Posaconazole

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 (5.5) ] • 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 Noxafil delayed-release tablet (N = 288), n (%) Voriconazole injection or oral (N = 287), n (%) Blood and lymphatic system disorder 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 to 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 Body System Posaconazole Injection Treatment Phase n=237 (%) Adverse reactions reported in patients with an onset during the posaconazole intravenous dosing phase of the study. Posaconazole Injection Treatment Phase or Subsequent Noxafil Oral Suspension Treatment Phase n=237 (%) 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. 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. Other clinically significant adverse reactions reported in less than 5% of patients in clinical trials of posaconazole are listed below: • Blood and lymphatic system disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated • Endocrine disorders: adrenal insufficiency • Nervous system disorders: paresthesia • Immune system disorders: allergic reaction [see Contraindications (4.1) ] • Cardiac disorders: torsades de pointes [see Warnings and Precautions (5.2) ] • Vascular disorders: pulmonary embolism • Gastrointestinal disorders: pancreatitis • Liver and Biliary System Disorders: hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice • Renal & Urinary System Disorders: renal failure acute Clinical Laboratory Values: In healthy volunteers and patients, elevation of liver test values did not appear to be associated with higher plasma concentrations of posaconazole. The number 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%), AST (13%), and bilirubin (13%). Table 14: Aspergillosis Treatment Study: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 N=Number of subjects 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. Number (%) of Patients with Change 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. Laboratory Parameter Posaconazole n/N (%) Voriconazole n/N (%) AST 22/281 (8) 21/285 (7) ALT 29/281 (10) 23/282 (8) Bilirubin 26/280 (9) 25/284 (9) Alkaline Phosphatase 12/282 (4) 20/284 (7) 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 CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase Number (%) of Patients with Change 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. 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

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-up phase ( 4.6 , 5.11 , 7.16 ) 4.1 Hypersensitivity Posaconazole injection 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 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 [see Warnings and Precautions (5.11) and Drug Interactions (7.16) ] .

11 DESCRIPTION Posaconazole is an azole antifungal agent. Posaconazole is available as an injection solution to be diluted before intravenous administration. Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3 R ,5 R )-5-(2,4-difluorophenyl)tetrahydro-5-(1 H -1,2,4-triazol-1ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1 S ,2 S )-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3 H -1,2,4-triazol-3-one with an empirical formula of C 37 H 42 F 2 N 8 O 4 and a molecular weight of 700.8. The chemical structure is: Posaconazole is a white to off-white color powder which is soluble in dichloromethane and practically insoluble in water. Posaconazole Injection Posaconazole injection is available as a sterile, clear colorless to yellow colored solution free of foreign matter. Each vial contains 300 mg of posaconazole and the following inactive ingredients: 6.68 g Betadex Sulfobutyl Ether Sodium (SBECD), 0.0033 g edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6, and water for injection. Posaconazole Chemical Structure

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 an 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 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. 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. 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 injection 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 Weight/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) 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. Greater than 40 kg (2 to less than 18 years of age) 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.

10 OVERDOSAGE There is no experience with overdosage of posaconazole injection. Posaconazole is not removed by hemodialysis.

