Jamp Posaconazole Product Monograph

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TABLE OF CONTENTS

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RECENT MAJOR LABEL CHANGES ........................................................................................... 2

TABLE OF CONTENTS ............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................... 5

• 1 INDICATIONS ............................................................................................................. 5

  • 1.1 Pediatrics .................................................................................................................. 5
  • 1.2 Geriatrics .................................................................................................................. 5
• 2 CONTRAINDICATIONS ................................................................................................ 5
• 3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................ 6

• 4 DOSAGE AND ADMINISTRATION ................................................................................. 6

  • 4.1 Dosing Considerations .............................................................................................. 6
  • 4.2 Recommended Dose and Dosage Adjustment ......................................................... 7
  • 4.4 Administration .......................................................................................................... 8
  • 4.5 Missed Dose ............................................................................................................. 8
• 5 OVERDOSAGE ............................................................................................................ 8
• 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 8

• 7 WARNINGS AND PRECAUTIONS ................................................................................. 9

  • 7.1 Special Populations ................................................................................................ 11
  • 7.1.1 Pregnant Women ............................................................................................. 11
  • 7.1.2 Breast-feeding .................................................................................................. 11
  • 7.1.3 Pediatrics .......................................................................................................... 12
  • 7.1.4 Geriatrics .......................................................................................................... 12

• 8 ADVERSE REACTIONS ............................................................................................... 12

  • 8.1 Adverse Reaction Overview ................................................................................... 12
  • 8.2 Clinical Trial Adverse Reactions .............................................................................. 12
  • 8.3 Less Common Clinical Trial Adverse Reactions ...................................................... 18
  • 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ................................................................................................... 20
  • 8.5 Post-Market Adverse Reactions ............................................................................. 20

• 9 DRUG INTERACTIONS ............................................................................................... 21

  • 9.1 Serious Drug Interactions ....................................................................................... 21
  • 9.2 Drug Interactions Overview ................................................................................... 21
  • 9.3 Drug-Behavioural Interactions ............................................................................... 21
  • 9.4 Drug-Drug Interactions ........................................................................................... 22
  • 9.5 Drug-Food Interactions .......................................................................................... 28
  • 9.6 Drug-Herb Interactions........................................................................................... 28
  • 9.7 Drug-Laboratory Test Interactions ......................................................................... 28

• 10 CLINICAL PHARMACOLOGY ...................................................................................... 29

  • 10.1 Mechanism of Action ....................................................................................... 29
  • 10.2 Pharmacodynamics .......................................................................................... 29
  • 10.3 Pharmacokinetics ............................................................................................. 29
• 11 STORAGE, STABILITY AND DISPOSAL ........................................................................ 33
• 12 SPECIAL HANDLING INSTRUCTIONS .......................................................................... 33

PART II: SCIENTIFIC INFORMATION ...................................................................................... 32

• 13 PHARMACEUTICAL INFORMATION ........................................................................... 34

• 14 CLINICAL TRIALS ...................................................................................................... 35

  • 14.3 Comparative Bioavailability Studies ................................................................. 41
• 15 MICROBIOLOGY ....................................................................................................... 44
• 16 NON-CLINICAL TOXICOLOGY .................................................................................... 47
• 17 SUPPORTING PRODUCT MONOGRAPHS ................................................................... 50

PATIENT MEDICATION INFORMATION ................................................................................. 51

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

JAMP Posaconazole (posaconazole) oral suspension is indicated for:

• Prophylaxis of Aspergillus and Candida infections in patients who are at high risk of developing these infections, such as patients with prolonged neutropenia or hematopoietic stem cell transplant (HSCT) recipients.
• Treatment of invasive aspergillosis in patients with disease that is refractory to amphotericin B or itraconazole, or in patients who are intolerant of these medicinal products. Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy.

Limited data on other fungal infections appears in the Clinical Trials section of the product monograph.

JAMP Posaconazole oral suspension is indicated in patients 13 years of age and older.

JAMP Posaconazole is also indicated for:

• Treatment of oropharyngeal candidiasis (OPC).

1.1 Pediatrics

Pediatrics (13 - 17 years of age): Safety and effectiveness in pediatric subjects below the age of 13 years have not been studied. A limited number of subjects between the ages of 13 and 17 have received posaconazole oral suspension including 11 patients in the refractory invasive fungal infection (rIFI) studies and 12 patients in the prophylaxis studies. The safety profile in these patients < 18 years appears similar to the safety profile observed in adults.

1.2 Geriatrics

Geriatrics (≥ 65 years of age): Limited evidence from clinical studies and experience suggests that use in the geriatric population is associated with no overall differences in safety or effectiveness.

