Submission Control Number: 120273

All trademark rights used under license (c) 2008 JANSSEN-ORTHO Inc.

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 10 DRUG INTERACTIONS 13 DOSAGE AND ADMINISTRATION 18 OVERDOSAGE 20 ACTION AND CLINICAL PHARMACOLOGY 21 STORAGE AND STABILITY 25 DOSAGE FORMS, COMPOSITION AND PACKAGING 25

PART II: SCIENTIFIC INFORMATION 26

PHARMACEUTICAL INFORMATION 26 DETAILED PHARMACOLOGY 27 MICROBIOLOGY 28 TOXICOLOGY 31 REFERENCES 37

PART III: CONSUMER INFORMATION. 41

PrSPORANOX * itraconazole capsules 100 mg Antifungal Agent

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

WARNINGS AND PRECAUTIONS - Special Populations, Geriatrics.

See

Pediatrics (< 18 years of age):

WARNINGS AND PRECAUTIONS - Special Populations,

No data available. See

Pediatrics.

CONTRAINDICATIONS

Congestive Heart Failure

SPORANOX capsules should not be administered to patients with evidence of ventricular

WARNINGS AND PRECAUTIONS - Serious Warnings and Precautions Cardiovascular, Use inPatients with Underlying Cardiac DiseaseADVERSE REACTIONS - Post-Market Adverse Drug Reactions DRUG INTERACTIONS - Drug-Drug Interactions, Calcium Channel Blockers).

dysfunction such as congestive heart failure (CHF) or a history of CHF except for the treatment of life-threatening or other serious infections (see

and

,

and

Drug Interactions

Coadministration of the following drugs is contraindicated with SPORANOX capsules (see WARNINGS AND PRECAUTIONS - Serious Warnings and Precautions and DRUG INTERACTIONS - Serious Drug Interactions):

• CYP3A4 metabolized substrates that can prolong the QT-interval e.g., cisapride, dofetilide, levacetylmethadol (levomethadyl), pimozide, and quinidine are contraindicated with SPORANOX capsules. Coadministration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and serious cardiac arrhythmias

• CYP3A4 metabolized HMG-CoA reductase inhibitors such as lovastatin and simvastatin

• Triazolam and oral midazolam

• Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine)

• Eletriptan

• Nisoldipine

SPORANOX capsules are contraindicated in patients with a known hypersensitivity to itraconazole or its excipients. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph. There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing SPORANOX capsules to patients with hypersensitivity to other azoles. SPORANOX capsules should not be administered for the treatment of onychomycosis or dermatomycoses (tinea corporis, tinea cruris, tinea pedis, pityriasis versicolor) to pregnant patients or to women contemplating pregnancy.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Congestive Heart Failure: SPORANOX capsules should not be administered to patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF except for the treatment of life-threatening or other serious infections. CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS - Cardiovascular, Use in Patients with Underlying Cardiac DiseaseADVERSE REACTIONS - Post-Market Adverse Drug Reactions DRUG INTERACTIONS - Drug-Drug Interactions, Calcium Channel Blockers)

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

,

and

.

Drug Interactions: Coadministration of cisapride, pimozide, quinidine, dofetilide or levacetylmethadol (levomethadyl) with SPORANOX (itraconazole) capsules or oral solution is contraindicated. SPORANOX, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with SPORANOX and/or other CYP3A4 inhibitors (see CONTRAINDICATIONS and DRUG INTERACTIONS - Serious Drug Interactions; Overview and Drug-Drug Interactions).

Liver Toxicity: WARNINGS

SPORANOX capsules have 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. It is advisable to monitor liver function. If clinical signs or symptoms develop that are consistent with liver disease, such as anorexia, nausea, vomiting, jaundice, fatigue, abdominal pain, dark urine, or pale stools, treatment should be discontinued and liver function testing performed. Continued use of SPORANOX capsules or reinstitution of treatment with SPORANOX capsules is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk (see

AND PRECAUTIONS - General, Information to be Provided to Patients; Hepatic/Biliary/Pancreatic, Hepatic Effects/Use in Patients with Hepatic Impairment and ADVERSE REACTIONS).

