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fluconazole 200 mg tablet

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Uses

Fluconazole is used in the treatment of various infections caused by Candida, including candidemia and disseminated candidiasis, oropharyngeal candidiasis, esophageal candidiasis, and vulvovaginal candidiasis.

Fluconazole also is used for the treatment of cryptococcal meningitis and for the treatment of blastomycosis, coccidioidomycosis, and histoplasmosis. Fluconazole has been used for the treatment of superficial fungal infections, dermatophytoses, onychomycosis, and pityriasis (tinea) versicolor. 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, 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).

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). Fluconazole therapy may be started pending results of these in vitro tests; however, once results are available, therapy should be adjusted accordingly. 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.

Candida Infections

Candidemia and Disseminated Candida Infections

Fluconazole is used for the treatment of candidemia, disseminated candidiasis (e.g., chronic disseminated hepatosplenic infections), and other serious Candida infections, including urinary tract infections, peritonitis, meningitis, osteoarticular infections (e.g., osteomyelitis, septic arthritis), intravascular infections (e.g., endocarditis, implantable cardiac device infections), pneumonia, endophthalmitis, and neonatal candidiasis (including CNS infections). The drug has been effective in the treatment of some Candida infections that did not respond to IV amphotericin B.

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). 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.

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. 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. If echinocandin- and azole-resistant Candida are suspected, IV amphotericin B is recommended; IV amphotericin B also is a reasonable alternative when echinocandins and fluconazole cannot be used because of intolerance, limited availability, or resistance. 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. 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.

For the treatment of candidemia in neutropenic patients, IDSA recommends an IV echinocandin (anidulafungin, caspofungin, micafungin) or, alternatively, IV amphotericin B for initial therapy. 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. 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. For infections known to be caused by C. krusei, an echinocandin, amphotericin B, or voriconazole is recommended.

For the treatment of disseminated candidiasis in neonates (neonatal candidiasis), IV amphotericin B usually is the drug of choice. 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. Fluconazole also has been used for prophylaxis to reduce the incidence of invasive candidiasis in low birthweight neonates at high risk.(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.

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). 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. For the treatment of symptomatic candiduria (e.g., cystitis, pyelonephritis, fungus balls) caused by fluconazole-susceptible Candida, fluconazole is the drug of choice. 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.

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. 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.

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. 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.

Fluconazole has been used with good results in some patients with endophthalmitis caused by Candida, but treatment failures have been reported. 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. 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; intravitreal amphotericin B or voriconazole may also be indicated.

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. 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).(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 http://www.idsociety.org should be consulted.

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.

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 infections and is considered a drug of choice for the treatment of moderate to severe disease. Fluconazole has produced clinical resolution of signs and symptoms of the infection in 79-100% of patients with oropharyngeal candidiasis; however, microbiologic cures generally have been obtained in 44-87% of patients and the rate of relapse may be high, especially in neutropenic patients. 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). 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). 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.

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

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. 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. Alternatives for systemic treatment of oropharyngeal candidiasis in HIV-infected adults and adolescents are itraconazole oral solution or posaconazole oral suspension; nystatin oral suspension is an alternative if topical treatment is used. For fluconazole-refractory oropharyngeal infections in HIV-infected adults and adolescents, posaconazole oral suspension is preferred; itraconazole oral solution is an alternative.

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. If secondary prophylaxis of oropharyngeal candidiasis is indicated, oral fluconazole is recommended; however, the potential for development of azole resistance should be considered.

For additional information on management of oropharyngeal candidiasis, the current clinical practice guidelines from IDSA available at http://www.idsociety.org 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 http://www.aidsinfo.nih.gov 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. 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 infections and is considered a drug of choice.

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. 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.

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

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

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

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. If secondary prophylaxis of esophageal candidiasis is indicated, oral fluconazole is recommended and posaconazole oral suspension is a possible alternative; however, the potential for development of azole resistance should be considered.

For additional information on management of esophageal candidiasis, the current clinical practice guidelines from IDSA available at http://www.idsociety.org 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 http://www.aidsinfo.nih.gov should be consulted.

Vulvovaginal Candidiasis

Oral fluconazole is used for the treatment of uncomplicated vulvovaginal candidiasis and for the treatment of complicated vulvovaginal candidiasis in nonpregnant women.

Vulvovaginal candidiasis frequently occurs during pregnancy. CDC states that topical (intravaginal) azole antifungals (not oral fluconazole) should be used for the treatment of vulvovaginal candidiasis during pregnancy.(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. 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. 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%. 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, econazole, miconazole, or terconazole. In addition, the single-dose oral fluconazole regimen appears to be as effective for uncomplicated vulvovaginal candidiasis as oral itraconazole or oral ketoconazole.

