VA Class:AM700

AHFS Class:

• Azoles 8:14.08

Generic Name(s):

• Fluconazole

Chemical Name:

• α-(2,4-Difluorophenyl)-α-(1 H -1,2,4-triazole-1-ylmethyl)-1 H -1,2,4-triazole-1-ethanol

Fluconazole, a synthetic triazole derivative, is an azole antifungal agent.1,5,51,68,84,124

Fluconazole is used in the treatment of various infections caused by Candida , including candidemia and disseminated candidiasis,1,2,51,64,68,124,322,324,331,394,410,411,425,436 oropharyngeal candidiasis,1,39,41,51,94,95,118,220,292,335,336,337,400,402,404,406,425,436,440,441 esophageal candidiasis,1,44,92,220,292,401,403,404,425,436,440,441 and vulvovaginal candidiasis.1,45,66,129,147,148,193,197,198,199,201,203,204,206,209,210,344,399,425,436,440

Fluconazole also is used for the treatment of cryptococcal meningitis1,30,31,32,33,65,93,143,144,145,152,153,292,427,436,440,441 and for the treatment of blastomycosis†,286,287,288,289,290,291,292,295,296,297,315,424,436 coccidioidomycosis†,54,97,115,125,220,292,298,299,300,315,316,426,436,440,441,464,465,466 and histoplasmosis†.312,313,316,428,436 Fluconazole has been used for the treatment of superficial fungal infections,3,51,99 dermatophytoses†,3,51,116,292,375,376,377,379,436,454 onychomycosis†,140,176,383,417,418,436,455,456,458,476,499,500 and pityriasis (tinea) versicolor.292,459,460,461,462,477,478 In addition, the drug is used for prevention of serious fungal infections (e.g., coccidioidomycosis, cryptococcosis, mucocutaneous candidiasis) in patients with human immunodeficiency virus (HIV) infection†,3,28,33,68,69,118,124,143,144,220,225,227,228,229,426,440,441 and for prevention of Candida infections in other immunocompromised individuals (e.g., cancer patients and bone marrow, hematopoietic stem cell†, and solid organ transplant recipients†).1,110,124,157,158,159,160,161,179,184,186,188,189,340,345,412,425,436,452

Prior to initiation of fluconazole therapy, appropriate specimens for fungal culture and other relevant laboratory studies (e.g., serology, histopathology) should be obtained in order to isolate and identify the causative organism(s).1 Fluconazole therapy may be started pending results of these in vitro tests; however, once results are available, therapy should be adjusted accordingly.1 If fluconazole in vitro susceptibility tests are performed, results should be interpreted cautiously since in vitro tests may not accurately reflect fluconazole's in vivo activity.2,3,7,9,51,55,56,58,59,77,78,80,87,88,98,107,108

Candida Infections

Candidemia and Disseminated Candida Infections

Fluconazole is used for the treatment of candidemia,1,124,322,324,331,394,410,411,425,436 disseminated candidiasis (e.g., chronic disseminated hepatosplenic infections),1,330,333,334,425 and other serious Candida infections, including urinary tract infections,1,37,49,64,94,425 peritonitis,1,36,47,64,68,94 meningitis,407,409,425 osteoarticular infections (e.g., osteomyelitis, septic arthritis),405,425 intravascular infections (e.g., endocarditis, implantable cardiac device infections),425 pneumonia,1,37,64,94 endophthalmitis,425 and neonatal candidiasis† (including CNS infections).292,425 The drug has been effective in the treatment of some Candida infections that did not respond to IV amphotericin B.64,67,83,118,405,411

While fluconazole may be better tolerated and easier to administer than IV amphotericin B, fluconazole-resistant strains of C. albicans are being isolated with increasing frequency from patients who have received prior fluconazole therapy (especially in HIV-infected patients) and some Candida infections (e.g., candidemia) are increasingly caused by strains that are intrinsically resistant to fluconazole (e.g., C. krusei ) or likely to be resistant or have reduced susceptibility to fluconazole (e.g., C. glabrata ).267,425 The choice of an antifungal for the treatment of candidemia or invasive Candida infections should 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 the treatment of candidemia in nonneutropenic patients or for empiric treatment of suspected invasive candidiasis† in nonneutropenic patients in intensive care units (ICUs), the Infectious Diseases Society of America (IDSA) recommends an IV echinocandin (anidulafungin, caspofungin, micafungin) for initial therapy.425 IDSA states that fluconazole (IV or oral) is an acceptable alternative for initial therapy in selected patients, including those who are not critically ill and are unlikely to have infections caused by fluconazole-resistant Candida .425 If echinocandin- and azole-resistant Candida are suspected, IV amphotericin B is recommended;425 IV amphotericin B also is a reasonable alternative when echinocandins and fluconazole cannot be used because of intolerance, limited availability, or resistance.425 IDSA states that transition from the echinocandin (or amphotericin B) to fluconazole can be considered (usually within 5-7 days) in patients who are clinically stable, have isolates susceptible to fluconazole (e.g., C. albicans ), and have negative repeat blood cultures after initial antifungal treatment.425 Although fluconazole has been considered the drug of choice for the treatment of infections caused by C. parapsilosis in nonneutropenic patients (based in part on concerns related to decreased in vitro susceptibility and resistance to echinocandins), IDSA states that there are no clinical studies to date indicating superiority of fluconazole over echinocandins for the treatment of C. parapsilosis infections.425

For the treatment of candidemia in neutropenic patients, IDSA recommends an IV echinocandin (anidulafungin, caspofungin, micafungin) or, alternatively, IV 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 and also can be used for step-down therapy during neutropenia in clinically stable patients who have fluconazole-susceptible isolates and documented bloodstream clearance.425 Voriconazole can be used as an alternative for initial therapy when broader antifungal coverage is required and also can be used as step-down therapy during neutropenia in clinically stable patients who have voriconazole-susceptible isolates and documented bloodstream clearance.425 For infections known to be caused by C. krusei , an echinocandin, amphotericin B, or voriconazole is recommended.425

For the treatment of disseminated candidiasis in neonates† (neonatal candidiasis), IV amphotericin B usually is the drug of choice.292,425 IDSA states that fluconazole is a reasonable alternative in those who have not been receiving fluconazole prophylaxis, and the American Academy of Pediatrics (AAP) states that fluconazole can be considered for step-down treatment after an initial response has been obtained with IV amphotericin B.292,425 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 Uses: Prevention of Candidiasis in Transplant Recipients, Cancer Patients, or Other Patients at High Risk.)

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

IDSA states that antifungal treatment is not recommended in patients with asymptomatic candiduria, unless there is a high risk of disseminated candidiasis (e.g., neutropenic patients, low birthweight infants [less than 1.5 kg], patients who will undergo urologic manipulations).425 These experts state that asymptomatic candiduria in neutropenic patients and low birthweight infants should be treated using regimens recommended for patients with candidemia and that patients undergoing urologic procedures who have asymptomatic candiduria should be treated with oral fluconazole or IV amphotericin B for several days before and after the procedures.425 For the treatment of symptomatic candiduria (e.g., cystitis, pyelonephritis, fungus balls) caused by fluconazole-susceptible Candida , fluconazole is the drug of choice.425 When fluconazole-resistant Candida (e.g., C. glabrata , C. krusei) are likely, IV amphotericin B or oral flucytosine is recommended for symptomatic cystitis, and IV amphotericin B (with or without oral flucytosine) or oral flucytosine alone is recommended for pyelonephritis and fungus balls.425

For the 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 that cannot be removed, long-term suppressive or maintenance therapy (secondary prophylaxis)† with fluconazole is recommended if the isolate is susceptible.425

For the 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 oral flucytosine) or an IV echinocandin (anidulafungin, caspofungin, micafungin) and follow-up treatment with fluconazole.425 If the isolate is susceptible, long-term suppressive or maintenance therapy (secondary prophylaxis)† with fluconazole is recommended to prevent recurrence in those with native valve endocarditis who cannot undergo valve replacement and in those with prosthetic valve endocarditis.425

Fluconazole has been used with good results in some patients with endophthalmitis† caused by Candida ,37,64,319 but treatment failures have been reported.318 Studies in rabbits indicate that fluconazole is distributed into the eye and that the drug inhibits growth of C. albicans in rabbit choroid-retina tissue and vitreous body when IV therapy is initiated within 24 hours postinoculation; the drug did not effectively inhibit growth of the organism when IV therapy was initiated 7 days postinoculation when the infection was well established.74 For the 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

Fluconazole is used prophylactically to reduce the incidence of candidiasis in bone marrow or hematopoietic stem cell transplant recipients† who are receiving chemotherapy or radiation therapy.1,110,124,157,158,159,160,161,179,184,186,188,189,425,436,452 The drug also has been used for primary prophylaxis of candidiasis in other patients considered at high risk for developing such infections (e.g., high-risk patients undergoing urologic procedures†, solid organ transplant recipients†, high-risk patients in ICUs†).96,110,116,124,425 (See Uses: Prevention of Candidiasis in Transplant Recipients, Cancer Patients, or Other Patients at High Risk.)

For additional information on management of candidemia and disseminated candidiasis, the current clinical practice guidelines from IDSA available at [Web] should be consulted.425

Oropharyngeal Candidiasis

Oral or IV fluconazole is used for the treatment of oropharyngeal candidiasis in immunocompromised adults with acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex (ARC), malignancy, or other serious underlying disease.39,40,41,92,95,124,335,336,337,400,402,404,406,425,436,440,441

Fluconazole appears to be at least as effective as and, in some cases, more effective than other antifungals used for initial treatment of oropharyngeal Candida infections39,335,336 and is considered a drug of choice for the treatment of moderate to severe disease.337,425,436,440,441 Fluconazole has produced clinical resolution of signs and symptoms of the infection in 79-100% of patients with oropharyngeal candidiasis;39,40,51,92,95,335,336,400 however, microbiologic cures generally have been obtained in 44-87% of patients and the rate of relapse may be high, especially in neutropenic patients.39,51,68,92,95,335,336,400 In a study in HIV-infected adults with oropharyngeal candidiasis, the response rate and mycologic eradication rate after 14 days of therapy were 100 and 75%, respectively, in those who received oral fluconazole (100 mg once daily) and were 65 and 20%, respectively, in those who received topical clotrimazole (10-mg oral lozenge 5 times daily).335 In another study, 14 days of therapy with oral fluconazole (100 mg once daily as an oral suspension) was more effective than 14 days of therapy with topical nystatin (500,000 units as an oral suspension 4 times daily).336 The mycologic cure rate was 60% in the fluconazole group and 6% in the nystatin group and the rate of relapse at day 42 was 27 and 11%, respectively.336

For the treatment of mild oropharyngeal candidiasis, IDSA recommends topical treatment with clotrimazole lozenges or miconazole buccal tablets;425 nystatin (oral suspension or tablets) is the recommended alternative.425 For moderate to severe disease, 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) are recommended as alternatives.425 Other alternatives for refractory oropharyngeal candidiasis are IV echinocandins (anidulafungin, caspofungin, micafungin) or IV amphotericin B.425

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

Routine long-term suppressive or maintenance therapy (secondary prophylaxis)† to prevent relapse or recurrence is not usually recommended in patients adequately treated for oropharyngeal candidiasis (including HIV-infected individuals), unless the patient has frequent or severe recurrences of oropharyngeal candidiasis.425,440 If secondary prophylaxis of oropharyngeal candidiasis is indicated, oral fluconazole is recommended;425,440 however, the potential for development of azole resistance should be considered.440,441

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

Esophageal Candidiasis

Oral or IV fluconazole is used for the treatment of esophageal candidiasis in adults with AIDS, malignancy, or other serious underlying disease, including progressive systemic sclerosis.44,173,401,403,404,425,436,440,441 Fluconazole appears to be at least as effective as and, in some cases, more effective than other antifungals used for initial treatment of esophageal Candida infections173 and is considered a drug of choice.337,425,436,440,441

In adults with esophageal candidiasis documented by endoscopy, fluconazole has produced clinical resolution of signs and symptoms of the infection in about 61-93% of patients.37,44,64,68,173 In one study in adults with esophageal candidiasis and progressive systemic sclerosis, fluconazole therapy produced mycologic cures in about 93% of patients within 2-4 weeks, but the relapse rate was almost 100% within 3 months after fluconazole therapy was discontinued.44

Esophageal candidiasis requires treatment with a systemic antifungal (not a topical antifungal).425,440,441

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

For the treatment of esophageal candidiasis in HIV-infected adults and adolescents, 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 in HIV-infected adults and adolescents, including fluconazole-refractory infections, these experts recommend posaconazole oral suspension or itraconazole oral solution;440 alternatives include an IV echinocandin (anidulafungin, caspofungin, micafungin), oral or IV voriconazole, or IV amphotericin B.440

Routine long-term suppressive or maintenance therapy (secondary prophylaxis)† to prevent relapse or recurrence is not usually recommended in patients adequately treated for esophageal candidiasis (including HIV-infected individuals) unless the patient has frequent or severe recurrences of esophageal candidiasis.425,440 If secondary prophylaxis of esophageal candidiasis is indicated, oral fluconazole is recommended425,440 and posaconazole oral suspension is a possible alternative;440 however, the potential for development of azole resistance should be considered.440,441

For additional information on management of esophageal candidiasis, the current clinical practice guidelines from IDSA available at [Web]425 and the current clinical practice guidelines from CDC, NIH, and IDSA on the prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]440,441 should be consulted.

Vulvovaginal Candidiasis

Oral fluconazole is used for the treatment of uncomplicated vulvovaginal candidiasis1,45,66,129,147,148,197,198,201,203,204,205,206,209,210,344,399,425,436,440 and for the treatment of complicated vulvovaginal candidiasis†344,348,349,425,436,440 in nonpregnant women.

Vulvovaginal candidiasis frequently occurs during pregnancy.344 CDC states that topical (intravaginal) azole antifungals (not oral fluconazole) should be used for the treatment of vulvovaginal candidiasis during pregnancy.344 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)

Uncomplicated Vulvovaginal Candidiasis

Oral fluconazole is effective for the treatment of uncomplicated vulvovaginal candidiasis when given as a single dose.344,440 A single 150-mg oral dose of fluconazole produces clinical cures (i.e., absence of vulvovaginal burning, itching, swelling, erythema, excoriation, dyspareunia, and/or ulceration and substantial decreases in vaginal discharge) 5-16 days after the dose in approximately 90-100% and mycologic cures in approximately 77-100% of nonpregnant women with uncomplicated vulvovaginal candidiasis.45,66,99,124,129,148,194,197,198,201,203,204,205,206,209,210,399 At 27-62 days after the single dose, clinical and mycologic cure rates are 61-90%, and the rate of relapse, reinfection, or recolonization is about 23%.1,45,66,124,129,147,194,201 Results of several studies in patients with uncomplicated vulvovaginal candidiasis suggest that a single 150-mg dose of oral fluconazole is as effective for this condition as multiple dose regimens of intravaginal clotrimazole,1,194,201,203,204,205,399 econazole,117,148,192,201 miconazole,1,117,201,206,210 or terconazole.117,201 In addition, the single-dose oral fluconazole regimen appears to be as effective for uncomplicated vulvovaginal candidiasis as oral itraconazole117,196,201,209 or oral ketoconazole.117,129,201

In controlled studies in patients with vulvovaginal candidiasis, clinical and mycologic cure rates at 14 and 30-35 days were similar in patients receiving oral fluconazole (given as a single 150-mg dose) compared with patients receiving intravaginal clotrimazole (given as a 100-mg vaginal tablet once daily for 7 days) or miconazole (given as a 100-mg vaginal cream once daily for 7 days).1,117,216 At 14 days, the clinical cure rate was reported to be about 95-96% with fluconazole and 95-97% with intravaginal clotrimazole or miconazole and the mycologic cure rate was reported to be 77-80% with fluconazole and 72-82% with intravaginal clotrimazole or miconazole.117,216 At 30-35 days, the clinical cure rate was reported to be about 69-75% with fluconazole and 72-80% with intravaginal clotrimazole or miconazole and the mycologic cure rate was reported to be 61-63% with fluconazole and 57-63% with intravaginal clotrimazole or miconazole.1,117,216

CDC, IDSA, and other clinicians recommend that uncomplicated vulvovaginal candidiasis (defined as vulvovaginal candidiasis that is mild to moderate, sporadic or infrequent, most likely caused by C. albicans , and occurring in immunocompetent women) in nonpregnant women should be treated with a topical (intravaginal) azole antifungal (e.g., butoconazole, clotrimazole, miconazole, terconazole, tioconazole) given in appropriate single-dose or short-course (1-3 days) regimens or, alternatively, oral fluconazole given in a single-dose regimen.344,348,349,350,352,425,436,440 These regimens generally have been associated with clinical and mycologic cure rates of 80-90% in otherwise healthy, nonpregnant women with uncomplicated infections.344,348,349,350,352 Some clinicians suggest that a single oral dose of fluconazole may offer some advantage over conventional intravaginal antifungal therapy45,46,51,116,195,197,198 since it ensures compliance and may reduce or eliminate concurrent rectal infections that may serve as a source of reinfection.45,46,66,195,196 In weighing the potential risks and benefits of oral versus intravaginal therapy, the potential for toxicity (e.g., hepatotoxicity) and drug interactions (see Drug Interactions) associated with oral therapy should be considered.344 The incidence of adverse effects is higher in patients receiving single oral doses of fluconazole compared with those receiving intravaginal antifungal therapy; and this also should be weighed carefully.1

Complicated and Recurrent Vulvovaginal Candidiasis

Oral fluconazole is used for the treatment of complicated vulvovaginal candidiasis†, including recurrent and severe infections.344,425,436,440 Complicated vulvovaginal candidiasis is defined as infections that are recurrent or severe, caused by Candida other than C. albicans , or occurring in women with underlying disease such as diabetes mellitus, debilitation, or immunocompromising conditions (e.g., HIV infection), or those receiving immunosuppressive therapy (e.g., corticosteroids).344,425 CDC recommends that vaginal cultures be obtained from women with complicated vulvovaginal candidiasis to confirm the clinical diagnosis and identify unusual species (e.g., C. glabrata ).344

Recurrent vulvovaginal candidiasis (usually defined as 4 or more episodes of symptomatic vulvovaginal candidiasis within a year) affects a small percentage of women (less than 5%).344,425 Although each individual episode caused by C. albicans may respond to a short course of intravaginal azole antifungal or oral fluconazole, some experts recommend a longer duration of initial therapy (e.g., 7-14 days of an intravaginal azole antifungal or a 3-dose regimen of oral fluconazole [100, 150, or 200 mg given every third day for a total of 3 doses]) to attempt mycologic remission before initiating a maintenance antifungal regimen.199,344,425 For the maintenance regimen, CDC and IDSA recommend oral fluconazole (100, 150, or 200 mg once weekly) for 6 months.344,425 If this regimen cannot be used, intermittent use of intravaginal treatments can be considered.344 These maintenance regimens can be effective in reducing recurrent infections; however, 30-50% of women will have recurrent disease once maintenance therapy is discontinued.344 Women with recurrent infections who are symptomatic and remain culture-positive despite maintenance antifungal therapy should be managed in consultation with a specialist.344

