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itraconazole 100 mg capsule generic sporanox, sporanox pulsepak

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Uses

Oral itraconazole capsules are used in immunocompromised and immunocompetent patients for the treatment of systemic fungal infections, including blastomycosis (pulmonary and extrapulmonary), histoplasmosis (including chronic cavitary pulmonary disease and disseminated, nonmeningeal disease), and aspergillosis (pulmonary and extrapulmonary). Itraconazole oral solution (but not itraconazole capsules) is used for the treatment of oropharyngeal and esophageal candidiasis. Itraconazole (given IV initially [IV preparation no longer commercially available in the US] followed by itraconazole oral solution) has been used for empiric antifungal therapy in febrile neutropenic patients. Oral itraconazole capsules are used in immunocompetent individuals for the treatment of tinea unguium (onychomycosis) of the toenail and/or fingernail caused by dermatophytes. Itraconazole also is used orally for prevention of serious fungal infections (e.g., coccidioidomycosis, cryptococcosis, histoplasmosis, mucocutaneous candidiasis) in patients with human immunodeficiency virus (HIV) infection.

Prior to initiation of oral itraconazole capsules for the treatment of systemic fungal infections, appropriate specimens for fungal culture and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained in order to isolate and identify the causative organism(s). Itraconazole therapy may be started pending results of these in vitro tests; however, once results are available, therapy should be adjusted accordingly.

Aspergillosis

Itraconazole is used in the treatment of pulmonary and extrapulmonary aspergillosis in patients who are intolerant of or who are refractory to IV amphotericin B.

The Infectious Diseases Society of America (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 IV amphotericin B, caspofungin, itraconazole, or voriconazole.

Itraconazole is not considered a drug of choice or preferred alternative for the treatment of invasive aspergillosis in HIV-infected individuals. For the treatment of invasive aspergillosis 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 voriconazole as the drug of choice; amphotericin B, caspofungin, and posaconazole are recommended as alternatives. Voriconazole also is considered the drug of choice for treatment of invasive aspergillosis in HIV-infected children; amphotericin B and caspofungin are alternatives. Because the drugs have similar mechanisms of action and cross-resistance may occur, itraconazole is not recommended for the treatment of aspergillosis refractory to voriconazole.

Itraconazole is recommended as an alternative for primary prophylaxis of aspergillosis in immunocompromised individuals at high risk of invasive aspergillosis. The IDSA considers posaconazole the drug of choice for primary prophylaxis of aspergillosis in neutropenic patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) and in hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD); itraconazole and micafungin are alternatives for prophylaxis in these individuals.

Clinical Experience

In a limited number of patients with invasive aspergillosis who did not respond to or could not tolerate IV amphotericin B, oral itraconazole capsules (200-400 mg daily given for a median duration of therapy of 3-4 months) have been effective as second-line therapy. In an open, multicenter study in adults with active invasive pulmonary aspergillosis (61% had received antifungal prophylaxis and some had received prior empiric antifungal therapy prior to study entry), itraconazole was given in a regimen that included IV itraconazole therapy initially (200 mg twice daily for 2 days then 200 mg once daily for 12 days; IV preparation no longer commercially available in the US) followed by oral itraconazole capsules (200 mg twice daily) for 12 weeks. At the end of itraconazole therapy, 39% had a complete or partial clinical response (intent-to-treat analysis) and the median time to response was 55 days. In a multicenter open study in patients with invasive aspergillosis who received oral itraconazole capsules (200 mg 3 times daily for 4 days, followed by 200 mg twice daily for at least 4 months; some patients received drug therapy for more than 12 months), therapy was effective in about 39% of patients.

Blastomycosis

Itraconazole is used for the treatment of pulmonary and extrapulmonary blastomycosis caused by Blastomyces dermatitidis.

The drugs of choice for the treatment of blastomycosis are oral itraconazole and IV amphotericin B. IV amphotericin B is preferred for initial treatment of severe infections, especially infections involving the CNS, and for initial treatment of presumptive blastomycosis in immunocompromised patients, including HIV-infected individuals.

Oral itraconazole is the drug of choice for the 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.

For the treatment of CNS blastomycosis, the 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 antifungalfor patients with blastomycosis.

The IDSA states that long-term suppressive or maintenance therapy (secondary prophylaxis) with oral 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 the prevention of opportunistic infections in individuals infected with HIV.

Candida Infections

Candidemia and Other Invasive Candida Infections

Itraconazole is not a drug of choice or a preferred alternative for the treatment of candidemia or other invasive Candida infections. Fluconazole or voriconazole usually is recommended when an azole antifungal is used for the treatment of candidemia.

Itraconazole has been used and is recommended as an alternative for initial empiric treatment of suspected invasive candidiasis in neutropenic patients. IV amphotericin B, caspofungin, or voriconazole are considered the drugs of choice in these patients; alternatives are fluconazole or itraconazole. An azole antifungal should not be used for empiric treatment of candidemia in patients who previously received an azole for prophylaxis.

Oropharyngeal Candidiasis

Itraconazole oral solution is used for the treatment of oropharyngeal candidiasis. Because topical effects and drug exposure may be greater with itraconazole oral solution than with itraconazole capsules, only itraconazole oral solution should be used for the treatment of oropharyngeal candidiasis.

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

For the treatment of oropharyngeal candidiasis in HIV-infected adults and adolescents, the 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) 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, and children) may benefit from secondary prophylaxis with oral fluconazole or itraconazole oral solution; however, the potential for azole resistance should be considered. Patients with fluconazole-refractory oropharyngeal candidiasis who responded to an echinocandin should receive voriconazole or posaconazole for secondary prophylaxis until antiretroviral therapy produces immune reconstitution.

Clinical Experience

In 2 controlled studies in patients with oropharyngeal candidiasis (92% were HIV-infected), a clinical response (defined as cured or improved) was attained in 71-84% of patients receiving itraconazole oral solution. There is some evidence that itraconazole oral solution is at least as effective as oral fluconazole tablets and may be more effective than oral clotrimazole lozenges for the treatment of oropharyngeal candidiasis. Itraconazole oral solution has been effective for the treatment of oropharyngeal candidiasis in some patients, including some HIV-infected individuals, who failed to respond to oral fluconazole.

Esophageal Candidiasis

Itraconazole oral solution is used for the treatment of esophageal candidiasis. Because topical effects and drug exposure may be greater with itraconazole oral solution than with itraconazole capsules, only itraconazole oral solution should be used for the treatment of esophageal candidiasis.

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

The 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 the treatment of esophageal candidiasis in HIV-infected adults and adolescents, the 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, the potential for azole resistance should be considered. Itraconazole is not included in current recommendations for secondary prophylaxis of esophageal candidiasis.

Clinical Experience

In a double-blind, randomized study in immunocompromised patients with esophageal candidiasis (93% were HIV-infected), a clinical response (defined as cured or improved) was attained in 94% of those who received itraconazole oral solution and 91% of those who received fluconazole tablets. The median time to response was similar in both groups (27 or 28 days). Follow-up of a group of patients who had a clinical response to the drug indicated that 18% of those who had received itraconazole and 27% of those who had received fluconazole had relapse of esophageal candidiasis within 30 days after treatment was discontinued.

Vulvovaginal Candidiasis

Oral itraconazole has been used for the 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 the treatment of vulvovaginal candidiasis, fluconazole is the only oral antifungal included in CDC recommendations for the treatment of uncomplicated or complicated vulvovaginal candidiasis.

Chromomycosis

Oral itraconazole has been used with some success for the treatment of chromomycosis (chromoblastomycosis) caused by various dematiaceous fungi (e.g., Cladosporium, Exophiala, Fonsecaea, Phialophora).

Coccidioidomycosis

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

Treatment of Coccidioidomycosis

Oral itraconazole is used for the treatment of coccidioidomycosis.

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).

The IDSA states 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 who have 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 or a positive coccidioidal serologic test alone) in HIV-infected adults and adolescents, the 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, the 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 the treatment of diffuse pulmonary or disseminated coccidioidomycosis (nonmeningeal) in HIV-infected infants and children, the 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, or children or other individuals, IV or oral fluconazole (with or without intrathecal amphotericin B) is considered the regimen of choice. Oral itraconazole has been recommended as an alternative to fluconazole in adults and adolescents. Consultation with an expert who has experience in treating coccidioidal meningitis is recommended.

Primary Prophylaxis to Prevent First Episode of Coccidioidomycosis

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

The CDC, NIH, and IDSA recommend that HIV-infected adults and adolescents living in areas where coccidioidomycosis is endemic (e.g., Southwestern US, parts of Central and South America) be tested annually for the disease using IgM or IgG serologic tests. Those with positive IgM or IgG serologic tests and CD4 T-cell counts less than 250/mm should receive oral fluconazole or oral itraconazole for primary prophylaxis against coccidioidomycosis since they are at increased risk of developing active coccidioidomycosis. 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

Itraconazole is used for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of coccidioidomycosis.

Because of the risk of relapse, any individual who was treated for coccidioidal meningitis should receive long-term (life-long) secondary prophylaxis with oral fluconazole or oral itraconazole.

