PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 16 DOSAGE AND ADMINISTRATION 24 OVERDOSAGE 26 ACTION AND CLINICAL PHARMACOLOGY 26 STORAGE AND STABILITY 30 SPECIAL HANDLING INSTRUCTIONS 30 DOSAGE FORMS, COMPOSITION AND PACKAGING 30

PART II: SCIENTIFIC INFORMATION 31

PHARMACEUTICAL INFORMATION 31 CLINICAL TRIALS 32 DETAILED PHARMACOLOGY 39 MICROBIOLOGY 42 TOXICOLOGY 45 REFERENCES 47

PART III: CONSUMER INFORMATION. 48

POSANOL(tm)

posaconazole

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. There is no information regarding cross-sensitivity between POSANOL(tm) and other azole antifungal agents. Caution should be used when prescribing POSANOL(tm) to patients with hypersensitivity to other azoles. Co-administration of POSANOL(tm) and ergot alkaloids. POSANOL(tm) may increase the plasma concentrations of ergot alkaloids, which may lead to ergotism (see the Drug Interactions section of the product monograph). Co-administration of POSANOL(tm) and certain medicinal products metabolized through the CYP3A4 system: terfenadine1, astemizole2, cisapride3, pimozide, and quinidine. Although not studied in vitro or in vivo, co-administration of these CYP3A4 substrates may result in increased plasma concentrations of those medicinal products, leading to potentially serious and/or life threatening adverse events, such as QT prolongation and rare occurrences of torsade de pointes (see the Drug Interactions section of the product monograph).

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Drug Interactions (see the Contraindications section and the Drug Interactions section of the product monograph)

Cardiovascular effects - QT interval prolongation (see the Cardiovascular section below)

Hepatic toxicity (see the Hepatic section below)

General

Hypersensitivity: There is no information regarding cross-sensitivity between POSANOL(tm) and other azole antifungal agents. Caution should be used when prescribing POSANOL(tm) to patients with hypersensitivity to other azoles. This medicine contains glucose. Patients with rare glucose-galactose malabsorption should not take this medicine. No data on the effects of POSANOL(tm) on the ability to drive and use machines are available.

1 Please note that terfenadine is no longer available on the Canadian market. 2 Please note that astemizole is no longer available on the Canadian market. 3 Please note that cisapride is no longer available on the Canadian market.

Carcinogenesis and Mutagenesis

Carcinogenicity studies did not reveal special hazards for humans. For information on animal data, see the Toxicology section of the product monograph.

Cardiovascular

POSANOL(tm) has been associated with prolongation of the QT interval of the electrocardiogram (ECG) in some patients. Prolongation of the QT interval may increase the risk of arrhythmia. Due to limited clinical experience, POSANOL(tm) should be administered with caution to patients with potentially proarrhythmic conditions such as congenital or acquired QTc prolongation, congestive heart failure, bradycardia, and acute myocardial ischemia. Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during POSANOL(tm) therapy. Caution should be exercised if POSANOL(tm) is used in patients taking other drugs that may prolong the QT interval, such as antipsychotics, tricyclic antidepressants, methadone, erythromycin, Class IA (e.g., procainamide, quinidine) and Class III (e.g., amiodarone, sotalol) antiarrhythmic agents. Drugs metabolized by the hepatic cytochrome P450 isoenzymes may be affected by POSANOL(tm) levels, with possible resulting QT effects. Such drugs include tacrolimus, HIV protease inhibitors and macrolide antibiotics. (See the Contraindications section, the Drug Interactions section and the Action and Clinical Pharmacology section of the product monograph.) During clinical development there was a single case of torsade de pointes in a patient taking POSANOL(tm). This report involved a seriously ill patient with multiple confounding risk factors. (See the Adverse Reactions - Less Common Clinical Trial Adverse Drug Reactions (< 2%) section of the product monograph.)

Dependence/Tolerance

There is no known abuse potential for POSANOL(tm).

Hematologic

Rare cases of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have been reported primarily among patients who had been receiving concomitant cyclosporine or tacrolimus for management of transplant rejection or graft vs. host disease (GVHD).

Hepatic/Biliary/Pancreatic

Hepatic toxicity: In clinical trials, there were infrequent cases of hepatic reactions (e.g., mild to moderate elevations in ALT (Alanine aminotransferase), AST (Aspartate aminotransferase), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) during treatment with POSANOL(tm). The elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption and rarely required drug discontinuation. Rarely, more severe hepatic reactions including cholestasis or hepatic failure were reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with POSANOL(tm). Monitoring of hepatic function: Liver function tests should be evaluated at the start of and during the course of POSANOL(tm) therapy. Patients who develop abnormal liver function tests during POSANOL(tm) therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of POSANOL(tm) should be considered if clinical signs and symptoms are consistent with development of worsening liver disease.

Special Populations

Pregnant Women: There is insufficient information on the use of POSANOL(tm) in pregnant women. The extent of exposure in pregnancy during clinical trials is very limited. There are no adequate and well-controlled studies in pregnant women. Studies in animals have shown reproductive toxicity (see the Toxicology section of the product monograph). The potential risk to humans is unknown. Women of childbearing potential must always use adequate contraceptive measures while on treatment. POSANOL(tm) should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Women: POSANOL(tm) is excreted into the milk of lactating rats (see the Toxicology section of the product monograph). The excretion of POSANOL(tm) in human breast milk has not been investigated. POSANOL(tm) should not be used by nursing mothers unless the benefit to the mother clearly outweighs the risk to the infant. Hepatic Impairment: POSANOL(tm) should be used with caution in patients with severe hepatic impairment. Prolonged elimination half-life may lead to increased exposure. Patients Taking Immunosuppressant: Cases of elevated cyclosporine levels resulting in rare serious adverse events, including nephrotoxicity and leukoencephalopathy, and death were reported in clinical efficacy studies. Dose reduction and more frequent clinical monitoring of cyclosporine, tacrolimus, and sirolimus should be preformed when POSANOL(tm) therapy is initiated. (See the Drug Interactions section of the product monograph.)

DRUG INTERACTIONS

Serious Drug Interactions

Contraindicated Drugs: ergot alkaloids, terfenadine, astemizole, cisapride, pimozide and quinidine (see the Contraindications section of the product monograph)

Drugs whose concomitant use should be avoided: cimetidine, rifabutin and phenytoin (see Tables 3 and 4 in the Drug Interactions section of the product monograph)

Drugs whose concomitant use requires consideration of dose reduction at initiation of concomitant treatment and close therapeutic monitoring of drug levels during treatment: cyclosporine, tacrolimus and sirolimus (see Table 4 in the Drug Interactions section of the product monograph)

Drugs whose concomitant use requires consideration of dose reduction and close monitoring for adverse events during treatment: vinca alkaloids, midazolam, HMG - CoA reductase inhibitors (statins), calcium channel blockers (see Table 4 in the Drug Interactions section of the product monograph)

Overview

Effect of Other Drugs on POSANOL(tm) Pharmacokinetics

POSANOL(tm) is metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p- glycoprotein efflux. Therefore, inhibitors or inducers of these clearance pathways may affect POSANOL(tm) plasma concentrations. POSANOL(tm) does not have any major circulating oxidative (CYP450 mediated) metabolites and its concentrations are thus unlikely to be altered by inhibitors of CYP450 enzymes.

