Congestive Heart Failure

SPORANOXO (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHFO

. If signs or symptoms of congestive heart failure occur during administration of SPORANOX

Capsules, discontinue administration. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (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, or dofetilide with SPORANOX(r) (itraconazole) Capsules, Injection or Oral Solution is contraindicated. SPORANOX(r), 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, or quinidine, concomitantly with SPORANOX(r) and/or other CYP3A4 inhibitors. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.

DESCRIPTION

SPORANOX(r) 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:

(insert structure)

(+-)-1-[(R *)-sec-butyl]-4-[p-[4-[p-[[(2R *,4S *)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-D2-1,2,4-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-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-D2- 1,2,4-triazolin-5-one or (+-)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-D2-1,2,4-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(r) Capsules contain 100 mg of itraconazole coated on sugar spheres. Inactive ingredients are gelatin, hydroxypropyl methylcellulose, polyethylene glycol (PEG) 20,000, starch, sucrose, titanium dioxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28.

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 are approximately 3.3 times higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. (See MICROBIOLOGY.)

The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study in 6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole was 55%. The oral bioavailability of itraconazole is maximal when SPORANOX(r) (itraconazole) Capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied in 6 healthy male volunteers who received, in a crossover design, single 100-mg doses of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6 volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this study, only itraconazole plasma concentrations were measured. The respective pharmacokinetic parameters for itraconazole are presented in the table below:

Doubling the SPORANOX(r) dose results in approximately a three-fold increase in the itraconazole plasma concentrations. Values given in the table below represent data from a crossover pharmacokinetics study in which 27 healthy male volunteers each took a single 200-mg dose of SPORANOX(r) Capsules with or without a full meal:

Absorption of itraconazole under fasted conditions in individuals with relative or absolute achlorhydria, such as patients with AIDS or volunteers taking gastric acid secretion suppressors (e.g., H2 receptor antagonists), was increased when SPORANOX(r) Capsules were administered with a cola beverage. Eighteen men with AIDS received single 200-mg doses of SPORANOX(r) Capsules under fasted conditions with 8 ounces of water or 8 ounces of a cola beverage in a crossover design. The absorption of itraconazole was increased when SPORANOX(r) Capsules were coadministered with a cola beverage, with AUC0-24 and C max increasing 75% +- 121% and 95% +- 128%, respectively. Thirty healthy men received single 200-mg doses of SPORANOX(r) Capsules under fasted conditions either 1) with water; 2) with water, after ranitidine 150 mg b.i.d. for 3 days; or 3) with cola, after ranitidine 150 mg b.i.d. for 3 days. When SPORANOX(r) Capsules were administered after ranitidine pretreatment, itraconazole was absorbed to a lesser extent than when SPORANOX(r) Capsules were administered alone, with decreases in AUC0-24 and Cmax of 39% +- 37% and 42% +- 39%, respectively. When SPORANOX(r) Capsules were administered with cola after ranitidine pretreatment, itraconazole absorption was comparable to that observed when SPORANOX(r) Capsules were administered alone. (See PRECAUTIONS: Drug Interactions.) Steady-state concentrations were reached within 15 days following oral doses of 50 mg to 400 mg daily. Values given in the table below are data at steady-state from a pharmacokinetics study in which 27 healthy male volunteers took 200-mg SPORANOX(r) Capsules b.i.d. (with a full meal) for 15 days:

*mean +- standard deviation 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 liters. 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. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions for more information.)

Special Populations:

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. x 1.73 m2, 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 (Tmax, Cmax, and AUC0-8). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. Hepatic Insufficiency: A pharmacokinetic study using a single 100-mg dose of itraconazole (one 100-mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. No statistically significant differences in AUC were seen between these two groups. A statistically significant reduction in mean C max (47%) and a twofold increase in the elimination half-life (37 +- 17 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. 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.) 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 SPORANOXO 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 SPORANOXO Capsules, SPORANOXO should be discontinued. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post- marketing Experience for more information.)

