Brand name: Sporanox
Drug class: Azoles
VA class: AM700
Chemical name: 4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-l]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one
CAS number: 84625-61-6

Medically reviewed by Drugs.com on Jan 22, 2024. Written by ASHP.

Introduction

Antifungal; azole (triazole derivative).

Uses for Itraconazole

Aspergillosis

Treatment of invasive aspergillosis. Considered an alternative, not a drug of choice.

Treatment of pulmonary and extrapulmonary aspergillosis in patients intolerant of, or whose disease is refractory to, IV amphotericin B.

IDSA considers voriconazole the drug of choice for primary treatment of invasive aspergillosis in most patients and IV amphotericin B the preferred alternative. For salvage therapy in patients refractory to or intolerant of primary antifungal therapy, IDSA recommends amphotericin B, caspofungin, micafungin, posaconazole, or itraconazole. For empiric or preemptive therapy of presumed aspergillosis, IDSA recommends amphotericin B, caspofungin, itraconazole, or voriconazole.

Not considered a drug of choice or preferred alternative for treatment of invasive aspergillosis in HIV-infected individuals. For treatment of invasive aspergillosis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend voriconazole as the drug of choice; voriconazole also considered the drug of choice for treatment of invasive aspergillosis in HIV-infected children. Because the drugs have similar mechanisms of action and cross-resistance may occur, itraconazole not recommended for treatment of aspergillosis refractory to voriconazole.

For primary prophylaxis of aspergillosis in immunocompromised individuals at high risk of invasive disease (i.e., neutropenic patients with acute myelogenous leukemia [AML] or myelodysplastic syndrome [MDS], hematopoietic stem cell transplant [HSCT] recipients with graft-versus-host disease [GVHD]), IDSA considers posaconazole the drug of choice; alternatives are itraconazole or micafungin.

Blastomycosis

Treatment of pulmonary and extrapulmonary blastomycosis caused by Blastomyces dermatitidis.

Drugs of choice are oral itraconazole or IV amphotericin B.

IV amphotericin B is preferred 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.

Itraconazole is the drug of choice for treatment of nonmeningeal, non-life-threatening blastomycosis, including mild to moderate pulmonary blastomycosis or mild to moderate disseminated blastomycosis (without CNS involvement), and also is recommended for follow-up therapy in patients with more severe infections after an initial response has been obtained with IV amphotericin B.

Azole antifungals should not be relied on for initial treatment of CNS blastomycosis. 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.

IDSA states that long-term suppressive or maintenance therapy (secondary prophylaxis)^{† [off-label]} with itraconazole may be required to prevent relapse or recurrence of blastomycosis in immunocompromised patients and in other patients who experience relapse despite appropriate therapy. Such prophylaxis is not addressed in current CDC, NIH, and IDSA guidelines for prevention of opportunistic infections in individuals infected with HIV.

Candidemia and Other Invasive Candida Infections

Not a drug of choice or preferred alternative for treatment of candidemia^{† [off-label]} or other invasive Candida infections^{† [off-label]}. Fluconazole or voriconazole usually are recommended when an azole antifungal is used for treatment of candidemia.

Has been used and is recommended as an alternative for initial empiric treatment of suspected invasive candidiasis in neutropenic patients^{† [off-label]}. IV amphotericin B, caspofungin, or voriconazole are drugs of choice in these patients; alternatives are fluconazole or itraconazole. Do not use an azole antifungal for empiric treatment in patients who previously received an azole for prophylaxis.

Oropharyngeal Candidiasis

Treatment of oropharyngeal candidiasis.

IDSA recommends topical treatment with clotrimazole lozenges or nystatin oral suspension for mild oropharyngeal candidiasis; oral fluconazole is recommended for moderate to severe disease. For refractory oropharyngeal candidiasis, including fluconazole-refractory infections, itraconazole oral solution, oral posaconazole, or oral voriconazole is recommended. An IV echinocandin (caspofungin, micafungin, anidulafungin) or IV amphotericin B also are recommended as alternatives for refractory infections.

For treatment of oropharyngeal candidiasis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend oral fluconazole as the preferred drug of choice for initial episodes; other drugs of choice are clotrimazole lozenges or nystatin oral suspension. Alternatives for initial episodes are itraconazole oral solution or oral posaconazole. For fluconazole-refractory infections in HIV-infected adults and adolescents, itraconazole oral solution or oral posaconazole is preferred; alternatives include IV amphotericin B, an IV echinocandin (caspofungin, micafungin, anidulafungin), or oral or IV voriconazole.

Although routine long-term suppressive or maintenance therapy (secondary prophylaxis)^{† [off-label]} to prevent relapse or recurrence is not usually recommended in patients adequately treated for oropharyngeal candidiasis, patients with frequent or severe recurrences, including HIV-infected adults, adolescents, or children, may benefit from secondary prophylaxis with oral fluconazole or itraconazole oral solution; however, consider the potential for azole resistance. Patients with fluconazole-refractory oropharyngeal candidiasis who responded to treatment with an echinocandin should receive voriconazole or posaconazole for secondary prophylaxis until antiretroviral therapy produces immune reconstitution.

Esophageal Candidiasis

Treatment of esophageal candidiasis.

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

IDSA recommends oral fluconazole as the preferred drug of choice for treatment of esophageal candidiasis; if oral therapy is not tolerated, IV fluconazole, IV amphotericin B, or an IV echinocandin (caspofungin, micafungin, anidulafungin) is recommended. For fluconazole-refractory infections, preferred alternatives are itraconazole oral solution, oral posaconazole, or oral or IV voriconazole; other alternatives are an IV echinocandin (caspofungin, micafungin, anidulafungin) or IV amphotericin B.

For treatment of esophageal candidiasis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend oral or IV fluconazole as the preferred drug of choice and itraconazole oral solution as the preferred alternative. Other alternatives include an IV echinocandin (caspofungin, micafungin, anidulafungin), oral or IV voriconazole, oral posaconazole, or IV amphotericin B. For refractory esophageal candidiasis, including fluconazole-refractory infections, in HIV-infected adults and adolescents, itraconazole oral solution or oral posaconazole is preferred; alternatives include IV amphotericin B, an IV echinocandin (caspofungin, micafungin, anidulafungin), or oral or IV voriconazole.

Although 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, patients with frequent or severe recurrences, including HIV-infected adults, adolescents, or children, may benefit from secondary prophylaxis with oral fluconazole or oral posaconazole; however, consider the potential for azole resistance. Patients with fluconazole-refractory esophageal candidiasis who responded to treatment with an echinocandin should receive voriconazole or posaconazole for secondary prophylaxis until antiretroviral therapy produces immune reconstitution. Itraconazole is not included in current recommendations for secondary prophylaxis of esophageal candidiasis.

Vulvovaginal Candidiasis

Has been used for treatment of uncomplicated vulvovaginal candidiasis^†.

Vulvovaginal candidiasis is usually treated with an intravaginal azole antifungal (e.g., butoconazole, clotrimazole, miconazole, terconazole, tioconazole) or a single-dose oral fluconazole regimen. Although some clinicians suggest that oral itraconazole or oral ketoconazole can be used as alternatives for treatment of vulvovaginal candidiasis, fluconazole is the only oral antifungal included in CDC recommendations for treatment of uncomplicated or complicated vulvovaginal candidiasis.

Chromomycosis

Has been used for treatment of chromomycosis^† (chromoblastomycosis) caused by various dematiaceous fungi (e.g., Cladosporium, Exophiala, Fonsecaea, Phialophora).