7 DRUG INTERACTIONS Posaconazole is primarily metabolized via UDP glucuronosyltransferase and is a substrate of p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Coadministration of drugs that can decrease the plasma concentrations of 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. Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole [see Clinical Pharmacology (12.3) ] . The following information was derived from data with Noxafil oral suspension or early tablet formulation unless otherwise noted. All drug interactions with Noxafil oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility) are considered relevant to posaconazole injection. Interaction Drug Interaction Rifabutin, phenytoin, efavirenz Avoid coadministration unless the benefit outweighs the risks ( 7.6 , 7.7 , 7.8 ) Other drugs metabolized by CYP3A4 Consider dosage adjustment and monitor for adverse effects and toxicity ( 7.1 , 7.10 , 7.11 ) Digoxin Monitor digoxin plasma concentrations ( 7.12 ) Fosamprenavir Monitor for breakthrough fungal infections ( 7.6 ) 7.1 Immunosuppressants Metabolized by CYP3A4 Sirolimus Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus [see Contraindications (4.2) and Clinical Pharmacology (12.3) ] . Tacrolimus Posaconazole has been shown to significantly increase the Cmax and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . Cyclosporine Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . 7.2 CYP3A4 Substrates Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs [see Contraindications (4.3) and Warnings and Precautions (5.2) ] . 7.3 HMG-CoA Reductase Inhibitors (Statins) Primarily Metabolized Through CYP3A4 Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4 [see Contraindications (4.4) and Clinical Pharmacology (12.3) ] . 7.4 Ergot Alkaloids Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Therefore, posaconazole is contraindicated with ergot alkaloids [see Contraindications (4.5) ] . 7.5 Benzodiazepines Metabolized by CYP3A4 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. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3) ] . 7.6 Anti-HIV Drugs Efavirenz: Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations [see Clinical Pharmacology (12.3) ] . It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks. Ritonavir and Atazanavir: Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs [see Clinical Pharmacology (12.3) ] . Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole. Fosamprenavir: Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended [see Clinical Pharmacology (12.3) ] . 7.7 Rifabutin Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, co-administration of rifabutin with posaconazole increases rifabutin plasma concentrations [see Clinical Pharmacology (12.3) ] . Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended. 7.8 Phenytoin Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations [see Clinical Pharmacology (12.3) ] . Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered. 7.10 Vinca Alkaloids Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with serious adverse reactions [see Warnings and Precautions (5.8) ] . Posaconazole may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. 7.11 Calcium Channel Blockers Metabolized by CYP3A4 Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. Dose reduction of calcium channel blockers may be needed. 7.12 Digoxin Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration. 7.14 Glipizide Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used. 7.16 Venetoclax Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax Cmax and AUC0-INF, which may increase venetoclax toxicities [see Contraindications (4.6) , Warnings and Precautions (5.11) ] . Refer to the venetoclax prescribing information for more information on the dosing instructions and the extent of increase in venetoclax exposure.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4) ] . 12.2 Pharmacodynamics Exposure Response Relationship Treatment of Invasive Aspergillosis Across a range of posaconazole plasma minimum concentrations (C min , range: 244 to 5663 ng/mL) following administration of posaconazole injection and Noxafil delayed-release tablets in patients treated for invasive aspergillosis in Aspergillosis Treatment Study, there was no association between posaconazole C min and treatment efficacy [see Clinical Pharmacology (12.3) and Clinical Studies (14.1) ] . Similarly, across a range of population pharmacokinetic model-predicted steady-state plasma average concentrations (C avg , range: 589 to 6315 ng/mL), there was no association between posaconazole C avg and treatment efficacy. 