Effects of POSANOL(tm) on Pharmacokinetics of Other Drugs

POSANOL(tm) is an inhibitor of CYP3A4 and thus the plasma levels of medicinal products that are metabolized through this enzyme pathway may increase when administered with POSANOL(tm).

Drug-Drug Interactions

The drugs listed in these tables are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated). The majority of drug interaction studies were performed with the POSANOL(tm) tablet, which is 36% less bioavailable than the suspension. The majority of drug interaction studies were performed using the 200mg QD schedule whereas the recommended dosing schedule depends on the indication and may be as high as 400mg BID (rIFIs) or 200mg TID (prophylaxis). As a result of these limitations, the maximal exposure was not studied in the majority of these drug interaction studies.

a: Ratio Estimate = ratio of co-administered drug plus POSANOL(tm) to POSANOL(tm) alone for Cmax or AUC b: AUC = area under the plasma concentration time curve

c: QD = once daily d: BID = twice a day

a: Ratio Estimate = ratio of co-administered drug plus POSANOL(tm) to POSANOL(tm) alone for Cmax or AUC b: AUC = area under the plasma concentration time curve

c: QD = once daily d: BID = twice a day

e: PO = per os

* NA: Not applicable if administered as an IV

Drug-Food Interactions

Table 5 - Established or Potential Drug-food Interactions

Drug-Herb Interactions

Interactions with herbal products have not been studied.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been studied.

DOSAGE AND ADMINISTRATION

Dosing Considerations

• Each dose of POSANOL(tm) should be administered with a meal, or with a nutritional supplement in patients who cannot tolerate food to enhance the oral absorption. For patients who cannot eat a full meal or tolerate an oral nutritional supplement, alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.

• Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections

• Co-administration of drugs that can decrease the plasma concentrations of POSANOL(tm) should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections. (See the Drug Interactions section of the product monograph.)

Recommended Dose and Dosage Adjustment

Table 6 - Recommended Dose According to Indication

Increasing the total daily dose above 800 mg does not further enhance the exposure to POSANOL(tm).

Use in renal impairment

POSANOL(tm) is not significantly renally eliminated. No dose adjustment is required in patients with renal dysfunction. (See the Action and Clinical Pharmacology section of the product monograph.)

Use in hepatic impairment

There are limited pharmacokinetic data in patients with hepatic insufficiency; therefore, no recommendation for dose adjustment can be made. In the small number of subjects studied who had hepatic insufficiency, there was an increase in half-life with a decrease in hepatic function (see the Action and Clinical Pharmacology section of the product monograph). Use with caution in patients with severe hepatic impairment. (See the Action and Clinical Pharmacology section of the product monograph.)

Use in Pediatrics (13 - 17 years)

A total of 11 patients 13 - 17 years of age were treated with 800 mg/day in a study for IFIs. . Additionally, 12 patients 13 - 17 years of age received 600 mg/day for prophylaxis of IFIs (studies C/I98-316 and P01899). The safety profile in these patients <18 years of age appears similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these pediatric patients, the pharmacokinetic profile appears to be similar to patients >=18 years of age (see the Action and Clinical Pharmacology section of the product monograph).

Missed Dose

If a dose of this medication is missed, it should be taken as soon as possible. This will help to keep a constant amount of medication in the blood. However, if it is almost time for the next dose, it might be better to skip the missed dose and to go back to the regular dosing schedule.

Administration

Shake well before each use.

OVERDOSAGE

During clinical trials, patients who received POSANOL(tm) doses up to 1,600 mg/day had no noted adverse reactions different from those reported with patients at the lower doses. In addition, accidental overdose was noted in one patient who took 1,200 mg BID for 3 days. No adverse reactions were noted by the investigator. In a trial of patients with severe hemodialysis-dependent renal dysfunction (Clcr <20 mL/min), POSANOL(tm) was not removed by hemodialysis. Activated charcoal may be used to remove unabsorbed drug.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

POSANOL(tm) is a potent inhibitor of the enzyme lanosterol 14a-demethylase, which catalyses an essential step in ergosterol biosynthesis. Consequently, POSANOL(tm)exhibits broad-spectrum antifungal activity against a variety of yeasts and moulds including species of Candida (including C. albicans isolates resistant to fluconazole, voriconazole and itraconazole, C. krusei and C. glabrata which are inherently less susceptible to fluconazole, and C. lusitaniae which is inherently less susceptible to amphotericin B), Aspergillus (including isolates resistant to fluconazole, voriconazole, itraconazole and amphotericin B) and organisms not previously regarded as being susceptible to azoles such as the zygomycetes (e.g., species of Absidia, Mucor, Rhizopus and Rhizomucor). In vitro POSANOL(tm) exhibited fungicidal activity against species of Aspergillus, dimorphic fungi (Blastomyces dermatitidis, Histoplasma capsulatum, Penicillium marneffei, and Coccidioides immitis) and some species of Candida. In animal infection models POSANOL(tm) was active against a wide variety of fungal infections caused by moulds or yeasts. However, there was no consistent correlation between minimum inhibitory concentration (MIC) and efficacy.

Pharmacodynamics

A correlation between total drug exposure (AUC) and clinical outcome has been observed. For subjects with Aspergillus infections, effective drug exposure appears to be higher than that for infections caused by Candida species, although the critical AUC/MIC ratio associated with clinical success is uncertain. It is particularly important to try to ensure that maximal plasma levels are achieved in patients infected with Aspergillus (see the Dosage and Administration section and the Action and Clinical Pharmacology - Pharmacokinetics section of the product monograph on recommended dose regimens and the effects of food on absorption).

Pharmacokinetics

The mean pharmacokinetic parameters in healthy volunteers following administration of POSANOL(tm) 400 mg BID for 7 days are displayed in Table 7.