Severe vulvovaginal candidiasis (i.e., extensive vulvar erythema, edema, excoriation, and fissure formation) usually has a lower clinical response rate to short courses of intravaginal or oral antifungal therapy.344 CDC and IDSA recommend that severe vulvovaginal candidiasis be treated with either 7-14 days of an intravaginal azole antifungal or a 2-dose regimen of oral fluconazole (150 mg repeated 3 days later).344,425

HIV-infected women have higher rates of vaginal Candida colonization, and symptomatic vulvovaginal candidiasis may occur more frequently and be more severe than in women without HIV infection.344,352,353 However, because there is no evidence to date that HIV-infected women have a lower response rate to intravaginal or oral antifungal regimens than other women,352,425 CDC, IDSA, and other clinicians recommend that treatment of vulvovaginal candidiasis in HIV-infected women should be the same as that in women without HIV infection.344,352,425,440 Routine long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent relapse or recurrence of vulvovaginal candidiasis is not usually recommended in HIV-infected or other women unless the patient has recurrent or severe infections.344,440 If secondary prophylaxis or maintenance therapy of vulvovaginal candidiasis is indicated, oral fluconazole (150 or 200 mg once weekly or 100 mg 3 times weekly) is recommended.344,425,440

Recurrent vulvovaginal candidiasis rarely may be caused by resistant strains of C. albicans or, more commonly, by other Candida with reduced susceptibility to azole antifungals (e.g., C. glabrata ).344,350,352,354,355,356,357,425 It has been suggested that repeated treatment of recurrent vulvovaginal candidiasis with intravaginal azole antifungals and widespread and/or injudicious use of these agents for self-medication of vulvovaginal candidiasis may favor the selection of Candida that are resistant to azole antifungals.350,352,354,355,356,357,425 Optimum therapy for the treatment of vulvovaginal candidiasis caused by Candida other than C. albicans has not been determined.344 CDC recommends 7-14 days of therapy with an antifungal (oral or intravaginal) other than fluconazole.344 If recurrence occurs, alternatives include topical (intravaginal) boric acid (600-mg gelatin capsule once daily for 14 days; no FDA-labeled preparation commercially available in the US).344,425 Referral to a specialist is advised.344

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

Coccidioidomycosis

Oral fluconazole is used for the 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

Treatment of Coccidioidomycosis

Fluconazole is used for the treatment of coccidioidal pulmonary infections, meningitis, and disseminated (extrapulmonary) infections involving soft tissue or bones and joints.54,97,115,125,220,292,298,299,300,426,436,440,441,464,465,466

Antifungal treatment may not be necessary in patients with mild, uncomplicated coccidioidal pneumonia since such infections often are self-limited and may resolve spontaneously.292,426 However, antifungal treatment is recommended for patients with more severe or rapidly progressing coccidioidal 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 state that an oral azole (fluconazole or itraconazole) usually is recommended for initial treatment of symptomatic pulmonary coccidioidomycosis and chronic fibrocavitary or disseminated (extrapulmonary) coccidioidomycosis.292,426,436,440 However, IV amphotericin B is recommended as an alternative and is preferred for initial treatment of severely ill patients (e.g., those with hypoxia or rapidly progressing disease), for immunocompromised individuals, or when azole antifungals cannot be used (e.g., pregnant women).292,426,440

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

For the treatment of diffuse pulmonary or disseminated coccidioidomycosis (nonmeningeal) 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 coccidioidomycosis, 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 the treatment of 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 the treatment of coccidioidal meningitis in HIV-infected adults, adolescents, and children or other individuals, IV or oral fluconazole (with or without intrathecal amphotericin B) is considered the regimen of choice.292,426,440,441 Oral itraconazole, oral posaconazole, and oral voriconazole are recommended as alternatives for the treatment of coccidioidal meningitis in adults and adolescents.426,440 Patients who do not respond to an azole antifungal alone may be candidates for intrathecal amphotericin B (with or without continued azole therapy) or IV amphotericin B used in conjunction with intrathecal amphotericin B;292,426,440,441 however, consultation with an expert who has experience in treating coccidioidal meningitis is recommended.292,440,441 Fluconazole has produced clinical and/or laboratory evidence of improvement when used alone or in conjunction with IV amphotericin B in adults with coccidioidal meningitis15,54,97,115,298 and has been used for the treatment of coccidioidal meningitis in both HIV-infected and HIV-negative individuals.298,464,465 Because fluconazole generally is well tolerated and exhibits favorable pharmacokinetics (e.g., is distributed into CSF in high concentrations following oral or IV administration), the drug is considered a good option for the treatment of coccidioidal meningitis.15,54,97,115,125,292,298,299,315,426,436,440,441

Primary Prophylaxis to Prevent First Episode of Coccidioidomycosis

Oral fluconazole is used in certain HIV-infected adults and adolescents for primary prophylaxis against coccidioidomycosis†.440

CDC, NIH, and IDSA recommend that HIV-infected adults and adolescents living 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) be tested annually for the disease using IgM or IgG serologic tests.440 Those with a newly positive IgM or IgG serologic test and CD4⁺ T-cell counts less than 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 Routine primary prophylaxis against coccidioidomycosis is not recommended in other HIV-infected adults and adolescents (e.g., those who reside in coccidioidomycosis endemic areas but do not have positive IgM or IgG serologic tests, those who reside in areas where the disease is not endemic)440 and is not recommended in HIV-infected infants and children.441

Prevention of Recurrence (Secondary Prophylaxis) of Coccidioidomycosis

Oral fluconazole is used for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of coccidioidomycosis†.426,440,441

Because of the risk of relapse, individuals who were treated for coccidioidal meningitis generally should receive long-term (life-long) secondary prophylaxis with oral fluconazole or oral itraconazole.426,440,441,465

CDC, NIH, and IDSA recommend that all HIV-infected adults, adolescents, and children who have been adequately treated for coccidioidomycosis should receive long-term secondary prophylaxis with oral fluconazole or oral itraconazole to prevent recurrence or relapse.440,441 Because HIV-infected adults and adolescents who had focal coccidioidal pneumonia and responded clinically to antifungal treatment may be at low risk for recurrence if their CD4⁺ T-cell count increases to greater than 250/mm³ in response to antiretroviral therapy, it may be reasonable to consider discontinuing secondary prophylaxis against coccidioidomycosis after 12 months, provided such individuals are monitored for recurrence (e.g., serial chest radiographs, coccidioidal serology).440 However, secondary prophylaxis should be continued indefinitely in HIV-infected adults and adolescents who were treated for more extensive coccidioidomycosis440 and in all HIV-infected children, regardless of the immune response to antiretroviral therapy.441 Consultation with an expert is recommended when making decisions regarding discontinuance of secondary prophylaxis against coccidioidomycosis.440

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

Cryptococcosis

Treatment of Cryptococcosis

Oral or IV fluconazole is used in immunocompetent or immunocompromised adults for the treatment of meningitis caused by Cryptococcus neoformans .1,28,29,30,31,32,33,93,292,303,304,305,306,310,311,427,436,440,441 Fluconazole is considered an alternative for initial (induction) therapy of cryptococcal infections involving the CNS, but is the drug of choice for follow-up (consolidation) therapy of these infections.28,29,31,32,65,93,116,152,220,292,303,305,306,427,436,440,441 Fluconazole also is used for the treatment of pulmonary cryptococcosis†, cryptococcemia†, and disseminated cryptococcal infections†.57,135,136,309,427

For the treatment of cryptococcal meningitis in HIV-infected adults, adolescents, and children, CDC, NIH, IDSA, and other clinicians state that the preferred regimen is initial (induction) therapy with IV amphotericin B (conventional or lipid formulation) 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

If an alternative regimen is necessary for the treatment of cryptococcal meningitis in HIV-infected adults, adolescents, and children who cannot receive the preferred regimen, some experts recommend initial (induction) and follow-up (consolidation) therapy with IV amphotericin B (conventional or lipid formulation) alone;427,441 induction therapy with IV amphotericin B (conventional or lipid formulation) given in conjunction with oral fluconazole, then consolidation therapy with oral fluconazole;427,440,441 induction 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 given 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 the treatment of cryptococcal CNS infections in organ transplant recipients, IDSA recommends initial (induction) therapy with IV amphotericin B liposomal or amphotericin B lipid complex given in conjunction with oral flucytosine for at least 2 weeks, then follow-up (consolidation) therapy with oral fluconazole given for 8 weeks.427 If the induction regimen does not include flucytosine, it should be continued for at least 4-6 weeks.427 For organ transplant recipients with mild to moderate pulmonary cryptococcosis (without diffuse pulmonary infiltrates) or 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, IDSA states that the preferred regimen for the treatment of cryptococcal meningitis is initial (induction) therapy with IV amphotericin B (conventional formulation) given in conjunction with oral flucytosine for at least 4 weeks (a 2-week period of induction therapy can be considered in those who are immunocompetent, are without uncontrolled underlying disease, and are at low risk for therapeutic failure), then follow-up (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 with cryptococcal meningitis.427

For the 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 the treatment of nonmeningeal, nonpulmonary cryptococcosis† in immunocompetent individuals if the infection occurs at a single site and fungemia is not present.427

Severe pulmonary cryptococcosis†, cryptococcemia†, and disseminated cryptococcal infections† in immunocompetent or immunosuppressed individuals should be treated using regimens recommended for cryptococcal meningitis.427

Clinical Experience

The relative efficacy of initial therapy with conventional IV amphotericin B (0.7 mg/kg daily) given with oral flucytosine (100 mg/kg daily) or placebo for 2 weeks followed by oral fluconazole (800 mg daily for 2 days, then 400 mg daily for 8 weeks) or oral itraconazole (600 mg daily for 3 days, then 400 mg daily for 8 weeks) has been evaluated in a double-blind multicenter trial in patients with AIDS-associated cryptococcal meningitis.307 At 2 weeks, CSF cultures were negative in 60% of those who received amphotericin B with flucytosine compared with 51% of those who received amphotericin B alone.307 The clinical response to oral fluconazole or oral itraconazole for follow-up therapy was similar, but the rate of CSF sterilization at 10 weeks was higher in those who received fluconazole (72%) compared with those who received itraconazole (60%).307

Fluconazole has been effective in the treatment of acute cryptococcal meningitis in some patients who failed to respond to amphotericin B therapy.30,32,93,304 However, there is some evidence that fluconazole may be less effective than amphotericin B during early therapy of acute cryptococcal meningitis in patients with AIDS and may produce slower sterilization of CSF.116,145,152,220 In a randomized, multicenter study comparing IV amphotericin B (mean dosage of 0.4-0.5 mg/kg daily for 10 weeks with or without concomitant oral flucytosine) with oral fluconazole (400 mg in the first day and 200-400 mg thereafter for 10 weeks) in AIDS patients with cryptococcal meningitis, therapy was effective in 40% of patients receiving amphotericin B and in 34% of those receiving fluconazole.152 Although overall mortality between patients receiving amphotericin B and patients receiving fluconazole was similar (14% in patients receiving amphotericin B versus 18% in patients receiving fluconazole), mortality was higher during the first 2 weeks of therapy in patients receiving fluconazole (15% versus 8% in those receiving amphotericin B).152 CSF cultures were positive for an average of about 42 or 64 days in patients receiving amphotericin B or fluconazole, respectively.152 In another study comparing amphotericin B (0.7 mg/kg daily for 1 week, followed by this dose 3 times weekly for 9 weeks combined with flucytosine 150 mg/kg daily) with oral fluconazole (400 mg daily for 10 weeks) in a limited number of AIDS patients with cryptococcal meningitis, initial therapy was effective in all patients receiving amphotericin B but in only 43% of patients receiving fluconazole; CSF cultures were positive for an average of about 16 and 41 days in patients receiving these respective therapies.145 While patient groups in this study were similar with respect to severity of cryptococcal infection, the helper/inducer (CD4⁺, T4⁺) T-cell count was lower in the fluconazole group, confounding interpretation.145

Primary Prophylaxis to Prevent First Episode of Cryptococcosis

Although there is some evidence that primary prophylaxis with fluconazole or itraconazole can reduce the frequency of cryptococcal disease in HIV-infected adults who have CD4⁺ T-cell counts less than 100/mm³,440,441 primary prophylaxis against cryptococcal disease in HIV-infected adults, adolescents, and children is not recommended in the US because of the relative infrequency of cryptococcal disease, lack of survival benefits associated with such prophylaxis, possibility of drug interactions, potential antifungal resistance, and cost.427,440,441

Some experts recommend routine testing for cryptococcal antigen (CrAg) in all newly diagnosed HIV-infected individuals if they have CD4⁺ T-cell counts of 100/mm³ or lower.440

Prevention of Recurrence (Secondary Prophylaxis) of Cryptococcosis

Oral fluconazole is used for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of cryptococcosis†.292,427,440,441

CDC, NIH, and IDSA recommend that all HIV-infected adults, adolescents, and children who have been adequately treated for cryptococcus should receive secondary prophylaxis to prevent recurrence.427,440,441 Oral fluconazole is the drug of choice for secondary prophylaxis of cryptococcosis in HIV-infected adults, adolescents, and children;427,440,441 some experts suggest that oral itraconazole is an alternative in those who cannot tolerate fluconazole,427,441 but the drug may be less effective than fluconazole in preventing relapse of cryptococcosis.427,440,441 Conventional 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

There is some evidence that the risk for recurrence of cryptococcosis is low in HIV-infected individuals who have been treated successfully with antifungal therapy, remain asymptomatic with regard to signs and symptoms of cryptococcosis, and have a sustained increase in CD4⁺ T-cell counts in response to antiretroviral therapy.440 CDC, NIH, and IDSA state that consideration can be given to discontinuing secondary prophylaxis against cryptococcosis in HIV-infected adults, adolescents, and children 6 years of age or older who are asymptomatic for cryptococcosis and have received secondary antifungal prophylaxis (maintenance therapy) for at least 1 year, are receiving antiretroviral therapy, have had undetectable or low plasma HIV RNA levels for at least 3 months, and have CD4⁺ T-cell counts of 100/mm³ or greater.427,440,441 If secondary prophylaxis against cryptococcosis is discontinued, the patient should be followed closely and serial cryptococcal serum antigen tests performed.427 These experts state that secondary prophylaxis against cryptococcosis should be reinitiated if the CD4⁺ T-cell count decreases to less than 100/mm³427,440,441 and/or the serum cryptococcal antigen titer increases.427

Maintenance therapy (secondary prophylaxis) with oral fluconazole also is 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

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

Cryptococcus gattii Infections

Although data are limited, CDC, NIH, and IDSA state that recommendations for the treatment of CNS, pulmonary, or disseminated infections caused by Cryptococcus gattii and recommendations for maintenance therapy (secondary prophylaxis) of C. gattii infections are the same as the recommendations for C. neoformans infections.427,440 IDSA states that single, small cryptococcoma may be treated with oral fluconazole; however, induction therapy with a regimen of IV amphotericin B (conventional formulation) and oral flucytosine given for 4-6 weeks, followed by consolidation therapy with fluconazole given for 6-18 months should be considered for very large or multiple cryptococcomas caused by C. gattii .427 Regimens that include IV amphotericin B (conventional or liposomal formulations), oral flucytosine, and fluconazole have been effective in a few patients with CNS infections known to be caused by C. gattii .450,451,480

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 Spectrum.)

Blastomycosis

Oral fluconazole has been used in the treatment of blastomycosis† caused by Blastomyces dermatitidis .292,286,287,288,289,290,291,292,424,436 Oral itraconazole and IV amphotericin B are the drugs of choice for the treatment of blastomycosis.289,296,297,315,316,424,436 Although oral fluconazole is considered an alternative for the treatment of blastomycosis,424,436 it may be less effective and should be used only when the drugs of choice are contraindicated or cannot be used.424

IV amphotericin B generally is the drug of choice for initial treatment of severe blastomycosis, especially infections involving the CNS, and for initial treatment of presumptive blastomycosis in immunocompromised patients, including HIV-infected individuals.290,296 Oral itraconazole is the preferred azole antifungal for the treatment of mild to moderate pulmonary blastomycosis or mild to moderate disseminated blastomycosis (without CNS involvement) and also is the preferred azole antifungal for follow-up therapy in patients with more severe infections after an initial response has been obtained with IV amphotericin B.289,291,295,296,315,424,436

For the treatment of CNS blastomycosis, IDSA recommends initial treatment with IV amphotericin B, followed by an oral azole antifungal.424 Although oral fluconazole, oral itraconazole, or oral voriconazole can be used for follow-up treatment of CNS blastomycosis, the most appropriate azole for such treatment is unclear.424 Azole antifungals should not be relied on for initial treatment of CNS blastomycosis.424 The fact that treatment failures have been reported when an oral antifungal (e.g., ketoconazole) was used in the treatment of cutaneous or pulmonary blastomycosis in patients who had asymptomatic or subclinical CNS involvement at the time of the initial diagnosis should be considered when selecting an antifungal for patients with blastomycosis.293,294

For additional information on management of blastomycosis, the current clinical practice guidelines from IDSA available at [Web] should be consulted.424

Histoplasmosis

Although oral fluconazole has been used with some success for the treatment of histoplasmosis† caused by Histoplasma capsulatum ,312,313,315,436 it may be less effective than itraconazole312,428,440,441 and fluconazole-resistant H. capsulatum have developed in some HIV-infected patients who failed to respond to the drug.428

The drugs of choice for the treatment of histoplasmosis, including histoplasmosis in HIV-infected individuals, are IV amphotericin B or oral itraconazole.292,315,316,428,436,440,441 IV amphotericin B is preferred for initial treatment of severe, life-threatening histoplasmosis, especially in immunocompromised patients such as those with HIV infection.292,220,313,315,316,428,436,440,441 Oral itraconazole generally is used for initial treatment of less severe disease (e.g., mild to moderate acute pulmonary histoplasmosis, chronic cavitary pulmonary histoplasmosis) and as follow-up therapy in the treatment of severe infections after a response has been obtained with IV amphotericin B.292,315,316,428,440,441 Other azole antifungals (fluconazole, ketoconazole, posaconazole, voriconazole) are considered second-line alternatives to itraconazole, but can be considered in patients who have less severe disease and cannot tolerate itraconazole.428,436,440,441

In HIV-infected adults and adolescents, oral itraconazole is the drug of choice when primary prophylaxis is indicated to prevent initial episodes of histoplasmosis428,440 and also is the drug of choice for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of histoplasmosis in HIV-infected adults, adolescents, and children.436,440,441 Although fluconazole may be less effective, some experts state that it can be considered an alternative for secondary prophylaxis against histoplasmosis in HIV-infected adults, adolescents, and children when itraconazole cannot be used.440,441

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

Sporotrichosis

Fluconazole has been used as an alternative agent for the treatment of lymphocutaneous and cutaneous sporotrichosis† caused by Sporothrix schenckii .429,436

IV amphotericin B usually 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 the 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 the treatment of cutaneous and lymphocutaneous sporotrichosis,429,436 it may be less effective than itraconazole292,429 and should be used only if the patient cannot tolerate itraconazole or other alternatives (oral terbinafine, oral potassium iodide, local hyperthermia).429

Fluconazole should not be used for the treatment of pulmonary, osteoarticular, or meningeal sporotrichosis.429

For additional information on management of sporotrichosis, the current clinical practice guidelines from IDSA available at [Web] should be consulted.429

Dermatophytoses

Oral fluconazole has been used in the 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 pedis374,436,478 ) caused by Epidermophyton , Microsporum , or Trichophyton .