12.3 Pharmacokinetics General Pharmacokinetic Characteristics Posaconazole Injection Posaconazole injection exhibits dose proportional pharmacokinetics after single doses between 200 and 300 mg in healthy volunteers and patients. The mean pharmacokinetic parameters after single doses with posaconazole injection in healthy volunteers and patients are shown in Table 18 . Table 18: Summary of Mean Pharmacokinetic Parameters (%CV) in Healthy Volunteers (30-minute infusion via peripheral venous line) and Patients (90 minute infusion via central venous line) after Dosing with Posaconazole Injection on Day 1 AUC 0-∞ = Area under the plasma concentration-time curve from time zero to infinity; AUC 0-12 = Area under the plasma concentration-time curve from time zero to 12 hr after the first dose on Day 1; C max = maximum observed concentration; t ½ = terminal phase half-life; CL = total body clearance; N/D = Not Determined Dose (mg) n AUC 0-∞ (ng∙hr/mL) AUC 0-12 (ng∙hr/mL) C max (ng/mL) t 1/2 (hr) CL (L/hr) Healthy Volunteers 200 9 35400 (50) 8840 (20) 2250 (29) 23.6 (23) 6.5 (32) 300 9 46400 (26) 13000 (13) 2840 (30) 24.6 (20) 6.9 (27) Patients 200 30 N/D 5570 (32) 954 (44) N/D N/D 300 22 N/D 8240 (26) 1590 (62) N/D N/D Table 19 displays the pharmacokinetic parameters of posaconazole in patients following administration of posaconazole injection 300 mg taken once a day for 10 or 14 days following twice daily dosing on Day 1. Table 19: Arithmetic Mean (%CV) of PK Parameters in Serial PK-Evaluable Patients Following Dosing of Posaconazole Injection (300 mg)* AUC 0-24 = area under the concentration-time curve over the dosing interval (i.e., 24 hours); C av = time-averaged concentrations (i.e., AUC 0-24h/24hr ); C min = POS trough level immediately before a subject received the dose of POS on the day specified in the protocol; C max = observed maximum plasma concentration; CV = coefficient of variation, expressed as a percent (%); Day = study day on treatment; T max = time of observed maximum plasma concentration. Day N C max (ng/mL) T max Median (minimum-maximum) (hr) AUC 0-24 (ng 300 mg dose administered over 90 minutes once a day following twice daily dosing on Day 1 hr/mL) C av (ng/mL) C min (ng/mL) 10/14 49 3280 (74) 1.5 (0.98 to 4.0) 36100 (35) 1500 (35) 1090 (44) Distribution The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226 to 295 L between studies and dose levels. Posaconazole is highly bound to human plasma 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. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Excretion Posaconazole injection is eliminated with a mean terminal half-life (t ½ ) of 27 hours and a total body clearance (CL) of 7.3 L/h. Specific Populations No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment). Race/Ethnicity In a population pharmacokinetic analysis of posaconazole, AUC was found to be 25% higher in Chinese patients relative to patients from other races/ethnicities. This higher exposure is not expected to be clinically relevant given the expected variability in posaconazole exposure. Patients Weighing More Than 120 kg Weight has a clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole weighing more than 120 kg may be at higher risk for lower posaconazole plasma concentrations compared to lower weight patients [see Use in Specific Populations (8.10) ] . Pediatric Patients The mean pharmacokinetic parameters after multiple-dose administration of posaconazole injection in neutropenic pediatric patients 2 to less than 18 years of age are shown in Table 29. Patients were enrolled into 2 age groups and received posaconazole injection doses at 6 mg/kg (0.6 to 1 times the recommended dose) with a maximum 300 mg dose once daily (twice daily on Day 1) [see Adverse Reactions (6.1) ] . Table 29: Summary of Steady-State Geometric Mean Pharmacokinetic Parameters (% Geometric CV) After Multiple Dosing with Posaconazole Injection 6 mg/kg 0.6 to 1 times the recommended dose in Pediatric Patients with Neutropenia or Expected Neutropenia IV= Posaconazole injection; AUC 0-24 = Area under the plasma concentration-time curve from time zero to 24 hr; C max = maximum observed concentration; C min = minimum observed plasma concentration; T max = time of maximum observed concentration; CL = apparent total body clearance Age Group Dose Type AUC 0-24 hr (ng·hr/mL) Cav Cav = time-averaged concentrations (i.e., AUC 0-24 hr/24hr ) (ng/mL) C max (ng/mL) C min (ng/mL) T max Median (minimum-maximum) (hr) CL Clearance (CL for IV) (L/hr) 2 to <7 Years IV 3100 (48.9) 1300 (48.9) 3060 (54.1) 626 (104.8) 1.75 (1.57 to 1.83) 3.27 (49.3) 7 to 17 years IV 44200 (41.5) 1840 (41.5) 3340 (39.4) 1160 (60.4) 1.75 (1.57 to 1.83) 4.76 (55.7) Based on a population pharmacokinetic model evaluating posaconazole pharmacokinetics and predicting exposures in pediatric patients, the exposure of steady-state posaconazole average concentration greater than or equal to 700 ng/mL in approximately 90% of patients is attained with the recommended dose of posaconazole. The population pharmacokinetic analysis of posaconazole in pediatric patients suggests that age, sex, renal impairment and ethnicity have no clinically meaningful effect on the pharmacokinetics of posaconazole. 12.4 Microbiology Mechanism of Action Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole. Resistance Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known. Antimicrobial Activity Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1) ] . Microorganisms Aspergillus spp. and Candida spp. Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

