³⁰⁰ ³¹⁵ ⁴²⁶ ⁴³⁶ ⁴⁴⁰ ⁴⁶⁵ Concomitant intracisternal, intraventricular, or intrathecal amphotericin B therapy has been used in some patients.⁹⁷ ⁴²⁶

Consultation with an expert experienced in treating coccidioidal meningitis is recommended.⁴⁴⁰

Primary Prophylaxis to Prevent First Episode of Coccidioidomycosis†

Oral

HIV-infected adults living in areas endemic for coccidioidomycosis who have newly positive IgM or IgG serologic test and CD4⁺ T-cell count <250/mm³: 400 mg once daily.⁴⁴⁰

Prevention of Recurrence (Secondary Prophylaxis) of Coccidioidomycosis†

Oral

HIV-infected adults: 400 mg once daily.⁴⁴⁰

Initiate secondary prophylaxis after primary infection has been adequately treated.⁴⁴⁰

HIV-infected adults who were treated for focal coccidioidal pneumonia and are receiving antiretroviral therapy: Consider discontinuing secondary prophylaxis against coccidioidomycosis after 12 months if CD4⁺ T-cell count ≥250/mm³, but continue monitoring for recurrence (e.g., serial chest radiographs, coccidioidal serology).⁴⁴⁰

HIV-infected adults who were treated for diffuse pulmonary or disseminated coccidioidomycosis or coccidioidal meningitis: Life-long secondary prophylaxis against coccidioidomycosis usually required.⁴⁴⁰

Cryptococcosis

Treatment of Cryptococcal Meningitis

Oral or IV

Manufacturer recommends 400 mg given as a single dose on first day, then 200-400 mg once daily.¹ Some evidence suggests that the 400-mg dosage is more effective than lower dosage.⁹³ ¹¹⁶ ¹¹⁷

HIV-infected adults: Induction therapy with IV amphotericin B and oral flucytosine given for at least 2 weeks, then consolidation therapy with oral fluconazole 400 mg (6 mg/kg) daily given for at least 8 weeks.⁴²⁷ ⁴⁴⁰

HIV-infected adults who cannot receive flucytosine: Induction therapy with IV amphotericin B and oral or IV fluconazole 400 mg daily given for at least 2 weeks, then consolidation therapy with oral fluconazole 400 mg daily given for at least 8 weeks.⁴⁴⁰ Some experts state that higher fluconazole dosage (800 mg daily) is preferred for induction and consolidation therapy when this regimen is used.⁴²⁷

HIV-infected adults who cannot receive amphotericin B: Induction therapy with oral or IV fluconazole 400–800 mg daily and oral flucytosine given for at least 4–6 weeks, then consolidation therapy with oral fluconazole 400 mg daily given for at least 8 weeks.⁴⁴⁰ Some experts recommend induction therapy using higher fluconazole dosage (preferably 1.2 g daily) and oral flucytosine given for 6 weeks, then consolidation therapy with fluconazole 400 mg daily.⁴²⁷

HIV-infected adults who cannot receive amphotericin B or flucytosine: ≥800 mg daily given for 10–12 weeks is recommended.⁴²⁷ IDSA states that a dosage ≥1.2 g daily is preferred when fluconazole monotherapy is used;⁴²⁷ dosage as high as 2 g daily has been used, but may be associated with toxicity.⁴²⁷ High dosage should be given in divided doses to minimize GI toxicity.⁴²⁷

Immunocompetent adults without HIV infection who are not transplant recipients: Induction therapy with IV amphotericin B and oral flucytosine given for at least 4 weeks, then consolidation therapy with oral fluconazole 400 mg daily given for at least 8 weeks.⁴²⁷ In those who are immunocompetent, are without uncontrolled underlying disease, and are at low risk for therapeutic failure, IDSA states that this induction regimen can be given for only 2 weeks, then consolidation therapy with oral fluconazole 800 mg (12 mg/kg) daily should be given for at least 8 weeks.⁴²⁷

Treatment of Cryptococcosis (Nonmeningeal)†

Oral

Immunocompetent or immunocompromised adults with mild to moderate pulmonary cryptococcosis: 400 mg (6 mg/kg) daily for 6–12 months.⁴²⁷

Immunocompetent adults with nonpulmonary cryptococcosis at a single site: 400 mg (6 mg/kg) daily for 6–12 months.⁴²⁷

Immunocompetent or immunocompromised adults with severe pulmonary cryptococcosis, cryptococcemia, or disseminated cryptococcosis: Use regimens recommended for adults with cryptococcal meningitis.⁴²⁷

Cryptococcosis in Organ Transplant Recipients†

Oral or IV

CNS disease: Induction therapy with IV amphotericin B and oral flucytosine given for at least 2 weeks, then consolidation therapy with oral fluconazole 400–800 mg (6–12 mg/kg) daily given for 8 weeks.⁴²⁷

Mild to moderate pulmonary disease (without pulmonary infiltrates) or other mild to moderate non-CNS disease: 400 mg (6 mg/kg) daily for 6–12 months.⁴²⁷

Prevention of Recurrence (Secondary Prophylaxis) of Cryptococcosis†

Oral

HIV-infected or other adults: 200 mg once daily.⁴²⁷ ⁴⁴⁰

Organ transplant recipients adequately treated for CNS cryptococcosis: 200–400 mg daily for 6–12 months.⁴²⁷

Initiate secondary prophylaxis after primary infection has been adequately treated and continue for at least 1 year.⁴⁴⁰

Consider discontinuing secondary prophylaxis against cryptococcosis in HIV-infected adults who are asymptomatic for cryptococcosis, have received such prophylaxis for ≥1 year, are receiving antiretroviral therapy, have had undetectable or low plasma HIV RNA levels for ≥3 months, and have CD4⁺ T-cell counts ≥100/mm³.⁴⁴⁰ Reinitiate secondary prophylaxis against cryptococcosis if CD4⁺ T-cell count decreases to <100/mm³.⁴⁴⁰

Histoplasmosis†

Treatment of Histoplasmosis†

Oral or IV

400–800 mg once daily.³¹⁵ ³¹⁶ ⁴²⁸ ⁴³⁶ Alternatively, 800 mg daily has been given for 12 weeks for induction therapy, followed by 400 mg daily.⁴²⁸

HIV-infected adults with less severe disease: 800 mg daily.⁴⁴⁰

Prevention of Recurrence (Secondary Prophylaxis) of Histoplasmosis†

Oral

HIV-infected adults: 400 mg daily.⁴⁴⁰

Consider discontinuing secondary prophylaxis against histoplasmosis in HIV-infected adults who have received such prophylaxis for ≥1 year, have negative fungal blood cultures and serum histoplasma antigen levels <2 ng/mL, have been receiving antiretroviral therapy for ≥6 months, and have CD4⁺ T-cell counts ≥150/mm³.⁴⁴⁰

Reinitiate secondary prophylaxis against histoplasmosis if CD4⁺ T-cell count decreases to <150/mm³.⁴⁴⁰

Sporotrichosis†

Lymphocutaneous and Cutaneous Sporotrichosis†

Oral

400–800 mg once daily.⁴²⁹ ⁴³⁶ Use only when other drugs cannot be used.⁴²⁹

Dermatophytoses†

Tinea Corporis†, Tinea Cruris†, or Tinea Pedis†

Oral

150 mg once weekly for 2–6 weeks has been effective.³⁷³ ³⁷⁴ ³⁷⁸

Tinea corporis involving small, well-defined lesions: 250 mg once weekly for 2–4 weeks has been recommended.³⁸³

Tinea pedis: 150–200 mg once weekly for 1–8 weeks has been recommended.³⁸³ ⁴³⁶

Onychomycosis†

Oral

100–450 mg once weekly for 2–12 months has been used.¹⁴⁰ ¹⁷⁶ ³⁸³ ⁴¹⁷ ⁴²⁰ ⁴²¹ ⁴⁵⁵ ⁴⁷⁹ ⁴⁹⁹ ⁵⁰⁰ Some clinicians recommend 150–300 mg once weekly for 3–6 months for fingernail infections or for 6–12 months for toenail infections.⁴³⁶ ⁵⁰⁰

Pityriasis (Tinea) Versicolor†

Oral

A single 400-mg dose has been used.²⁹² ⁴⁶¹ ⁴⁶² Alternatively, 150 mg has been given once weekly for 2 or 4 weeks⁴⁶⁰ ⁴⁶² or 300 mg has been given once weekly for 2 weeks.⁴⁵⁹

Prevention of Candidiasis in Transplant Recipients, Cancer Patients, or Other Patients at High Risk

