Posaconazole

Posaconazole is an azole antifungal indicated as follows: • Posaconazole injection is indicated for the treatment of invasive aspergillosis in adults and pediatric patients 2 years of age and older who weigh 10 kg or greater. • Posaconazole injection is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy as follows: o Posaconazole injection : adults and pediatric patients 2 years of age and older who weigh 10 kg or greater.

1.1Treatment of Invasive Aspergillosis Posaconazole

injection is indicated for the treatment of invasive aspergillosis in adults and pediatric patients 2 years of age and older who weigh 10 kg or greater.

1.2Prophylaxis of Invasive Aspergillus and Candida Infections

Posaconazole injection is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy as follows: Posaconazole injection: adults and pediatric patients 2 years of age and older who weigh 10 kg or greater.

2 DOSAGE AND ADMINISTRATION • Posaconazole injection must be administered through an in-line filter. • Administer posaconazole injection by intravenous infusion over approximately 90 minutes via a central venous line. ( 2.1 , 2.6 ) • Do NOT administer posaconazole injection as an intravenous bolus injection. • See the full prescribing information for important administration instructions and preparation instructions for posaconazole injection. ( 2.5 , 2.6 ) • For adult and pediatric patients aged 2 years of age and older, see the Full Prescribing Information for dosing recommendations for posaconazole injection based on the indication, age, and weight associated with the dosage form. ( 1.1 , 1.2 , 2.1 , 2.2 , 2.3 )

2.1Important Administration Instructions Posaconazole

injection Administer via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes . Do NOT administer posaconazole injection as an intravenous bolus injection.

2.2Recommended Dosage of Posaconazole Injection in Adult

Patients The recommended dosage of posaconazole injection in adult patients for the treatment of invasive aspergillosis, prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised is shown in Table 1 . Table 1: Recommended Dosage of Posaconazole Injection in Adult Patients Dosage Duration of Therapy Treatment of Invasive Aspergillosis* Posaconazole Injection: Loading dose: 300 mg posaconazole injection intravenously twice a day on the first day. Maintenance dose: 300 mg posaconazole injection intravenously once a day, starting on the second day. Loading dose: 1 day Maintenance dose: Recommended total duration of therapy is 6 to 12 weeks.

Prophylaxis of Invasive Aspergillus and Candida Infections Posaconazole Injection: Loading dose: 300 mg posaconazole injection intravenously twice a day on the first day. Maintenance dose: 300 mg posaconazole injection intravenously once a day thereafter. Loading dose: 1 day Maintenance dose: Duration of therapy is based on recovery from neutropenia or immunosuppression. * Switching between the posaconazole injection and delayed-release tablets is acceptable.

A loading dose is not required when switching between dosage forms.

2.3Recommended Dosage of Posaconazole Injection for the Treatment

of Invasive Aspergillosis and Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients 2 Years of Age and Older The recommended dosage of posaconazole injection in pediatric patients 2 years of age and older who weigh 10 kg or greater for the treatment of invasive aspergillosis and prophylaxis of invasive Aspergillus and Candida infections is shown in Table 2 . Table 2: Recommended Dosage of Posaconazole Injection for the Treatment of Invasive Aspergillosis* and Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients (2 Years of Age and Older) Recommended Pediatric Dosage Duration of Therapy Posaconazole Injection (patients weighing 10 kg or greater): Loading dose: 6 mg/kg up to a maximum of 300 mg twice daily on the first day Maintenance dose: 6 mg/kg up to a maximum of 300 mg once daily, starting on the second day. Treatment of invasive aspergillosis: Recommended total duration of therapy is 6 to 12 weeks. Prophylaxis of invasive Aspergillus and Candida infections: Duration of therapy is based on recovery from neutropenia or immunosuppression. * Switching between the intravenous and delayed-release tablets is acceptable.

A loading dose is not required when switching between formulations.