12.1 Mechanism of Action Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4) ] .

12.2 Pharmacodynamics Exposure Response Relationship Treatment of Invasive Aspergillosis Across a range of posaconazole plasma minimum concentrations (C min , range: 244 to 5663 ng/mL) following administration of posaconazole injection and Noxafil delayed-release tablets in patients treated for invasive aspergillosis in Aspergillosis Treatment Study, there was no association between posaconazole C min and treatment efficacy [see Clinical Pharmacology (12.3) and Clinical Studies (14.1) ] . Similarly, across a range of population pharmacokinetic model-predicted steady-state plasma average concentrations (C avg , range: 589 to 6315 ng/mL), there was no association between posaconazole C avg and treatment efficacy.

12.3 Pharmacokinetics General Pharmacokinetic Characteristics Posaconazole Injection Posaconazole injection exhibits dose proportional pharmacokinetics after single doses between 200 and 300 mg in healthy volunteers and patients. The mean pharmacokinetic parameters after single doses with posaconazole injection in healthy volunteers and patients are shown in Table 18 . Table 18: Summary of Mean Pharmacokinetic Parameters (%CV) in Healthy Volunteers (30-minute infusion via peripheral venous line) and Patients (90 minute infusion via central venous line) after Dosing with Posaconazole Injection on Day 1 AUC 0-∞ = Area under the plasma concentration-time curve from time zero to infinity; AUC 0-12 = Area under the plasma concentration-time curve from time zero to 12 hr after the first dose on Day 1; C max = maximum observed concentration; t ½ = terminal phase half-life; CL = total body clearance; N/D = Not Determined Dose (mg) n AUC 0-∞ (ng∙hr/mL) AUC 0-12 (ng∙hr/mL) C max (ng/mL) t 1/2 (hr) CL (L/hr) Healthy Volunteers 200 9 35400 (50) 8840 (20) 2250 (29) 23.6 (23) 6.5 (32) 300 9 46400 (26) 13000 (13) 2840 (30) 24.6 (20) 6.9 (27) Patients 200 30 N/D 5570 (32) 954 (44) N/D N/D 300 22 N/D 8240 (26) 1590 (62) N/D N/D Table 19 displays the pharmacokinetic parameters of posaconazole in patients following administration of posaconazole injection 300 mg taken once a day for 10 or 14 days following twice daily dosing on Day 1. Table 19: Arithmetic Mean (%CV) of PK Parameters in Serial PK-Evaluable Patients Following Dosing of Posaconazole Injection (300 mg)* AUC 0-24 = area under the concentration-time curve over the dosing interval (i.e., 24 hours); C av = time-averaged concentrations (i.e., AUC 0-24h/24hr ); C min = POS trough level immediately before a subject received the dose of POS on the day specified in the protocol; C max = observed maximum plasma concentration; CV = coefficient of variation, expressed as a percent (%); Day = study day on treatment; T max = time of observed maximum plasma concentration. Day N C max (ng/mL) T max Median (minimum-maximum) (hr) AUC 0-24 (ng 300 mg dose administered over 90 minutes once a day following twice daily dosing on Day 1 hr/mL) C av (ng/mL) C min (ng/mL) 10/14 49 3280 (74) 1.5 (0.98 to 4.0) 36100 (35) 1500 (35) 1090 (44) Distribution The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226 to 295 L between studies and dose levels. Posaconazole is highly bound to human plasma 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. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Excretion Posaconazole injection is eliminated with a mean terminal half-life (t ½ ) of 27 hours and a total body clearance (CL) of 7.3 L/h. Specific Populations No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment). Race/Ethnicity In a population pharmacokinetic analysis of posaconazole, AUC was found to be 25% higher in Chinese patients relative to patients from other races/ethnicities. This higher exposure is not expected to be clinically relevant given the expected variability in posaconazole exposure. Patients Weighing More Than 120 kg Weight has a clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole weighing more than 120 kg may be at higher risk for lower posaconazole plasma concentrations compared to lower weight patients [see Use in Specific Populations (8.10) ] . Pediatric Patients The mean pharmacokinetic parameters after multiple-dose administration of posaconazole injection in neutropenic pediatric patients 2 to less than 18 years of age are shown in Table 29. Patients were enrolled into 2 age groups and received posaconazole injection doses at 6 mg/kg (0.6 to 1 times the recommended dose) with a maximum 300 mg dose once daily (twice daily on Day 1) [see Adverse Reactions (6.1) ] . Table 29: Summary of Steady-State Geometric Mean Pharmacokinetic Parameters (% Geometric CV) After Multiple Dosing with Posaconazole Injection 6 mg/kg 0.6 to 1 times the recommended dose in Pediatric Patients with Neutropenia or Expected Neutropenia IV= Posaconazole injection; AUC 0-24 = Area under the plasma concentration-time curve from time zero to 24 hr; C max = maximum observed concentration; C min = minimum observed plasma concentration; T max = time of maximum observed concentration; CL = apparent total body clearance Age Group Dose Type AUC 0-24 hr (ng·hr/mL) Cav Cav = time-averaged concentrations (i.e., AUC 0-24 hr/24hr ) (ng/mL) C max (ng/mL) C min (ng/mL) T max Median (minimum-maximum) (hr) CL Clearance (CL for IV) (L/hr) 2 to <7 Years IV 3100 (48.9) 1300 (48.9) 3060 (54.1) 626 (104.8) 1.75 (1.57 to 1.83) 3.27 (49.3) 7 to 17 years IV 44200 (41.5) 1840 (41.5) 3340 (39.4) 1160 (60.4) 1.75 (1.57 to 1.83) 4.76 (55.7) Based on a population pharmacokinetic model evaluating posaconazole pharmacokinetics and predicting exposures in pediatric patients, the exposure of steady-state posaconazole average concentration greater than or equal to 700 ng/mL in approximately 90% of patients is attained with the recommended dose of posaconazole. The population pharmacokinetic analysis of posaconazole in pediatric patients suggests that age, sex, renal impairment and ethnicity have no clinically meaningful effect on the pharmacokinetics of posaconazole.

20241216

2

3 DOSAGE FORMS AND STRENGTHS Posaconazole injection Posaconazole injection 300 mg/16.7 mL (18 mg/mL) is available as a clear, colorless to yellow sterile liquid in a single-dose vial. • Posaconazole injection: 300 mg/16.7 mL (18 mg/mL) in a single dose vial ( 3 )

posaconazole posaconazole posaconazole posaconazole BETADEX SULFOBUTYL ETHER SODIUM EDETATE DISODIUM HYDROCHLORIC ACID SODIUM HYDROXIDE WATER