Bone Marrow Transplant (BMT) Recipients

Oral or IV

400 mg once daily.¹ ¹⁵⁷ ³⁴⁰

In patients in whom severe granulocytopenia (neutrophil count <500/mm³) is anticipated, initiate several days before expected onset of neutropenia and continue for 7 days after neutrophil count is >1000/mm³.¹

Antifungal prophylaxis not usually recommended if anticipated duration of neutropenia is <7 days.⁴²²

Hematologic Stem Cell Transplant (HSCT) Recipients†

Oral or IV

400 mg once daily.⁴²⁵ ⁴⁵²

Initiate on the day of HSCT transplantation (i.e., day 0) and continue until engraftment occurs (i.e., approximately 30 days after HSCT) or until 7 days after neutrophil count is >1000/mm³.⁴⁵²

High-risk Patients in ICUs†

Oral or IV

High-risk patients in ICUs with known high incidence of invasive candidiasis: 400 mg (6 mg/kg) once daily.⁴²⁵

Prescribing Limits

Pediatric Patients

Treatment of Fungal Infections

Oral or IV

Maximum of 600 mg daily.¹

Special Populations

Renal Impairment

Treatment of Fungal Infections

Oral or IV

Adults with impaired renal function receiving multiple doses: Adjust dosage in response to degree of impairment based on patient’s measured or estimated Cl_cr.¹ ¹²⁴ Manufacturer recommends an initial loading dose of 50–400 mg (based on the type of infection being treated), then give 100% of the usual daily dose to those with Cl_cr >50 mL/minute and give 50% of the usual daily dose to those with Cl_cr ≤50 mL/minute.¹ Further dosage adjustments may be necessary depending on patient condition.¹

Dialysis patients receiving multiple doses: Give 100% of the usual daily dose after each dialysis period;¹ on days patient does not receive dialysis, give reduced dosage based on Cl_cr.¹

Adults with impaired renal function receiving single-dose regimen for treatment of vulvovaginal candidiasis: Modification of dosage not needed.¹

Children with impaired renal function: Pharmacokinetics not studied;¹ make dosage adjustments similar to those recommended for adults.¹

Geriatric Patients

Adjust dosage based on Cl_cr.¹ (See Renal Impairment under Dosage.)

Cautions for Fluconazole

Contraindications

Hypersensitivity to fluconazole or any ingredient in the formulation.¹
Concomitant use with drugs that are known to prolong the QT interval and are metabolized by CYP3A4 (e.g., astemizole, cisapride, pimozide, quinidine).¹ (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Hepatotoxicity

Serious hepatic reactions (e.g., necrosis, clinical hepatitis, cholestasis, fulminant hepatic failure) have been reported rarely.¹ ¹²⁴ ²¹⁶ ²⁵³ ²⁵⁴ ²⁵⁵ ²⁵⁶ ²⁵⁷ A clear relationship between these hepatic effects and daily dosage, duration of therapy, gender, or age has not been demonstrated.¹

While hepatotoxicity usually has been reversible, fatalities have occurred,¹ ¹²⁴ ²¹⁶ ²⁵⁴ ²⁵⁵ ²⁵⁶ ²⁵⁷ principally in patients with serious underlying disease (e.g., AIDS, malignancy) who were receiving other drugs concomitantly.¹ ¹²⁴ ²¹⁶ ²⁵³ ²⁵⁴ ²⁵⁵ ²⁵⁶ ²⁵⁷

Mild, transient increases (1.5–3 times ULN) in serum concentrations of AST,¹⁹ ²⁸ ³⁹ ⁶⁴ ⁶⁸ ⁹⁴ ALT,¹⁹ ²⁸ ³⁹ ⁶² ⁶⁴ ⁶⁸ ⁹⁴ ⁹⁶ alkaline phosphatase,²⁸ ³⁷ ⁴⁴ ⁶⁴ ⁶⁸ γ-glutamyltransferase (GGT, γ-glutamyl transpeptidase, GGTP),³⁷ ⁶⁴ ⁶⁸ and bilirubin¹⁹ ⁶⁸ have been reported.¹⁵ ¹⁹ ²⁸ ³² ³⁷ ³⁹ ⁴⁴ ⁶⁵ ⁶⁸ ⁹⁴ ¹⁴⁹

In most reported cases, concentrations returned to pretreatment levels either during or after fluconazole therapy and were not associated with hepatotoxicity.¹⁵ ⁶⁸ ⁹⁴ However, higher increases in serum transaminase concentrations (≥8 times the ULN), which required discontinuance of the drug, also have occurred.¹ ²⁸ ³² ⁶⁵ ⁶⁸

If abnormal liver function test results occur, monitor patient for the development of more severe hepatic injury.¹

If signs and symptoms consistent with liver disease develop, discontinue fluconazole.¹

Dermatologic Reactions

Rash¹ ²⁸ ³² ⁶² ⁶⁴ ⁶⁵ ⁹⁴ ¹⁴² (including diffuse rash accompanied by eosinophilia)⁹⁴ and pruritus²⁸ ⁶² ¹⁶³ have been reported.¹ ⁹⁴

Exfoliative skin disorders have been reported rarely in patients with serious underlying disease (principally AIDS or malignancy);¹ ¹²⁴ ¹⁴² fatalities have been reported.¹

Stevens-Johnson syndrome,¹ ⁹³ ¹⁵⁰ which can be fatal,¹ also has been reported.

If rash develops in patient with deep-seated fungal infection, monitor closely and discontinue fluconazole if lesions progress.¹ ¹²⁴

If rash that may be attributable to fluconazole develops in patient with superficial fungal infection, discontinue the drug.¹

Fetal/Neonatal Morbidity

Rare and distinct pattern of birth defects (e.g., brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, congenital heart disease) observed in infants born to women who received high-dose fluconazole (400–800 mg daily) for serious, life-threatening fungal infections during most or all of first trimester.¹ ²⁵⁸ ⁴⁹² ⁴⁹³ ⁴⁹⁴ ⁴⁹⁵ (See Pregnancy under Cautions.)

Available human data to date do not suggest increased risk of congenital anomalies when fluconazole used as a single 150-mg oral dose for treatment of vulvovaginal candidiasis in pregnant women.¹ ⁴⁹² (See Pregnancy under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis (including angioedema, face edema, and pruritus) has been reported rarely.¹ ¹⁶³ Angioedema and anaphylactic reactions have been reported rarely in women who received a single oral dose for treatment of vulvovaginal candidiasis.¹

Cross-hypersensitivity

Although information concerning cross-sensitivity between fluconazole and other triazole or imidazole antifungals is not available, manufacturer states that fluconazole should be used with caution in individuals hypersensitive to other azoles.¹

General Precautions

Cardiovascular Effects

Prolonged QT interval reported with some azoles, including fluconazole.¹ ⁴⁴⁸ Torsades de pointes reported rarely.¹ ⁴⁴⁸

Most reported cases involved seriously ill patients with multiple confounding risk factors that may have contributed (e.g., structural heart disease, electrolyte abnormalities, concomitant drugs).¹ ⁴⁴⁸

Use with caution in patients with potentially proarrhythmic conditions and risk factors for QT prolongation.¹ ⁴⁴⁸

Selection and Use of Antifungals

Diflucan powder for oral suspension contains sucrose; do not use in patients with hereditary fructose, glucose-galactose malabsorption, and sucrase-isomaltase deficiency.¹

Prior to use of fluconazole, appropriate specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained to isolate and identify causative organisms.¹

Superinfection with nonsusceptible fungi (e.g., C. krusei) may occur;¹ alternative antifungal therapy may be required.¹

CNS Effects

Dizziness or seizures may occur occasionally and should be considered in patients who drive or operate machines.¹

Specific Populations

Pregnancy

FDA alerted clinicians in April 2016 that it is reviewing safety data regarding use of oral fluconazole during pregnancy and advised cautious prescribing of the drug until the review is completed.⁴⁹⁶

Category C when used as a single 150-mg oral dose for treatment of vulvovaginal candidiasis.¹ Classification based on data available to FDA at that time indicating single 150-mg oral dose not associated with increased risk of congenital anomalies.¹ Data from a recent Danish study indicated increased risk of spontaneous abortion (i.e., miscarriage during gestational weeks 7 through 22) in pregnant women treated with oral fluconazole (most women received total cumulative dose of 150–300 mg) compared with matched control pregnancies not exposed to oral fluconazole.⁴⁹⁷ FDA is reviewing data from the Danish study and additional data;⁴⁹⁶ after completing the review, FDA will communicate its conclusions and updated recommendations regarding use of the single-dose 150-mg oral fluconazole regimen during pregnancy.⁴⁹⁶

Category D when used for all other indications (e.g., treatment of oropharyngeal or esophageal candidiasis, cryptococcal meningitis, prevention of Candida infections).¹ Congenital abnormalities reported in infants born to women who received high-dose fluconazole (400–800 mg daily) for treatment of serious, life-threatening fungal infections during most or all of the first trimester.¹ ²⁵⁸ ⁴⁹² ⁴⁹³ ⁴⁹⁴ ⁴⁹⁵ ⁴⁹⁶

CDC states use topical (intravaginal) azoles (not oral fluconazole) for treatment of vulvovaginal candidiasis during pregnancy.³⁴⁴

Patients who are pregnant or actively trying to become pregnant should talk to their clinician about alternatives for treatment of vulvovaginal candidiasis.⁴⁹⁶

IDSA states avoid use of fluconazole for treatment of serious fungal infections (e.g., blastomycosis^†, candidiasis, histoplasmosis^†, coccidioidomycosis^†, cryptococcosis) during pregnancy.⁴²⁴ ⁴²⁵ ⁴²⁶ ⁴²⁷ ⁴²⁸

If used during pregnancy or if patient becomes pregnant while receiving fluconazole, inform patient of potential hazard to the fetus.¹ ⁴⁹⁶ (See Fetal/Neonatal Morbidity under Cautions.)