The CDC, NIH, and IDSA recommend that all HIV-infected adults, adolescents, or 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 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.

Cryptococcosis

Although not considered a drug of choice or a preferred alternative, oral itraconazole has been used for the treatment of cryptococcosis.

For the treatment of cryptococcal meningitis in HIV-infected adults, adolescents, and children, the CDC, NIH, and IDSA state that the preferred regimen is initial (induction) therapy with IV amphotericin B (conventional formulation) 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, the IDSA and others state that itraconazole can be considered an alternative for induction and consolidation therapy of cryptococcosis if all other alternative regimens have failed or are not available.

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

Severe pulmonary cryptococcosis, cryptococcemia, and disseminated cryptococcal 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. The CDC, NIH, and IDSA recommend oral fluconazole as the drug of choice for secondary prophylaxis of cryptococcosis in HIV-infected adults, adolescents, and children; oral itraconazole is considered an alternative in those who cannot tolerate fluconazole, but may be less effective than fluconazole.

Although data are limited, the 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 the recommendations for C. neoformans infections.

For more complete information on the treatment and prevention of cryptococcosis,

Histoplasmosis

Itraconazole is used for the treatment and prevention of histoplasmosis caused by Histoplasma capsulatum.

Treatment of Histoplasmosis

Itraconazole is used for the treatment of histoplasmosis, including chronic cavitary pulmonary disease and disseminated nonmeningeal disease.

The drugs of choice for the treatment of histoplasmosis are IV amphotericin B and oral itraconazole; oral ketoconazole and oral fluconazole are considered alternatives. 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.

For the treatment of moderately severe to severe acute pulmonary histoplasmosis or progressive disseminated histoplasmosis in HIV-infected adults and adolescents and other adults, the CDC, NIH, and IDSA recommend initial treatment with IV amphotericin B and follow-up treatment with oral itraconazole. Itraconazole has been used alone for the treatment of disseminated histoplasmosis in patients with HIV infection, and the manufacturer states that data from a limited number of patients indicate that the response rate of histoplasmosis to itraconazole therapy in HIV-infected individuals is similar to that in patients not infected with the virus. However, the clinical course of histoplasmosis in HIV-infected individuals generally is more severe and usually requires long-term maintenance therapy to prevent relapse.

For the treatment of progressive disseminated histoplasmosis in children, the 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 the treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected infants and children, the 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 the treatment of mild to moderate disseminated histoplasmosis in children, including HIV-infected infants and children, this regimen is not recommended for more severe infections.

For the treatment of meningitis caused by H. capsulatum in HIV-infected adults, adolescents, or children and other individuals, the CDC, NIH, and IDSA recommend initial treatment with IV amphotericin B and follow-up treatment with oral itraconazole.

For more complete information on the treatment of histoplasmosis,

Primary Prophylaxis to Prevent First Episode of Histoplasmosis

HIV-infected adults and adolescents with CD4 T-cell counts less than 150/mm 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.

Prevention of Recurrence (Secondary Prophylaxis) of Histoplasmosis

HIV-infected adults, adolescents, and 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

Itraconazole has been used in the treatment of microsporidiosis.

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

Although albendazole usually is the drug of choice for the treatment of intestinal or disseminated microsporidiosis (except infections caused by Enterocytozoon bienuesi or Vittaforma corneae), some clinicians suggest that itraconazole used in conjunction with albendazole is a possible alternative for disseminated microsporidiosis, especially infections caused by Trachipleistophora or Anncaliia.

Onychomycosis

Oral itraconazole capsules are used in immunocompetent individuals for the treatment of onychomycosis of the toenails (with or without fingernail involvement) and onychomycosis of the fingernails caused by dermatophytes (tinea unguium). Prior to administration of itraconazole capsules for the treatment of onychomycosis, appropriate nail specimens should be obtained for microbiologic studies (e.g., potassium hydroxide [KOH] preparation, fungal culture, nail biopsy) to confirm the diagnosis.(See Cautions: Precautions and Contraindications.)

Clinical Experience

In double-blind, placebo-controlled studies in patients with onychomycosis of the toenails, oral itraconazole (200 mg as capsules given once daily for 12 consecutive weeks) resulted in a mycologic cure in 54% of patients; 35% were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% had mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months; however, 21% of those considered an overall success had relapse of onychomycosis.

In a double-blind, placebo-controlled study in patients with onychomycosis of the fingernails, oral itraconazole given in a pulse-dosing regimen (200 mg as capsules twice daily for the first week, no itraconazole during weeks 2-4, and 200 mg as capsules twice daily during the fifth week) resulted in a mycologic cure in 61% of patients; 56% were considered an overall success and 47% had mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months; there were no relapses in those who were considered an overall success.

Paracoccidioidomycosis

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

Penicilliosis

Oral itraconazole is used in the treatment of penicilliosis caused by Penicillium marneffei.

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

Chronic suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole is recommended to prevent relapse of penicilliosis in HIV-infected adults and adolescents who respond to an initial treatment regimen of IV amphoteric B and/or oral itraconazole. Limited data indicate that secondary prophylaxis with oral itraconazole can be discontinued in those who are receiving antiretroviral therapy and have CD4 T-cell counts that have remained greater than 100/mm for 6 months or longer. However, secondary prophylaxis should be reinitiated if the CD4 T-cell count decreases to less than 100/mm or if penicilliosis recurs.

Sporotrichosis

Itraconazole is used in the 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 the treatment of cutaneous, lymphocutaneous, or mild pulmonary or osteoarticular sporotrichosis and for follow-up treatment in more severe infections after a response has been obtained with IV amphotericin B.

Zygomycosis

Itraconazole has been used in a limited number of patients for the treatment of basidiobolomycosis, a zygomycosis caused by Basidiobolus ranarum. Itraconazole has been effective in a few patients for the treatment of subcutaneous basidiobolomycosis or the treatment of GI basidiobolomycosis.

B. ranarum has been isolated worldwide from decaying vegetation and soil and from the GI tracts of reptiles, amphibians, fish, and insectivorous bats (including in the US). Basidiobolomycosis most commonly occurs in tropical and subtropical regions such as eastern and western Africa and infection usually manifests as painless, subcutaneous nodules of the limbs, trunk, or buttocks secondary to traumatic inoculation. GI infections are extremely rare and possibly the result of ingestion of contaminated soil (especially near rivers or lakes) or fruits or vegetables contaminated with soil or feces from infected reptiles or amphibians.

From April 1994 through May 1999, 7 cases of GI basidiobolomycosis were identified in Arizona. Most cases of GI basidiobolomycosis have been successfully treated with oral itraconazole (400 mg daily given for 3-19 months) after partial surgical resection of the GI tract; however, it is unclear whether a clinical response would have been obtained if itraconazole had been used alone without surgical intervention. Although ketoconazole also has been reported to be effective in at least one patient, amphotericin B has been ineffective for the treatment of GI basidiobolomycosis in several patients.

Empiric Therapy in Febrile Neutropenic Patients

Itraconazole (given IV initially followed by itraconazole oral solution; IV preparation no longer commercially available in the US) has been used for empiric therapy of presumed fungal infections in febrile neutropenic patients.

Clinical Experience

Safety and efficacy of itraconazole for this indication has been evaluated in an open, randomized study in febrile neutropenic adults with hematologic malignancies; patients received either itraconazole (200 mg IV twice daily for 2 days, then 200 mg IV once daily from days 3-14 followed by itraconazole oral solution 200 mg twice daily to complete up to 28 days of therapy) or conventional IV amphotericin B (0.7-1 mg/kg daily for up to 28 days). The therapeutic success rate (defined as patient survival with resolution of fever and neutropenia within 28 days of therapy, absence of emergent fungal infections, use of study drug without premature discontinuance because of toxicity or lack of efficacy, and therapy for 3 or more days) was 47% for itraconazole and 38% for amphotericin B (intent-to-treat analysis). Although the overall response rate was higher in those receiving itraconazole, more patients receiving itraconazole discontinued the drug because of persistent fever or changed antifungal therapy because of fever and more patients receiving amphotericin B discontinued the drug because of intolerance.

Dosage and Administration

Reconstitution and Administration

Itraconazole is administered orally.

Itraconazole also has been administered by IV infusion; however, an IV preparation of the drug is no longer commercially available in the US.

Oral Administration

Bioavailability of oral itraconazole varies depending on whether the drug is administered as capsules or as an oral solution, and the manufacturer states that these preparations should not be used interchangeably.

The possibility that GI absorption of the drug may be decreased when gastric acid production is decreased (e.g., in patients with hypochlorhydria, including some individuals with human immunodeficiency virus [HIV] infection) should be considered.(See Pharmacokinetics: Absorption.)

Capsules

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

The capsules should not be used for the treatment of oropharyngeal or esophageal candidiasis; efficacy has not been established and this formulation may be less effective than the oral solution for these infections.

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

Oral Solution

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

For the 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.

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

Dosage

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

Itraconazole appears to undergo saturable metabolism in the liver; therefore, increases in dosage can result in more than proportional increases in plasma concentrations.