General

SPORANOX capsules and SPORANOX 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. SPORANOX oral solution is indicated only for the treatment of oral and/or esophageal candidiasis. Due to the pharmacokinetic properties, SPORANOX capsules are not recommended for initiation of treatment in patients with immediately life- threatening systemic fungal infections.

Carcinogenesis and Mutagenesis

See Product Monograph Part II: TOXICOLOGY - Carcinogenicity for discussion on animal data.

Cardiovascular

Cardiac Dysrhythmias

Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl) or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with itraconazole is contraindicated (see CONTRAINDICATIONS and DRUG INTERACTIONS - Serious Drug Interactions and Drug-Drug Interactions).

Use in Patients with Underlying Cardiac Disease

SPORANOX has been associated with reports of CHF. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg than among those receiving lower total daily doses. This suggests that the risk of heart failure might increase with the total daily dose of itraconazole. SPORANOX capsules should not be administered for the treatment of onychomycosis or dermatomycoses in patients with evidence of ventricular dysfunction such as CHF or a history of CHF. SPORANOX capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. The benefit/risk assessment should take into consideration factors such as the severity of the indication, the dosing regimen (e.g. total daily dose), and the individual risk factors for congestive heart failure. These risk factors include cardiac disease, such as ischemic and valvular disease; significant pulmonary disease, such as chronic obstructive pulmonary disease; renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of congestive heart failure, treated with caution, and monitored for signs and symptoms of congestive heart failure during treatment; if such signs or symptoms do occur during treatment, SPORANOX capsules should be discontinued (see DRUG INTERACTIONS and ADVERSE REACTIONS - Post-Market Adverse Drug Reactions). Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study (n=8) of SPORANOX for injection, a transient asymptomatic decrease of the left ventricular ejection fraction was observed using gated SPECT imaging; this resolved before the next infusion, 12 hours later. Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when coadministering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX and nisoldipine is contraindicated. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post- marketing period among patients being treated for onychomycosis and/or systemic fungal infections (see ADVERSE REACTIONS - Post-Market Adverse Drug Reactions).

Ear/Nose/Throat

Hearing Loss

Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine, which is contraindicated (see CONTRAINDICATIONS and DRUG INTERACTIONS). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Gastrointestinal

Use in Patients with Decreased Gastric Acidity

Absorption of itraconazole from SPORANOX capsules is impaired when gastric acidity is decreased. In patients also receiving acid-neutralizing medicines (e.g. aluminum hydroxide), these should be administered at least 2 hours after the intake of SPORANOX capsules. In patients with achlorhydria, such as certain AIDS patients on acid secretion suppressors (e.g. H2-antagonists, proton pump inhibitors), it is advisable to administer SPORANOX capsules with a cola beverage.

Hepatic/Biliary/Pancreatic

Hepatic Effects/Use in Patients with Hepatic Impairment

Rare cases of serious hepatotoxicity (including liver failure and death) have been observed with SPORANOX treatment. 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. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with SPORANOX capsules is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving SPORANOX capsules. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. Such signs and symptoms include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, abdominal pain, dark urine or pale stools (see WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions; General, Information to be Provided to Patients and ADVERSE REACTIONS). Itraconazole binds extensively to plasma proteins. Limited data are available on the use of oral itraconazole in patients with hepatic impairment. In cirrhotic patients, the mean terminal half-life of itraconazole was increased by 131% and its mean Cmax decreased by 47% (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency). Caution should be exercised when this drug is administered in this patient population.

