NOXAFIL

Noxafil (posaconazole) is an azole antifungal agent. Noxafil is available as an injection solution to be diluted before intravenous administration, delayed-release tablet, oral suspension, and for delayed-release oral suspension intended for oral administration. Noxafil PowderMix for delayed-release oral suspension must be reconstituted before oral 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-1-ylmethyl)-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 powder with a low aqueous solubility. Noxafil Injection Noxafil injection is available as a clear colorless to yellow, 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. Noxafil Delayed-Release Tablets Noxafil delayed-release tablet is a yellow, coated, oblong tablet containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: croscarmellose sodium, hydroxypropylcellulose, hypromellose acetate succinate, iron oxide yellow, Macrogol/PEG 3350, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol partially hydrolyzed, silicon dioxide, talc, and titanium dioxide. Noxafil Oral Suspension Noxafil oral suspension is a white, cherry-flavored immediate-release suspension containing 40 mg of posaconazole per mL and the following inactive ingredients: artificial cherry flavor, citric acid monohydrate, glycerin, liquid glucose, polysorbate 80, purified water, simethicone, sodium benzoate, sodium citrate dihydrate, titanium dioxide, and xanthan gum. Noxafil PowderMix for Delayed-Release Oral Suspension Noxafil PowderMix for delayed-release oral suspension is supplied as a component of a kit. Each kit contains Noxafil as an off-white to yellowish powder for delayed-release oral suspension, a bottle of mixing liquid, two 3 mL (green) notched tip syringes, two 10 mL (blue) notched tip syringes, two mixing cups, and one bottle adapter for the mixing liquid bottle. Noxafil PowderMix for delayed-release oral suspension contains 300 mg of posaconazole and the following inactive ingredient: hypromellose acetate succinate. The mixing liquid contains: anhydrous citric acid, antifoam Af emulsion, berry citrus sweet flavor, carboxymethylcellulose sodium, carrageenan calcium sulfate trisodium phosphate, glycerin, methylparaben, microcrystalline cellulose, potassium sorbate, propylparaben, purified water, sodium citrate, sodium phosphate monobasic monohydrate, sodium saccharin, sorbitol solution, and xanthan gum. Once reconstituted, the Noxafil PowderMix for delayed-release oral suspension will be cloudy and free of clumps. Chemical Structure

Noxafil is an azole antifungal indicated as follows: Noxafil injection and Noxafil delayed-release tablets are indicated for the treatment of invasive aspergillosis in adults and pediatric patients 13 years of age and older. ( 1.1 ) Noxafil 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 ) Noxafil injection: adults and pediatric patients 2 years of age and older Noxafil delayed-release tablets: adults and pediatric patients 2 years of age and older who weigh greater than 40 kg Noxafil oral suspension: adults and pediatric patients 13 years of age and older Noxafil PowderMix for delayed-release oral suspension: pediatric patients 2 years of age and older who weigh 40 kg or less Noxafil oral suspension is indicated for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in adult and pediatric patients aged 13 years and older. ( 1.3 ) 1.1 Treatment of Invasive Aspergillosis Noxafil ® injection and Noxafil delayed-release tablets are indicated for the treatment of invasive aspergillosis in adults and pediatric patients 13 years of age and older. 1.2 Prophylaxis of Invasive Aspergillus and Candida Infections Noxafil is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy [see Clinical Studies (14.1) ] as follows: Noxafil injection: adults and pediatric patients 2 years of age and older Noxafil delayed-release tablets: adults and pediatric patients 2 years of age and older who weigh greater than 40 kg Noxafil oral suspension: adults and pediatric patients 13 years of age and older Noxafil PowderMix for delayed-release oral suspension: pediatric patients 2 years of age and older who weigh 40 kg or less 1.3 Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole Noxafil oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole in adults and pediatric patients 13 years of age and older.