Table 7- Mean Pharmacokinetic Parameters of POSANOL(tm) in Healthy Volunteers

Dose proportional increases in plasma exposure (AUC) to POSANOL(tm) were observed following single oral doses from 50 mg to 800 mg and following multiple dose administration from 50 mg BID to 400 mg BID. No further increases in exposure were observed when the dose was increased from 400 BID to 600 mg BID in febrile neutropenic patients or those with rIFIs. Absorption: POSANOL(tm) is absorbed with a median Tmax of ~3 to 5 hours. Dose proportional increases in plasma exposure (AUC) to POSANOL(tm) were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg BID to 400 mg BID. No further increases in exposure were observed when the dose was increased from 400 mg BID to 600 mg BID in febrile neutropenic patients or those with rIFIs. Steady-state plasma concentrations are attained at 7 to 10 days following multiple-dose administration. Following single-dose administration of 200 mg, the mean AUC and Cmax of POSANOL(tm)are approximately 3 times higher when administered with a nonfat meal and approximately 4 times higher when administered with a high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of 400 mg, the mean AUC and Cmax of POSANOL(tm) are approximately 3 times higher when administered with a liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 8). In order to assure attainment of adequate plasma concentrations, it is recommended to administer POSANOL(tm) with food or a nutritional supplement. (See the Dosage and Administration section of the product monograph.)

a: Median [min-max]

b: The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between 4 hrs and 36 hrs)

c: n=15 for AUC(I), CL/F and t1/2 d: n=10 for AUC(I), CL/F and t1/2 Distribution: POSANOL(tm) has an apparent volume of distribution of 1,774 L, suggesting extensive extravascular distribution and penetration into the body tissues. POSANOL(tm) is highly protein bound (>98%), predominantly to albumin. Metabolism: POSANOL(tm) primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). SPOSANOL(tm) does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. Excretion: POSANOL(tm) is eliminated with a mean half-life (t1/2) of 35 hours (range 20 to 66 hours) and a total body clearance (CL/F) of 32 L/hr. POSANOL(tm) is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).

Summary of Pharmacokinetic Parameters

The mean (%CV) [min-max] POSANOL(tm) average steady-state plasma concentrations (Cav) and steady-state pharmacokinetic parameters in patients following administration of 200 mg TID and 400 mg BID of the oral suspension are provided in Table 9.

Note: Cav based on observed data; other pharmacokinetic parameters based on estimates from population

pharmacokinetic analyses

a: Oral suspension administration

b: Allogeneic hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease

c: Neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes

d: Febrile neutropenic patients or patients with refractory invasive fungal infections, Cav n=24 e: AUC (0-24 hr) for 200 mg TID and AUC (0-12 hr) for 400 mg BID

f: Not done

The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.

Special Populations and Conditions

Pediatrics

: Mean trough plasma concentrations from 12 patients 8 - 17 years of age were similar to concentrations from 194 patients 18 - 64 years of age. No pharmacokinetic data are available from pediatric patients less than 8 years of age.

Geriatrics: The pharmacokinetics of POSANOL(tm) are comparable in young and elderly subjects (>=65 years of age). No adjustment in the dosage of POSANOL(tm) is necessary in elderly patients (>=65 years of age) based on age. Gender: The pharmacokinetics of POSANOL(tm) are comparable in men and women. No adjustment in the dosage of POSANOL(tm) is necessary based on gender. Race: The AUC and Cmax of POSANOL(tm) decreased slightly in Black subjects relative to Caucasian subjects. No other races were studied. Hepatic Insufficiency: The pharmacokinetic data in subjects with hepatic impairment was not sufficient to determine if dose adjustment is necessary in patients with hepatic dysfunction. It is recommended that POSANOL(tm) be used with caution in patients with hepatic impairment. (See the Warnings and Precautions section and the Dosage and Administration section of the product monograph.) Renal Insufficiency: Following single-dose administration of 400 mg of the oral suspension, there was no significant effect of mild (Clcr: 50-80 mL/min/1.73m2, n=6) and moderate (Clcr: 20- 49 mL/min/1.73m2, n=6) renal insufficiency on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal insufficiency (Clcr: <20 mL/min/1.73m2), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (Clcr: >80 mL/min/1.73m2); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal insufficiency as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections. (See the Dosage and Administration section of the product monograph.)

STORAGE AND STABILITY

Store at room temperature (15 to 30degC). Do not freeze. Do not use past expiry date on the label.

Shelf life

After first opening the container: 4 weeks

SPECIAL HANDLING INSTRUCTIONS

The oral suspension must be shaken well before each use.

DOSAGE FORMS, COMPOSITION AND PACKAGING

POSANOL(tm) Oral Suspension is a white, cherry flavored immediate-release suspension containing 40 mg of posaconazole per mL and the following inactive ingredients: artificial cherry flavor, citric acid monohydrate, glycerin, liquid glucose, polysorbate 80, purified water, simethicone, sodium benzoate, sodium citrate dihydrate, titanium dioxide, and xanthan gum. 105 mL of oral suspension in a 123 mL bottle (glass amber type IV) closed with a plastic child- resistant cap (polypropylene) and a measuring spoon (polystyrene) with 2 graduations: 2.5 mL and 5 mL.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: posaconazole Chemical name: 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1- ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2- hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one Molecular formula and molecular mass: C37H42F2N8O4 700.8 Structural formula: Physicochemical properties: Posaconazole is a white powder which is insoluble in hexanes, deionized water, pH 3 buffer, pH 5 buffer, pH 7 buffer and 0.1N NaOH, very slightly soluble in 0.1N HCl, slightly soluble in ethanol, and sparingly soluble in acetonitrile, methanol and acetone. pH and pKa values: pH: 5.9 (10 mg/mL aqueous slurry) Dissociation Constant (potentiometric titration): 3.6 (piperazine) Melting range: 167.9degC - 169.2degC

CLINICAL TRIALS

Study P01899 and Study C/I98-316

Two large, randomised, controlled studies were conducted using posaconazole as prophylaxis for the prevention of IFIs among patients at high risk.

Study demographics and trial design

FLU: fluconazole

ITZ: itraconazole

Study P01899 was a randomised, evaluator-blinded study that compared posaconazole oral suspension (200 mg three times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg BID) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes. The primary efficacy endpoint was the incidence of proven/probable IFIs as determined by an independent, blinded external expert panel during the on-treatment period. A key secondary endpoint was the incidence of proven/probable IFIs at 100 days post- randomization. The mean duration of therapy was comparable between the two treatment groups (29 days, posaconazole; 25 days, fluconazole/itraconazole).

Study C/I98-316 was a randomised, double-blind trial that compared posaconazole oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily) as prophylaxis against IFIs in allogeneic HSCT recipients with GVHD. The primary efficacy endpoint was the incidence of proven/probable IFIs at 16 weeks post-randomization as determined by an independent, blinded external expert panel. A key secondary endpoint was the incidence of proven/probable IFIs during the on-treatment period (first dose to last dose of study medication + 7 days). The mean duration of therapy was comparable between the two treatment groups (80 days, posaconazole; 77 days, fluconazole).

Study results

Prophylaxis of IFIs

In both prophylaxis studies, aspergillosis was the most common breakthrough infection. There were significantly fewer breakthrough Aspergillus infections in patients receiving posaconazole prophylaxis when compared to control patients receiving fluconazole or itraconazole. See Tables 12 and 13 for results from both studies.