2 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 posaconazole and other azole antifungal agents. Caution should be used when prescribing JAMP Posaconazole to patients with hypersensitivity to other azoles.
• Co-administration of JAMP Posaconazole and ergot alkaloids. Posaconazole may increase the plasma concentrations of ergot alkaloids, which may lead to ergotism (see 9 DRUG INTERACTIONS).
• Co-administration of JAMP Posaconazole and certain medicinal products metabolized through the CYP3A4 system: terfenadine, astemizole, cisapride, 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 9 DRUG INTERACTIONS).
• Co-administration of JAMP Posaconazole and HMG-CoA reductase inhibitors (statins) that are primarily metabolized through CYP3A4, since increased plasma concentration of these drugs can lead to rhabdomyolysis.
• Co-administration of JAMP Posaconazole and sirolimus. Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity.
• 3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• The prescriber should follow the specific dosing instructions for oral suspension.
• The tablet, oral suspension and intravenous solution are not to be used interchangeably due to the differences in the dosing of each formulation.
• Each dose of JAMP Posaconazole oral suspension 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, an 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 JAMP Posaconazole 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 9 DRUG INTERACTIONS).
• Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower posaconazole plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections.
• 4.2 Recommended Dose and Dosage Adjustment

Recommended Dose

Table 1 – Recommended Dosing for JAMP Posaconazole oral suspension

a: Increasing the total daily dose of oral suspension above 800 mg does not further enhance the exposure to JAMP Posaconazole.

Dosage Adjustment

Use in Renal Impairment

The pharmacokinetics of posaconazole oral suspension are not significantly affected by renal impairment. Therefore, no dose adjustment is necessary for oral dosing in patients with mild to severe renal impairment. However, due to the variability in exposure with posaconazole oral therapy, patients with severe renal impairment should be monitored closely for breakthrough fungal infections (see 7 WARNINGS AND PRECAUTIONS and 10 CLINICAL PHARMACOLOGY).

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 10 CLINICAL PHARMACOLOGY). Use with caution in patients with severe hepatic impairment (see 10 CLINICAL PHARMACOLOGY).

Use in Pediatrics (13 - 17 years)

A total of 11 patients 13 - 17 years of age were treated with 800 mg/day posaconazole oral suspension in a study for IFIs. Additionally, 12 patients 13 - 17 years of age received 600 mg/day of posaconazole oral suspension 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 10 CLINICAL PHARMACOLOGY).

• 4.4 Administration

JAMP Posaconazole Oral Suspension

JAMP Posaconazole oral suspension, posaconazole delayed-release tablets and posaconazole intravenous solution are NOT interchangeable due to the differences in the dosing of each formulation. Follow the specific dosage recommendations for each of these formulations.

JAMP Posaconazole Oral Suspension is intended for oral administration only.

Shake JAMP Posaconazole oral suspension well before each use.

4.5 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.

5 OVERDOSAGE

There is no experience with overdosage of posaconazole delayed release tablets.

During clinical trials, patients who received posaconazole oral suspension 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 posaconazole oral suspension for 3 days. No adverse reactions were noted by the investigator.

In a trial of patients with severe hemodialysis-dependent renal dysfunction (Cl_cr < 20 mL/min), posaconazole was not removed by hemodialysis.

Activated charcoal may be used to remove unabsorbed drug.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 2 – Dosage Forms, Strengths, Composition and Packaging

JAMP Posaconazole oral suspension is a white oral suspension with characteristic cherry flavour odour containing 40 mg of posaconazole per mL and the following inactive ingredients: Artificial cherry flavour, citric acid monohydrate, glycerin, liquid glucose, polysorbate 80, purified water, simethicone, sodium benzoate, sodium citrate monohydrate, titanium dioxide and xanthan gum.

105 mL of oral suspension in a 125 mL glass bottle (amber glass type IΙΙ) closed with polypropylene child resistant cap and a measuring spoon (polystyrene) with 2 graduations 2.5 mL and 5 mL.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

JAMP Posaconazole oral suspension is not interchangeable with the delayed release tablets or intravenous solution of posaconazole (see 4 DOSAGE AND ADMINISTRATION).

Hypersensitivity: There is no information regarding cross-sensitivity between posaconazole and other azole antifungal agents. Caution should be used when prescribing JAMP Posaconazole 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 posaconazole on the ability to drive and use machines are available.

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

Posaconazole 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, JAMP Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions such as congenital or acquired QT_c 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 JAMP Posaconazole therapy.

Caution should be exercised if JAMP Posaconazole 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 isoenzyme CYP3A4 may be affected by posaconazole levels, with possible resulting QT effects. Such drugs include tacrolimus, HIV protease inhibitors and macrolide antibiotics (see 2 CONTRAINDICATIONS, 9 DRUG INTERACTIONS and 10 CLINICAL PHARMACOLOGY). During clinical development there was a single case of torsade de pointes in a patient taking posaconazole. This report involved a seriously ill patient with multiple confounding risk factors (see 8 ADVERSE REACTIONS, Less Common Clinical Trial Adverse Drug Reactions (< 2%)).

Dependence/Tolerance

There is no known abuse potential for posaconazole.

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 posaconazole. 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 posaconazole.