MICROBIOLOGY

Mechanism of Action:

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

Activity In Vitro and In Vivo: Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Itraconazole also exhibits varying in vitro activity against Sporothrix schenckii, Trichophyton species, Candida krusei, and other Candida species. The bioactive metabolite, hydroxyitraconazole, has not been evaluated against Histoplasma capsulatum and Blastomyces dermatitidis. Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents. Itraconazole administered orally was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Fungistatic activity has been demonstrated against disseminated fungal infections caused by Blastomyces dermatitidis, Histoplasma duboisii, Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii, Trichophyton rubrum, and Trichophyton mentagrophytes. Itraconazole administered at 2.5 mg/kg and 5 mg/kg via the oral and parenteral routes increased survival rates and sterilized organ systems in normal and immunosuppressed guinea pigs with disseminated Aspergillus fumigatus infections. Oral itraconazole administered daily at 40 mg/kg and 80 mg/kg increased survival rates in normal rabbits with disseminated disease and in immunosuppressed rats with pulmonary Aspergillus fumigatus infection, respectively. Itraconazole has demonstrated antifungal activity in a variety of animal models infected with Candida albicans and other Candida species.

Resistance:

Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy.

Several in vitro studies have reported that some fungal clinical isolates, including Candida species, with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed. The relevance of these in vitro susceptibility data to clinical outcome remains to be elucidated. Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits 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.

Description of Clinical Studies:

Blastomycosis:

Analyses were conducted on data from two open-label, non- concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases.

Histoplasmosis:

Analyses were conducted on data from two open-label, non- concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases.

Histoplasmosis in HIV-infected patients:

Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.

Aspergillosis:

Analyses were conducted on data from an open-label, "single-patient- use" protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.

Onychomycosis of the toenail: Analyses were conducted on data from three double- blind, placebo-controlled studies (N=214 total; 110 given SPORANOXa Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOXa Capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).

Onychomycosis of the fingernail:

Analyses were conducted on data from a

double-blind, placebo-controlled study (N=73 total; 37 given SPORANOXa Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOXa Capsules b.i.d., followed by a 3-week period without SPORANOXa, which was followed by a second 1-week pulse of 200 mg of SPORANOXa Capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed.

CONTRAINDICATIONS

Congestive Heart Failure: SPORANOXO (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, and ADVERSE REACTIONS: Post-marketing Experience.) Drug Interactions: Concomitant administration of SPORANOXa (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, pimozide, quinidine, dofetilide, and triazolam are contraindicated with SPORANOXa. HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with SPORANOXa. (See BOX WARNING, and PRECAUTIONS: Drug Interactions.) SPORANOXa should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOXa 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 SPORANOXa to patients with hypersensitivity to other azoles.

WARNINGS

SPORANOXa (itraconazole) Capsules and SPORANOXa Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

Hepatic EffectsSPORANOXa 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 SPORANOXO use or reinstitution of treatment with SPORANOXO 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, or quinidine concomitantly with SPORANOX(r) and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOXa is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) Cardiac Disease: SPORANOXO Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. SPORANOXO Capsules should not be used for other indications 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 SPORANOXO 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 SPORANOXO Capsules, discontinue administration. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOXO 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. 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, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.)

PRECAUTIONS

General: Rare cases of serious hepatotoxicity have been observed with SporanoxO 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 SporanoxO 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 SporanoxO. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. If neuropathy occurs that may be attributable to SporanoxO capsules, the treatment should be discontinued. SPORANOXa (itraconazole) Capsules should be administered after a full meal. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This increase relative to the effects of a full meal is unknown. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.)

Information for Patients:

The topical effects of mucosal exposure may be different between the SPORANOX(r) Capsules and Oral Solution. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. SPORANOX(r) Capsules should not be used interchangeably with SPORANOX(r) Oral Solution. Instruct patients to take SPORANOXa Capsules with a full meal. Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOXO administration, they should discontinue SPORANOXO and contact their healthcare provider immediately. Instruct patients to stop SporanoxO treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. 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. SPORANOXa may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with SPORANOXa. 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 SPORANOXa 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. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. SPORANOXa may not be effective in patients concomitantly taking SPORANOXa and one of these drugs. Therefore, administration of these drugs with SPORANOXa is not recommended. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take SPORANOXa concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of SPORANOXa.

Table 1. Selected Drugs that are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by SPORANOXa 1

This list is not all-inclusive.

2Contraindicated with SPORANOXa based on clinical and/or pharmacokinetics studies. (See WARNINGS and below.)

For information on parenterally administered midazolam, see the Benzodiazepine paragraph below.