Immune

Use in Acquired Immunodeficiency Syndrome (AIDS) and Neutropenic Patients

Studies with itraconazole in neutropenic and AIDS patients have indicated that itraconazole plasma concentrations are lower than those in healthy subjects (particularly in those patients who are achlorhydric); therefore, monitoring of the itraconazole plasma concentrations and a dose adjustment, if necessary, are recommended. In one study, adequate plasma concentrations of itraconazole (measured by HPLC) for antifungal prophylaxis in neutropenic patients were greater than 250 ng/mL. Inadequate plasma concentrations were frequently found in patients whose antineoplastic therapy predisposed them to very poor oral absorption and frequent vomiting. In this case, antiemetics can be coadministered and it is particularly important that SPORANOX capsules be administered with meals. There has been one report of reduced itraconazole absorption when taken with didanosine. Since the excipients in the didanosine formulation are known to have an acid-neutralizing effect, and since the absorption of itraconazole can be affected by the level of acidity in the stomach, it is recommended that didanosine be administered at least 2 hours after dosing with SPORANOX capsules. The results from a study in which 8 HIV-infected individuals were treated with zidovudine, 8 +- 0.4 mg/kg/day with or without SPORANOX capsules 100 mg b.i.d., showed that the pharmacokinetics of zidovudine were not affected during concomitant administration of SPORANOX capsules. In patients with AIDS having received treatment for a systemic fungal infection such as sporotrichosis, blastomycosis or histoplasmosis and who are considered at risk for relapse, the treating physician should evaluate the need for a maintenance treatment.

Neurologic

If neuropathy occurs that may be attributable to SPORANOX capsules, the treatment should be discontinued.

Renal

Use in Patients with Renal Insufficiency

Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency). In a few patients, hypokalemia has been reported. Consequently, serum potassium should be monitored in patients at risk during high-dose itraconazole therapy. Itraconazole cannot be removed by dialysis.

Special Populations

Women of Child-Bearing Age:

In women of child-bearing potential, an effective form of contraception must be used during therapy. SPORANOX should not be administered to women of child-bearing potential for the treatment of onychomycosis or dermatomycoses 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 SPORANOX therapy and for 2 months following the end of treatment.

Pregnant Women:

There are no studies available on the use of itraconazole in pregnant women; therefore, SPORANOX capsules should be used in pregnancy only if the benefit outweighs the potential risk. Itraconazole has been shown to produce teratogenic effects (major skeletal and secondary soft tissue defects) when administered at high doses (40 mg/kg/day,

5 times MRHD or higher) to pregnant rats. When administered to pregnant mice at high doses (80 mg/kg/day, 10 times MRHD or higher) itraconazole has been shown to produce encephaloceles and/or macroglossia. SPORANOX capsules should not be used for the treatment of onychomycosis or dermatomycoses in pregnant patients or in women contemplating pregnancy (see CONTRAINDICATIONS). There is limited information on the use of itraconazole during pregnancy. During post-marketing experience, cases of congenital abnormalities have been reported. These cases included skeletal, genitourinary tract, cardiovascular and ophthalmic malformations, as well as chromosomal and multiple malformations. A causal relationship with SPORANOX capsules has not been established.

Nursing Women:

Itraconazole is excreted in human milk; therefore, the patient should be advised to discontinue nursing while taking SPORANOX capsules.

Pediatrics (< 18 years of age): Product Monograph Part II: TOXICOLOGY

The efficacy and safety of SPORANOX capsules have not been established in children. No pharmacokinetic data are available in children. A small number of patients from age 3 to 16 years have been treated with 100 mg/day of itraconazole for systemic fungal infections and no serious adverse events have been reported. Toxicological studies have shown that itraconazole, when administered to rats, can produce bone toxicity. While no such toxicity has been reported in adult patients, the long-term effect of itraconazole in children is unknown (see

).

Since clinical data on the use of SPORANOX capsules in pediatric patients is limited, SPORANOX capsules should not be used in children unless the potential benefit outweighs the potential risks.

Geriatrics (> 65 years of age):

The pharmacokinetics of SPORANOX capsules after single and repeated dosing of 100 mg once daily in 12 elderly subjects were found to be similar to those in young and middle-aged adults. Therefore, no dose adjustments are required in elderly patients.

Monitoring and Laboratory Tests

Plasma levels 3 to 4 hours after dosing with itraconazole should be monitored in patients requiring treatment for more than one month, in patients with systemic mycoses who have factors predisposing to poor absorption (such as achlorhydria, renal insufficiency, neutropenia, AIDS) or in those who are taking drugs which may alter itraconazole absorption or metabolism (such as rifampicin and phenytoin). Due to the presence of an active metabolite, monitoring of plasma levels by bioassay will indicate plasma levels roughly 3 times higher than will monitoring by high-performance liquid chromatography, unless solvent conditions for the HPLC assay are adjusted to allow simultaneous detection of both the parent drug and this metabolite (hydroxy-itraconazole). Liver function monitoring should be done in patients with pre-existing hepatic abnormalities, or those who have experienced liver toxicity with other medications and should also be considered in all patients receiving treatment with SPORANOX capsules. Hypokalemia has been reported in a few patients. Therefore, serum potassium should be monitored in patients at risk during high-dose itraconazole therapy.