Dosage of itraconazole capsules should be based on the type and severity of infection, identity of the causative organism, and patient's response to therapy.

To ensure adequate plasma concentrations of itraconazole (especially in patients with life-threatening fungal infections), the Infectious Diseases Society of America (IDSA) and other experts recommend that itraconazole plasma concentrations be determined, usually after 2 weeks of therapy.

General Adult Dosage for Treatment of Serious, Life-threatening Systemic Fungal Infections

For the treatment of life-threatening systemic fungal infections, the manufacturer states that oral itraconazole capsules should be initiated using a loading dosage. Although clinical studies evaluating the safety and efficacy of oral itraconazole capsules did not include a loading dosage, the manufacturer states that, based on pharmacokinetic considerations, oral itraconazole capsules should be initiated in life-threatening infections in adults using an initial loading dosage of 200 mg 3 times daily (600 mg daily) for the first 3 days of therapy. Subsequent therapy then can be continued at the usual oral dosage of 200-400 mg daily.

The manufacturer states that itraconazole therapy should be continued for at least 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 Aspergillosis in Adults

For the treatment of pulmonary or extrapulmonary aspergillosis in adults who do not respond to or cannot tolerate IV amphotericin B, the recommended dosage of itraconazole capsules is 200-400 mg daily. For the treatment of invasive aspergillosis, the IDSA and other clinicians recommend a dosage of 200 mg 3 times daily for 3 days, then 200 mg twice daily.

For empiric or preemptive therapy of presumed aspergillosis, the IDSA recommends that itraconazole be given in a dosage of 200 mg twice daily.

Primary Prophylaxis to Prevent Aspergillosis in Adults

If itraconazole is used as an alternative for primary prophylaxis of aspergillosis in immunocompromised individuals at high risk of invasive aspergillosis (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]), the IDSA recommends a dosage of 200 mg twice daily.

Blastomycosis

Treatment of Blastomycosis in Adults

For the treatment of pulmonary or extrapulmonary blastomycosis in adults, the manufacturer recommends that itraconazole capsules be administered in an initial dosage of 200 mg once daily. If there is no apparent improvement or there is evidence of progression of the fungal infection at this dosage, the manufacturer recommends increasing the dosage in 100-mg increments daily up to a maximum dosage of 400 mg daily. Oral itraconazole dosages exceeding 200 mg daily should be divided into 2 doses daily.

For the treatment of mild to moderate pulmonary or mild to moderate disseminated blastomycosis (without CNS involvement) in adults, the IDSA recommends that itraconazole be given in a dosage of 200 mg 3 times daily for 3 days, then 200 mg once or twice daily for 6-12 months.

For the treatment of moderately severe to severe pulmonary or moderately severe to severe disseminated blastomycosis (without CNS involvement) in adults, the IDSA recommends an initial regimen of IV amphotericin B given for 1-2 weeks or until a response is obtained, followed by itraconazole given in a dosage of 200 mg 3 times daily for 3 days, then 200 mg twice daily. The total treatment duration should be 6-12 months for pulmonary blastomycosis or at least 12 months for disseminated extrapulmonary blastomycosis or for immunocompromised individuals.

For the treatment of CNS blastomycosis in adults, the IDSA recommends an initial regimen of IV amphotericin B given for 4-6 weeks, followed by itraconazole given in a dosage of 200 mg 2 or 3 times daily for at least 12 months and until CSF abnormalities resolve.

Prevention of Recurrence (Secondary Prophylaxis) of Blastomycosis in Adults

When itraconazole is used for prevention of recurrence (secondary prophylaxis) of blastomycosis in immunosuppressed adults at risk, the IDSA recommends a dosage of 200 mg daily.

Life-long secondary prophylaxis may be necessary if immunosuppression cannot be reversed. In HIV-infected adults, the IDSA states that discontinuance of secondary prophylaxis against blastomycosis can be considered after at least 12 months if the patient is receiving antiretroviral therapy and CD4 T-cell counts have remained greater than 150/mm for at least 6 months.

Treatment of Blastomycosis in Children

For the treatment of mild to moderate blastomycosis in children, the IDSA recommends that itraconazole be given in a dosage of 10 mg/kg daily (up to 400 mg daily) for 6-12 months.

For the treatment of moderately severe to severe blastomycosis in children, the IDSA recommends an initial regimen of IV amphotericin B given for 1-2 weeks, followed by itraconazole given in a dosage of 10 mg/kg daily (up to 400 mg daily) for a total treatment duration of 12 months.

Candida Infections

Treatment of Oropharyngeal Candidiasis in Adults and Adolescents

For the treatment of oropharyngeal candidiasis in adults, the manufacturer recommends that itraconazole oral solution be given in a dosage of 200 mg (20 mL) daily for 1-2 weeks. Clinical signs and symptoms generally resolve within several days. When itraconazole oral solution is used for retreatment of oropharyngeal candidiasis in adults who have not responded to or are refractory to oral fluconazole therapy, the manufacturer recommends a dosage of 100 mg (10 mL) twice daily. A response to itraconazole in these patients generally is evident within 2-4 weeks; however, relapse may be expected shortly after the drug is discontinued. The manufacturer states that data are limited to date regarding the safety of long-term use of itraconazole oral solution (i.e., longer than 6 months).

For the treatment of oropharyngeal candidiasis, including fluconazole-refractory infections, in HIV-infected adults and adolescents, the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and IDSA recommend that itraconazole oral solution be given in a dosage of 200 mg daily for 7-14 days.

Prevention of Recurrence (Secondary Prophylaxis) of Oropharyngeal Candidiasis in Adults and Adolescents

If long-term suppressive or maintenance therapy (secondary prophylaxis) with itraconazole oral solution is used in HIV-infected adults or adolescents with frequent or severe recurrences of oropharyngeal candidiasis, the CDC, NIH, and IDSA recommend a dosage of 200 mg daily.

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 if the CD4 T-cell count increases to 200/mm in response to antiretroviral therapy.

Treatment of Oropharyngeal Candidiasis in Children

If itraconazole oral solution is used for the treatment of oropharyngeal candidiasis in HIV-infected infants and children, the CDC, NIH, and IDSA recommend a dosage of 2.5 mg/kg twice daily (up to 200 mg daily) for 7-14 days.

If itraconazole oral solution is used for the treatment of fluconazole-refractory oropharyngeal candidiasis in HIV-infected infants and children, the CDC, NIH, and IDSA recommend a dosage of 2.5 mg/kg twice daily (up to 200-400 mg daily) for 7-14 days.

Treatment of Esophageal Candidiasis in Adults and Adolescents

For the treatment of esophageal candidiasis in adults, the manufacturer recommends that itraconazole oral solution be given in a dosage of 100 mg (10 mL) daily; however, depending on the patient's response to the drug, a dosage up to 200 mg (20 mL) daily may be given. The manufacturer states that oral itraconazole therapy should be administered for a minimum of 3 weeks in patients with esophageal candidiasis, and should be continued for 2 weeks after symptoms resolve.

For the treatment of esophageal candidiasis, including fluconazole-refractory infections, in HIV-infected adults and adolescents and other individuals, the CDC, NIH, and IDSA recommend that itraconazole oral solution be given in a dosage of 200 mg daily for 14-21 days.

Treatment of Esophageal Candidiasis in Children

If itraconazole oral solution is used for the treatment of esophageal candidiasis in HIV-infected infants and children, the CDC, NIH, and IDSA recommend a dosage of 2.5 mg/kg twice daily or 5 mg/kg once daily for 14-21 days.

Treatment of Vulvovaginal Candidiasis in Adults and Adolescents

If itraconazole is used as an alternative for the treatment of vulvovaginal candidiasis, some clinicians recommend a dosage of 200 mg twice daily for 1 day.

For the treatment of vulvovaginal candidiasis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend that the oral solution be given in a dosage of 200 mg daily for 3-7 days.

Empiric Treatment of Suspected Candidiasis in Neutropenic Patients

If itraconazole is used as an alternative for initial empiric treatment of suspected candidiasis in neutropenic patients, the IDSA recommends a dosage of 200 mg twice daily. The drug should not be used for empiric treatment in patients who previously received prophylaxis with an azole antifungal.

Coccidioidomycosis

Treatment of Coccidioidomycosis in Adults and Adolescents

For the treatment of coccidioidomycosis, the IDSA and others recommend that adults receive itraconazole in a dosage of 200 mg 2 or 3 times daily. Uncomplicated coccidioidal pneumonia generally is treated for 3-6 months; diffuse pneumonia and chronic progressive fibrocavitary pneumonia generally are treated for at least 1 year.

For the treatment of mild (nonmeningeal) coccidioidomycosis (e.g., focal pneumonia or positive coccidioidal serologic test alone) in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend that itraconazole be given in a dosage of 200 mg 3 times daily for 3 days, then 200 mg twice daily.

If itraconazole is used as an alternative to fluconazole for the treatment of meningeal coccidioidomycosis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend a dosage of 200 mg 3 times daily for 3 days, then 200 mg twice daily. Consultation with an expert who has experience in treating coccidioidal meningitis is recommended.