Oral fluconazole (3-6 mg/kg daily for 2-6 weeks) has been effective for the treatment of tinea capitis† in children 1.5-16 years of age,375,377,379 and has resulted in a clinical and mycologic cure in about 88-90% of patients.375,379 For the treatment of tinea corporis†, tinea cruris†, or tinea pedis† in adults, oral fluconazole has been effective when given in a once-weekly regimen (150 mg once weekly for 2-6 weeks),373,374,378 and there is evidence that this once-weekly regimen is as effective as a once-daily regimen of the drug (50 mg once daily) for the treatment of these infections.374 Results of a randomized study indicate that the eradication rate at the end of treatment in patients with tinea corporis or tinea cruris is 82-88% in those receiving the once-weekly regimen or 94-100% in those receiving the once-daily regimen; at 1-month follow-up, the overall eradication rates were 91-100 or 91-94%, respectively.374

Tinea corporis and tinea cruris generally can be effectively treated using a topical antifungal; however, an oral antifungal regimen may be necessary if the disease is extensive, dermatophyte folliculitis is present, the infection is chronic or does not respond to topical therapy, or the patient is immunocompromised or has coexisting disease.292,380,381,382,383,384,386,478 Tinea capitis and tinea barbae generally are treated using an oral antifungal regimen.292,372,381,383,385,387,478 While topical antifungals usually are effective for the treatment of uncomplicated tinea manuum and tinea pedis,292,381,382,384,386,436,419,478 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

Oral fluconazole has been used for the treatment of onychomycosis†.140,383,417,418,420,436,455,456,458,476,477,499,500

Selection of the most appropriate regimen for treatment of onychomycosis depends on the severity and extent of nail involvement, organisms involved, reported cure rates, adverse effects, drug interactions, cost, and patient and clinician preference.499,500 Onychomycosis generally is 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 has been recommended as an alternative in patients those who cannot tolerate terbinafine or itraconazole,383,436,455,458 but may be less effective than the other oral antifungals.140,176,420,421,455,476,477,479,500

Pityriasis (Tinea) Versicolor

Oral fluconazole has been used in the 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.292,459,460,463,477,478

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

Fluconazole is used prophylactically to reduce the incidence of candidiasis 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 or radiation therapy†.1,110,124,126,157,158,159,160,161,179,180,182,183,184,185,186,188,189,207,340,341,342,345,412,422,425,436,452 Fluconazole also is used to prevent Candida infections in high-risk patients undergoing urologic procedures†425 and for prevention of invasive candidiasis in high-risk patients in ICUs†425 and in low birthweight neonates† at high risk.292,425,471,472,473,474,475

There is some evidence that fluconazole prophylaxis in transplant and cancer patients can reduce the frequency of oropharyngeal and/or systemic candidiasis during the period prior to neutrophil recovery.96,124,126,157,158,159,179,180,183,184,340,345 In addition, fluconazole prophylaxis may reduce the need for empiric antifungal therapy in such patients.184,185 Efficacy of oral fluconazole (400 mg once daily) for prophylaxis against fungal infections in neutropenic patients has been evaluated in a randomized, placebo-controlled study involving 274 cancer patients 18-80 years of age receiving cytotoxic chemotherapy or conditioning therapy for BMT.412 While the percentage of patients not requiring empiric therapy with IV amphotericin B therapy was similar in both groups (57% of those receiving fluconazole and 50% of those receiving placebo required no such therapy), complete success without fungal colonization was achieved in 37% of those receiving fluconazole and 20% of those receiving placebo.412 In addition, there was a lower incidence of superficial fungal infections in those receiving fluconazole (7%) than in those receiving placebo (18%), and only 3% of those receiving fluconazole developed definite invasive fungal infections compared with 17% of those receiving placebo.412 While fluconazole prophylaxis did not affect the overall mortality rate, intent-to-treat analysis indicates that the number of deaths attributable to definite invasive fungal infection was lower in the fluconazole group (1 of 15) than in the placebo group (6 of 15).412

Use of primary antifungal prophylaxis in cancer patients undergoing myelosuppressive therapy or patients undergoing BMT or solid organ transplantation has been controversial,96,110,111,116,157,159,180,182,191 particularly since such prophylaxis may predispose the patient to colonization with resistant fungi and/or result in the emergence of highly resistant organisms.96,110,111,116,154,155,159,180,182,191 Some retrospective studies have shown an increased risk of colonization with C. krusei in BMT recipients and in neutropenic patients who received fluconazole prophylaxis;154,155,189 in one study, about 41% of patients receiving fluconazole had colonization with C. krusei compared with 17% of those not receiving fluconazole.154

IDSA and other experts recommend primary prophylaxis against Candida infections in neutropenic patients when the risk of invasive candida infection is substantial (e.g., allogeneic HSCT recipients, patients with acute leukemia undergoing intensive remission-induction or salvage-induction chemotherapy) and states that an azole antifungal (fluconazole, itraconazole, posaconazole, voriconazole) or IV echinocandin (caspofungin or micafungin) can be used.422,452 These experts state that antifungal prophylaxis is not recommended if the anticipated duration of neutropenia is less than 7 days.422 If primary prophylaxis is used to prevent invasive candidiasis in high-risk adults in ICUs, IDSA recommends fluconazole as the drug of choice and IV echinocandins (anidulafungin, caspofungin, micafungin) as alternatives.425

Fluconazole 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 Although such prophylaxis has been controversial since there is concern that it may be associated with emergence of resistant fungi or increased colonization with fluconazole-resistant Candida ,292,471,472 there is some evidence from retrospective and randomized controlled trials that fluconazole prophylaxis in low birthweight neonates 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 (less than 1 kg) in nurseries that have high rates of neonatal invasive candidiasis.292,425

For additional information on prevention of fungal infections in neutropenic patients, the current clinical practice guidelines from IDSA available at [Web] should be consulted.422,425

Administration

Fluconazole is administered orally or by IV infusion.1

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

Oral Administration

Fluconazole may be given orally without regard to meals.1

Fluconazole powder for oral suspension should be reconstituted at the time of dispensing by adding 24 mL of distilled or purified water to the container labeled as containing 0.35 or 1.4 g of the drug to provide a suspension containing 50 or 200 mg/5 mL, respectively.1 The bottle should be shaken vigorously to suspend the powder;1 in addition, the suspension should be shaken well just prior to administration.1

IV Administration

IV infusions of fluconazole should be administered once daily at a rate not exceeding 200 mg/hour.1 Fluconazole injections for IV infusion should be inspected visually for discoloration and particulate matter prior to administration whenever solution and container permit.1 The injection for IV infusion should be discarded if the solution is cloudy or precipitated or if the seal is not intact.1

Viaflex^® Plus containers of fluconazole should be checked for minute leaks by firmly squeezing the bag.1 The injection should be discarded if the container seal is not intact or leaks are found or if the solution is cloudy or contains a precipitate.1 Additives should not be introduced into the plastic injection container.1 The injection 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

Dosage

Oral and IV dosage of fluconazole are identical.1

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

Dosage of the drug should be based on the type and severity of the infection, identity of the causative organism, and the patient's renal function and response to therapy.1,124 Fluconazole therapy should be continued until clinical parameters and/or laboratory tests indicate that active fungal infection has subsided; an inadequate period of treatment may lead to recurrence of active infection.1,124

Adult Dosage

Candidemia and Disseminated Candida Infections

For the treatment of systemic candidiasis (candidemia, disseminated candidiasis, pneumonia), the manufacturer states that adults have received fluconazole in a dosage of 400 mg daily.1

For the treatment of urinary tract infections or peritonitis, the manufacturer states that fluconazole has been given in a dosage of 50-200 mg daily.1

For the treatment of candidemia in nonneutropenic or neutropenic adults, the Infectious Diseases Society of America (IDSA) recommends a loading dose of 800 mg (12 mg/kg) of fluconazole on the first day of therapy, followed by 400 mg (6 mg/kg) daily with treatment continued for 2 weeks after documented clearance of Candida from the bloodstream, resolution of candidemia symptoms, and resolution of neutropenia.425

For the treatment of chronic disseminated candidiasis (hepatosplenic) in adults who are clinically stable, IDSA recommends that fluconazole be given in a dosage of 400 mg (6 mg/kg) daily.425 These experts recommend that severely ill patients receive IV amphotericin B initially for several weeks, then follow-up therapy with fluconazole in a dosage of 400 mg (6 mg/kg) daily.425 Antifungal treatment should be continued until lesions resolve (usually several months) and should be continued through periods of immunosuppression.425

For the treatment of CNS candidiasis, IDSA recommends an initial regimen of IV amphotericin B (with or without oral flucytosine) for several weeks, then follow-up therapy with fluconazole in a dosage of 400-800 mg (6-12 mg/kg) daily.425 Antifungal treatment should be continued until signs and symptoms, CSF abnormalities, and radiologic abnormalities have resolved.425

When fluconazole is used for the treatment of urinary tract infections caused by fluconazole-susceptible Candida , IDSA recommends that adults receive fluconazole in a dosage of 200 mg (3 mg/kg) daily for 2 weeks for the treatment of symptomatic cystitis or 200-400 mg (3-6 mg/kg) daily for 2 weeks for the treatment of pyelonephritis.425

For the treatment of osteoarticular infections caused by Candida , IDSA recommends that adults receive fluconazole in a dosage of 400 mg (6 mg/kg) daily given for 6-12 months in those with osteomyelitis or for 6 weeks in those with septic arthritis.425 If septic arthritis involved a prosthetic device that cannot be removed, long-term suppressive or maintenance therapy (secondary prophylaxis)† with fluconazole given in a dosage of 400 mg (6 mg/kg) daily is recommended to prevent recurrence.425

For the treatment of endocarditis (native or prosthetic valve) or implantable cardiac device infections caused by Candida , IDSA recommends an initial regimen of IV amphotericin B (with or without oral flucytosine) or an IV echinocandin (anidulafungin, caspofungin, micafungin), then follow-up treatment with fluconazole in a dosage of 400-800 mg (6-12 mg/kg) daily.425 Antifungal treatment should be continued for at least 6 weeks after valve replacement surgery.425 Long-term suppressive or maintenance therapy (secondary prophylaxis)† with fluconazole given in dosage of 400-800 mg (6-12 mg/kg) daily is recommended to prevent recurrence in those with native valve endocarditis who cannot undergo valve replacement and in those with prosthetic valve endocarditis.425

For the treatment of chorioretinitis (with or without vitritis) caused by Candida , IDSA recommends a loading dose of 800 mg (12 mg/kg) of fluconazole on the first day of therapy, followed by 400-800 mg (6-12 mg/kg) daily for at least 4-6 weeks.425 If there is macular involvement, intravitreal amphotericin B or voriconazole may also be indicated.425

Oropharyngeal Candidiasis

For the treatment of oropharyngeal candidiasis, the manufacturer recommends that fluconazole be given in a dosage of 200 mg as a single dose on day 1, then 100 mg once daily.1 Although clinical evidence of oropharyngeal candidiasis generally resolves within several days following initiation of fluconazole therapy, the manufacturer recommends that the drug be continued for at least 2 weeks to decrease the likelihood of relapse.1

For the treatment of moderate to severe oropharyngeal candidiasis, IDSA recommends that adults receive fluconazole in a dosage of 100-200 mg daily for 7-14 days.425

For the treatment of oropharyngeal candidiasis in adults and adolescents with human immunodeficiency virus (HIV) infection, the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and IDSA recommend that fluconazole be given in a dosage of 100 mg daily for 7-14 days.440

If long-term suppressive or maintenance therapy (secondary prophylaxis)† with fluconazole is used in HIV-infected adults and adolescents with frequent or severe recurrences of oropharyngeal candidiasis, a dosage of 100 mg once daily or 3 times weekly is recommended.440 Although only limited data are available regarding the safety of discontinuing secondary prophylaxis against oropharyngeal candidiasis in HIV-infected individuals, consideration can be given to discontinuing such prophylaxis in HIV-infected adults if the CD4⁺ T-cell count increases to greater than 200/mm³ in response to antiretroviral therapy.440

Esophageal Candidiasis

For the treatment of esophageal candidiasis, the manufacturer recommends that adults receive fluconazole in a dosage of 200 mg as a single dose on day 1, followed by 100 mg once daily.1 Dosages up to 400 mg once daily may be used depending on the patient's response.1 The manufacturer recommends that fluconazole therapy be continued for a minimum of 3 weeks and for at least 2 weeks after symptoms have resolved.1

For the treatment of esophageal candidiasis, IDSA recommends that adults receive fluconazole in a dosage of 200-400 mg (3-6 mg/kg) daily for 14-21 days.425

For the treatment of esophageal candidiasis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend that adults receive fluconazole in a dosage of 100 mg (up to 400 mg) once daily for 14-21 days.440

If long-term suppressive or maintenance therapy (secondary prophylaxis)† with fluconazole is used in HIV-infected adults and adolescents with frequent or severe recurrences of esophageal candidiasis, a dosage of 100-200 mg daily440 or, alternatively, 100-200 mg 3 times weekly is recommended.425 Although only limited data are available regarding the safety of discontinuing secondary prophylaxis against esophageal candidiasis in HIV-infected individuals, consideration can be given to discontinuing such prophylaxis in these HIV-infected adults if the CD4⁺ T-cell count increases to greater than 200/mm³ in response to antiretroviral therapy.440

Vulvovaginal Candidiasis

For the treatment of uncomplicated vulvovaginal candidiasis in nonpregnant women, the usual dosage of oral fluconazole is a single (1 day only) 150-mg oral dose.1,344,425,436

For the treatment of recurrent vulvovaginal candidiasis† in nonpregnant women, CDC recommends that 100, 150, or 200 mg of oral fluconazole be given every third day for 3 doses (i.e., days 1, 4, and 7) to attempt mycologic remission.344 Then, to prevent recurrence, a maintenance regimen of 100, 150, or 200 mg of oral fluconazole should be given once weekly for 6 months.344 IDSA recommends a maintenance regimen of 150 mg of oral fluconazole given once weekly for 6 months.425

For the treatment of severe vulvovaginal candidiasis† in nonpregnant women, CDC recommends a 2-dose regimen of oral fluconazole (two 150-mg doses given 72 hours [3 days] apart).344 IDSA recommends that 150 mg of oral fluconazole be given once every 72 hours for a total of 2 or 3 doses.425

For the treatment of uncomplicated vulvovaginal candidiasis or recurrent or severe vulvovaginal candidiasis† in nonpregnant HIV-infected women, CDC, NIH, and IDSA recommend the same regimens used for the treatment of these infections in women without HIV infection.440

Blastomycosis

If oral fluconazole is used as an alternative for the treatment of mild to moderate pulmonary or mild to moderate disseminated blastomycosis† without CNS involvement in adults, IDSA recommends a dosage of 400-800 mg daily.424

If oral fluconazole is used for follow-up therapy in the treatment of CNS blastomycosis† in adults after an initial regimen of IV amphotericin B given for 4-6 weeks, IDSA recommends that fluconazole be given in a dosage of 800 mg daily for at least 12 months and until CSF abnormalities have resolved.424

Coccidioidomycosis

For the treatment of coccidioidomycosis†, IDSA and others recommend that adults receive oral or IV fluconazole in a dosage of 400-800 mg once daily.426,436 For diffuse pneumonia or disseminated coccidioidomycosis (nonmeningeal), fluconazole usually is used in conjunction with IV amphotericin B or as follow-up after an initial regimen of IV amphotericin B.426 The duration of treatment for uncomplicated coccidioidal pneumonia usually is 3-6 months;426 the total duration of treatment for diffuse pneumonia and chronic progressive fibrocavitary pneumonia usually is at least 1 year.426

For the treatment of mild coccidioidomycosis (e.g., focal pneumonia) in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend that oral fluconazole be given in a dosage of 400 mg once daily.440 This dosage also is recommended for the treatment of severe, nonmeningeal coccidioidomycosis (e.g., diffuse pulmonary infection) in HIV-infected adults and adolescents, but the drug usually is used in conjunction with IV amphotericin B or as follow-up after an initial regimen of IV amphotericin B.440

For the treatment of coccidioidal meningitis† in HIV-infected adults and adolescents or other individuals, a fluconazole dosage of 400-800 mg once daily has been recommended.298,300,315,436,440 Concomitant intracisternal, intraventricular, or intrathecal amphotericin B therapy has been used in some patients.97,426 Consultation with an expert who has experience in treating coccidioidal meningitis is recommended.440

When primary prophylaxis against coccidioidomycosis† is indicated in HIV-infected adults and adolescents who live in areas endemic for coccidioidomycosis, have a newly positive IgM or IgG serologic test suggesting imminent active disease, and have CD4⁺ T-cell counts less than 250/mm³, CDC, NIH, and IDSA recommend that fluconazole be given in a dosage of 400 mg once daily.440

For long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of coccidioidomycosis† in HIV-infected adults and adolescents who have been adequately treated for the disease, CDC, NIH, and IDSA recommend that fluconazole be given in a dosage of 400 mg once daily.440 In HIV-infected adults and adolescents with a history of adequately treated focal coccidioidal pneumonia, discontinuance of secondary prophylaxis against coccidioidomycosis can be considered after 12 months if they are receiving antiretroviral therapy and have CD4⁺ T-cell counts of 250/mm³ or greater.440 Such patients should be monitored for recurrence (e.g., serial chest radiographs, coccidioidal serology).440 In HIV-infected adults and adolescents with a history of adequately treated diffuse pulmonary or disseminated coccidioidomycosis (including meningeal infections), secondary prophylaxis against coccidioidomycosis should be continued lifelong, regardless of antiretroviral therapy or immune reconstitution.440

Cryptococcosis

For the treatment of cryptococcal meningitis, the manufacturer recommends that adults receive fluconazole in a dosage of 400 mg as a single dose on day 1, followed by 200-400 mg once daily for 10-12 weeks after the CSF is sterile.1 Some evidence suggests that the 400-mg dosage is more effective than lower dosage in the treatment of this infection.93,116,117

For the treatment of cryptococcal meningitis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend a regimen than includes initial (induction) therapy with IV amphotericin B and oral flucytosine given for at least 2 weeks, then follow-up (consolidation) therapy with oral fluconazole given in a dosage of 400 mg (6 mg/kg) once daily and continued for at least 8 weeks.427,440

For the treatment of cryptococcal meningitis in HIV-infected adults who cannot receive flucytosine, IDSA recommends induction therapy with IV amphotericin B given in conjunction with oral or IV fluconazole 800 mg daily for at least 2 weeks, then consolidation therapy with oral fluconazole given in a dosage of 800 mg daily and continued for at least 8 weeks.427 For the treatment of cryptococcal meningitis in HIV-infected adults who cannot receive IV amphotericin B or oral flucytosine, IDSA states that fluconazole can be given as monotherapy in a dosage of 800 mg daily or higher (preferably 1.2 g daily or higher) and continued for 10-12 weeks.427 Although fluconazole dosage as high as 2 g daily has been used, this dosage may be associated with toxicity.427 If high fluconazole dosage is used, the daily dosage should be given in divided doses to minimize GI toxicity.427