Coccidioidomycosis

Treatment and prevention of coccidioidomycosis^† caused by Coccidioides immitis or C. posadasii. A drug of choice.

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

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

For treatment of clinically mild coccidioidomycosis (e.g., focal pneumonia or a positive coccidioidal serologic test alone) in HIV-infected adults or adolescents, CDC, NIH, and IDSA recommend oral fluconazole or oral itraconazole. For treatment of diffuse pulmonary coccidioidomycosis or extrathoracic disseminated (nonmeningeal) coccidioidomycosis 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) followed by an oral azole alone.

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

For treatment of coccidioidal meningitis in HIV-infected adults, adolescents, or children or for other individuals, fluconazole (with or without intrathecal amphotericin B) is the regimen of choice. Itraconazole may be an alternative to fluconazole in adults and adolescents. Consultation with an expert is recommended.

In HIV-infected adults and adolescents who live in areas where coccidioidomycosis is endemic, CDC, NIH, and IDSA recommend primary prophylaxis against coccidioidomycosis^† in those who have positive IgM or IgG serologic tests and CD4⁺ T-cell counts <250/mm³ since these individuals may be at increased risk for development of active infections. Oral fluconazole or oral itraconazole should be used for primary prophylaxis against coccidioidomycosis in these HIV-infected adults and adolescents. Primary prophylaxis against coccidioidomycosis is not recommended in HIV-infected children.

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

Long-term (life-long) suppressive or maintenance therapy (secondary prophylaxis)^† with oral fluconazole or oral itraconazole also is necessary in any individual treated for coccidioidal meningitis.

Cryptococcosis

Has been used for treatment of cryptococcosis^†. Not a drug of choice or preferred alternative.

For treatment of cryptococcal meningitis in HIV-infected adults, adolescents, and children, CDC, NIH, and IDSA state that the preferred regimen is initial (induction) therapy with IV amphotericin B given in conjunction with oral flucytosine, then follow-up (consolidation) therapy with oral fluconazole. Although data are limited and use of the drug is discouraged, IDSA and others state that itraconazole can be considered an alternative for induction and consolidation therapy if all other alternative regimens have failed or are not available.

For treatment of mild to moderate pulmonary cryptococcosis in immunocompetent individuals, the regimen of choice is oral fluconazole. Although data are limited, IDSA states that itraconazole, voriconazole, and posaconazole are acceptable alternatives in immunocompetent individuals if fluconazole is unavailable or contraindicated.

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

HIV-infected adults, adolescents, and children who have been adequately treated for cryptococcus should receive long-term suppressive or maintenance therapy (secondary prophylaxis)^† to prevent recurrence or relapse. CDC, NIH, and IDSA recommend oral fluconazole as the drug of choice for secondary prophylaxis of cryptococcosis in HIV-infected individuals; oral itraconazole is considered an alternative in those who cannot tolerate fluconazole, but may be less effective than fluconazole.

Although data are limited, IDSA states that recommendations for treatment of CNS or disseminated infections caused by Cryptococcus gattii and recommendations for secondary prophylaxis of C. gattii infections are the same as recommendations for C. neoformans infections.

Histoplasmosis

Treatment of histoplasmosis caused by Histoplasma capsulatum, including chronic cavitary pulmonary disease and disseminated nonmeningeal disease.

Drugs of choice for treatment of histoplasmosis are IV amphotericin B and 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 treatment of severe infections after a response has been obtained with IV amphotericin B.

For treatment of moderately severe to severe acute pulmonary histoplasmosis or progressive disseminated histoplasmosis in HIV-infected adults and adolescents and other adults, CDC, NIH, and IDSA recommend initial treatment with IV amphotericin B and follow-up treatment with oral itraconazole.

For treatment of progressive disseminated histoplasmosis in children, IDSA states that IV amphotericin B or an initial regimen of IV amphotericin B and follow-up treatment with oral itraconazole can be used. For treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected infants and children, CDC, NIH, and IDSA recommend initial treatment with IV amphotericin B and follow-up treatment with oral itraconazole. Although oral itraconazole may be used alone for treatment of mild to moderate disseminated histoplasmosis in children, including HIV-infected infants and children, it is not recommended for more severe infections.

HIV-infected adults or adolescents with CD4⁺ T-cell counts <150/mm³ who are at high risk because they reside in areas where histoplasmosis is highly endemic should receive primary prophylaxis^† against initial episodes of histoplasmosis. Itraconazole is the drug of choice for primary prophylaxis against histoplasmosis in these HIV-infected adults and adolescents. Primary prophylaxis against histoplasmosis is not recommended in HIV-infected children.

HIV-infected adults, adolescents, or children and other immunosuppressed individuals who have been adequately treated for histoplasmosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis)^† to prevent recurrence or relapse. Itraconazole is the drug of choice for secondary prophylaxis against histoplasmosis^†.

Microsporidiosis

Treatment of microsporidiosis^†.

Has been effective in a few cases of keratoconjunctivitis or sinusitis caused by Encephalitozoon. Regimen of choice for ocular microsporidiosis is fumagillin (not commercially available in the US) used in conjunction with albendazole.

Alternative for disseminated microsporidiosis, especially infections caused by Trachipleistophora or Anncaliia; used in conjunction with albendazole. Albendazole usually is the drug of choice for intestinal or disseminated microsporidiosis (except infections caused by Enterocytozoon bienuesi or Vittaforma corneae).

Onychomycosis

Treatment of onychomycosis of the toenails (with or without fingernail involvement) and onychomycosis of the fingernails caused by dermatophytes (tinea unguium).

Paracoccidioidomycosis

Treatment of paracoccidioidomycosis^† (South American blastomycosis) caused by Paracoccidioides brasiliensis.

IV amphotericin B is the drug of choice for initial treatment of severe paracoccidioidomycosis. Oral itraconazole is the drug of choice for treatment of less severe or localized paracoccidioidomycosis and for follow-up in more severe infections after initial treatment with IV amphotericin B.

Penicilliosis

Treatment of penicilliosis^† caused by Penicillium marneffei.

For treatment of severe or disseminated P. marneffei infections, including in HIV-infected adults or adolescents, an initial regimen of IV amphotericin B followed by oral itraconazole is recommended. Oral itraconazole can be used alone for treatment of mild infections.

Chronic suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole is recommended to prevent relapse of penicilliosis^† in HIV-infected adults or adolescents who respond to an initial treatment regimen of IV amphoterin B and/or oral itraconazole.

Sporotrichosis

Treatment of sporotrichosis^† caused by Sporothrix schenckii.

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

Zygomycosis

Treatment of GI basidiobolomycosis^†, a zygomycosis caused by Basidiobolus ranarum.

Has been effective in a few patients for the treatment of subcutaneous basidiobolomycosis.

GI basidiobolomycosis has been successfully treated with oral itraconazole after partial surgical resection of the GI tract; unclear whether a clinical response would have been obtained if itraconazole had been used alone without surgical intervention.

Empiric Therapy in Febrile Neutropenic Patients

Has been used for empiric therapy of presumed fungal infections in febrile neutropenic patients.

Related/similar drugs

ciprofloxacin, fluconazole, Augmentin, amoxicillin / clavulanate, nystatin, nystatin topical, vancomycin

Itraconazole Dosage and Administration

Administration

Administer orally.

Has been administered by IV infusion, but an IV preparation is no longer commercially available in the US.

Oral Administration

Oral bioavailability varies depending on whether the drug is administered as capsules or the oral solution; these preparations should not be used interchangeably.