Primary Prophylaxis to Prevent First Episode of Coccidioidomycosis in Adults and Adolescents

If itraconazole is used for primary prophylaxis against coccidioidomycosis in HIV-infected adults and adolescents who live in areas where the disease is endemic, have positive IgM or IgG serologic tests indicating an increased risk for development of active infection, and have CD4 T-cell counts less than 250/mm, the CDC, NIH, and IDSA recommend a dosage of 200 mg twice daily.

Consideration can be given to discontinuing primary prophylaxis against coccidioidomycosis if CD4 T-cell counts remain greater than 250/mm for 6 months. Primary prophylaxis should be reinitiated if CD4 T-cell counts decrease to less than 250/mm.

Prevention of Recurrence (Secondary Prophylaxis) of Coccidioidomycosis in Adults and Adolescents

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, the CDC, NIH, and IDSA recommend that itraconazole be given in a dosage of 200 mg twice 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 greater than 250/mm.

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.

Treatment of Coccidioidomycosis in Children

For the treatment of mild coccidioidomycosis (nonmeningeal) (e.g., focal pneumonia) in HIV-infected infants and children, the CDC, NIH, and IDSA recommend that itraconazole be given in a dosage of 5-10 mg/kg twice daily for 3 days, then 2-5 mg/kg twice daily.

For the treatment of diffuse pulmonary or disseminated coccidioidomycosis (nonmeningeal) in HIV-infected infants and children, the CDC, NIH, and IDSA recommend an initial regimen of IV amphotericin B given until a response is obtained, followed by itraconazole given in a dosage of 5-10 mg/kg twice daily for 3 days, then 2-5 mg/kg twice daily (up to 400 mg daily).

Uncomplicated coccidioidal pneumonia is generally treated for 3-6 months; diffuse pneumonia and chronic progressive fibrocavitary pneumonia generally are treated for at least 1 year.

Prevention of Recurrence (Secondary Prophylaxis) of Coccidioidomycosis in Children

For long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of coccidioidomycosis in HIV-infected infants and children who have been adequately treated for the disease, the CDC, NIH, and IDSA recommend that itraconazole be given in a dosage of 2-5 mg/kg (up to 200 mg) twice daily.

Secondary prophylaxis against coccidioidomycosis should be continued lifelong in HIV-infected infants and children, regardless of antiretroviral therapy or immune reconstitution.

Cryptococcosis

Treatment of Cryptococcosis in Adults and Adolescents

For the treatment of mild to moderate pulmonary cryptococcosis (nonmeningeal) in immunocompetent adults, the IDSA states that itraconazole can be given in a dosage of 200 mg twice daily for 6-12 months.

As an alternative regimen for the treatment of cryptococcal meningitis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend an initial (induction) regimen of IV amphotericin B given for at least 2 weeks, then a follow-up (consolidation) regimen of itraconazole 200 mg twice daily for 8 weeks or until CD4 T-cell count remains at 200/mm or greater for at least 6 months as the result of antiretroviral therapy.

For the treatment of cryptococcal meningoencephalitis in HIV-infected adults, the IDSA states that itraconazole given in a dosage of 200 mg twice daily for 10-12 weeks can be considered as an alternative regimen, 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 that the oral solution may be preferred (instead of capsules) if itraconazole is used for the treatment of cryptococcosis.

Prevention of Recurrence (Secondary Prophylaxis) of Cryptococcosis in Adults and Adolescents

If itraconazole is used for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of cryptococcosis in HIV-infected adults and adolescents who have been adequately treated for the disease, the CDC, NIH, and IDSA recommend a dosage of 200 mg once or twice daily. There is some evidence that the twice-daily regimen is more effective for secondary prophylaxis than the once-daily regimen.

The IDSA states that consideration can be given to discontinuing secondary prophylaxis against cryptococcosis 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 of 100/mm. If secondary prophylaxis against cryptococcosis is discontinued, the patient should be followed closely and serial cryptococcal serum antigen tests performed. Secondary prophylaxis against cryptococcosis should be reinitiated if CD4 T-cell counts decrease to less than 100/mm and/or the serum cryptococcal antigen titer increases.

Other experts state that HIV-infected adults and adolescents 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 against cryptococcosis in HIV-infected adults and adolescents who are asymptomatic for cryptococcosis, are receiving antiretroviral therapy, and have had CD4 T-cell counts of 200/mm or greater for more than 6 months. Secondary prophylaxis against cryptococcosis should be reinitiated if CD4 T-cell counts decrease to less than 200/mm.

Treatment of Cryptococcosis in Children

If itraconazole is used as an alternative regimen for the treatment of CNS cryptococcosis in HIV-infected infants and children, the CDC, NIH, and IDSA recommend an initial (induction) regimen of IV amphotericin B given for at least 2 weeks, then a follow-up (consolidation) regimen of itraconazole given in a dosage of 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.

Prevention of Recurrence (Secondary Prophylaxis) of Cryptococcosis in Children

If itraconazole is used for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of cryptococcosis in HIV-infected infants or children who have been adequately treated for the disease, the CDC, NIH, and IDSA recommend a dosage of 5 mg/kg (up to 200 mg) daily.

HIV-infected infants and children with a history of cryptococcosis usually should receive life-long secondary prophylaxis to prevent recurrence. Consideration can be given to discontinuing secondary prophylaxis in HIV-infected children 6 years of age or older who are asymptomatic for cryptococcosis and have received secondary prophylaxis for at least 6 months, have been receiving antiretroviral therapy for at least 6 months, and have had CD4 T-cell counts of 200/mm or greater for at least 6 months. Secondary prophylaxis against cryptococcosis should be reinitiated if CD4 T-cell count decreases to less than 200/mm.

Histoplasmosis

Treatment of Histoplasmosis in Adults and Adolescents

For the treatment of chronic cavitary pulmonary histoplasmosis or disseminated, nonmeningeal histoplasmosis, the manufacturer recommends that adults receive itraconazole capsules in a dosage of 200 mg once daily. If there is evidence of progression or no apparent improvement, dosage may be increased in 100-mg increments daily up to a maximum dosage of 400 mg daily. The usual duration of treatment is at least 12 months.

For the treatment of mild to moderate acute pulmonary histoplasmosis when treatment is considered necessary (i.e., symptomatic for at least 1 month), the IDSA recommends that itraconazole be given in a dosage of 200 mg 3 times daily for 3 days, then 200 mg once or twice daily for 6-12 weeks.

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

For the treatment of chronic cavitary pulmonary histoplasmosis, the IDSA recommends that itraconazole be given in a dosage of 200 mg 3 times daily for 3 days, then 200 mg once or twice daily for at least 1 year. Because of the risk of relapse, some clinicians prefer a duration of 18-24 months.

For the treatment of mild to moderate disseminated histoplasmosis, the IDSA recommends that itraconazole be given in a dosage of 200 mg 3 times daily for 3 days, then 200 mg twice daily for at least 1 year.

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

For the treatment of histoplasmosis with symptomatic mediastinal granuloma or with complications (pericarditis, rheumatologic syndromes, symptomatic mediastinal lymphadenitis) that require treatment with corticosteroids, the IDSA recommends that itraconazole be given in a dosage of 200 mg 3 times daily for 3 days, then 200 mg once or twice daily for 6-12 weeks.

For the treatment of less severe disseminated histoplasmosis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend that itraconazole be given in a dosage of 200 mg 3 times daily for 3 days, then 200 mg twice daily for at least 12 months.

For the treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend an 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.

For the treatment of CNS histoplasmosis in HIV-infected adults and adolescents or other adults, the CDC, NIH, and IDSA recommend an 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) if itraconazole is used for the treatment of histoplasmosis.

Primary Prophylaxis to Prevent First Episode of Histoplasmosis in Adults and Adolescents

For primary prophylaxis to prevent histoplasmosis in immunosuppressed adults, the IDSA recommends that itraconazole be given in a dosage of 200 mg daily.

If itraconazole is used for primary prophylaxis to prevent histoplasmosis in HIV-infected adults and adolescents with CD4 T-cell counts of 150/mm or lower who are at high risk (occupational exposure, reside in a community hyperendemic for histoplasmosis), the CDC, NIH, and IDSA recommend a dosage of 200 mg daily.

Discontinuance of primary prophylaxis against histoplasmosis can be considered in HIV-infected adults and adolescents receiving antiretroviral therapy if CD4 T-cell counts exceed 150/mm for 6 months. Primary prophylaxis against histoplasmosis should be reinitiated if CD4 T-cell count decreases to 150/mm or lower.

Prevention of Recurrence (Secondary Prophylaxis) of Histoplasmosis in Adults and Adolescents

For long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of histoplasmosis in HIV-infected adults and adolescentsand other immunosuppressed adults who have been adequately treated for the disease, the CDC, NIH, and IDSA recommend that itraconazole be given in a dosage of 200 mg daily.

HIV-infected adults and 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 adults and adolescents who have negative Histoplasma blood cultures, have serum Histoplasma antigen levels less than 2 ng/mL, have received itraconazole for at least 12 months, 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 CD4 T-cell count decreases to less than 150/mm.