For the treatment of cryptococcal meningitis in HIV-infected adults and adolescents who cannot receive amphotericin B, CDC, NIH, and IDSA recommend induction therapy with oral or IV fluconazole given in a dosage of 400 or 800 mg daily in conjunction with oral flucytosine for at least 2 weeks, then consolidation therapy with oral fluconazole given in a dosage of 400 mg daily and continued for at least 8 weeks.440 Alternatively, if oral or IV fluconazole is used alone for induction therapy, these experts recommend that the drug be given in a dosage of 1.2 g daily for at least 2 weeks, then consolidation therapy with oral fluconazole be given in a dosage of 400 mg daily and continued for at least 8 weeks.440

For the treatment of CNS cryptococcosis in adult organ transplant recipients, IDSA recommends induction therapy with IV amphotericin B liposomal or IV amphotericin B lipid complex 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 For the treatment of mild to moderate pulmonary cryptococcosis (without pulmonary infiltrates) or other mild to moderate non-CNS disease, IDSA recommends fluconazole in a dosage of 400 mg (6 mg/kg) daily for 6-12 months.427

For the treatment of cryptococcal meningitis in immunocompetent adults without HIV infection who are not transplant recipients, IDSA recommends induction therapy with IV amphotericin B in conjunction with oral flucytosine given for at least 4 weeks, then consolidation therapy with oral fluconazole given in a dosage of 400 mg daily and continued for 8 weeks.427 If the patient is immunocompetent without uncontrolled, underlying disease and is 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 administered in a dosage of 800 mg (12 mg/kg) daily should be given for 8 weeks.427

For the treatment of mild to moderate pulmonary cryptococcosis† (nonmeningeal) in immunocompetent or immunocompromised adults, IDSA recommends that fluconazole be given in a dosage of 400 mg (6 mg/kg) daily for 6-12 months.427 This same dosage can be used for the treatment of nonpulmonary cryptococcosis at a single site† (nonmeningeal).427

Severe pulmonary cryptococcosis†, cryptococcemia†, or disseminated cryptococcosis† in immunocompetent or immunocompromised adults should be treated using a regimen recommended for adults with cryptococcal meningitis.427

For long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of cryptococcosis† in adult organ transplant recipients or immunocompetent adults without HIV infection who are not transplant recipients who have been adequately treated for CNS cryptococcosis, the usual dosage of oral fluconazole is 200-400 mg once daily for 6-12 months.427

For long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of cryptococcosis† in HIV-infected adults and adolescents or other adults and adolescents who have had documented, adequately treated cryptococcal meningitis, the usual dosage of oral fluconazole is 200 mg once daily.427,440 Secondary prophylaxis should be initiated after the primary infection has been adequately treated and usually is continued for at least 1 year.440 Consideration can be given to discontinuing secondary prophylaxis against cryptococcosis in HIV-infected adults who are asymptomatic for cryptococcosis and have received secondary antifungal prophylaxis for at least 1 year, are receiving antiretroviral therapy, have had undetectable or low plasma HIV RNA levels for at least 3 months, and have CD4⁺ T-cell counts of 100/mm³ or greater.427,440 Secondary prophylaxis against cryptococcosis should be reinitiated if the CD4⁺ T-cell count decreases to less than 100/mm³427,440,441 and/or the serum cryptococcal antigen titer increases.427

Histoplasmosis

If fluconazole is used for the treatment of histoplasmosis†, a dosage of 400-800 mg once daily is recommended.315,316,428,436 A fluconazole regimen of 800 mg daily given for 12 weeks, then 400 mg daily has been used.428

If fluconazole is used as an alternative for treatment of less severe histoplasmosis† in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend a dosage of 800 mg daily.440

If fluconazole is used as an alternative for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of histoplasmosis† in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend a dosage of 400 mg daily.440 Consideration can be given to discontinuing secondary prophylaxis against histoplasmosis in HIV-infected adults and adolescents who have received secondary antifungal prophylaxis for at least 1 year, have negative fungal blood cultures and serum histoplasma antigen levels less than 2 ng/mL, have been receiving antiretroviral therapy for at least 6 months, and have CD4⁺ T-cell counts of 150/mm³ or greater.440 Secondary prophylaxis against histoplasmosis should be reinitiated if the CD4⁺ T-cell count decreases to less than 150/mm³.440

Sporotrichosis

If oral fluconazole is used for the treatment of lymphocutaneous and cutaneous sporotrichosis†, a dosage of 400-800 mg once daily is recommended in adults when other drugs cannot be used.429,436

Dermatophytoses

For the treatment of dermatophytoses†, oral fluconazole has been given in a dosage of 150 mg once weekly for 2-6 weeks.373,374,378 For the treatment of tinea corporis that involves small, well-defined lesions, some clinicians recommend that oral fluconazole be given in a dosage of 250 mg once weekly for 2-4 weeks.383

For the treatment of tinea pedis†, some clinicians recommend that oral fluconazole be given in a dosage of 150-200 mg once weekly for 1-8 weeks.383,436

Onychomycosis

For the treatment of onychomycosis†, oral fluconazole has been given in a dosage of 100-450 mg once weekly for 2-12 months.140,176,383,417,421,455,479,499,500 Some clinicians recommend that oral fluconazole be given in a dosage of 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

For the treatment of pityriasis (tinea) versicolor†, adults have received oral fluconazole as a single 400-mg dose.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

For the prevention of candidiasis in bone marrow transplant (BMT) recipients, the recommended dosage of fluconazole is 400 mg once daily.1,157,340 In patients in whom severe granulocytopenia (neutrophil count less than 500/ mm³) is anticipated, fluconazole therapy should be initiated several days before expected onset of neutropenia and should be continued for 7 days after the neutrophil count exceeds 1000/mm³.1 Antifungal prophylaxis is not usually recommended if the anticipated duration of neutropenia is less than 7 days.422

For the prevention of Candida infections in hematopoietic stem cell transplant (HSCT) recipients†, adults and adolescents should receive oral or IV fluconazole in a dosage of 400 mg once daily.452 Fluconazole prophylaxis should be initiated on the day of transplantation (i.e., day 0) and continued until engraftment occurs (i.e., approximately 30 days after HSCT) or until 7 days after the neutrophil count exceeds 1000/mm³.452

If fluconazole is used for prophylaxis against candidiasis in high-risk patients in intensive care units (ICUs)† with a known high incidence of invasive candidiasis, IDSA states that the drug should be given in a dosage of 400 mg (6 mg/kg) once daily.425

Pediatric Dosage

The usual oral or IV dosage of fluconazole in pediatric patients ranges from 3-12 mg/kg once daily;1,292 dosages exceeding 600 mg daily are not recommended.1 The manufacturer states that a dosage of 3, 6, or 12 mg/kg daily in pediatric patients is equivalent to a dosage of 100, 200, or 400 mg daily, respectively, in adults.1 Some older children may have clearances similar to those of adults.1

Based on limited pharmacokinetic data, the manufacturer recommends that premature neonates (gestational age 26-29 weeks) receive the usual pediatric dosage once every 72 hours during the first 2 weeks of life and then the usual pediatric dosage once daily thereafter.1

Candidemia and Disseminated Candida Infections

The usual dosage of fluconazole for the treatment of systemic Candida infections in pediatric patients is 6-12 mg/kg daily.1,292

For the treatment of meningitis or septicemia caused by susceptible Candida , neonates and infants 3 months of age or younger† have received fluconazole in a dosage of 5-6 mg/kg once daily given orally or by IV infusion over 1 hour.394,409,410 In some neonates and infants with septicemia, an initial loading dose of 10 mg/kg was administered followed by 5 mg/kg once daily.392,394

If fluconazole is used as an alternative for the treatment of neonatal candidiasis†, IDSA and the American Academy of Pediatrics (AAP) recommend a dosage of 12 mg/kg daily for at least 3 weeks.292,425

Oropharyngeal Candidiasis

For the treatment of oropharyngeal candidiasis in pediatric patients, the recommended dosage of fluconazole is 6 mg/kg on day 1, followed by 3 mg/kg once daily.1,292 The manufacturer recommends that treatment be continued for a minimum of 2 weeks to decrease the likelihood of relapse.1

For the treatment of oropharyngeal candidiasis in HIV-infected infants and children, CDC, NIH, and IDSA recommend that fluconazole be given in a dosage of 6-12 mg/kg (up to 400 mg) once daily for 7-14 days.441

If long-term suppressive or maintenance therapy (secondary prophylaxis)† with fluconazole is used in HIV-infected infants and children with frequent or severe recurrences of oropharyngeal candidiasis, a dosage of 3-6 mg/kg (up to 200 mg) once daily is recommended.425,441 Limited data are available regarding the safety of discontinuing secondary prophylaxis against oropharyngeal candidiasis in HIV-infected individuals.441 In HIV-infected infants and children, consideration can be given to discontinuing such prophylaxis when the CD4⁺ T-cell count or percentage increases to CDC immunologic category 2 or 1.441

Esophageal Candidiasis

For the treatment of esophageal candidiasis in pediatric patients, the manufacturer recommends 6 mg/kg of fluconazole on day 1, followed by 3 mg/kg once daily.1,292 Dosage may be increased up to 12 mg/kg daily if necessary, based on the condition of the patient and the response to the drug.1 The manufacturer recommends that treatment be continued for a minimum of 3 weeks and for at least 2 weeks after symptoms have resolved.1

For the treatment of esophageal candidiasis in HIV-infected infants and children, CDC, NIH, and IDSA recommend that fluconazole be given in a dosage of 6-12 mg/kg (up to 600 mg) once daily for a minimum of 3 weeks and for at least 2 weeks after symptoms resolve.441

If long-term suppressive or maintenance therapy (secondary prophylaxis)† with fluconazole is used in HIV-infected infants and children with frequent or severe recurrences of esophageal candidiasis, a dosage of 3-6 mg/kg (up to 200 mg) once daily is recommended.425,440 Limited data are available regarding the safety of discontinuing secondary prophylaxis against esophageal candidiasis in HIV-infected individuals.441 In HIV-infected infants and children, consideration can be given to discontinuing such prophylaxis when the CD4⁺ T-cell count or percentage increases to CDC immunologic category 2 or 1.441

Coccidioidomycosis

For the treatment of mild to moderate coccidioidomycosis (nonmeningeal)† (e.g., focal pneumonia) in HIV-infected infants and children, CDC, NIH, and IDSA recommend that oral or IV fluconazole be given in a dosage of 6-12 mg/kg (up to 400 mg) once daily.441 If oral or IV fluconazole is used for the treatment of diffuse pulmonary or disseminated coccidioidomycosis (nonmeningeal)† in HIV-infected infants and children who cannot receive IV amphotericin B, these experts recommend a dosage of 12 mg/kg (up to 800 mg) once daily.441

For the treatment of coccidioidal meningitis† in HIV-infected infants and children, CDC, NIH, and IDSA recommend that oral or IV fluconazole be given in a dosage of 12 mg/kg (up to 800 mg) once daily.441 Consultation with an expert in treating coccidioidal meningitis is recommended.292

For prevention of recurrence (secondary prophylaxis) of coccidioidomycosis† in HIV-infected infants and children, CDC, NIH, and IDSA recommend that fluconazole be given in a dosage of 6 mg/kg (up to 400 mg) once daily.441 Secondary prophylaxis should be initiated after the primary infection has been adequately treated and continued indefinitely in HIV-infected infants and children, regardless of antiretroviral therapy or immune reconstitution.441

Cryptococcosis

The manufacturer recommends that cryptococcal meningitis in pediatric patients be treated with an initial 12-mg/kg dose on day 1, followed by 6 mg/kg once daily for 10-12 weeks after the CSF becomes culture negative.1 Dosage may be increased to 12 mg/kg daily if necessary based on the condition of the patient and the response to the drug.1

For the treatment of cryptococcal meningitis in HIV-infected infants and children, CDC, NIH, and IDSA recommend a regimen that includes induction therapy with IV amphotericin B given in conjunction with oral flucytosine for at least 2 weeks, then consolidation therapy with oral or IV fluconazole given in a dosage of 12 mg/kg on day 1 and then 10-12 mg/kg (up to 800 mg) once daily for at least 8 weeks.441

For the treatment of cryptococcal meningitis in HIV-infected infants and children who cannot receive IV amphotericin B, CDC, NIH, and IDSA recommend induction therapy with oral or IV fluconazole given in a dosage of 12 mg/kg on day 1 and 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 given in a dosage of 10-12 mg/kg (up to 800 mg) once daily for at least 8 weeks.441

For the treatment of localized cryptococcosis without CNS involvement† (e.g., isolated pulmonary disease), CDC, NIH, and IDSA recommend that HIV-infected infants and children receive fluconazole in a dosage of 12 mg/kg on day 1 and then 6-12 mg/kg (up to 600 mg) once daily.427,441 The duration of treatment depends on the clinical response and site and severity of infection.441 A duration of 6-12 months has been recommended.427

For the treatment of disseminated or severe pulmonary cryptococcosis without CNS involvement† in HIV-infected infants and children who cannot receive amphotericin B, CDC, NIH, and IDSA recommend that fluconazole be given in a dosage of 12 mg/kg on day 1 and then 6-12 mg/kg (up to 600 mg) once daily.441 The duration of treatment depends on the clinical response and site and severity of infection.441 A duration of 6-12 months has been recommended.427

For long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of cryptococcosis† in HIV-infected infants and children who have been treated for cryptococcal meningitis, fluconazole is given in a dosage of 6 mg/kg (up to 200 mg) once daily.441 Secondary prophylaxis should be initiated after the primary infection has been adequately treated and usually is continued for at least 1 year.441 Consideration can be given to discontinuing secondary prophylaxis against cryptococcosis in HIV-infected children 6 years of age or older who are asymptomatic for cryptococcosis, have received secondary prophylaxis for at least 1 year, are receiving antiretroviral therapy, have had undetectable or low plasma HIV RNA levels for at least 3 months, and have CD4⁺ T-cell counts of 100/mm³ or higher.441 Secondary prophylaxis against cryptococcosis should be reinitiated if the CD4⁺ T-cell count decreases to less than 100/mm³.441

Histoplasmosis

If oral fluconazole is used as an alternative for treatment of less severe histoplasmosis† in HIV-infected infants and children, CDC, NIH, and IDSA recommend a dosage of 3-6 mg/kg (up to 200 mg) once daily for acute primary pulmonary histoplasmosis.441

If oral fluconazole is used as an alternative for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of histoplasmosis† in HIV-infected infants and children, CDC, NIH, and IDSA recommend a dosage of 3-6 mg/kg (up to 200 mg) once daily.441 Consideration can be given to discontinuing secondary prophylaxis against histoplasmosis in HIV-infected infants and children who have received secondary prophylaxis for at least 1 year, have negative fungal blood cultures and serum histoplasma antigen levels less than 2 ng/mL, have been receiving antiretroviral therapy for at least 6 months, and have CD4⁺ T-cell percentage greater than 15% (CD4⁺ T-cell counts exceeding 150/mm³ in those 6 years of age or older).441 Secondary prophylaxis against histoplasmosis should be reinitiated if these parameters are not met.441

Dermatophytoses

For the treatment of tinea capitis† in children 1.5-16 years of age, oral fluconazole has been given in a dosage of 3-6 mg/kg daily for 2-6 weeks.375,377,379 AAP recommends a dosage of 6 mg/kg daily for 3-6 weeks.292

For the treatment of tinea corporis† or tinea cruris† in children, some clinicians recommend that oral fluconazole be given in a dosage of 150 mg once weekly for 2-6 weeks.476

For the treatment of tinea manuum† or tinea pedis† in children, some clinicians recommend that oral fluconazole be given in a dosage of 150 mg once weekly for 4-6 weeks.476

Onychomycosis

For the treatment of onychomycosis† in children, some clinicians recommend that oral fluconazole be given in a dosage of 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

Pityriasis (Tinea) Versicolor

For the treatment of pityriasis (tinea) versicolor†, children 11 years of age or older have received oral fluconazole as a single 400-mg dose.462 Alternatively, 150 mg has been given once weekly for 4 weeks.460,462

Prevention of Candida Infections in Hematopoietic Stem Cell Transplant Recipients

For the prevention of Candida infections in HSCT recipients†, children 6 months to 13 years of age should receive oral or IV fluconazole in a dosage of 3-6 mg/kg daily (maximum 600 mg daily).452 Fluconazole prophylaxis should be initiated on the day of transplantation (i.e., day 0) and continued until engraftment occurs (i.e., approximately 30 days after HSCT) or until 7 days after the neutrophil count exceeds 1000/mm³.452

Prevention of Candida Infections in Low Birthweight Neonates

For prophylaxis to reduce the incidence of invasive candidiasis in low birthweight neonates† at high risk, oral or IV fluconazole has been given in a variety of dosage regimens.425,471,472,473,474,475 If fluconazole prophylaxis is used in neonates at high risk, antifungal resistance, toxicity, and neurodevelopmental outcomes should be monitored.425

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

For prophylaxis in low birthweight neonates (less than 1 kg) at high risk, AAP recommends that fluconazole be initiated with a dose of 3 mg/kg given IV during the first 48-72 hours after birth, followed by 3 mg/kg IV twice weekly for 4-6 weeks or until IV access is no longer required for care.292

Dosage in Renal Impairment

In patients with impaired renal function receiving multiple doses, fluconazole dosage must be modified in response to the degree of impairment and should be based on the patient's measured or estimated creatinine clearance.1,124 The patient's creatinine clearance (Cl_cr) can be estimated by using the following formula:

Cl_cr male = [(140 - age) × weight (in kg)] / [72 × serum creatinine (in mg/dL)]

Cl_cr female = 0.85 × Cl_cr male

The manufacturer recommends that adults with impaired renal function receive an initial loading dose of 50-400 mg of fluconazole (based on the type of infection being treated), then patients with creatinine clearances exceeding 50 mL/minute should receive 100% of the usual daily dose and those with creatinine clearances of 50 mL/minute or less should receive 50% of the usual daily dose.1 Patients who are undergoing regular dialysis should receive 100% of the usual daily dose after each dialysis period;1 on days the patient is not receiving dialysis, reduced dosage based on creatinine clearance should be used.1 These dosage recommendations are based on the pharmacokinetics of the drug following multiple doses; further dosage adjustments may be necessary depending on the condition of the patient.1

The manufacturer states that modification of the recommended single-dose regimen of oral fluconazole for the treatment of vulvovaginal candidiasis is not necessary in patients with impaired renal function.1

The manufacturer states that the pharmacokinetics of fluconazole have not been studied in children with impaired renal function; recommendations for dosage reduction in such children should parallel those recommended for adults.1

Although fluconazole generally is well tolerated,1,2,15,28,29,30,31,33,37,39,40,43,51,57,61,62,64,68,124 there have been rare reports of serious hepatotoxicity (including some fatalities) in patients receiving the drug.1,254,255,256,257 Adverse effects have been reported in about 5-30% of patients receiving fluconazole for 7 days or longer1,61,64,68,94,124 and have been severe enough to require discontinuance of the drug in about 1-2.8% of patients.1,61,64,68,94,95,96,124,142 In addition, adverse effects have been reported in 26-31% of women receiving a single 150-mg oral dose of fluconazole for the treatment of vulvovaginal candidiasis.1