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). 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. 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.

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. These regimens generally have been associated with clinical and mycologic cure rates of 80-90% in otherwise healthy, nonpregnant women with uncomplicated infections. Some clinicians suggest that a single oral dose of fluconazole may offer some advantage over conventional intravaginal antifungal therapy since it ensures compliance and may reduce or eliminate concurrent rectal infections that may serve as a source of reinfection. 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. 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.

Complicated and Recurrent Vulvovaginal Candidiasis

Oral fluconazole is used for the treatment of complicated vulvovaginal candidiasis, including recurrent and severe infections. 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). 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).

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%). 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. For the maintenance regimen, CDC and IDSA recommend oral fluconazole (100, 150, or 200 mg once weekly) for 6 months. If this regimen cannot be used, intermittent use of intravaginal treatments can be considered. These maintenance regimens can be effective in reducing recurrent infections; however, 30-50% of women will have recurrent disease once maintenance therapy is discontinued. Women with recurrent infections who are symptomatic and remain culture-positive despite maintenance antifungal therapy should be managed in consultation with a specialist.

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. 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).

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. 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, 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. 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. 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.

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). 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. Optimum therapy for the treatment of vulvovaginal candidiasis caused by Candida other than C. albicans has not been determined. CDC recommends 7-14 days of therapy with an antifungal (oral or intravaginal) other than fluconazole. 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). Referral to a specialist is advised.

For additional information on management of vulvovaginal candidiasis, the current CDC guidelines available at http://www.cdc.gov/std, the current clinical practice guidelines from IDSA available at http://www.idsociety.org, 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 http://www.aidsinfo.nih.gov should be consulted.

Coccidioidomycosis

Oral fluconazole is used for the treatment and prevention of coccidioidomycosis caused by Coccidioides immitis or C. posadasii.

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.

Antifungal treatment may not be necessary in patients with mild, uncomplicated coccidioidal pneumonia since such infections often are self-limited and may resolve spontaneously. 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).

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. 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).

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. 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. 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.

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. 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. 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).

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. Oral itraconazole, oral posaconazole, and oral voriconazole are recommended as alternatives for the treatment of coccidioidal meningitis in adults and adolescents. 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; however, consultation with an expert who has experience in treating coccidioidal meningitis is recommended. Fluconazole has produced clinical and/or laboratory evidence of improvement when used alone or in conjunction with IV amphotericin B in adults with coccidioidal meningitis and has been used for the treatment of coccidioidal meningitis in both HIV-infected and HIV-negative individuals. 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.

Primary Prophylaxis to Prevent First Episode of Coccidioidomycosis

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

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. Those with a newly positive IgM or IgG serologic test and CD4 T-cell counts less than 250/mm should receive oral fluconazole for primary prophylaxis against coccidioidomycosis (preemptive antifungal therapy) since they are at increased risk of developing active coccidioidomycosis. 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) and is not recommended in HIV-infected infants and children.

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.

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.

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. 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/mm 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). However, secondary prophylaxis should be continued indefinitely in HIV-infected adults and adolescents who were treated for more extensive coccidioidomycosis and in all HIV-infected children, regardless of the immune response to antiretroviral therapy. Consultation with an expert is recommended when making decisions regarding discontinuance of secondary prophylaxis against coccidioidomycosis.

For additional information on management of coccidioidomycosis, the current clinical practice guidelines from IDSA available at http://www.idsociety.org 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 http://www.aidsinfo.nih.gov 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. 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. Fluconazole also is used for the treatment of pulmonary cryptococcosis, cryptococcemia, and disseminated cryptococcal infections.

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.

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; induction therapy with IV amphotericin B (conventional or lipid formulation) given in conjunction with oral fluconazole, then consolidation therapy with oral fluconazole; induction therapy with oral or IV fluconazole used in conjunction with oral flucytosine, then consolidation therapy with oral fluconazole; or induction and consolidation therapy with oral fluconazole given alone. These alternative regimens may be less effective and are recommended only in patients who cannot tolerate or have not responded to the preferred regimen.

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. If the induction regimen does not include flucytosine, it should be continued for at least 4-6 weeks. 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.

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. 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.

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. 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.

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

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. 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. 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%).

Fluconazole has been effective in the treatment of acute cryptococcal meningitis in some patients who failed to respond to amphotericin B therapy. 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. 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. 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). CSF cultures were positive for an average of about 42 or 64 days in patients receiving amphotericin B or fluconazole, respectively. 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. 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.

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/mm, 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.

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/mm or lower.

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.