2.5Preparation of Posaconazole Injection Preparation of Posaconazole

Injection: • Remove the vial of posaconazole injection from the refrigerator and allow to equilibrate to room temperature prior to use. • To prepare the required dose, aseptically transfer one vial of posaconazole injection (containing 300 mg of posaconazole in 16.7 mL of solution) to an intravenous bag or bottle of one of the following compatible diluents to achieve a final posaconazole concentration between 1 mg/mL and 2 mg/mL: o 0.45% Sodium Chloride Injection o 0.9% Sodium Chloride Injection o 5% Dextrose Injection o 5% Dextrose and 0.45% Sodium Chloride Injection o 5% Dextrose and 0.9% Sodium Chloride Injection o 5% Dextrose and 20 mEq Potassium Chloride Injection Use of other diluents is not recommended because they may result in particulate formation. • Discard any unused posaconazole injection from the vial. • Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Once admixed, the diluted posaconazole infusion solution ranges from colorless to yellow (variations of color within this range do not affect the quality of the product). • Immediately use the diluted posaconazole infusion solution, once admixed. If not used immediately, refrigerate (2 to 8°C (36 to 46°F)) the diluted posaconazole infusion solution up to 24 hours.

Discard any unused portion. Incompatible Diluents Co-administration of drug products besides the infusion solutions or products stated above are not recommended because this may result in particulate formation. The following diluents were determined to be incompatible with posaconazole injection; thus, do not dilute posaconazole injection with them: • Lactated Ringer’s Injection • Lactated Ringer’s and 5% Dextrose Injection • 4.2% Sodium Bicarbonate Injection

2.6Administration of Diluted Posaconazole Infusion Solution

See Dosage and Administration for the preparation instructions for the diluted Posaconazole Solution. Important Administration Instructions for the Diluted Posaconazole Infusion Solution • Must administer diluted posaconazole infusion solution through a 0.22-micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter. • Administer diluted posaconazole infusion solution via a central venous line, including a central venous catheter (CVC) or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes • If a CVC or PICC are not available, may administer diluted posaconazole solution once through a peripheral venous catheter by intravenous infusion over approximately 30 minutes to bridge the period during which a CVC or PICC are replaced, inserted, or unavailable for use (e.g., the CVC is being used for intravenous treatment with another product). However, do not administer diluted posaconazole infusion solution more than once via peripheral venous catheter because in clinical trials, multiple peripheral infusions given through the same vein resulted in infusion site reactions . • When multiple dosing is required, the infusion should be done via a central venous line.

Additional Administration Instructions for the Diluted Posaconazole Infusion Solution • Administer diluted posaconazole infusion solution intravenously through the same intravenous line (or cannula) with the following compatible infusion solutions: o 0.45% Sodium Chloride Injection o 0.9% Sodium Chloride Injection o 5% Dextrose Injection o 5% Dextrose and 0.45% Sodium Chloride Injection o 5% Dextrose and 0.9% Sodium Chloride Injection o 5% Dextrose and 20 mEq potassium chloride Injection • Administer diluted posaconazole infusion solution intravenously at the same time through the same intravenous line (or cannula) with the following intravenous drug products prepared in 5% Dextrose Injection or 0.9% Sodium Chloride Injection: o Amikacin Sulfate Injection o Caspofungin Acetate for Injection o Ciprofloxacin Injection o Daptomycin for Injection o Dobutamine Injection o Famotidine Injection o Filgrastim Injection o Gentamicin Injection o Hydromorphone Hydrochloride Injection o Levofloxacin Injection o Lorazepam Injection o Meropenem for Injection o Micafungin for Injection o Morphine Sulfate Injection o Norepinephrine Bitartrate Injection o Potassium Chloride Injection o Vancomycin Hydrochloride for Injection

2.11Dosage Modifications in Patients with Renal Impairment

Avoid the use of posaconazole injection in patients with eGFR less than 50 mL/minute/1.73 m 2 , unless an assessment of the benefit/risk to the patient justifies its use. If the decision is made to use posaconazole injection in patients with eGFR less than 50 mL/minute/1.73 m 2 , closely monitor serum creatinine levels, and, if increases occur, consider changing to oral posaconazole therapy. The recommended dosage of posaconazole injection in patients with eGFR 50 to 90 mL/minute/1.73 m 2 is the same as those with normal renal function.

