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Pharmacokinetics and Metabolism
NOTE: The plasma concentrations reported below were measured by high-performance liquid chromatography (HPLC) specific for itraconazole. When itraconazole in plasma is measured by a bioassay, values reported may be higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. (See Microbiology.)
The pharmacokinetics of SPORANOX® (itraconazole) Injection (200 mg b.i.d. for two days, then 200 mg q.d. for five days) followed by oral dosing of SPORANOX® (itraconazole injection) Capsules were studied in patients with advanced HIV infection. Steady-state plasma concentrations were reached after the fourth dose for itraconazole and by the seventh dose for hydroxyitraconazole. Steady-state plasma concentrations were maintained by administration of SPORANOX® Capsules, 200 mg b.i.d. Pharmacokinetic parameters for itraconazole and hydroxyitraconazole are presented in the table below:
|Capsule, 200 mg b.i.d.
|Cmax (ng/mL)||2856 ± 866*||1906 ± 612||2010 ± 1420||2614 ± 1703|
|tmax (hr)||1.08 ± 0.14||8.53 ± 6.36||3.92 ± 1.83||5.92 ± 6.14|
|AUC0-12h (ng•h/mL)||--||-||18768 ± 13933||28516 ± 19149|
|AUC0-24h (ng•h/mL)||30605 ± 8961||42445 ± 13282||--||-|
|* mean ± standard deviation|
The estimated mean ±SD half-life at steady-state of itraconazole after intravenous infusion was 35.4 ± 29.4 hours. In previous studies, the mean elimination half-life for itraconazole at steady-state after daily oral administration of 100 to 400 mg was 30-40 hours.
The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is 99.5%. Following intravenous administration, the volume of distribution of itraconazole averaged 796 ± 185 L.
Each intravenous dose of 200 mg itraconazole contains 8g hydroxypropyl-βcyclodextrin to increase the solubility of itraconazole. The pharmacokinetic profiles of each are described below. (See Special Populations-Renal Insufficiency.)
Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites. Hydroxyitraconazole, the major metabolite, has in vitro antifungal activity comparable to itraconazole. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Based on an oral dose, fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of itraconazole and the active metabolite hydroxyitraconazole account for less than 1% of an intravenous dose. Itraconazole is excreted mainly as inactive metabolites in urine (35%) and feces (54%) within one week of an oral dose. No single excreted metabolite represents more than 5% of a dose. Itraconazole mean total plasma clearance is 278 ± 79 mL/min following intravenous administration. A mean of 89.2% of the administered intravenous dose of hydroxypropyl-β-cyclodextrin is excreted in urine. (See CONTRAINDICATIONS and PRECAUTIONS: DRUG INTERACTIONS for more information.)
A small fraction ( < 1%) of an intravenous dose of itraconazole is excreted unchanged in urine.
After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (CrCl 50-79 mL/min), moderate (CrCl 20-49 mL/min), and severe renal impairment (CrCl < 20 mL/min) were similar to that in healthy subjects (range of means 42-49 hr vs 48 hr in renally impaired patients and healthy subjects, respectively). Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function.
Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxyitraconazole. (See CONTRAINDICATIONS, PRECAUTIONS and DOSAGE AND ADMINISTRATION.)
In patients with normal renal function, the pharmacokinetic profile of hydroxypropylβ-cyclodextrin, an ingredient of SPORANOX® (itraconazole injection) intravenous formulation, has a short half-life of 1 to 2 hours, and demonstrates no accumulation following successive daily doses. In healthy subjects and in patients with mild to severe renal insufficiency, the majority of an 8 g dose of hydroxypropyl-β-cyclodextrin (per 200 mg itraconazole) is eliminated in the urine. Following a single intravenous dose of itraconazole 200 mg, clearance of hydroxypropyl-β-cyclodextrin was reduced in subjects with mild, moderate, and severe renal impairment, resulting in higher exposure to hydroxypropyl-β-cyclodextrin; in these subjects, half-life values were increased over normal values by approximately two-, four-, and six-fold, respectively. In these patients, successive infusions may result in accumulation of hydroxypropyl-β-cyclodextrin until steady state is reached. Hydroxypropyl-β-cyclodextrin is removed by hemodialysis.