Treatment of Histoplasmosis in Children

For the treatment of acute pulmonary histoplasmosis in children, the IDSA recommends that itraconazole be given in a dosage of 5-10 mg/kg daily (up to 400 mg daily) in 2 divided doses.

For the treatment of progressive disseminated histoplasmosis in children, the IDSA recommends an initial regimen of IV amphotericin B given for 2-4 weeks, followed by itraconazole given in a dosage of 5-10 mg/kg daily (up to 400 mg daily) 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.

For the treatment of mild disseminated histoplasmosis in HIV-infected infants and children, the CDC, NIH, and IDSA recommend that itraconazole (oral solution) be given in a dosage of 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.

For the treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected infants and children, the CDC, NIH, and IDSA recommend an initial regimen of IV amphotericin B given for at least 1-2 weeks, followed by itraconazole (oral solution) given in a dosage of 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.

For the treatment of CNS histoplasmosis in HIV-infected infants and children, the CDC, NIH, and IDSA recommend an initial regimen of IV amphotericin B given for 4-6 weeks, followed by itraconazole (oral solution) given in a dosage of 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.

Prevention of Recurrence (Secondary Prophylaxis) of Histoplasmosis in Children

For long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of histoplasmosis in HIV-infected infants or children and other immunosuppressed children who have been adequately treated for the disease, the CDC, NIH, and IDSA recommend that itraconazole (oral solution) be given in a dosage of 5 mg/kg (up to 200 mg) twice daily.

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 or older who have negative Histoplasma blood cultures, have serum Histoplasma antigen levels less than 2 ng/mL, have received itraconazole for at least 12 months, 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 CD4 T-cell counts decrease to less than 150/mm.

Microsporidiosis

For the treatment of keratoconjunctivitis and sinusitis caused by Encephalitozoon, itraconazole has been given in a dosage of 200 mg daily for 8 weeks.

For the treatment of disseminated microsporidiosis caused by Trachipleistophora or Anncaliia, some clinicians recommend that itraconazole be given in a dosage of 400 mg daily in conjunction with oral albendazole.

Onychomycosis

For the treatment of onychomycosis of the fingernails (without toenail involvement), itraconazole capsules are given in a pulse-dosing regimen that involves administering 200 mg of the drug twice daily during the first week, no itraconazole during weeks 2-4, and 200 mg of itraconazole twice daily during the fifth week.

For the treatment of onychomycosis of the toenails (with or without fingernail involvement), the recommended oral dosage of itraconazole capsules is 200 mg once daily for 12 consecutive weeks. A pulse-dosing regimen that involves administering itraconazole capsules in a dosage of 400 mg once daily for one week each month for 3 months also has been effective for the treatment of onychomycosis of the toenails (tinea unguium).

Penicilliosis

Treatment of Penicilliosis

For the treatment of severe penicilliosis, an initial regimen of IV amphotericin B is given for 2 weeks, followed by oral itraconazole given in a dosage of 400 mg daily for 10 weeks. For the treatment of mild infections when an initial oral regimen in adequate, oral itraconazole in a dosage of 400 mg daily for 8 weeks is recommended.

Prevention of Recurrence (Secondary Prophylaxis) of Penicilliosis

For long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of penicilliosis in HIV-infected adults and adolescents who have been adequately treated, oral itraconazole should be given in a dosage of 200 mg daily. Secondary prophylaxis can be discontinued in those who are receiving antiretroviral therapy and have CD4 T-cell counts that have remained greater than 100/mm for 6 months or longer. Secondary prophylaxis should be reinitiated if the CD4 T-cell count decreases to less than 100/mm.

Sporotrichosis

Treatment of Sporotrichosis in Adults

For the treatment of cutaneous or lymphocutaneous sporotrichosis, the IDSA and others recommend that adults receive itraconazole in a dosage of 200 mg once daily. If a response is not obtained, dosage may be increased to 200 mg twice daily. Treatment should be continued for 2-4 weeks after all lesions have resolved; the usual duration of treatment is 3-6 months.

For the treatment of osteoarticular sporotrichosis, the IDSA states that adults should receive itraconazole in a dosage of 200 mg twice daily for at least 12 months. If used as follow-up after a response has been obtained with an initial regimen of IV amphotericin B, itraconazole should be continued for a total treatment duration of at least 12 months.

For the treatment of mild pulmonary sporotrichosis, the IDSA recommends that adults receive itraconazole in a dosage of 200 mg twice daily for at least 12 months.

For the treatment of severe or life-threatening pulmonary or disseminated sporotrichosis, the IDSA recommends that adults receive an 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.

For the treatment of meningeal sporotrichosis, the IDSA recommends that adults receive an 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 that the oral solution may be preferred (instead of capsules) if itraconazole is used for the treatment of sporotrichosis.

Treatment of Sporotrichosis in Children

For the treatment of cutaneous or lymphocutaneous sporotrichosis in children, the IDSA recommends that itraconazole be given in a dosage of 6-10 mg/kg daily (up to 400 mg daily). Treatment should be continued for 2-4 weeks after all lesions have resolved; the usual duration of treatment is 3-6 months.

For the treatment of disseminated sporotrichosis in children, the IDSA recommends an initial regimen of IV amphotericin B given until a response is obtained, followed by itraconazole given in a dosage of 6-10 mg/kg daily (up to 400 mg daily) for a total duration of at least 12 months.

Empiric Therapy in Febrile Neutropenic Patients

For empiric therapy of presumed fungal infections in febrile neutropenic patients, an initial IV regimen of itraconazole has been used (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). Treatment is then switched to itraconazole oral solution given in a dosage of 200 mg (20 mL) twice daily until clinically important neutropenia has resolved. Safety and efficacy of itraconazole administered for longer than 28 days for this indication are not known.

For empiric therapy of presumed fungal infections in patients with chemotherapy-induced neutropenia, the IDSA recommends that oral itraconazole be given in a dosage of 200 mg twice daily.

Dosage in Renal and Hepatic Impairment

Only limited data are available on the use of itraconazole in patients with renal impairment, and the drug should be used with caution in such patients.(See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)

Only limited data are available on the use of itraconazole in patients with hepatic impairment, and the drug should be used with caution in such patients.(See Precautions Related to Hepatic Effects under Cautions: Precautions and Contraindications.)

Cautions

Itraconazole generally is well tolerated. However, serious potentially life-threatening adverse effects, including congestive heart failure (CHF), pulmonary edema, and hepatotoxicity, have occurred rarely in patients receiving itraconazole. In clinical studies evaluating itraconazole for the treatment of systemic fungal infections, adverse effects requiring discontinuance of the drug occurred in up to 11% of patients; the median duration of therapy before discontinuance was 81 days (range: 2-776 days). In patients receiving oral itraconazole capsules for the treatment of onychomycosis of the toenails or fingernails, adverse effects requiring temporary or permanent discontinuance of the drug occurred in 1-4% of patients. The most frequent adverse effects of itraconazole involve the GI tract, and the frequency of adverse effects may be increased during prolonged therapy.

GI Effects

Adverse GI effects have been reported in about 1-11% of patients receiving itraconazole for the treatment of systemic fungal infections or oropharyngeal or esophageal candidiasis or for empiric anti-fungal therapy. These adverse GI effects usually are transient and respond to symptomatic treatment without alteration of itraconazole therapy; however, reduction of dosage or discontinuance of the drug occasionally may be required.

Nausea is the most frequently reported adverse effect of itraconazole, occurring in 9-11% of patients receiving the drug for the treatment of systemic fungal infections, oropharyngeal or esophageal candidiasis, or for empiric anti-fungal therapy. However, this effect occasionally has been reported to occur more frequently. Vomiting has occurred in about 5-7%, diarrhea in about 3-10%, and abdominal pain or anorexia in about 1-3% of patients being treated for systemic fungal infections, oropharyngeal or esophageal candidiasis, or for empiric antifungal prophylaxis. Constipation, dyspepsia, dysphagia, flatulence, gastritis, taste perversion, and ulcerative stomatitis also have been reported.

In patients receiving oral itraconazole capsules for the treatment of onychomycosis of the fingernails (a pulse-dosing regimen consisting of two 1-week treatment periods given 3 weeks apart), abdominal pain, constipation, dyspepsia, nausea, gingivitis, and ulcerative stomatitis were reported in 3-5%. In those receiving itraconazole capsules for the treatment of onychomycosis of the toenails (a continuous dosing regimen for 12 consecutive weeks), abdominal pain, diarrhea, dyspepsia, and flatulence were reported in 7% and constipation, gastritis, gastroenteritis, increased appetite, and nausea were reported in 3-4% of patients. Adverse GI effects requiring temporary or permanent discontinuance of itraconazole capsules occurred in 4% of those receiving the drug for the treatment of toenail infections.

Dermatologic and Sensitivity Reactions

Rash has occurred in 3-9% of patients receiving itraconazole for the treatment of systemic fungal infections, oropharyngeal or esophageal candidiasis, or for empiric anti-fungal therapy. Rash tends to occur more frequently in immunocompromised patients who are receiving immunosuppressive therapy. Pruritus has occurred in up to 3% of patients with systemic fungal infections or oropharyngeal or esophageal candidiasis receiving itraconazole. Urticaria, angioedema, alopecia, and toxic epidermal necrolysis also have been reported in patients receiving itraconazole. In addition, anaphylaxis and Stevens-Johnson syndrome occurred rarely in patients receiving the drug.