Monitoring of hepatic function: Liver function tests should be evaluated at the start of and during the course of JAMP Posaconazole therapy. Patients who develop abnormal liver function tests during JAMP Posaconazole 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 JAMP Posaconazole should be considered if clinical signs and symptoms are consistent with development of worsening liver disease.

Hepatic Impairment: JAMP Posaconazole should be used with caution in patients with severe hepatic impairment. Prolonged elimination half-life may lead to increased exposure.

Immune

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 and tacrolimus should be performed when JAMP Posaconazole therapy is initiated (see 9 DRUG INTERACTIONS ).

Neurologic

Vincristine Toxicity: Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options (see 9 DRUG INTERACTIONS).

Other

Venetoclax Toxicity: Concomitant administration of posaconazole with venetoclax (a CYP3A4 substrate) may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS) and neutropenia (see 9 DRUG INTERACTIONS). Refer to the venetoclax Product Monograph for detailed guidance.

Renal

Renal impairment: Due to the variability in exposure with posaconazole oral therapy, patients with severe renal impairment should be monitored closely for breakthrough fungal infections (see 4 DOSAGE AND ADMINISTRATION and 10 CLINICAL PHARMACOLOGY).

• 7.1 Special Populations

7.1.1 Pregnant Women

There is insufficient information on the use of posaconazole 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 16 NON-CLINICAL TOXICOLOGY). The potential risk to humans is unknown. Women of childbearing potential must always use adequate contraceptive measures while on treatment. JAMP Posaconazole should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

7.1.2 Breast-feeding

Nursing Women: Posaconazole is excreted into the milk of lactating rats (see 16 NON-CLINICAL TOXICOLOGY). The excretion of posaconazole in human breast milk has not been investigated. JAMP Posaconazole should not be used by nursing mothers unless the benefit to the mother clearly outweighs the risk to the infant.

Hepatic Impairment: JAMP Posaconazole 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 and tacrolimus should be performed when JAMP Posaconazole therapy is initiated (see 9 DRUG INTERACTIONS).

Vincristine Toxicity: Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options (see 9 DRUG

INTERACTIONS).

7.1.3 Pediatrics

Safety and efficacy for posaconazole in pediatric patients less than 13 years of age have not been established.

7.1.4 Geriatrics

Evidence from clinical studies and experience suggests that safety and effectiveness of posaconazole are similar in geriatric and adult subjects.

• 8 ADVERSE REACTIONS
• 8.1 Adverse Reaction Overview

The safety of posaconazole oral suspension therapy has been assessed in 1,844 patients and healthy volunteers enrolled in clinical trials and from post-marketing experience. This includes 605 patients in the prophylaxis studies, 796 in OPC/rOPC studies and 428 patients treated for invasive fungal infections (IFIs). Posaconazole therapy was given to 171 patients for ≥ 6 months, with 58 patients receiving posaconazole therapy for ≥ 12 months.

The most frequently reported adverse reactions reported across the whole population of healthy volunteers and patients were nausea (6%) and headache (6%).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Clinical Trial Safety Experience with Posaconazole Oral Suspension Studies P01899 and C/I98-316

Study P01899 was a randomised, evaluator-blinded study that compared posaconazole oral suspension (200 mg three times a day (TID)) with fluconazole suspension (400 mg QD) or itraconazole oral solution (200 mg BID) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS). The mean duration of therapy was comparable between the two treatment groups (29 days, posaconazole; 25 days, fluconazole/itraconazole). In this study, 304 patients were randomly assigned to posaconazole therapy and 240 patients were assigned to fluconazole, and 58 were assigned to itraconazole therapy as the local standard of care.

Study C/I98-316 was a randomised, double-blind trial that compared posaconazole oral suspension (200 mg TID) with fluconazole capsules (400 mg QD) as prophylaxis against IFIs in allogeneic HSCT recipients with GVHD. The mean duration of therapy was comparable between the two treatment groups (80 days, posaconazole; 77 days, fluconazole). In this study, 301 patients were randomly assigned to posaconazole therapy and 299 patients were assigned to fluconazole therapy.

Table 3 - Treatment-related adverse reactions reported in Posaconazole Oral Suspension, fluconazole and itraconazole subjects reported at an incidence of ≥ 1% for the prophylaxis studies C/I98-316 and P01899

The most common treatment-related serious adverse events (1% each) in the combined prophylaxis studies were bilirubinemia, increased hepatic enzymes, hepatocellular damage, nausea, and vomiting.

Studies P01893 and P00041

Study P01893 was an open-label, randomized, parallel group, study of the safety, tolerability, efficacy, and pharmacokinetic profile of posaconazole in the treatment of immunocompromised patients with rIFI or in febrile neutropenic subjects who required empiric antifungal therapy. Posaconazole oral suspension was given as follows: 200 mg administered 4 times daily (QID), 400 mg QID, 800 mg BID for 2 days followed by 400 mg BID, 600 mg BID, or 800 mg administered every day, respectively, for the remainder of the study. For subjects with rIFIs, daily administration of the study drug was continued for a maximum duration of 6 months. For febrile neutropenic subjects, daily administration of the study drug was continued until after completion of the study or until the recovering absolute neutrophil count reached 500 cells/mm3. In this study, 98 patients were randomized and 93 received posaconazole therapy.