Table 12- Results from Clinical Study C/I98-316 in Prophylaxis of IFIs

In Study P01899, a significant decrease in all cause mortality in favour of posaconazole was observed [posaconazole 49/304 (16%) vs. fluconazole/itraconazole 67/298 (22%) P = 0.048]. Based on Kaplan-Meier estimates, the probability of survival up to day 100 after randomization, was significantly higher for posaconazole recipients; this survival benefit was demonstrated when the analysis considered all causes of death (P = 0.0354) as well as IFI-related deaths (P = 0.0209). In Study C/I98-316, overall mortality was similar (posaconazole, 25%; fluconazole, 28%); however, the proportion of IFI-related deaths was significantly lower in the posaconazole group (4/301) compared with the fluconazole group (12/299; P = 0.0413).

Study P00041

Study demographics and trial design

Patients were enrolled to receive posaconazole for treatment if the investigator confirmed a diagnosis of invasive aspergillosis, in accordance with the European Organization for Research and Treatment-Mycoses Study Group (EORTC-MSG) criteria, and if they were refractory to at least 7 days of antifungal therapy (defined as failure to improve or as disease progression) or were intolerant of conventional therapy, as defined by renal impairment, severe infusion-related toxicity, or other organ dysfunction or were considered to be at high risk for development of toxicity on the basis of underlying disease or concomitant receipt of nephrotoxic medications. The majority of patients received amphotericin B (including lipid formulations, total n=98) and/or itraconazole (total n=51) as prior therapy for invasive aspergillosis prior to treatment with posaconazole. Of the 104 posaconazole-treated subjects who received prior antifungal therapy, five patients were refractory to voriconazole and five were refractory to an echinocandin. Patients were administered posaconazole 800 mg/day in divided doses. The majority of patients were severely immunocompromised with underlying conditions such as hematologic malignancies, including bone marrow transplantation; solid organ transplantation; solid tumors and/or AIDS. The duration of previous antifungal therapy was similar in both the posaconazole and control populations. The median duration of posaconazole treatment (for treatment of all pathogens) in this study was 102.5 days (range 1-372 days). The median duration of posaconazole treatment (for the modified intent to treat subset) of patients with invasive aspergillosis was 56 days (range 1-372 days).

Study results

Invasive aspergillosis

The efficacy and survival benefit of oral posaconazole for the treatment of invasive aspergillosis in patients with disease refractory to amphotericin B (including liposomal formulations) (n=98), itraconazole (n=51), voriconazole (n=5) or echinocandins (n=5) or in patients who were intolerant of these medicinal products, was demonstrated in 107 patients. An independent expert panel reviewed all patient data, including diagnosis of invasive aspergillosis, refractoriness and intolerance to previous therapy, and clinical outcome in a parallel and blinded fashion with an external control group of 86 patients (acquired via a retrospective review of medical records) treated with standard therapy mostly at the same time and at the same sites as the patients enrolled in the posaconazole trial. A success was defined as either complete resolution (complete response) or a clinically meaningful improvement (partial response) of all signs, symptoms and radiographic findings attributable to the fungal infection. Stable, non-progressive disease and failure were considered to be a non-success. Most of the cases of aspergillosis were considered to be refractory in both the posaconazole group (88%) and in the external control group (79%). The majority of the subjects (74% for posaconazole and 78% for control) had a pulmonary site of infection; of the remainder, 9% of the subjects in each group had disseminated fungal infection (with or without pulmonary involvement), and the remainder had extrapulmonary infections. Among the extrapulmonary infections, the CNS was the site of infection in four (4%) subjects in the posaconazole-treated group and two (2%) in the control group. As shown in Table 15, a successful global response at end of treatment was seen in 42% of posaconazole-treated patients compared to 26% of the external group (P = 0.006). This was not a prospective, randomized, controlled study and so all comparisons with the external control group should be viewed with caution.

Table 15 - Overall Efficacy of posaconazole at the End of Treatment for Invasive Aspergillosis in Comparison to an External Control Group

includes other less common species or species unknown

+

Odds Ratio represents the response rate of posaconazole versus control and is based on a logistic regression model that adjusts for key prognostic variables (age, site of infection, baseline neutropenia, duration of prior antifungal therapy, region of enrollment, and basis of enrollment (refractory disease or intolerance), and 5 other variables that showed imbalance between the treatment groups (race, enrollment time, nonmalignant hematologic disorder, renal disease, and hepatic disease).

The cumulative rates of survival at 30 days and at the end of posaconazole therapy were 74% and 38%, respectively; for control subjects, those survival rates were 49% and 22%, respectively. As determined on the basis of a log rank statistic, a survival benefit for posaconazole compared to standard treatment was observed (P < 0.001).

Other Serious Fungal Pathogens

Posaconazole has been shown to be effective against the following additional pathogens when other therapy had been ineffective or when the patient had developed intolerance of the prior therapy:

• Zygomycosis (n=11) with disease that is refractory to amphotericin B or in patients who are

intolerant of amphotericin B.

Fusariosis

(n=18) with disease that is refractory to amphotericin B or in patients who are intolerant of amphotericin B.

Chromoblastomycosis/mycetoma

(n=11) with disease that is refractory to itraconazole or in patients who are intolerant of itraconazole.

Coccidioidomycosis

(n=16) with disease that is refractory to amphotericin B, itraconazole or fluconazole or in patients who are intolerant of these therapies.

Study C/I97-331

Study demographics and trial design

A randomised, evaluator-blind, controlled study was completed in HIV-infected patients with azole-susceptible OPC. The primary efficacy variable was the clinical success rate (defined as cure or improvement) after 14 days of treatment. Patients were treated with posaconazole or fluconazole oral suspension (both- posaconazole and fluconazole were given as follows: 100 mg BID for 1 day followed by 100 mg once a day for 13 days).

Study results

Treatment of Azole-susceptible OPC

The clinical and mycological response rates from the above study are shown in the Table 17 below. Posaconazole and fluconazole demonstrated equivalent clinical success rates at Day 14 as well as 4 weeks after the end of treatment. However, posaconazole demonstrated a significantly better sustained mycological response rate 4 weeks after the end of treatment than fluconazole.

*Statistically significant (P = 0.0376)

Clinical success rate was defined as the number of cases assessed as having a clinical response (cure or improvement) divided by the total number of cases eligible for analysis.

Mycological response rate was defined as mycological success (<= 20 CFU/mL) divided by the total number of cases eligible for analysis.

Study C/I97-330

Study demographics and trial design

The primary efficacy parameter in Study C/I97-330 was the clinical success rate (cure or improvement) after 4 weeks of treatment. HIV-infected patients were treated with posaconazole 400 mg BID with an option for further treatment during a 3-month maintenance period.