The possibility that GI absorption may be decreased in patients with hypochlorhydria (e.g., HIV-infected individuals) should be considered. (See Absorption under Pharmacokinetics.)

Capsules

The capsules should be administered with a full meal to ensure maximal absorption of the drug.

Capsules should not be used for treatment of oropharyngeal or esophageal candidiasis; efficacy not established, may be less effective than oral solution for these infections.

If capsules are given in a dosage >200 mg daily, daily dosage should be divided into 2 doses.

Oral Solution

The oral solution should be administered without food to ensure maximal absorption of the drug.

For treatment of oropharyngeal or esophageal candidiasis, the recommended dosage of itraconazole oral solution should be vigorously swished in the mouth (10 mL at a time) for several seconds and then swallowed.

Manufacturer states that data are limited to date regarding the safety of long-term use of itraconazole oral solution (i.e., >6 months).

Dosage

Because of differences in oral bioavailability, itraconazole capsules and oral solution should not be used interchangeably.

Only the oral solution (not capsules) is indicated for treatment of oropharyngeal or esophageal candidiasis.

To ensure adequate plasma concentrations of itraconazole (especially in patients with life-threatening fungal infections), IDSA and others recommend that itraconazole plasma concentrations be determined, usually after 2 weeks of therapy.

Pediatric Patients

Blastomycosis†

Treatment of Blastomycosis†

Oral

Mild to moderate blastomycosis: IDSA recommends 10 mg/kg daily (up to 400 mg daily) for 6–12 months.

Moderately severe to severe blastomycosis: IDSA recommends an initial regimen of IV amphotericin B given for 1–2 weeks, followed by itraconazole 10 mg/kg daily (up to 400 mg daily) for a total treatment duration of 12 months.

Candida Infections†

Treatment of Oropharyngeal Candidiasis†

Oral

HIV-infected infants and children (oral solution): 2.5 mg/kg twice daily (up to 200 mg daily) for 7–14 days.

HIV-infected infants and children with fluconazole-refractory infections (oral solution): 2.5 mg/kg twice daily (up to 200–400 mg daily) for 7–14 days.

HIV-infected adolescents (oral solution): 200 mg daily for 7–14 days. Same dosage can be used for fluconazole-refractory infections.

Prevention of Recurrence (Secondary Prophylaxis) of Oropharyngeal Candidiasis†

Oral

HIV-infected adolescents (oral solution): 200 mg daily.

Secondary prophylaxis not usually recommended; use only if patient has frequent or severe recurrences. Consider discontinuing secondary prophylaxis if CD4⁺ T-cell count increases to ≥200/mm³ in response to antiretroviral therapy.

Treatment of Esophageal Candidiasis†

Oral

HIV-infected infants and children (oral solution): 2.5 mg/kg twice daily or 5 mg/kg once daily for 14–21 days.

HIV-infected adolescents (oral solution): 200 mg daily for 14–21 days.

Treatment of Vulvovaginal Candidiasis†

Oral

HIV-infected adolescents (oral solution): 200 mg daily for 3–7 days.

Coccidioidomycosis†

Treatment of Coccidioidomycosis (Nonmeningeal)†

Oral

HIV-infected infants and children with mild coccidioidomycosis (e.g., focal pneumonia): 5–10 mg/kg twice daily for 3 days, then 2–5 mg/kg twice daily.

HIV-infected infants and children with diffuse pulmonary or disseminated coccidioidomycosis: Initial regimen of IV amphotericin B given until a response is obtained, followed by itraconazole 5–10 mg/kg twice daily for 3 days, then 2–5 mg/kg twice daily (up to 400 mg daily).

HIV-infected adolescents with mild coccidioidomycosis (e.g., focal pneumonia or positive coccidioidal serologic test alone): 200 mg 3 times daily for 3 days, then 200 mg twice daily.

Treatment of Coccidioidal Meningitis†

Oral

HIV-infected adolescents with meningeal coccidioidomycosis: 200 mg 3 times daily for 3 days, then 200 mg twice daily.

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

Primary Prophylaxis to Prevent First Episode of Coccidioidomycosis†

Oral

HIV-infected adolescents living in areas endemic for coccidioidomycosis who have positive IgM or IgG serologic test and CD4⁺ T-cell count <250/mm³: 200 mg twice daily.

Consider discontinuing primary prophylaxis if CD4⁺ T-cell count is >250/mm³ for 6 months. Reinitiate primary prophylaxis against coccidioidomycosis if CD4⁺ T-cell count decreases to <250/mm³.

Prevention of Recurrence (Secondary Prophylaxis) of Coccidioidomycosis†

Oral

HIV-infected infants and children: 2–5 mg/kg (up to 200 mg) twice daily.

HIV-infected adolescents: 200 mg twice daily.

Initiate secondary prophylaxis after primary infection has been adequately treated.

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

HIV-infected adolescents with history of focal coccidioidal pneumonia who responded to antifungal treatment, are receiving antiretroviral therapy, and have CD4⁺ T-cell counts >250/mm³: Consider discontinuing secondary prophylaxis against coccidioidomycosis after 12 months, but continue monitoring for recurrence (e.g., serial chest radiographs, coccidioidal serology).

HIV-infected adolescents with history of diffuse pulmonary or disseminated coccidioidomycosis or history of coccidioidal meningitis: Continue life-long secondary prophylaxis against coccidioidomycosis, regardless of antiretroviral therapy or immune reconstitution.

Cryptococcosis†

Treatment of Cryptococcosis†

Oral

HIV-infected infants and children with CNS cryptococcosis: Initial (induction) regimen of IV amphotericin B given for at least 2 weeks, then follow-up (consolidation) regimen of itraconazole 200 mg 3 times daily for 3 days, then 5–10 mg/kg (maximum 200 mg) once or twice daily for at least 8 weeks.

HIV-infected adolescents with CNS cryptococcosis: Initial (induction) regimen of IV amphotericin B given for at least 2 weeks, then follow-up (consolidation) regimen of itraconazole 200 mg twice daily for 8 weeks or until CD4⁺ T-cell count is ≥200/mm³ for at least 6 months as the result of antiretroviral therapy.

Some clinicians suggest the oral solution may be preferred (instead of capsules) for treatment of cryptococcosis.

Prevention of Recurrence (Secondary Prophylaxis) of Cryptococcosis†

Oral

HIV-infected infants and children (oral solution): 5 mg/kg (up to 200 mg) daily.

HIV-infected adolescents: 200 mg daily.

Initiate secondary prophylaxis after primary infection has been adequately treated.

HIV-infected infants and children with a history of cryptococcosis usually should receive life-long suppressive therapy to prevent recurrence. Consideration can be given to discontinuing secondary prophylaxis in HIV-infected children ≥6 years of age who are asymptomatic for cryptococcosis, have received secondary prophylaxis for ≥6 months, have been receiving antiretroviral therapy for ≥6 months, and have CD4⁺ T-cell counts ≥200/mm³ for ≥6 months. Reinitiate secondary prophylaxis against cryptococcosis if CD4⁺ T-cell count decreases to <200/mm³.

HIV-infected adolescents with a history of cryptococcosis usually should receive life-long secondary prophylaxis to prevent recurrence. Some experts state that consideration can be given to discontinuing secondary prophylaxis in HIV-infected adolescents who are asymptomatic for cryptococcosis, are receiving antiretroviral therapy, and have CD4⁺ T-cell counts ≥200/mm³ for >6 months. Reinitiate secondary prophylaxis against cryptococcosis if CD4⁺ T-cell count decreases to <200/mm³.