Antiarrhythmics: The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with SPORANOXa may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOXa and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) Concomitant administration of digoxin and SPORANOXa has led to increased plasma concentrations of digoxin. Anticonvulsants: Reduced plasma concentrations of itraconazole were reported when SPORANOXa 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 SPORANOXa 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 SPORANOXa and carbamazepine may inhibit the metabolism of carbamazepine. 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(r) may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of SPORANOXa could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended. Antineoplastics: SPORANOXa 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(r) could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOXa and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) Benzodiazepines: Concomitant administration of SPORANOXa 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 SPORANOXa 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: Edema has been reported in patients concomitantly receiving SPORANOXa and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary. Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information). Gastric Acid Suppressors/Neutralizers: Reduced plasma concentrations of itraconazole were reported when SPORANOXa Capsules were administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. Therefore, SPORANOXa should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after administration of SPORANOXa Capsules. In a clinical study, when SPORANOXa Capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced. Gastrointestinal Motility Agents: Coadministration of SPORANOX(r) with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOXa with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) HMG CoA-Reductase Inhibitors: Human pharmacokinetic data suggest that SPORANOXa inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of SPORANOXa with HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) Immunosuppressants: Concomitant administration of SPORANOXa and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of SPORANOX(r) and sirolimus could increase plasma concentrations of sirolimus. Macrolide Antibiotics: Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean C max and AUC 0-Y= of itraconazole increased by 44% (90% CI: 119-175%) and 36% (90% CI: 108-171%), respectively. Non-nucleoside 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 SPORANOXa and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with SPORANOXa 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. 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(r) 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 SPORANOXa 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 SPORANOXa and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when SPORANOXa and protease inhibitors must be given concomitantly.

Other:

In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with SPORANOXa may increase plasma concentrations of alfentanil. Human pharmacokinetic data suggest that concomitant administration of SPORANOXa and buspirone results in significant increases in plasma concentrations of buspirone. SPORANOXa 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 SPORANOXa and trimetrexate may inhibit the metabolism of trimetrexate. SPORANOXa 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 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. 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 (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T1/2 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 (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. SPORANOXa should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. SPORANOXa should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOXa should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Effective contraception should be continued throughout SPORANOXa therapy and for 2 months following the end of treatment. Nursing Mothers: Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOXa 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 SPORANOXa have not been established in pediatric patients. No pharmacokinetic data on SPORANOXa Capsules 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 events have been reported. SPORANOXa 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.

HIV-Infected Patients:

Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased.

OVERDOSAGE

Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed. Limited data exist on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1000 mg of SPORANOXa (itraconazole) Oral Solution or up to 3000 mg of SPORANOXa (itraconazole) Capsules, the adverse event profile was similar to that observed at recommended doses.

DOSAGE AND ADMINISTRATION

SPORANOXa (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption. SPORANOXa Capsules is a different preparation than SPORANOXa Oral Solution and should not be used interchangeably.

Treatment of Blastomycosis and Histoplasmosis:

The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses.

Treatment of Aspergillosis:

A daily dose of 200 to 400 mg is recommended.

Treatment in Life-Threatening Situations:

In life-threatening situations, a loading dose should be used whether given as oral capsules or intravenously.

IV Injection: the recommended intravenous dose is 200 mg b.i.d. for four consecutive doses, followed by 200 mg once daily thereafter. Each intravenous dose should be infused over 1 hour. The safety and efficacy of SPORANOXa Injection administered for greater than 14 days is not known. See complete prescribing information for SPORANOXa (itraconazole) Injection. Capsules: although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment. Treatment should be continued for a minimum of three 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. SPORANOXa Capsules and SPORANOXa Oral Solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

Treatment of Onychomycosis:

Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks.

Treatment of Onychomycosis: Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without SPORANOXa.

HOW SUPPLIED

SPORANOXa (itraconazole) Capsules are available containing 100 mg of itraconazole, with a blue opaque cap and pink transparent body, imprinted with "JANSSEN" and "SPORANOX 100." The capsules are supplied in unit-dose blister packs of 3 x 10 capsules (NDC 50458-290-01), bottles of 30 capsules (NDC 50458-290-04) and in the PulsePak(r) containing 7 blister packs x 4 capsules each (NDC 50458-290-28). Store at controlled room temperature 15deg-25degC (59deg-77degF). Protect from light and moisture. Keep out of reach of children.

a

Janssen 2001 7501618

Patent Nos. 4,267,179; 5,633,015 Revised June 2002

Distributed by: JANSSEN PHARMACEUTICA PRODUCTS, L.P. Titusville, New Jersey 08560, USA Capsule contents manufactured by:

JANSSEN

JANSSEN PHARMACEUTICA N.V. PHARMACEUTICA Beerse, Belgium PRODUCTS, L.P.