Noxafil oral suspension is not substitutable with Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations. ( 2.1 , 2.2 , 2.3 , 2.8 ) Noxafil injection must be administered through an in-line filter. Administer Noxafil injection by intravenous infusion over approximately 90 minutes via a central venous line. ( 2.1 ) Do NOT administer Noxafil injection as an intravenous bolus injection. ( 2.1 ) Administer Noxafil delayed-release tablets with or without food. ( 2.1 ) Administer Noxafil oral suspension with a full meal. ( 2.1 ) Administer Noxafil PowderMix for delayed-release oral suspension with food. ( 2.1 ) Administer Noxafil PowderMix for delayed-release oral suspension with the provided notched tip syringes only. ( 2.1 ) Table 1: Recommended Dosage in Adult Patients Indication Dosage Form, Dose, and Duration of Therapy Treatment of invasive Aspergillosis Noxafil Injection: Loading dose : 300 mg Noxafil injection intravenously twice a day on the first day. Maintenance dose : 300 mg Noxafil injection intravenously once a day thereafter. Recommended total duration of therapy is 6 to 12 weeks. ( 2.2 ) Noxafil Delayed-Release Tablets: Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose : 300 mg (three 100 mg delayed-release tablets) once a day thereafter. Recommended total duration of therapy is 6 to 12 weeks. ( 2.2 ) Switching between the intravenous and delayed-release tablets is acceptable. A loading dose is not required when switching between formulations. ( 2.2 ) Prophylaxis of invasive Aspergillus and Candida infections Noxafil Injection: Loading dose : 300 mg Noxafil injection intravenously twice a day on the first day. Maintenance dose : 300 mg Noxafil injection intravenously once a day thereafter. Duration of therapy is based on recovery from neutropenia or immunosuppression. ( 2.2 , 2.3 ) Noxafil Delayed-Release Tablets: Loading dose : 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose : 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Duration of therapy is based on recovery from neutropenia or immunosuppression. ( 2.2 , 2.3 ) Noxafil Oral Suspension: 200 mg (5 mL) three times a day. Duration of therapy is based on recovery from neutropenia or immunosuppression. ( 2.2 , 2.3 ) Oropharyngeal Candidiasis (OPC) Noxafil Oral Suspension: Loading dose : 100 mg (2.5 mL) twice a day on the first day. Maintenance dose : 100 mg (2.5 mL) once a day for 13 days. ( 2.2 , 2.3 ) OPC Refractory (rOPC) to Itraconazole and/or Fluconazole Noxafil Oral Suspension: 400 mg (10 mL) twice a day. Duration of therapy is based on the severity of the patient's underlying disease and clinical response. ( 2.2 , 2.3 ) For pediatric patients, see the Full Prescribing Information for dosing recommendations for Noxafil injection , Noxafil delayed-release tablets , Noxafil oral suspension , and Noxafil PowderMix for delayed-release oral suspension based on the age and indication associated with the dosage form. ( 1.1 , 1.2 , 1.3 , 2.1 , 2.3 ) 2.1 Important Administration Instructions Non-substitutable Noxafil oral suspension is not substitutable with Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration (2.2 , 2.3 , 2.8) ]. Noxafil 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, Noxafil 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 Noxafil injection as an intravenous bolus injection. Noxafil delayed-release tablets Swallow tablets whole. Do not divide, crush, or chew. Administer with or without food [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . For patients who cannot eat a full meal, Noxafil delayed-release tablets should be used instead of Noxafil oral suspension for the prophylaxis indication. Noxafil delayed-release tablets generally provide higher plasma drug exposures than Noxafil oral suspension under both fed and fasted conditions [see Dosage and Administration (2.6) ] . Noxafil oral suspension Administer with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal [see Dosage and Administration (2.6) ]. Co-administration 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 [see Drug Interactions (7.6 , 7.7 , 7.8 , 7.9 , 7.13) ]. Noxafil PowderMix for delayed-release oral suspension Administer with food [see Clinical Pharmacology (12.3) ] . Administration with alcohol is not recommended [see Drug Interactions (7.15) ] . To ensure delivery of the correct dose, ONLY the provided notched tip syringes must be used for preparation and administration. The design of the notched tip syringe prevents aggregation of the suspension during preparation and administration [see Dosage and Administration (2.8) ] . 