POSACONAZOLE

Indications and Usage ( 1.1 , 1.2 ) 1/2026 Dosage and Administration ( 2 ) 1/2026

1 INDICATIONS AND USAGE Posaconazole is an azole antifungal indicated as follows: • Posaconazole is indicated for the treatment of invasive aspergillosis as follows: ( 1.1 ) o Posaconazole injection : adults and pediatric patients 2 years of age and older who weigh 10 kg or greater. • 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 ) o Posaconazole injection : adults and pediatric patients 2 years of age and older who weigh 10 kg or greater. 1.1 Treatment of Invasive Aspergillosis Posaconazole injection is indicated for the treatment of invasive aspergillosis as follows : • Posaconazole injection: adults and pediatric patients 2 years of age and older who weigh 10 kg or greater 1.2 Prophylaxis of Invasive Aspergillus and Candida Infections Posaconazole injection is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy as follows: • Posaconazole injection: adults and pediatric patients 2 years of age and older who weigh 10 kg or grea ter

2 DOSAGE AND ADMINISTRATION • Posaconazole injection must be administered through an in-line filter. ( 2.6 ) • Administer posaconazole injection by intravenous infusion over approximately 90 minutes via a central venous line. ( 2.1 , 2.6 ) • Do NOT administer posaconazole injection as an intravenous bolus injection. ( 2.1 ) • See the full prescribing information for important administration instructions and preparation instructions for posaconazole injection ( 2.5 , 2.6 ) • For adult and pediatric patients aged 2 years of age and older, see the Full Prescribing Information for dosing recommendations for posaconazole injection based on the indication, age, and weight associated with the dosage form ( 1.1 , 1.2 , 2.1 , 2.2 , 2.3 ) 2.1 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 (2.6) ] . • Do NOT administer posaconazole injection as an intravenous bolus injection . 2.2 Recommended Dosage of Posaconazole Injection in Adult Patients The recommended dosage of posaconazole injection in adult patients for the treatment of invasive aspergillosis, prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised is shown in Table 1 [see Dosage and Administration (2.5 , 2.6) and Clinical Pharmacology (12.3) ] . Table 1: Recommended Dosage of Posaconazole Injection in Adult Patients Dosage Duration of Therapy Treatment of Invasive Aspergillosis Switching between the posaconazole injection and delayed-release tablets is acceptable. A loading dose is not required when switching between dosage forms. 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 Recommended Dosage of Posaconazole Injection for the Treatment of Invasive Aspergillosis and Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients 2 Years of Age and Older Posaconazole injection The recommended dosage of posaconazole injection in pediatric patients 2 years of age and older who weigh 10 kg or greater for the treatment of invasive aspergillosis and prophylaxis of invasive Aspergillus and Candida infections is shown in Table 2 [see Dosage and Administration (2.5 , 2.6 ) and Clinical Pharmacology (12.3) ] . Table 2: Recommended Dosage of Posaconazole Injection for the Treatment of Invasive Aspergillosis Switching between the intravenous and delayed-release tablets is acceptable. A loading dose is not required when switching between formulations . and Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients (2 Years of Age and Older) Recommended Pediatric Dosage by Formulatio n Duration of Therapy Posaconazole Injection (patients weighing 10 kg or greater ): Loading dose : 6 mg/kg up to a maximum of 300 mg twice daily on the first da y Maintenance dose : 6 mg/kg up to a maximum of 300 mg once daily, starting on the second day . Treatment of invasive aspergillosis : Recommended total duration of therapy is 6 to 12 weeks. Prophylaxis of invasive Aspergillus and Candida infections: Duration of therapy is based on recovery from neutropenia or immunosuppression. 2.5 Preparation of Po …

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 )

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 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) ] .

6 ADVERSE REACTIONS The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling: • Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2) ] • Electrolyte and Disturbances [see Warnings and Precautions (5.3) ] • Pseudoaldosteronism [see Warnings and Precautions (5.4) ] • 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. Treatment of Invasive Aspergillosis in Adults and Adolescents (Posaconazole Injection and Noxafil Delayed-Release Tablets) The safety of posaconazole injection and Noxafil delayed-release tablets 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 adult and pediatric patients 14 years of age and older (288 in posaconazole group, 287 in voriconazole group (voriconazole for injection or voriconazole tablets)) with proven, probable or possible invasive aspergillosis were included. The median duration of treatment was 67 days for posaconazole injection or Noxafil delayed-release tablets and 64 days for voriconazole. In this study, 55% to 60% of patients started intravenous treatment with posaconazole injection or voriconazole (voriconazole injection). The median duration of the first instance of intravenous treatment (before switching to oral treatment or discontinuing or completing study treatment) was 9 days for both groups. Table 7 presents adverse reactions reported at an incidence of ≥ 10% in either one of the treatment groups in Aspergillosis Treatment Study. Adverse reactions leading to treatment discontinuation were reported for 34% of patients. The most commonly reported adverse reactions (> 2% of patients) leading to treatment discontinuation were septic shock, respiratory failure, and bronchopulmonary aspergillosis in the posaconazole group, and septic shock and acute myeloid leukemia in the voriconazole group. The most frequently reported adverse reactions in the posaconazole-treated group were pyrexia (28%), hypokalemia (28%), and nausea (23%). Table 7: Adverse Reactions in at Least 10% of Adults and Adolescents Receiving Posaconazole Injection or Noxafil Delayed-Release Tablets for the Treatment of Invasive Aspergillosis Adverse Reactions Posaconazole injection or Noxafil delayed-release tablets (n = 288) (%) Voriconazole for injection or Voriconazole tablets (n = 287) (%) Percentage of Patients Reporting any Adverse Reaction 97.6 97.6 Hypokalemia 28.5 17.1 Pyrexia 28.1 25.1 Nausea 22.6 17.8 Diarrhea 18.1 18.1 Vomiting 18.1 13.6 Alanine aminotransferase increased 14.6 12.9 Febrile neutropenia 14.6 13.2 Aspartate aminotransferase increased 13.2 12.5 Pneumonia 12.5 9.1 Headache 12.2 8.7 Constipation 11.1 8.0 Edema peripheral 11.1 8.4 Epistaxis 11.1 5.9 Cough 10.4 8.4 Abdominal pain 10.1 8.4 Hypomagnesemia 10.1 6.3 Clinical Trial Experience with Posaconazole Injection for Prophylaxis of Invasive Aspergillus and Candida Infections Administration of multiple doses of posaconazole inject …