1. Patient Information

2. SPORANOX(r)

3. (itraconazole) Capsules

1. This summary contains important information about SPORANOX (SPOR-ah- nox).

2. This information is for patients who have been prescribed SPORANOX to treat fungal nail

3. infections. If your doctor prescribed SPORANOX for medical problems other than

4. fungal nail infections, ask your doctor if there is any information in this summary

5. that does not apply to you. Read this information carefully each time you start to use

6. SPORANOX. This information does not take the place of discussion between you and

7. your doctor. Only your doctor can decide if SPORANOX is the right treatment for you.

8. If you do not understand some of this information or have any questions, talk with your

9. doctor or pharmacist.

What Is The Most Important Information I Should Know About SPORANOX?

1. SPORANOX is used to treat fungal nail infections. However, SPORANOX is not for

2. everyone. Do not take SPORANOX for fungal nail infections if you have had heart

3. failure, including congestive heart failure. You should not take SPORANOX if you

SPORANOX PPI

are taking certain medicines that could lead to serious or life-threatening medical

problems.

(See "Who Should Not Take SPORANOX?" below).

1. If you have had heart, lung, liver, kidney or other serious health problems, ask your doctor

2. if it is safe for you to take SPORANOX.

What Happens If I Have A Fungal Nail Infection?

1. Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus

2. infects the tip or sides of a nail, the infected part of the nail may turn yellow or brown. If

3. not treated, the fungus may spread under the nail towards the cuticle. If the fungus

4. spreads, more of the nail may change color, may become thick or brittle, and the tip of the

5. nail may become raised. In some patients, this can cause pain and discomfort.

What Is SPORANOX?

1. SPORANOX is a prescription medicine used to treat fungal infections of the toenails and

2. fingernails. It is also used to treat some types of fungal infections in other areas of your

3. body. We do not know if SPORANOX works in children with fungal nail infections or if

SPORANOX PPI

it is safe for children to take.

1. SPORANOX comes in the form of capsules and liquid (oral solution). The capsule and

2. liquid forms work differently, so you should not use one in place of the other. This Patient

3. Information discusses only the capsule form of SPORANOX. You will get these capsules

4. in a medicine bottle or a SPORANOX PulsePak(r). The PulsePak contains 28 capsules for

5. treatment of your fungal nail infection.

1. SPORANOX goes into your bloodstream and travels to the source of the infection

2. underneath the nail so that it can fight the infection there. Improved nails may not be

3. obvious for several months after the treatment period is finished because it usually takes

4. about 6 months to grow a new fingernail and 12 months to grow a new toenail.

Who Should Not Take SPORANOX?

1. SPORANOX is not for everyone. Your doctor will decide if SPORANOX is the right

2. treatment for you. Some patients should not take SPORANOX because they may have

3. certain health problems or may be taking certain medicines that could lead to serious

4. or life-threatening medical problems.

SPORANOX PPI

1. Tell your doctor and pharmacist the name of all the prescription and non-prescription

2. medicines you are taking, including dietary supplements and herbal remedies. Also tell

3. your doctor about any other medical conditions you have had, especially heart, lung, liver

4. or kidney conditions.

Never

take SPORANOX if you:

*

have had heart failure, including congestive heart failure.

1. * are taking any of the medicines listed below. Dangerous or even life-threatening

2. abnormal heartbeats could result:

3. * quinidine (such as Cardioquin(r), Quinaglute(r), Quinidex(r))

4. * dofetilide (such as TikosynO)

5. * cisapride (such as Propulsid(r))

6. * pimozide (such as Orap(r))

1. * are taking any of the following medicines:

SPORANOX PPI

* lovastatin (such as Mevacor(r), AdvicorO)

* simvastatin (such as Zocor(r))

* triazolam (such as Halcion(r))

* midazolam (such as Versed(r))

1. * have ever had an allergic reaction to itraconazole or any of the other ingredients in

2. SPORANOX Capsules. Ask your doctor or pharmacist for a list of these

3. ingredients.

What Should I Know About SPORANOX and Pregnancy or Breast Feeding?

1. Never take SPORANOX if you have a fungal nail infection and are pregnant or planning

2. to become pregnant within 2 months after you have finished your treatment.

1. If you are able to become pregnant, you should use effective birth control during

2. SPORANOX treatment and for 2 months after finishing treatment. Ask your doctor about

3. effective types of birth control.

SPORANOX PPI

If you are breast-feeding, talk with your doctor about whether you should take Sporanox.

How Should I Take SPORANOX?

Always take SPORANOX Capsules during or right after a full meal.

Your doctor will decide the right dose for you. Depending on your infection, you will

take SPORANOX once a day for 12 weeks, or twice a day for 1 week in a "pulse" dosing

schedule. You will receive either a bottle of capsules or a PulsePak. Do not skip any

doses. Be sure to finish all your SPORANOX as prescribed by your doctor.

