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Diflucan

Pronunciation

Generic Name: Fluconazole
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

Introduction

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

Uses for Diflucan

Blastomycosis

Alternative for treatment of blastomycosis 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 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 (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 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 (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 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 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 425 and current CDC, NIH, and IDSA clinical practice guidelines for prevention and treatment of opportunistic infections in HIV-infected individuals available at 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

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

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 ,344 current IDSA clinical practice guidelines available at ,425 and current CDC, NIH, and IDSA clinical practice guidelines on prevention and treatment of opportunistic infections in HIV-infected individuals available at 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 426 and current CDC, NIH, and IDSA clinical practice guidelines on prevention and treatment of opportunistic infections in HIV-infected individuals available at 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 427 and current CDC, NIH, and IDSA clinical practice guidelines on prevention and treatment of opportunistic infections in HIV-infected individuals available at 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 428 and current CDC, NIH, and IDSA clinical practice guidelines on prevention and treatment of opportunistic infections in HIV-infected individuals available at 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 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 procedures425 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 422 425 for additional information on prevention of fungal infections in immunocompromised patients.

Diflucan 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 Clcr.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 Clcr >50 mL/minute and give 50% of the usual daily dose to those with Clcr ≤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 Clcr.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 Clcr.1 (See Renal Impairment under Dosage.)

Cautions for Diflucan

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 Clcr.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

Interactions for Diflucan

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

Diflucan 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 Clcr.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

For information on systemic interactions resulting from concomitant use, see Interactions.

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

AHFS DI Essentials. © Copyright 2017, Selected Revisions October 3, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

References

1. Pfizer. Diflucan (fluconazole) tablets, injection - for intravenous infusion only, and oral suspension prescribing information. New York, NY; 2014 Mar.

2. Saag MS, Dismukes WE. Azole antifungal agents: emphasis on new triazoles. Antimicrob Agents Chemother. 1988; 32:1-8. [PubMed 2831809]

3. Dismukes WE. Azole antifungal drugs: old and new. Ann Intern Med. 1988; 109:177-9. [PubMed 2839058]

4. Aberg JA, Price RW, Heeren DM et al. A pilot study of the discontinuation of antifungal therapy for disseminated cryptococcal disease in patients with acquired immunodeficiency syndrome, following immunologic response to antiretroviral therapy. J Infect Dis. 2002; 185:1179-82. [PubMed 11930330]

5. Rogers TE, Galgiani JN. Activity of fluconazole (UK 49,858) and ketoconazole against Candida albicans in vitro and in vivo. Antimicrob Agents Chemother. 1986; 30:418-22. [PubMed 3022641]

6. Warnock DW, Burcke J, Cope NJ et al. Fluconazole resistance in Candida glabrata. Lancet. 1988; 2:1310. [PubMed 2904031]

7. de Fernandez EP, Patino MM, Graybill JR et al. Treatment of cryptococcal meningitis in mice with fluconazole. J Antimicrob Chemother. 1986; 18:261-70. [PubMed 3019986]

8. Graybill JR, Palou E, Ahrens J. Treatment of murine histoplasmosis with UK 49,858 (fluconazole). Am Rev Respir Dis. 1986; 134:768-70. [PubMed 3021035]

9. Kobayashi GS, Travis S, Medoff G. Comparison of the in vitro and in vivo activity of the bis-triazole derivative UK 49,858 with that of amphotericin B against Histoplasma capsulatum. Antimicrob Agents Chemother. 1986; 29:660-2. [PubMed 3010852]

10. Odds FC, Cheesman SL, Abbott AB. Suppression of ATP in Candida albicans by imidazole and derivative antifungal agents. J Med Vet Med. 1985; 23:415-24.

11. Mickelsen PA, Viano-Paulson MC, Stevens DA et al. Clinical and microbiological features of infection with Malassezia pachydermatis in high-risk infants. J Infect Dis. 1988; 157:1163-8. [PubMed 3373021]

12. Humphrey MJ, Jevons S, Tarbit MH. Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans. Antimicrob Agents Chemother. 1985; 28:648-53. [PubMed 3004323]

13. Ebden P, Neill P, Farrow PR. Sputum levels of fluconazole in humans. Antimicrob Agents Chemother. 1989; 33:963-4. [PubMed 2548443]

14. Foulds G, Brennan DR, Wajszczuk C et al. Fluconazole penetration into cerebrospinal fluid in humans. J Clin Pharmacol. 1988; 28:363-6. [PubMed 2839557]

15. Tucker RM, Williams PL, Arathoon EG et al. Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis. Antimicrob Agents Chemother. 1988; 32:369-73. [PubMed 2835002]

16. Drew RH, Perfect JR, Gallis HA. Use of fluconazole in a patient with documented malabsorption of ketoconazole. Clin Pharm. 1988; 7:622-3. [PubMed 2844468]

17. Hanger DP, Jevons S, Shaw JTB. Fluconazole and testosterone: in vivo and in vitro studies. Antimicrob Agents Chemother. 1988; 32:646-8. [PubMed 2840013]

18. Devenport MH, Crook D, Wynn V et al. Metabolic effects of low-dose fluconazole in healthy female users and non-users of oral contraceptives. Br J Clin Pharmacol. 1989; 27:851-9. [PubMed 2547410]

19. Holmes J, Clements D. Jaundice in HIV positive haemophiliac. Lancet. 1989; 1:1027. [PubMed 2565508]

20. Purba HS, Back DJ. Effect of fluconazole (UK-49,858) on antipyrine metabolism. Br J Clin Pharmacol. 1986; 21:603P.

21. Ehninger G, Jaschonek K, Schuler U et al. Interaction of fluconazole with cyclosporin. Lancet. 1989; 2:104-5. [PubMed 2567846]

22. Sugar AM, Saunders C, Idelson BA et al. Interaction of fluconazole and cyclosporine. Ann Intern Med. 1989; 110:844. [PubMed 2540690]

23. Collignon P, Hurley B. Interaction between fluconazole and cyclosporin. Lancet. 1989; 2:867-8. [PubMed 2571795]

24. Collignon P, Hurley B, Mitchell D. Interaction of fluconazole with cyclosporin. Lancet. 1989; 1:1262. [PubMed 2566800]

25. Mitchell AS, Holland JT. Fluconazole and phenytoin: a predictable interaction. BMJ. 1989; 298:1315. [PubMed 2544241]

26. Kidd D, Ranaghan EA, Morris TCM. Hypokalaemia in patients with acute myeloid leukaemia after treatment with fluconazole. Lancet. 1989; 1:1017.

27. Anon. Cryptococcosis and AIDS. Lancet. 1988; 1:1434-6. [PubMed 2898587]

28. Sugar AM, Saunders C. Oral fluconazole as suppressive therapy of disseminated cryptococcosis in patients with acquired immunodeficiency syndrome. Am J Med. 1988; 85:481-9. [PubMed 2845779]

29. Dupont B, Drouhet E. Cryptococcal meningitis and fluconazole. Ann Intern Med. 1987; 106:778. [PubMed 3032037]

30. Byrne WR, Wajszczuk CP. Cryptococcal meningitis in the acquired immunodeficiency syndrome (AIDS): successful treatment with fluconazole after failure of amphotericin B. Ann Intern Med. 1988; 108:384-5. [PubMed 2829678]

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