Lactation

Distributed into milk at concentrations similar to those achieved in plasma.¹ ²⁶¹ Use with caution in nursing women.¹

Pediatric Use

Efficacy in children <6 months of age not established, but the drug has been used safely and effectively in neonates and children <6 months of age (including neonates as young as 1 day of age).¹ ³⁹¹ ³⁹² ³⁹⁴ ⁴⁰⁸ ⁴⁰⁹ ⁴¹⁰

Adverse effects in children generally have been similar to those in adults.¹ ³⁹³ ³⁹⁵

Geriatric Use

Some evidence that rash, vomiting, and diarrhea occur more frequently in patients ≥65 years of age than in younger adults, but the discontinuance rate in geriatric patients has been similar to that in younger patients.¹ There have been more reports of anemia and acute renal failure in geriatric patients than in those <65 years of age, but clinical importance unclear since there is a natural increase in reported incidence of these in geriatric individuals.¹

Insufficient experience in controlled clinical studies in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹ Other clinical experience has not revealed age-related differences in response.¹

Substantially eliminated by kidneys; assess renal function periodically since geriatric patients more likely to have decreased renal function.¹ Adjust dosage based on Cl_cr.¹ (See Renal Impairment under Dosage and Administration.)

Hepatic Impairment

Use with caution.¹

Renal Impairment

Use with caution;¹ dosage adjustments required based on degree of renal impairment.¹ ¹²⁴ Plasma concentrations are higher and half-life prolonged.¹ ³⁷ ⁵⁷ ⁶⁷ ¹⁰⁵ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

GI effects (nausea, vomiting, abdominal pain, diarrhea), rash, transient increases in liver enzymes and bilirubin.¹ ¹⁹ ²⁸ ³² ³⁹ ⁶² ⁶⁴ ⁶⁵ ⁶⁸ ⁹⁴ ⁹⁵ ⁹⁶

Drug Interactions

Drugs Metabolized by Hepatic Microsomal Enzymes

Fluconazole is a potent inhibitor of CYP2C9 and a moderate inhibitor of CYP3A4.¹ Because fluconazole has a long half-life, the enzyme-inhibiting effects of the drug persist for 4–5 days following discontinuance.¹ Concomitant use of fluconazole and drugs metabolized by CYP2C9 or 3A4 may result in increased plasma concentrations of the concomitant drug; use caution and monitor closely.¹

Drugs that Prolong the QT Interval

Concomitant use of fluconazole with drugs known to prolong the QT interval and that are metabolized by CYP3A4 is contraindicated.¹