13.2 Animal Toxicology and/or Pharmacology In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2 to 8 weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5-month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and a similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to 9 months of age). There were no drug-related increases in the incidence of brain ventricle enlargement when treated and control animals were compared in a separate study of 10-week-old dogs dosed with intravenous posaconazole for 13 weeks with a 9-week recovery period or a follow-up study of 31-week-old dogs dosed for 3 months.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2-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 twice daily oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400 mg twice daily oral suspension 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 twice daily oral suspension regimen. Mutagenesis Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study. Impairment of Fertility Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 × the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 × the 400 mg twice daily oral suspension regimen).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2-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 twice daily oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400 mg twice daily oral suspension 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 twice daily oral suspension regimen. Mutagenesis Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study. Impairment of Fertility Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 × the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 × the 400 mg twice daily oral suspension regimen). 13.2 Animal Toxicology and/or Pharmacology In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2 to 8 weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5-month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and a similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to 9 months of age). There were no drug-related increases in the incidence of brain ventricle enlargement when treated and control animals were compared in a separate study of 10-week-old dogs dosed with intravenous posaconazole for 13 weeks with a 9-week recovery period or a follow-up study of 31-week-old dogs dosed for 3 months.

ANDA211500

Posaconazole

posaconazole

67457-665

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL – 300 mg/16.7 mL NDC 67457-665-20 Posaconazole Injection 300 mg/16.7 mL (18 mg/mL) For Intravenous Use Only Requires further dilution prior to infusion. Discard Unused Portion Sterile Mylan Rx only Single-Dose Vial Each vial contains: 300 mg posaconzole/16.7 mL. Each mL contains: 18 mg Inactive ingredients: 6.68 g betadex sulfobutyl either sodium , 0.0033 g edetate disodium, and hyrochloric acid and sodium hydroxide to adjust pH to 2.6. Usual Dosage: See prescribing information. Read accompanying directions carefully for the preparation of Posaconazole Injection. Posaconazole Injection is a clear, colorless to yellow, sterile injection. Variations in color within this range do not affect the quality of the product. Stored refrigerated at 2° to 8°C (36° to 46°F). Diluted Posaconazole Injection solution in the intravenous bag (or bottle) if not used immediately, can be stored up to 24 hours refrigerated 2° to 8°C (36° to 46°F). Manufactured for: Mylan Institutional LLC Morgantown, WV 26505 U.S.A. Manufactured by: Mylan Institutional Galway, Ireland Mylan.com Posaconazole Injection Carton Label 300 mg/16.7 mL

Warnings and Precautions, Pseudoaldosteronism ( 5.4 ) 10/2024

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Drug Interactions Advise patients to inform their physician immediately if they: • develop severe diarrhea or vomiting. • are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4. • are currently taking a cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath. • are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole. Serious and Potentially Serious Adverse Reactions Advise patients to inform their physician immediately if they: • notice a change in heart rate or heart rhythm or have a heart condition or circulatory disease. Posaconazole can be administered with caution to patients with potentially proarrhythmic conditions. • are pregnant, plan to become pregnant, or are nursing. • have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feel more tired than usual or feel like they have the flu. • have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole. The trademarks referenced herein are owned by their respective companies. Manufactured for: Mylan Institutional LLC Morgantown, WV 26505 U.S.A. Manufactured by: Mylan Institutional Galway, Ireland 50102462 DECEMBER 2024