If you have ever had liver problems, your doctor should do a blood test to check your condition. If you haven't had liver problems, your doctor may recommend blood tests to check the condition of your liver because patients taking SPORANOX can

develop liver problems.

If you forget to take or miss doses of SPORANOX, ask your doctor what you should do

with the missed doses.

The SPORANOX PulsePak

SPORANOX PPI

If you use the PulsePak, you will take SPORANOX for 1 week and then take no

SPORANOX for the next 3 weeks before repeating the 1-week treatment. This is called

"pulse dosing." The SPORANOX PulsePak contains enough medicine for one "pulse" (1

week of treatment).

The SPORANOX PulsePak comes with special instructions. It contains 7 pouches--one

for each day of treatment. Inside each pouch is a card containing 4 capsules. Looking at

the back of the card, fold it back along the dashed line and peel away the backing so that

you can remove 2 capsules.

Take 2 capsules in the morning and 2 capsules in the evening. This means you

will take 4 capsules a day for 7 days. At the end of 7 days, you will have taken all

of the capsules in the PulsePak box.

After you finish the PulsePak, do not take any SPORANOX for the next 3 weeks.

Even though you are not taking any capsules during this time, SPORANOX keeps

working inside your nails to help fight the fungal infection.

SPORANOX PPI

You will need more than one "pulse" to treat your fungal nail infection. When

your doctor prescribes another pulse treatment, be sure to get your refill before the

end of week 4.

What Are the Possible Side Effects of SPORANOX?

The most common side effects that cause people to stop treatment either for a short time

or completely include: skin rash, high triglyceride test results, high liver test results, and

digestive system problems (such as nausea, bloating, and diarrhea).

Stop SPORANOX and call your doctor right away

if you develop shortness of breath;

have unusual swelling of your feet, ankles or legs; suddenly gain weight; are unusually

tired; cough up white or pink phlegm; or have unusual fast heartbeats. In rare cases,

patients taking SPORANOX could develop serious heart problems, and these could be

warning signs of heart failure.

SPORANOX PPI

Stop SPORANOX and call your doctor right away

if you become unusually tired; lose

your appetite; or develop nausea or vomiting, a yellow color to your skin or eyes, or dark

colored urine or pale stools (bowel movements). In rare cases, patients taking

SPORANOX could develop serious liver problems and these could be warning signs.

Call your doctor right away

if you develop tingling or numbness in your extremities

(hands or feet).

These are not all the side effects of SPORANOX. Your doctor or pharmacist can give you

a more complete list.

What Should I Do If I Take An Overdose of SPORANOX?

If you think you took too much SPORANOX, call your doctor or local poison control

center, or go to the nearest hospital emergency room right away.

How Should I Store SPORANOX?

Keep all medicines, including SPORANOX, out of the reach of children.

SPORANOX PPI

Store SPORANOX Capsules and the PulsePak at room temperature in a dry place away

from light.

General Advice About SPORANOX

Medicines are sometimes prescribed for conditions that are not mentioned in patient

information leaflets. Do not use SPORANOX for a condition for which it was not

prescribed. Do not give SPORANOX to other people, even if they have the same

symptoms you have. It may harm them.

This leaflet summarizes the most important information about SPORANOX. If you would

like more information, talk with your doctor. You can ask your doctor or pharmacist for

information about SPORANOX that is written for health professionals.

You can also call 1-800-JANSSEN or visit the SPORANOX Internet site at

www.sporanox.com and the Janssen Internet site at www.us.janssen.com.

This patient information has been approved by the U.S. Food and Drug Administration.

SPORANOX PPI

The following are registered trademarks of their respective manufacturers: Mevacor(r) (Merck & Co., Inc.), Zocor(r) (Merck & Co., Inc.), Halcion(r) (Pharmacia), Versed(r) (Roche Pharmaceuticals), Cardioquin(r) (The Purdue Frederick Company),

Quinaglute(r) (Berlex Laboratories), Quinidex(r) (A.H. Robins), TikosynTM (Pfizer, Inc.), Propulsid(r) (Janssen Pharmaceutica Products, L.P.), and Orap(r) (Gate Pharmaceuticals)

Corporate Logo

(c) Janssen Pharmaceutica Products, L.P. 2002

Part Number

Printed in USA/ April, 2002.

SPORANOX PPI

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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

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/s/

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Renata Albrecht

7/17/02 12:42:21 PM