7 DRUG INTERACTIONS Table 15 and Table 17 include drugs with clinically important drug interactions when administered concomitantly with posaconazole and instructions for preventing or managing them. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse reactions or loss of efficacy [see Clinical Pharmacology (12.3) ] . The following information was derived from data with Noxafil oral suspension or another posaconazole tablet formulation unless otherwise noted. All clinically important drug interactions with Noxafil oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility), are considered relevant to clinically important drug interactions with posaconazole injection. Consult the labeling of concomitantly used drugs to obtain further information about interactions with posaconazole. Interaction Drug Interaction Rifabutin, phenytoin, efavirenz Avoid coadministration unless the benefit outweighs the risks ( 7.1 , 7.2 ) Other drugs metabolized by CYP3A4 Consider dosage adjustment and monitor for adverse effects and toxicity ( 7.2 ) Digoxin Monitor digoxin plasma concentrations ( 7.2 ) Fosamprenavir Monitor for breakthrough fungal infections ( 7.1 ) 7.1 Effects of Other Drugs on Posaconazole 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. Concomitant use of posaconazole with drugs that can decrease the plasma posaconazole concentrations should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections. Table 15: Drug Interactions Affecting Posaconazole When Administered Concomitantly with Other Drugs UDP-Glucuronidase Inducers Mechanism and Clinical Effect(s) Posaconazole is a UDP-glucuronosyltransferase substrate. Concomitant use of posaconazole with UDP-glucuronidase inducers may decrease posaconazole exposure [see Clinical Pharmacology (12.3) ], which may reduce the effectiveness of posaconazole. Prevention or Management Efavirenz Avoid concomitant use of posaconazole with efavirenz, unless the benefit outweighs the risks. Rifabutin Avoid concomitant use of posaconazole with rifabutin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor closely for breakthrough fungal infections. See Table 17 for rifabutin monitoring considerations when posaconazole affects rifabutin via CYP3A4 inhibition. Phenytoin Avoid concomitant use of posaconazole with phenytoin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor for breakthrough fungal infections. See Table 17 for phenytoin monitoring considerations when posaconazole affects phenytoin via CYP3A4 inhibition. Fosamprenavir Mechanism and Clinical Effect(s) Concomitant use of posaconazole with fosamprenavir may lead to decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3) ], which may reduce effectiveness of posaconazole. Prevention or Management If concomitant use of posaconazole with fosamprenavir is needed, monitor closely for breakthrough fungal infections. 7.2 Effects of Posaconazole on Other Drugs Posaconazole is a strong CYP3A4 inhibitor. Therefore, concomitant use of posaconazole may increase plasma concentrations of drugs that are CYP3A4 substrates [see Clinical Pharmacology (12.3) ] . Table 17: Drug Interactions Affecting Drugs Administered Concomitantly with Posaconazole Digoxin Clinical Effect(s) Increased digoxin plasma concentrations have been reported in patients who received concomitant posaconazole and digoxin. Prevention or Management Monitor digoxin plasma concentrations during concomitant use of posaconazole. Glipizide Clinical …

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 were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses ≥ 1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of posaconazole in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, doses of ≥ 3 times the clinical exposure caused an increase in resorptions (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 populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen. 8.2 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 Treatment of Invasive Aspergillosis The safety and effectiveness of posaconazole injection have been established for the treatment of invasive aspergillosis in pediatric patients 2 years of age and older. Use of posaconazole for these pediatric indications is supported by evidence from adequate and well-controlled studies of posaconazole in adults and safety and pharmacokinetic (PK) data from two pediatric studies [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] . The safety of posaconazole in pediatric patients for these pediatric indications was consistent with the known safety profile of posaconazole in adults [see Adverse Reactions (6.1) ] . The safety and effectiveness of posaconazole have not been established in pediatric patients less than 2 years of age . Prophylaxis of Invasive Aspergillus …

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

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.

11 DESCRIPTION Posaconazole injection contains posaconazole, an azole antifungal agent. 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, for intravenous use, is a clear colorless to yellow colored solution, without preservatives sterile liquid essentially 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. Each 1 mL of posaconazole injection contains 30 mg of sodium. Posaconazole Chemical Structure

10 OVERDOSAGE There is no experience with overdosage of posaconazole injection. During the clinical trials, some patients received Noxafil oral suspension up to 1,600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1,200 mg twice daily Noxafil oral suspension for 3 days. No related adverse reactions were noted by the investigator. Posaconazole is not removed by hemodialysis.

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 serum rubber stopper and flip off seal (NDC 31722-370-31) 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) ].