Posaconazole

1 INDICATIONS AND USAGE Posaconazole is an azole antifungal indicated as follows: Posaconazole injection is indicated for the treatment of invasive aspergillosis in adults and pediatric patients 13 years of age and older. ( 1.1 ) Posaconazole 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: ( 1.2 ) Posaconazole injection: adults and pediatric patients 2 years of age and older 1.1 Treatment of Invasive Aspergillosis Posaconazole injection is indicated for the treatment of invasive aspergillosis in adults and pediatric patients 13 years of age and older. 1.2 Prophylaxis of Invasive Aspergillus and Candida Infections Posaconazole 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 [see Clinical Studies ( 14.1 )] as follows: Posaconazole injection: adults and pediatric patients 2 years of age and older

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 ) Do NOT administer Posaconazole injection as intravenous bolus injection. ( 2.1 ) Table 1 : Recommended Dosage in Adult Patients Indication Dosage Form, Dose, and 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 thereafter. Recommended total duration of therapy is 6 to 12 weeks. ( 2.2 ) Prophylaxis of Posaconazole Injection: invasive Loading dose : 300 mg Posaconazole injection Aspergillus and intravenously twice a day on the first day. Candida Maintenance dose : 300 mg Posaconazole injection intravenously once a day thereafter infections Duration of therapy is based on recovery from neutropenia or immunosuppression. ( 2.2 , 2.3 ) For pediatric patients, see the Full Prescribing Information for dosing recommendations for Posaconazole injection , based on the age and indication associated with the dosage form. ( 1.1 , 1.2 , 2.1 , 2.3 ) 2.1 Important 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 [see Dosage and Administration ( 2.4 )] . If a central venous catheter is not available, Posaconazole injection may be administered through a peripheral venous catheter by slow intravenous infusion over 30 minutes only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other intravenous treatment. When multiple dosing is required, the infusion should be done via a central venous line. Do NOT administer Posaconazole injection as an intravenous bolus injection. 2.2 Dosing Regimen in Adult Patients Table 1: Dosing Regimens in Adult Patients Indication Dose and Frequency 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. Switching between the intravenous and delayed-release tablets is acceptable. A loading dose is not required when switching between formulations. 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. 2.3 Dosing Regimen in Pediatric Patients (ages 2 to less than 18 years of age) The recommended dosing regimen of Posaconazole for pediatric patients 2 to less than 18 years of age is shown in Table 2 [see Clinical Pharmacology ( 12.3 )]. Table 2: Posaconazole Injection Dosing Regimens for Pediatric Patients (ages 2 to less than 18 years of age) Recommended Pediatric Dosage and Formulation Indication Age Injection Duration of therapy Prophylaxis of invasive Aspergillus and Candida infections Less than or equal to 40 kg (2 to less than 18 years of age) Greater than 40 kg (2 to less than 18 years of age) 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 Duration of therapy is based on recovery from neutropenia or immunosuppression. Treatment of invasive Aspergillosis 13 to less than 18 years of age regardless of weight. 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. Switching between the intravenous and delayed-release tablets is acceptable. A loading dose is not required when switching between formulations. Loading dose: 1 day Maintenance dose: Recommended total duration of therapy is 6 to 12 weeks. 2.4 Preparation, Intravenous Line Compatibility, and Administration of Posaconazole Injection Preparation: Equilibrate the refrigerated vial of Posaconazole injection to room temperature. To prepare the required dose, aseptically transfer one vial (16.7 mL) of Posaconazole injection (containing 300 mg of posaconazole in solution) to an intravenous bag (or bottle) of a compatible admixture diluent (as described in Table 5 ), to achieve a final concentration of posaconazole that is between 1 mg/mL and 2 mg/mL. Use of other diluents is not recommended because they may result in particulate formation. Posaconazole injection is a single-dose sterile solution without preservatives. Discard any unused portion from the vial. Once admixed, the diluted solution of Posaconazole in the intravenous bag (or bottle) should be used immediately. If not used immediately, the solution can be stored up to 24 hours refrigerated 2 to 8°C (36 to 46°F). Discard any unused portion. Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Once admixed, the solution of Posaconazole ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product. Intravenous Line Compatibility: A study was conducted to evaluate physical compatibility of Posaconazole injection with injectable drug products and commonly used intravenous diluents during simulated Y-site infusion. Compatibility was determined through visual observations, measurement of particulate matter and turbidity. Compatible diluents and drug products are listed in Tables 5 and 6 below. Any diluents or drug products not listed in the tables below should not be co-administered through the same intravenous line (or cannula). Posaconazole injection can be infused at the same time through the same intravenous line (or cannula) with the following compatible diluents: Table 5: Compatible Diluents 0.45% sodium chloride 0.9% sodium chloride 5% dextrose in water 5% dextrose and 0.45% sodium chloride 5% dextrose and 0.9% sodium chloride 5% dextrose and 20 mEq potassium chloride Posaconazole injection can be infused at the same time through the same intravenous line (or cannula) with the following drug products prepared in 5% dextrose in water or sodium chloride 0.9%. Co-administration of drug products prepared in other diluents may result in particulate formation. Table 6: Compatible Drugs Amikacin sulfate Caspofungin Ciprofloxacin Daptomycin Dobutamine hydrochloride Famotidine Filgrastim Gentamicin sulfate Hydromorphone hydrochloride Levofloxacin Lorazepam Meropenem Micafungin Morphine sulfate Norepinephrine bitartrate Potassium chloride Vancomycin hydrochloride Incompatible Diluents: Posaconazole injection must not be diluted with the following diluents: Lactated Ringer's solution 5% dextrose with Lactated Ringer's solution 4.2% sodium bicarbonate Administration: Posaconazole injection must be administered through a 0.22-micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter. Administer via a central venous line, including a central venous catheter or PICC by slow infusion over approximately 90 minutes. Posaconazole injection is not for bolus administration. If a central venous catheter is not available, Posaconazole injection may be administered through a peripheral venous catheter only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other treatment. When multiple dosing is required, the infusion should be done via a central venous line. When administered through a peripheral venous catheter, the infusion should be administered over approximately 30 minutes. Note: In clinical trials, multiple peripheral infusions given through the same vein resulted in infusion site reactions [see Adverse Reactions ( 6.1 )] . 2.9 Dosage Adjustments in Patients with Renal Impairment Posaconazole injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Posaconazole injection. In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <50 mL/min), receiving the Posaconazole injection, accumulation of the intravenous vehicle, Betadex Sulfobutyl Ether Sodium (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.

4 CONTRAINDICATIONS Known hypersensitivity to posaconazole or other azole antifungal agents. ( 4.1 ) Coadministration of Posaconazole with the following drugs is contraindicated; Posaconazole increases concentrations and toxicities of: Sirolimus: ( 4.2 , 5.1 , 7.1 ) 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 , 7.3 ) Ergot alkaloids ( 4.5 , 7.4 ) Venetoclax: in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp of phase ( 4.6 , 5.10 , 7.16 ) 4.1 Hypersensitivity Posaconazole is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents. 4.2 Use 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 [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] . 4.3 QT 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 [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.2 )] . 4.4 HMG-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 [see Drug Interactions ( 7.3 ) and Clinical Pharmacology ( 12.3 )] . 4.5 Use with Ergot Alkaloids Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [see Drug Interactions ( 7.4 )] . 4.6 Use with Venetoclax Coadministration of Posaconzole 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 [see Warnings and Precautions ( 5.10 ) and Drug Interactions ( 7.16 )].

Not available.

