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 C ₃₅ H ₃₈ CI ₂ N ₈ O ₄ 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-(beta)-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.

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.

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 .)

MICROBIOLOGY

Mechanism of Action:   In vitro studies have demonstrated that itraconazole inhibits the cytochrome P-450-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, Sporothix 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 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 the ¹⁴ 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 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.

INDICATIONS AND USAGE

SPORANOX® (itraconazole) Injection is indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients:

1. Blastomycosis, pulmonary and extrapulmonary;
2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis; and
3. 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.

CONTRAINDICATIONS

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. Astemizole, cisapride, oral midazolam, pimozide, quinidine, and triazolam are contraindicated with SPORANOX®, HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with SPORANOX®. (See BOX WARNING , and PRECAUTIONS : Drug Interactions .)

SPORANOX® is contraindicated in 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® to patients with hypersensitivity to other azoles.

WARNINGS

SPORANOX® (itraconazole) Injection contains the excipient hydroxypropyl-(beta)-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 .)

Hepatitis   There have been rare cases of reversible idiosyncratic hepatitis reported among patients taking SPORANOX® Capsules. SPORANOX® has been associated with rare cases of serious hepatotoxicity, including fatalities, primarily in patients with serious underlying medical conditions taking multiple medications. The causal association with SPORANOX® is uncertain. If clinical signs and symptoms develop that are consistent with liver disease and may be attributable to itraconazole, SPORANOX® should be discontinued.

Cardiac Dysrhythmias:   Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using astemizole, cisapride, pimozide or quinidine concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX® is contraindicated. (See BOX WARNING , CONTRAINDICATIONS , and PRECAUTIONS : Drug Interactions .)

PRECAUTIONS

General:   Hepatic enzyme test values should be monitored in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications. Hepatic enzyme test values should be monitored periodically in all patients receiving continuous treatment for more than 1 month, or at any time a patient develops signs or symptoms suggestive of liver dysfunction.

As severe renal impairment prolongs the elimination rate of hydroxypropyl-(beta)-cyclodextrin, SPORANOX® (itraconazole) Injection should not be used in patients with severe renal dysfunction (creatinine clearance < 30 mL/min). (See CLINICAL PHARMACOLOGY : Special populations .)

Information for Patients:   SPORANOX® Injection contains the excipient hydroxypropyl-(beta)-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 .)

Drug Interactions:   Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur.

(See Table 1 below and the following drug class subheadings that follow):

1. SPORANOX® may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with SPORANOX®. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant SPORANOX® therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.
2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. SPORANOX® may not be effective in patients concomitantly taking SPORANOX® and one of these drugs. Therefore, administration of these drugs with SPORANOX® is not recommended.
3. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take SPORANOX® concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of SPORANOX®.

Antiarrhythmics:   The class IA antiarrhythmic quinidine is known to prolong the QT interval. Coadministration of quinidine with SPORANOX® increases plasma concentrations of quinidine which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and quinidine is contraindicated. (See BOX WARNING , CONTRAINDICATIONS , and WARNINGS .)

Concomitant administration of digoxin and SPORANOX® has led to increased plasma concentrations of digoxin.

Anticonvulsants:   Reduced plasma concentrations of itraconazole were reported when SPORANOX® was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of SPORANOX® and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and carbamazepine may inhibit the metabolism of carbamazepine.

Antihistamines:   Coadministration of astemizole with SPORANOX® has led to elevated plasma concentrations of astemizole and desmethylastemizole which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® with astemizole is contraindicated. (See BOX WARNING , CONTRAINDICATIONS , and WARNINGS .)

Antimycobacterials:   Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. SPORANOX® may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of SPORANOX® could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended.

Antineoplastics:   SPORANOX® may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids.

Antipsychotics:   Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with SPORANOX® could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and pimozide is contraindicated. (See BOX WARNING , CONTRAINDICATIONS , and WARNINGS .)

Benzodiazepines:   Concomitant administration of SPORANOX® and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of SPORANOX® and oral midazolam or triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS .) If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged.

Calcium Channel Blockers:   SPORANOX® may inhibit the metabolism of the dihydropyridines and verapamil.

Gastrointestinal Motility Agents:   Coadministration of SPORANOX® with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® with cisapride is contraindicated. (See BOX WARNING , CONTRAINDICATIONS , and WARNINGS .)

HMG CoA-Reductase Inhibitors:   Human pharmacokinetic data suggest that SPORANOX® inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant adminstration of SPORANOX® and lovastatin or simvastatin is contraindicated. (See CONTRAINDICATIONS and WARNINGS .)

Immunosuppressants:   Concomitant administration of SPORANOX® and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of SPORANOX® and sirolimus could increase plasma concentrations of sirolimus.

Macrolide Antibiotics:   Clarithromycin is a known inhibitor of CYP3A4 and may increase plasma concentrations of itraconazole. There is no data regarding the pharmacokinetic effects of other macrolides on itraconazole.

Oral Hypoglycemic Agents:   Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when SPORANOX® and oral hypoglycemic agents are coadministered.