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 Noxafil Injection: Loading dose : 300 mg Noxafil injection intravenously twice a day on the first day. Maintenance dose : 300 mg Noxafil injection intravenously once a day, starting on the second day. Noxafil Delayed-Release Tablets: Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose : 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Switching between the intravenous and delayed-release tablets is acceptable. A loading dose is not required when switching between formulations. Loading dose: 1 day Maintenance dose: Recommended total duration of therapy is 6 to 12 weeks. Prophylaxis of invasive Aspergillus and Candida infections Noxafil Injection: Loading dose : 300 mg Noxafil injection intravenously twice a day on the first day. Maintenance dose : 300 mg Noxafil injection intravenously once a day thereafter. Noxafil Delayed-Release Tablets: Loading dose : 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose : 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Noxafil Oral Suspension: 200 mg (5 mL) three times a day. Loading dose : 1 day Maintenance dose : Duration of therapy is based on recovery from neutropenia or immunosuppression. Oropharyngeal Candidiasis (OPC) Noxafil Oral Suspension: Loading dose : 100 mg (2.5 mL) twice a day on the first day. Maintenance dose : 100 mg (2.5 mL) once a day thereafter. Loading dose : 1 day Maintenance dose : 13 days OPC Refractory (rOPC) to Itraconazole and/or Fluconazole Noxafil Oral Suspension: 400 mg (10 mL) twice a day. Duration of therapy is based on the severity of the patient’s underlying disease and clinical response. 2.3 Dosing Regimen in Pediatric Patients (ages 2 to less than 18 years of age) The recommended dosing regimen of Noxafil for pediatric patients 2 to less than 18 years of age is shown in Tables 2 , 3 , and 4 [see Dosage and Administration (2.5 , 2.6 , 2.8) and Clinical Pharmacology (12.3) ]. Noxafil PowderMix for delayed-release oral suspension is not recommended for use in patients who weigh greater than 40 kg because the recommended dosage cannot be achieved with this formulation. Table 2: Noxafil Delayed-Release Tablet and Noxafil Injection Dosing Regimens for Pediatric Patients (ages 2 to less than 18 years of age) Recommended Pediatric Dosage and Formulation Indication Weight/Age Delayed-Release Tablet 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) Not Applicable Loading dose: 6 mg/kg up to a maximum of 300 mg twice daily on the first day Duration of therapy is based on recovery from neutropenia or immunosuppression. Greater than 40 kg (2 to less than 18 years of age) Loading dose: 300 mg twice daily on the first day Maintenance dose: 300 mg once daily Maintenance dose: 6 mg/kg up to a maximum of 300 mg once daily Treatment of invasive Aspergillosis 13 to less than 18 years of age regardless of weight. Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Loading dose: 300 mg Noxafil injection intravenously twice a day on the first day. Loading dose: 1 day Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Maintenance dose: 300 mg Noxafil injection intravenously once a day, starting on the second day. Maintenance dose: Recommended total duration of therapy is 6 to 12 weeks. Switching between the intravenous and delayed-release tablets is acceptable. A loading dose is not required when switching between formulations. Switching between the intravenous and delayed-release tablets is acceptable. A loading dose is not required when switching between formulations. Table 3: Noxafil Oral Suspension Dosing Regimens for Pediatric Patients (ages 13 to less than 18 years of age) Indication Loading Dose (volume) and frequency Maintenance Dose (volume) and frequency Duration of therapy Prophylaxis of invasive Aspergillus and Candida infections 200 mg (5 mL) three times a day 200 mg (5 mL) three times a day Duration of therapy is based on recovery from neutropenia or immunosuppression. Oropharyngeal Candidiasis (OPC) 100 mg (2.5 mL) twice daily on the first day 100 mg (2.5 mL) once daily 13 days OPC Refractory (rOPC) to Itraconazole and/or Fluconazole 400 mg (10 mL) twice daily 400 mg (10 mL) twice daily Duration of therapy is based on the severity of the patient’s underlying disease and clinical response. Table 4: Noxafil PowderMix for Delayed-Release Oral Suspension Dosing Regimen in Pediatric Patients (ages 2 to less than 18 years of age, weighing 10 to 40 kg) Indication Weight (kg) Loading Dose (volume) Maintenance Dose (volume) Prophylaxis of invasive Aspergillus and Candida infections 10 to less than 12 90 mg (3 mL) twice