Specific Drugs

Drug	Interaction	Comments
Amphotericin B	In vitro evidence of antagonism against Candida or Aspergillus fumigatus²³¹ ²³²	Use concomitantly with caution and close monitoring,¹ ²³² ²³⁵ ²³⁶ especially in immunocompromised patients²³² ²³⁵ ²³⁶
Antacids (aluminum- or magnesium-containing)	No clinically important effect on fluconazole pharmacokinetics¹ ⁶¹ ²⁴⁹
Anticoagulants, oral (warfarin)	Possible increased PT;¹ ⁴⁸ ⁶¹ ⁹¹ ²⁵¹ bleeding events (bruising, epistaxis, GI bleeding, hematuria, melena) reported¹	Monitor PT or other appropriate tests closely if used with warfarin; reduce anticoagulant dosage if necessary¹ ⁶¹ ⁶² ⁶⁸ ⁹¹ ²⁵¹
Anticonvulsants (carbamazepine, phenytoin)	Carbamazepine: Increased carbamazepine concentrations and increased risk of toxicity¹ ³⁷⁰ Phenytoin: Increased phenytoin concentrations and AUC and increased risk of toxicity;¹ ²⁵ ⁶¹ ¹²⁴ ¹⁴¹ fluconazole pharmacokinetics not affected¹⁴¹	Carbamazepine: Use concomitantly with caution and close monitoring;¹ carbamazepine dosage based on carbamazepine concentrations and clinical effect may be necessary¹ Phenytoin: Use concomitantly with caution and close monitoring;¹ carefully monitor phenytoin concentrations;¹ ⁶¹ ¹⁴¹ adjust phenytoin dosage as needed whenever fluconazole is initiated or discontinued⁶¹ ⁹¹ ¹⁴¹
Antidepressants, tricyclics (amitriptyline, nortriptyline)	Possible increased tricyclic antidepressant concentrations and increased risk of CNS toxicity¹ ³⁶⁷	Use concomitantly with caution and close monitoring;¹ consider monitoring S-amitriptyline and/or 5-nortriptyline concentrations when concomitant therapy is initiated and after 1 week of concomitant therapy;¹ adjust antidepressant dosage if needed¹
Antidiabetic agents, sulfonylureas (glipizide, glyburide, tolbutamide)	Increased plasma concentrations and AUCs of the antidiabetic agent; symptoms of hypoglycemia reported¹ ⁶¹ ⁹¹	Monitor blood glucose and observe patient for signs and symptoms of hypoglycemia; adjust dosage of antidiabetic agent as necessary¹ ⁶¹ ⁹¹
Antihistamines (astemizole, terfenadine)	Possible pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., cardiac arrhythmias, prolonged QT interval)¹⁶⁴ ¹⁶⁵ ¹⁶⁶ ¹⁶⁷ ¹⁶⁸ ¹⁶⁹ ¹⁷¹ ¹⁷² ¹⁷⁴ ¹⁷⁵ ³⁴⁷	Concomitant administration of terfenadine and fluconazole (≥400) is contraindicated; monitor closely if lower fluconazole dosages used¹
Antimycobacterial agents (rifabutin, rifampin)	Rifabutin: Substantially increased rifabutin concentrations and AUC;²⁴¹ possible increased risk of adverse effects (e.g., uveitis)²⁴¹ ²⁴² ²⁴³ Rifampin: Increased rifampin concentrations;¹ ⁹¹ ²⁴⁴ decreased fluconazole AUC and possible decreased fluconazole efficacy¹ ⁹¹ ²⁴⁴ ²⁴⁵	Rifabutin: Use concomitantly with caution and close monitoring¹ Rifampin: Use concomitantly with caution and close monitoring;¹ consider increasing fluconazole dosage¹
Antiretrovirals, HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs)	Delavirdine: No clinically important effects on delavirdine or fluconazole pharmacokinetics³⁸⁹ ⁴³⁴ Efavirenz: No clinically important effects on efavirenz or fluconazole pharmacokinetics²⁰⁰ ³⁷¹ Etravirine: Substantially increased etravirine concentrations and AUC;²⁰⁰ ⁴⁴⁷ no change in fluconazole concentrations⁴⁴⁷ Nevirapine: Increased nevirapine concentrations;²⁰⁰ ⁴³⁵ no effect on fluconazole concentrations;⁴³⁵ possible increased risk of hepatotoxicity²⁰⁰ Rilpivirine: Possible increased rilpivirine concentrations²²⁶	Delavirdine: Dosage adjustments not needed³⁸⁹ Efavirenz: Dosage adjustments not needed³⁷¹ Etravirine: Dosage adjustments not needed for either drug;²⁰⁰ ⁴⁴⁷ use caution because of limited safety data regarding increased etravirine concentrations⁴⁴⁷ Nevirapine: Use concomitantly with caution;⁴³⁵ monitor closely for nevirapine-associated adverse effects²⁰⁰ ⁴³⁵ or use alternative antiretroviral²⁰⁰ Rilpivirine: Dosage adjustments of rilpivirine not needed;²²⁶ monitor for breakthrough fungal infections²²⁶
Antiretrovirals, HIV nucleoside reverse transcriptase inhibitors (NRTIs)	Didanosine: No clinically important effects on didanosine or fluconazole pharmacokinetics²¹⁸ Stavudine: Pharmacokinetic interactions unlikely⁴³⁸ Zidovudine: Increased zidovudine concentrations and AUC¹ ²¹⁷	Zidovudine: Use concomitantly with caution and close monitoring;¹ ²¹⁷ monitor for zidovudine-associated adverse effects;¹ ²¹⁷ consider reducing zidovudine dosage¹
Antiretrovirals, HIV protease inhibitors (PIs)	Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Clinically important pharmacokinetic interactions not observed and are unlikely²⁰⁰ ⁴⁴⁶ Indinavir: No clinically important effects on pharmacokinetics of indinavir or fluconazole³⁶⁸ Lopinavir/ritonavir: Clinically important interactions not expected⁴³³ Ritonavir: No clinically important effects on ritonavir pharmacokinetics;⁴³² minor increase in ritonavir concentrations and AUC²⁴⁸ ⁴³² Saquinavir: Increased saquinavir concentrations and AUC;¹ ²⁰⁰ ⁴⁸¹ data not available regarding ritonavir-boosted saquinavir²⁰⁰ Ritonavir-boosted tipranavir: Increased tipranavir peak plasma concentrations and AUC;²⁰⁰ ⁴⁴⁵ no change in fluconazole pharmacokinetics⁴⁴⁵	Ritonavir-boosted or cobicistat-boosted atazanavir: Dosage adjustments not needed²⁰⁰ Indinavir: Dosage adjustment not needed³⁶⁸ Ritonavir: Dosage adjustment not needed⁴³² Saquinavir: Use concomitantly with caution and close monitoring;¹ saquinavir dosage adjustment may be necessary;¹ Ritonavir-boosted saquinavir: Dosage adjustments not needed²⁰⁰ Ritonavir-boosted tipranavir: Dosage adjustments not needed;⁴⁴⁵ fluconazole dosage >200 mg daily not recommended;²⁰⁰ ⁴⁴⁵ if high-dose fluconazole is indicated, consider alternative antiretroviral²⁰⁰
Benzodiazepines (midazolam, triazolam)	Midazolam: Increased midazolam peak plasma concentrations and AUC and possible prolonged sedative effects reported with oral or IV fluconazole;¹ ³⁶⁹ ⁴⁸² ⁴⁸³ no effect on fluconazole concentrations or AUC⁴⁸² Triazolam: Increased peak plasma triazolam concentrations and AUC; prolonged triazolam half-life¹	Short-acting benzodiazepines metabolized by CYP: Use concomitantly with caution and close monitoring¹ ; monitor for manifestations of benzodiazepine toxicity;¹ consider decreasing benzodiazepine dosage as needed¹ ³⁶⁹
Calcium-channel blocking agents (amlodipine, felodipine, isradipine, nifedipine, verapamil)	Possible increased systemic exposure to calcium-channel blocking agents metabolized by CYP3A4¹	Use concomitantly with caution and close monitoring;¹ monitor frequently for adverse events¹
Cisapride	Increased cisapride concentrations and increased risk of adverse effects (e.g., cardiac effects);¹ prolonged QT interval and torsades de pointes reported¹	Concomitant use contraindicated¹
Corticosteroids	Prednisone: Acute adrenal cortex insufficiency reported when 3-month fluconazole regimen was discontinued in liver transplant patient receiving prednisone¹	Prednisone: Use concomitantly with caution and close monitoring;¹ if used concomitantly for prolonged periods of time, carefully monitor for adrenal cortex insufficiency when fluconazole is discontinued¹
Cyclophosphamide	Increased serum bilirubin and serum creatinine¹	Use concomitantly with caution and close monitoring;¹ consider the risks of increased serum bilirubin and serum creatinine¹
Diuretics, thiazides	Increased fluconazole concentrations and AUC¹ ¹²⁴	Use concomitantly with caution and close monitoring;¹ fluconazole dosage adjustment probably not necessary¹
Estrogens/progestins	Possible increased AUCs of ethinyl estradiol, levonorgestrel, and norethindrone¹ ¹⁸ ⁶¹ ⁶⁸ ⁴³⁹ Fluconazole dosage of 50–200 mg daily unlikely to interfere with oral contraceptive efficacy¹ ⁴³⁹
Flucytosine	In vitro evidence of synergistic, additive, or indifferent antifungal effects against C. neoformans; no evidence of antagonism²³⁹
HCV protease inhibitors	Simeprevir: Possible increased simeprevir concentrations¹⁸⁷	Simeprevir: Concomitant use not recommended¹⁸⁷
HCV replication complex inhibitors		Daclatasvir: Dosage adjustments not needed¹⁷⁸
Histamine H₂-receptor antagonists (cimetidine)	Decreased fluconazole concentrations and AUC¹ ⁶¹ ⁶⁸ ⁹¹	Not considered clinically important⁶¹ ⁶⁸ ⁹¹
HMG-CoA reductase inhibitors (statins)	Increased risk of myopathy and rhabdomyolysis when used concomitantly with statins metabolized by CYP3A4 (atorvastatin, simvastatin) or 2C9 (fluvastatin)¹ Fluvastatin: Prolonged fluvastatin half-life and increased fluvastatin AUC and peak plasma concentrations⁴⁸⁶ Pravastatin: No clinically important effects on pravastatin pharmacokinetics⁴⁸⁶	If concomitant therapy necessary, monitor CK and monitor for symptoms of myopathy and rhabdomyolysis;¹ if substantial increase in CK occurs or myopathy/rhabdomyolysis is diagnosed or suspected, discontinue statin¹
Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)	Cyclosporine: Increased cyclosporine concentrations and AUC,¹ ²² ²³ ²⁴ ⁶¹ ⁶⁸ ⁹¹ especially in renal transplant recipients²² ²³ ²⁴ ⁶⁸ Tacrolimus: Increased serum tacrolimus concentrations with oral tacrolimus;¹ clinically important interaction not observed with IV tacrolimus;¹ increased tacrolimus concentrations have been associated with nephrotoxicity¹ Sirolimus: Increased sirolimus concentrations¹	Cyclosporine: Use concomitantly with caution;¹ closely monitor cyclosporine plasma concentrations and serum creatinine;¹ ²² ²³ adjust cyclosporine dosage based on plasma concentrations¹ ²² ²³ Tacrolimus: Use concomitantly with caution and close monitoring;¹ decrease tacrolimus dosage based on tacrolimus concentrations¹ Sirolimus: Use concomitantly with caution and close monitoring;¹ adjust sirolimus dosage based on sirolimus concentrations and clinical effects¹
Losartan	Decreased AUC and peak plasma concentrations of the active losartan metabolite¹ ⁴⁸⁷	Use concomitantly with caution and close monitoring;¹ consider possibility of decreased losartan therapeutic effect;⁴⁸⁷ closely monitor BP¹
Macrolides	Azithromycin: No clinically important pharmacokinetic interactions¹ Erythromycin: Possible increased risk of prolonged QT interval, torsades de pointes, and subsequent sudden cardiac death¹	Erythromycin: Avoid concomitant use¹
Nonsteroidal anti-inflammatory agents (NSAIAs)	Celecoxib: Increased celecoxib AUC and peak plasma concentrations¹ Flurbiprofen: Increased flurbiprofen AUC and peak plasma concentrations¹ Ibuprofen: Increased AUC and peak plasma concentrations of pharmacologically active S-isomer of ibuprofen¹ ⁴⁸⁴ Other NSAIAs metabolized by CYP2C9 (e.g., diclofenac, meloxicam, naproxen): Possible increased NSAIA exposure¹	Celecoxib: Use concomitantly with caution and close monitoring;¹ reduction of celecoxib dosage by 50% may be necessary¹ Other NSAIAs metabolized by CYP2C9: Use concomitantly with caution and close monitoring;¹ frequently monitor for NSAIA-associated adverse events;¹ NSAIA dosage adjustment may be necessary⁴⁸⁴
Opiate agonists (alfentanil, fentanyl, methadone)	Alfentanil: Reduced alfentanil clearance and volume of distribution and prolonged alfentanil half-life¹ ⁴⁸⁵ Fentanyl: Substantially delayed elimination of fentanyl;¹ ⁴⁹⁰ elevated fentanyl concentrations may lead to respiratory depression;¹ fatality possibly related to fentanyl intoxication reported in patient receiving fentanyl and fluconazole¹ ⁴⁸⁹ Methadone: Increased methadone concentrations and AUC⁴⁸⁸	Alfentanil: Use concomitantly with caution and close monitoring; alfentanil dosage adjustment may be necessary¹ Fentanyl: Use concomitantly with caution and close monitoring¹ Methadone: Use concomitantly with caution and close monitoring; methadone dosage adjustment may be necessary¹
Pimozide	Possible increased pimozide concentrations; potential for QT interval prolongation¹	Concomitant use contraindicated¹
Quinidine	Possible inhibition of quinidine metabolism;¹ potential for QT interval prolongation¹	Concomitant use contraindicated¹
Theophylline	Increased theophylline concentrations and AUC¹	Use concomitantly with caution and close monitoring; carefully monitor theophylline concentrations¹
Tofacitinib	Increased peak concentration and AUC of tofacitinib¹	If used concomitantly, reduce tofacitinib dosage to 5 mg once daily¹
Tretinoin	Pseudotumor cerebri reported in patient receiving tretinoin (all-trans-retinoic acid) and fluconazole; CNS effects resolved when fluconazole discontinued¹	Use concomitantly with caution and close monitoring; consider possibility of adverse CNS effects¹
Vinca alkaloids (vinblastine, vincristine)	Possible increased vinca alkaloid concentrations with possible neurotoxicity¹	Use concomitantly with caution and close monitoring¹
Voriconazole	Increased voriconazole peak plasma concentrations and AUC;¹ dosage adjustments of voriconazole or fluconazole do not overcome this pharmacokinetic interaction¹	Avoid concomitant use; if voriconazole used sequentially after fluconazole, monitor patient closely for voriconazole-associated adverse events, particularly during first 24 hours after last fluconazole dose¹