Evaluation of some adverse effects and establishment of a causal relationship to fluconazole have been difficult since the drug has been used in many patients with serious underlying diseases, including leukemia, cancer, and acquired immunodeficiency syndrome (AIDS), who were receiving multiple drugs concomitantly.37,64,65,94,95,96,142 In some cases, the underlying fungal infection being treated (e.g., meningitis) may have caused or contributed to the reported effect (e.g., nervous system effects).65,94 In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematologic function and hepatic abnormalities have been observed during treatment with fluconazole or comparative agents, but the clinical importance and relation to treatment is uncertain.1 The manufacturer states that adverse effects have been reported more frequently in patients with human immunodeficiency virus (HIV) infection than in patients without HIV infection; however, the proportion of patients requiring discontinuance of fluconazole because of severe adverse effects is similar in both groups.1

GI Effects

Mild to moderate nausea,1,2,18,28,32,37,39,40,62,64,65,66,68,92,94,95,96 vomiting,1,28,65,94,95,96 abdominal pain,1,28,46,64,66,68,94 and diarrhea1,64,92,94 have been reported in about 1.5-8.5% of patients receiving fluconazole.1,68,94 Only rarely were such adverse GI effects severe enough to require discontinuance of the drug.68,94 Flatus,28 bloating,32 dry mouth,1,40 hiccups,64 heartburn,66 and anorexia28,94 have been reported rarely. Adverse GI effects have been reported in about 15% of women receiving a single dose of fluconazole for the treatment of vulvovaginal candidiasis;1,216 abdominal pain, nausea, diarrhea, dyspepsia, and dysgeusia occurred in about 6, 7, 3, 1, and 1% of such women, respectively.1

Dermatologic and Sensitivity Reactions

Rash,1,28,32,62,64,65,94,142 including diffuse rash accompanied by eosinophilia,94 and pruritus28,62,163 have been reported in up to about 5% of patients receiving fluconazole.1,94 Exfoliative skin disorders have been reported rarely in patients with serious underlying disease (principally AIDS or malignancy) receiving fluconazole;1,124,142 fatalities have been reported.1 Stevens-Johnson syndrome,1,93,150 which can be fatal,1 also has been reported in patients receiving fluconazole. However, a definite causal relationship between exfoliative skin eruptions and the drug has not been established, since most patients were receiving multiple drugs concomitantly with fluconazole.1,124 Acute generalized exanthematous pustulosis and increased sweating also have been reported during postmarketing experience.1

Anaphylaxis1,163 has been reported rarely in patients receiving fluconazole. Angioedema and anaphylactic reactions have been reported rarely in women who received a single 150-mg oral dose of fluconazole for the treatment of vulvovaginal candidiasis.1

Hepatic Effects

Serious hepatic reactions (e.g., necrosis, clinical hepatitis, cholestasis, fulminant hepatic failure) have been reported rarely in patients receiving fluconazole therapy.1,124,216,253,254,255,256,257 The manufacturer states that 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 been reported.1,124,216,254,255,256,257 Fatalities principally have occurred in patients with serious underlying disease (e.g., AIDS, malignancy) who were receiving fluconazole concomitantly with other drugs;1,124,216,253,254,255,256,257 however, at least one fatality involved an immunocompetent geriatric individual with renal impairment who developed fulminant hepatic necrosis within 10 days after fluconazole therapy was initiated.256

Mild, transient increases (1.5-3 times the upper limit of normal) in serum concentrations of AST (SGOT),19,28,39,64,68,94 ALT (SGPT),19,28,39,62,64,68,94,96 alkaline phosphatase,28,37,44,64,68γ-glutamyltransferase (GGT, γ-glutamyl transpeptidase, GGTP),37,64,68 and bilirubin19,68 have been reported in about 5-7%37,68,94 of patients receiving fluconazole.15,19,28,32,37,39,44,65,68,149 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 or more times the upper limit of normal), which required discontinuance of the drug, have been reported in about 1% of patients receiving fluconazole.1,28,32,65,68 Any patient who develops abnormal liver function test results while receiving fluconazole should be closely monitored for the development of more severe hepatic injury.1 (See Cautions: Precautions and Contraindications.)

Cardiovascular Effects

Prolonged QT interval has occurred in patients receiving azole antifungals.1,448 Prolonged QT interval and torsades de pointes have been reported rarely during postmarketing surveillance in patients receiving fluconazole.1,448 Most reported cases involved seriously ill patients with multiple confounding risk factors (e.g., structural heart disease, electrolyte abnormalities, concomitant drugs) that may have contributed to these events.1,448

Nervous System Effects

Dizziness1,18,28,40,94 and headache1,18,68,94 have been reported in up to about 2% of patients receiving fluconazole.1,68,94 Somnolence,1,18 insomnia,1 delirium/coma,94 dysesthesia,94 psychiatric disturbances,94 malaise,1,94 asthenia,1 paresthesia of hands and feet,1,163 tremor,1 and fatigue1,18,94 have been reported rarely. Seizures1,32,94 also have been reported and have occurred in at least one AIDS patient immediately following administration of a single 100-mg oral dose of the drug.32 Adverse nervous system effects have been reported in about 14-20% of women receiving a single dose of fluconazole for the treatment of vulvovaginal candidiasis;1 headache and dizziness occurred in about 13 and 1% of such women, respectively.1

Hematologic Effects

Eosinophilia has been reported in some patients receiving fluconazole.28,94 Anemia,94 leukopenia,1,94 neutropenia,94,142 and thrombocytopenia1,28,94,252 also have been reported. In at least one AIDS patient, thrombocytopenia occurred during fluconazole therapy and resolved following discontinuance of the drug.28 Severe thrombocytopenia that required treatment and necessitated discontinuance of fluconazole therapy also has been reported.252

Endocrine Effects

Studies using usual dosages of fluconazole have not shown evidence of adverse effects related to possible inhibition of testosterone or steroid synthesis.2,3,15,17,18,39,51,64,91 In one study in healthy premenopausal women receiving fluconazole, there was no effect on serum estradiol concentrations or on serum cortisol stimulation response.18 Results of studies in men receiving oral fluconazole dosages of 25-400 mg once daily for up to 30 days indicate that serum testosterone concentrations are unaffected by the drug.17,64 The manufacturer states that in healthy adults who receive fluconazole dosages of 200-400 mg once daily for up to 14 days, there are only small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, or ACTH-stimulated cortisol response.1

Other Adverse Effects

Fever,1,64,94 edema,64,163 pleural effusion,64 oliguria,64 hypotension,163 arthralgia/myalgia,1,94 and finger stiffness have been reported rarely in patients receiving fluconazole.64

Hypokalemia,26,94 which required potassium replacement therapy and/or discontinuance of fluconazole, has occurred occasionally, including in several neutropenic patients with acute myeloid leukemia.26 Increased serum creatinine and BUN concentrations also have been reported.94 Mild (1.5-2 times the upper limit of normal) increases in serum concentrations of creatine kinase (CK, creatine phosphokinase, CPK) have been reported in at least one patient with coccidioidal meningitis who received fluconazole concomitantly with intrathecal amphotericin B.15

Alopecia1,398 has been reported in patients receiving fluconazole. In a retrospective study of patients who received fluconazole (100-800 mg daily) for the treatment of systemic fungal infections, alopecia was reported in up to 20% of patients.398 Alopecia occurred in both men and women, usually was evident at about 3 months (range: 2 weeks to 7 months) after initiation of fluconazole therapy, and resolved in most patients within about 6 months after discontinuance of the drug or dosage reduction.398 Alopecia involved varying degrees of loss of scalp hair in all patients, but about 30% of patients also reported substantial loss of facial, axillary, pubic, leg, or chest hair.398

Precautions and Contraindications

Fluconazole is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1 Although information concerning cross-sensitivity between fluconazole and other triazole or imidazole antifungals is not available, the manufacturer states that fluconazole should be used with caution in individuals hypersensitive to other azoles.1

Fluconazole should be used with caution in patients with hepatic impairment.1 Although serious adverse hepatic effects have been reported only rarely with fluconazole, the possibility that these effects may occur during fluconazole therapy should be considered.1 (See Cautions: Hepatic Effects.) Fluconazole should be discontinued if signs and symptoms consistent with liver disease develop.1 If abnormal liver function test results occur during fluconazole therapy, the patient should be monitored for the development of more severe hepatic injury.1

Fluconazole should be used with caution in patients with renal impairment.1 (See Dosage and Administration: Dosage in Renal Impairment.)

Patients receiving fluconazole who drive or operative machinery should be cautioned to take into account that dizziness or seizures may occur occasionally.1

Diflucan^® powder for oral suspension contains sucrose and should not be used in patients with hereditary fructose, glucose-galactose malabsorption, and sucrase-isomaltase deficiency.1

Use of fluconazole may result in overgrowth of nonsusceptible strains of Candida other than C. albicans , including C. krusei .1 Superinfection caused by nonsusceptible strains of Candida has been reported in some patients receiving fluconazole; these patients may require alternative antifungal therapy.1

Because prolonged QT interval and torsades de pointes have occurred in patients receiving fluconazole, the drug should be used with caution in patients with potentially proarrhythmic conditions and risk factors for QT prolongation.1,448 (See Cautions: Cardiovascular Effects.) Concomitant use of fluconazole and drugs that are metabolized by the cytochrome P450 (CYP) isoenzyme 3A4 and are known to prolong the QT interval (e.g., astemizole [no longer commercially available in the US], cisapride, pimozide, quinidine) is contraindicated.1 (See Drug Interactions: Drugs that Prolong the QT Interval.)

Because potentially fatal exfoliative skin disorders have been reported rarely in patients with a serious underlying disease receiving fluconazole, the possibility that these effects can occur should be considered.1 (See Cautions: Dermatologic and Sensitivity Reactions.) If a patient with deep-seated fungal infection develops rash during fluconazole therapy, the patient should be monitored closely and the drug discontinued if the lesions progress.1,124 If rash that may be attributable to fluconazole develops in a patient with superficial fungal infections, the drug should be discontinued.1

Pediatric Precautions

The manufacturer states that efficacy of fluconazole in children younger than 6 months has not been established; however, the drug has been used safely and effectively in neonates and children younger than 6 months of age (including neonates as young as 1 day of age).1,391,392,394,408,409,410

Adverse effects reported in children receiving fluconazole generally have been similar to those reported in adults.1,393,395 In phase II/III trials in pediatric patients 1 day to 17 years of age who received fluconazole in dosages up to 15 mg/kg daily, adverse effects occurred in 13% and were severe enough to require discontinuance of the drug in 2.3% of patients.1 GI effect, including vomiting, abdominal pain, nausea, and diarrhea, occurred in 2-5% of these pediatric patients.1 Adverse effects reported when oral or IV fluconazole has been used in neonates and infants (3-6 mg/kg daily) have included transient increases in serum transaminase concentrations,63,149,392,394,410 vomiting,394 and eosinophilia;392 severe thrombophlebitis was reported in at least one neonate.394

Geriatric Precautions

Rash, vomiting, and diarrhea have been reported more frequently in geriatric adults than in younger adults.1 Although anemia and acute renal failure occurred more frequently in patients 65 years of age and older than in those 12-65 years of age during postmarketing surveillance, the relationship of these events to fluconazole is unknown.1

Clinical studies of fluconazole did not include a sufficient number of patients 65 years of age or older to determine whether geriatric patients respond differently for each indication than younger individuals.1 Other reported clinical experience has not identified differences in response between geriatric and younger patients.1

Fluconazole is primarily excreted by the kidneys as unchanged drug.1 Because geriatric patients may have decreased renal function, careful dosage selection and monitoring of renal function are advised.1

Mutagenicity and Carcinogenicity

There was no evidence of mutagenicity when fluconazole was tested with or without metabolic inactivation in 4 strains of Salmonella typhimurium or in the mouse lymphoma L5178Y system.1 In addition, there was no evidence of chromosomal mutations in vivo on murine bone marrow cells following administration of fluconazole or in vitro on human lymphocytes exposed to fluconazole concentrations of 1 mg/mL.1

There was no evidence of carcinogenicity in studies in mice and rats receiving oral fluconazole dosages of 2.5-10 mg/kg daily (approximately 2-7 times the usual human dosage) for 24 months.1 However, there was an increased incidence of hepatocellular adenomas in male rats receiving an oral fluconazole dosage of 5 or 10 mg/kg daily.1

Pregnancy, Fertility, and Lactation

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

There are no adequate and controlled studies to date using fluconazole in pregnant women.1

Congenital abnormalities have been reported in infants born to women who received high-dose fluconazole (400-800 mg daily) for the treatment of serious, life-threatening fungal infections during most or all of the first trimester.1,258,492,493,494,495,496 These reports have involved a rare and distinct pattern of birth defects that includes brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease1,492 and are similar to those reported in animal reproduction studies.492 Based on these data, FDA reclassified high-dose fluconazole (400-800 mg daily) as pregnancy category D1,492 (i.e., there is positive evidence of human fetal risk based on human data, but potential benefits of the drug in pregnant women with serious or life-threatening conditions may be acceptable despite its risks).492

Because human data available at that time did not identify an increased risk of congenital anomalies with the use of fluconazole administered as a single 150-mg oral dose for the treatment of vulvovaginal candidiasis,1,492 the single-dose oral fluconazole regimen was classified by FDA as pregnancy category C (see Users Guide).1,492 Data from a recent Danish study designed to assess the association between use of oral fluconazole during pregnancy and risk of spontaneous abortion and stillbirth indicate an increased risk of spontaneous abortion (i.e., miscarriage during gestational weeks 7 through 22) in pregnant women treated with oral fluconazole (most women received a total cumulative dose of 150-300 mg) compared with matched control pregnancies not exposed to oral fluconazole.497 Therefore, FDA alerted clinicians that it is reviewing data from the Danish study and additional data and, after completing the review, will communicate its conclusions and updated recommendations regarding use of the single-dose 150-mg oral fluconazole regimen during pregnancy.496

The US Centers for Disease Control and Prevention (CDC) states that topical (intravaginal) azole antifungals (not oral fluconazole) should be used for the treatment of vulvovaginal candidiasis during pregnancy.344

The Infectious Diseases Society of America (IDSA) states that use of fluconazole for the treatment of serious fungal infections (e.g., blastomycosis†, candidiasis, histoplasmosis†, coccidioidomycosis†, cryptococcosis) should be avoided during pregnancy.424,425,426,427,428

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

If fluconazole is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1,496

In several reproduction studies in pregnant rabbits receiving oral fluconazole dosages of 5, 10, 20, 25, or 75 mg/kg once daily1,117 during organogenesis, maternal weight gain was impaired at all dosage levels and abortions occurred with the 75-mg/kg dosage (approximately 20-60 times the usual human dosage); no adverse fetal effects were detected.1 In studies in pregnant rats receiving oral fluconazole during organogenesis, maternal weight gain was impaired and placental weights were increased at dosages of 25 mg/kg once daily.1 Although there were no fetal effects in rats receiving oral fluconazole in a dosage of 5 or 10 mg/kg once daily, increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification occurred in those receiving oral dosages of 25 mg/kg or greater once daily.1 When oral fluconazole dosages of 80 mg/kg once daily (approximately 20-60 times the usual human dosage) to 320 mg/kg once daily were used in these rats, there was an increase in embryolethality and fetal abnormalities (i.e., wavy ribs, cleft palate, abnormal craniofacial ossification).1 These adverse effects in rats may be attributed to a species-specific effect of fluconazole on estrogen synthesis since lowered estrogen is known to cause effects on pregnancy, organogenesis, and parturition.1 There is no evidence to date that estrogen concentrations are decreased in women receiving fluconazole.1 (See Cautions: Other Adverse Effects.)

Fertility

Reproduction studies in male and female rats receiving fluconazole in an oral dosage of 5, 10, or 20 mg/kg once daily or an IV dosage of 5, 25, or 75 mg/kg once daily did not reveal evidence of impaired fertility; however, onset of parturition was delayed slightly with the 20-mg/kg oral dosage.1 In one study in rats receiving an IV fluconazole dosage of 5, 20, or 40 mg/kg once daily, dystocia and prolongation of parturition occurred in a few dams with the 20-mg/kg (approximately 5-15 times the usual human dosage) and 40-mg/kg dosages but not with the 5-mg/kg dosage.1 Disturbances in parturition in rats were reflected by a slight increase in the number of stillborn pups and a decrease in neonatal survival; these effects presumably are related to a species-specific estrogen-lowering effect caused by high doses of fluconazole.1

Lactation

Fluconazole is distributed into human milk in concentrations similar to those achieved in plasma.1,261 Administration of a single 150-mg oral dose to several nursing women resulted in peak plasma fluconazole concentrations of 2.61 mcg/mL (range: 1.57-3.65 mcg/mL).1,117 Fluconazole should be used with caution in nursing woman.1

While fluconazole can alter the pharmacokinetics of certain drugs that undergo hepatic metabolism, the magnitude of such alterations appears to be less than those associated with ketoconazole;91 however, comparative studies have not been performed to date.117 In addition, the possibility that the risk of developing such interactions may be increased at relatively high fluconazole dosages (e.g., 200 mg daily or more) should be considered.124

Drugs Metabolized by Hepatic Microsomal Enzymes

Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4.1 Because fluconazole has a long half-life, its enzyme-inhibiting effects 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.1 When fluconazole is used concomitantly with drugs metabolized by these enzymes, caution should be used and the patient carefully monitored.1

Drugs Affecting Gastric Acidity

Studies in fasting, healthy adults indicate that GI absorption of fluconazole is not affected substantially by concomitant use of drugs that decrease gastric acid output or increase gastric pH.1,16,61,68,91,124,249,250 When a single 100-mg oral dose of fluconazole was administered 2 hours after a single 400-mg oral dose of cimetidine, the area under the plasma concentration-time curve (AUC) of fluconazole was decreased 13% and peak plasma fluconazole concentrations were decreased by 21%1,61,68,91 ; these effects were not considered clinically important.61,68,91 Administration of antacids containing aluminum hydroxide or magnesium hydroxide either with or immediately prior to a single 100-mg oral dose of fluconazole had no effect on absorption or elimination of the antifungal.1,61,249

Drugs that Prolong the QT Interval

Concomitant use of fluconazole with drugs that are metabolized by CYP3A4 and known to prolong the QT interval (e.g., cisapride, astemizole, pimozide, quinidine) is contraindicated.1 Concomitant use with erythromycin should be avoided (see Erythromycin under Drugs Interactions: Macrolides).1