5 WARNINGS AND PRECAUTIONS • Calcineurin-Inhibitor Toxicity : Posaconazole increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. • Arrhythmias and QTc Prolongation : Posaconazole has been shown to prolong the QTc interval and cause cases of TdP. Administer with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs known to prolong QTc interval and metabolized through CYP3A4. ( 5.2 , 7.2 ) • Electrolyte Disturbances : Monitor and correct, especially those involving potassium (K + ), magnesium (Mg ++ ), and calcium (Ca ++ ), before and during posaconazole therapy. • Pseudoaldosteronism : Manifested by the onset or worsening of hypertension, and abnormal laboratory findings. Monitor blood pressure and potassium levels, and manage as necessary. • Hepatic Toxicity : Elevations in liver tests may occur. Discontinuation should be considered in patients who develop abnormal liver tests or monitor liver tests during treatment. • Renal Impairment : Posaconazole injection should be avoided in patients with moderate or severe renal impairment (eGFR less than 50 mL/min/1.73 m 2 ), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole injection. ( 5.6 , 8.6 ) • Concomitant Use with Midazolam : Posaconazole can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available. ( 5.7 , 7.2 ) • Vincristine Toxicity : Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions; reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. ( 5.8 , 7.2 ) • Venetoclax Toxicity : Concomitant administration of posaconazole with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome, neutropenia, and serious infections; monitor for toxicity and reduce venetoclax dose. ( 4.6 , 5.11 , 7.2 )

5.1Calcineurin-Inhibitor Toxicity Concomitant

administration of posaconazole with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors . Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.

5.2Arrhythmias and

QT Prolongation Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole. Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval.

Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18 to 85 years of age) administered Noxafil ® (posaconazole) oral suspension 400 mg twice daily with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline 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 healthy subject administered posaconazole had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline. Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions.

Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 .

5.3Electrolyte Disturbances Electrolyte

disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.

5.4Pseudoaldosteronism Pseudoaldosteronism,

manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevated 11-deoxycortisol), has been reported with posaconazole use in the postmarket setting. Monitor blood pressure and potassium levels and manage as necessary. Management of pseudoaldosteronism may include discontinuation of posaconazole, substitution with an appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone receptor antagonists.

5.5Hepatic Toxicity Hepatic

reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole.

These severe hepatic reactions were seen primarily in subjects receiving the Noxafil ® (posaconazole) oral suspension 800 mg daily (400 mg twice daily or 200 mg four times a day) in clinical trials. Liver tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver tests during posaconazole therapy should be monitored for the development of more severe hepatic injury.

Patient management should include laboratory evaluation of hepatic function (particularly liver tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.

5.6Renal Impairment Posaconazole

injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m 2 ), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m 2 ), receiving the posaconazole injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral posaconazole therapy .

5.7Midazolam Toxicity Concomitant

administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects .

5.8Vincristine 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 .

5.11Venetoclax Toxicity Concomitant

administration of posaconazole, a strong CYP3A4 inhibitor, with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS), neutropenia, and serious infections. In patients with CLL/SLL, administration of posaconazole during initiation and the ramp-up phase of venetoclax is contraindicated . Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering posaconazole with venetoclax . Refer to the venetoclax prescribing information for dosing instructions.

4 CONTRAINDICATIONS • Known hypersensitivity to posaconazole or other azole antifungal agents. • Coadministration of posaconazole with the following drugs is contraindicated; posaconazole increases concentrations and toxicities of: • Sirolimus ( 4.2 , 7.2 ) • CYP3A4 substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of torsades de pointes (TdP) ( 4.3 , 5.2 , 7.2 ) • HMG-CoA Reductase Inhibitors Primarily Metabolized through CYP3A4 ( 4.4 , 7.2 ) • Ergot alkaloids ( 4.5 , 7.2 ) • Venetoclax: In patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp-up phase ( 4.6 , 5.11 , 7.2 )

4.1Hypersensitivity Posaconazole

is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.