DRUG INTERACTIONS

Serious Drug Interactions

• Concomitant administration of SPORANOX with levacetylmethadol (levomethadyl), dofetilide, quinidine, cisapride and pimozide may result in serious cardiovascular events.

• Concomitant administration of SPORANOX with ergot alkaloids, such as dihydroergotamine, ergometrine, ergotamine and methylergometrine (methylergonovine) may result in serious and/or life-threatening ischemia.

• Concomitant administration of SPORANOX with HMG-CoA reductase inhibitors, such as lovastatin and simvastatin, may increase the risk of skeletal muscle toxicity including rhabdomyolysis.

• Concomitant administration of SPORANOX with benzodiazepines, such as midazolam and triazolam, could potentiate and prolong hypnotic and sedative effects.

• Concomitant administration of SPORANOX with fentanyl could increase or prolong fentanyl plasma concentrations and may cause potentially fatal respiratory depression.

• Concomitant administration of eletriptan with SPORANOX can elevate plasma eletriptan concentrations which could result in serious adverse events.

• Concomitant administration of SPORANOX and nisoldipine is contraindicated. (See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and

Drug-Drug Interactions.)

Overview

Itraconazole and its major metabolite, hydroxy-itraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (see Table 1.2 below and the following drug class subheadings):

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. 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.

Drug-Drug Interactions

Table 1.2 Selected drugs that are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by itraconazole1

This list is not all-inclusive.

2Contraindicated with SPORANOX based on clinical and/or pharmacokinetic studies (see WARNINGS AND PRECAUTIONS and below).

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

Antiarrhythmics: CONTRAINDICATIONS WARNINGS AND PRECAUTIONS

The class IA antiarrhythmics quinidine and disopyramide, and class III antiarrhythmics, such as dofetilide, are known to prolong the QT interval. Coadministration of quinidine or dofetilide with SPORANOX may increase plasma concentrations of quinidine or dofetilide, which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX and quinidine or dofetilide is contraindicated (see

and

).

Concomitant administration of digoxin or disopyramide and SPORANOX has led to increased plasma concentrations of digoxin (likely via inhibition of P-glycoprotein) or disopyramide. Patients should be carefully monitored if SPORANOX is coadministered with either of these drugs.

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.

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, which could lead to increased plasma concentration of these antineoplastic agents.

Antipsychotics: CONTRAINDICATIONS WARNINGS AND PRECAUTIONS

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

and

).

Benzodiazepines: CONTRAINDICATIONS WARNINGS AND PRECAUTIONS

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

and

). 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 SPORANOX 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 coadministering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX and nisoldipine is contraindicated. (See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS - Post-Market Adverse Drug Reactions).

Ergot Alkaloids: CONTRAINDICATIONS

Concomitant administration of SPORANOX with ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) is contraindicated due to the risk of cerebral and/or peripheral ischemia (see

). In some cases, concomitant use of potent CYP3A4 inhibitors (protease inhibitors, macrolide antibiotics and antifungal agents) with ergot alkaloids has resulted in serious and/or life-threatening ischemia, including fatalities and cases of gangrene.

Gastric Acid Suppressors/Neutralizers: Reduced plasma concentrations of itraconazole were reported when SPORANOX capsules were administered concomitantly with H2-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 H2-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.

Gastrointestinal Motility Agents: CONTRAINDICATIONS WARNINGS AND PRECAUTIONS

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

and

).

Glucocorticosteroids:

SPORANOX markedly increased systemic exposure to oral and intravenous dexamethasone (3.7-fold and 3.3-fold increases, respectively), inhaled budesonide (4.2-fold increase), fluticasone and methylprednisolone, and enhanced their adrenal-suppressant effect. Careful follow-up is recommended when itraconazole is coadministered with these drugs.