Fluconazole Pharmacokinetics

Absorption

Bioavailability

Pharmacokinetics are similar following IV or oral administration.¹ ⁶¹ ¹⁰⁵

Rapidly and almost completely absorbed from GI tract;¹ ² ⁵¹ ⁶¹ ⁶⁷ ⁶⁸ peak plasma concentrations attained within 1–2 hours.¹ ⁶⁸ ⁹⁹ ¹⁰⁵

Oral bioavailability ≥90% in healthy, fasting adults.¹ ⁶¹ ⁶⁸ ¹⁰⁵ ¹²⁴ ¹³¹

Oral bioavailability in HIV-infected adults appears to be similar to that reported for healthy adults.²¹⁹ ²²³

Unlike some imidazoles (e.g., ketoconazole), GI absorption of fluconazole does not appear to be affected by gastric pH.¹ ¹⁶ ⁶¹ ⁶⁸ ⁹¹ ¹²⁴ ²⁴⁹ ²⁵⁰

Oral suspensions are bioequivalent to tablets.¹

Food

Administration with a high-fat meal does not affect fluconazole peak plasma concentrations or AUC compared with administration in the fasting state.¹

Distribution

Extent

Widely distributed into body tissues and fluids following oral or IV administration.¹ ⁶¹ ⁶² ⁶⁴ ⁷⁶ ¹⁰² ¹⁰³ ¹⁰⁵

Concentrations attained in urine and skin may be 10 times higher than concurrent plasma concentrations.¹ ¹⁰⁵

Concentrations attained in saliva,¹ ⁶¹ ¹⁰⁵ sputum,¹ ¹³ ⁶¹ ¹⁰⁵ nails,¹ blister fluid,¹ ¹⁰⁵ blister skin,¹ ¹⁰⁵ and vaginal tissue¹ are approximately equal to concurrent plasma concentrations.¹ ¹³ ⁶¹ ⁹⁹ ¹⁰⁵

Unlike some azoles (e.g., itraconazole, ketoconazole), fluconazole readily distributes into CSF following oral or IV administration;¹ ² ³ ¹⁴ ¹⁵ ²⁹ ³⁰ ³⁶ ⁵⁴ ⁶¹ ⁶² ¹⁰² ¹⁰⁵ CSF concentrations may be 50–94% of concurrent plasma concentrations, regardless of the degree of meningeal inflammation.¹ ² ³ ¹⁴ ¹⁵ ²⁹ ³⁰ ⁵⁴ ⁶¹ ⁶² ⁶⁷ ¹⁰² ¹⁰⁵

Crosses the placenta in rats; not known whether crosses the placenta in humans.¹¹⁷

Distributed into human milk in concentrations similar to those attained in plasma.¹ ²⁶¹

Plasma Protein Binding

Unlike some azoles (e.g., itraconazole, ketoconazole, miconazole), which are highly protein bound, fluconazole is only 11–12% bound to plasma proteins.¹ ² ³ ¹² ⁵¹ ⁶² ⁶⁷ ⁷⁸ ⁸⁴ ¹⁰⁵ ¹²⁴

Elimination

Elimination Route

Eliminated principally by renal excretion.¹ ²

Approximately 60–80% of a single oral or IV dose excreted in urine unchanged;¹ ² ³ ¹² ⁵¹ ⁶¹ ⁶⁸ ¹⁰⁵ ¹¹⁷ about 11% is excreted in urine as metabolites.¹ ⁵¹ ⁶¹ ¹⁰⁵

Small amounts excreted in feces.⁶⁸

Removed by hemodialysis.¹ ³⁷

Removed by peritoneal dialysis.⁴⁷

Half-life

Adults with normal renal function: Approximately 30 hours (range: 20–50 hours).¹ ² ³ ¹² ¹³ ¹⁴ ⁶¹ ⁶² ⁶⁷ ⁶⁸ ⁷⁸ ¹⁰⁵

Children: 19.5–25 hours following a single oral dose in those 9 months to 13 years of age and 15.2–17.6 hours following multiple IV doses in those 5–15 years of age.¹

Neonates: Decreases over time, averaging 88 hours after the first dose and 55 hours after the fifth dose (day 13).²⁵⁹

Special Populations

Elimination half-life not affected by impaired hepatic function.¹¹⁷

In impaired renal function, plasma concentrations are higher and half-life prolonged;¹ ³⁷ ⁵⁷ ⁶⁷ ¹⁰⁵ elimination half-life is inversely proportional to Cl_cr.¹

Renal clearance may be lower in geriatric patients than in younger adults,¹ ¹²⁴ apparently because of decreased kidney function in this age group.¹

Stability

Storage

Oral

Tablets

<30°C.¹

For Suspension

<30°C.¹

Following reconstitution, store between 5–30°C;¹ protect from freezing.¹ Discard unused oral suspension 2 weeks after reconstitution.¹

Parenteral

Injection for IV Infusion

Glass bottles: 5–30°C;¹ protect from freezing.¹

Viaflex plastic containers: 5–25°C (may be exposed to temperatures up to 40°C); protect from freezing.¹

Compatibility

Parenteral

Solution CompatibilityHID

Compatible
Dextrose 5% in water
Ringer’s injection, lactated

Drug Compatibility

Admixture CompatibilityHID
Compatible
Acyclovir sodium
Amikacin sulfate
Amphotericin B
Cefazolin sodium
Ceftazidime
Ciprofloxacin
Clindamycin phosphate
Gentamicin sulfate
Heparin sodium
Meropenem
Metronidazole
Morphine sulfate
Potassium chloride
Ranitidine HCl with ondansetron HCl
Theophylline
Incompatible
Co-trimoxazole

