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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® (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: Parameter Injection Day 7 n=29 Capsule, 200 mg b.i.d. Day 36 n=12 itraconazole hydroxyitraconazole itraconazole hydroxyitraconazole 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.) Special Populations Renal Insufficiency 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.) Hepatic Insufficiency 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.) 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. 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. 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. 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. 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. Overview of Efficacy (Intent-to-Treat Population) Efficacy Parameters SPORANOX® N=179 (%) Amphotericin B N=181 (%) Success 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 Persistent fever 20 7 Change in antifungal medication due to fever 13 1 Emergent fungal infection 10 9 Documented bacterial or viral infection 7 8 Insufficient response 6 5 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).

SPORANOX® (itraconazole) Injection Congestive Heart Failure: When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. If signs or symptoms of congestive heart failure occur during administration of SPORANOX® (itraconazole) Injection, continued SPORANOX® use should be reassessed. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: DRUG INTERACTIONS and ADVERSE REACTIONS: Post-marketing Experience for more information.) Drug Interactions: Coadministration of cisapride, pimozide, quinidine, dofetilide, or levacetylmethadol (levomethadyl) with SPORANOX® (itraconazole) Capsules, Injection or Oral Solution is contraindicated. SPORANOX® (itraconazole injection) , a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with SPORANOX® (itraconazole injection) and/or other CYP3A4 inhibitors. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: DRUG INTERACTIONS for more information.) 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-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2 1,2,4-triazolin-5-one mixture with (±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2S*,4R*)-2(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4yl]methoxy]phenyl]-1-piperazinyl]phenyl]- Δ2-1,2,4-triazolin-5-one. or (±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]- Δ2-1,2,4-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-β-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® (itraconazole injection) 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.

INDICATIONS SPORANOX® (itraconazole) Injection/Oral Solution is indicated for empiric therapy of febrile neutropenic patients with suspected fungal infections. (NOTE: In a comparative trial, the overall response rate for itraconazole-treated subjects was higher than for amphotericin B-treated subjects. However, compared to amphotericin B-treated subjects, a larger number of itraconazole-treated subjects discontinued treatment due to persistent fever and a change in antifungal medication due to fever. Whereas, a larger number of amphotericin B-treated subjects discontinued due to drug intolerance. (See Clinical Studies section.) SPORANOX® (itraconazole) Injection is also indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: Blastomycosis, pulmonary and extrapulmonary; Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis; and Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information). DOSAGE AND ADMINISTRATION Use only the components [SPORANOX® (itraconazole) Injection ampule, 0.9% Sodium Chloride Injection, USP (Normal Saline) bag and filtered infusion set] provided in the kit: DO NOT SUBSTITUTE. SPORANOX® (itraconazole injection) Injection should not be diluted with 5% Dextrose Injection, USP, or with Lactated Ringer's Injection, USP, alone or in combination with any other diluent. The compatibility of SPORANOX® (itraconazole injection) Injection with diluents other than 0.9% Sodium Chloride Injection, USP (Normal Saline) is not known. NOT FOR IV BOLUS INJECTION. NOTE: After reconstitution, the diluted SPORANOX® (itraconazole injection) Injection may be stored refrigerated (2-8°C) or at room temperature (15-25°C) for up to 48 hours, when protected from direct light. During administration, exposure to normal room light is acceptable. NOTE: Use only a dedicated infusion line for administration of SPORANOX® (itraconazole injection) Injection. Do not introduce concomitant medication in the same bag nor through the same line as SPORANOX® (itraconazole injection) Injection. Other medications may be administered after flushing the line/catheter with 0.9% Sodium Chloride Injection, USP, as described below, and removing and replacing the entire infusion line. Alternatively, utilize another lumen, in the case of a multi-lumen catheter. Correct preparation and administration of SPORANOX® (itraconazole injection) Injection are necessary to ensure maximal efficacy and safety. A precise mixing ratio is required in order to obtain a stable admixture. It is critical to maintain a 3.33 mg/mL itraconazole:diluent ratio. Failure to maintain this concentration will lead to the formation of a precipitate. Add the full contents (25 mL) of the SPORANOX® (itraconazole injection) Injection ampule into the infusion bag provided, which contains 50 mL of 0.9% Sodium Chloride Injection, USP (Normal Saline). Mix gently after the solution is completely transferred. Withdraw and discard 15 mL of the solution before administering to the patient. Using a flow control device, infuse 60 mL of the dilute solution (3.33 mg/mL = 200 mg itraconazole, pH apx. 4.8) intravenously over 60 minutes, using an extension line and the infusion set provided. After administration, flush the infusion set with 15-20 mL of 0.9% Sodium Chloride Injection, USP, over 30 seconds-15 minutes, via the two-way stopcock. Do not use Bacteriostatic Sodium Chloride Injection, USP. The compatibility of SPORANOX® (itraconazole injection) Injection with flush solutions other than 0.9% Sodium Chloride Injection, USP (Normal Saline) is not known. Discard the entire infusion line. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Empiric Therapy in Febrile, Neutropenic Patients with Suspected Fungal Infections (ETFN) The recommended dose of SPORANOX® (itraconazole injection) Injection is 200 mg b.i.d. for four doses, followed by 200 mg once daily for up to 14 days. Each intravenous dose should be infused over 1 hour. Treatment should be continued with SPORANOX® (itraconazole injection) Oral Solution 200 mg (20 mL) b.i.d. until resolution of clinically significant neutropenia. The safety and efficacy of SPORANOX® (itraconazole injection) use exceeding 28 days in ETFN is not known. Treatment of Blastomycosis, Histoplasmosis and Aspergillosis The recommended intravenous dose is 200 mg b.i.d. for four doses, followed by 200 mg q.d. Each intravenous dose should be infused over 1 hour. For the treatment of blastomycosis, histoplasmosis and aspergillosis, SPORANOX® (itraconazole injection) can be given as oral capsules or intravenously. The safety and efficacy of SPORANOX® (itraconazole injection) Injection administered for greater than 14 days is not known. Total itraconazole therapy (SPORANOX® (itraconazole injection) Injection followed by SPORANOX® (itraconazole injection) Capsules) should be continued for a minimum of 3 months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Use in Patients with Renal Impairment Limited data are available on the use of intravenous itraconazole in patients with renal impairment. Hydroxypropyl-β-cyclodextrin, a required component of SPORANOXintravenous formulation, is eliminated through glomerular filtration. Therefore, in patients with severe renal impairment (defined as creatinine clearance below 30 mL/min), the use of SPORANOX® IV is contraindicated. (See CONTRAINDICATIONS.) 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. (see CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, and PRECAUTIONS.) Use in Patients with Hepatic Impairment Limited data are available on the use of itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and PRECAUTIONS). HOW SUPPLIED SPORANOX® (itraconazole) Injection for intravenous infusion is supplied as a kit (NDC 50458-298-01), containing one 25 mL colorless glass ampule of itraconazole 10 mg/mL sterile, pyrogen-free solution (NDC 50458-297-10), one 50 mL bag (100 mL capacity) of 0.9% Sodium Chloride Injection, USP (Normal Saline) and one filtered infusion set. Store at or below 25°C (77°F). Protect from light and freezing. Keep out of reach of children. Manufactured for: Ortho Biotech Products, L.P Raritan, NJ 08869. Manufactured by: Hospira, Inc. Lake Forest, IL 60045. Revised March 2009.