HMG-CoA Reductase Inhibitors: CONTRAINDICATIONS WARNINGS AND PRECAUTION

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 with HMG-CoA reductase inhibitors, such as lovastatin and simvastatin, is contraindicated (see

and

S).

-HT1 Receptor Agonists: CONTRAINDICATIONS)

Coadministration of eletriptan with SPORANOX can elevate plasma eletriptan concentrations which could result in serious adverse events. Therefore, concomitant use of eletriptan with SPORANOX is contraindicated (see

.

Immunosuppressants:

Concomitant administration of SPORANOX and cyclosporine, tacrolimus or sirolimus has led to increased plasma concentrations of these immunosuppressants.

Macrolide Antibiotics: Erythromycin and clarithromycin are known inhibitors of CYP3A4 (see Table 1.2) 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 Cmax and AUC0-[?] 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 SPORANOX and nevirapine is not recommended.

Nucleoside Reverse Transcriptase Inhibitors:

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.

Oral Anticoagulants:

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

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 co- administered.

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. Coadministration of lopinavir/ritonavir and itraconazole leads to significant increase of itraconazole concentrations. Caution is advised when SPORANOX and protease inhibitors must be given concomitantly.

Other:

• Levacetylmethadol (levomethadyl) is known to prolong the QT interval and is metabolized by CYP3A4. Co-administration of levacetylmethadol with SPORANOX could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX and levacetylmethadol is contraindicated.

• Halofantrine has the potential to prolong the QT interval at high plasma concentrations.

Caution is advised when SPORANOX and halofantrine are administered concomitantly. 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. Itraconazole may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. A lower dose of trazodone should be considered. In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. An in vitro rat liver model 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. Cilostazol is a CYP 3A4 metabolized drug that should be used with caution when co- administered with SPORANOX. Fentanyl plasma concentrations could be increased or prolonged by concomitant use of SPORANOX and may cause potentially fatal respiratory depression.

Drug-Food Interactions

For optimal absorption, SPORANOX capsules should be taken immediately after a full meal (see ACTION AND CLINICAL PHARMACOLOGY - Pharmacokinetics).

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

When SPORANOX therapy is indicated, the type of organism responsible for the infection should be isolated and identified; however, therapy may be initiated prior to obtaining these results when clinically warranted. SPORANOX capsules is a different preparation than SPORANOX oral solution and should not be used interchangeably.

For maximal absorption, it is essential to administer SPORANOX capsules immediately after a full meal (ACTION AND CLINICAL PHARMACOLOGY). WARNINGS AND PRECAUTIONS

see

See

for treatment of patients with decreased gastric acidity.

Concomitant administration of SPORANOX with certain medications may require a dose adjustment for either SPORANOX or for the other medication (see DRUG INTERACTIONS).

Patients with Hepatic Impairment

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Hepatic Effects/Use in Patients with Hepatic Impairment; ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).

Patients with Renal Impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population (see WARNINGS AND PRECAUTIONS, Renal, Use in Patients with Renal Insufficiency; ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency).

Recommended Dose and Dosage Adjustment

SPORANOX capsules should be administered at a dose of 100-400 mg/day. Dosage recommendations vary according to the infection treated.

Oral Candidiasis:

The recommended dose is 100 mg daily for 2 weeks. The dose should be increased to 200 mg/day in patients with AIDS and neutropenic patients.

Esophageal Candidiasis:

The recommended dose is 100 mg daily for 4 weeks. The dose should be increased to 200 mg/day in patients with AIDS and neutropenic patients.

Blastomycosis and Chronic Pulmonary Histoplasmosis

The recommended dose is 200 mg once daily. 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 per day should be given in 2 divided doses. Treatment 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.

Other Systemic Mycoses

Table 1.3 Dosing recommendations for other systemic mycoses

Dermatomycoses

Standard Dosages:

Tinea corporis/Tinea cruris

The recommended dose is 100 mg once daily for 14 consecutive days.

Tinea pedis

The recommended dose is 100 mg once daily for 28 consecutive days.