6 ADVERSE REACTIONS The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling: Hypersensitivity [see Contraindications ( 4.1 )] Arrhythmias and QT Prolongation [see Warnings and Precautions ( 5.2 )] Hepatic Toxicity [see Warnings and Precautions ( 5.4 )] Adult Patients: Common adverse reactions in studies with Posaconazole in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. ( 6.1 ) 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical 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. Clinical Trial Experience in Adults Clinical Trial Experience with Posaconazole Injection and Noxafil ® Delayed-Release Tablets for the Treatment of Invasive Aspergillosis The safety of Posaconazole injection and Noxafil ® delayed-release tablet was assessed in a randomized, double-blind, active-controlled clinical study of Posaconazole injection and Noxafil ® delayed-release tablets versus voriconazole for treatment of invasive aspergillosis (Aspergillosis Treatment Study). A total of 575 (288 in Posaconazole arm, 287 in voriconazole arm) adult and pediatric patients 13 years of age and older with proven, probable or possible invasive aspergillosis were included. The median duration of treatment was 67 days for Posaconazole injection or Noxafil ® delayed-release tablet and 64 days for voriconazole, with 55% to 60% of subjects starting treatment with the IV formulation of either drug. The median duration of the first instance of IV 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 groups in Aspergillosis Treatment Study. Adverse reactions leading to treatment discontinuation were reported for 33.9% of subjects. The most commonly reported adverse reactions (>2% of subjects) leading to treatment discontinuation were septic shock, respiratory failure, and bronchopulmonary aspergillosis in the Posaconazole arm, and septic shock and acute myeloid leukemia in the voriconazole arm. Table 7: Posaconazole Invasive Aspergillosis Treatment Study: Adverse Reactions in at Least 10% of Subjects Treated with Posaconazole Injection or Noxafil ® Delayed-Release Tablets System Organ Class Posaconazole injection or tablet (N = 288), n (%) Voriconazole injection or oral (N = 287), n (%) Blood and lymphatic system disorders Anemia 25 (8.7) 29 (10.1) Febrile neutropenia 42 (14.6) 38 (13.2) Gastrointestinal disorders Abdominal pain 29 (10.1) 24 (8.4) Constipation 32 (11.1) 23 (8.0) Diarrhea 52 (18.1) 52 (18.1) Nausea 65 (22.6) 51 (17.8) Vomiting 52 (18.1) 39 (13.6) General disorders and administration site conditions Edema peripheral 32 (11.1) 24 (8.4) Pyrexia 81 (28.1) 72 (25.1) Infections and infestations Pneumonia 36 (12.5) 26 (9.1) Investigations Alanine aminotransferase increased 42 (14.6) 37 (12.9) Aspartate aminotransferase increased 38 (13.2) 36 (12.5) Blood alkaline phosphatase increased 21 (7.3) 29 (10.1) Metabolism and nutrition disorders Hypokalemia 82 (28.5) 49 (17.1) Hypomagnesemia 29 (10.1) 18 (6.3) Nervous system disorders Headache 35 (12.2) 25 (8.7) Respiratory, thoracic and mediastinal disorders Cough 30 (10.4) 24 (8.4) Epistaxis 32 (11.1) 17 (5.9) The most frequently reported adverse reactions in the Posaconazole-treated group were pyrexia (28%), hypokalemia (28%), and nausea (23%). Clinical Trial Experience with Posaconazole Injection for Prophylaxis Multiple doses of Posaconazole injection administered 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 18-82 years, 19% of patients were ≥65 years of age), and were 95% white and 8% Hispanic. Ten patients received a single dose of 200 mg Posaconazole injection, 21 patients received 200 mg daily dose for a median of 14 days, and 237 patients received 300 mg daily dose for a median of 9 days. Table 8 presents adverse reactions observed in patients treated with Posaconazole injection 300 mg daily dose in the Posaconazole Injection Study. Each patient received a loading dose, 300 mg twice on Day 1. Following Posaconazole intravenous therapy, patients received Noxafil ® oral suspension to complete 28 days of total Posaconazole therapy. Table 8: Posaconazole Injection Study: Adverse Reactions in at Least 10% of Subjects Treated with Posaconazole Injection 300 mg Daily Dose *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. Body System Posaconazole Injection Treatment Phase n=237 (%)* Posaconazole Injection Treatment Phase or Subsequent Noxafil ® Oral Suspension Treatment Phase n=237 (%) † Subjects Reporting any Adverse Reaction 220 (93) 235 (99) Blood and Lymphatic System