Y-Site CompatibilityHID
Compatible
Acyclovir sodium
Aldesleukin
Allopurinol sodium
Amifostine
Amikacin sulfate
Aminophylline
Amiodarone HCl
Ampicillin sodium–sulbactam sodium
Anidulafungin
Aztreonam
Benztropine mesylate
Bivalirudin
Caspofungin acetate
Cefazolin sodium
Cefepime HCl
Cefotetan disodium
Cefoxitin sodium
Ceftaroline fosamil
Chlorpromazine HCl
Cisatracurium besylate
Daptomycin
Dexamethasone sodium phosphate
Dexmedetomidine HCl
Diltiazem HCl
Dimenhydrinate
Diphenhydramine HCl
Dobutamine HCl
Docetaxel
Dopamine HCl
Doripenem
Doxorubicin HCl liposome injection
Droperidol
Etoposide phosphate
Famotidine
Fenoldopam mesylate
Filgrastim
Fludarabine phosphate
Foscarnet sodium
Gallium nitrate
Ganciclovir sodium
Gemcitabine HCl
Gentamicin sulfate
Granisetron HCl
Heparin sodium
Hetastarch in lactated electrolyte injection (Hextend)
Immune globulin intravenous
Leucovorin calcium
Linezolid
Lorazepam
Melphalan HCl
Meperidine HCl
Meropenem
Metoclopramide HCl
Metronidazole
Midazolam HCl
Morphine sulfate
Nafcillin sodium
Nitroglycerin
Ondansetron HCl
Oritavancin diphosphate
Oxacillin sodium
Paclitaxel
Pancuronium bromide
Pemetrexed disodium
Penicillin G potassium
Phenytoin sodium
Piperacillin sodium–tazobactam sodium
Prochlorperazine edisylate
Promethazine HCl
Propofol
Quinupristin-dalfopristin
Ranitidine HCl
Remifentanil HCl
Sargramostim
Tacrolimus
Telavancin HCl
Teniposide
Theophylline
Thiotepa
Ticarcillin disodium–clavulanate potassium
Tigecycline
Tobramycin sulfate
Vancomycin HCl
Vasopressin
Vecuronium bromide
Vinorelbine tartrate
Zidovudine
Incompatible
Amphotericin B
Amphotericin B cholesteryl sulfate complex
Ampicillin sodium
Calcium gluconate
Cefotaxime sodium
Ceftriaxone sodium
Cefuroxime sodium
Chloramphenicol sodium succinate
Clindamycin phosphate
Co-trimoxazole
Diazepam
Digoxin
Furosemide
Haloperidol lactate
Hydroxyzine HCl
Imipenem–cilastatin sodium
Pentamidine isethionate
Variable
Ceftazidime

Actions and Spectrum

Triazole-derivative azole antifungal.² ³ ⁵ ²⁸ ⁵¹ ⁶¹ ⁶⁷ ⁶⁸ ⁷⁶ ⁷⁸ ⁸⁴ ¹²⁴
Presumably exerts its antifungal activity by altering cellular membranes resulting in increased membrane permeability, leakage of essential elements (e.g., amino acids, potassium), and impaired uptake of precursor molecules (e.g., purine and pyrimidine precursors to DNA).² ⁵¹ ⁶¹ ⁷⁶ ⁷⁹ Inhibits CYP 14-α-desmethylase in susceptible fungi, which leads to accumulation of C-14 methylated sterols (e.g., lanosterol) and decreased concentrations of ergosterol.¹ ² ³ ⁵¹ ⁶¹ ⁷⁶ ⁷⁹ ⁸⁴
Usually fungistatic in action.¹ ⁵¹ ⁷⁵ ²⁶⁸
Spectrum of antifungal activity includes many fungi, including yeasts and dermatophytes.¹ ³ ⁵¹ ⁷⁸ ⁸⁷ ⁸⁸ Inactive against bacteria.¹¹⁷
Candida: Active in vitro and in vivo against C. albicans,¹ ⁵ ⁴⁹ ⁵¹ ⁸⁹ ¹⁰² ³⁵⁹ ³⁶⁰ ³⁶³ ³⁶⁵ C. dubliniensis,¹ ³⁹⁰ C. guilliermondii,¹ ³⁶⁵ C. kefyr,¹ C. parapsilosis,¹ ³⁵⁹ ³⁶² ³⁶³ ³⁶⁵ C. lusitaniae,¹ ³⁸⁶ and C. tropicalis.¹ ¹⁰³ ³⁵⁹ ³⁶² ³⁶³ C. krusei are intrinsically resistant to fluconazole and many strains of C. glabrata also are resistant or have reduced susceptibility to the drug.¹ ²⁶⁷ ²⁷⁵ ³⁴⁶ ³⁵⁹ ³⁶⁰ ³⁶² ³⁶³ ³⁶⁵ Some strains of C. duobushaemulonii inhibited in vitro by fluconazole;⁴⁹⁸ C. haemulonii and C. auris (often misidentified as C. haemulonii, C. famata, or Rhodotorula glutinis) generally resistant to fluconazole in vitro.⁴⁹⁸
Other fungi: Active against Blastomyces dermatitidis,³⁵⁸ Coccidioides immitis,¹ ⁴⁶⁷ C. posadasii,⁴⁶⁷ ⁴⁶⁸ Cryptococcus neoformans,¹ ⁷ ³⁰ ⁵¹ ⁵⁵ ¹⁰² ¹⁰⁷ ³⁵⁹ and Histoplasma capsulatum.⁸ ⁹ ⁵¹ ¹⁰⁰ May be active in vitro against some strains of C. gattii,⁴⁴⁹ ⁴⁵⁰ but there is in vitro evidence that fluconazole may be less active against C. gattii than some other azoles (e.g., itraconazole, posaconazole, voriconazole).⁴⁴⁹
Fluconazole generally is inactive against Aspergillus in vitro.⁵¹ ¹⁰¹ Inactive against Malassezia pachydermatis¹¹ and Scopulariopsis, including S. acremonium and S. brevicaulis.³⁶⁶ Although a few strains of Penicillium marneffei may be inhibited in vitro by fluconazole concentrations,⁴⁶⁹ ⁴⁷⁰ most strains tested are resistant to the drug.⁴⁷⁰
Candida and C. neoformans with decreased in susceptibility to fluconazole have been reported.²⁶⁵ ²⁶⁶ ²⁶⁷ ²⁷² ²⁷³ ²⁷⁵ ²⁸² ³⁴³ ³⁴⁶ Prolonged or intermittent use of oral fluconazole in immunocompromised patients has been suggested as a major contributing factor to emergence of fluconazole resistance in Candida.²⁶⁵ ²⁶⁶ ²⁶⁷ ²⁶⁹ ²⁷¹ ²⁷⁶ ²⁷⁸ ²⁸⁴ ²⁸⁵
Fluconazole-resistant fungi also may be cross-resistant to other azole antifungals (e.g., itraconazole, ketoconazole, posaconazole, voriconazole).⁵ ⁶ ⁶⁷ ⁸⁷ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁷⁸ ²⁶⁹ ²⁷⁵ ²⁷⁷ ²⁷⁸ ²⁷⁹ ³⁴⁶

Advice to Patients

Importance of completing full course of therapy.¹ An inadequate period of treatment may lead to recurrence of active infection.¹
When driving or operating machinery, patients receiving fluconazole should take into account that dizziness or seizures may occur occasionally.¹
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.¹
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹
Importance of advising patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Fluconazole
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	For suspension	50 mg/5 mL*	Diflucan	Pfizer
			Fluconazole for Oral Suspension
		200 mg/5 mL	Diflucan	Pfizer
			Fluconazole for Oral Suspension
	Tablets	50 mg*	Diflucan	Pfizer
			Fluconazole Tablets
		100 mg*	Diflucan	Pfizer
			Fluconazole Tablets
		150 mg*	Diflucan	Pfizer
			Fluconazole Tablets
		200 mg*	Diflucan	Pfizer
			Fluconazole Tablets

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Fluconazole in Dextrose
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV infusion only	2 mg/mL (200 or 400 mg) in 5.6% Dextrose*	Diflucan in Iso-osmotic Dextrose Injection (in Viaflex Plus [Baxter])	Pfizer
			Fluconazole in Iso-osmotic Dextrose Injection

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Fluconazole in Sodium Chloride
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV infusion only	2 mg/mL (200 or 400 mg) in 0.9% Sodium Chloride*	Diflucan in Iso-osmotic Sodium Chloride Injection (in glass and Viaflex Plus [Baxter])	Pfizer
			Fluconazole in Iso-osmotic Sodium Chloride Injection

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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410. Huttova M, Hartmanova I, Kralinsky K et al. Candida fungemia in neonates treated with fluconazole: report of forty cases, including eight with meningitis. Pediatr Infect Dis J. 1998; 17:1012-5. http://www.ncbi.nlm.nih.gov/pubmed/9849984?dopt=AbstractPlus

411. Robinson LG, Jain L, Kourtis AP. Persistent candidemia in a premature infant treated with fluconazole. Pediatr Infect Dis J. 1999; 18:735-7. http://www.ncbi.nlm.nih.gov/pubmed/10462351?dopt=AbstractPlus

412. Rotstein C, Bow EJ, Laverdiere M et al. Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. Clin Infect Dis. 1999; 28:331-40. http://www.ncbi.nlm.nih.gov/pubmed/10064252?dopt=AbstractPlus

413. Havlir DV, Dube MP, McCutchan JA et al. Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with AIDS. Clin Infect Dis. 1998; 27:1369-75. http://www.ncbi.nlm.nih.gov/pubmed/9868644?dopt=AbstractPlus

414. Mylonakis E, Flanigan TP. Editorial response: antifungal prophylaxis with weekly fluconazole for patients with AIDS. Clin Infect Dis. 1998; 27:1376-8. http://www.ncbi.nlm.nih.gov/pubmed/9868645?dopt=AbstractPlus

415. Gripshover BM, Valdez H, Salata RA et al. Withdrawal of fluconazole suppressive therapy for thrush in patients responding to combination antiviral therapy including protease inhibitors. AIDS. 1998; 12:2513-4. http://www.ncbi.nlm.nih.gov/pubmed/9875599?dopt=AbstractPlus

416. Saag MS, Cloud GA, Graybill JR et al. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. Clin Infect Dis. 1999; 28:291-6. http://www.ncbi.nlm.nih.gov/pubmed/10064246?dopt=AbstractPlus

417. Scher RK, Breneman D, Rich P et al. Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail. J Am Acad Dermatol. 1998; 38:S77-86.