Histoplasmosis†

Treatment of Histoplasmosis†

Oral

Acute pulmonary histoplasmosis: IDSA recommends 5–10 mg/kg daily (up to 400 mg daily) given in 2 divided doses.

Progressive disseminated histoplasmosis: IDSA recommends initial regimen of IV amphotericin B given for 2–4 weeks, followed by itraconazole 5–10 mg/kg daily (up to 400 mg daily) given in 2 divided doses for a total duration of 3 months. A longer duration may be necessary in children with severe disease or with immunosuppression or primary immunodeficiency syndromes.

HIV-infected infants and children with mild disseminated histoplasmosis (oral solution): 2–5 mg/kg (up to 200 mg) 3 times daily for 3 days, then 2–5 mg/kg (up to 200 mg) twice daily for 12 months.

HIV-infected infants and children with moderately severe to severe disseminated histoplasmosis: Initial regimen of IV amphotericin B given for at least 1–2 weeks, followed by itraconazole (oral solution) 2–5 mg/kg (up to 200 mg) 3 times daily for 3 days, then 2–5 mg/kg (up to 200 mg) twice daily for 12 months.

HIV-infected infants and children with CNS histoplasmosis: Initial regimen of IV amphotericin B given for 4–6 weeks, followed by itraconazole (oral solution) 2–5 mg/kg (up to 200 mg) 3 times daily for 3 days, then 2–5 mg/kg (up to 200 mg) twice daily for at least 12 months and until CSF abnormalities resolve and histoplasmal antigen is undetectable.

HIV-infected adolescents with less severe disseminated histoplasmosis: 200 mg 3 times daily for 3 days, then 200 mg twice daily for at least 12 months.

HIV-infected adolescents with moderately severe to severe disseminated histoplasmosis: Initial regimen of IV amphotericin B given for at least 2 weeks or until a response is obtained, followed by itraconazole 200 mg 3 times daily for 3 days, then 200 mg twice daily for a total duration of at least 12 months and until histoplasmal antigen is undetectable.

HIV-infected adolescents with CNS histoplasmosis: Initial regimen of IV amphotericin B given for 4–6 weeks or until a response is obtained, followed by itraconazole 200 mg 2 or 3 times daily for at least 12 months and until CSF abnormalities resolve and histoplasmal antigen is undetectable.

Some clinicians suggest the oral solution may be preferred (instead of capsules) for treatment of histoplasmosis.

Primary Prophylaxis to Prevent First Episode of Histoplasmosis†

Oral

HIV-infected adolescents with CD4⁺ T-cell counts ≤150/mm³ who are at high risk because they reside in areas where histoplasma is highly endemic: 200 mg daily.

Consider discontinuing primary prophylaxis in HIV-infected adolescents receiving antiretroviral therapy if CD4⁺ T-cell count >150/mm³ for 6 months. Reinitiate primary prophylaxis if CD4⁺ T-cell count decreases to ≤150/mm³.

Prevention of Recurrence (Secondary Prophylaxis) of Histoplasmosis†

Oral

HIV-infected infants and children and other immunosuppressed children and children who experience relapse after adequate treatment (oral solution): 5 mg/kg daily (up to 200 mg daily).

HIV-infected adolescents: 200 mg daily.

Initiate secondary prophylaxis after primary infection has been adequately treated.

HIV-infected infants and children with a history of histoplasmosis usually should receive life-long suppressive therapy to prevent recurrence. Consideration can be given to discontinuing secondary prophylaxis in HIV-infected children ≥6 years of age who have negative Histoplasma blood cultures, have serum Histoplasma antigen <2 ng/mL, have received itraconazole for ≥12 months, have been receiving antiretroviral therapy for ≥6 months, and have CD4⁺ T-cell counts ≥150/mm³. Reinitiate secondary prophylaxis against histoplasmosis if CD4⁺ T-cell count decreases to <150/mm³.

HIV-infected adolescents with a history of histoplasmosis should receive life-long suppressive therapy to prevent recurrence. Consideration can be given to discontinuing secondary prophylaxis in HIV-infected adolescents who have negative Histoplasma blood cultures, have serum Histoplasma antigen <2 ng/mL, have received itraconazole for ≥12 months, have been receiving antiretroviral therapy for ≥6 months, and have CD4⁺ T-cell counts ≥150/mm³. Reinitiate secondary prophylaxis against histoplasmosis if CD4⁺ T-cell count decreases to <150/mm³.

Penicilliosis†

Treatment of Penicilliosis†

Oral

HIV-infected adolescents with mild penicilliosis: 400 mg daily for 8 weeks.

HIV-infected adolescents with severe penicilliosis: Initial regimen of IV amphotericin B given for 2 weeks, followed by itraconazole 400 mg daily for 10 weeks.

Prevention of Recurrence (Secondary Prophylaxis) of Penicilliosis†

Oral

HIV-infected adolescents: 200 mg daily.

Initiate secondary prophylaxis after primary infection has been adequately treated.

Limited data indicate secondary prophylaxis may be discontinued in HIV-infected adolescents who are receiving antiretroviral therapy and have CD4⁺ T-cell counts >100/mm³ for ≥6 months. Reinitiate secondary prophylaxis against penicilliosis if CD4⁺ T-cell count decreases to <100/mm³.

Sporotrichosis†

Treatment of Sporotrichosis†

Oral

Cutaneous or lymphocutaneous sporotrichosis: IDSA recommends 6–10 mg/kg daily (up to 400 mg daily). Continue for 2–4 weeks after all lesions have resolved; usual duration is 3–6 months.

Disseminated sporotrichosis: IDSA recommends initial regimen of IV amphotericin B given until a response is obtained, followed by itraconazole 6–10 mg/kg daily (up to 400 mg daily) for a total duration of at least 12 months.

Some clinicians suggest the oral solution may be preferred (instead of capsules) for treatment of sporotrichosis.

Adults

General Adult Dosage

Treatment of Serious, Life-threatening Systemic Fungal Infections

Oral

Capsules: Manufacturer recommends initial loading dosage of 200 mg 3 times daily (600 mg daily) for the first 3 days, then 200–400 mg daily thereafter.

Usually continued for 3 months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment can result in recurrence of active infection.

Aspergillosis

Treatment of Pulmonary or Extrapulmonary Aspergillosis

Oral

Capsules: 200–400 mg daily.

Invasive Aspergillosis

Oral

IDSA and others recommend 200 mg 3 times daily for 3 days, then 200 mg twice daily.

Empiric or Preemptive Therapy of Presumed Aspergillosis†

Oral

IDSA recommends 200 mg twice daily.

Primary Prophylaxis to Prevent Aspergillosis†

Oral

Immunocompromised individuals at high risk of invasive aspergillosis: IDSA recommends 200 mg twice daily.

Blastomycosis

Treatment of Pulmonary or Extrapulmonary Blastomycosis

Oral

Capsules: Manufacturer recommends 200 mg once daily. If there is evidence of progression or no apparent improvement, increase dosage in 100-mg increments daily up to a maximum dosage of 400 mg daily. Usual duration is 6–12 months.

Mild to moderate pulmonary or mild to moderate disseminated blastomycosis (without CNS involvement): IDSA recommends 200 mg 3 times daily for 3 days, then 200 mg once or twice daily for 6–12 months.

Moderately severe to severe pulmonary blastomycosis (without CNS involvement): IDSA recommends an initial regimen of IV amphotericin B given for 1–2 weeks or until a response is obtained, followed by itraconazole 200 mg 3 times daily for 3 days, then 200 mg twice daily for a total treatment duration of 6–12 months.