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. Oral fluconazole is the drug of choice for secondary prophylaxis of cryptococcosis in HIV-infected adults, adolescents, and children; some experts suggest that oral itraconazole is an alternative in those who cannot tolerate fluconazole, but the drug may be less effective than fluconazole in preventing relapse of cryptococcosis. 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.

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. 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/mm or greater. If secondary prophylaxis against cryptococcosis is discontinued, the patient should be followed closely and serial cryptococcal serum antigen tests performed. These experts state that secondary prophylaxis against cryptococcosis should be reinitiated if the CD4 T-cell count decreases to less than 100/mm and/or the serum cryptococcal antigen titer increases.

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.

For additional information on management of cryptococcosis, the current clinical practice guidelines from IDSA available at http://www.idsociety.org 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 http://www.aidsinfo.nih.gov 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. 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. 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.

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).(See Spectrum.)

Blastomycosis

Oral fluconazole has been used in the treatment of blastomycosis caused by Blastomyces dermatitidis. Oral itraconazole and IV amphotericin B are the drugs of choice for the treatment of blastomycosis. Although oral fluconazole is considered an alternative for the treatment of blastomycosis, it may be less effective and should be used only when the drugs of choice are contraindicated or cannot be used.

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. 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.

For the treatment of CNS blastomycosis, IDSA recommends initial treatment with IV amphotericin B, followed by an oral azole antifungal. 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. Azole antifungals should not be relied on for initial treatment of CNS blastomycosis. 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.

For additional information on management of blastomycosis, the current clinical practice guidelines from IDSA available at http://www.idsociety.org should be consulted.

Histoplasmosis

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

The drugs of choice for the treatment of histoplasmosis, including histoplasmosis in HIV-infected individuals, are IV amphotericin B or oral itraconazole. IV amphotericin B is preferred for initial treatment of severe, life-threatening histoplasmosis, especially in immunocompromised patients such as those with HIV infection. 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. 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.

In HIV-infected adults and adolescents, oral itraconazole is the drug of choice when primary prophylaxis is indicated to prevent initial episodes of histoplasmosis 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. 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.

For additional information on management of histoplasmosis, the current clinical practice guidelines from IDSA available at http://www.idsociety.org 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 http://www.aidsinfo.nih.gov should be consulted.

Sporotrichosis

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

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. 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.

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

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

For additional information on management of sporotrichosis, the current clinical practice guidelines from IDSA available at http://www.idsociety.org should be consulted.

Dermatophytoses

Oral fluconazole has been used in the treatment of certain dermatophytoses (e.g., tinea capitis, tinea corporis, tinea cruris, tinea pedis) 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, and has resulted in a clinical and mycologic cure in about 88-90% of patients. 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), 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. 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.

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. Tinea capitis and tinea barbae generally are treated using an oral antifungal regimen. While topical antifungals usually are effective for the treatment of uncomplicated tinea manuum and tinea pedis, 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.

Onychomycosis

Oral fluconazole has been used for the treatment of onychomycosis.

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. 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. Oral fluconazole has been recommended as an alternative in patients those who cannot tolerate terbinafine or itraconazole, but may be less effective than the other oral antifungals.

Pityriasis (Tinea) Versicolor

Oral fluconazole has been used in the treatment of pityriasis (tinea) versicolor caused by Malassezia furfur (Pityrosporum orbiculare or P. ovale).

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%). 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.

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. Fluconazole also is used to prevent Candida infections in high-risk patients undergoing urologic procedures and for prevention of invasive candidiasis in high-risk patients in ICUs and in low birthweight neonates at high risk.

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. In addition, fluconazole prophylaxis may reduce the need for empiric antifungal therapy in such patients. 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. 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. 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. 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).

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

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. These experts state that antifungal prophylaxis is not recommended if the anticipated duration of neutropenia is less than 7 days. 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.

Fluconazole has been used for prophylaxis to reduce the incidence of invasive candidiasis in low birthweight neonates at high risk. 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, 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. 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.

For additional information on prevention of fungal infections in neutropenic patients, the current clinical practice guidelines from IDSA available at http://www.idsociety.org should be consulted.

Dosage and Administration

Administration

Fluconazole is administered orally or by IV infusion.

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

Oral Administration

Fluconazole may be given orally without regard to meals.

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. The bottle should be shaken vigorously to suspend the powder; in addition, the suspension should be shaken well just prior to administration.

IV Administration

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

Viaflex Plus containers of fluconazole should be checked for minute leaks by firmly squeezing the bag. 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. Additives should not be introduced into the plastic injection container. 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.

Dosage

Oral and IV dosage of fluconazole are identical.

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.

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. 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.

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.

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.

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.