4.2Use with Sirolimus Posaconazole

is contraindicated with sirolimus. Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity .

4.3QT Prolongation with Concomitant Use with CYP3A4

Substrates Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes .

4.4HMG-CoA Reductase Inhibitors Primarily Metabolized

Through CYP3A4 Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis .

4.5Use with Ergot Alkaloids Posaconazole

may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism .

4.6Use with Venetoclax Coadministration of

posaconazole with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome .

8.1Pregnancy Risk Summary Based on

findings from animal data, posaconazole may cause fetal harm when administered to pregnant women. Available data for use of posaconazole in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, skeletal malformations were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses ≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of posaconazole in healthy volunteers.

In pregnant rabbits dosed orally during organogenesis, doses of ≥ 3 times the clinical exposure caused an increase in resorptions . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data: Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen.

No malformations were seen in rabbits dosed during organogenesis (Gestational Days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen.

8.6Renal Impairment Posaconazole Injection Avoid

use of posaconazole injection in patients with eGFR less than 50 mL/minute/1.73 m 2 unless the benefit/risk to the patient justifies its use. The inactive ingredient in posaconazole injection, Betadex Sulfobutyl Ether Sodium (SBECD) is expected to accumulate in patients with reduced renal function. Safety and effectiveness of posaconazole injection have not been established in patients with less than 50 mL/minute/1.73 m 2 . If treatment with posaconazole injection is unavoidable in patients with eGFR less than 50 mL/minute/1.73 m 2 , monitor serum creatinine levels.

If serum creatinine increases, consider changing to oral posaconazole therapy.

The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling: • Arrhythmias and QT Prolongation • Electrolyte Disturbances • Pseudoaldosteronism • Hepatic Toxicity • Adult Patients : Common adverse reactions in studies with posaconazole in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. • Pediatric Patients : Common adverse reactions (incidence >20% receiving 6 mg/kg posaconazole injection) in a study in pediatric patients are pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis. To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at 866-770-7144 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment of Invasive Aspergillosis in Adults and Adolescents (Posaconazole Injection and Noxafil ® (posaconazole) Delayed-Release Tablets) The safety of posaconazole injection and Noxafil ® (posaconazole) delayed-release tablets was assessed in a randomized, double-blind, active-controlled clinical study of posaconazole injection and Noxafil ® (posaconazole) delayed-release tablets versus voriconazole for treatment of invasive aspergillosis (Aspergillosis Treatment Study). A total of 575 adult and pediatric patients 14 years of age and older (288 in the posaconazole group, 287 in voriconazole group (voriconazole for injection or voriconazole tablets)) with proven, probable or possible invasive aspergillosis were included.

The median duration of treatment was 67 days for posaconazole injection or Noxafil ® (posaconazole) delayed-release tablets and 64 days for voriconazole. In this study, 55% to 60% of patients started intravenous treatment with posaconazole injection or voriconazole (voriconazole for injection). The median duration of the first instance of intravenous treatment (before switching to oral treatment or discontinuing or completing study treatment) was 9 days for both groups.

Table 7 presents adverse reactions reported at an incidence of ≥10% in either one of the treatment groups in the Aspergillosis Treatment Study. Adverse reactions leading to treatment discontinuation were reported for 34% of patients. The most commonly reported adverse reactions (>2% of patients) leading to treatment discontinuation were septic shock, respiratory failure, and bronchopulmonary aspergillosis in the posaconazole group, and septic shock and acute myeloid leukemia in the voriconazole group.