Moderately severe to severe disseminated blastomycosis (without CNS involvement): IDSA recommends an initial regimen of IV amphotericin B given for 1–2 weeks or until a response is obtained, followed by itraconazole 200 mg 3 times daily for 3 days, then 200 mg twice daily for a total treatment duration of at least 12 months.

CNS blastomycosis: IDSA recommends an initial regimen of IV amphotericin B given for 4–6 weeks, followed by itraconazole 200 mg 2 or 3 times daily for at least 12 months and until CSF abnormalities resolve.

Prevention of Recurrence (Secondary Prophylaxis) of Blastomycosis†

Oral

Immunocompromised adults: IDSA recommends 200 mg daily.

Life-long secondary prophylaxis may be necessary if immunosuppression cannot be reversed. In HIV-infected adults, consider discontinuing secondary prophylaxis after at least 12 months if patient is receiving antiretroviral therapy and CD4⁺ T-cell count is >150/mm³ for at least 6 months.

Candida Infections

Treatment of Oropharyngeal Candidiasis

Oral

Oral solution: Manufacturer recommends 200 mg (20 mL) daily for 1–2 weeks. Clinical signs and symptoms generally resolve within several days.

Retreatment in patients who failed to respond to or are refractory to oral fluconazole: Manufacturer recommends 100 mg (10 mL) twice daily. A response to itraconazole in these patients generally is evident within 2–4 weeks; relapse may be expected shortly after the drug is discontinued.

HIV-infected adults (oral solution): 200 mg daily for 7–14 days.

Prevention of Recurrence (Secondary Prophylaxis) of Oropharyngeal Candidiasis†

Oral

HIV-infected adults (oral solution): 200 mg daily.

Secondary prophylaxis not usually recommended; use only if patient has frequent or severe recurrences. Consider discontinuing secondary prophylaxis if CD4⁺ T-cell count increases to ≥200/mm³ in response to antiretroviral therapy.

Treatment of Esophageal Candidiasis

Oral

Oral solution: Manufacturer recommends 100 mg (10 mL) daily; depending on patient response, up to 200 mg (20 mL) daily may be given. Manufacturer states usual duration is at least 3 weeks; continue for 2 weeks after symptoms resolve.

HIV-infected adults and other adults (oral solution): 200 mg daily for 14–21 days.

Treatment of Vulvovaginal Candidiasis†

Oral

200 mg twice daily for 1 day recommended by some clinicians.

HIV-infected adults (oral solution): 200 mg daily for 3–7 days.

Empiric Treatment of Suspected Candidiasis in Neutropenic Patients†

Oral

IDSA recommends 200 mg twice daily. Do not use in patients who previously received prophylaxis with an azole antifungal.

Coccidioidomycosis†

Treatment of Coccidioidomycosis (Nonmeningeal)†

Oral

200 mg 2 or 3 times daily.

HIV-infected adults with mild coccidioidomycosis (e.g., focal pneumonia or positive coccidioidal serologic test alone): 200 mg 3 times daily for 3 days, then 200 mg twice daily. Uncomplicated coccidioidal pneumonia usually treated for 3–6 months.

Treatment of Coccidioidal Meningitis†

Oral

HIV-infected adults with meningeal coccidioidomycosis: 200 mg 3 times daily for 3 days, then 200 mg twice daily.

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

Primary Prophylaxis to Prevent First Episode of Coccidioidomycosis†

Oral

HIV-infected adults living in areas endemic for coccidioidomycosis who have positive IgM or IgG serologic test and CD4⁺ T-cell count <250/mm³: 200 mg twice daily.

Consider discontinuing primary prophylaxis if CD4⁺ T-cell count is >250/mm³ for 6 months. Reinitiate primary prophylaxis against coccidioidomycosis if CD4⁺ T-cell count decreases to <250/mm³.

Prevention of Recurrence (Secondary Prophylaxis) of Coccidioidomycosis†

Oral

HIV-infected adults: 200 mg twice daily.

Initiate secondary prophylaxis after primary infection has been adequately treated.

HIV-infected adults with history of focal coccidioidal pneumonia who are receiving antiretroviral therapy and have CD4⁺ T-cell counts >250/mm³: Consider discontinuing secondary prophylaxis against coccidioidomycosis after 12 months, but continue monitoring for recurrence (e.g., serial chest radiographs, coccidioidal serology).

HIV-infected adults with history of diffuse pulmonary or disseminated coccidioidomycosis or history of coccidioidal meningitis: Continue life-long secondary prophylaxis against coccidioidomycosis, regardless of antiretroviral therapy or immune reconstitution.

Cryptococcosis†

Treatment of Cryptococcosis†

Oral

Immunocompetent adults with mild to moderate pulmonary (nonmeningeal) cryptococcosis: 200 mg twice daily for 6–12 months.

HIV-infected adults with cryptococcal meningitis: Initial (induction) regimen of IV amphotericin B given for at least 2 weeks, then follow-up (consolidation) regimen of itraconazole 200 mg twice daily for 8 weeks or until CD4⁺ T-cell count is ≥200/mm³ for at least 6 months as the result of antiretroviral therapy.

HIV-infected adults with cryptococcal meningoencephalitis: IDSA states itraconazole 200 mg twice daily given for 10–12 weeks can be considered as an alternative for both induction and consolidation therapy, although use of this regimen is discouraged and should be used only when all other alternative regimens have failed or are not available.

Some clinicians suggest the oral solution may be preferred (instead of capsules) for treatment of cryptococcosis.

Prevention of Recurrence (Secondary Prophylaxis) of Cryptococcosis†

Oral

HIV-infected adults: 200 mg once or twice daily. Some evidence that the twice-daily regimen is more effective for secondary prophylaxis than the once-daily regimen.

Initiate secondary prophylaxis after primary infection has been adequately treated.

IDSA states that consideration can be given to discontinuing secondary prophylaxis in HIV-infected adults who have received at least 1 year of antifungal treatment, are receiving antiretroviral therapy, have had undetectable or low plasma HIV RNA levels for at least 3 months, and have CD4⁺ T-cell counts >100/mm³. If secondary prophylaxis against cryptococcosis is discontinued, the patient should be followed closely and serial cryptococcal serum antigen tests performed. Reinitiate secondary prophylaxis against cryptococcosis if CD4⁺ T-cell count decreases to <100/mm³ and/or serum cryptococcal antigen titer increases.

Other experts state that HIV-infected adults with a history of cryptococcosis generally should receive life-long suppressive therapy to prevent recurrence unless immune reconstitution occurs in response to antiretroviral therapy. These experts state that consideration can be given to discontinuing secondary prophylaxis in HIV-infected adults who are asymptomatic for cryptococcosis, are receiving antiretroviral therapy, and have CD4⁺ T-cell counts ≥200/mm³ for >6 months. Reinitiate secondary prophylaxis against cryptococcosis if CD4⁺ T-cell count decreases to <200/mm³.

Histoplasmosis

Treatment of Histoplasmosis

Oral

Chronic cavitary pulmonary histoplasmosis or disseminated, nonmeningeal histoplasmosis (capsules): Manufacturer recommends 200 mg once daily. If there is evidence of progression or no apparent improvement, increase dosage in 100-mg increments daily up to a maximum dosage of 400 mg daily. Usual duration is at least 12 months.

Mild to moderate acute pulmonary histoplasmosis when treatment is considered necessary (i.e., symptomatic for >1 month): IDSA recommends 200 mg 3 times daily for 3 days, then 200 mg once or twice daily for 6–12 weeks.