PATIENT INFORMATION SPORANOX® (itraconazole injection) Injection contains the excipient hydroxypropyl-β-cyclodextrin which produced pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of these findings is unknown. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of Fertility.) Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Advise patients to inform their physicians if any hearing loss symptoms occur.

OVERDOSE Itraconazole is not removed by dialysis. There are limited data on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1000 mg of SPORANOX® (itraconazole) Oral Solution or up to 3000 mg of SPORANOX® (itraconazole injection) Capsules, or b.i.d. dosing for four days with SPORANOX® (itraconazole injection) Injection, the adverse event profile was similar to that observed at recommended doses. CONTRAINDICATIONS Drug Interactions Concomitant administration of SPORANOX® (itraconazole) Capsules, Injection, or Oral Solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide, triazolam and levacetylmethadol (levomethadyl) are contraindicated with SPORANOX® (itraconazole injection) . HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with SPORANOX® (itraconazole injection) . Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) are contraindicated with SPORANOX®. (See BOX WARNING, and PRECAUTIONS: DRUG INTERACTIONS.) SPORANOX® (itraconazole injection) is contraindicated for patients who have shown hypersensitivity to itraconazole or its excipients. There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing SPORANOX® (itraconazole injection) to patients with hypersensitivity to other azoles. SPORANOX IV cannot be used when administration of Sodium Chloride Injection is contraindicated. The excipient hydroxypropyl-β-cyclodextrin is eliminated through glomerular filtration. Therefore, SPORANOX IV is contraindicated in patients with severe renal impairment (defined as creatinine clearance below 30 mL/min). (See CLINICAL PHARMACOLOGY: Special Populations, PRECAUTIONS, and DOSAGE AND ADMINISTRATION.)