14 CLINICAL STUDIES 14.1 Treatment of Invasive Aspergillosis with Posaconazole Injection and Noxafil Delayed-Release Tablets Aspergillosis Treatment Study (NCT01782131) was a randomized, double-blind, controlled trial which evaluated the safety and efficacy of posaconazole injection and Noxafil delayed-release tablets versus voriconazole for primary treatment of invasive fungal disease caused by Aspergillus species. Eligible patients had proven, probable, or possible invasive fungal infections per the European Organization for Research and Treatment of Cancer/Mycoses Study Group, EORTC/MSG criteria. Patients were stratified by risk for mortality or poor outcome where high risk included a history of allogeneic bone marrow transplant, liver transplant, or relapsed leukemia undergoing salvage chemotherapy. The median age of patients was 57 years (range 14 to 91 years), with 27.8% of patients aged ≥65 years; 5 patients were pediatric patients 14 to 16 years of age, of whom 3 were treated with posaconazole and 2 with voriconazole. The majority of patients were male (59.8%) and white (67.1%). With regard to risk factors for invasive aspergillosis, approximately two-thirds of the patients in the study had a recent history of neutropenia, while approximately 20% with a history of an allogeneic stem cell transplant. Over 80% of subjects in each treatment group had infection limited to the lower respiratory tract (primarily lung), while approximately 11% to 13% also had infection in another organ. Invasive aspergillosis was proven or probable in 58.1% of patients as classified by independent adjudicators blinded to study treatment assignment. At least one Aspergillus species was identified in 21% of the patients; A. fumigatus and A. flavus were the most common pathogens identified. Patients randomized to receive posaconazole were given a dose of 300 mg once daily (twice daily on Day 1) IV or tablet. Patients randomized to receive voriconazole were given a dose of 6 mg/kg twice daily Day 1 followed by 4 mg/kg twice daily IV, or oral 300 mg twice daily Day 1 followed by 200 mg twice daily. The recommended initial route of administration was IV; however, patients could begin oral therapy if clinically stable and able to tolerate oral dosing. The transition from IV to oral therapy occurred when the patient was clinically stable. The protocol recommended duration of therapy was 84 days with a maximum allowed duration of 98 days. Median treatment duration was 67 days for posaconazole patients and 64 days for voriconazole patients. Overall, 55% to 60% of patients began treatment with the IV formulation with a median duration of 9 days for the initial IV dosing. The Intent to Treat (ITT) population included all patients randomized and receiving at least one dose of study treatment. All-cause mortality through Day 42 in the overall population (ITT) was 15.3% for posaconazole patients compared to 20.6% for voriconazole patients for an adjusted treatment difference of -5.3% with a 95% confidence interval of -11.6 to 1.0%. Consistent results were seen in patients with proven or probable invasive aspergillosis per EORTC criteria (see Table 30 ). Table 30: Posaconazole Injection and Noxafil Delayed-Release Tablets Invasive Aspergillosis Treatment Study: All-Cause Mortality Through Day 42 Posaconazole Injection and Noxafil Delayed- Release Tablets Voriconazole Population N n (%) N n (%) Difference Adjusted treatment difference based on Miettinen and Nurminen’s method stratified by randomization factor (risk for mortality/poor outcome), using Cochran-Mantel-Haenszel weighting scheme. (95% CI) Intent to Treat 288 44 (15.3) 287 59 (20.6) -5.3 (-11.6, 1.0) Proven/Probable Invasive Aspergillosis 163 31 (19.0) 171 32 (18.7) 0.3 (-8.2, 8.8) Global clinical response at Week 6 was assessed by a blinded, independent adjudication committee based upon prespecified clinical, radiologic, and mycologic criteria. In the subgroup of patients with proven or probable invasive aspergillosis per EORTC criteria, the global clinical response of success (complete or partial response) at Week 6 was seen in 44.8% for posaconazole-treated patients compared to 45.6% for voriconazole-treated patients (see Table 31 ). Table 31: Posaconazole Injection and Noxafil Delayed-Release Tablets Invasive Aspergillosis Treatment Study: Successful Global Clinical Response Successful Global Clinical Response was defined as survival with a partial or complete response at Week 6 Posaconazole Voriconazole Population N Success N Success Difference Adjusted treatment difference based on Miettinen and Nurminen’s method stratified by randomization factor (risk for mortality/poor outcome), using Cochran-Mantel-Haenszel weighting scheme. (95% CI) Proven/Probable Invasive Aspergillosis 163 73 (44.8) 171 78 (45.6) -0.6 (-11.2, 10.1)

8.5 Geriatric Use No overall differences in the safety of posaconazole injection were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for any formulation of posaconazole in geriatric patients. No clinically meaningful differences in the pharmacokinetics of posaconazole were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology (12.3) ] . Of the 279 patients treated with posaconazole injection in the Posaconazole Injection Study, 52 (19%) were greater than 65 years of age. Of the 288 patients randomized to posaconazole injection in the Aspergillosis Treatment Study, 85 (29%) were ≥65 years of age. No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.