Moderately severe to severe acute pulmonary histoplasmosis: IDSA recommends an initial regimen of IV amphotericin B given for 1–2 weeks, followed by itraconazole 200 mg 3 times daily for 3 days, then 200 mg twice daily for a total treatment duration of 12 weeks.

Chronic cavitary pulmonary histoplasmosis: IDSA recommends 200 mg 3 times daily for 3 days, then 200 mg once or twice daily for at least 1 year. Because of relapse risk, some clinicians prefer a duration of 18–24 months.

Mild to moderate disseminated histoplasmosis: IDSA recommends 200 mg 3 times daily for 3 days, then 200 mg twice daily for at least 1 year.

Moderately severe to severe progressive disseminated histoplasmosis: IDSA recommends an initial regimen of IV amphotericin B given for 1–2 weeks, followed by itraconazole 200 mg 3 times daily for 3 days, then 200 mg twice daily for a total treatment duration of at least 12 months.

Histoplasmosis with symptomatic mediastinal granuloma or with complications (pericarditis, rheumatologic syndromes, symptomatic mediastinal lymphadenitis) that require treatment with corticosteroids: 200 mg 3 times daily for 3 days, then 200 mg once or twice daily for 6–12 weeks.

HIV-infected adults with less severe disseminated histoplasmosis: 200 mg 3 times daily for 3 days, then 200 mg twice daily for at least 12 months.

HIV-infected adults with moderately severe to severe disseminated histoplasmosis: Initial regimen of IV amphotericin B given for at least 2 weeks or until a response is obtained, then follow-up regimen of itraconazole 200 mg 3 times daily for 3 days, then 200 mg twice daily for a total duration of at least 12 months and until histoplasmal antigen is undetectable.

CNS histoplasmosis in HIV-infected adults or other adults: Initial regimen of IV amphotericin B given for 4–6 weeks or until a response is obtained, then follow-up regimen of itraconazole 200 mg 2 or 3 times daily for at least 12 months and until CSF abnormalities resolve and histoplasmal antigen is undetectable.

Some clinicians suggest the oral solution may be preferred (instead of capsules) for treatment of histoplasmosis.

Primary Prophylaxis to Prevent First Episode of Histoplasmosis†

Oral

Immunosuppressed adults: IDSA recommends 200 mg daily.

HIV-infected adults with CD4⁺ T-cell counts ≤150/mm³ who are at high risk because they live in areas where histoplasmosis is endemic: 200 mg daily.

Consider discontinuing primary prophylaxis against histoplasmosis in HIV-infected adults receiving antiretroviral therapy if CD4⁺ T-cell count is >150/mm³ for 6 months. Reinitiate primary prophylaxis against histoplasmosis if CD4⁺ T-cell count decreases to ≤150/mm³.

Prevention of Recurrence (Secondary Prophylaxis) of Histoplasmosis†

Oral

HIV-infected adults and other immunosuppressed adults: 200 mg daily.

Initiate secondary prophylaxis after primary infection has been adequately treated.

HIV-infected adults with a history of histoplasmosis should receive life-long suppressive therapy to prevent recurrence. Consideration can be given to discontinuing secondary prophylaxis in HIV-infected adults who have negative Histoplasma blood cultures, have serum Histoplasma antigen <2 ng/mL, have received itraconazole for ≥12 months, have been receiving antiretroviral therapy for ≥6 months, and have CD4⁺ T-cell counts ≥150/mm³. Reinitiate secondary prophylaxis against histoplasmosis if CD4⁺ T-cell count decreases to <150/mm³.

Microsporidiosis†

Oral

Keratoconjunctivitis and sinusitis caused by Encephalitozoon: 200 mg daily for 8 weeks has been used.

Disseminated microsporidiosis caused by Trachipleistophora or Anncaliia: 400 mg daily in conjunction with albendazole has been recommended.

Onychomycosis

Onychomycosis of the Fingernails (Without Toenail Involvement)

Oral

Capsules: Manufacturer recommends a pulse-dosing regimen of 200 mg twice daily during the first week, no itraconazole during weeks 2–4, then 200 mg twice daily during the fifth week.

Onychomycosis of the Toenails (With or Without Fingernail Involvement)

Oral

Capsules: Manufacturer recommends 200 mg once daily for 12 consecutive weeks.

Capsules: a pulse-dosing regimen of 400 mg once daily for one week each month for 3 months^† also has been effective.

Penicilliosis†

Treatment of Penicilliosis†

Oral

HIV-infected adults with mild penicilliosis: 400 mg daily for 8 weeks.

HIV-infected adults with severe or disseminated penicilliosis: Initial regimen of IV amphotericin B given for 2 weeks, followed by itraconazole 400 mg daily for 10 weeks.

Prevention of Recurrence (Secondary Prophylaxis) of Penicilliosis†

Oral

HIV-infected adults: 200 mg daily.

Initiate secondary prophylaxis after primary infection has been adequately treated.

Limited data indicate secondary prophylaxis may be discontinued in HIV-infected adults who are receiving antiretroviral therapy and have CD4⁺ T-cell counts >100/mm³ for ≥6 months. Reinitiate secondary prophylaxis against penicilliosis if CD4⁺ T-cell count decreases to <100/mm³.

Sporotrichosis†

Treatment of Sporotrichosis†

Oral

Cutaneous or lymphocutaneous sporotrichosis: IDSA and others recommend 200 mg once daily. If a response is not obtained, increase dosage to 200 mg twice daily. Continue for 2–4 weeks after all lesions have resolved; usual duration is 3–6 months.

Osteoarticular sporotrichosis: IDSA recommends 200 mg twice daily for at least 12 months. If itraconazole is used after a response has been obtained with an initial regimen of IV amphotericin B, continue itraconazole for a total treatment duration of at least 12 months.

Mild pulmonary sporotrichosis: IDSA recommends 200 mg twice daily for at least 12 months.

Severe or life-threatening pulmonary or disseminated sporotrichosis: IDSA recommends initial regimen of IV amphotericin B given until a response is obtained, followed by itraconazole 200 mg twice daily continued for a total treatment duration of at least 12 months.

Meningeal sporotrichosis: IDSA recommends initial regimen of IV amphotericin B given for at least 4–6 weeks and until a response is obtained, followed by itraconazole 200 mg twice daily continued for a total treatment duration of at least 12 months.

Some clinicians suggest the oral solution may be preferred (instead of capsules) for treatment of sporotrichosis.

Empiric Therapy in Febrile Neutropenic Patients

IV, then Oral

Initially, 200 mg IV twice daily for 4 doses, then 200 mg IV once daily for up to 14 days (IV preparation no longer commercially available in the US). After 14 days, switch to itraconazole oral solution in a dosage of 200 mg (20 mL) twice daily until clinically important neutropenia has resolved. Safety and efficacy of itraconazole administered for >28 days for this indication are not known.

Oral

Empiric therapy in chemotherapy-induced neutropenia: IDSA recommends 200 mg twice daily.

Special Populations

Hepatic Impairment

Use caution; only limited data available. (See Hepatic Impairment under Cautions.)

Renal Impairment

Use caution; only limited data available. (See Renal Impairment under Cautions.)

Cautions for Itraconazole

Contraindications

• Hypersensitivity to itraconazole or any ingredient in the formulation.