Prolongation of the QT interval and QT interval corrected for rate (QT_c) and, rarely, serious cardiovascular effects, including arrhythmias (e.g., ventricular tachycardia, atypical ventricular tachycardia [torsades de pointes, ventricular fibrillation]), cardiac arrest, palpitations, hypotension, dizziness, syncope, and death, have been reported in patients receiving recommended dosages of terfenadine or astemizole (neither antihistamine currently is commercially available in the US) concomitantly with another azole antifungal, ketoconazole.164,165,166,167,168,169,171,172,174,175,347 Ketoconazole can markedly inhibit the metabolism of astemizole or terfenadine, probably via inhibition of the cytochrome P-450 microsomal enzyme system, resulting in increased plasma concentrations of unchanged drug (to measurable levels) and reduced clearance of the active desmethyl or carboxylic acid metabolite, respectively.165,172,174,175 Such alterations in the pharmacokinetics of these antihistamines may be associated with prolongation of the QT and QT_c intervals.164,165,167,168,169,171,174,175 Similar alterations in the pharmacokinetics of these antihistamines and/or adverse cardiac effects also have been reported in patients receiving the drugs concomitantly with itraconazole,164,174 although in vitro data suggest that itraconazole may have a less pronounced effect than ketoconazole on the pharmacokinetics of astemizole.174 Studies have been performed to determine whether similar interactions occur with concomitant use of terfenadine and fluconazole.1 In one study, concomitant use of terfenadine and fluconazole (at a dosage of 200 mg daily) did not result in prolongation of QT interval; however, use of higher fluconazole dosages (400 or 800 mg daily) in another study resulted in increased plasma concentrations of terfenadine.1 The manufacturer of fluconazole has stated that concomitant use of terfenadine and fluconazole in a daily dosage of 400 mg or greater has been contraindicated and it was recommended that patients be carefully monitored if lower fluconazole dosages (i.e., less than 400 mg daily) were administered in patients receiving terfenadine.1

Concomitant use of fluconazole and cisapride (currently commercially available in the US only under a limited-access protocol) may result in increased plasma cisapride concentrations and has rarely been associated with adverse cardiac events including torsades de pointes.1 In a placebo-controlled, randomized, multiple-dose study in individuals receiving fluconazole (200 mg daily), initiation of cisapride (20 mg 4 times daily) after 7 days of fluconazole therapy resulted in a 102-192% increase in the AUC and a 92-153% increase in peak plasma concentrations of cisapride.1 In addition, administration of fluconazole to individuals receiving cisapride (20 mg 4 times daily for 5 days) resulted in a significant increase in the QT interval corrected for rate.1 The manufacturer of fluconazole states that concomitant use of fluconazole and cisapride is contraindicated.1

Concomitant use of erythromycin and fluconazole may increase the risk of QT interval prolongation and torsades de pointes and subsequent sudden cardiac death.1 Concomitant use of erythromycin and fluconazole should be avoided.1

Anticoagulants

Increased prothrombin time has been reported in patients receiving fluconazole concomitantly with a coumarin anticoagulant (e.g., warfarin).1,48,61,91,251 In one study in healthy adults receiving 200 mg of fluconazole daily or placebo, area under the prothrombin time versus time (for a 7-day post-warfarin period) curve for a single 15-mg warfarin dose increased by about 12% when concomitant fluconazole versus placebo were compared.1,91 Increased prothrombin times also have been reported when lower dosages of fluconazole (100 mg once daily) were administered concomitantly with warfarin sodium.251 Concomitant use of fluconazole with nicoumalone (a coumarin anticoagulant not commercially available in the US) resulted in increased prothrombin time and intracranial hemorrhage in at least one patient.48 Prothrombin times should be monitored carefully when fluconazole is used concomitantly with a coumarin anticoagulant.1,61,62,68,91,251

Antidiabetic Agents

Administration of fluconazole in individuals receiving tolbutamide, glyburide, or glipizide has resulted in increased AUCs and peak plasma concentrations and reduced metabolism of the antidiabetic agent.1,61,91 The mean increase in AUC or peak plasma concentrations of tolbutamide, glyburide, or glipizide reported in healthy adults receiving concomitant fluconazole is 26-49 or 11-19%, respectively.1 Clinically important hypoglycemia may be precipitated by concomitant use of oral hypoglycemic agents and fluconazole, and at least one fatality has been reported from hypoglycemia in a patient receiving glyburide and fluconazole concomitantly.1 In several individuals, symptoms consistent with hypoglycemia occurred; oral glucose therapy was necessary in a few cases.1,124

If fluconazole is used concomitantly with tolbutamide, glyburide, glipizide, or any other oral sulfonylurea antidiabetic agent, blood glucose concentrations should be monitored carefully and dosage of the antidiabetic agent adjusted as necessary.1,61,91

Antifungal Agents

Amphotericin B

Although the clinical importance is unclear, results of in vitro studies evaluating the antifungal effects of amphotericin B used concomitantly with fluconazole or other azole antifungals (e.g., clotrimazole, itraconazole, ketoconazole) against Candida albicans , C. pseudotropicalis , C. glabrata , or Aspergillus fumigatus indicate that antagonism can occur with these combinations.231,232 Since amphotericin B exerts its antifungal activity by binding to sterols in the fungal cell membrane and azole antifungals act by altering the cell membrane, antagonism is theoretically possible; however, it is unclear whether such antagonism actually would occur in vivo.233 Results of studies evaluating combined use of fluconazole and amphotericin B in animal models of aspergillosis, candidiasis, or cryptococcosis have been conflicting.1,232,233,234 While antagonism occurred in some models ( A. fumigatus infection in mice, rabbits, or rats treated with amphotericin B and fluconazole), the combination resulted in additive or indifferent effects in other models (e.g., C. albicans or Cryptococcus neoformans infection in mice or rabbits treated with amphotericin B and fluconazole).1,232,233,234 In a few studies evaluating the drugs in murine cryptococcosis or candidiasis, sequential use of an initial large dose of amphotericin B followed by an azole antifungal (e.g., fluconazole) was uniformly effective in prolonging survival and decreasing fungal burden.232 Because further study is needed regarding the interaction between azole antifungals and amphotericin B, it has been suggested that fluconazole and amphotericin B be used concomitantly with caution and close monitoring,1,232,235,236 particularly in immunocompromised patients.232,235,236

Results of an in vitro study indicate that the combination of amphotericin B and fluconazole may be synergistic, additive, or indifferent against Pseudallescheria boydii ; there was no evidence of antagonism.237

Flucytosine

In an in vitro study, the combination of fluconazole and flucytosine was synergistic, additive, or indifferent against Cryptococcus neoformans ; there was no evidence of antagonism.239 Synergism generally did not occur if the C. neoformans isolates had fluconazole MICs of 8 mcg/mL or greater.239 It has been suggested that synergism between the drugs may occur because fluconazole damages the fungal cell membrane allowing greater intracellular penetration of flucytosine.239

Voriconazole

In healthy men, concomitant use of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg once daily for 4 days) resulted in a 79 and 57% increase in AUC and peak plasma concentration of voriconazole, respectively.1 Reduced dosage or dosing frequency of voriconazole and fluconazole did not overcome this pharmacokinetic interaction.1 Concomitant use of voriconazole and fluconazole is not recommended and should be avoided.1 If voriconazole is used sequentially after fluconazole, the patient should be monitored closely for voriconazole-associated adverse events, particularly during the first 24 hours after the last fluconazole dose.1

Antimycobacterial Agents

Rifabutin

Concomitant use of fluconazole (200 mg daily) and rifabutin (300 mg daily) in individuals with human immunodeficiency virus (HIV) infection results in substantially increased plasma concentrations and AUCs of rifabutin and its major metabolite (LM565).241 This effect presumably occurs via inhibition of CYP isoenzymes involved in metabolism of rifabutin and may account in part for the increased incidence of certain adverse effects (e.g., uveitis) reported with concomitant rifabutin and fluconazole therapy.241,242,243

Rifabutin and fluconazole should be used concomitantly with caution and close monitoring.1

Rifampin

Concomitant use of fluconazole and rifampin may affect the pharmacokinetics of both drugs.1,244 Administration of a single 200-mg oral dose of fluconazole in healthy adults receiving rifampin (600 mg daily) resulted in approximately a 25% decrease in the AUC and a 20% decrease in the plasma half-life of fluconazole.1,91 There also is some evidence that concomitant use of fluconazole and rifampin results in increased rifampin plasma concentrations compared with administration of rifampin alone.244 The clinical importance of this possible pharmacokinetic interaction between fluconazole and rifampin is unclear; however, it has been suggested that such an interaction may have contributed to relapse of cryptococcal meningitis in a few patients who were receiving fluconazole concomitantly with rifampin.245

Rifampin and fluconazole should be used concomitantly with caution and close monitoring.1 The manufacturer of fluconazole states that, depending on clinical circumstances, consideration can be given to increasing fluconazole dosage when the drug is administered concomitantly with rifampin.1

Antiretroviral Agents

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Delavirdine

Concomitant use of delavirdine (300 mg every 8 hours) and fluconazole (400 mg daily) for 2 weeks in HIV-infected patients was well tolerated and did not appear to affect the pharmacokinetics of either drug.389,434 Dosage adjustments are not necessary in patients receiving delavirdine and fluconazole concomitantly.389

Efavirenz

Concomitant use of efavirenz (400 mg daily) and fluconazole (200 mg daily) for 7 days in healthy individuals did not result in clinically important changes in the pharmacokinetics of either drug;371 dosage adjustments are not necessary in patients receiving the drugs concomitantly.200,371

Etravirine

Concomitant use of etravirine and fluconazole results in substantial increases in etravirine plasma concentrations and AUC,200,447 but does not have a clinically important effect on fluconazole concentrations.447 Although dosage adjustments are not needed for either drug if etravirine is used concomitantly with fluconazole,200,447 these drugs should be used concomitantly with caution200,447 because only limited data are available regarding the safety of increased etravirine concentrations.447

Nevirapine

Concomitant use of nevirapine and fluconazole may result in increased nevirapine concentrations,200,435 but has no effect on fluconazole concentrations.435 If nevirapine and fluconazole are used concomitantly, the patient should be monitored for nevirapine toxicity since the risk of hepatotoxicity may be increased.200 Alternatively, a different antiretroviral agent can be used.200

Rilpivirine

Concomitant use of fluconazole and rilpivirine may result in increased rilpivirine plasma concentrations.226 If rilpivirine is used concomitantly with fluconazole, rilpivirine dosage adjustments are not needed;226 however, the patient should be monitored for breakthrough fungal infections.226

HIV Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Concomitant use of fluconazole appears to interfere with the metabolism and clearance of zidovudine.1,217 In one study in men with HIV infection who received zidovudine (200 mg every 8 hours) alone or in conjunction with fluconazole (400 mg daily), the AUC of zidovudine was increased 74% (range: 20-173%), peak serum zidovudine concentrations were increased 84% (range: -1 to 227%), and the terminal elimination half-life of the drug was increased 128% (range: -4 to 189%) in patients receiving concomitant fluconazole.1,217 Zidovudine and fluconazole should be used concomitantly with caution and close monitoring.1,217 Patients should be monitored closely for zidovudine-associated adverse effects,1,217 and zidovudine dosage reductions may be considered.1

In one limited study in patients with HIV infection receiving oral didanosine (3.2-7.8 mg/kg daily), concomitant use of oral fluconazole (200 mg every 12 hours for 2 doses, then 200 mg once daily for 6 days) did not result in any clinically important differences in the AUC of didanosine, peak serum didanosine concentrations, or time to peak concentrations.218

Concomitant use of fluconazole and stavudine does not result in a clinically important alteration in the pharmacokinetics of either drug.438

HIV Protease Inhibitors (PIs)

Atazanavir

Pharmacokinetic interactions have not been observed and are unlikely if atazanavir (unboosted, ritonavir-boosted , or cobicistat-boosted ) is used concomitantly with fluconazole.200,446 Dosage adjustments are not necessary if ritonavir-boosted or cobicistat-boosted atazanavir is used concomitantly with fluconazole.200

Indinavir

Concomitant use of indinavir (1 g every 8 hours) and fluconazole (400 mg once daily) for 1 week resulted in a slight decrease in the AUC of indinavir and no change in the AUC of fluconazole.368 This pharmacokinetic interaction is not considered clinically important;368 dosage adjustments are not necessary in patients receiving indinavir concomitantly with fluconazole.368

Lopinavir

Clinically important pharmacokinetic interactions between the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) and fluconazole are not expected.433

Ritonavir

Concomitant use of ritonavir (200 mg every 6 hours for 4 days) and fluconazole (400 mg on day 1, then 200 mg daily for 4 days) resulted in a 12 and 15% increase in the AUC and peak plasma concentration of ritonavir, respectively.248 Dosage adjustments are not needed.432

Saquinavir

Concomitant use of saquinavir (1200 mg as Invirase^® 3 times daily) and fluconazole (single 400-mg dose on day 2, then 200 mg daily) has resulted in approximate increases of 50 and 56% in saquinavir AUC and peak plasma concentrations, respectively.1,481 This interaction is a result of inhibition of CYP3A4 with decreased metabolism of saquinavir and inhibition of P-glycoprotein.1 Saquinavir and fluconazole should be used concomitantly with caution and close monitoring; saquinavir dosage may need to be adjusted.1

Data are not available regarding concomitant use of ritonavir-boosted saquinavir and fluconazole;200 some experts state that dosage adjustments are not needed.200

Tipranavir

Concomitant use of ritonavir-boosted tipranavir and fluconazole results in increased tipranavir peak plasma concentrations and AUC,200,445 but does not affect the pharmacokinetics of fluconazole.445

Although dosage adjustments are not needed,445 fluconazole dosage should not exceed 200 mg daily in patients receiving ritonavir-boosted tipranavir.200,445 If high-dose fluconazole is indicated, an alternative antiretroviral should be considered.200

Calcium-channel Blocking Agents

Fluconazole has the potential to increase systemic exposure to certain dihydropyridine calcium channel blocking agents (amlodipine, felodipine, isradipine, nifedipine, verapamil) that are metabolized by CYP3A4.1 Calcium channel blocking agents and fluconazole should be used concomitantly with caution and close monitoring;1 patients should be monitored frequently for adverse events.1

CNS Agents

Anticonvulsants

Concomitant use of carbamazepine and fluconazole has resulted in a 30% increase in carbamazepine concentrations and has increased carbamazepine-associated toxicity, presumably as the result of fluconazole inhibiting CYP isoenzymes involved in metabolism of the anticonvulsant.1,370 Carbamazepine and fluconazole should be used concomitantly with caution and close monitoring;1 carbamazepine dosage adjustment may be necessary based on plasma carbamazepine concentrations and clinical effect.1

Concomitant use of fluconazole and phenytoin has resulted in increased plasma phenytoin concentrations1,25,141 and AUC141 and has resulted in phenytoin toxicity.25,124 In one study in healthy adults, minimum plasma phenytoin concentrations increased 128% and the AUC of the drug increased 75% during concomitant fluconazole administration;1,141 fluconazole pharmacokinetics were not affected.141 It has been suggested that such alterations in phenytoin pharmacokinetics result from fluconazole-induced inhibition of metabolism of the anticonvulsant.91,141 Phenytoin and fluconazole should be used concomitantly with caution and close monitoring.1 Plasma phenytoin concentrations should be monitored carefully,1,141 and dosage of the anticonvulsant adjusted as needed whenever fluconazole is initiated or discontinued.61,91,141

Antipsychotics

Although data are lacking, concomitant use of fluconazole and pimozide may result in increased plasma pimozide concentrations with the potential for QT interval prolongation and, rarely, torsades de pointes.1 Concomitant use of fluconazole and pimozide is contraindicated.1

Benzodiazepines

Concomitant use of oral or IV fluconazole and midazolam results in substantial increases in the peak plasma concentration and AUC of midazolam (AUC increased 244-272%) and can increase the psychomotor effects of the benzodiazepine;1,482 peak plasma concentration and AUC of fluconazole are not affected.482 This pharmacokinetic interaction appears to be more pronounced with oral fluconazole than with IV fluconazole.1,482 In mechanically ventilated patients sedated with IV midazolam, concomitant use of IV fluconazole resulted in a 20-300% increase in plasma midazolam concentrations in some patients within 18-48 hours after the first dose of fluconazole.369 In addition, administration of oral fluconazole to healthy individuals receiving IV midazolam reportedly results in a 50% decrease in clearance of the benzodiazepine.369,483 Administration of fluconazole to healthy individuals receiving oral midazolam resulted in a 3.5-fold increase in midazolam AUC, a 2.5-fold increase in peak plasma midazolam concentrations, and prolonged midazolam half-life.483 If a short-acting benzodiazepine metabolized by CYP isoenzymes is used in a patient receiving fluconazole, the patient should be carefully monitored and a decrease in benzodiazepine dosage considered.1 Because of concerns that prolonged sedation may occur if fluconazole is administered to patients sedated with IV midazolam, some clinicians suggest that a decrease in the midazolam dosage be considered if there is evidence of increased sedation during concomitant fluconazole therapy.369

Concomitant use of fluconazole and a single dose of triazolam has resulted in a 50% increase in the AUC of triazolam and a 20-32% increase in peak plasma triazolam concentrations and has prolonged the half-life of triazolam by 25-50%.1 Triazolam and fluconazole should be used concomitantly with caution and close monitoring; adjustment of triazolam dosage may be necessary.1

Nonsteroidal Anti-inflammatory Agents

Concomitant use of fluconazole (200 mg daily) and celecoxib (200 mg) has increased the peak plasma concentration and AUC of celecoxib by 68 and 134%, respectively.1

Concomitant use of flurbiprofen and fluconazole has increased the peak plasma concentration and AUC of flurbiprofen by 23 and 81%, respectively.1

When ibuprofen (single 400-mg dose) was administered to healthy individuals receiving oral fluconazole (400 mg on day 1 and 200 mg on day 2), the peak plasma concentration and AUC of the pharmacologically active S-isomer of ibuprofen were increased by about 15 and 82%, respectively.1,484

Although data are lacking, fluconazole has the potential to increase systemic exposure to other nonsteroidal anti-inflammatory agents (NSAIAs) that are metabolized by CYP2C9 (e.g., diclofenac, lornoxicam [not commercially available in the US], meloxicam, naproxen).1

NSAIAs and fluconazole should be used concomitantly with caution and close monitoring.1 Patients should be monitored frequently for NSAIA-associated adverse events; NSAIA dosage adjustment may be needed.1,484

Opiate Agonists

Concomitant use of alfentanil and oral or IV fluconazole in healthy individuals reduced alfentanil clearance by 55%, reduced alfentanil volume of distribution by 19%, and nearly doubled the mean elimination half-life of the drug.485 This interaction may be a result of inhibition of CYP3A4 by fluconazole.1 Alfentanil and fluconazole should be used concomitantly with caution and close monitoring;485 adjustment of alfentanil dosage may be necessary.1

Concomitant use of a single IV dose of fentanyl in healthy adults receiving oral fluconazole resulted in substantially delayed fentanyl elimination.1,490 Elevated fentanyl concentrations may lead to respiratory depression.1 A fatality possibly related to fentanyl intoxication has been reported in a patient who received concomitant fluconazole and transdermal fentanyl.1,489 Fentanyl and fluconazole should be used concomitantly with caution and close monitoring.1

When fluconazole (200 mg daily) was administered for 14 days to individuals receiving stable doses of methadone, mean methadone AUC and peak plasma concentration were increased 35 and 27%, respectively, and methadone clearance was reduced 24%.488 Methadone and fluconazole should be used concomitantly with caution and close monitoring; methadone dosage adjustment may be necessary.1