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. 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. Antifungal treatment should be continued until lesions resolve (usually several months) and should be continued through periods of immunosuppression.

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. Antifungal treatment should be continued until signs and symptoms, CSF abnormalities, and radiologic abnormalities have resolved.

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.

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. 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.

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. Antifungal treatment should be continued for at least 6 weeks after valve replacement surgery. 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.

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. If there is macular involvement, intravitreal amphotericin B or voriconazole may also be indicated.

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. 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.

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.

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.

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. 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/mm in response to antiretroviral therapy.

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. Dosages up to 400 mg once daily may be used depending on the patient's response. The manufacturer recommends that fluconazole therapy be continued for a minimum of 3 weeks and for at least 2 weeks after symptoms have resolved.

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.

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.

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 daily or, alternatively, 100-200 mg 3 times weekly is recommended. 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/mm in response to antiretroviral therapy.

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.

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. Then, to prevent recurrence, a maintenance regimen of 100, 150, or 200 mg of oral fluconazole should be given once weekly for 6 months. IDSA recommends a maintenance regimen of 150 mg of oral fluconazole given once weekly for 6 months.

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). IDSA recommends that 150 mg of oral fluconazole be given once every 72 hours for a total of 2 or 3 doses.

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.

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.

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.

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. 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. The duration of treatment for uncomplicated coccidioidal pneumonia usually is 3-6 months; the total duration of treatment for diffuse pneumonia and chronic progressive fibrocavitary pneumonia usually is at least 1 year.

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. 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.

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. Concomitant intracisternal, intraventricular, or intrathecal amphotericin B therapy has been used in some patients. Consultation with an expert who has experience in treating coccidioidal meningitis is recommended.

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/mm, CDC, NIH, and IDSA recommend that fluconazole be given in a dosage of 400 mg once daily.

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. 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/mm or greater. Such patients should be monitored for recurrence (e.g., serial chest radiographs, coccidioidal serology). 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.

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. Some evidence suggests that the 400-mg dosage is more effective than lower dosage in the treatment of this infection.

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.

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. 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. Although fluconazole dosage as high as 2 g daily has been used, this dosage may be associated with toxicity. If high fluconazole dosage is used, the daily dosage should be given in divided doses to minimize GI toxicity.

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. 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.

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. 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.

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. 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.

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. This same dosage can be used for the treatment of nonpulmonary cryptococcosis at a single site (nonmeningeal).

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

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.

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. Secondary prophylaxis should be initiated after the primary infection has been adequately treated and usually is continued for at least 1 year. 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/mm or greater. Secondary prophylaxis against cryptococcosis should be reinitiated if the CD4 T-cell count decreases to less than 100/mm and/or the serum cryptococcal antigen titer increases.

Histoplasmosis

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

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.

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. 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/mm or greater. Secondary prophylaxis against histoplasmosis should be reinitiated if the CD4 T-cell count decreases to less than 150/mm.

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.

Dermatophytoses

For the treatment of dermatophytoses, oral fluconazole has been given in a dosage of 150 mg once weekly for 2-6 weeks. 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.

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.

Onychomycosis

For the treatment of onychomycosis, oral fluconazole has been given in a dosage of 100-450 mg once weekly for 2-12 months. 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.

Pityriasis (Tinea) Versicolor

For the treatment of pityriasis (tinea) versicolor, adults have received oral fluconazole as a single 400-mg dose. Alternatively, 150 mg has been given once weekly for 2 or 4 weeks or 300 mg has been given once weekly for 2 weeks.

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. In patients in whom severe granulocytopenia (neutrophil count less than 500/ mm) 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/mm. Antifungal prophylaxis is not usually recommended if the anticipated duration of neutropenia is less than 7 days.

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. 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/mm.

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.

Pediatric Dosage

The usual oral or IV dosage of fluconazole in pediatric patients ranges from 3-12 mg/kg once daily; dosages exceeding 600 mg daily are not recommended. 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. Some older children may have clearances similar to those of adults.

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.

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.

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. In some neonates and infants with septicemia, an initial loading dose of 10 mg/kg was administered followed by 5 mg/kg once daily.

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.

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. The manufacturer recommends that treatment be continued for a minimum of 2 weeks to decrease the likelihood of relapse.

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.

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. Limited data are available regarding the safety of discontinuing secondary prophylaxis against oropharyngeal candidiasis in HIV-infected individuals. 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.

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. 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. The manufacturer recommends that treatment be continued for a minimum of 3 weeks and for at least 2 weeks after symptoms have resolved.

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.

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. Limited data are available regarding the safety of discontinuing secondary prophylaxis against esophageal candidiasis in HIV-infected individuals. 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.