• Concomitant use with certain drugs metabolized by CYP3A4 isoenzymes (e.g., cisapride, lovastatin, midazolam, pimozide, quinidine, dofetilide, simvastatin, triazolam). (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Hepatotoxicity

Serious hepatotoxicity, including liver failure and death, has occurred rarely and has been reported in patients with or without preexisting liver disease or a serious underlying medical condition. Some cases occurred within the first week of itraconazole therapy.

Mild transient increases in serum liver enzyme concentrations may occur. Increased serum hepatic enzymes (greater than twice the ULN) that required temporary or permanent discontinuance of the drug has occurred in patients receiving itraconazole capsules for treatment of onychomycosis of the toenails (using a 12-week continuous dosing regimen).

Should not be used in patients with increased serum hepatic enzymes, active liver disease, or a history of liver toxicity with other drugs unless the potential benefits exceed the risks.

Monitor serum hepatic enzyme concentrations in any patient with preexisting hepatic impairment and in those who have experienced liver toxicity with other drugs. In addition, consider monitoring serum hepatic enzymes in all patients receiving itraconazole.

Itraconazole should be discontinued immediately and the risks and benefits of continuing therapy with the drug reassessed if signs and symptoms consistent with liver disease develop.

Cardiac Effects

CHF, peripheral edema, and pulmonary edema have been reported in immunocompromised or immunocompetent patients receiving itraconazole for treatment of systemic fungal infections and also have been reported in immunocompetent patients receiving oral itraconazole capsules for treatment of onychomycosis.

Heart failure reported more frequently in those receiving itraconazole dosage of 400 mg daily, but has been reported in those receiving lower dosage.

Manufacturer states itraconazole capsules should not be used for treatment of onychomycosis in patients with evidence of ventricular dysfunction, such as CHF or history of CHF, and should not be used for other indications in patients with evidence of ventricular dysfunction, unless benefits clearly outweigh risks. Discontinued itraconazole oral capsules in patients who develop CHF while receiving the drug.

Manufacturer states itraconazole oral solution should not be used for treatment of systemic fungal infections in patients with evidence of ventricular dysfunction, such as CHF or history of CHF, except for treatment of life-threatening or other serious infections when benefits clearly outweigh risks. If CHF occurs during therapy with itraconazole oral solution, carefully monitor patient and evaluate therapeutic options (including possible discontinuance of the drug).

Clinicians should carefully review the risks and benefits of itraconazole therapy in patients with risk factors for CHF (e.g., those with cardiac disease such as ischemic and valvular disease, clinically important pulmonary disease such as chronic obstructive pulmonary disease, or renal failure and other edematous disorders). If itraconazole is considered necessary in patients with risk factors for CHF, they should be informed of the signs and symptoms of CHF and carefully monitored during therapy.

Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients receiving cisapride, pimozide, levomethadyl (no longer commercially available in the US), or quinidine concomitantly with itraconazole or other CYP3A4 inhibitors. (See Interactions.)

Warnings Related to Oral Solution

Safety and efficacy of itraconazole oral solution has been established only for treatment of oropharyngeal and esophageal candidiasis; the oral solution should not be used interchangeably with the capsules for treatment of other fungal infections.

Oral solution not evaluated for treatment of oropharyngeal and/or esophageal candidiasis in severely neutropenic patients. Oral solution not recommended for initial treatment in patients at immediate risk of systemic candidiasis.

Variable itraconazole concentrations reported in cystic fibrosis patients receiving the oral solution. If oral solution is used in cystic fibrosis patients and an adequate response is not obtained, consider using alternative therapy. (See Pediatric Use under Cautions.)

Oral solution contains hydroxypropyl-β-cyclodextrin (HP-β-CD) as an excipient. HP-β-CD has produced pancreatic adenocarcinomas in rat carcinogenicity studies, but similar effects were not observed in a mouse carcinogenicity study. The clinical relevance of this finding is not known.

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis and Stevens-Johnson syndrome reported rarely.

Cross-hypersensitivity

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

General Precautions

Neuropathy

Although a causal relationship has not been established, neuropathy (including peripheral neuropathy) has occurred rarely in patients receiving itraconazole.

Discontinue itraconazole if neuropathy occurs that may be attributable to the drug.

Otic Effects

Transient or permanent hearing loss reported in patients receiving itraconazole. In some reported cases, patient was also receiving quinidine, a drug that is contraindicated during itraconazole therapy. (See Specific Drugs under Interactions.)

Hearing loss usually resolves when itraconazole is discontinued, but persists in some patients.

If hearing loss occurs, discontinue itraconazole.

Superinfection

Overgrowth of nonsusceptible fungi may occur. These patients may require alternative antifungal therapy.

Selection and Use of Antifungals for Onychomycosis

Prior to administration of itraconazole, appropriate nail specimens for microbiologic studies (e.g., potassium hydroxide [KOH] preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.

When selecting an antifungal for treatment of onychomycosis, consider reported adverse effects and risk of serious effects, possibility of drug interactions, need for prolonged therapy, cost, and risk of relapse.

Toenail infections generally require more prolonged antifungal therapy than fingernail infections.

Specific Populations

Pregnancy

Category C.

Although causal relationship not established, congenital abnormalities (skeletal, genitourinary tract, cardiovascular, ophthalmic) and chromosomal and multiple malformations have been reported during postmarketing experience when the drug was used in pregnant women.

Do not use for treatment of onychomycosis in pregnant women or women contemplating pregnancy.

Lactation

Distributed into human milk. Weigh expected benefits against potential risks to the infant.

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Has been recommended by IDSA and others for treatment of some fungal infections (e.g., blastomycosis, oropharyngeal candidiasis, coccidioidomycosis^†, histoplasmosis, sporotrichosis^†) in children^†, including HIV-infected infants, children, and adolescents^†.

The manufacturer states that a limited number of patients 3–16 years of age with systemic nonmeningeal fungal infections have received itraconazole capsules in a dosage of 100 mg daily and a limited number of pediatric patients 6 months to 12 years of age requiring systemic antifungal therapy have received itraconazole oral solution in a dosage of 5 mg/kg once daily for 2 weeks without any unusual adverse effects.

Data from a pharmacokinetic study evaluating itraconazole oral solution in patients with cystic fibrosis indicate that itraconazole concentrations are variable in such patients and trough concentrations attained in children <16 years of age are lower than those attained in patients 16–28 years of age. Consider using alternative therapy if the oral solution is used in cystic fibrosis patients and an adequate response is not obtained.

Long-term effects of itraconazole therapy on bone growth in children not known. Data from rat studies indicate that itraconazole induces bone defects, including decreased bone plate activity, thinning of the zona compacta of large bones, and increased bone fragility. Bone toxicity observed in animals has not been reported to date in adults receiving itraconazole.

Geriatric Use

Use caution in geriatric patients.

Transient or permanent hearing loss reported in geriatric patients receiving itraconazole. In some reported cases, patient was also receiving quinidine, a drug that is contraindicated during itraconazole therapy. (See Specific Drugs under Interactions.)

Hepatic Impairment

Use caution; only limited data available on use in patients with hepatic impairment. Prolonged half-life in patients with cirrhosis. (See Pharmacokinetics.) This prolonged half-life in cirrhotic patients should be considered when deciding to initiate concomitant therapy with drugs that are metabolized by CYP3A4. (See Interactions.)

Use of itraconazole in patients with increased serum hepatic enzymes, active liver disease, or a history of liver toxicity with other drugs is strongly discouraged unless there is a serious or life-threatening situation when potential benefits outweigh risks.

Monitor serum hepatic enzyme concentrations in patients with preexisting hepatic impairment and in those who have experienced liver toxicity with other drugs.