Tricyclic Antidepressants

Concomitant use of amitriptyline or nortriptyline and fluconazole has resulted in increased serum concentrations of the tricyclic antidepressant367 and may increase adverse effects of the antidepressants.1 CNS toxicity has been reported in a few patients receiving amitriptyline and fluconazole concomitantly.367 It has been suggested that fluconazole may interfere with metabolism of amitriptyline by inhibition of CYP isoenzymes involved in metabolism of the antidepressant.367 Fluconazole and amitriptyline or nortriptyline should be used concomitantly with caution and close monitoring.1 The manufacturer of fluconazole states that S-amitriptyline and/or 5-nortriptyline may be measured when concomitant therapy is initiated and after 1 week of concomitant use;1 dosage of amitriptyline or nortriptyline should be adjusted if necessary.1

Corticosteroids

In a liver transplant recipient receiving prednisone who received a 3-month course of fluconazole, acute adrenal cortex insufficiency occurred when fluconazole was discontinued.1 This may be a consequence of increased CYP3A4 activity and enhanced metabolism of prednisone as a result of fluconazole discontinuance.1 Prednisone and fluconazole should be used concomitantly with caution and close monitoring; if the drugs are used concomitantly for a prolonged period of time, the patient should be monitored carefully for adrenal cortex insufficiency when fluconazole is discontinued.1

Cyclophosphamide

Concomitant use of cyclophosphamide and fluconazole results in increased concentrations of serum bilirubin and serum creatinine.1 Cyclophosphamide and fluconazole should be used concomitantly with caution and close monitoring; the risk of increased serum bilirubin and serum creatinine should be considered.1

Estrogens and Progestins

Concomitant use of oral fluconazole and oral estrogen-progestin contraceptives may affect the pharmacokinetics of the contraceptives.1,18,61,68,439 Although limited data indicate that fluconazole may inhibit metabolism of ethinyl estradiol, levonorgestrel, and norethindrone, there is no evidence that fluconazole induces metabolism of these hormones.1 When fluconazole is used in the dosage range of 50-200 mg daily concomitantly with combined oral contraceptives,1 interference with oral contraceptive efficacy is unlikely.1,439

In healthy premenopausal women who received a single dose of oral contraceptive before and after receiving oral fluconazole given in a low dosage (50 mg once daily for 10 days), the mean increase in AUCs of ethinyl estradiol and levonorgestrel were 6% (range: -47 to 108%) and 17% (range: -33 to 141%), respectively.1 Although some women had ethinyl estradiol and levonorgestrel concentrations that were decreased 47 and 33%, respectively, the manufacturer suggests that this may have been the result of random variation.1 In a controlled study in healthy women who received a single dose of oral contraceptive following a 10-day regimen of placebo or oral fluconazole (200 mg once daily), AUCs of both levonorgestrel and ethinyl estradiol were increased substantially in those who received oral fluconazole compared with placebo; mean increases in AUCs of ethinyl estradiol and levonorgestrel were 38% (range: -11 to 101%) and 25% (range: -12 to 82%), respectively.1

In another placebo-controlled study, women who had received a full cycle of an oral contraceptive preparation containing ethinyl estradiol and norethindrone received a once-weekly fluconazole regimen (300 mg once weekly) or placebo during the second and third cycles of contraceptive use.1,439 During fluconazole treatment, the mean AUCs of ethinyl estradiol and norethindrone were increased by 24 and 13%, respectively, compared with placebo.1,439 Fluconazole did not cause a decrease in the ethinyl estradiol AUC in any individual and caused only a slight (less than 5%) decrease in the AUC of norethindrone.1,439

Halofantrine

Concomitant use of fluconazole and halofantrine (not commercially available in the US) may result in increased halofantrine concentrations because of CYP3A4 inhibition by fluconazole.1,491 Halofantrine and fluconazole should be used concomitantly with caution and close monitoring.1

HCV Antivirals

HCV Protease Inhibitor

Simeprevir

Concomitant use of simeprevir and fluconazole may result in increased plasma concentrations of simeprevir.187

Concomitant use of fluconazole and simeprevir is not recommended.187

HCV Replication Complex Inhibitor

Daclatasvir

If fluconazole and daclatasvir are used concomitantly, daclatasvir dosage adjustments are not needed.178

HMG-CoA Reductase Inhibitors

When fluconazole is used concomitantly with a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin) that is metabolized by CYP3A4 (e.g., atorvastatin, simvastatin) or 2C9 (e.g., fluvastatin), the risk of myopathy and rhabdomyolysis is increased.1 If concomitant therapy is necessary, creatinine kinase (CK, creatine phosphokinase, CPK) should be monitored and the patient assessed for symptoms of myopathy and rhabdomyolysis.1 If a substantial increase in CK occurs or myopathy or rhabdomyolysis is diagnosed or suspected, the statin should be discontinued.1

In a placebo-controlled crossover study, a single dose of fluvastatin (40 mg on day 4) administered to healthy individuals receiving oral fluconazole (400 mg on day 1, then 200 mg daily on days 2-4) resulted in an 84% increase in fluvastatin AUC, a 44% increase in fluvastatin peak plasma concentration, and an 80% prolongation of fluvastatin half-life, but did not affect the AUC of fluconazole.486

Fluconazole had no clinically important effect on pravastatin pharmacokinetics in a placebo-controlled crossover study in healthy individuals.486

Immunosuppressive Agents

Cyclosporine

Concomitant use of fluconazole and cyclosporine may result in increased plasma cyclosporine concentrations,1,22,23,24,61,68,91 especially when the drugs are used in renal transplant recipients.22,23,24,68 In several studies in bone marrow transplant recipients receiving cyclosporine maintenance therapy, administration of 100- or 200-mg oral doses of fluconazole once daily for 14 days resulted in only slight increases in plasma cyclosporine concentrations, which were not considered clinically important.1,21,81,91 However, administration of usual oral dosages of fluconazole to renal transplant recipients (with or without impaired renal function) receiving cyclosporine has resulted in increases in the AUC and peak plasma concentrations of the immunosuppressive agent.1,22,24 In one study in renal transplant patients who had received at least 6 months of cyclosporine therapy and had been receiving a stable cyclosporine dosage for at least 6 weeks, administration of fluconazole 200 mg daily for 14 days resulted in a mean increase of 60 or 157% in peak or minimum cyclosporine plasma concentrations, respectively, and a mean decrease of 45% in the apparent oral clearance of the drug.1 In addition, increased serum creatinine concentrations, which returned to pretreatment levels with dosage reduction of both drugs, have been reported in patients receiving fluconazole and cyclosporine concomitantly.91 While the mechanism of this possible interaction is not known, displacement of cyclosporine from protein-binding sites is unlikely since fluconazole is only minimally protein bound.91

Fluconazole and cyclosporine should be used concomitantly with caution and close monitoring.1 Plasma cyclosporine concentrations and serum creatinine should be monitored carefully;1,22,23 cyclosporine dosage should be decreased based on plasma concentrations of the immunosuppressive agent.1,22,23

Tacrolimus

Concomitant use of oral tacrolimus and fluconazole has resulted in a fivefold increase in serum concentrations of tacrolimus as the result of inhibition of intestinal CYP3A4; clinically important alterations in pharmacokinetics were not observed with IV tacrolimus.1 Increased tacrolimus concentrations have been associated with nephrotoxicity.1

Tacrolimus and fluconazole should be used concomitantly with caution and close monitoring.1 Tacrolimus dosage should be decreased based on tacrolimus concentrations.1

Sirolimus

Concomitant use of sirolimus and fluconazole results in increased plasma concentrations of the immunosuppressive agent, probably as a result of decreased sirolimus metabolism secondary to inhibition of CYP3A4 and P-glycoprotein.1

Sirolimus and fluconazole should be used concomitantly with caution and close monitoring.1 Sirolimus dosage should be adjusted based on sirolimus concentrations and clinical effects.1

Losartan

When a single dose of losartan (50 mg on day 4) was administered to healthy individuals receiving fluconazole (400 mg on day 1, then 200 mg on days 2-4), the AUC and mean peak plasma concentration of the active losartan metabolite (E-3174) were decreased 30 and 47%, respectively, and the half-life of E-3174 was increased by 167%.487

Losartan and fluconazole should be used concomitantly with caution and close monitoring.1 Because fluconazole inhibits metabolism of losartan to its active metabolite (E-3174) and the metabolite is principally responsible for angiotensin II receptor antagonism during losartan therapy, the possibility of decreased therapeutic effect should be considered487 and blood pressure closely monitored.1

Macrolides

Azithromycin

Concomitant use of a single 1.2-g dose of azithromycin and a single 800-mg dose of fluconazole did not alter the pharmacokinetics of either drug.1

Erythromycin

Concomitant use of erythromycin and fluconazole should be avoided because of the potential for an increased risk of adverse cardiovascular effects (prolonged QT interval, torsades de pointes) and subsequent sudden cardiac death.1

Quinidine

Concomitant use of quinidine and fluconazole may result in inhibition of quinidine metabolism.1 Quinidine has been associated with QT interval prolongation and rare occurrences of torsades de pointes.1 (See Drug Interactions: Drugs that Prolong the QT Interval.)

Concomitant use of quinidine and fluconazole is contraindicated.1

Theophylline

Concomitant use of theophylline and fluconazole increases serum theophylline concentrations.1 In a study in healthy adults, administration of a single dose of IV aminophylline (6 mg/kg) after 14 days of oral fluconazole (200 mg daily) resulted in a 21 or 13% increase in the mean AUC or peak plasma concentration of theophylline, respectively, and a mean decrease of 16% in theophylline clearance; the half-life of theophylline increased from 6.6 to 7.9 hours.1

Theophylline and fluconazole should be used concomitantly with caution and close monitoring.1 Serum theophylline concentrations should be monitored carefully in patients receiving fluconazole.1

Thiazide Diuretics

In healthy adults receiving 100-mg doses of fluconazole, concomitant administration of 50-mg doses of hydrochlorothiazide resulted in a 43% increase in peak plasma fluconazole concentrations and a 45% increase in the AUC of fluconazole compared with results obtained when the antifungal was given alone.1 These changes are attributed to a 30% decrease in renal clearance of fluconazole.1 Fluconazole and hydrochlorothiazide should be used concomitantly with caution and close monitoring;1 adjustment of fluconazole dosage probably is not necessary.1

Tofacitinib

Concomitant use of fluconazole (400 mg on day 1, then 200 mg once daily for 6 days) and tofacitinib (single 30-mg dose on day 5) in healthy individuals increased the mean peak plasma concentration and AUC of tofacitinib by 27 and 79%, respectively, compared with administration of tofacitinib alone.1

If tofacitinib and fluconazole are used concomitantly, tofacitinib dosage should be reduced from 5 mg twice daily to 5 mg once daily.1

Tretinoin

Pseudotumor cerebri has been reported in a patient who received tretinoin (all-trans retinoic acid) and fluconazole concomitantly;1 this adverse CNS effect resolved after discontinuance of fluconazole.1 Tretinoin and fluconazole should be used concomitantly with caution and close monitoring; the possibility of adverse CNS effects should be considered.1

Vinca Alkaloids

Although data are not available, inhibition of CYP3A4 by fluconazole may result in increased plasma levels of concomitant vinca alkaloids (e.g., vinblastine, vincristine) and possible neurotoxicity.1 Vinca alkaloids and fluconazole should be used concomitantly with caution and close monitoring.1

Acute Toxicity

Manifestations

Limited information is available on the acute toxicity of fluconazole in humans.1 In mice and rats receiving very high dosages of fluconazole, decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex, and cyanosis occurred.1 There were no fatalities in mice and rats receiving fluconazole doses of 1 g/kg or less.117 At higher doses (1-2 g/kg), death occurred 1.5 hours to 3 days after the dose;117 in some cases, death was preceded by clonic seizures.1 There have been reports of fluconazole overdosage accompanied by hallucination and paranoid behavior in humans.1

Treatment

If acute overdosage of fluconazole occurs, supportive and symptomatic treatment should be initiated.1 If indicated, the stomach should be emptied by gastric lavage.1 Elimination of fluconazole can be facilitated by hemodialysis; plasma concentrations of the drug generally are decreased 50% by a 3-hour period of hemodialysis.1

Mechanism of Action

Fluconazole usually is fungistatic in action.1,51,75,268 Fluconazole and other triazole-derivative antifungals (e.g., itraconazole, terconazole) appear to have a mechanism of action similar to that of the imidazole-derivative antifungals (e.g., butoconazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole).2,3,51,62,68,76,79 Like imidazoles, fluconazole 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 Although the exact mechanism of action of fluconazole and other triazoles has not been fully determined, the drugs inhibit cytochrome P-450 14-α-desmethylase in susceptible fungi, which leads to accumulation of C-14 methylated sterols (e.g., lanosterol) and decreased concentrations of ergosterol.2,3,51,61,76,79,84 It appears that this may occur because a nitrogen atom (-4) in the triazole molecule binds to the heme iron of cytochrome P-450 14-α-desmethylase in susceptible fungi.2,51 Unlike some imidazoles (e.g., clotrimazole, econazole, miconazole, oxiconazole) that suppress ATP concentrations in intact cells and spheroplasts of C. albicans ,50 fluconazole does not appear to have an appreciable effect on ATP concentrations in the organism.10 It is unclear whether this effect is related to the in vivo antifungal effects of the drugs.50 Fluconazole generally is fungistatic against Candida albicans when the organism is in either the stationary or early logarithmic phase of growth.51

Fluconazole and other triazoles (e.g., itraconazole) have a high affinity for fungal P-450 enzymes and only a weak affinity for mammalian P-450 enzymes1,15,17,18,51,61,76,124 and are more specific inhibitors of fungal cytochrome P-450 systems than many imidazoles (e.g., ketoconazole).17,51,61,68,76,124 The drug does not appear to have any effect on cholesterol synthesis in mammalian liver homogenates.17 In an in vitro study using rat Leydig cells, fluconazole concentrations of 10 mcg/mL caused less than a 30% inhibition of basal testosterone production whereas the same concentration of ketoconazole caused a 95% inhibition.17 Further study is needed to fully evaluate whether fluconazole affects P-450 enzyme systems and steroid synthesis in humans.17,18,85 While there is some evidence that fluconazole has only a minimal inhibitory effect on microsomal cytochrome P-450 systems,15,17,20,51,76 other evidence suggests that the drug may have a potent inhibitory effect.20,76,85,86 Results of an in vitro study using rat liver indicate that fluconazole may act as a potent inducer of some hepatic cytochrome P-450 enzymes systems involved in drug metabolism, acting as an enzyme inhibitor at low concentrations and an inducer at high concentrations.76 Unlike most imidazoles (e.g., ketoconazole), fluconazole appears to have only minimal, if any, effects on human steroid synthesis, including production of cholesterol, testosterone, and estrogen in dosages up to 400 mg daily.1,15,17,18,61,64,67,124

Results of in vitro studies using human polymorphonuclear leukocytes (PMNs) obtained from healthy individuals indicate that exposure of PMNs to fluconazole concentrations of 1-50 mcg/mL does not appreciably affect PMN function, including chemotaxis, phagocytosis, and oxidative metabolism, and does not interfere with intracellular killing of C. albicans blastoconidia.75 The drug also does not affect lymphocyte proliferation in vitro.127,128

Spectrum

Fluconazole is active against many fungi, including yeasts and dermatophytes.1,3,51,78,87,88 Fluconazole does not appear to have antibacterial activity.117

In Vitro Susceptibility Testing

Like imidazole derivatives and other triazole derivatives, results of in vitro fluconazole susceptibility tests are method dependent, and MIC values vary depending on the culture medium used, incubation temperature, pH, and inoculum size.2,3,5,6,7,9,51,58,59,61,80,87,98,124 In addition, currently available in vitro tests do not necessarily reflect the in vivo susceptibility of many fungi (especially Candida ).2,3,7,9,51,55,56,58,59,61,77,78,80,87,88,98,107,108,124,263 Consequently, in vivo animal models of fungal infections may provide a more accurate assessment of the antifungal effectiveness of fluconazole than currently available in vitro susceptibility tests.2,3,8,9,56,58,69,61,98,107,108,124 While fluconazole is less active on a weight basis in vitro than many other antifungals (e.g., itraconazole, ketoconazole, miconazole), the drug often is as or more active than these agents in vivo.2,5,7,8,39,51,57,88,89,90,102,124 The reasons for the current lack of correlation between results of in vitro and in vivo tests are unclear.51,59 It has been suggested that substances contained in media used for in vitro susceptibility testing, especially complex media, may antagonize fluconazole.5,59,77,80 Other factors also probably contribute to the apparent poor correlation between in vitro and in vivo results.5,88,102,103,107

Fungi

When results of in vitro susceptibility tests are compared, fluconazole appears to be less active than ketoconazole against most susceptible organisms since MICs of fluconazole reported for C. albicans , C. neoformans , and H. capsulatum generally are 4-16 times higher than those reported for ketoconazole.2,3,5,7,8,39,51,88,103 However, results of studies using the drugs in various animal models of fungal infections indicate that, despite higher MIC values in vitro, the in vivo effectiveness of fluconazole is equal to or, in many cases, greater than the in vivo effectiveness of ketoconazole.2,5,7,39,51,56,88,90 This difference may occur because results of fluconazole in vitro susceptibility tests are affected to a greater extent than those of ketoconazole and/or because pharmacologic differences between the drugs (e.g., fluconazole's higher oral bioavailability and lower protein binding) affect the in vivo effectiveness of the drugs.5,88,90

Candida

In vitro, fluconazole is active against some strains of Candida ,1,5,6,49,51,102,103 including some strains of C. albicans ,1,5,49,51,89,102,359,360,363,365 C. dubliniensis ,1,390 C. guilliermondii ,1,365 C. kefyr ,1 C. glabrata ,1,359 C. parapsilosis ,1,359,362,363,365 C. lusitaniae ,1,386 and C. tropicalis .1,103,359,362,363 In vitro, susceptible strains of C. albicans ,359,360,365 C. guilliermondii ,365 C. parapsilosis ,362,365 and C. tropicalis 362 usually are inhibited by fluconazole concentrations of 0.03-8 mcg/mL. In one study evaluating in vitro susceptibility of clinical isolates of C. dubliniensis obtained from patients with or without human immunodeficiency virus (HIV) infection, most strains were inhibited by fluconazole concentrations of 0.125-1 mcg/mL, but some strains had reduced susceptibility to the drug and required fluconazole concentrations of 8-32 mcg/mL for in vitro inhibition.390,386

C. krusei are intrinsically resistant to fluconazole and many strains of C. glabrata also are resistant or have reduced susceptibility to the drug.1,267,275,343,346,359,360,362,363,365(See Resistance.)