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. 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.

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

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. 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.

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. Dosage may be increased to 12 mg/kg daily if necessary based on the condition of the patient and the response to the drug.

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.

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.

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. The duration of treatment depends on the clinical response and site and severity of infection. A duration of 6-12 months has been recommended.

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. The duration of treatment depends on the clinical response and site and severity of infection. A duration of 6-12 months has been recommended.

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. Secondary prophylaxis should be initiated after the primary infection has been adequately treated and usually is continued for at least 1 year. 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/mm or higher. Secondary prophylaxis against cryptococcosis should be reinitiated if the CD4 T-cell count decreases to less than 100/mm.

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.

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. 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/mm in those 6 years of age or older). Secondary prophylaxis against histoplasmosis should be reinitiated if these parameters are not met.

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. AAP recommends a dosage of 6 mg/kg daily for 3-6 weeks.

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.

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.

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. 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.

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. Alternatively, 150 mg has been given once weekly for 4 weeks.

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). 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/mm.

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. If fluconazole prophylaxis is used in neonates at high risk, antifungal resistance, toxicity, and neurodevelopmental outcomes should be monitored.

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.

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.

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. The patient's creatinine clearance (Clcr) can be estimated by using the following formula:

Clcr male = [(140 - age) x weight (in kg)] / [72 x serum creatinine (in mg/dL)]Clcr female = 0.85 x Clcr 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. Patients who are undergoing regular dialysis should receive 100% of the usual daily dose after each dialysis period; on days the patient is not receiving dialysis, reduced dosage based on creatinine clearance should be used. 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.

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.

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.

Cautions

Although fluconazole generally is well tolerated, there have been rare reports of serious hepatotoxicity (including some fatalities) in patients receiving the drug. Adverse effects have been reported in about 5-30% of patients receiving fluconazole for 7 days or longer and have been severe enough to require discontinuance of the drug in about 1-2.8% of patients. 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.

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. 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). 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. 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.

GI Effects

Mild to moderate nausea, vomiting, abdominal pain, and diarrhea have been reported in about 1.5-8.5% of patients receiving fluconazole. Only rarely were such adverse GI effects severe enough to require discontinuance of the drug. Flatus, bloating, dry mouth, hiccups, heartburn, and anorexia 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; abdominal pain, nausea, diarrhea, dyspepsia, and dysgeusia occurred in about 6, 7, 3, 1, and 1% of such women, respectively.

Dermatologic and Sensitivity Reactions

Rash, including diffuse rash accompanied by eosinophilia, and pruritus have been reported in up to about 5% of patients receiving fluconazole. Exfoliative skin disorders have been reported rarely in patients with serious underlying disease (principally AIDS or malignancy) receiving fluconazole; fatalities have been reported. Stevens-Johnson syndrome, which can be fatal, 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. Acute generalized exanthematous pustulosis and increased sweating also have been reported during postmarketing experience.

Anaphylaxis 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.

Hepatic Effects

Serious hepatic reactions (e.g., necrosis, clinical hepatitis, cholestasis, fulminant hepatic failure) have been reported rarely in patients receiving fluconazole therapy. The manufacturer states that a clear relationship between these hepatic effects and daily dosage, duration of therapy, gender, or age has not been demonstrated. While hepatotoxicity usually has been reversible, fatalities have been reported. Fatalities principally have occurred in patients with serious underlying disease (e.g., AIDS, malignancy) who were receiving fluconazole concomitantly with other drugs; 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.

Mild, transient increases (1.5-3 times the upper limit of normal) in serum concentrations of AST (SGOT), ALT (SGPT), alkaline phosphatase, γ-glutamyltransferase (GGT, γ-glutamyl transpeptidase, GGTP), and bilirubin have been reported in about 5-7% of patients receiving fluconazole. In most reported cases, concentrations returned to pretreatment levels either during or after fluconazole therapy and were not associated with hepatotoxicity. 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. Any patient who develops abnormal liver function test results while receiving fluconazole should be closely monitored for the development of more severe hepatic injury.(See Cautions: Precautions and Contraindications.)

Cardiovascular Effects

Prolonged QT interval has occurred in patients receiving azole antifungals. Prolonged QT interval and torsades de pointes have been reported rarely during postmarketing surveillance in patients receiving fluconazole. 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.

Nervous System Effects

Dizziness and headache have been reported in up to about 2% of patients receiving fluconazole. Somnolence, insomnia, delirium/coma, dysesthesia, psychiatric disturbances, malaise, asthenia, paresthesia of hands and feet, tremor, and fatigue have been reported rarely. Seizures 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. 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; headache and dizziness occurred in about 13 and 1% of such women, respectively.