In patients receiving oral itraconazole capsules for the treatment of onychomycosis of the fingernails or toenails, pruritus and rash were reported in 5-8% of patients; these adverse effects required temporary or permanent discontinuance of itraconazole capsules in 3%.

Nervous System Effects

Headache and dizziness have been reported in 2-4% of patients receiving itraconazole for the treatment of systemic fungal infections, oropharyngeal or esophageal candidiasis, or for empiric anti-fungal prophylaxis. Somnolence, decreased libido, insomnia, depression, and tremor have occurred in up to 1% of patients. Although a causal relationship to itraconazole has not been established, neuropathy (including peripheral neuropathy) has occurred rarely in patients receiving the drug.

In patients receiving oral itraconazole capsules for the treatment of onychomycosis of the fingernails (a pulse-dosing regimen consisting of two 1-week treatment periods given 3 weeks apart), headache was reported in 8% and anxiety, depression, fatigue, and malaise were reported in 3%. In those receiving itraconazole capsules for the treatment of onychomycosis of the toenails (a continuous dosing regimen for 12 consecutive weeks), headache was reported in 10% and asthenia, dizziness, and tremor were reported in 2-4% of patients. Adverse nervous system effects (headache, malaise, vertigo) requiring temporary or permanent discontinuance of itraconazole capsules occurred in 1% of those receiving the drug for the treatment of toenail infections.

Cardiovascular Effects

CHF, peripheral edema, and pulmonary edema have been reported rarely in patients receiving itraconazole for the treatment of systemic fungal infections and/or onychomycosis. Results from animal studies indicate that IV administration of itraconazole is associated with a dose-related negative inotropic effect. In addition, IV administration of itraconazole in healthy individuals (IV preparation no longer commercially available in the US) has resulted in transient, asymptomatic decreases in left ventricular ejection fraction (observed using gated SPECT imaging) which resolved before the next infusion, 12 hours later.

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

The manufacturer states that itraconazole oral capsules should be discontinued in patients who develop CHF while receiving the drug. If CHF occurs during therapy with itraconazole oral solution, the manufacturer states that the patient should be carefully monitored and therapeutic options (including possible discontinuance of the drug) should be evaluated.(See Precautions Related to Cardiovascular Effects under Cautions: Precautions and Contraindications.)

Hypertension has been reported in up to 3% of patients receiving itraconazole for the treatment of systemic fungal infections and has been reported in less than 1% of patients receiving itraconazole for other uses.

Ventricular fibrillation secondary to itraconazole-induced hypokalemia has been reported in a patient with HIV infection and blastomycosis receiving high dosage of the drug (e.g., 400 mg twice daily).(See Cautions: Electrolyte and Metabolic Effects.) Serious adverse cardiovascular effects, including death, cardiac arrest, QT interval prolongation, ventricular tachycardia, and atypical ventricular tachycardia (torsades de pointes), have occurred rarely in patients receiving itraconazole concomitantly with certain drugs.(See Precautions related to Cardiovascular Effects under Cautions: Precautions and Contraindications.)

Hepatic Effects

Hepatic function abnormalities, manifested principally as mild transient increases in serum liver enzyme concentrations, have occurred in about 3% of patients receiving itraconazole. However, 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. Hepatitis has been reported during postmarketing surveillance.

In patients receiving oral itraconazole capsules for the treatment of onychomycosis of the toenails (a continuous dosing regimen for 12 consecutive weeks), increased serum hepatic enzymes (greater than twice the upper limit of normal) that required temporary or permanent discontinuance of the drug have occurred in 4% of patients.

Itraconazole should be discontinued immediately and the risks and benefits of continuing therapy with the drug should be reassessed if signs and symptoms consistent with liver disease develop during therapy with the drug.(See Precautions Related to Hepatic Effects under Cautions: Precautions and Contraindications.)

Electrolyte and Metabolic Effects

Hypokalemia has been reported in 2-9% of patients receiving itraconazole for the treatment of systemic fungal infections or oropharyngeal or esophageal candidiasis or for empiric antifungal prophylaxis. Itraconazole-induced hypokalemia may be mild to severe, may require potassium replacement and/or discontinuance of the drug, and has occurred principally at dosages of 400 mg daily or higher.(See Cautions: Precautions and Contraindications.) Edema (e.g., pedal) has occurred in up to 4% of patients with systemic fungal infections receiving itraconazole.

Adrenal insufficiency, gynecomastia, and male breast pain have occurred patients receiving the drug. Itraconazole generally does not appear to inhibit testicular or adrenal steroidogenesis substantially at usual dosages. However, at relatively high dosages (e.g., 600 mg daily or more) and/or with accumulation of the drug, adrenal suppression, which appears to be distinct from that associated with ketoconazole, may occur. Although a causal relationship to itraconazole has not been established, hypertriglyceridemia or hyperglycemia has been reported in patients receiving itraconazole.

Genitourinary Effects

Albuminuria and impotence have occurred in about 1% of patients with systemic fungal infections receiving itraconazole. Urinary tract infection, cystitis, renal function abnormality, and menstrual disorder also have occurred in patients receiving itraconazole.

Otic Effects

Transient or permanent hearing loss has been reported in patients receiving itraconazole.(See Cautions: Geriatric Precautions.) In some reported cases, the patient was also receiving quinidine, a drug that is contraindicated during itraconazole therapy.(See Drug Interactions: Antiarrhythmic Agents.)

If hearing loss occurs during itraconazole therapy, the drug should be discontinued. Although hearing loss usually resolves when itraconazole is discontinued, it can persist in some patients.

Other Adverse Effects

Fatigue, fever, bursitis, myalgia, pain, herpes zoster infection, and injury have occurred in up to 7% of patients receiving itraconazole. Rhinitis, upper respiratory tract infection, sinusitis, and pharyngitis have been reported in up to 9% of itraconazole-treated patients. Neutropenia also has occurred in patients receiving the drug.

Precautions and Contraindications

Precautions Related to Cardiovascular Effects

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

The manufacturer states that itraconazole capsules should not be used for the 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. Itraconazole oral capsules should be discontinued in patients who develop CHF while receiving the drug.

The manufacturer states that itraconazole oral solution should not be used in patients with evidence of ventricular dysfunction, such as CHF or history of CHF, except for the treatment of life-threatening or other serious infections when benefits clearly outweigh risks. If CHF occurs in patients receiving the oral solution, the patient should be carefully monitored and therapeutic options (including possible discontinuance of the drug) should be evaluated.

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.

Because itraconazole and its major metabolite, hydroxyitraconazole, are potent inhibitors of the cytochrome P-450 (CYP) 3A4 isoenzyme system, concomitant use of the antifungal with drugs metabolized by these enzymes can increase plasma concentrations of these drugs resulting in potential increases in their therapeutic and adverse effects. Serious adverse cardiovascular effects (QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death) have been reported in patients receiving itraconazole concomitantly with certain drugs metabolized by CYP3A4 enzymes (e.g., cisapride [no longer available in the US only under a limited-access protocol], dofetilide, pimozide, quinidine, levomethadyl [no longer commercially available in the US]), and concomitant use with these drugs is contraindicated.(See Drug Interactions.)

Precautions Related to Hepatic Effects

Because rare cases of serious hepatotoxicity have been reported with itraconazole, including some cases within the first week of therapy (see Cautions: Hepatic Effects), use of itraconazole is strongly discouraged 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.

Itraconazole should be used with caution in patients with hepatic impairment since only limited data are available regarding use of the drug in such patients. The prolonged itraconazole elimination half-life reported in cirrhotic patients (see Pharmacokinetics) should be considered when deciding to initiate concomitant therapy with drugs that are metabolized by CYP3A4.(See Drug Interactions.)

Serum hepatic enzyme concentrations should be monitored in any patient with preexisting hepatic function abnormalities and in those who have experienced liver toxicity with other drugs. In addition, serum hepatic enzyme monitoring should be considered for all patients receiving itraconazole, especially those who receive itraconazole therapy continuously for longer than 1 month.

Itraconazole should be discontinued immediately and liver function testing performed if signs and symptoms consistent with liver disease develop during therapy. The risks and benefits of itraconazole should be reassessed in these patients.

Patients should be instructed to stop itraconazole immediately and contact their clinician if any signs or symptoms of liver dysfunction occur, including unusual fatigue, dark urine, pale stool, anorexia, nausea, vomiting, or jaundice, so that appropriate laboratory testing can be performed.

Other Precautions and Contraindications

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

If neuropathy occurs that may be attributable to itraconazole, the drug should be discontinued.

Because itraconazole may cause hypokalemia, some clinicians recommended that serum potassium concentrations be monitored in patients receiving relatively high dosages and/or prolonged therapy with the drug.(See Cautions: Electrolyte and Metabolic Effects.)