Study results

Treatment of Azole-refractory OPC

In Study C/I97-330, a 75% (132/176) clinical success rate and a 36.5% (46/126) mycological response rate (<= 20 CFU/mL) were achieved after 4 weeks of posaconazole treatment. Clinical success rates ranged from 71% to 100%, inclusive, for all azole-resistant Candida species identified at Baseline, including C. glabrata and C. krusei.

DETAILED PHARMACOLOGY

Pharmacodynamics

ECG evaluation

No placebo - controlled, randomized, Phase 1 study with a positive control arm for QT prolongation was performed in order to evaluate the effect of posaconazole on the QT interval. Multiple, time-matched ECGs collected over a 12 h period were recorded at baseline and steady- state from 173 healthy male and female volunteers (18 to 85 years of age) administered posaconazole 400 mg BID with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia (F)) interval change was -5 msec following administration of the recommended clinical dose. A decrease in the QTc (F) interval (- 3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc (F) interval change from baseline was <0 msec (- 8 msec). No subject administered posaconazole had a QTc (F) interval of >= 500 msec or an increase >= 60 msec in their QTc (F) interval from baseline.

Pharmacokinetics

Summary of the mean pharmacokinetic parameters in patients

The general pharmacokinetic findings across the clinical program in both healthy volunteers and patients were consistent, in that posaconazole was slowly absorbed and slowly eliminated with an extensive volume of distribution. In addition, the phenomenon of dose-limited absorption of posaconazole at 800 mg/day was observed both in healthy volunteers and patients. The exposure to posaconazole following administration of 400 mg BID was ~3 times higher in healthy volunteers than in patients, without additional safety findings at the higher concentrations.

Absorption

Posaconazole is absorbed with a median tmax of 3 h (patients) and 5 h (healthy volunteers). The pharmacokinetics of posaconazole are linear following single and multiple dose administration of up to 800 mg. No further increases in exposure were observed when doses above 800 mg daily were administered to patients and healthy volunteers. There is no effect of altered pH on the absorption of posaconazole. Dividing the total posaconazole daily dose (800 mg) as 400 mg BID results in a 184% higher exposure relative to once-a-day administration in patients.

Distribution

Posaconazole has a large apparent volume of distribution (1, 744 L) suggesting extensive penetration into the peripheral tissues. Posaconazole is highly protein bound (> 98%), predominantly to serum albumin.

Metabolism

Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites and its concentrations are thus unlikely to be altered by inhibitors of CYP450 enzymes. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.

Excretion

Posaconazole is slowly eliminated with a mean half-life (t1/2) of 35 h (range 20 to 66 h) and a total body clearance of 32 L/h. Posaconazole is predominantly excreted in the feces (77% of radiolabeled dose) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 14% of the radiolabeled dose excreted in urine (< 0.2% of the radiolabeled dose is parent drug). Steady state is attained following 7 to 10 days of multiple-dose administration.

Special Populations and Conditions

Pediatrics

Following administration of 800 mg per day of posaconazole as a divided dose for treatment of IFIs, mean trough plasma concentrations from 12 patients 8 - 17 years of age (776 ng/mL) were similar to concentrations from 194 patients 18 - 64 years of age (817 ng/mL). No pharmacokinetic data are available from pediatric patients less than 8 years of age. Similarly, in the prophylaxis studies, the mean steady-state posaconazole Cav was comparable among 10 adolescents (13 - 17 years of age) to Cav achieved in adults (>= 18 years of age).

Geriatrics

An increase in Cmax (26%) and AUC (29%) was observed in elderly subjects (24 subjects

>=

65 years of age) relative to younger subjects (24 subjects 18 - 45 years of age). However, in a

population pharmacokinetic analysis (Study P01899) age did not influence the pharmacokinetics of posaconazole. Further, in clinical efficacy trials, the safety profile of posaconazole between the young and elderly patients was similar. Therefore, no dose adjustment is required for age.

Gender

The pharmacokinetics of posaconazole are comparable in men and women. No adjustment in the dosage of posaconazole is necessary based on gender.

Race

Results from a multiple dose study in healthy volunteers (n=56) indicated that there was only a slight decrease (16%) in the AUC and Cmax of posaconazole in Black subjects relative to Caucasian subjects, therefore, no dose adjustment for race is required.

Hepatic Insufficiency

In a small number of subjects (n=12) studied with hepatic insufficiency (Child-Pugh class A, B or C), Cmax values generally decreased with the severity of hepatic dysfunction (545, 414 and 347 ng/mL for the mild, moderate, and severe groups, respectively), even though the Cmax values (mean 508 ng/mL) for the normal subjects were consistent with previous trials in healthy volunteers. In addition, an increase in half-life was also associated with a decrease in hepatic function (26.6, 35.3, and 46.1 h for the mild, moderate, and severe groups, respectively), as all groups had longer half-life values than subjects with normal hepatic function (22.1 h). Due to the limited pharmacokinetic data in patients with hepatic insufficiency, no recommendation for dose adjustment can be made.

Renal Insufficiency

Following single-dose administration, there was no effect of mild and moderate renal insufficiency (n=18, Clcr >= 20 mL/min/1.73 m2) on posaconazole pharmacokinetics, therefore, no dose adjustment is required. In subjects with severe renal insufficiency (n=6, Clcr <20 mL/min/1.73 m2), the exposure of posaconazole was highly variable (96% CV) compared to the exposure in the other renal groups (< 40% CV). However, as posaconazole is not significantly renally eliminated, an effect of severe renal insufficiency on the pharmacokinetics of posaconazole is not expected and no dose adjustment is recommended. Posaconazole is not removed by hemodialysis.