Hematologic Effects

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

Endocrine Effects

Studies using usual dosages of fluconazole have not shown evidence of adverse effects related to possible inhibition of testosterone or steroid synthesis. In one study in healthy premenopausal women receiving fluconazole, there was no effect on serum estradiol concentrations or on serum cortisol stimulation response. 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. 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.

Other Adverse Effects

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

Hypokalemia, which required potassium replacement therapy and/or discontinuance of fluconazole, has occurred occasionally, including in several neutropenic patients with acute myeloid leukemia. Increased serum creatinine and BUN concentrations also have been reported. 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.

Alopecia 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. 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. 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.

Precautions and Contraindications

Fluconazole is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation. 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.

Fluconazole should be used with caution in patients with hepatic impairment. 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.(See Cautions: Hepatic Effects.) Fluconazole should be discontinued if signs and symptoms consistent with liver disease develop. If abnormal liver function test results occur during fluconazole therapy, the patient should be monitored for the development of more severe hepatic injury.

Fluconazole should be used with caution in patients with renal impairment.(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.

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

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

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.(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.(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.(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. If rash that may be attributable to fluconazole develops in a patient with superficial fungal infections, the drug should be discontinued.

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).

Adverse effects reported in children receiving fluconazole generally have been similar to those reported in adults. 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. GI effect, including vomiting, abdominal pain, nausea, and diarrhea, occurred in 2-5% of these pediatric patients. 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, vomiting, and eosinophilia; severe thrombophlebitis was reported in at least one neonate.

Geriatric Precautions

Rash, vomiting, and diarrhea have been reported more frequently in geriatric adults than in younger adults. 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.

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. Other reported clinical experience has not identified differences in response between geriatric and younger patients.

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

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. 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.

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. However, there was an increased incidence of hepatocellular adenomas in male rats receiving an oral fluconazole dosage of 5 or 10 mg/kg daily.

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.

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

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. 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 disease and are similar to those reported in animal reproduction studies. Based on these data, FDA reclassified high-dose fluconazole (400-800 mg daily) as pregnancy category D (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).

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, the single-dose oral fluconazole regimen was classified by FDA as pregnancy category C . 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. 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.

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.

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.

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

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.

In several reproduction studies in pregnant rabbits receiving oral fluconazole dosages of 5, 10, 20, 25, or 75 mg/kg once daily 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. 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. 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. 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). 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. There is no evidence to date that estrogen concentrations are decreased in women receiving fluconazole.(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. 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. 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.

Lactation

Fluconazole is distributed into human milk in concentrations similar to those achieved in plasma. 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). Fluconazole should be used with caution in nursing woman.

Drug Interactions

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; however, comparative studies have not been performed to date. 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.

Drugs Metabolized by Hepatic Microsomal Enzymes

Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. Because fluconazole has a long half-life, its enzyme-inhibiting effects persist for 4-5 days following discontinuance. Concomitant use of fluconazole and drugs metabolized by CYP2C9 or 3A4 may result in increased plasma concentrations of the concomitant drug. When fluconazole is used concomitantly with drugs metabolized by these enzymes, caution should be used and the patient carefully monitored.

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. 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%; these effects were not considered clinically important. 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.

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. Concomitant use with erythromycin should be avoided (see Erythromycin under Drugs Interactions: Macrolides).

Prolongation of the QT interval and QT interval corrected for rate (QTc) 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. 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. Such alterations in the pharmacokinetics of these antihistamines may be associated with prolongation of the QT and QTc intervals. 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, although in vitro data suggest that itraconazole may have a less pronounced effect than ketoconazole on the pharmacokinetics of astemizole. Studies have been performed to determine whether similar interactions occur with concomitant use of terfenadine and fluconazole. 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. 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.

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. 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. 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. The manufacturer of fluconazole states that concomitant use of fluconazole and cisapride is contraindicated.

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

Anticoagulants

Increased prothrombin time has been reported in patients receiving fluconazole concomitantly with a coumarin anticoagulant (e.g., warfarin). 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. Increased prothrombin times also have been reported when lower dosages of fluconazole (100 mg once daily) were administered concomitantly with warfarin sodium. 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. Prothrombin times should be monitored carefully when fluconazole is used concomitantly with a coumarin anticoagulant.

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. 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. 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. In several individuals, symptoms consistent with hypoglycemia occurred; oral glucose therapy was necessary in a few cases.

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.

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. 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. Results of studies evaluating combined use of fluconazole and amphotericin B in animal models of aspergillosis, candidiasis, or cryptococcosis have been conflicting. 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). 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. 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, particularly in immunocompromised patients.

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.