Patients receiving itraconazole should be informed that hearing loss can occur and should be advised about the importance of discontinuing itraconazole and contacting a clinician if any symptoms of hearing loss occur.(See Cautions: Otic Effects.)

The manufacturer states that itraconazole oral solution has not been evaluated for the treatment of oropharyngeal and/or esophageal candidiasis in severely neutropenic patients. The oral solution is not recommended for initial treatment in patients at immediate risk of systemic candidiasis.

Variable itraconazole concentrations have been reported in cystic fibrosis patients receiving the oral solution. If itraconazole oral solution is used in cystic fibrosis patients and an adequate response is not obtained, consideration should be given to using alternative therapy.(See Cautions: Pediatric Precautions.)

Oral itraconazole should be used with caution in patients with renal impairment. Only limited data are available on the use of oral itraconazole in such patients. Wide interindividual variations in the area under the concentration-time curve (AUC) have been reported in patients with renal impairment.(See Pharmacokinetics.)

Pediatric Precautions

The safety and efficacy of itraconazole in children younger than 18 years of age have not been established.

Itraconazole has been recommended by the Infectious Diseases Society of America (IDSA) and other experts for the 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 without unusual adverse effect. In addition, a limited number of pediatric patients 6 months to 12 years of age requiring systemic antifungal treatment 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 plasma itraconazole concentrations are variable in such patients and trough itraconazole concentrations attained in children younger than 16 years of age are lower than those in patients 16-28 years of age. If itraconazole oral solution is used in cystic fibrosis patients and an adequate response is not obtained, consideration should be given to initiating alternative therapy.

The long-term effects of itraconazole therapy on bone growth in children are not known. Data from animal studies have shown that itraconazole induces bone defects in rats receiving dosages as low as 20 mg/kg daily (2.5 times the maximum recommended human dosage). The defects included decreased bone plate activity, thinning of the zona compacta of large bones, and increased bone fragility. At a dosage of 80 mg/kg daily (10 times the maximum recommended human dosage) for longer than 1 year or 160 mg/kg daily (20 times the maximum recommended human dosage), the drug induced small tooth pulp with hypocellular appearance in some rats. Bone toxicity observed in animals has not been reported to date in adults receiving the drug.

Geriatric Precautions

Itraconazole should be used with caution in geriatric patients.

Transient or permanent hearing loss has been reported in some geriatric patients receiving itraconazole. In some reported cases, the patient was also receiving quinidine, a drug that is contraindicated during itraconazole therapy.(See Drug Interactions: Antiarrhythmic Agents.)

Mutagenicity and Carcinogenicity

There was no evidence of mutagenicity when itraconazole was assayed in appropriate bacterial, mammalian, and nonmammalian test systems.

There was no evidence of carcinogenicity in mice receiving oral itraconazole for 23 months at dosages up to 80 mg/kg daily (about 10 times the maximum recommended human dosage). There was a slight increase in the incidence of soft tissue sarcoma in male rats receiving 25 mg/kg daily (3.1 times the maximum recommended human dosage). These sarcomas may have been a consequence of hypercholesterolemia, a response to chronic itraconazole administration observed in rats but not in dogs or humans. An increase in the incidence of squamous cell carcinoma of the lung was observed in female rats receiving 50 mg/kg of itraconazole daily (6.25 times the maximum recommended human dosage). Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increased incidence in this study was not statistically significant.

Commercially available itraconazole oral solution and itraconazole injection contain 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. It has been estimated that, based on body surface area comparisons, patients receiving the usual dosage of commercially available itraconazole oral solution would be exposed to concentrations of HP-β-CD that are equivalent to 1.7 times that the exposure of the lowest dose used in the rat study.

Pregnancy, Fertility, and Lactation

Pregnancy

Itraconazole has been shown to be teratogenic and embryotoxic in mice and rats. In addition, although a causal relationship with itraconazole has not been 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.

There are no adequate and controlled studies evaluating itraconazole in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

For the treatment of onychomycosis, use of itraconazole is contraindicated in pregnant women and also is contraindicated in women contemplating pregnancy. If itraconazole therapy for the treatment of onychomycosis is initiated in a woman of childbearing potential, the first dose of the drug should be given on the second or third day of the next normal menstrual period and measures should be taken to ensure that effective contraception is continued throughout itraconazole therapy and for 2 additional months following discontinuance of the drug.

In reproduction studies, itraconazole caused a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosages of approximately 40-160 mg/kg daily (5-20 times the maximum recommended human dosage) and in mice at dosages of approximately 80 mg/kg daily (10 times the maximum recommended human dosage). Teratogenicity consisted of major skeletal defects in rats and encephaloceles and/or macroglossia in mice.

Fertility

Although parental toxicity was observed, reproduction studies in male and female rats receiving oral itraconazole dosages up to 40 mg/kg daily (5 times the maximum recommended human dosage) did not reveal evidence of impaired fertility. More severe parental toxicity, including death, occurred at a dosage of 160 mg/kg daily (20 times the maximum recommended human dosage).

Lactation

Itraconazole is distributed into human milk and the expected benefits of itraconazole for the nursing woman should be weighed against the potential risk to the infant from exposure to the drug. Because of the potential for transmission of HIV to an uninfected child, the US Centers for Disease Control and Prevention (CDC) currently recommends that HIV-infected women not breastfeed infants.

Drug Interactions

Antiarrhythmic Agents

Concomitant use of quinidine or dofetilide (antiarrhythmics that increase the QT interval) and itraconazole is contraindicated. Administration of itraconazole with quinidine or dofetilide would be expected to increase plasma concentrations of the antiarrhythmic agent which could result in serious adverse cardiovascular effects. Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients receiving quinidine concomitantly with itraconazole and/or other drugs that inhibit the cytochrome P-450 (CYP) 3A4 isoenzyme.

Concomitant use of disopyramide and itraconazole may result in increased plasma concentrations of the antiarrhythmic agent. Disopyramide and itraconazole should be used concomitantly with caution.

Concomitant use of digoxin and itraconazole may result in increased plasma concentrations of the antiarrhythmic agent, possibly as a result of inhibition of P-glycoprotein.

Antilipemic Agents

Concomitant use of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (e.g., atorvastatin, cerivastatin, lovastatin, simvastatin) and itraconazole may increase plasma concentrations of these antilipemic agents resulting in increased effects and increased risk of toxicity (e.g., myopathy including rhabdomyolysis). Concomitant use of itraconazole and these antilipemic agents is contraindicated.

Antiretroviral Agents

HIV Entry Inhibitors

Concomitant use of maraviroc and itraconazole may result in increased concentrations of maraviroc. If maraviroc is used concomitantly with itraconazole, consideration should be given to reducing the maraviroc dosage to 150 mg twice daily.

HIV Protease Inhibitors (PIs)

Pharmacokinetic interactions are likely if itraconazole is used in patients receiving HIV protease inhibitors (PIs) (e.g., atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir), especially if ritonavir-boosted PI regimens are used. Concomitant use may result in altered serum concentrations of the PIs and/or the antifungal.

Atazanavir

If atazanavir (with or without low-dose ritonavir) is used in patients receiving itraconazole, increased concentrations of both itraconazole and atazanavir are possible and clinicians should consider monitoring itraconazole plasma concentrations to guide dosage adjustments of the antifungal. High itraconazole dosage (greater than 200 mg daily) is not recommended in patients receiving ritonavir-boosted atazanavir, unless plasma concentrations of the antifungal are used to guide dosage.

Darunavir

If ritonavir-boosted darunavir is used in patients receiving itraconazole, increased concentrations of both itraconazole and darunavir are possible and clinicians should consider monitoring itraconazole plasma concentrations to guide dosage adjustments of the antifungal. High itraconazole dosage (greater than 200 mg daily) is not recommended in patients receiving ritonavir-boosted darunavir, unless plasma concentrations of the antifungal are used to guide dosage.

Fosamprenavir

If fosamprenavir (with or without low-dose ritonavir) is used in patients receiving itraconazole, increased concentrations of both itraconazole and fosamprenavir are possible and clinicians should consider monitoring itraconazole plasma concentrations to guide dosage adjustments of the antifungal. High itraconazole dosage (greater than 200 mg daily) is not recommended in patients receiving ritonavir-boosted fosamprenavir, unless plasma concentrations of the antifungal are used to guide dosage.

Indinavir

If indinavir (with or without low-dose ritonavir) is used in patients receiving itraconazole, increased concentrations of both itraconazole and indinavir are possible and clinicians should consider monitoring itraconazole plasma concentrations to guide dosage adjustments of the antifungal.

If itraconazole is used concomitantly with indinavir (without low-dose ritonavir), some experts recommend that indinavir be given in a dosage of 600 mg every 8 hours and that itraconazole dosage should not exceed 200 mg twice daily. Appropriate dosage of ritonavir-boosted indinavir has not been established for patients receiving concomitant itraconazole; high itraconazole dosage (greater than 200 mg daily) is not recommended, unless plasma concentrations of the antifungal are used to guide dosage.

Lopinavir

If itraconazole is used with the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir), some experts recommend that clinicians should consider not exceeding an itraconazole dosage of 200 mg daily or should consider monitoring itraconazole plasma concentrations.