The most frequently reported adverse reactions in the posaconazole-treated group were pyrexia (28%), hypokalemia (28%), and nausea (23%). Table 7: Adverse Reactions in at least 10% of Adults and Adolescents Receiving Posaconazole Injection or Noxafil ® (posaconazole) Delayed-Release Tablets for the Treatment of Invasive Aspergillosis Adverse Reactions Posaconazole injection or Noxafil ® (posaconazole) delayed-release tablets n = 288 (%) Voriconazole for injection or Voriconazole tablets n = 287 (%) Percentage of Patients Reporting any Adverse Reaction 97.6

97.6Hypokalemia

28.5

17.1Pyrexia

28.1

25.1Nausea

22.6

17.8Diarrhea

18.1

18.1Vomiting

18.1

13.6Alanine

aminotransferase increased 14.6

12.9Febrile

neutropenia 14.6

13.2Aspartate

aminotransferase increased 13.2

12.5Pneumonia

12.5

9.1Headache

12.2

8.7Constipation

11.1

8.0Edema

peripheral 11.1

8.4Epistaxis

11.1

5.9Cough

10.4

8.4Abdominal

pain 10.1

8.4Hypomagnesemia

10.1

6.3Clinical Trial Experience with Posaconazole Injection

for Prophylaxis of Invasive Aspergillus and Candida Infections Administration of multiple doses of posaconazole injection via a peripheral venous catheter were associated with thrombophlebitis (60% incidence). Therefore, in subsequent studies, posaconazole injection was administered via central venous catheter . The safety of posaconazole injection has been assessed in 268 patients in a clinical trial. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole injection when given as antifungal prophylaxis (Posaconazole Injection Study).

Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 55% male, had a mean age of 51 years (range 18 to 82 years, 19% of patients were ≥65 years of age), and were 95% White and 8% Hispanic. In this study, 10 patients received a single dose of 200 mg posaconazole injection, 21 patients received 200 mg daily dosage for a median of 14 days, and 237 patients received 300 mg daily dosage for a median of 9 days (the 200 mg dosage is not a recommended dosage for prophylaxis of invasive Aspergillus and Candida infections in adults . In the 300 mg daily dosage group each patient received a loading intravenous dose of posaconazole injection 300 mg twice on Day 1, then intravenous posaconazole injection therapy, and finally Noxafil ® (posaconazole) oral suspension to complete 28 days of total posaconazole therapy. Table 8 presents adverse reactions observed in patients treated with the posaconazole injection 300 mg daily dosage group in the Posaconazole Injection Study.

The most frequently reported adverse reactions with an onset during the intravenous posaconazole injection phase of dosing with 300 mg once daily were diarrhea (32%), hypokalemia (22%), pyrexia (21%), and nausea (19%). These adverse reactions were consistent with those seen in studies with Noxafil ® (posaconazole) oral suspension. Table 8: Adverse Reactions in at least 10% of Adults Receiving Posaconazole Injection for the Prophylaxis of Invasive Aspergillus and Candida infections Adverse Reactions Posaconazole Injection Treatment Phase n=237* (%) Posaconazole Injection Treatment Phase or Subsequent Noxafil ® (posaconazole) Oral Suspension Treatment Phase n=237 † (%) Percentage of Patients Reporting any Adverse Reaction 93 99 Diarrhea 32 39 Hypokalemia 22 28 Pyrexia 21 31 Nausea 19 30 Rash 15 24 Headache 14 21 Epistaxis 14 17 Abdominal Pain 13 17 Chills 12 16 Edema Peripheral 12 15 Vomiting 12 19 Hypomagnesemia 11 13 Decreased appetite 10 12 Cough 9 13 Constipation 8 13 Fatigue 8 10 Hypertension 8 11 Petechiae 8 10 Anemia 7 10 Dyspnea 7 10 Thrombocytopenia 7 11 Abdominal Pain Upper 6 11 * Adverse reactions reported in patients with an onset during the posaconazole intravenous dosing phase of the study. † Adverse reactions reported with an onset at any time during the study in patients who were treated for up to 28 days of posaconazole therapy.

Liver Test Abnormalities in the Clinical Trials with Noxafil ® (posaconazole) Oral Suspension for the Treatment of Invasive Aspergillosis The number and percentage of patients treated for invasive aspergillosis with clinically significant liver test abnormalities at any time during the Aspergillosis Treatment Study is provided in Table 14. Liver test abnormalities present prior to the initiation of study drug included: ALT (22% of the patients), AST (13% of the patients), and bilirubin (13% of the patients). Table 14: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 (Aspergillosis Treatment Study) Number (%) of Patients with Change* Laboratory Parameter Posaconazole n/N (%) Voriconazole n/N (%) AST 22/281 21/285 ALT 29/281 23/282 Bilirubin 26/280 25/284 Alkaline Phosphatase 12/282 20/284 *Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study.