Study P00041 was an open-label, non-comparative study of the safety and efficacy of posaconazole as treatment of IFIs in patients who had disease which was refractory to amphotericin B (including liposomal formulations) or itraconazole or in patients who were intolerant of these medicinal products. Patients were administered posaconazole oral suspension 800 mg/day in divided doses. In this study, 330 patients received posaconazole therapy. The median duration of posaconazole therapy was 102.5 days (1 – 609 days). 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.

Studies C/I97-331, C/I97-330 and P00298

Study C/I97-331 was a randomised, evaluator-blinded, controlled study in HIV-infected patients with azole-susceptible OPC. 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 QD for 13 days). In this study, 182 patients received posazonazole therapy and 184 patients received fluconazole therapy.

Study C/I97-330 was an open-label, non-comparative study in 199 HIV-infected patients with azole- refractory OPC treated with one of two posaconazole regimens: 400 mg BID for 3 days, followed by 400 mg QD for 25 days with an option for further treatment during a 3-month maintenance period, or 400 mg BID for 28 days.

Study P00298 was an open-label, non-comparative, long-term safety study in 100 HIV-infected patients with azole-refractory OPC treated with posaconazole 400 mg BID for up to 15 months. A total of 60 of these patients had been previously treated in Study C/I97-330 and 1 patient had been previously treated in Study P00041.

Table 4 - Treatment-related adverse reactions reported in Posaconazole Oral Suspension-treated subjects (divided into subgroups Bone Marrow Transplant [BMT], non-BMT, Non-Refractory OPC & Refractory OPC) by body systems reported at an incidence of ≥ 2% for the rIFI studies (P01893 & P00041) and OPC studies (C/I97-331, C/I97-330 & P00298)

Adverse Reactions

Treatment-related serious adverse events reported in 428 patients with IFIs (1% each) included altered concentration of other medicinal products, increased hepatic enzymes, nausea, rash, and vomiting.

Adverse events were reported more frequently in the pool of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse events (SAEs) were reported in 55% (132/239). The most commonly reported SAEs were fever (13%) and neutropenia (10%).

Treatment-related SAEs were reported for 14% (34/239) of these patients and included neutropenia (5%) and abdominal pain (2%). Posaconazole was discontinued in two patients who developed neutropenia that was considered serious and treatment-related. All other reported treatment-related SAEs occurred in < 1% of subjects on posaconazole.

8.3 Less Common Clinical Trial Adverse Reactions

Less Common Clinical Trial Adverse Drug Reactions (< 2%)

Benign and Malignant Neoplasms: lipoma, Kaposi’s sarcoma.

Blood and Lymphatic System: abnormal blood gases not otherwise specified (NOS), abnormal platelets, anemia aggravated, blood neutrophil count decreased, bone marrow aplasia, coagulation disorder, coagulation time increased, eosinophilia, hematoma, hemoglobin decreased, hemorrhage NOS, leukopenia, lymphadenopathy, neutropenia aggravated, neutrophilia, pancytopenia, platelet count decreased, platelet count increased, prothrombin decreased, prothrombin time prolonged, purpura, splenomegaly, white blood cell count decreased.

In addition, 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 GVHD.

Cardiovascular: abnormal ECG, abnormal ECG specific, aortic valve sclerosis, arrhythmia, atherosclerosis, atrial fibrillation, atrial fibrillation aggravated, atrial flutter, AV block, bradycardia, bundle branch block, cardiac failure, cardiomegaly, cardio-respiratory arrest, cerebrovascular accident NOS, deep venous thrombosis NOS, dependent edema, ejection fraction decreased, extrasystoles, flushing, hot flushes, hypotension, hypotension postural, ischemia, mitral valve disease NOS, myocardial infarction, palpitation, premature atrial contractions, premature ventricular contractions, pulmonary embolism, sinus tachycardia, sudden death, supraventricular tachycardia, tachycardia, vascular disorder, ventricular hypertrophy, ventricular tachycardia.

During clinical development there was a single case of torsade de pointes in a patient taking posaconazole. This report involved a seriously ill patient with multiple confounding, potentially contributory risk factors, such as a history of palpitations, recent cardiotoxic chemotherapy, hypokalemia, and hypomagnesemia.

Ear and Labyrinth: earache, hearing impairment, tinnitus, vertigo, vestibular disorder.

Endocrine: adrenal insufficiency, glucocorticoids decreased, gonadotropins decreased.

Eye: conjunctivitis, diplopia, dry eyes, eye irritation, eye pain, periorbital edema, photophobia, scotoma.