Renal Impairment

Use caution; only limited data available on use in patients with renal impairment.

Wide interindividual variations in AUC reported in patients with renal impairment. (See Absorption: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

GI effects (nausea, vomiting, diarrhea, abdominal pain, anorexia); rash and pruritus; CNS effects (headache, dizziness); hypokalemia.

Drug Interactions

Metabolized by CYP3A.

Itraconazole and its major metabolite, hydroxyitraconazole, inhibit CYP3A4.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A with possible alteration in metabolism of itraconazole and/or the other drug.

Specific Drugs

Itraconazole Pharmacokinetics

Absorption

Bioavailability

Oral bioavailability varies depending on whether the drug is administered as capsules or the oral solution; these preparations are not bioequivalent.

When administered under optimum conditions for GI absorption (oral solution under fasting conditions or oral capsules with food), the oral solution is more bioavailable than capsules.

When a single 200-mg dose is given as capsules (with a meal), peak plasma concentrations usually attained within 5 hours and average 302 ng/mL. When a single 200-mg dose of itraconazole is given as the oral solution (without food), peak plasma concentrations usually attained within 2.2 hours and average 544 ng/mL.

Food

When itraconazole capsules are used, bioavailability is maximal when administered with food. Food decreases the rate of absorption, but increases peak plasma concentrations and AUC of the oral capsules.

When itraconazole oral solution is used, bioavailability is maximal when administered under fasting conditions. Food decreases the rate and extent of absorption of the oral solution.

Special Populations

In cirrhotic patients who received a single 100-mg itraconazole capsule, mean peak plasma concentrations were 47% lower, but overall exposure (based on AUC) was similar to that in healthy individuals. Data not available regarding long-tem use in such patients.

Single-dose study in uremic patients (mean Cl_cr 13 mL/minute per 1.73 m²) indicates AUC is slightly decreased compared with healthy individuals. Wide interindividual variation in AUC reported in uremic patients and in patients undergoing hemodialysis or CAPD.

Oral absorption of itraconazole is impaired when gastric acid production is decreased. In fasting individuals with relative or absolute achlorhydria (e.g., HIV-infected individuals, those receiving a histamine H₂-receptor antagonist), peak plasma concentrations and AUC are increased when itraconazole oral capsules are administered with a cola beverage compared with administration with water.

In patients with cystic fibrosis receiving itraconazole oral solution (2.5 mg/kg twice daily for 14 days), itraconazole concentrations were variable and trough concentrations attained in children <16 years of age were lower than those in patients 16–28 years of age.

Distribution

Extent

Itraconazole is highly lipophilic and is distributed into nail matrix, bed, and plate following oral administration, persisting in these tissues for several months after discontinuance of the drug.

Distributed into human milk.

Plasma Protein Binding

Itraconazole is 99.8% and hydroxyitraconazole is 99.5% bound to plasma proteins.

Elimination

Metabolism

Metabolized principally in the liver by CYP3A4 isoenzyme to several metabolites. Hydroxyitraconazole, the major metabolite, has antifungal activity.

Saturable metabolism may occur with multiple dosing.

Elimination Route

Approximately 40% of a dose is eliminated in urine as inactive metabolites, <0.03% is eliminated in urine as unchanged drug, and 3–18% is eliminated in feces as unchanged drug.

Itraconazole not appreciably removed by hemodialysis or peritoneal dialysis.

Half-life

Adults receiving oral capsules (200 mg twice daily with a meal): Half-life of itraconazole is 64 hours and half-life of hydroxyitraconazole is 56 hours at steady state.

Adults receiving oral solution (200 mg daily without food): Half-life of itraconazole is 39.7 hours and half-life of hydroxyitraconazole is 27.3 hours at steady state.

Special Populations

Children 6 months to 12 years of age receiving oral solution (5 mg/kg once daily): Half-life of itraconazole is 35.8 hours and half-life of hydroxyitraconazole is 17.7 hours at steady state.

In cirrhotic patients who received a single 100-mg itraconazole dose as capsules, the elimination half-life was 37 hours (compared with 16 hours following a single dose in healthy individuals). Data not available regarding long-tem use in such patients.

Stability

Storage

Oral

Capsules

15–25°C; protect from light and moisture.

Solution

≤25°C; do not freeze.

Actions and Spectrum

• Triazole-derivative azole antifungal.

• Both itraconazole and its major metabolite, hydroxyitraconazole, have antifungal activity.

• Usually fungistatic in action.

• Presumably exerts its antifungal activity by altering cellular membranes resulting in increased membrane permeability, leakage of essential elements (e.g., amino acids, potassium), and impaired uptake of precursor molecules (e.g., purine and pyrimidine precursors to DNA). Inhibits cytochrome P-450 14-α-desmethylase in susceptible fungi, which leads to accumulation of C-14 methylated sterols (e.g., lanosterol) and decreased concentrations of ergosterol.

• Spectrum of antifungal activity includes many fungi, including yeasts and dermatophytes.

• Candida: Active in vitro and in vivo against C. albicans, C. guilliermondii, C. krusei, C. parapsilosis, and C. tropicalis. Some strains of C. lusitaniae are inhibited in vitro by itraconazole.

• Dermatophytes: Active against Epidermophyton, Microsporum, Trichophyton mentagrophytes, and T. rubrum.

• Other fungi: Active against Aspergillus (including A. flavus, A. fumigatus, A. niger, and A. terreus), Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, C. gattii, Histoplasma capsulatum, H. duboisii, Paracoccidioides brasiliensis, Penicillium marneffei, and Sporothrix schenckii. Some zygomycetes, including some strains of Rhizopus, Mucor, Absidia, Rhizomucor, Cunninghamella, and Apophysomyces elegans, are inhibited in vitro by itraconazole. The drug has some activity against Basidiobolus ranarum.

• Itraconazole is not active against Fusarium, Scedosporium, or Scopulariopsis, including S. acremonium and S. brevicaulis.

• Strains of fungi resistant to itraconazole have been isolated in vitro and from patients who received prolonged therapy with the drug. Itraconazole-resistant fungi may be cross-resistant to other azole antifungals (e.g., fluconazole, ketoconazole).

Advice to Patients

• Advise patients that only the oral solution should be used for treatment of oropharyngeal or esophageal candidiasis; the oral solution and capsules are not interchangeable.

• When using itraconazole capsules, importance of taking with a full meal.

• When using itraconazole oral solution, importance of taking without food (if possible) to maximize absorption. Importance of vigorously swishing solution in the mouth for several seconds before swallowing.

• Instruct patients to immediately discontinue itraconazole and contact their clinician if any signs or symptoms of liver dysfunction occur (e.g., unusual fatigue, dark urine, pale stool, anorexia, nausea, vomiting, jaundice) so that appropriate laboratory testing can be performed.

• Inform patients, especially those with risk factors for CHF (e.g., those with cardiac disease such as ischemic and valvular disease, clinically important pulmonary disease such as chronic obstructive pulmonary disease, or renal failure and other edematous disorders) about the signs and symptoms of CHF and importance of immediately discontinuing itraconazole and contacting their clinician if any of these symptoms occur.

• Inform patients that hearing loss can occur; hearing loss usually resolves when itraconazole is discontinued, but persists in some patients. Importance of discontinuing itraconazole and contacting clinician if any symptoms of hearing loss occur.

• Inform patient that HP-β-CD, an excipient present in the oral solution, has been associated with pancreatic adenocarcinoma in rats but that clinical relevance to humans in unknown.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

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

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

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

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Frequently asked questions

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• How do I get rid of nail fungus?
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