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. Synergism generally did not occur if the C. neoformans isolates had fluconazole MICs of 8 mcg/mL or greater. It has been suggested that synergism between the drugs may occur because fluconazole damages the fungal cell membrane allowing greater intracellular penetration of flucytosine.

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. Reduced dosage or dosing frequency of voriconazole and fluconazole did not overcome this pharmacokinetic interaction. Concomitant use of voriconazole and fluconazole is not recommended and should be avoided. 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.

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). 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.

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

Rifampin

Concomitant use of fluconazole and rifampin may affect the pharmacokinetics of both drugs. 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. There also is some evidence that concomitant use of fluconazole and rifampin results in increased rifampin plasma concentrations compared with administration of rifampin alone. 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.

Rifampin and fluconazole should be used concomitantly with caution and close monitoring. 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.

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. Dosage adjustments are not necessary in patients receiving delavirdine and fluconazole concomitantly.

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; dosage adjustments are not necessary in patients receiving the drugs concomitantly.

Etravirine

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

Nevirapine

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

Rilpivirine

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

HIV Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Concomitant use of fluconazole appears to interfere with the metabolism and clearance of zidovudine. 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. Zidovudine and fluconazole should be used concomitantly with caution and close monitoring. Patients should be monitored closely for zidovudine-associated adverse effects, and zidovudine dosage reductions may be considered.

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.

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

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. Dosage adjustments are not necessary if ritonavir-boosted or cobicistat-boosted atazanavir is used concomitantly with fluconazole.

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. This pharmacokinetic interaction is not considered clinically important; dosage adjustments are not necessary in patients receiving indinavir concomitantly with fluconazole.

Lopinavir

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

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. Dosage adjustments are not needed.

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. This interaction is a result of inhibition of CYP3A4 with decreased metabolism of saquinavir and inhibition of P-glycoprotein. Saquinavir and fluconazole should be used concomitantly with caution and close monitoring; saquinavir dosage may need to be adjusted.

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

Tipranavir

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

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

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. Calcium channel blocking agents and fluconazole should be used concomitantly with caution and close monitoring; patients should be monitored frequently for adverse events.

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. Carbamazepine and fluconazole should be used concomitantly with caution and close monitoring; carbamazepine dosage adjustment may be necessary based on plasma carbamazepine concentrations and clinical effect.

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

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. Concomitant use of fluconazole and pimozide is contraindicated.

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; peak plasma concentration and AUC of fluconazole are not affected. This pharmacokinetic interaction appears to be more pronounced with oral fluconazole than with IV fluconazole. 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. In addition, administration of oral fluconazole to healthy individuals receiving IV midazolam reportedly results in a 50% decrease in clearance of the benzodiazepine. 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. 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. 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.

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%. Triazolam and fluconazole should be used concomitantly with caution and close monitoring; adjustment of triazolam dosage may be necessary.

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.

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

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.

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).

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

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. This interaction may be a result of inhibition of CYP3A4 by fluconazole. Alfentanil and fluconazole should be used concomitantly with caution and close monitoring; adjustment of alfentanil dosage may be necessary.

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

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%. Methadone and fluconazole should be used concomitantly with caution and close monitoring; methadone dosage adjustment may be necessary.

Tricyclic Antidepressants

Concomitant use of amitriptyline or nortriptyline and fluconazole has resulted in increased serum concentrations of the tricyclic antidepressant and may increase adverse effects of the antidepressants. CNS toxicity has been reported in a few patients receiving amitriptyline and fluconazole concomitantly. It has been suggested that fluconazole may interfere with metabolism of amitriptyline by inhibition of CYP isoenzymes involved in metabolism of the antidepressant. Fluconazole and amitriptyline or nortriptyline should be used concomitantly with caution and close monitoring. 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; dosage of amitriptyline or nortriptyline should be adjusted if necessary.

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. This may be a consequence of increased CYP3A4 activity and enhanced metabolism of prednisone as a result of fluconazole discontinuance. 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.

Cyclophosphamide

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

Estrogens and Progestins

Concomitant use of oral fluconazole and oral estrogen-progestin contraceptives may affect the pharmacokinetics of the contraceptives. 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. When fluconazole is used in the dosage range of 50-200 mg daily concomitantly with combined oral contraceptives, interference with oral contraceptive efficacy is unlikely.

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. 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. 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.

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. During fluconazole treatment, the mean AUCs of ethinyl estradiol and norethindrone were increased by 24 and 13%, respectively, compared with placebo. 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.

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. Halofantrine and fluconazole should be used concomitantly with caution and close monitoring.

HCV Antivirals

HCV Protease Inhibitor

Simeprevir

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

Concomitant use of fluconazole and simeprevir is not recommended.