Animal Pharmacology

The administration of a single oral dose of 30 mg/kg of posaconazole did not modify cardiovascular, gastrointestinal, behavioral, neurologic, or autonomic function in the rat. A single intravenous dose of a lipid-containing formulation of posaconazole (bolus) at 30 or 60 mg/kg did not demonstrate changes in respiratory rate, tidal volume, or minute volume, or in behavior, neurologic or autonomic function, compared with vehicle-treated rats. A single dose of 3 or 10 mg/kg did not affect renal function. In vitro effects of posaconazole on ventricular repolarization were evaluated by measuring both the action potential and the recombinant hERG channel current. In Purkinje fibers isolated from dog heart, exposure to posaconazole at measured concentrations of 25 ng/mL (36 nM), 69 ng/mL (98 nM) and 365 ng/mL (521 nM) induced a small (<10%) but statistically significant increase in action potential duration at 60% (APD60) and/or 90% (APD90) repolarization. In mouse L-929 cells stably transfected with the human a-subunit (hERG) of the cardiac delayed rectifier, IKr, a measured concentration of 770 ng/mL (1.1 mM) posaconazole decreased hERG current by 7%. Accounting for protein binding, the drug concentration in the hERG assay was 18-times the free posaconazole Cmax value in healthy volunteers. Changes of the magnitude noted in the recombinant hERG channel and isolated Purkinje fiber systems would be unlikely to elicit QT interval prolongation in vivo. At an oral dose of 90 mg/kg in rats, posaconazole was associated with a minimal increase in systolic (13 to 23 mm Hg) and mean arterial (10 to 19 mm Hg) blood pressures after four weeks of dosing. There were no changes in heart rate. After four weeks of dosing, rats given posaconazole had a decreased intraventricular systolic diameter and increased fractional shortening, which may be indicative of increased cardiac contractility. However, there was no concomitant increase in stroke volume. No other echocardiographic indices of cardiac function were altered by posaconazole. Cardiovascular parameters in monkeys were assessed in two safety pharmacology studies with the lipid-containing intravenous formulation of posaconazole. No posaconazole-related effects on heart rate, arterial blood pressure, ECG intervals (RR, PR, QRS, QT, QTc), or ECG morphology and rhythm were observed following seven days of dosing at doses up to 40 mg/kg. The lowest mean AUC (0-24 hr) was observed on Day 1 and was 141 mg[? ]hr/mL, which is 2.4- fold a human AUC exposure of 59 mg[? ]hr/mL. The absence of QT or QTc interval changes at 40 mg/kg posaconazole intravenously in conscious monkeys indicates a low potential for posaconazole to produce QT or QTc interval prolongation.

MICROBIOLOGY

Posaconazole has been shown in vitro and in clinical infections to be active against the following microorganisms (see the Indications and Clinical Use section of the product monograph): Aspergillus species (A. fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus, A. ochraceus), Candida species (C. albicans, C. glabrata, C. krusei, C. parapsilosis), Coccidioides immitis, Fonsecaea pedrosoi, Pseudallescheria boydii and species of Exophiala, Fusarium, Rhizomucor, Mucor, and Rhizopus. Additionally, the following in vitro data are available (see Tables 19 and 20). The results of such studies do not necessarily correlate with clinical outcome. The safety and effectiveness of posaconazole in treating clinical infections due to these microorganisms have not been established in clinical trials. The posaconazole MIC90 values for mould strains tested are summarized in Table 19.

a: minimal inhibitory concentration at which 90% of the strains tested are inhibited from growth

b: When the number of strains tested was <10, the range of MICs is indicated in parentheses.

The posaconazole MIC90 values for yeast strains tested are summarized in Table 20.

a: minimal inhibitory concentration at which 90% of the strains tested are inhibited from growth

b: When the number of strains tested was <10, the range of MICs is indicated in parentheses.

Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

Drug Resistance

C. albicans strains resistant to posaconazole could not be generated in the laboratory; spontaneous laboratory Aspergillus fumigatus mutants exhibiting a decrease in susceptibility to posaconazole arose at a frequency of 1x10-8 to 1x10-9. Clinical isolates of Candida albicans and Aspergillus fumigatus exhibiting significant decreases in posaconazole susceptibility are rare. In those rare instances where decreased susceptibility was noted, there was no clear correlation between decreased susceptibility and clinical failure. Clinical success has been observed in patients infected with organisms resistant to other azoles; consistent with these observations posaconazole was active in vitro against many Aspergillus and Candida strains that developed resistance to other azoles and/or amphotericin B. Breakpoints for posaconazole have not been established for any fungi.

Antifungal medicinal products combinations

When combinations of posaconazole with either amphotericin B or caspofungin were tested in vitro and in vivo there was little or no antagonism and in some instances there was an additive effect. The clinical significance of these results is unknown.

TOXICOLOGY

Acute Toxicity

The maximum non-lethal dose for a single oral dose of posaconazole was greater than 1,500 mg/kg in mice, greater than 4,000 mg/kg in rats and greater than 2,000 mg/kg in dogs.

Long-Term Toxicity

Repeated-dose toxicity studies of posaconazole were conducted in mice for up to three months, in rats for up to six months, and in dogs and monkeys for up to one year. Posaconazole causes several toxicologic effects that occur with other antifungal substances in the azole class, i.e., hyperplasia of the adrenal glands (mice, rats and dogs), phospholipidosis of lung and lymphoid tissues (all species), disseminated intravascular coagulation (dogs only), bone thinning/fractures (rats only), hepatocellular adenomas (mice only), findings secondary to the interruption of steroidogenesis and fetal toxicity (rats and rabbits). Additional findings not previously reported with other marketed antifungal agents include neuronal phospholipidosis in dogs and increased urinary calcium excretion in dogs and rats. In a twelve-month study in dogs with doses of posaconazole up to 30 mg/kg, neuronal phospholipidosis occurred after approximately three months of dosing, did not progress in severity over time and was present at the end of a three-month post dose period. There were no neurologic or degenerative changes in affected neurons and no functional changes in affected dogs. There were no posaconazole-related neurotoxicity or neuropathology findings in monkeys when administered daily doses of 180 mg/kg for twelve months.

Reproductive Toxicity

There was no effect on fertility in male rats dosed up to a high-dose of 180 mg/kg. There was no effect on fertility in female rats up to a high-dose of 45 mg/kg. In a rat embryo-fetal development study, there were no posaconazole-related effects on pregnancy rate and numbers of corpora lutea, implantations and resorptions. At a dose of 27 mg/kg, skeletal variations and malformations occurred. The no-effect dose was 9 mg/kg for maternal and fetal effects in rats. In a rabbit embryo-fetal development study with doses of 20, 40 and 80 mg/kg, there were no posaconazole-related effects on pregnancy rate, and numbers of corpora lutea and implantations. In the 40 and 80 mg/kg-dosed rabbits, there were increases in resorptions and skeletal variations. In a perinatal and postnatal development study in rats at doses of 6, 18 or 36 mg/kg, there were no posaconazole-related effects on the various indicators of physical and functional development, as well as behavioral responses, in the F1 pups.

Mutagenicity

Posaconazole was evaluated in a bacterial mutagenicity, human peripheral blood lymphocyte, Chinese hamster ovary and mouse micronucleus studies. Posaconazole did not exhibit any genotoxic potential.

Carcinogenicity

No drug-related neoplasms were recorded in rats or mice treated with posaconazole for two years at doses below the maximum tolerated dose. In a two-year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9 or 3.5 times the exposure achieved with a 400 mg BID, respectively, based on steady-state AUC in healthy volunteers administered a high fat meal (400 mg BID regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8 times the exposure achieved with a 400 mg BID regimen.

Local Tolerance

Studies to evaluate local tolerance of posaconazole indicated a low potential for acute dermal toxicity and no potential for irritation or sensitization.