418. Ling MR, Swinyer LJ, Jarratt MT et al. Once-weekly fluconazole (450 mg) for 4, 6, or 99 months of treatment for distal subungual onychomycosis of the toenail. J Am Acad Dermatol. 1998; 38:S95-102.

419. Elewski BE, Hay RJ. Update on the management of onychomycosis: highlights of the third annual international summit on cutaneous antifungal therapy. Clin Infect Dis. 1996; 23:305-13. http://www.ncbi.nlm.nih.gov/pubmed/8842269?dopt=AbstractPlus

420. Trepanier EF, Amsden GW. Current issues in onychomycosis. Ann Pharmacother. 1998; 32:204-14. http://www.ncbi.nlm.nih.gov/pubmed/9496407?dopt=AbstractPlus

421. Niewerth M, Korting HC. Management of onychomycosis. Drugs. 1999; 58:38:283-96.

422. Freifeld AG, Bow EJ, Sepkowitz KA et al. Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Disease Society of America. Clin Infect Dis. 2011; 52:e56-93 Updates may be available at IDSA website at www.idsociety.org.

424. Chapman SW, Dismukes WE, Proia LA et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2008; 46:1801-12. Updates may be available at IDSA website at www.idsociety.org. http://www.ncbi.nlm.nih.gov/pubmed/18462107?dopt=AbstractPlus

425. Pappas PG, Kauffman CA, Andes DR et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2015; :. Updates may be available at IDSA website at www.idsociety.org.

426. Galgiani JN, Ampel NM, Blair JE et al. Coccidioidomycosis. Clin Infect Dis. 2005; 41:1217-23. Updates may be available at IDSA website at www.idsociety.org. http://www.ncbi.nlm.nih.gov/pubmed/16206093?dopt=AbstractPlus

427. Perfect JR, Dismukes WE, Dromer F et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010; 50:291-322. Updates may be available at IDSA website at www.idsociety.org. http://www.ncbi.nlm.nih.gov/pubmed/20047480?dopt=AbstractPlus

428. Wheat LJ, Freifeld AG, Kleiman MB et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007; 45:807-25. Updates may be available at IDSA website at www.idsociety.org. http://www.ncbi.nlm.nih.gov/pubmed/17806045?dopt=AbstractPlus

429. Kauffman CA, Bustamante B, Chapman SW et al. Clinical practice guidelines for the management of sporotrichosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007; 45:1255-65. Updates may be available at IDSA website at www.idsociety.org. http://www.ncbi.nlm.nih.gov/pubmed/17968818?dopt=AbstractPlus

430. Powderly WG, Mayer KH, Perfect JR. Diagnosis and treatment of oropharyngeal candidiasis in patients infected with HIV: a critical reassessment. AIDS Res Hum Retroviruses. 1999; 15:1405-12. http://www.ncbi.nlm.nih.gov/pubmed/10555102?dopt=AbstractPlus

432. Cato A, Cao G, Hsu A et al. Evaluation of the effect of fluconazole on the pharmacokinetics of ritonavir. Drug Metab Dispos. 1997; 25:1104-6. http://www.ncbi.nlm.nih.gov/pubmed/9311629?dopt=AbstractPlus

433. Abbott Laboratories. Kaletra (lopinavir/ritonavir) tablet, film coated and solution prescribing information. North Chicago, IL; 2010 Jun.

434. Pfizer. Rescriptor (delavirdine mesylate) tablets prescribing information. New York, NY; 2008 May.

435. Boehringer Ingelheim. Viramune (nevirapine) tablets and oral suspension prescribing information. Ridgefield, CT; 2010 Jun.

436. . Antifungal drugs. Treat Guidel Med Lett. 2012; 10:61-8; quiz 69-70. http://www.ncbi.nlm.nih.gov/pubmed/22825657?dopt=AbstractPlus

438. Piscitelli SC, Kelly G, Walker RE et al. A multiple drug interaction study of stavudine with agents for opportunistic infections in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 1999; 43:647-50. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=89174&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/10049281?dopt=AbstractPlus

439. Hilbert J, Messig M, Kuye O et al. Evaluation of interaction between fluconazole and oral contraceptive in healthy women. Obstet Gynecol. 2001; 98:218-23. http://www.ncbi.nlm.nih.gov/pubmed/11506836?dopt=AbstractPlus

440. Panel on Opportunistic Infection in HIV-infected Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (September 17, 2015). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

441. Panel on Opportunistic Infection in HIV-exposed and HIV-infected children, US Department of Health and Human Services (HHS). Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected children: recommendations from the National Institutes of Health, Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics (Nov 6, 2013). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

442. Anon. Drugs for parasitic infections. Treat Guidel Med Lett. 2010; 8 (suppl). From the Medical Letter website. http://www.medletter.com

445. Boehringer Ingelheim. Aptivus (tipranavir) capsules and oral suspension prescribing information. Ridgefield, CT; 2010 Apr.

446. Bristol-Myers Squibb. Reyataz (atazanavir sulfate) capsules and oral powder prescribing information. Princeton, NJ; 2015 Sept.

447. Tibotec Therapeutics. Intelence (etravirine) tablets prescribing information. Raritan, NJ; 2010 Feb.

448. McMahon JH, Grayson ML. Torsades de pointes in a patient receiving fluconazole for cerebral cryptococcosis. Am J Health Syst Pharm. 2008; 65:619-23. http://www.ncbi.nlm.nih.gov/pubmed/18359968?dopt=AbstractPlus

449. Gomez-Lopez A, Zaragoza O, Dos Anjos Martins M et al. In vitro susceptibility of Cryptococcus gattii clinical isolates. Clin Microbiol Infect. 2008; 14:727-30. http://www.ncbi.nlm.nih.gov/pubmed/18558948?dopt=AbstractPlus

450. Okamoto K, Hatakeyama S, Itoyama S et al. Cryptococcus gattii genotype VGIIa infection in man, Japan, 2007. Emerg Infect Dis. 2010; 16:1155-7. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3321916&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/20587194?dopt=AbstractPlus

451. Grosse P, Tintelnot K, Söllner O et al. Encephalomyelitis due to Cryptococcus neoformans var gattii presenting as spinal tumour: case report and review of the literature. J Neurol Neurosurg Psychiatry. 2001; 70:113-6. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1763492&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/11118259?dopt=AbstractPlus

452. Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of CDC, the Infectious Diseases Society of America, and the American Society of Blood and Marrow Transplantation. MMWR Recomm Rep. 2000; 49(RR-10):1-125. http://www.cdc.gov/mmwr/PDF/rr/rr4910.pdf

453. Stemmer SM, Maor Y, Hardan I. Oral fluconazole for empiric treatment of prolonged fever in neutropenic patients: prospective study in 250 consecutive patients after stem cell transplantation. Am J Clin Oncol. 2004; 27:328-32. http://www.ncbi.nlm.nih.gov/pubmed/15289723?dopt=AbstractPlus

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455. Brown SJ. Efficacy of fluconazole for the treatment of onychomycosis. Ann Pharmacother. 2009; 43:1684-91. http://www.ncbi.nlm.nih.gov/pubmed/19776299?dopt=AbstractPlus

456. Roberts DT, Taylor WD, Boyle J et al. Guidelines for treatment of onychomycosis. Br J Dermatol. 2003; 148:402-10. http://www.ncbi.nlm.nih.gov/pubmed/12653730?dopt=AbstractPlus

457. de Berker D. Clinical practice. Fungal nail disease. N Engl J Med. 2009; 360:2108-16. http://www.ncbi.nlm.nih.gov/pubmed/19439745?dopt=AbstractPlus

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463. Drake LA, Dincehart SM, Farmer ER et al. Guidelines of care for superficial mycotic infections of the skin: pityriasis (tinea) versicolor. J Am Acad Dermatol. 1996; 34:287-9. http://www.ncbi.nlm.nih.gov/pubmed/8642095?dopt=AbstractPlus