These data are presented in the form n/N, where n represents the number of patients who met the criterion as indicated, and N represents the number of patients who had a baseline observation and at least one post-baseline observation. N=Number of patients for a given laboratory test with a baseline value of CTC Grade 0, 1, or 2 and at least one post-baseline value. CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT = Alanine Aminotransferase.

In healthy volunteers and patients, elevation of liver test values did not appear to be associated with higher plasma posaconazole concentrations. Clinical Trials in Pediatric Patients 2 Years of Age and Older The safety of Posaconazole injection and Noxafil ® PowderMix (posaconazole) for delayed-release oral suspension for prophylaxis of invasive fungal infections was evaluated in an open -label uncontrolled dose-ranging pharmacokinetic and safety study of posaconazole injection and Noxafil ® PowderMix (posaconazole) for delayed-release oral suspension (Pediatric Study 1, NCT02452034). In this study, 115 immunocompromised pediatric patients 2 to less than 18 years of age with known or expected neutropenia initially received posaconazole injection (up to 6 mg/kg twice daily for the first day and then up to 6 mg/kg for at least 7 days), and then 63 patients were transitioned to Noxafil ® PowderMix (posaconazole) for delayed-release oral suspension (up to 6 mg/kg once daily).

The mean overall treatment duration was 21 days including a mean duration of 14 days (range: 1 to 28 days) on posaconazole injection and a mean duration of 12 days (range: 2 to 18 days) on Noxafil ® PowderMix (posaconazole) for delayed-release oral suspension . In this study, the reported adverse reaction profile of posaconazole injection and Noxafil ® PowderMix (posaconazole) for delayed-release oral suspension in pediatric patients was consistent with the safety profile of posaconazole in adults. The most common adverse reactions that occurred in greater than 20% of pediatric patients who received posaconazole injection and Noxafil ® PowderMix (posaconazole) for delayed-release oral suspension were pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis. The safety of posaconazole injection, Noxafil ® (posaconazole) delayed-release tablets, and Noxafil ® PowderMix (posaconazole) for delayed-release oral suspension for the treatment of invasive aspergillosis was evaluated in an open-label, non-comparative clinical study in 31 pediatric patients 2 to less than 18 years of age with a diagnosis of possible, probable, or proven invasive aspergillosis (Pediatric Study 2, NCT04218851).

In this study, all 31 pediatric patients initially received posaconazole injection (6 mg/kg twice daily on the first day and then 6 mg/kg once daily) for the treatment of invasive aspergillosis; 12 patients were transitioned to Noxafil ® (posaconazole) delayed-release tablets (300 mg once daily) if they weighed ≥40 kg, and 10 patients were transitioned to Noxafil ® PowderMix (posaconazole) for delayed-release oral suspension (based on weight) if they weighed 10 to 40 kg . The mean overall treatment duration was 50 days including 15 days (range 2 to 78 days) on posaconazole injection, 54 days (range: 6 to 80 days) on Noxafil ® (posaconazole) delayed-release tablets, and 44 days (range 7 to 76 days) on Noxafil ® PowderMix (posaconazole) for delayed-release oral suspension. The reported adverse reaction profile of posaconazole injection, Noxafil ® (posaconazole) delayed-release tablets, and Noxafil ® PowderMix (posaconazole) for delayed-release oral suspension in pediatric patients was consistent with the known safety profile of posaconazole in adults. The most common adverse reactions that occurred in greater than 20% of pediatric patients who received any of the three formulations of posaconazole were vomiting, pyrexia, abdominal pain, liver test abnormalities, and hypertension.

6.2Postmarketing Experience The

following adverse reaction has been identified during the post-approval use of posaconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Endocrine Disorders: Pseudoaldosteronism