Gastrointestinal: abdominal distention, abdominal pain aggravated, abdominal tenderness, ascites, ascites aggravated, bowel motility decreased, cheilitis, diverticulitis aggravated, dysphagia, eructation, esophagitis, esophagus ulceration, feces malodorous, gastritis, gastroenteritis, gastroesophageal reflux, gastrointestinal tract hemorrhage, hiccup, gingivitis, glossitis, hemorrhagic diarrhea, hemorrhagic gastritis, ileus, loose stools, melena, mouth ulceration, odynophagia, pancreatic enzymes NOS increased, pancreatitis, proctalgia, retching, saliva altered, stomatitis, tenesmus, thirst, tongue discoloration, tongue disorder, tooth discoloration, vomiting aggravated.

General and Administration Site Conditions: appetite increased, death, drug interaction, edema, fall, fatigue aggravated, fistula, generalized edema, influenza-like symptoms, laboratory test abnormality, legs edema, malaise, pain, pallor, peripheral edema, rigors.

Hepatobiliary: asterixis, biliary sludge, bilirubinemia aggravated, cholestasis, hepatic failure, hepatitis, hepatitis aggravated, hepatitis cholestatic, hepatocellular damage, hepatomegaly, hepatosplenomegaly, jaundice, liver tenderness.

Immune System: allergic reaction, allergy, GVHD aggravated, hypersensitivity reaction, non-specific inflammation, sarcoidosis aggravated, Stevens Johnson syndrome.

Infections and Infestations: catheter related infection, non-herpetic cold sores, esophageal candidiasis, fungal infection, moniliasis, oral candidiasis, pneumonia, pseudomonas aeruginosa infection, sinusitis, upper respiratory tract infection, urinary tract infection.

Injury and Poisoning: drug toxicity NOS, ecchymoses, overdose NOS, skin trauma.

Metabolism and Nutrition: amylase increased, dehydration, electrolyte abnormality, hypercalcemia, hypercholesterolemia, hypercholesterolemia aggravated, hyperlipemia, hypernatremia, hyperphosphatemia, hyperproteinemia, hypertriglyceridemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hyponatremia, hypophosphatemia, lipase increased, malnutrition, metabolic acidosis, metabolic disorder NOS, NPN increased, renal tubular acidosis, vitamin K deficiency.

Musculoskeletal and Connective Tissue: arthralgia, arthralgia aggravated, back pain, bone pain, chest wall pain, extremities cramps, fasciitis, flank pain, legs cramps, muscle cramps, muscle weakness, musculoskeletal pain, neck stiffness.

Nervous System: abnormal EEG, areflexia, ataxia, central nervous system (CNS) dysfunction, delirium, dysphonia, dystonia, encephalopathy, gait abnormal aggravated, headache aggravated, hemiparesis, hyperkinesia, hyperreflexia, hypoesthesia, hyporeflexia, hypotonia, impaired cognition, impaired concentration, memory impairment, meningism, meningitis, migraine, mononeuritis, neuritis, neuropathy, paraplegia, peripheral neuropathy, restless leg syndrome, sciatica, speech disorder, stupor, twitching.

Psychiatric: abnormal dreaming, altered mental status, amnesia, anxiety, anxiety aggravated, confusion, depression, depression psychotic, emotional lability, libido decreased, nightmare, psychosis, sleep disorder.

Renal and Urinary System: abnormal urine, albuminuria, BUN increased, dysuria, hematuria, micturition disorder, micturition frequency, nephritis interstitial, nocturia, renal calculus, renal failure, renal failure acute, renal insufficiency aggravated, urinary tract obstruction NOS.

Reproductive System and Breast: balanoposthitis, breast pain.

Respiratory, Thoracic and Mediastinal: atelectasis, chest pain, nonproductive cough, dry throat, dyspnea, dyspnea aggravated, epistaxis, epistaxis aggravated, interstitial pneumonia, nasal congestion, nasal irritation, pharyngitis, pneumonitis, postnasal drip, pulmonary hypertension, pulmonary infiltration, rales, respiratory disorder, rhinitis, rhinorrhea.

Surgical and Medical Procedures: cardioversion.

Skin and Subcutaneous Tissue: acne, alopecia, dermatitis, dry skin, erythema, erythematous rash, face edema, fissures, follicular rash, furunculosis, macular rash, maculopapular rash, night sweats, pruritic rash, rash aggravated, seborrhea, skin disorder, skin nodule, urticaria, vesicular rash.

• 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings Clinical Chemistry Findings

In (uncontrolled) trials of patients with IFIs treated with posaconazole oral suspension doses

≥ 800 mg/day, the incidence of clinically significant liver function test abnormalities was: ALT and AST (> 3 X Upper Limit Normal [ULN]) 6% and 5%, respectively; total bilirubin (> 1.5 X ULN) 4%; and alkaline phosphatase (> 3 X ULN) 4%. In healthy volunteers, elevation of hepatic enzymes did not appear to be associated with higher plasma concentrations of posaconazole. In patients, the majority of abnormal liver function tests results showed minor and transient changes and rarely led to discontinuation of therapy. In the comparative trials of patients infected with HIV and OPC treated with posaconazole oral suspension at doses up to 400 mg, the incidence of clinically significant liver function test abnormalities was as follows; ALT and AST (> 3 X ULN), 1% and 3%, respectively: total bilirubin (> 1.5 X ULN), < 1%; and alkaline phosphatase (> 3 X ULN), 1%.