Nelfinavir

If nelfinavir is used in patients receiving itraconazole, increased concentrations of both itraconazole and nelfinavir are possible and clinicians should consider monitoring itraconazole plasma concentrations to guide dosage adjustments of the antifungal.

Saquinavir

If ritonavir-boosted saquinavir is used in patients receiving itraconazole, altered plasma concentrations of both itraconazole and saquinavir are possible and clinicians should consider monitoring itraconazole plasma concentrations. Appropriate dosage for concomitant use has not been established, but decreased itraconazole dosage may be warranted.

Tipranavir

If ritonavir-boosted tipranavir is used in patients receiving itraconazole, increased concentrations of both itraconazole and tipranavir are possible and clinicians should consider monitoring itraconazole plasma concentrations to guide dosage adjustments of the antifungal.

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Efavirenz

Concomitant use of efavirenz and itraconazole results in decreased plasma concentrations and area under the concentration-time curve (AUC) of itraconazole and its major metabolite, hydroxyitraconazole, but does not affect efavirenz concentrations.

The manufacturer of efavirenz states that an alternative antifungal should be considered instead of itraconazole in patients receiving efavirenz. Some experts state that itraconazole plasma concentrations should be monitored in patients receiving efavirenz and dosage of the antifungal may need to be adjusted.

Etravirine

Concomitant use of etravirine and itraconazole may result in decreased itraconazole concentrations and increased etravirine concentrations. Dosage adjustment of itraconazole may be needed depending on other concomitantly administered drugs.

Nevirapine

Concomitant use of nevirapine and itraconazole may result in decreased plasma concentrations of itraconazole and increased nevirapine concentrations,

Itraconazole and nevirapine should not be used concomitantly. Some experts state that if itraconazole and nevirapine are used concomitantly, consideration should be given to monitoring plasma concentrations of both drugs.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Zidovudine

Concomitant use of zidovudine and itraconazole does not affect the pharmacokinetics of zidovudine.

Astemizole and Terfenadine

Concomitant use of itraconazole and astemizole or terfenadine (drugs no longer commercially available in the US) is contraindicated. Rare cases of serious adverse cardiovascular effects, including death, ventricular tachycardia, and atypical ventricular tachycardia (torsades de pointes), have occurred in patients receiving itraconazole and terfenadine concomitantly. Similar effects have been reported when ketoconazole, a structurally similar antifungal, was used concomitantly with terfenadine. The antifungals appear to inhibit the metabolism of astemizole or terfenadine, probably via inhibition of the CYP isoenzyme 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 have been associated with prolongation of the QT and QTc intervals.

Benzodiazepines

Concomitant use of itraconazole and benzodiazepines (e.g., alprazolam, diazepam, oral midazolam, triazolam) may result in increased plasma concentrations of these benzodiazepines that could potentiate and prolong the sedative and hypnotic effects of the drugs. Concomitant use of itraconazole and oral midazolam or triazolam is contraindicated; if midazolam is administered parenterally in patients receiving itraconazole, special precaution and patient monitoring is required since the sedative effect of the benzodiazepine may be prolonged.

Calcium-channel Blocking Agents

Itraconazole may inhibit metabolism of calcium-channel blocking agents (e.g., nifedipine, felodipine, verapamil). In addition, calcium-channel blocking agents can have negative inotropic effects, which may be additive to those of itraconazole. Edema has been reported in patients receiving itraconazole and a dihydropyridine calcium-channel blocker concomitantly.

Because of an increased risk of congestive heart failure (CHF), itraconazole should be used with caution in patients receiving a calcium-channel blocker and appropriate dosage adjustments may be necessary.

Concomitant use of itraconazole and nisoldipine is contraindicated because concomitant use of these drugs results in a clinically important increase in nisoldipine plasma concentrations that cannot be managed by dosage reduction.

Carbamazepine

Concomitant use of carbamazepine and itraconazole may result in increased carbamazepine concentrations and decreased itraconazole concentrations.

Cilostazol

Because cilostazol is metabolized by CYP3A4, concomitant use with itraconazole may result in increased cilostazol plasma concentrations.

Cisapride

Concomitant use of itraconazole and cisapride (currently commercially available in the US only under a limited-access protocol) is contraindicated since itraconazole inhibits metabolism of cisapride and such use can result in increased plasma cisapride concentrations and increase the potential for serious adverse cardiovascular effects.

Corticosteroids

Concomitant use of corticosteroids (e.g., budesonide, dexamethasone, fluticasone, methylprednisolone) and itraconazole may result in increased plasma concentrations of the corticosteroid.

Eletriptan

Because eletriptan is metabolized by CYP3A4, concomitant use with itraconazole may result in increased eletriptan plasma concentrations.

Ergot Alkaloids

Concomitant use of ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine) and itraconazole may result in increased concentrations of the ergot alkaloid and may cause ergotism (i.e., risk for venospasm potentially leading to cerebral ischemia and/or ischemia of the extremities). Concomitant use of ergot alkaloids and itraconazole is contraindicated.

Fentanyl

Concomitant use of fentanyl and itraconazole may result in increased plasma fentanyl concentrations and increased potential for fatal respiratory depression.

Halofantrine

Concomitant use of halofantrine (not commercially available in the US) and itraconazole may result in increased plasma halofantrine concentrations increased risk of prolonged QT interval.Halofantrine and itraconazole should be used concomitantly with caution.

Pimozide

Concomitant use of pimozide and itraconazole is contraindicated. Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients receiving pimozide concomitantly with itraconazole and/or other drugs that inhibit the CYP3A4 enzyme.

Phosphodiesterase Type 5 Inhibitors

Itraconazole is a potent inhibitor of CYP3A4, and concomitant use in patients receiving a phosphodiesterase type 5 (PDE5) inhibitor (sildenafil, tadalafil, vardenafil) can substantially increase plasma concentrations of the PDE5 inhibitor and may increase the risk of adverse effects (e.g., hypotension, visual changes, priapism) associated with these agents.

Sildenafil

The manufacturer of sildenafil recommends that a starting dose of 25 mg of sildenafil be considered in patients receiving itraconazole.

Tadalafil

Although specific studies evaluating concomitant use of tadalafil and itraconazole are not available, the manufacturer of tadalafil recommends that patients receiving potent CYP3A4 inhibitors receive no more than 10 mg of tadalafil once every 72 hours. If a once-daily tadalafil regimen is used in patients receiving itraconazole, no more than 2.5 mg of tadalafil should be given once daily.

Vardenafil

The manufacturer of vardenafil recommends that patients receiving itraconazole in a dosage of 400 mg daily should receive no more than a single 2.5-mg dose of vardenafil in a 24-hour period and those receiving itraconazole in a dosage of 200 mg daily should receive no more than a single 5-mg dose of vardenafil in a 24-hour period.

Pharmacokinetics

Absorption

Following oral administration of itraconazole, 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), itraconazole oral solution is more bioavailable than itraconazole capsules.

When a single 200-mg dose is given as capsules (with a meal), peak plasma concentrations are 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 are attained within 2.2 hours and average 544 ng/mL.

When itraconazole capsules are used, bioavailability is maximal when administered with food. Food decreases the rate of absorption, but increases peak plasma concentrations and area under the concentration-time curve (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.

Oral absorption of itraconazole is impaired when gastric acid production is decreased. In fasting individuals with relative or absolute achlorhydria, such as individuals with human immunodeficiency virus (HIV) infection or 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 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 are not available regarding long-tem use in such patients.

Data from a single-dose study in uremic patients (mean creatinine clearance 13 mL/minute per 1.73 m) indicate that the AUC of itraconazole in these patients is slightly decreased compared with healthy individuals. Wide interindividual variations in AUC were reported in uremic patients and in patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).

Data from a pharmacokinetic study evaluating itraconazole oral solution (2.5 mg/kg twice daily for 14 days) in patients with cystic fibrosis indicate that itraconazole concentrations are variable in such patients and trough concentrations attained in children younger than 16 years of age are lower than those in patients 16-28 years of age.

Distribution

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

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

Itraconazole is distributed into human milk.

Elimination

Itraconazole is metabolized principally in the liver by cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) to several metabolites. Hydroxyitraconazole, the major metabolite, has antifungal activity.

Saturable metabolism may occur with multiple dosing.

Approximately 40% of an itraconazole dose is eliminated in urine as inactive metabolites, less than 0.03% is eliminated in urine as unchanged drug, and 3-18% is eliminated in feces as unchanged drug.

In adults receiving itraconazole oral capsules (200 mg twice daily with a meal), the half-life of itraconazole is 64 hours and the half-life of hydroxyitraconazole is 56 hours at steady state.

In adults receiving itraconazole oral solution (200 mg daily without food), the half-life of itraconazole is 39.7 hours and the half-life of hydroxyitraconazole is 27.3 hours at steady state.

In children 6 months to 12 years of age receiving itraconazole oral solution (5 mg/kg once daily), the half-life of itraconazole is 35.8 hours and the 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 are not available regarding long-tem use of itraconazole in such patients.

Itraconazole is not appreciably removed by hemodialysis or peritoneal dialysis.

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