DESCRIPTION

SPORANOX® is the brand name for itraconazole, a synthetic 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 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 Cl 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) Oral Solution contains 10 mg of itraconazole per mL, solubilized by hydroxypropyl-(beta)-cyclodextrin (400 mg/mL) as a molecular inclusion complex. SPORANOX® Oral Solution is clear and yellowish in color with a target pH of 2. Other ingredients are hydrochloric acid, propylene glycol, purified water, sodium hydroxide, sodium saccharin, sorbitol, cherry flavor 1, cherry flavor 2 and caramel flavor.

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 absolute bioavailability of itraconazole administered as a non-marketed solution formulation under fed conditions was 55% in 6 healthy male volunteers. However, the bioavailability of SPORANOX® (itraconazole) Oral Solution is increased under fasted conditions reaching higher maximum plasma concentrations (C _max ) in a shorter period of time. In 27 healthy male volunteers, the steady-state area under the plasma concentration versus time curve (AUC _0-24h ) of itraconazole (SPORANOX® Oral Solution, 200 mg daily for 15 days) under fasted conditions was 131 ± 30% of that obtained under fed conditions. Therefore, unlike SPORANOX® Capsules, it is recommended that SPORANOX® Oral Solution be administered without food. Presented in the table below are the steady-state (Day 15) pharmacokinetic parameters for itraconazole and hydroxyitraconazole (SPORANOX® Oral Solution) under fasted and fed conditions:

The bioavailability of SPORANOX® Oral Solution relative to SPORANOX® Capsules was studied in 30 healthy male volunteers who received 200 mg of itraconazole as the oral solution and capsules under fed conditions. The AUC _0-(infinity) from SPORANOX® Oral Solution was 149 ± 68% of that obtained from SPORANOX® Capsules; a similar increase was observed for hydroxyitraconazole. In addition, a cross study comparison of itraconazole and hydroxyitraconazole pharmacokinetics following the administration of single 200 mg doses of SPORANOX® Oral Solution (under fasted conditions) or SPORANOX® Capsules (under fed conditions) indicates that when these two formulations are administered under conditions which optimize their systemic absorption, the bioavailability of the solution relative to capsules is expected to be increased further. Therefore, it is recommended that SPORANOX® Oral Solution and SPORANOX® Capsules not be used interchangeably. The following table contains pharmacokinetic parameters for itraconazole and hydroxyitraconazole following single 200 mg doses of SPORANOX® Oral Solution (n=27) or SPORANOX® Capsules (n=30) administered to healthy male volunteers under fasted and fed conditions, respectively:

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/minute following intravenous administration.

Special Populations:

Pediatrics   The pharmacokinetics of SPORANOX® Oral Solution were studied in 26 pediatric patients requiring systemic antifungal therapy. Patients were stratified by age: 6 months to 2 years (n=8), 2 to 5 years (n=7) and 5 to 12 years (n=11), and received itraconazole oral solution 5 mg/kg once daily for 14 days. Pharmacokinetic parameters at steady-state (Day 14) were not significantly different among the age strata and are summarized in the table below for all 26 patients:

Renal Insufficiency:   A pharmacokinetic study using a single 200-mg dose of itraconazole (four 50-mg capsules) was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73 m ² , the bioavailability was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (T _max, C _max, and AUC _0-8 . Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups.

Hepatic Insufficiency:   Patients with impaired hepatic function should be carefully monitored when taking itraconazole. The prolonged elimination half-life of itraconazole observed 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 . Intraconazole 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

Resistence:   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 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) Oral Solution is indicated for the treatment of oropharyngeal and esophageal candidiasis.

Description of Clinical Studies:

Oropharyngeal Candidiasis:   Two randomized, controlled studies for the treatment of oropharyngeal candidiasis have been conducted (total n=344). In one trial, clinical response to either 7 or 14 days of itraconazole oral solution, 200 mg/day, was similar to fluconazole tablets and averaged 84% across all arms. Clinical response in this study was defined as cured or improved (only minimal signs and symptoms with no visible lesions). Approximately 5% of subjects were lost to follow-up before any evaluations could be performed. Response to 14 days therapy of itraconazole oral solution was associated with a lower relapse rate than 7 days of itraconazole therapy. In another trial, the clinical response rate (defined as cured or improved) for itraconazole oral solution was similar to clotrimazole troches and averaged approximately 71% across both arms, with approximately 3% of subjects lost to follow-up before any evaluations could be performed. Ninety-two percent of the patients in these studies were HIV seropositive.

In an uncontrolled, open-label study of selected patients clinically unresponsive to fluconazole tablets (n=74, all patients HIV seropositive), patients were treated with itraconazole oral solution 100 mg b.i.d. (Clinically unresponsive to fluconazole in this study was defined as having received a dose of fluconazole tablets at least 200 mg/day for a minimum of 14 days.) Treatment duration was 14-28 days based on response. Approximately 55% of patients had complete resolution of oral lesions. Of patients who responded and then entered a follow-up phase (n=22), all relapsed within 1 month (median 14 days) when treatment was discontinued. Although baseline endoscopies had not been performed, several patients in this study developed symptoms of esophageal candidiasis while receiving therapy with itraconazole oral solution. Itraconazole oral solution has not been directly compared to other agents in a controlled trial of similar patients.

Esophageal Candidiasis:   A double-blind randomized study (n=119, 111 of whom were HIV seropositive) compared itraconazole oral solution (100 mg/day) to fluconazole tablets (100 mg/day). The dose of each was increased to 200 mg/day for patients not responding initially. Treatment continued for 2 weeks following resolution of symptoms, for a total duration of treatment of 3-8 weeks. Clinical response (a global assessment of cured or improved) was not significantly different between the two study arms, and averaged approximately 86% with 8% lost to follow-up. Six of 53 (11%) itraconazole-treated patients and 12/57 (21%) fluconazole-treated patients were escalated to the 200 mg dose in this trial. Of the subgroup of patients who responded and entered a follow-up phase (n=88), approximately 23% relapsed across both arms within 4 weeks.