In the comparative trials of hematopoietic stem cell recipients or patients with AML receiving posaconazole oral suspension as prophylaxis at doses up to 600 mg, the incidence of clinically significant liver function test abnormalities was as follows; ALT and AST (> 3 X ULN), 12% and 4%, respectively: total bilirubin (> 1.5 X ULN), 8%; and alkaline phosphatase (> 3 X ULN), 2%.

8.5 Post-Market Adverse Reactions

The following adverse events have been reported during the post-approval use of posaconazole in the US and Europe. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency. A causal relationship to posaconazole could not be excluded for these adverse events, which included:

• Blood and lymphatic system: agranulocytosis;
• Hepatobiliary: cytolytic hepatitis, toxic hepatitis (including fatality);
• Endocrine Disorders: pseudoaldosteronism;
• Cardiovascular: QT prolongation, torsades de pointes;
• Infections and infestations: Trichosporon sepsis.

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

The interactions described in the following subsections apply to posaconazole delayed-release tablets and posaconazole oral suspension unless otherwise specified.

The following information was derived from data with posaconazole oral suspension or early tablet formulation.

• 9.2 Drug Interactions Overview

Effects of Other Drugs on posaconazole Pharmacokinetics

Posaconazole is metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate from p- glycoprotein efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. 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.

Effects of Posaconazole on Pharmacokinetics of Other Drugs

Posaconazole is a strong inhibitor of CYP3A4 and thus the plasma levels of medicinal products that are metabolized through this enzyme pathway may increase when administered with posaconazole oral suspension.

9.3 Drug-Behavioural Interactions

Not applicable.

9.4 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 posaconazole oral suspension or early tablet formulation, which is 36% less bioavailable than the oral suspension. Although in some drug interaction studies posaconazole exposure levels were lower than observed in the patient population, the drug interactions described below are considered relevant for posaconazole oral suspension at the recommended doses.

Table 5 – Summary of the Effect of Co-administered Drugs on Posaconazole in Healthy Volunteers

H₂ receptor antagonists, proton pump inhibitors (PPIs) and antacids

Gastrointestinal Motility Agents

Table 6 - Summary of the Effect of Posaconazole on Co-administered Drugs in Healthy Volunteers and Patients

a: Ratio Estimate = ratio of co-administered drug plus posaconazole to posaconazole alone for C_max or AUC b: AUC = area under the plasma concentration time curve

c: QD = once daily d: BID = twice a day e: IV = intravenous f: PO = per os

• 9.5 Drug-Food Interactions

Table 7 – Established or Potential Drug-Food Interactions

9.6 Drug-Herb Interactions

Interactions with herbal products have not been studied.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been studied.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Posaconazole is an azole antifungal agent. Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane.

10.2 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 4 DOSAGE AND ADMINISTRATION and 10 CLINICAL PHARMACOLOGY, Pharmacokinetics).

Exposure Response Relationship:

In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS or HSCT recipients with GVHD, a wide range of plasma exposures to posaconazole was noted following administration of posaconazole oral suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (C_avg) and efficacy outcomes (Table 8). A lower C_avg may be associated with an increased risk of treatment failure.

Table 8 – Posaconazole Oral Suspensions Exposure Analysis (C_avg) in Clinical Trials

C_avg = the average posaconazole concentration when measured at steady state

a: Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS b: HSCT recipients with GVHD

c: Defined as failure to achieve global response at the end of therapy

d: Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections

• 10.3 Pharmacokinetics

General Pharmacokinetic Characteristics:

Dose-proportional increases in plasma exposure (AUC) to posaconazole oral suspension 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 in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg BID to 600 mg BID in febrile neutropenic patients or those with refractory invasive fungal infections.

The mean (%CV) [min-max] posaconazole oral suspension average steady-state plasma concentrations (C_avg) 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.

Table 9: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Posaconazole Oral Suspension 200 mg TID and 400 mg BID

C_avg = the average posaconazole concentration when measured at steady state

^* Oral suspension administration

^† AUC_{(0-24 hr)} for 200 mg TID and AUC_{(0-12 hr)} for 400 mg BID

^‡ HSCT recipients with GVHD

^§ Not done

^¶ Neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes

^# Febrile neutropenic patients or patients with refractory invasive fungal infections, C_avg n=24

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

Absorption:

Posaconazole oral suspension is absorbed with a median t_max of ~ 3 to 5 hours. Dose proportional increases in plasma exposure (AUC) to posaconazole oral suspension 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 C_max of posaconazole oral suspension are approximately 3 times higher when administered with a non-fat 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 C_max of posaconazole oral suspension are approximately 3 times higher when administered with a liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 10). In order to assure attainment of adequate plasma concentrations, it is recommended to administer posaconazole oral suspension with food or a nutritional supplement (see 4 DOSAGE AND ADMINISTRATION).