Pityriasis versicolor

The recommended dose is 200 mg once daily for 7 consecutive days.

Alternative Dosages:

Shorter dosing schedules have also been found to be effective in the treatment of tinea corporis/tinea cruris and tinea pedis. The shorter dosages are:

Tinea corporis/tinea cruris:

200 mg o.d. for 7 consecutive days;

Tinea pedis:

200 mg b.i.d. for 7 consecutive days.

Equivalency between standard and alternative dosages was not established. Patients with chronic recalcitrant tinea pedis may benefit from the standard dosage of a lower daily dose (100 mg) for a longer period of time (4 weeks).

Onychomycosis

The recommended clinical dose for onychomycosis is: A one-week treatment course consists of 200 mg twice daily for 7 days. Treatment with 2 one- week courses is recommended for fingernail infections and 3 one-week courses for toenail infections. The one-week courses are always separated by a 3-week drug-free interval. Clinical response will become evident as the nail regrows, following discontinuation of the treatment.

Table 1.4 Recommended clinical dose for onychomycosis

*A pulse equals a one-week course of treatment.

Tissue Elimination of itraconazole

Elimination of itraconazole from skin and nail tissues is slower than from plasma. Optimal clinical and mycological responses are reached 2 to 4 weeks after the cessation of treatment for skin infections and 6 to 9 months after the cessation of treatment for nail infections.

Missed Dose

Physicians should use clinical judgment based on the type and severity of the infection.

Administration

SPORANOX capsules must be swallowed whole.

OVERDOSAGE

There is no experience of overdosage with itraconazole; however, based on animal toxicity data, symptoms of a gastrointestinal or central nervous system nature may be expected to occur. Although no data are available for SPORANOX, administration of activated charcoal absorbs almost all commonly ingested drugs, and should be administered as quickly as possible to most patients who ingest potentially toxic amounts. Standard supportive treatment should be applied as necessary. It has been reported that itraconazole cannot be removed by dialysis. No specific antidote is available.

ACTION AND CLINICAL PHARMACOLOGY

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 and yeast cell membranes. This inhibition leads to deteriorated membranes, disturbed enzyme activities, and an uncoordinated synthesis of chitin, all together contributing to the antifungal activity. The inhibition of ergosterol synthesis has been attributed to interference with the reactions involved in the removal of the 14-a-methyl group of the precursor of ergosterol, lanosterol. Itraconazole has a very low affinity for mammalian P450 enzymes in contrast to fungal P450 enzymes. Itraconazole is fungitoxic to dermatophytes and yeasts.

Pharmacodynamics

In vitro

A 50% inhibition of the cholesterol biosynthesis is obtained in vitro in human lymphocytes with itraconazole at a concentration of 4 x 10-7M, which is more than 100 times the concentration of itraconazole needed to produce a 50% inhibition of the ergosterol synthesis in Candida albicans. Up to a concentration of 10-5M, itraconazole did not inhibit the cytochrome P450 dependent aromatization of androstenedione to estrogens by human placental microsomes.