Polyenes:   Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphoterecin B. However, the clinical significance of this drug effect has not been clearly defined.

Protease Inhibitors:   Concomitant administration of SPORANOX® and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of SPORANOX® and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when SPORANOX® and protease inhibitors must be given concomitantly.

Reverse Transcriptase Inhibitors:   Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with SPORANOX® Capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8 ± 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied.

Other:

• In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with SPORANOX® may increase plasma concentrations of alfentanil.
• Human pharmacokinetic data suggest that concomitant administration of SPORANOX® and buspirone results in significant increases in plasma concentrations of buspirone.
• SPORANOX® may inhibit the metabolism of methylprednisolone.
• In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazaole potently inhibits the metabolism of trimetrexate. Although there are no data regarding the effect of itraconazole on trimetrexate metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and trimetrexate may inhibit the metabolism of trimetrexate.
• SPORANOX® enhances the anticoagulant effect of coumarin-like drugs, such as warfarin.

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 10 × the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1 × 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 (6.25 × 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-(beta)-cyclodextrin (HP-(beta)-CD), the solubilizing excipient used in SPORANOX® 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-(beta)-CD at the recommended clinical dose of SPORANOX® 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-(beta)-CD to potential carcinogenic effects for SPORANOX® Injection is uncertain.

Itraconazole produced no mutagenic effects when assayed in 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 ( Drosphila melanogaster ) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T ¹ / ₂ 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 (5 × 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 (20 × 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 (5-20 × MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10 × 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® should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk.

Nursing Mothers:   Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX® 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 safety and efficacy of SPORANOX® have not been established in pediatric patients. No pharmacokinetic data on SPORANOX® 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® 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 (2.5 × 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 (10 × MRHD) over 1 year or 160 mg/kg/day (20 × 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® 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.

ADVERSE REACTIONS

Rare cases of reversible idiosyncratic hepatitis have been reported among patients taking SPORANOX® (itraconazole) Capsules. SPORANOX® has been associated with rare cases of serious hepatotoxicity, including fatalities, primarily in patients with serious underlying medical conditions who are taking multiple medications. The causal association with SPORANOX® is uncertain. If clinical signs and symptoms consistent with liver disease develop and could be attributed to itraconazole, SPORANOX® should be discontinued. (See WARNINGS .)

Adverse events considered at least possibly drug related are listed below and are based on the experience of 360 patients treated with SPORANOX® Injection in four pharmacokinetic, one uncontrolled and four active controlled studies where the control was amphotericin B or fluconazole. Nearly all patients were neutropenic or were otherwise immunocompromised and were treated empirically for febrile episodes, for documented systemic fungal infections, or in trials to determine pharmacokinetics. The dose of SPORANOX® Injection was 200 mg twice daily for the first two days followed by a single daily dose of 200 mg for the remainder of the intravenous treatment period. The majority of patients received between 7 and 14 days of SPORANOX® Injection.

The following adverse events occurred in less than 1% of patients in clinical trials of SPORANOX® Injection: constipation, hyperglycemia, hepatitis, fever, rigors, dyspnea, and hypotension.

Post-marketing Experience

In worldwide post-marketing experience with SPORANOX® Capsules, allergic reactions, including rash, pruritus, urticaria, angioedema, and, in rare instances, anaphylaxis and Stevens-Johnson syndrome, have been reported. Post-marketing experiences have also included reports of elevated liver enzymes and rarely, hepatitis. Although the causal association with SPORANOX® is uncertain, rare cases of alopecia, hypertriglyceridemia, menstrual disorders, and neutropenia, and isolated cases of neuropathy have also been reported.

OVERDOSAGE

Itraconazole is not removed by dialysis.

There are limited data on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 100 mg of SPORANOX® (itraconazole) Oral Solution or up to 3000 mg of SPORANOX® Capsules, the adverse event profile was similar to that observed at recommended doses.

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® Injection should not be diluted with 5% Dextrose Injection, USP, or with Lactated Ringer' Injection, USP, alone or in combination with any other diluent. The compatibility of SPORANOX® 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® 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® Injection. Do not introduce concomitant medication in the same bag nor through the same line as SPORANOX® 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.

Add the full contents (25 mL) of the SPORANOX® 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. Using a flow control device, infuse 60 mL of the dilute solution (3.33 mg/mL = 200 mg itraconazole, pH apx. 48) 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. 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.

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® can be given as oral capsules or intravenously. The safety and efficacy of SPORANOX® Injection administered for greater than 14 days is not known.

Total itraconazole therapy (SPORANOX® Injection followed by SPORANOX® 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.

SPORANOX® Injection should not be used in patients with creatinine clearance < 30 mL/min.

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.

Distributed by:

Ortho Biotech Products, L.P.

Raritan, NJ 08869                                     631-10-938-2

Manufactured by:        U.S. Patents 4,267,179; 4,791,111

Abbott Laboratories, Inc.                              58-6011-R2

                                                                     March 2000

North Chicago, IL 60064                           ©JPPLP 2000

PRODUCT PHOTO(S):