Immunotoxicity Studies

A series of immunotoxicology studies in mice indicate minimal changes in immune function (decreased antibody forming cell response and increased natural killer cell activity) and minimal changes in populations of lymphocytes, NK cells and monocytes in the blood and/or spleen in the 30 and 90 mg/kg groups after one and three months of dosing. The NEL for these changes was 10 mg/kg. The changes in the immune system parameters in the immunotoxicity studies were minimal and reversible, indicating that administration of posaconazole had no permanent effect on the function of the immune system.

REFERENCES

1. Cacciapuoti A., Loebenberg D., Corcoran E., Menzel F Jr., Moss EL Jr., Norris C., Michalski M., Raynor K., Halpern J., Mendrick C., Arnold B., Antonacci B., Parmegiani R., Yarosh- Tomaine T., Miller GH., and Hare RS. In Vitro and In Vivo Activities of SCH 56592 (Posaconazole), a New Triazole Antifungal Agent, Against Aspergillus and Candida. Antimicrobial Agents & Chemotherapy. 44(8):2017-22, 2000 Aug.

2. Manavathu EK., Cutright JL., Loebenberg D., and Chandrasekar PH. A Comparative Study of the In Vitro Susceptibilities of Clinical and Laboratory-Selected Resistant Isolates of Aspergillus spp. to Amphotericin B, Itraconazole, Voriconazole and Posaconazole (SCH 56592). Journal of Antimicrobial Chemotherapy. 46(2):229-34, 2000 Aug.

3. Mellinghoff IK., Winston DJ., Mukwaya G., and Schiller GJ. Treatment of Scedosporium Apiospermum Brain Abscesses with Posaconazole. Clinical Infectious Diseases. 34(12):1648-50, 2002 Jun 15.

4. Nomeir AA., Kumari P., Hilbert MJ., Gupta S., Loebenberg D., Cacciapuoti A., Hare R., Miller GH., Lin CC., and Cayen MN. Pharmacokinetics of SCH 56592, a New Azole Broad- Spectrum Antifungal Agent, in Mice, Rats, Rabbits, Dogs, and Cynomolgus Monkeys. Antimicrobial Agents & Chemotherapy. 44(3):727-31, 2000 Mar.

5. Petraitiene R., Petraitis V., Groll AH., Sein T., Piscitelli S., Candelario M., Field-Ridley A., Avila N., Bacher J., and Walsh TJ. Antifungal Activity and Pharmacokinetics of Posaconazole (SCH 56592) in Treatment and Prevention of Experimental Invasive Pulmonary Aspergillosis: Correlation with Galactomannan Antigenemia. Antimicrobial Agents & Chemotherapy. 45(3):857-69, 2001 Mar.

6. Sabatelli F. Patel R, Mann PA, Mendrick CA, Norris CC, Hare R, Loebenberg, D, Black TA, and McNicholas PM. I2006. In vitro activities of Posaconazole, Fluconazole, Itraconazole, Voriconazole, and Amphotericin B against a large collection of clinically important moulds and yeasts. Antimicrobial Agents & Chemotherapy. 50(6): 2009-15, 2006 Jun.

7. Tobon AM., Arango M., Fernandez D., and Restrepo A. Mucormycosis (Zygomycosis) in a Heart-Kidney Transplant Recipient: Recovery After Posaconazole Therapy. Clinical Infectious Diseases. 36(11):1488-91, 2003 Jun 1.

8. Van Burik JH., Hare RS., Solomon HF., Corrado ML. and Kontoyiannis DP. Posaconazole Is Effective as Salvage Therapy in Zygomycosis: A Retrospective Summary of 91 Cases. Clinical Infectious Diseases. 42: e61-5, 2006 Apr 1.

9. Vazquez JA., Skiest DJ., Nieto L., Northland R., Sanne I., Gogate J., Greaves W., and Isaacs

R. A Multicenter Randomized Trial Evaluating Posaconazole versus Fluconazole for the Treatment of Oropharyngeal Candidiasis in Subjects with HIV/AIDS. Clinical Infectious Diseases. 42: 1179-86, 2006 Apr 15.

PART III: CONSUMER INFORMATION

POSANOL(tm)

posaconazole oral suspension

This leaflet is part III of a three-part "Product Monograph" published when POSANOL(tm) was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about POSANOL(tm). Contact your doctor or pharmacist if you have any questions about the drug.

Read all of this leaflet carefully before you start taking this medicine. Keep this leaflet; you may need to read it again. This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours.

ABOUT THIS MEDICATION

What the medication is used for:

• POSANOL(tm) can be used to prevent invasive fungal infections

caused by Aspergillus and Candida in patients 13 years of age

or older whose immune systems may be weakened due to other medicines or diseases.

POSANOL(tm) can be used to treat the following types of fungal infections in patients 13 years of age or older:

• Infections caused by fungi of the Aspergillus family that have not improved during treatment with the anti-fungal medicines amphotericin B or itraconazole or when these medicines have had to be stopped.

POSANOL(tm) can be used to treat, in patients 13 years of age or older, infections in the mouth or throat area known as "thrush", caused by fungi called Candida.

What it does:

SPRIAFIL belongs to a group of medicines called triazole antifungal agents. These medicines are used to treat a wide variety of fungal infections. POSANOL(tm) works by killing or stopping the growth of some types of fungi that can cause infections in humans.

When it should not be used:

If you are hypersensitive (allergic) to posaconazole or to any of

the excipients (see What the important nonmedicinal

ingredients are

section).

If you are taking the following medicines, as they may interact

with POSANOL(tm)

• ergot alkaloids

• cisapride

• pimozide

• quinidine

• terfenadine

• astemizole

What the medicinal ingredient is

: Posaconazole

What the important nonmedicinal ingredients are:

Artificial cherry flavor, citric acid monohydrate, glycerin, liquid glucose, polysorbate 80, purified water, simethicone, sodium benzoate, sodium citrate dihydrate, titanium dioxide, and xanthan gum. You may also refer to the POSANOL(tm) labels for a full listing of nonmedicinal ingredients.

If you know that you have intolerance to glucose, please tell your doctor before being treated with POSANOL(tm).

What dosage forms it comes in

: 40 mg/mL oral suspension

POSANOL(tm) is a white, cherry flavored, 105 mL oral suspension packaged in amber glass bottles. A measuring spoon is provided with each bottle for measuring 2.5 and 5 mL doses of the drug product.