Disorder Anemia 16 (7) 23 (10) Thrombocytopenia 17 (7) 25 (11) Gastrointestinal Disorders Abdominal Pain Upper 15 (6) 25 (11) Abdominal Pain 30 (13) 41 (17) Constipation 18 (8) 31 (13) Diarrhea 75 (32) 93 (39) Nausea 46 (19) 70 (30) Vomiting 29 (12) 45 (19) General Disorders and Administration Site Conditions Fatigue 19 (8) 24 (10) Chills 28 (12) 38 (16) Edema Peripheral 28 (12) 35 (15) Pyrexia 49 (21) 73 (31) Metabolism and Nutrition Disorders Decreased appetite 23 (10) 29 (12) Hypokalemia 51 (22) 67 (28) Hypomagnesemia 25 (11) 30 (13) Nervous System Disorders Headache 33 (14) 49 (21) Respiratory, Thoracic and Mediastinal Disorders Cough 21 (9) 31 (13) Dyspnea 16 (7) 24 (10) Epistaxis 34 (14) 40 (17) Skin and Subcutaneous Tissue Disorders Petechiae 20 (8) 24 (10) Rash 35 (15) 56 (24) Vascular Disorders Hypertension 20 (8) 26 (11) The most frequently reported adverse reactions with an onset during the Posaconazole intravenous 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 ® oral suspension. Clinical Trial Experience in Pediatrics Clinical Trial Experience in Pediatric Patients (2 to less than 18 Years of Age) The safety of Posaconazole injection and Noxafil ® PowderMix for delayed-release oral suspension for prophylaxis of invasive fungal infections has been assessed in an open label uncontrolled dose-ranging PK and safety study (Posaconazole injection/ Noxafil ® PowderMix for delayed-release oral suspension Pediatric Study 1, NCT02452034); hereinafter referred to as Posaconazole Pediatric Study) in 115 immunocompromised pediatric patients 2 to less than 18 years of age with known or expected neutropenia. Posaconazole injection and Noxafil ® PowderMix for delayed-release oral suspension was administered at daily doses of up to 6 mg/kg (twice daily on day 1) in three dose cohorts. All 115 subjects initially received Posaconazole injection for at least 7 days, and 63 subjects were transitioned to Noxafil ® PowderMix for delayed-release oral suspension. The mean overall treatment duration for all treated subjects was 20.6 days with 14.3 days (range: 1 to 28 days) on Posaconazole injection and 11.6 days (range: 2 to 18 days) on Noxafil ® PowderMix for delayed-release oral suspension [see Clinical Pharmacology ( 12.3 )]. Table 15 presents adverse reactions observed in greater than or equal to 10% of pediatric patients treated with Posaconazole in the Posaconazole Pediatric Study. Reported adverse reaction profile of Posaconazole in pediatric patients was consistent with the safety profile of Posaconazole in adults. The most common adverse reactions (occurring in greater than 20% of pediatric patients receiving 6 mg/kg Posaconazole injection and Noxafil ® PowderMix for delayed-release oral suspension daily dose) were pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis. Table 15: Adverse Reactions in at Least 10% of Pediatric Patients Treated with Posaconazole Injection and Noxafil ® PowderMix for Delayed-Release Oral Suspension Adverse Reaction Posaconazole Injection and Noxafil ® PowderMix for Delayed-Release Oral Suspension 6 mg/kg Dose Cohort n=49 (%) Posaconazole Injection and Noxafil ® PowderMix for Delayed-Release Oral Suspension All Dose Cohorts n=115 (%) Pyrexia 16 (33) 50 (43) Febrile neutropenia 15 (31) 25 (22) Vomiting 12 (24) 30 (26) Mucosal inflammation 11 (22) 32 (28) Pruritus 11 (22) 18 (16) Hypertension 10 (20) 20 (17) Hypokalemia 10 (20) 16 (14) Stomatitis 10 (20) 13 (11) Diarrhea 9 (18) 25 (22) Nausea 9 (18) 18 (16) Abdominal pain 8 (16) 20 (17) Decreased appetite 7 (14) 17 (15) Rash 7 (14) 18 (16) Alanine aminotransferase increased 6 (12) 8 (7) Headache 6 (12) 16 (14) Aspartate aminotransferase increased 5 (10) 8 (7) The number of patients receiving Posaconazole in the Posaconazole Pediatric Study who had changes in liver tests from Grade 0, 1, or 2 at baseline to Grade 3 or 4 is presented in Table 16 . Table 16: Posaconazole Pediatric Study: Changes in Liver Tests from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 *Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation. CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase Number (%) of Patients with Change* Pediatric Study 1 Laboratory Parameter Posaconazole Injection and Noxafil ® PowderMix for Delayed- Release Oral Suspension (6 mg/kg daily) n=49 (%) AST 2/49 (4) ALT 3/49 (6) Bilirubin 0/48 (0) Alkaline Phosphatase 0/48 (0) 6.2 Postmarketing 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. Endocrine Disorders: Pseudoaldosteronism