Sporanox Injection (Itraconazole Injection) - Description and Clinical Pharmacology

DESCRIPTION

For intravenous infusion (NOT FOR IV BOLUS INJECTION)

SPORANOX® is the brand name for itraconazole, a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature:

(±)-1-[(R *)- sec -butyl]-4-[ p -[4-[ p -[[(2 R *,4 S *)-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-(DELTA) ²-1,2,4-triazolin-5-one mixture with (±)-1-[(R *)- sec -butyl]-4-[ p -[4-[ p -[[(2 S *,4 R *)-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy] phenyl]-1-piperazinyl]phenyl]-(DELTA) ²-1,2,4-triazolin-5-one.

or

(±)-1-[(RS)- sec -butyl]-4-[ p -[4-[ p -[[(2 R,4 S)-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-(DELTA) ²-1,2,4-triazolin-5-one.

Itraconazole has a molecular formula of C₃₅H₃₈Cl₂N₈O₄ and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1.

SPORANOX® (itraconazole) Injection is a sterile pyrogen-free clear, colorless to slightly yellow solution for intravenous infusion. Each mL contains 10 mg of itraconazole, solubilized by hydroxypropyl-cyclodextrin (400 mg) as a molecular inclusion complex, with 3.8 µL hydrochloric acid, 25 µL propylene glycol, and sodium hydroxide for pH adjustment to 4.5, in water for injection. SPORANOX® Injection is packaged in 25 mL colorless glass ampules, containing 250 mg of itraconazole, contents of which are diluted in 50 mL 0.9% Sodium Chloride Injection, USP (Normal Saline) prior to infusion. When properly administered, contents of one ampule will supply 200 mg of itraconazole.

CLINICAL PHARMACOLOGY

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® 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:

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. Approximately 93-101% of hydroxypropyl-(beta)-cyclodextrin was excreted unchanged in the urine within 12 hours after dosing.

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.

Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Itraconazole total plasma clearance averaged 381 ± 95 mL/min following intravenous administration. Approximately 80-90% of hydroxypropyl-(beta)-cyclodextrin is eliminated through the kidneys. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions for more information.)

SPECIAL POPULATIONS

Renal Insufficiency:    Plasma concentrations of itraconazole in patients with mild to moderate renal insufficiency were comparable to those obtained in healthy subjects. The majority of the 8-gram dose of hydroxypropyl-(beta)-cyclodextrin was eliminated in the urine during the 120-hour collection period in normal subjects and in patients with mild to severe renal insufficiency. Following a single intravenous dose of 200 mg to subjects with severe renal impairment (creatinine clearance </= 19 mL/minute), clearance of hydroxypropyl-(beta)-cyclodextrin was reduced six-fold compared with subjects with normal renal function. SPORANOX® Injection should not be used in patients with creatinine clearance < 30 mL/min.

In patients with mild to moderate renal impairment, SPORANOX® Injection should be used with caution. Serum creatinine levels should be closely monitored and, if renal toxicity is suspected, consideration should be given to changing to SPORANOX® Capsules.

Hepatic Insufficiency:    Patients with impaired hepatic function should be carefully monitored when taking itraconazole. The prolonged elimination half-life of itraconazole observed in a clinical trial with itraconazole capsules in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.)

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® 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® 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.)

MICROBIOLOGY

Mechanism of Action:    In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

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. The bioactive metabolite, hydroxyitraconazole, has not been evaluated against Histoplasma capsulatum and Blastomyces dermatitidis. 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.

Resistance:    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.

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 the¹⁴ C-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 anti-fungal 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.

CLINICAL STUDIES

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.