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 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® to patients with hypersensitivity to other azoles.

WARNINGS

SPORANOX® (itraconazole) Oral Solution and SPORANOX® Capsules should not be used interchangeably. Only SPORANOX® Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. SPORANOX® Oral Solution 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 Carcinogenesis, Mutagenesis, and Impairment of Fertility .)

Hepatitis   Rare cases of reversible idiosyncratic hepatitis have been reported among patients taking SPORANOX® Capsules. SPORANOX® has been associated with rare cases of serious hepatotoxicity, including death, 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 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.

Information for Patients:   Only SPORANOX® Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. SPORANOX® Oral Solution 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 relevence of these findings is unknown. (See Carcinogenesis, Mutagenesis, and Impairment of Fertility .)

Taking SPORANOX® Oral Solution under fasted conditions improves the systemic availability of itraconazole. Instruct patients to take SPORANOX® Oral Solution without food, if possible.

Instruct patients to report any signs and symptoms that may suggest liver dysfunction so that the appropriate laboratory testing can be done. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine or pale stools.

Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions.

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 intraconazole.
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.

Anticoagulants:   SPORANOX® enhances the anticoagulant effect of coumarin-like drugs, such as warfarin.

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 desmethyl-astemizole 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.

Gastric Acid Suppressors/Neutralizers:   Reduced plasma concentrations of itraconazole were reported when SPORANOX® Capsules were administered concomitantly with H ₂ -receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. Therefore, SPORANOX® should be administered with a cola beverage if the patient has achlorhydria or is taking H ₂ -receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after administration of SPORANOX® Capsules. In a clinical study, when SPORANOX® Capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced. However, as itraconazole is already dissolved in SPORANOX® Oral Solution, the effect of H ₂ antagonists is expected to be substantially less than with the capsules. Nevertheless, caution is advised when the two drugs are coadministered.

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 administration 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.

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 amphotericin 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 100mg 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 ketoconazole 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.

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® 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.

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/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 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 efficacy and safety of SPORANOX® have not been established in pediatric patients. A pharmacokinetic study was conducted with SPORANOX® Oral Solution in 26 pediatric patients, ages 6 months to 12 years, requiring systemic antifungal treatment. Itraconazole was dosed at 5 mg/kg once daily for two weeks and no serious unexpected adverse events were reported. (See CLINICAL PHARMACOLOGY .)

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.

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. )

U.S. adverse experience data are derived from 350 immunocompromised patients (332 HIV seropositive/AIDS) treated for oropharyngeal or esophageal candidiasis. The table below lists adverse events reported by at least 2% of patients treated with SPORANOX® Oral Solution in U.S. clinical trials. Data on patients receiving comparator agents in these trials are included for comparison.

Adverse events reported by less than 2% of patients in U.S. clinical trials with SPORANOX® included: adrenal insufficiency, asthenia, back pain, dehydration, dyspepsia, dysphagia, flatulence, gynecomastia, hematuria, hemorrhoids, hot flushes, implantation complication, infection unspecified, injury, insomnia, male breast pain, myalgia, pharyngitis, pruritus, rhinitis, rigors, stomatitis ulcerative, taste perversion, tinnitus, upper respiratory tract infection, vision abnormal, and weight decrease. Edema, hypokalemia and menstrual disorders have been reported in clinical trials with itraconazole capsules.

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, neutropenia, and isolated cases of neuropathy have also been reported.

OVERDOSAGE

Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed.

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® Capsules, the adverse event profile was similar to that observed at recommended doses.

DOSAGE AND ADMINISTRATION

The solution should be vigorously swished in the mouth (10 mL at a time) for several seconds and swallowed.

The recommended dosage of SPORANOX® (itraconazole) Oral Solution for oropharyngeal candidiasis is 200 mg (20 mL) daily for 1 to 2 weeks. Clinical signs and symptoms of oropharyngeal candidiasis generally resolve within several days.

For patients with oropharyngeal candidiasis unresponsive/refractory to treatment with fluconazole tablets, the recommended dose is 100 mg (10 mL) b.i.d. For patients responding to therapy, clinical response will be seen in 2 to 4 weeks. Patients may be expected to relapse shortly after discontinuing therapy. Limited data on the safety of long-term use (>6 months) of SPORANOX® Oral Solution are available at this time.

The recommended dosage of SPORANOX® Oral Solution for esophageal candidiasis is 100 mg (10 mL) daily for a minimum treatment of three weeks. Treatment should continue for 2 weeks following resolution of symptoms. Doses up to 200 mg (20 mL) per day may be used based on medical judgement of the patient' response to therapy.

SPORANOX® Oral Solution and SPORANOX® Capsules should not be used interchangeably. Patients should be instructed to take SPORANOX® Oral Solution without food, if possible. Only SPORANOX® Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

HOW SUPPLIED

SPORANOX® (itraconazole) Oral Solution is available in 150 mL amber glass bottles (NDC 50458-295-15) containing 10 mg of itraconazole per mL.

Store at or below 25°C (77°F). Do not freeze.

631-10-939-2

U.S. Patent Nos. 4,267,179; 4,791,111; 5,707,975; 4,727,064

February 1997, February 2000

© JPPLP 2000

Manufactured by:

Janssen Pharmaceutica N.V.

Beerse, Belgium

Distributed by:

Ortho Biotech Products, L.P.

Raritan, NJ 08869

PRODUCT PHOTO(S):