WARNINGS SPORANOX® (itraconazole) Injection contains the excipient hydroxypropylβ-cyclodextrin which produced pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of these findings is unknown. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of Fertility.) Hepatic Effects SPORANOX® (itraconazole injection) has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. Continued SPORANOX® (itraconazole injection) use or reinstitution of treatment with SPORANOX® (itraconazole injection) is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: INFORMATION FOR PATIENTS and ADVERSE REACTIONS.) Cardiac Dysrhythmias Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with SPORANOX® (itraconazole injection) and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX® is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: DRUG INTERACTIONS.) Cardiac Disease SPORANOX® (itraconazole injection) Injection should not be used in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX® (itraconazole injection) therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of SPORANOX® (itraconazole injection) Injection, monitor carefully and consider other treatment alternatives which may include discontinuation of SPORANOX® Injection administration. Itraconazole has been shown to have a negative inotropic effect. 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. SPORANOX® (itraconazole injection) has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses. Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX® (itraconazole injection) and nisoldipine is contraindicated. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CLINICAL PHARMACOLOGY: Special Populations, PRECAUTIONS: DRUG INTERACTIONS, and ADVERSE REACTIONS: Post-marketing Experience for more information.) PRECAUTIONS Hepatotoxicity Rare cases of serious hepatotoxicity have been observed with SPORANOX® (itraconazole injection) treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with SPORANOX® (itraconazole injection) is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving SPORANOX® (itraconazole injection) . Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. Neuropathy If neuropathy occurs that may be attributable to SPORANOX® (itraconazole injection) Injection, the treatment should be discontinued. Hearing Loss Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNING: DRUG INTERACTIONS, CONTRAINDICATIONS: DRUG INTERACTIONS and PRECAUTIONS: DRUG INTERACTIONS). The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Carcinogenesis, Mutagenesis and Impairment of Fertility Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10x the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1x MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25x MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant. Hydroxypropyl-β-cyclodextrin (HP-β-CD), the solubilizing excipient used in SPORANOX® (itraconazole injection) Injection and Oral Solution, was found to produce pancreatic exocrine hyperplasia and neoplasia when administered orally to rats at doses of 500, 2000 or 5000 mg/kg/day for 25 months. Adenocarcinomas of the exocrine pancreas produced in the treated animals were not seen in the untreated group and are not reported in the historical controls. Development of these tumors may be related to a mitogenic action of cholecystokinin. This finding was not observed in the mouse carcinogenicity study at doses of 500, 2000 or 5000 mg/kg/day for 22-23 months; however, the clinical relevance of these findings is unknown. Based on body surface area comparisons, the exposure to humans of HP-β-CD at the recommended clinical dose of SPORANOX® (itraconazole injection) Oral Solution, is approximately equivalent to 1.7 times the exposure at the lowest dose in the rat study. The relevance of the findings with orally administered HP-β-CD to potential carcinogenic effects for SPORANOX® Injection is uncertain. Itraconazole produced no mutagenic effects when assayed in a DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats. Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5x MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20x MRHD). Pregnancy Teratogenic Effects Pregnancy Category C. Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day (5-20x MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10x MRHD). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. There are no studies in pregnant women. SPORANOX® (itraconazole injection) should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. During post-marketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS: Post-marketing Experience.) Nursing Mothers Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX® (itraconazole injection) therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants. Pediatric Use The efficacy and safety of SPORANOX® (itraconazole injection) have not been established in pediatric patients. No pharmacokinetic data on SPORANOX® (itraconazole injection) Capsules or Injection are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse effects have been reported. SPORANOX® (itraconazole injection) Oral Solution (5 mg/kg/day) has been administered to pediatric patients (N=26, ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5x MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10x MRHD) over 1 year or 160 mg/kg/day (20x MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients. Geriatric Use Clinical studies of SPORANOX® (itraconazole injection) Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNING: DRUG INTERACTIONS, CONTRAINDICATIONS: DRUG INTERACTIONS and PRECAUTIONS: DRUG INTERACTIONS). Itraconazole should be used with care in elderly patients (see PRECAUTIONS). Renal Impairment Hydroxypropyl-β-cyclodextrin, when administered intravenously, is eliminated through glomerular filtration. Therefore, in patients with severe renal impairment defined as creatinine clearance below 30 mL/min, SPORANOX IV is contraindicated (see CONTRAINDICATIONS). 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 IV 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. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, and DOSAGE AND ADMINISTRATION for further information.). Hepatic Impairment Studies have not been conducted with intravenous itraconazole in patients with hepatic impairment. Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (see CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and DOSAGE AND ADMINISTRATION.)