In patients with mild (defined as creatinine clearance 50-80 mL/min) and moderate (defined as creatinine clearance 30-49 mL/min) renal impairment, SPORANOX® (itraconazole injection) Injection should be used with caution. Serum creatinine levels should be closely monitored and, if renal toxicity is suspected, consideration should be given to modifying the antifungal regimen to an alternate medication with similar antimycotic coverage. SPORANOX® (itraconazole injection) Injection is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). (See CONTRAINDICATIONS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION.)
Studies have not been conducted with intravenous itraconazole in patients with hepatic impairment. Itraconazole is predominantly metabolized in the liver. Patients with impaired hepatic function should be carefully monitored when taking itraconazole. A pharmacokinetic study using a single oral 100-mg dose of itraconazole (one 100-mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole based on AUC, was similar in cirrhotic patients and in healthy subjects. The prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. Data are not available in cirrhotic patients during long-term use of itraconazole. (See BOX WARNING, CONTRAINDICATIONS, PRECAUTIONS: DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION.)
Decreased Cardiac Contractility
When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX® (itraconazole injection) Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of SPORANOX® (itraconazole injection) Injection, monitor carefully and consider other treatment alternatives which may include discontinuation of SPORANOX® Injection administration. (See WARNINGS, PRECAUTIONS: DRUG INTERACTIONS and ADVERSE REACTIONS: Post-marketing Experience for more information.)
Mechanism of Action
Activity In Vitro and In Vivo
Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Itraconazole also exhibits varying in vitro activity against Sporothrix schenckii, Trichophyton species, Candida krusei, and other Candida species.
Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro. Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.
The bioactive metabolite, hydroxyitraconazole, has not been evaluated against Histoplasma capsulatum, Blastomyces dermatitidis, Zygomycete, Fusarium spp., Scedosporium spp. and Scopulariopsis spp. Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents.
Itraconazole administered orally was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Fungistatic activity has been demonstrated against disseminated fungal infections caused by Blastomyces dermatitidis, Histoplasma duboisii, Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii, Trichophyton rubrum, and Trichophyton mentagrophytes.
Itraconazole administered at 2.5 mg/kg and 5 mg/kg via the oral and parenteral routes increased survival rates and sterilized organ systems in normal and immunosuppressed guinea pigs with disseminated Aspergillus fumigatus infections. Oral itraconazole administered daily at 40 mg/kg and 80 mg/kg increased survival rates in normal rabbits with disseminated disease and in immunosuppressed rats with pulmonary Aspergillus fumigatus infection, respectively. Itraconazole has demonstrated antifungal activity in a variety of animal models infected with Candida albicans and other Candida species.
Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy.
Several in vitro studies have reported that some fungal clinical isolates, including Candida species, with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed. The relevance of these in vitro susceptibility data to clinical outcome remains to be elucidated.
Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro.
Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.
Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown.
Empiric Therapy in Febrile Neutropenic Patients
An open randomized trial compared the efficacy and safety of itraconazole (intravenous followed by oral solution) with amphotericin B for empiric therapy in 384 febrile, neutropenic patients with hematologic malignancies who had suspected fungal infections. Patients received either itraconazole (injection, 200 mg b.i.d. for 2 days followed by 200 mg once daily for up to 14 days, followed by oral solution, 200 mg b.i.d.) or amphotericin B (total daily dose of 0.7-1.0 mg/kg body weight). The longest treatment duration was 28 days. An outcome assignment of “success” required (a) patient survival with resolution of fever and neutropenia within 28 days of treatment, (b) absence of emergent fungal infections, (c) no discontinuation of therapy due to toxicity or lack of efficacy, and (d) treatment for three or more days. The success rate using an intent-to-treat analysis was 47% for the itraconazole group and 38% for the amphotericin B arm.
Overview of Efficacy (Intent-to-Treat Population)
|Unevaluable*||84 (47%)||68 (38%)|
|Failure||24 (13%)||44 (24%)|
|Reason for Failure||71 (40%)||69 (38%)|
|Intolerance after > 3 days of antifungal medication||12||37|
|Change in antifungal medication due to fever||13||1|
|Emergent fungal infection||10||9|
|Documented bacterial or viral infection||7||8|
|Deterioration of signs and symptoms||2||0|
|Death after > 3 days antifungal medication||1||2|
|Resolution of fever||131 (73%)||127 (70%)|
|Survival||161 (90%)||156 (86%)|
|* Treatment duration ≤ 3 days (including patients who died within 3 days, withdrew because of adverse events or were deemed ineligible due to a confirmed pre-treatment infection).|
Last reviewed on RxList: 5/18/2009
This monograph has been modified to include the generic and brand name in many instances.
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