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 12 DOSAGE AND ADMINISTRATION 17 OVERDOSAGE 18 ACTION AND CLINICAL PHARMACOLOGY 18 STORAGE AND STABILITY 20 DOSAGE FORMS, COMPOSITION AND PACKAGING 20

PART II: SCIENTIFIC INFORMATION 21

PHARMACEUTICAL INFORMATION 21 CLINICAL TRIALS 22 DETAILED PHARMACOLOGY 24 MICROBIOLOGY 29 TOXICOLOGY 32 REFERENCES 37

PART III: CONSUMER INFORMATION. 39

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SPORANOX

itraconazole oral solution 10 mg/mL Antifungal Agent

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Congestive Heart Failure

SPORANOX oral solution should not be administered to patients with evidence of

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

ventricular 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 oral solution (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 oral solution. Co-administration 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 oral solution is 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 oral solution to patients with hypersensitivity to other azoles.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Congestive Heart Failure: SPORANOX oral solution 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 oral solution, 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: SPORANOX oral solution 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. 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 oral solution or reinstitution of treatment with SPORANOX oral solution is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk (see WARNINGS 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 oral solution and SPORANOX capsules should not be used interchangeably. SPORANOX oral solution is indicated only for the treatment of oropharyngeal and/or esophageal candidiasis. The efficacy of SPORANOX oral solution for other indications is unknown. The two dosage forms have different absorption profiles (see Product Monograph Part II: DETAILED PHARMACOLOGY - Human Pharmacokinetics). SPORANOX oral solution contains the excipient hydroxypropyl-b-cyclodextrin, which produced adenocarcinomas of the exocrine pancreas in a rat but not in a similar mouse carcinogenicity study (see Product Monograph Part II: TOXICOLOGY - Carcinogenicity). The clinical relevance of these findings is unknown.

Patients on Continuous Treatment

In patients receiving continuous treatment of more than one month and in patients developing symptoms such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine, it is advisable to monitor liver function. If tests are abnormal, treatment should be terminated.

Information to be Provided to Patients

• The topical effects of mucosal exposure may be different between the SPORANOX capsules and oral solution. SPORANOX oral solution is indicated only for oral and/or esophageal candidiasis. SPORANOX capsules should not be used interchangeably with SPORANOX oral solution.

• For optimal absorption, itraconazole oral solution should be taken without food.

• Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX administration, they should discontinue SPORANOX and contact their health professional immediately.

• Instruct patients to stop SPORANOX treatment immediately and contact their health professional 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.

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 oral solution should not be used in patients with evidence of ventricular dysfunction such as CHF or a history of CHF 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.

DRUG INTERACTIONS

Serious Drug Interactions

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

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

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

• Concomitant administration of SPORANOX oral solution 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.

(See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and

Drug-Drug Interactions.)

• Concomitant administration of SPORANOX and nisoldipine is contraindicated.

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 drug class subheadings that follow):

1. SPORANOX may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with SPORANOX. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant SPORANOX therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.

2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole.

SPORANOX may not be effective in patients concomitantly taking SPORANOX and one of these drugs. Therefore, administration of these drugs with SPORANOX is not recommended. 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:

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 CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS). Concomitant administration of digoxin or disopyramide and SPORANOX has led to clinically significant increases in 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 hydroxy-itraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. SPORANOX may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of SPORANOX could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended.

Antineoplastics:

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

Antipsychotics: 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 WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS, Post-Market Adverse

Drug Reactions

for more information).

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. However, as itraconazole is already dissolved in SPORANOX oral solution, the effect of H2-receptor antagonists is expected to be substantially less than the capsules. Nevertheless, caution is advised when the two drugs are coadministered.

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) 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 PRECAUTIONS

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

).

-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 coadministered.

Polyenes:

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

Protease Inhibitors:

Concomitant administration of SPORANOX and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of SPORANOX and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. 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 oral solution should be taken without food (see Product Monograph Part II: DETAILED PHARMACOLOGY - Human Pharmacokinetics, Absorption).

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 oral solution may be 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.

For optimal absorption, itraconazole oral solution should be taken without food.

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

Oral Candidiasis:

The recommended dosage of itraconazole oral solution for oral candidiasis is 200 mg daily in a single dose or divided doses; treatment should continue for 1-2 weeks to decrease the likelihood of relapse.

Esophageal Candidiasis:

The recommended dosage for esophageal candidiasis is 100 mg daily for a minimum treatment of three weeks. Treatment should continue for two weeks following resolution of symptoms. Doses of up to 200 mg per day may be used based on medical assessment of the patient's response to therapy.

Administration

The solution should be swished in the oral cavity and swallowed. There should be no rinsing after swallowing.

OVERDOSAGE

There is no experience of overdosage with SPORANOX oral solution; 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

Itraconazole, a triazole derivative, has a broad-spectrum activity; with respect to Candida spp., its activity includes C. albicans, C. glabrata and C. krusei. In vitro studies have demonstrated that itraconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect.

Pharmacodynamics

See Product Monograph Part II: DETAILED PHARMACOLOGY.

Pharmacokinetics

Absorption:

The oral bioavailability of itraconazole is maximal when SPORANOX oral solution is taken without food. During chronic administration, steady-state is reached after

1-2 weeks. Peak plasma levels are observed 2 hours (fasting) to 5 hours (with food) following oral administration. After repeated once-a-day administration of itraconazole 200 mg in fasting condition, steady-state plasma concentrations of itraconazole fluctuate between 1 and 2 ug/mL (trough to peak). When the oral solution is taken with food, steady-state plasma concentrations of itraconazole are about 25% lower.

Distribution:

The plasma protein binding of itraconazole is 99.8%. Itraconazole is extensively distributed into tissues that are prone to fungal invasion. Concentrations in human lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three 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 in vitro a comparable antifungal activity to itraconazole. Plasma levels of hydroxy-itraconazole are about two times higher than those of itraconazole.

Excretion:

After repeated oral administration, elimination of itraconazole from plasma is biphasic with a terminal half-life of 1.5 days. 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 35% of the dose is excreted as metabolites in the urine within one week.

Special Populations and Conditions

Pediatrics: Product Monograph Part II: DETAILED PHARMACOLOGY - Human Pharmacokinetics

Limited pharmacokinetic data are available in pediatric patients (see

).

Geriatrics:

No data are available in geriatric patients.

Hepatic Insufficiency:

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: WARNINGS AND PRECAUTIONS, Renal

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

). 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.

Cystic Fibrosis:

In cystic fibrosis patients, variability in therapeutic levels of itraconazole was observed with steady-state dosing of oral solution using 2.5 mg/kg b.i.d. Steady-state concentrations of > 250 ng/mL were achieved in approximately 50% of subjects greater than 16 years of age, but in none of the patients less than 16 years of age. If a patient does not respond to SPORANOX oral solution, consideration should be given to switching to alternative therapy.

STORAGE AND STABILITY

SPORANOX oral solution should be stored at 15EC-25EC. Discard remaining unused product three months after opening bottle. Keep out of the reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Composition

Each millilitre of SPORANOX oral solution contains 10 mg of itraconazole as well as: hydroxypropyl-ss-cyclodextrin, sorbitol, propylene glycol, hydrochloric acid, cherry flavour 1 and 2, caramel flavour, sodium saccharin, sodium hydroxide and purified water.

Dosage Forms and Packaging

SPORANOX oral solution is available as a 10 mg itraconazole per mL solution, with 150 mL in each amber glass bottle.