In vivo

In male volunteers, basal serum levels of cholesterol remained similar to the control values obtained before itraconazole treatment of 100 mg o.d. for one month. Long-term administration of itraconazole (up to 400 mg/day for up to a maximum of 2 years) indicated a slight decrease in plasma cholesterol in 67 patients who had a baseline cholesterol plasma level higher than 200 mg/dL. Only 9.5% of patients showed a shift to a somewhat higher plasma cholesterol level. Similar results were observed in 29 patients with baseline cholesterol levels of at least 250 mg/dL and itraconazole therapy (50-400 mg/day) for a minimum of 3 months. Twenty-three patients showed a reduction and 6 patients had an increased cholesterol level. In this study, the overall decrease in cholesterol did not coincide with alterations in the triglyceride levels. There was no significant effect of itraconazole 100 or 200 mg taken daily for 35 days on the serum levels of 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol in 12 volunteers. In volunteers receiving single or multiple doses of itraconazole for up to 30 days, no effect on serum levels of the following hormones were observed: basal plasma cortisol, testosterone, aldosterone, cortisol response to cosyntropin (ACTH) and plasma prolactin and response of plasma prolactin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to an intravenous luteinizing hormone-releasing hormone (LHRH) challenge. Plasma progesterone and estradiol levels measured once weekly (before, during and for 2 weeks after a 5-week administration period of itraconazole 200 mg/day) and saliva progesterone concentrations measured daily during the 5-week administration reflected a totally normal hormonal profile throughout the menstrual cycle. In healthy female volunteers with normal, regular menstrual cycles, a single 300 mg dose of itraconazole taken during the late follicular phase did not modify the circadian variation in plasma 17b-estradiol levels. The same dose taken during the luteal phase had no effects on 17b-estradiol and progesterone levels. Male patients with superficial mycoses who received 50 or 100 mg itraconazole for up to 2 months showed no change in levels of testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol. In 15 patients with systemic mycoses receiving 200 to 400 mg/day itraconazole, adrenal function was studied before and after 12.4 +- 5 (7-24) months of treatment. No change in the response of plasma cortisol to ACTH stimulation was observed. Average testosterone values measured in these patients before and after itraconazole were not statistically significantly different. However, one of eight patients treated with itraconazole 600 mg/day for severe or refractory systemic fungal infection, demonstrated a blunted cortisol response after one month of treatment. Reduction of the dose to 400 mg/day was associated with resolution of the symptoms associated with adrenal insufficiency and an improved cortisol response. The administration of 200 mg itraconazole daily for 5 weeks had no significant influence on the heart rate, blood pressure, ECG-intervals and systolic time intervals in volunteers. This finding was confirmed in cancer patients who received 50 mg itraconazole daily for 48 weeks. In 6 healthy volunteers, itraconazole 200 mg daily did not seem to have a negative influence on immune functions. After 5 weeks of itraconazole treatment, only values for OKT4 positive lymphocyte showed a significant shift from 42 +- 3.3% to 53 +- 3.3%. This increase, as well as shifts in the other immunological parameters, remained within the normal ranges.

Pharmacokinetics

Absorption:

The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study using 6 healthy male volunteers. The total plasma clearance averaged 381 +- 95 mL/min and the apparent volume of distribution averaged 796 +- 185 L. The observed absolute oral bioavailability of itraconazole was 55%.

The oral bioavailability of itraconazole capsules is maximal when the capsules are given immediately after a full meal. The pharmacokinetics of itraconazole were studied using 6 healthy male volunteers who received, in a cross-over design, single 100 mg doses of itraconazole as a polyethylene glycol capsule, with or without food. The same 6 volunteers also received 50 mg or 200 mg with food in a crossover design. In this study, only itraconazole plasma concentrations were measured.

Table 1.5 Pharmacokinetic parameters for itraconazole

Values are means +- standard deviation

Doubling the SPORANOX dose results in approximately a 3-fold increase in the itraconazole plasma concentrations. Values given in Table 1.6 represent data from a crossover pharmacokinetic study in which 27 healthy male volunteers each took a single 200 mg dose of SPORANOX capsules with or without food.

Table 1.6 Crossover pharmacokinetic study of itraconazole in healthy male volunteers

Values are means +- standard deviation

Steady-state concentrations were reached within 15 days following oral doses of 50-400 mg daily. Values given in Table 1.7 are data at steady-state from a pharmacokinetic study in which 27 healthy male volunteers took 200 mg SPORANOX capsules b.i.d. (with food) for 15 days.

Table 1.7 Steady-state pharmacokinetic study of itraconazole in healthy male volunteers

Values are means +- standard deviation

Results of the pharmacokinetic study suggest that itraconazole may undergo saturation metabolism with multiple dosing.

Distribution:

The plasma protein binding of itraconazole is 99.8% and that of hydroxy- itraconazole is 99.5%.

Concentrations of itraconazole in whole blood are 60% of those in plasma. Uptake in keratinous tissues, especially the skin, is up to 5 times higher than in plasma, and elimination of itraconazole is related to epidermal regeneration. Therefore, therapeutic levels in the skin persist for 2 to 4 weeks after discontinuation of a 4-week treatment. Therapeutic levels of itraconazole in nails persist for 6 to 9 months after cessation of treatment. Itraconazole is also present in sebum and to a lesser extent in sweat. Itraconazole is extensively distributed into tissues which are prone to fungal invasion. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be 2 to 3 times higher than the corresponding plasma concentration.