In vitro, some strains of C. duobushaemulonii have been inhibited by fluconazole concentrations of 1-16 mcg/mL.498 C. haemulonii and C. auris (often misidentified as C. haemulonii , C. famata , or Rhodotorula glutinis ) generally are resistant to fluconazole in vitro.498

Other Fungi

Fluconazole has in vitro activity against some strains of Cryptococcus neoformans .1,7,30,51,55,102,107,359 In vitro, some strains of C. neoformans are inhibited by fluconazole concentrations of 0.125-12.8 mcg/mL.7,50,58,102,359 Although fluconazole may be active in vitro against some strains of C. gattii ,449,450 there is in vitro evidence that fluconazole may be less active against C. gattii than some other azoles (e.g., itraconazole, posaconazole, voriconazole).449

Coccidioides immitis and C. posadasii are inhibited in vitro by fluconazole.467,468 In one study, the mean MIC of fluconazole for these organisms was 8 mcg/mL.467

Fluconazole is active in vitro against some strains of Histoplasma capsulatum .8,9,51,100 A wide range of fluconazole MICs has been reported for this organism.8,9,15,100,107 In some in vitro studies, MICs of fluconazole reported for H. capsulatum were 0.125-4 mcg/mL;8 however, in other studies, MICs ranged from 16-250 mcg/mL.9,100,107 In addition, some amphotericin B-susceptible strains of H. capsulatum with fluconazole MICs exceeding 1000 mcg/mL have been reported.107

Some strains of Blastomyces dermatitidis are inhibited in vitro by fluconazole concentrations of 2.5-10 mcg/mL, but other strains require concentrations of 20-80 mcg/mL for in vitro inhibition.358

Fluconazole is inactive against Malassezia pachydermatis in vitro.11 The drug generally is inactive against Aspergillus in vitro.51,101

Although a few strains of Penicillium marneffei may be inhibited in vitro by fluconazole concentrations of 4-8 mcg/mL,469,470 most strains tested are resistant to the drug.470 In vitro, fluconazole is considerably less active than itraconazole or ketoconazole against P. marneffei .469,470

Scopulariopsis , including S. acremonium and S. brevicaulis , generally are resistant to fluconazole in vitro.366

In Vivo Susceptibility Testing

In vivo studies using various animal models (e.g., mice, rats, rabbits) and standard laboratory strains of fungi indicate that oral or IV fluconazole has fungistatic activity against a variety of fungal infections.2,3,5,7,8,9,51,55,59,60,89,102,103,106,107,108,109 Activity of the drug against fungi in these in vivo studies was generally evaluated based on increased survival rate and reduction of fungal burden in the animals' organs.5,7,8,9,55,59,60,61,62,89,102,103,106,107,108,109 Fluconazole has been active in vivo in both normal and immunosuppressed mice, rats, and rabbits against systemic and local infections caused by C. albicans , including endophthalmitis, endocarditis, pyelonephritis, and intestinal, vaginal, and disseminated candidiasis;2,5,51,55,59,60,61,62,74,89,102,103,106 in several studies, fluconazole was at least as effective as amphotericin B (alone or combined with flucytosine) and more effective than ketoconazole in vivo against these infections.2,5,51,60,61,62,89 Fluconazole also has been effective in vivo in animals against systemic C. parapsilosis infections.89 Although fluconazole was active in vivo in mice against infections caused by C. tropicalis or C. glabrata , the drug was less effective against these infections than amphotericin B; neither fluconazole nor amphotericin B were effective in reducing tissue concentrations of C. krusei in these mice.56

Fluconazole has been effective in vivo in mice and rabbits against infections caused by C. neoformans , including meningitis and pulmonary infections.2,7,51,61,62,102 The drug generally has been effective against systemic infections, including pulmonary infections, caused by H. capsulatum in normal and immunosuppressed mice,2,8,9,51,61,100,107,109 and was as effective as9,100 or less effective than107,109 amphotericin B. Fluconazole also generally has been effective in mice against systemic infections, including intracranial infections, caused by C. immitis ;2,51,61,108 pulmonary infections in mice caused by Blastomyces dermatitidis ;2,51,61,90,122 and infections in mice caused by Paracoccidioides brasiliensis .2 Results of in vivo testing of fluconazole activity against Aspergillus have been conflicting.51,61,101 In some in vivo studies in normal or immunosuppressed mice or rabbits, high dosages of the drug (60-120 mg/kg daily) were effective against infections caused by A. flavus and A. fumigatus .1,51,61,101 However, in at least one in vivo study in mice, fluconazole was ineffective against experimental aspergillosis.51

In in vivo models of dermatomycoses, fluconazole has been effective against pityriasis (tinea) versicolor caused by Malassezia furfur ( Pityrosporum orbiculare or P. ovale ) and infections caused by Trichophyton 3,51,106 or Microsporum canis .124

Resistance

Resistance to fluconazole can be produced in vitro by serial passage of Candida albicans in the presence of increasing concentrations of the drug.274 Some Candida species are intrinsically resistant to fluconazole (e.g., C. krusei ), and many strains of C. glabrata are resistant or have reduced susceptibility to the drug.1,265,266,267,275,343,346 In addition, strains of Candida with decreased in vitro susceptibility to fluconazole have been isolated with increasing frequency.265,266,267,275,343,346 Fluconazole-resistant strains of C. albicans , C. glabrata ,275 C. lusitaniae , C. norvegensis ,270 C. parapsilosis ,277 and C. tropicalis 265,267,269 have been isolated from patients receiving fluconazole. Strains of Cryptococcus neoformans with decreased susceptibility to fluconazole also have been isolated from patients receiving the drug.267,272,273,282 Prolonged or intermittent use of oral fluconazole in immunocompromised patients has been suggested as a major contributing factor to the emergence of fluconazole resistance in Candida .265,266,267,269,271,276,278,284,285 In one study evaluating the in vitro susceptibility of Candida isolates obtained from patients with candidemia, 72% of the isolates obtained from patients who had received prior fluconazole therapy had decreased in vitro susceptibility to fluconazole (MIC greater than 8 mcg/mL) compared with only 12% of isolates obtained from patients who had not previously received fluconazole.267 There is evidence that decreased in vitro susceptibility to fluconazole may correlate with clinical failure in the treatment of Candida infections (e.g., esophageal candidiasis) in HIV-infected patients.269,271,283,284 Emergence of fluconazole-resistant strains of C. albicans also have been reported rarely in immunocompetent patients receiving the drug.280

Several mechanisms for decreased susceptibility to fluconazole have been suggested, including reduced intracellular accumulation of the drug as the result of defective lipids or sterols in the fungal cell membrane or active efflux of the drug or mutation of fungal 14-α-desmethylase leading to diminished affinity for the enzyme.266,273,274,275,279,346 In one in vitro study, fluconazole-resistant strains of C. albicans reverted to susceptible phenotypes when grown without the presence of fluconazole.274

Fluconazole-resistant fungi also may be cross-resistant to other azole antifungals (e.g., itraconazole, ketoconazole, posaconazole, voriconazole).5,6,67,87,102,103,104,269,275,277,278,279,346

While the clinical importance is unclear, fluconazole-resistant strains of C. albicans that were cross-resistant to amphotericin B have been isolated from a few immunocompromised individuals, including leukemia patients364 and HIV-infected individuals.266 In addition, a few isolates of Cryptococcus neoformans with decreased susceptibility to fluconazole have shown cross resistance to amphotericin B.273

Pharmacokinetics

Absorption

The pharmacokinetics of fluconazole are similar following IV or oral administration.1,61,105 The drug is rapidly and almost completely absorbed from the GI tract,1,2,51,61,67,68 and there is no evidence of first-pass metabolism.51,105

Oral bioavailability of fluconazole exceeds 90% in healthy, fasting adults;1,61,68,105,124,131 peak plasma concentrations of the drug generally are attained within 1-2 hours after oral administration.1,68,99,105 Results of a few limited studies indicate that oral bioavailability of fluconazole in adults with human immunodeficiency virus (HIV) infection appears to be similar to that reported for healthy adults.219,223

The manufacturer states that the commercially available fluconazole suspensions are bioequivalent to the 100-mg fluconazole tablets.1

Unlike some imidazole-derivative antifungals (e.g., ketoconazole), GI absorption of fluconazole does not appear to be affected by gastric pH.1,16,61,68,91,124,249,250 In one patient with achlorhydria who received 100-mg oral doses of fluconazole once daily, plasma concentrations of the drug 2 hours after a dose were similar to those reported at the same time interval in healthy adults.16 Studies in healthy, fasting adults indicate that peak plasma concentrations, areas under the concentration-time curves (AUCs), time to peak plasma concentrations, and elimination half-life of fluconazole are not affected substantially by concurrent administration of drugs that increase gastric pH.1,61,68,91,249,250 (See Drug Interactions: Drugs Affecting Gastric Acidity.)

Peak plasma fluconazole concentrations and AUCs increase in proportion to the dose over the oral dosage range of 50-400 mg.1,105,124,131 Steady-state plasma concentrations of fluconazole are attained within 5-10 days following oral doses of 50-400 mg given once daily.1,105 The manufacturer states that when fluconazole therapy is initiated with a single loading dose equal to twice the usual daily dosage and followed by the usual dosage given once daily thereafter, plasma concentrations of the drug reportedly approach steady state by the second day of therapy.1

In healthy, fasting adults who received a single 1-mg/kg oral dose of fluconazole, peak plasma concentrations of the drug averaged 1.4 mcg/mL.2,12,62 Following oral administration of a single 400-mg dose of fluconazole in healthy, fasting adults, peak plasma concentrations average 6.72 mcg/mL (range: 4.12-8.1 mcg/mL).1 In adults with coccidioidal meningitis who received oral fluconazole in a dosage of 50 or 100 mg daily, peak serum concentrations of the drug ranged from 2.5-3.5 or 4.5-8 mcg/mL, respectively, and were attained in 2-6 hours; serum concentrations averaged 1.2 or 3.1 mcg/mL, respectively, at 24-27 hours after a dose.15

In healthy adults receiving 50- or 100-mg doses of fluconazole given once daily by IV infusion over 30 minutes, serum concentrations of the drug 1 hour after dosing on the sixth or seventh day of therapy ranged from 2.14-2.81 or 3.86-4.96 mcg/mL, respectively.14

In children 9 months to 13 years of age, oral administration of a single 2- or 8-mg/kg dose of fluconazole resulted in mean peak plasma concentrations of 2.9 or 9.8 mcg/mL, respectively.1 In a multiple-dose study in children 5-15 years of age, IV administration of 2-, 4-, or 8-mg/kg doses of fluconazole resulted in mean peak plasma concentrations of 5.5, 11.4, or 14.1 mcg/mL, respectively.1 In a limited study in premature neonates who received 6-mg/kg doses of fluconazole IV every 72 hours, peak serum concentrations of the drug ranged from 3.7-10.2 mcg/mL after the first dose and from 6-17.8 mcg/mL after the third dose (day 7).259

Food

Data from a pharmacokinetic study in healthy individuals indicate that administration with a high-fat meal does not affect peak plasma concentrations or AUC of fluconazole compared with administration in the fasting state.1

Distribution

Fluconazole is widely distributed into body tissues and fluids following oral or IV administration.1,61,62,64,76,102,103,105 Studies in mice using IV doses of radiolabeled fluconazole indicate that the drug is evenly distributed throughout body tissues.2,51,124 In adult humans with normal renal function, concentrations of the drug 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 Concentrations attained in vaginal secretions following administration of a single 150-mg oral dose reportedly are about 40-86% of concurrent plasma concentrations.1,99,202 Fluconazole concentrations in prostatic tissue reportedly average about 30% of concurrent plasma concentrations.260 In adults with bronchiectasis who received a single 150-mg oral dose of fluconazole, sputum concentrations of the drug in samples obtained at 4 and 24 hours after the dose averaged 3.7 and 2.23 mcg/mL, respectively, and were approximately equal to concurrent plasma concentrations.13 Studies in rabbits indicate that high concentrations of fluconazole are attained in the cornea, aqueous humor, and vitreous body following IV administration; these concentrations were higher in inflamed than uninflamed eyes.74

Fluconazole, unlike some azole-derivative antifungals (e.g., itraconazole, ketoconazole), distributes readily into CSF following oral or IV administration;1,2,3,14,15,29,30,36,54,61,62,102,105 CSF concentrations of fluconazole 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 In adults with coccidioidal meningitis who received an oral fluconazole dosage of 50 or 100 mg daily, CSF concentrations of the drug in samples obtained 0.5-8 hours after a dose averaged 0.7-2.1 or 3.5-5.3 mcg/mL, respectively.15

The apparent volume of distribution of fluconazole approximates that of total body water1,12,13,61,76 and has been reported to be 0.7-1 L/kg.2,12,13,51,61,62,68,105,124 In a limited study, the estimated volume of distribution at steady state of fluconazole was slightly lower in HIV-infected adults than in healthy adults.219

Unlike some azole-derivative antifungals (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

It is not known whether fluconazole crosses the placenta in humans.117 The drug crosses the placenta in rats, and concentrations in amniotic fluid, placenta, fetus, and fetal liver are approximately equal to maternal plasma concentrations.117 Fluconazole is distributed into human milk in concentrations similar to those attained in plasma.1,261 Following administration of a single 150-mg oral dose in nursing women, peak plasma fluconazole concentrations were 2.61 mcg/mL (range: 1.57-3.65 mcg/mL)1,117

Elimination

The plasma elimination half-life of fluconazole in adults with normal renal function is approximately 30 hours (range: 20-50 hours).1,2,3,12,13,14,61,62,67,68,78,105 In one study, plasma elimination half-life of the drug was 22 hours after the first day of therapy and 23.8 and 28.6 hours after 7 and 26 days of therapy, respectively.2,62 In a limited, single-dose study in HIV-infected adults, the plasma elimination half-life of fluconazole averaged 32 hours (range: 25-42 hours) in those with absolute helper/inducer (CD4⁺, T4⁺) T-cell counts greater than 200mm³ and 50 hours (range: 32-69 hours) in those with CD4⁺ T-cell counts less than 200mm³.219 In other single-dose studies in a limited number of HIV-infected adults with CD4⁺ T-cell counts less than 200mm³, the plasma elimination half-life of the drug averaged 35-40 hours (range 22-75 hours).223,224

The mean plasma half-life of fluconazole in children 9 months to 15 years of age has ranged from about 15-25 hours.1 In a limited study in premature neonates who received IV fluconazole once every 72 hours, the plasma half-life decreased over time, averaging 88 hours after the first dose and 55 hours after the fifth dose (day 13).259

In patients with impaired renal function, plasma concentrations of fluconazole are higher and the half-life prolonged;1,37,57,67,105 elimination half-life of the drug is inversely proportional to the patient's creatinine clearance.1 In addition, elimination of the drug may be impaired in geriatric patients because of decreased kidney function in this age group.1,124 The elimination half-life of fluconazole reportedly is not affected by impaired hepatic function.117

In healthy adults, fluconazole is eliminated principally by renal excretion.1,2 Renal clearance of the drug averages 0.27 mL/minute per kg in adults with normal renal function.12 In a limited, single-dose study, renal clearance of fluconazole averaged 0.79 L/hour in healthy adults, 0.58 L/hour in HIV-infected adults with CD4⁺ T-cell counts greater than 200mm³, and 0.2 L/hour in those with CD4⁺ T-cell counts less than 200mm³.219 Approximately 60-80% of a single oral or IV dose of fluconazole is excreted in urine unchanged,1,2,3,12,51,61,68,105,117 and about 11% is excreted in urine as metabolites.1,51,61,105 Small amounts of the drug are excreted in feces.68

Fluconazole is removed by hemodialysis1,37 and peritoneal dialysis.47 The amount of the drug removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate).37 A 3-hour period of hemodialysis generally decreases plasma concentrations of the drug by 50%.1,37 In 2 adults with fungal peritonitis undergoing continuous ambulatory peritoneal dialysis (CAPD) and receiving an oral fluconazole dosage of 100 mg/kg daily, concentrations of the drug in peritoneal dialysis fluid ranged from 2.3-9 mcg/mL and concurrent plasma concentrations ranged from 3.2-9 mcg/mL.47

Chemistry and Stability

Chemistry

Fluconazole, a synthetic triazole derivative, is an azole antifungal agent.1,2,3,5,28,51,61,67,68,76,78,84,124 The drug is structurally related to imidazole-derivative azole antifungals (e.g., butoconazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole) since it contains a 5-membered azole ring attached by a carbon-nitrogen bond to other aromatic rings.2,3,84 However, imidazoles have 2 nitrogens in the azole ring (imidazole ring) and fluconazole and other triazoles (e.g., itraconazole, terconazole) have 3 nitrogens in the ring (triazole ring).2,3,84

Replacement of the imidazole ring with a triazole ring apparently results in increased antifungal activity and an expanded antifungal spectrum of activity.51,121 In addition to this triazole ring, fluconazole contains a second triazole ring and thus is a bistriazole derivative.76,84,121 Presence of these triazole rings may contribute to fluconazole's resistance to first-pass metabolism and the drug's low lipophilicity and protein binding.76,84 However, other structural modifications to bistriazole derivatives also affect these characteristics since itraconazole, which also is a bistriazole, is highly lipophilic and protein bound and undergoes extensive hepatic metabolism.76,121 Presence of a halogenated phenyl ring increases antifungal activity of bistriazole derivatives and the 2,4-difluorophenyl derivative (fluconazole) has an aqueous solubility suitable for IV formulation.84

Fluconazole occurs as a white crystalline powder1 and is slightly soluble in water,1 having an aqueous solubility of 8 mg/mL at 37°C.84 The drug has a solubility of 25 mg/mL in alcohol at room temperature.117 Fluconazole has a pK_a of 1.76 at 24°C in 0.1 M sodium chloride.117 Fluconazole injections are sterile, iso-osmotic solutions of the drug in a sodium chloride or dextrose diluent; each mL contains 2 mg of fluconazole and either 9 mg of sodium chloride or 56 mg of dextrose.1 The injections have an osmolarity of 300-315 mOsm/L;117 the pH ranges from 4-8 in the sodium chloride diluent and from 3.5-6.5 in the dextrose diluent.1

Stability

Fluconazole tablets should be stored in tight containers117 at a temperature less than 30°C; fluconazole powder for oral suspension should be stored at a temperature less than 30°C.1 After reconstitution, refrigeration of fluconazole oral suspension is not necessary and freezing of the suspension should be avoided.1 The manufacturer states that the reconstituted suspension is stable for 14 days when stored at 5-30°C and any unused suspension should be discarded after this period.1

Commercially available fluconazole injection provided in glass bottles should be stored at 5-30°C and protected from freezing.1 Fluconazole injection provided in Viaflex^® Plus plastic containers should be stored at 5-25°C and protected from freezing; brief exposure of the drug in Viaflex^® Plus containers to temperatures up to 40°C will not adversely affect the injection.1 Commercially available fluconazole injection in glass or plastic containers is stable for 24 or 18 months, respectively, following the date of manufacture.117,215 The Viaflex^® Plus plastic containers are fabricated from specially formulated polyvinyl chloride (PVC).1 The amount of water that can permeate from inside the container into the overwrap is insufficient to substantially affect the solution.1 Solutions in contact with the plastic can leach out some of its chemical components in very small amounts (e.g., bis(2-ethylhexyl)phthalate BEHP, DEHP in up to 5 ppm) within the expiration period of the injection; however, safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.1 Additives should not be introduced into the glass117 or Viaflex^® Plus containers1 of commercially available fluconazole injection.

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

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