Table 10 - The Mean (%CV) [min-max] Posaconazole Oral Suspension Pharmacokinetic Parameters Following Single-Dose Suspension Administration of 200 mg and 400 mg Under Fed and Fasted Conditions

a: Median [min-max]

b: The subject with t_max 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 t_½ d: n=10 for AUC(I), CL/F and t_½

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

Distribution:

Posaconazole has a mean (CV%) volume of distribution of 287 L (24%) in healthy volunteers. Posaconazole is highly bound to human proteins (> 98%), predominantly to 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. The excreted metabolites in urine and feces account for ~ 17% of the administered radiolabeled dose.

Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p- glycoprotein (P-gp) efflux. Inhibitors of inducers of these clearance pathways may affect posaconazole plasma concentrations.

In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole.

Elimination:

Posaconazole oral suspension is predominantly eliminated in the feces (77% of the 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).

Posaconazole oral suspension is eliminated with a mean half-life (t½) of 35 hours (range 20 to 66 hours) and apparent total body clearance (CL/F) of 32 L/hr.

Special Populations and Conditions

• Pediatrics:

  Following administration of 800 mg per day of posaconazole oral suspension as a divided dose for treatment of IFIs, 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 posaconazole oral suspension are comparable in young and elderly subjects (≥ 65 years of age). No adjustment in the dosage of JAMP Posaconazole is necessary in elderly patients (≥ 65 years of age) based on age.
• Sex: The pharmacokinetics of posaconazole oral suspension are comparable in men and women. No adjustment in the dosage of JAMP Posaconazole is necessary based on gender.

• Ethnic Origin: The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of posaconazole oral suspension is necessary based on race.

  The AUC and C_max of posaconazole oral suspension 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 JAMP Posaconazole oral suspension be used with caution in patients with hepatic impairment (see 7 WARNINGS and PRECAUTIONS and 4 DOSAGE AND ADMINISTRATION).
• Renal Insufficiency: Following single-dose administration of 400 mg of the oral suspension, there was no significant effect of mild (GFR: 50-80 mL/min/1.73m², n=6) and moderate (GFR: 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 (GFR: < 20 mL/min/1.73m²), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (GFR: > 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 with posaconazole oral therapy, patients with severe renal impairment should be monitored closely for breakthrough fungal infections (see 7 WARNINGS and PRECAUTIONS and 4 DOSAGE AND ADMINISTRATION).
• Obesity: Pharmacokinetic modeling for posaconazole suggests that patients weighing greater than 120 kg may have lower posaconazole exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections in patients weighing more than 120 kg.

11 STORAGE, STABILITY AND DISPOSAL

Storage

Store at room temperature 15-30°C. Do not freeze. Do not use past expiry date on the label.

Shelf life

After first opening the container: 4 weeks.

12 SPECIAL HANDLING INSTRUCTIONS

The oral suspension must be shaken well before each use.

PART II: SCIENTIFIC INFORMATION

13 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 g/mol

Structural formula:

Physicochemical properties: Posaconazole is a white to off white color solid powder which is soluble in dichloromethane and practically insoluble in water.

Product Characteristics:

pH and pKa values:

pH (1% w/v aqueous suspension at about 25°C): Average 6.03

Dissociation Constant (by HPLC): 3.10 (Acetonitrile : water )

Melting range: 165.1°C - 165.9°C

14 CLINICAL TRIALS

Pharmacokinetics and Safety of Posaconazole Oral Suspension in Patients Study P01899 and Study C/I98-316

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

Study demographics and trial design

Table 11 - Summary of Patient Demographics and Trial Design for Pivotal Study P01899

a: TID = three times a day b: QD = once daily

c: BID = twice a day

FLU: fluconazole, ITZ: itraconazole

Study P01899 was a randomised, evaluator-blinded study that compared posaconazole oral suspension (200 mg TID) with fluconazole suspension (400 mg QD) or itraconazole oral solution (200 mg BID) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS. 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).

Table 12 - Summary of Patient Demographics and Trial Design for Pivotal Study C/I98-316

a: TID = three times a day b: QD = once daily

Study C/I98-316 was a randomised, double-blind trial that compared posaconazole oral suspension (200 mg TID) with fluconazole capsules (400 mg QD) 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 13 and 14 for results from both studies.

Table 13 - Results from Clinical Study C/I98-316 in Prophylaxis of IFIs

Table 14 - Results from Clinical Study P01899 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

Table 15 – Summary of Patient Demographics and Trial Design for Pivotal Study P00041

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 oral suspension 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 16, 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 16 - 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 oral suspension 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 oral suspension 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

Table 17 - Summary of Patient Demographics and Trial Design for Pivotal Study C/I97-331

a: BID = twice a day b: QD = once daily

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 QD 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 18 below. Posaconazole and fluconazole demonstrated equivalent clinical success rates at Day 14 as well as

4 weeks after the end of treatment. However, posaconazole oral suspension demonstrated a significantly better sustained mycological response rate 4 weeks after the end of treatment than fluconazole.