Metabolism:

Itraconazole is extensively metabolized by the liver into a large number of metabolites. One of the metabolites is hydroxy-itraconazole, which has antifungal activity comparable to itraconazole in vitro. Antifungal drug levels measured by bioassay were about 3 times those of itraconazole assayed by high-performance liquid chromatography. The main metabolic pathways were oxidative scission of the dioxolane ring, aliphatic oxidation at the

1-methylpropyl substituent, N-dealkylation of this 1-methylpropyl substituent, oxidative degradation of the piperazine ring and triazolone scission.

Excretion:

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. After one week, urinary excretion amounted to 35% of the dose and fecal excretion represented 54% of the dose.

Special Populations and Conditions

Pediatrics: WARNINGS AND PRECAUTIONS - Special Populations, Pediatrics.

No data available. See

Geriatrics: WARNINGS AND PRECAUTIONS - Special Populations, Geriatrics. Hepatic Insufficiency:

See

Itraconazole is predominantly metabolized in the liver. Pharmacokinetic

data for patients with hepatic insufficiency is limited to subjects who received a single 100 mg dose of SPORANOX capsules. A pharmacokinetic study using a single 100 mg dose of itraconazole (one 100 mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. A statistically significant reduction in mean Cmax (47%; mean cirrhotic Cmax 87 +- 18ng/mL, mean healthy Cmax 164 +- 34 ng/mL) and a twofold increase in the elimination half-life (37 +- 7 hrs and 16 +- 5 hrs, respectively) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC was similar in cirrhotic patients and in healthy subjects (mean cirrhotic AUC 1449 +- 207ng.h/mL, mean healthy AUC 1856 +- 388 ng.h/mL). Data are not available in cirrhotic patients during long-term use of itraconazole 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 medicines metabolized by CYP3A4. (See WARNINGS AND PRECAUTIONS - Hepatic/Biliary/Pancreatic). Renal Insufficiency: Limited data are available on the use of itraconazole in patients with renal insufficiency. Caution should be exercised when the drug is administered in this patient population (see WARNINGS AND PRECAUTIONS, Renal). Pharmacokinetic data in renally impaired patients is limited to subjects who received a single 200 mg dose of SPORANOX capsules. 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; continuous ambulatory peritoneal dialysis: n=5). Mean +- SD pharmacokinetic parameters are summarized below.

Mean pharmacokinetic parameters in renally impaired patients receiving a single 200 mg oral dose of itraconazole

Plasma concentration vs. time profiles showed wide inter-subject variation in all three groups. In uremic subjects (mean CrCl 13 mL/min/1.73m2), mean plasma concentrations and overall exposure, based on AUC[? ], were slightly reduced compared with healthy subject in a previous study (AUC[?] values of 3454 +- 3132 vs. 4161 +- 1949 ng hr/mL in uremic patients and healthy subjects, respectively). Cmax and AUC0-8h values were reduced 30-40% in hemodialysis patients on non-dialysis days, compared to uremic patients (see above table), and further reduced 10-20% on dialysis days. In CAPD patients, Cmax and AUC0-8h values were reduced to one-third the values seen in non-dialyzed uremic patients.

STORAGE AND STABILITY

SPORANOX capsules should be stored at room temperature (15-30degC). They should be protected from light and moisture. Keep out of the reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms

SPORANOX capsules are available as pink and blue capsules containing 100 mg of itraconazole in a pellet formulation. Capsules are imprinted in white with "JANSSEN" on the cap and "SPORANOX" on the body.

Composition

Each SPORANOX capsule contains 100 mg of itraconazole as well as: sugar spheres (NF), hydroxypropylmethylcellulose, gelatin, polyethylene glycol, titanium dioxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28.

Packaging

SPORANOX capsules are supplied in HDPE bottles of 30 and pulsepak * cartons of 7 blister cards containing 4 capsules. The pulsepak * is specifically designed for use in the treatment of onychomycosis.