8.4 Pediatric Use The safety and effectiveness of posaconazole injection for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged 2 and older who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy. The safety and effectiveness of posaconazole injection for the treatment of invasive aspergillosis have been established in pediatric patients aged 13 years and older. Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adult and pediatric patients and additional pharmacokinetic and safety data in pediatric patients 2 years of age and older [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14) ] . The safety and effectiveness of posaconazole have not been established in pediatric patients younger than 2 years of age.

8.1 Pregnancy 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 (cranial malformations and missing ribs) and maternal toxicity (reduced food consumption and reduced body weight gain) 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, increased resorptions, reduced litter size, and reduced body weight gain of females were seen at doses 5 times the exposure achieved with the 400 mg twice daily oral suspension regimen. Doses of ≥ 3 times the clinical exposure caused an increase in resorptions in these rabbits (see Data ) . 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 population 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 USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) • Pediatrics: Safety and effectiveness in patients younger than 2 years of age have not been established. ( 8.4 ) • Severe Renal Impairment: Monitor closely for breakthrough fungal infections. ( 8.6 ) 8.1 Pregnancy 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 (cranial malformations and missing ribs) and maternal toxicity (reduced food consumption and reduced body weight gain) 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, increased resorptions, reduced litter size, and reduced body weight gain of females were seen at doses 5 times the exposure achieved with the 400 mg twice daily oral suspension regimen. Doses of ≥ 3 times the clinical exposure caused an increase in resorptions in these rabbits (see Data ) . 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 population 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. 8.2 Lactation Risk Summary There are no data on the presence of posaconazole in human milk, the effects on the breastfed infant, or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for posaconazole and any potential adverse effects on the breastfed child from posaconazole or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of posaconazole injection for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged 2 and older who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy. The safety and effectiveness of posaconazole injection for the treatment of invasive aspergillosis have been established in pediatric patients aged 13 years and older. Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adult and pediatric patients and additional pharmacokinetic and safety data in pediatric patients 2 years of age and older [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14) ] . The safety and effectiveness of posaconazole have not been established in pediatric patients younger than 2 years of age. 8.5 Geriatric Use No overall differences in the safety of posaconazole injection were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for any formulation of posaconazole in geriatric patients. No clinically meaningful differences in the pharmacokinetics of posaconazole were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology (12.3) ] . Of the 279 patients treated with posaconazole injection in the Posaconazole Injection Study, 52 (19%) were greater than 65 years of age. Of the 288 patients randomized to posaconazole injection in the Aspergillosis Treatment Study, 85 (29%) were ≥65 years of age. No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out. 8.6 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 (eGFR <50 mL/min), 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 [see Dosage and Administration (2.9) and Warnings and Precautions (5.6) ] . 8.7 Hepatic Impairment It is recommended that no dose adjustment of posaconazole injection is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2) and Warnings and Precautions (5.5) ] . However, a specific study has not been conducted with posaconazole injection. 8.8 Gender The pharmacokinetics of posaconazole are comparable in males and females. No adjustment in the dosage of posaconazole is necessary based on gender. 8.9 Race The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of posaconazole is necessary based on race. 8.10 Weight 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 particularly when using Noxafil oral suspension [see Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Posaconazole Injection Posaconazole injection is available as a clear, colorless to yellow sterile liquid in single-dose Type I glass vials closed with bromobutyl rubber stopper and aluminum seal (NDC 67457-665-20) containing 300 mg of posaconazole in 16.7 mL of solution (18 mg of posaconazole per mL). 16.2 Storage and Handling Posaconazole Injection Posaconazole injection vial should be stored refrigerated at 2° to 8°C (36° to 46°F). Storage conditions for the diluted solution are presented in another section of the prescribing information [see Dosage and Administration (2.4) ] .