Table 18 - Clinical Success Rates and Mycological Response Rates in OPC

*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

Table 19 - Summary of Patient Demographics and Trial Design for Pivotal Study C/I97-330

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 oral suspension 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.

• 14.3 Comparative Bioavailability Studies

A double-blind, single-dose, crossover oral bioequivalence study of ^PrJAMP Posaconazole (posaconazole) Oral Suspension 40 mg/mL (JAMP Pharma Corporation, Canada) and ^PrPosanol® Posaconazole Oral Suspension 40 mg/mL (Merck Canada Inc.), following a single oral dose of 400 mg (10 mL of 40 mg/mL) was conducted in 24 healthy adult Asian subjects under fed conditions. A summary of the comparative bioavailability data from the 24 subjects who completed the study is presented in following table.

Table 20 - Summary of The Comparative Bioavailability Data

¹ Due to the long elimination half-life of posaconazole, AUC_I and T_1/2 could not be accurately estimated from the data obtained in this study.

² JAMP Posaconazole (posaconazole) Oral Suspension, 40 mg/mL, JAMP Pharma Corporation, Canada

^{3 Pr}Posanol^® (posaconazole) Oral Suspension, 40 mg/mL, Merck Canada Inc.

⁴ Expressed as the median (range) only

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 oral suspension 400 mg BID with a high-fat meal. In this pooled analysis, the mean QT_c (Fridericia (F)) interval change was -5 msec following administration of the recommended clinical dose. A decrease in the QT_c (F) interval (- 3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QT_c (F) interval change from baseline was < 0 msec

(- 8 msec). No subject administered posaconazole had a QT_c (F) interval of ≥ 500 msec or an increase

≥ 60 msec in their QT_c (F) interval from baseline.

Pharmacokinetics (see ACTION AND CLINICAL PHARMACOLOGY)

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.

The exposure to posaconazole following administration of 400 mg oral suspension BID was ~ 3 times higher in healthy volunteers than in patients, without additional safety findings at the higher concentrations.

Special Populations and Conditions

Pediatrics

Following administration of 800 mg per day of posaconazole oral suspension 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 C_avg was comparable among 10 adolescents (13 - 17 years of age) to C_avg achieved in adults (≥ 18 years of age).

Geriatrics

An increase in C_max (26%) and AUC (29%) was observed in elderly subjects (24 subjects ≥ 65 years of age) receiving the posaconazole oral suspension 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 oral suspension. Further, in clinical efficacy trials, the safety profile of posaconazole oral suspension 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

There is insufficient data among different races with posaconazole delayed-release tablets.

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

Weight

Pharmacokinetic modeling for posaconazole suggests that patients weighing greater than 120 kg may have lower posaconazole exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections in patients weighing more than 120 kg.

Hepatic Insufficiency

In a small number of subjects (n=12) studied with hepatic insufficiency (Child-Pugh class A, B or C), C_max 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 C_max 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, GFR ≥ 20 mL/min/1.73 m²) on posaconazole pharmacokinetics, therefore, no dose adjustment is required. In subjects with severe renal insufficiency (n=6, GFR < 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. Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections.

Animal Pharmacology

Posaconazole Oral Therapy 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 IV 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 α-subunit (hERG) of the cardiac delayed rectifier, I_Kr, a measured concentration of

770 ng/mL (1.1 mcM) posaconazole decreased hERG current by 7%. Accounting for protein binding, the drug concentration in the hERG assay was 18-times the free posaconazole C_max 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 IV formulation of posaconazole. No posaconazole–related effects on heart rate, arterial blood pressure, ECG intervals (RR, PR, QRS, QT, QT_c), 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 mcg⋅hr/mL, which is 2.4-fold a human AUC exposure of 59 mcg⋅hr/mL. The absence of QT or QT_c interval changes at 40 mg/kg posaconazole intravenously in conscious monkeys indicates a low potential for posaconazole to produce QT or QT_c interval prolongation.

15 MICROBIOLOGY

Posaconazole is a potent inhibitor of the enzyme lanosterol 14α-demethylase, which catalyses an essential step in ergosterol biosynthesis. Consequently, posaconazole 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 posaconazole 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 posaconazole 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.

Posaconazole has been shown in vitro and in clinical infections to be active against the following microorganisms (see 1 INDICATIONS): 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 15 and 16). 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 21.

Table 21 - MIC₉₀ Values for Mould Strains Tested

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 22.

Table 22 - MIC₉₀ Values for Yeast Strains Tested

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.

16 NON-CLINICAL TOXICOLOGY

General 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.

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.

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.

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.

Reproductive and Developmental Toxicology: 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.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. ^PrPOSANOL®, ((posaconazole), Solution for Injection 300 mg/vial (18 mg/mL), Delayed-Release Tablets 100 mg, Oral Suspension 40 mg/mL), Submission Control 254862, Product Monograph, Merck Canada Inc., (JAN 04, 2022)