464. Fisher BT, Chiller TM, Prasad PA et al. Hospitalizations for coccidioidomycosis at forty-one children’s hospitals in the United States. Pediatr Infect Dis J. 2010; 29:243-7. http://www.ncbi.nlm.nih.gov/pubmed/19934792?dopt=AbstractPlus

465. Drake KW, Adam RD. Coccidioidal meningitis and brain abscesses: analysis of 71 cases at a referral center. Neurology. 2009; 73:1780-6. http://www.ncbi.nlm.nih.gov/pubmed/19933980?dopt=AbstractPlus

466. Burwell LA, Park BJ, Wannemuehler KA et al. Outcomes among inmates treated for coccidioidomycosis at a correctional institution during a community outbreak, Kern County, California, 2004. Clin Infect Dis. 2009; 49:e113-9. http://www.ncbi.nlm.nih.gov/pubmed/19886797?dopt=AbstractPlus

467. Ramani R, Chaturvedi V. Antifungal susceptibility profiles of Coccidioides immitis and Coccidioides posadasii from endemic and non-endemic areas. Mycopathologia. 2007; 163:315-9. http://www.ncbi.nlm.nih.gov/pubmed/17484074?dopt=AbstractPlus

468. Cordeiro RA, Brilhante RS, Rocha MF et al. In vitro activities of caspofungin, amphotericin B and azoles against Coccidioides posadasii strains from Northeast, Brazil. Mycopathologia. 2006; 161:21-6. http://www.ncbi.nlm.nih.gov/pubmed/16389480?dopt=AbstractPlus

469. Sar B, Boy S, Keo C et al. In vitro antifungal-drug susceptibilities of mycelial and yeast forms of Penicillium marneffei isolates in Cambodia. J Clin Microbiol. 2006; 44:4208-10. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1698326&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/16971649?dopt=AbstractPlus

470. Imwidthaya P, Thipsuvan K, Chaiprasert A et al. Penicillium marneffei: types and drug susceptibility. Mycopathologia. 2001; 149:109-15. http://www.ncbi.nlm.nih.gov/pubmed/11307592?dopt=AbstractPlus

471. Healy CM, Baker CJ. Fluconazole prophylaxis in the neonatal intensive care unit. Pediatr Infect Dis J. 2009; 28:49-52. http://www.ncbi.nlm.nih.gov/pubmed/19106754?dopt=AbstractPlus

472. Aziz M, Patel AL, Losavio J et al. Efficacy of fluconazole prophylaxis for prevention of invasive fungal infection in extremely low birth weight infants. Pediatr Infect Dis J. 2010; 29:352-6. http://www.ncbi.nlm.nih.gov/pubmed/19934791?dopt=AbstractPlus

473. Manzoni P, Stolfi I, Pugni L et al. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med. 2007; 356:2483-95. http://www.ncbi.nlm.nih.gov/pubmed/17568029?dopt=AbstractPlus

474. Reed BN, Caudle KE, Rogers PD. Fluconazole prophylaxis in high-risk neonates. Ann Pharmacother. 2010; 44:178-84. http://www.ncbi.nlm.nih.gov/pubmed/20040701?dopt=AbstractPlus

475. Manzoni P, Mostert M, Jacqz-Aigrain E et al. The use of fluconazole in neonatal intensive care units. Arch Dis Child. 2009; 94:983-7. http://www.ncbi.nlm.nih.gov/pubmed/19723639?dopt=AbstractPlus

476. Gupta AK, Cooper EA, Montero-Gei F. The use of fluconazole to treat superficial fungal infections in children. Dermatol Clin. 2003; 21:537-42. http://www.ncbi.nlm.nih.gov/pubmed/12956206?dopt=AbstractPlus

477. Gupta AK, Ryder JE, Nicol K et al. Superficial fungal infections: an update on pityriasis versicolor, seborrheic dermatitis, tinea capitis, and onychomycosis. Clin Dermatol. 2003 Sep-Oct; 21:417-25.

478. Gupta AK, Cooper EA, Ryder JE et al. Optimal management of fungal infections of the skin, hair, and nails. Am J Clin Dermatol. 2004; 5:225-37. http://www.ncbi.nlm.nih.gov/pubmed/15301570?dopt=AbstractPlus

479. Finch JJ, Warshaw EM. Toenail onychomycosis: current and future treatment options. Dermatol Ther. 2007 Jan-Feb; 20:31-46.

480. Galanis E, Hoang L, Kibsey P et al. Clinical presentation, diagnosis and management of Cryptococcus gattii cases: Lessons learned from British Columbia. Can J Infect Dis Med Microbiol. 2009; 20:23-8. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2690522&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/20190892?dopt=AbstractPlus

481. Koks CH, Crommentuyn KM, Hoetelmans RM et al. The effect of fluconazole on ritonavir and saquinavir pharmacokinetics in HIV-1-infected individuals. Br J Clin Pharmacol. 2001; 51:631-5. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2014488&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/11422025?dopt=AbstractPlus

482. Ahonen J, Olkkola KT, Neuvonen PJ. Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. Eur J Clin Pharmacol. 1997; 51:415-9. http://www.ncbi.nlm.nih.gov/pubmed/9049584?dopt=AbstractPlus

483. Olkkola KT, Ahonen J, Neuvonen PJ. The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analg. 1996; 82:511-6. http://www.ncbi.nlm.nih.gov/pubmed/8623953?dopt=AbstractPlus

484. Hynninen VV, Olkkola KT, Leino K et al. Effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of s-(+)- and R-(-)-Ibuprofen. Antimicrob Agents Chemother. 2006; 50:1967-72. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1479148&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/16723553?dopt=AbstractPlus

485. Palkama VJ, Isohanni MH, Neuvonen PJ et al. The effect of intravenous and oral fluconazole on the pharmacokinetics and pharmacodynamics of intravenous alfentanil. Anesth Analg. 1998; 87:190-4. http://www.ncbi.nlm.nih.gov/pubmed/9661572?dopt=AbstractPlus

486. Kantola T, Backman JT, Niemi M et al. Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J Clin Pharmacol. 2000; 56:225-9. http://www.ncbi.nlm.nih.gov/pubmed/10952477?dopt=AbstractPlus

487. Kaukonen KM, Olkkola KT, Neuvonen PJ. Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174. Eur J Clin Pharmacol. 1998; 53:445-9. http://www.ncbi.nlm.nih.gov/pubmed/9551703?dopt=AbstractPlus

488. Cobb MN, Desai J, Brown LS et al. The effect of fluconazole on the clinical pharmacokinetics of methadone. Clin Pharmacol Ther. 1998; 63:655-62. http://www.ncbi.nlm.nih.gov/pubmed/9663180?dopt=AbstractPlus

489. Hallberg P, Martén L, Wadelius M. Possible fluconazole-fentanyl interaction-a case report. Eur J Clin Pharmacol. 2006; 62:491-2. http://www.ncbi.nlm.nih.gov/pubmed/16758267?dopt=AbstractPlus

490. Saari TI, Laine K, Neuvonen M et al. Effect of voriconazole and fluconazole on the pharmacokinetics of intravenous fentanyl. Eur J Clin Pharmacol. 2008; 64:25-30. http://www.ncbi.nlm.nih.gov/pubmed/17987285?dopt=AbstractPlus

491. Babalola CP, Kolade YT, Olaniyi AA et al. Effect of fluconazole on the pharmacokinetics of halofantrine in healthy volunteers. J Clin Pharm Ther. 2009; 34:677-82. http://www.ncbi.nlm.nih.gov/pubmed/20175801?dopt=AbstractPlus

492. Food and Drug Administration. FDA Drug Safety Communication: Use of long-term, high-dose Diflucan (fluconazole) during pregnancy may be associated with birth defects in infants. Rockville, MD; 2011 Aug 3. From FDA website. Accessed 2011 Aug 9. http://www.fda.gov/Drugs/DrugSafety/ucm266030.htm

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494. Lee BE, Feinberg M, Abraham JJ et al. Congenital malformations in an infant born to a woman treated with fluconazole. Pediatr Infect Dis J. 1992; 11:1062-4. http://www.ncbi.nlm.nih.gov/pubmed/1461702?dopt=AbstractPlus

495. Aleck KA, Bartley DL. Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am J Med Genet. 1997; 72:253-6. http://www.ncbi.nlm.nih.gov/pubmed/9332650?dopt=AbstractPlus

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498. Kathuria S, Singh PK, Sharma C et al. Multidrug-Resistant Candida auris Misidentified as Candida haemulonii: Characterization by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry and DNA Sequencing and Its Antifungal Susceptibility Profile Variability by Vitek 2, CLSI Broth Microdilution, and Etest Method. J Clin Microbiol. 2015; 53:1823-30. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4432077&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/25809970?dopt=AbstractPlus

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