It is recommended that the spoon is rinsed with water after each administration and before storage.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

• Drug Interactions (See the When it should not be used section and the Interactions With This Medication section)

• Heart Effects (See the Warnings and Precautions section and the Side Effects and What To Do About Them section)

• Liver Problems (See the Warnings and Precautions

section and the Side Effects and What To Do About Them section)

BEFORE you use POSANOL(tm) talk to your doctor or pharmacist if:

• you have had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole or voriconazole;

• you are taking certain drugs that suppress your immune system like cyclosporine, tacrolimus and sirolimus. Serious and rare fatal

toxicity from cyclosporine has occurred when taken in combination with POSANOL(tm). Therefore the doctor may adjust the dosage of these immune suppressants and monitor their blood levels when taken with POSANOL(tm).

you have or have had liver problems;

you are taking or have taken any other medicines, even those that are obtained without a prescription. Some medicines may affect the way POSANOL(tm) works or POSANOL(tm) may affect the way they work. Please see the section "Interactions with this medication" for medicines which may interact with POSANOL(tm).

you have any of the following conditions: history of heart disease, or an irregular beat;

you are a nursing mother. Do not breast feed while being treated with POSANOL(tm) unless you are told by your doctor.

you are pregnant or planning on becoming pregnant. Do not use POSANOL(tm) during pregnancy unless you are told by your doctor. Use effective contraception if you are a woman who could become pregnant. Contact your doctor immediately if you become pregnant while being treated with POSANOL(tm).

you think you have galactose intolerance or glucose-galactose malabsorption. Please check with your doctor before starting to take POSANOL(tm) suspension since it contains glucose.

Your doctor may ask you to have your blood tested during treatment with POSANOL(tm).

Please inform your doctor if you experience sleepiness or blurred vision, which can affect your ability to drive or operate machinery.

Contact your doctor if you develop severe diarrhea or vomiting, as these conditions may limit the effectiveness of POSANOL(tm).

Certain medications may affect the levels of POSANOL(tm) and these combinations should be avoided if possible. Tell your doctor if you are taking or if you plan to stop taking any of the following:

• rifabutin or rifampin (a medicine to treat bacterial

infections like tuberculosis)

phenytoin (a medicine to treat seizures)

cimetidine (a medicine to treat stomach ulcers)

POSANOL(tm) may cause changes in the blood levels of certain medications you may be using. Tell your doctor if you are taking or plan to stop taking any of the following medicines before starting treatment with POSANOL(tm), as dose adjustment or monitoring may be needed:

• vinca alkaloids (used to treat cancer)

• cyclosporine (used in transplant patients)

• tacrolimus (used in transplant patients)

• sirolimus (used in transplant patients)

• rifabutin (a medicine to treat bacterial infections)

• midazolam (used as a sedative to help sleep)

• statins (used to treat high cholesterol)

• calcium channel blockers (used to treat high blood

pressure)

digoxin (used to treat heart failure)

PROPER USE OF THIS MEDICATION

POSANOL(tm) must only be used as directed by your doctor. Your doctor will monitor your response and condition to determine what POSANOL dose is needed. Shake well before each use.

Usual dose (adults and children 13 years of age and older): Take each dose of POSANOL(tm) with food or with a nutritional supplement if you are unable to eat a full meal, to help absorb the medicine well.

INTERACTIONS WITH THIS MEDICATION

Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines, even those not prescribed.

The following list of medicines should not be taken during your course of POSANOL(tm) treatment:

• cisapride * (a medicine for stomach problems)

• pimozide (a medicine for treating mental illness)

• quinidine (a medicine for treating irregular heart beat)

• ergot alkaloids (a medicine to treat migraines along

with other indications)

terfenadine * (a medicine to treat allergies)

astemizole * (a medicine to treat allergies)

*

no longer marketed in Canada

Your doctor will determine how long the duration of your treatment will be and may change your dose depending on your condition. Do not stop treatment early because your infection may not be fully cured. If you are given POSANOL(tm) for preventing infections, take the full course as prescribed by your doctor, as your immune system may still be weakened and you may need treatment to prevent an infection from occurring even if you feel well.

Overdose:

If you take more POSANOL(tm) than prescribed (or someone else takes your suspension) you should seek medical advice from your doctor or healthcare professional immediately. Take your bottle of

POSANOL(tm) suspension with you.

Missed dose:

If you miss taking a dose of POSANOL(tm), take it as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not

take a double dose to make up for the forgotten dose.

which have been reported primarily among patients who had been receiving concomitant cyclosporine or tacrolimus for management of transplant rejection or graft vs. host disease.

If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like all medicines, POSANOL(tm) can have side effects. If side effects do occur, most are likely to be minor and temporary. Please tell your doctor or healthcare professional if you experience any reaction that is continuous, bothersome or you think is serious.

Common side effects (occurring in at least 1 in 100 patients) are

: Headache; dizziness; numbness or tingling; sleepiness; feeling or being sick; loss of appetite; stomach pain; diarrhea; upset stomach; nausea; vomiting; flatulence (excessive gas in the digestive tract); dry mouth; abnormal liver function tests; rash; weakness; tiredness; a decrease in white blood cells (that can increase the risk of infections); fever; abnormal amounts of salts in the blood.

Other reported side effects include infrequent cases of liver reactions (e.g., mild to moderate elevations in liver tests called ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis). The elevations in liver function tests were generally reversible when POSANOL(tm) was stopped, and in some instances these tests went back to normal without stopping POSANOL(tm). These effects rarely required stopping POSANOL(tm). Rarely, more severe liver reactions including cholestasis (back-up of bile in the liver) or liver failure were reported in patients with serious underlying medical conditions (e.g., leukemia or other blood cancers) during treatment with POSANOL(tm). As POSANOL(tm) has been known to affect the liver in patients who already have liver problems, your doctor may wish to monitor the function of your liver by doing blood tests. Some of the symptoms of liver problems include yellowing of the eyes or skin, "flu-like" feeling or feeling more tired than usual, stomach pains, light colored stools, nausea or vomiting. Please let your doctor know if you have any of these symptoms.

Uncommon and rare treatment related serious or medically

This is not a complete list of side effects. For any unexpected

(tm)

significant adverse events reported during clinical trials with posaconazole have included poor functioning of the adrenal gland; heart problems including very fast heartbeat, very slow heartbeat, irregular heartbeat including Torsade de Pointes; abnormal findings on heart tests (like ECGs that show heart rhythm), severe allergic reactions, including widespread blistering rash and skin peeling. There have been rare cases of hemolytic uremic syndrome (a serious problem with the blood vessels causing low red blood cell counts and kidney failure) and thrombotic thrombocytopenic purpura (a serious blood problem causing bruising, confusion, fever, and low blood clotting cell counts),

effects while taking POSANOL

pharmacist.

, contact your doctor or

HOW TO STORE IT

Keep out of the reach and sight of children. Store at room temperature (15 to 30degC). Do not freeze. Do not use this product after the expiry date stated on the label. Once opened, use the suspension within 4 weeks.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax: 866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness

Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

For this document plus the full product monograph, prepared for health professionals, please contact the sponsor, Schering-Plough Canada Inc. at: 1-800-463-5442. This leaflet was prepared by Schering-Plough Canada Inc. Last revised: June 11, 2008