HCV Replication Complex Inhibitor

Daclatasvir

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

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. If concomitant therapy is necessary, creatinine kinase (CK, creatine phosphokinase, CPK) should be monitored and the patient assessed for symptoms of myopathy and rhabdomyolysis. If a substantial increase in CK occurs or myopathy or rhabdomyolysis is diagnosed or suspected, the statin should be discontinued.

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.

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

Immunosuppressive Agents

Cyclosporine

Concomitant use of fluconazole and cyclosporine may result in increased plasma cyclosporine concentrations, especially when the drugs are used in renal transplant recipients. 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. 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. 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. 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. 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.

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

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. Increased tacrolimus concentrations have been associated with nephrotoxicity.

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

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.

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

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%.

Losartan and fluconazole should be used concomitantly with caution and close monitoring. 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 considered and blood pressure closely monitored.

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.

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.

Quinidine

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

Concomitant use of quinidine and fluconazole is contraindicated.

Theophylline

Concomitant use of theophylline and fluconazole increases serum theophylline concentrations. 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.

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

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. These changes are attributed to a 30% decrease in renal clearance of fluconazole. Fluconazole and hydrochlorothiazide should be used concomitantly with caution and close monitoring; adjustment of fluconazole dosage probably is not necessary.

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.

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

Tretinoin

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

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. Vinca alkaloids and fluconazole should be used concomitantly with caution and close monitoring.

Pharmacokinetics

Absorption

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

Oral bioavailability of fluconazole exceeds 90% in healthy, fasting adults; peak plasma concentrations of the drug generally are attained within 1-2 hours after oral administration. 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.

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

Unlike some imidazole-derivative antifungals (e.g., ketoconazole), GI absorption of fluconazole does not appear to be affected by gastric pH. 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. 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.(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. Steady-state plasma concentrations of fluconazole are attained within 5-10 days following oral doses of 50-400 mg given once daily. 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.

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. 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). 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.

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.

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. 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. 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).

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.

Distribution

Fluconazole is widely distributed into body tissues and fluids following oral or IV administration. Studies in mice using IV doses of radiolabeled fluconazole indicate that the drug is evenly distributed throughout body tissues. 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; concentrations attained in saliva, sputum, nails, blister fluid, blister skin, and vaginal tissue are approximately equal to concurrent plasma concentrations. Concentrations attained in vaginal secretions following administration of a single 150-mg oral dose reportedly are about 40-86% of concurrent plasma concentrations. Fluconazole concentrations in prostatic tissue reportedly average about 30% of concurrent plasma concentrations. 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. 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.

Fluconazole, unlike some azole-derivative antifungals (e.g., itraconazole, ketoconazole), distributes readily into CSF following oral or IV administration; CSF concentrations of fluconazole may be 50-94% of concurrent plasma concentrations regardless of the degree of meningeal inflammation. 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.

The apparent volume of distribution of fluconazole approximates that of total body water and has been reported to be 0.7-1 L/kg. 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.

Unlike some azole-derivative antifungals (e.g., itraconazole, ketoconazole, miconazole), which are highly protein bound, fluconazole is only 11-12% bound to plasma proteins.

It is not known whether fluconazole crosses the placenta in humans. The drug crosses the placenta in rats, and concentrations in amniotic fluid, placenta, fetus, and fetal liver are approximately equal to maternal plasma concentrations. Fluconazole is distributed into human milk in concentrations similar to those attained in plasma. 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)

Elimination

The plasma elimination half-life of fluconazole in adults with normal renal function is approximately 30 hours (range: 20-50 hours). 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. 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 200mm and 50 hours (range: 32-69 hours) in those with CD4 T-cell counts less than 200mm. In other single-dose studies in a limited number of HIV-infected adults with CD4 T-cell counts less than 200mm, the plasma elimination half-life of the drug averaged 35-40 hours (range 22-75 hours).

The mean plasma half-life of fluconazole in children 9 months to 15 years of age has ranged from about 15-25 hours. 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).

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

In healthy adults, fluconazole is eliminated principally by renal excretion. Renal clearance of the drug averages 0.27 mL/minute per kg in adults with normal renal function. 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 200mm, and 0.2 L/hour in those with CD4 T-cell counts less than 200mm. Approximately 60-80% of a single oral or IV dose of fluconazole is excreted in urine unchanged, and about 11% is excreted in urine as metabolites. Small amounts of the drug are excreted in feces.

Fluconazole is removed by hemodialysis and peritoneal dialysis. The amount of the drug removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate). A 3-hour period of hemodialysis generally decreases plasma concentrations of the drug by 50%. 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.

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