daily on the first day 90 mg (3 mL) once daily 12 to less than 17 120 mg (4 mL) twice daily on the first day 120 mg (4 mL) once daily 17 to less than 21 150 mg (5 mL) twice daily on the first day 150 mg (5 mL) once daily 21 to less than 26 180 mg (6 mL) twice daily on the first day 180 mg (6 mL) once daily 26 to less than 36 210 mg (7 mL) twice daily on the first day 210 mg (7 mL) once daily 36 to 40 240 mg (8 mL) twice daily on the first day 240 mg (8 mL) once daily 2.4 Preparation, Intravenous Line Compatibility, and Administration of Noxafil Injection Preparation: Equilibrate the refrigerated vial of Noxafil (posaconazole) injection to room temperature. To prepare the required dose, aseptically transfer one vial (16.7 mL) of Noxafil 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. Noxafil injection is a single-dose sterile solution without preservatives. Discard any unused portion from the vial. Once admixed, the diluted solution of Noxafil 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 Noxafil 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 Noxafil 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). Noxafil 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 Noxafil 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: Noxafil 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: Noxafil 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. Noxafil injection is not for bolus administration. If a central venous catheter is not available, Noxafil 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) ] . 2.5 Administration Instructions for Noxafil Delayed-Release Tablets Swallow tablets whole. Do not divide, crush, or chew. Administer Noxafil delayed-release tablets with or without food [see Clinical Pharmacology (12.3) ]. 2.6 Administration Instructions for Noxafil Oral Suspension Shake Noxafil oral suspension well before use. Administer with measured dosing spoon (see Figure 1 ) provided. Figure 1: A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL. Rinse the spoon with water after each administration and before storage. Administer each dose of Noxafil oral suspension during or immediately (i.e., within 20 minutes) following a full meal [see Clinical Pharmacology (12.3) ]. For patients who cannot eat a full meal, Noxafil delayed-release tablets should be used instead of Noxafil oral suspension for the prophylaxis indication. Noxafil delayed-release tablets provide higher plasma drug exposures than Noxafil oral suspension under fasted conditions [see Dosage and Administration (2.1) ]. In patients who cannot eat a full meal and for whom Noxafil delayed-release tablets or Noxafil injection are not options, administer each dose of Noxafil oral suspension with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale). For patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage and who do not have the option of taking Noxafil delayed-release tablets or Noxafil injection, an alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections. Figure 1 2.7 Non-substitutability between Noxafil Oral Suspension and Other Formulations Noxafil oral suspension is not substitutable with Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration (2.2 , 2.3) ]. 2.8 Preparation and Administration Instructions for Noxafil PowderMix for Delayed-Release Oral Suspension (pediatric patients ages 2 to less than 18 years of age) For details on preparation and administration of Noxafil PowderMix for delayed-release oral suspension, see Instructions for Use . Preparation Instructions Do not open packet in the Noxafil PowderMix kit until ready to prepare the medicine. Remove cap from the mixing liquid and push the bottle adapter into the neck of the bottle. Once in place, the bottle adapter stays in the bottle. Remove 9 mL of mixing liquid using the provided BLUE syringe. Put the cap back on the bottle. ONLY the mixing liquid in the kit should be used to prepare Noxafil PowderMix for delayed-release oral suspension. Using the provided mixing cup, combine 9 mL of mixing liquid and the entire contents of one packet in the Noxafil PowderMix kit and mix. Each single-use packet in the Noxafil PowderMix kit contains 300 mg of posaconazole to be suspended in 9 mL of mixing liquid giving a final concentration of approximately 30 mg per mL. Shake the mixing cup vigorously for 45 seconds to mix the powder and mixing liquid from the Noxafil PowderMix kit. Check to make sure the powder is mixed. The mixture should look cloudy and free of clumps. The reconstituted suspension must be used within 1 hour. Discard unused portion of the prepared drug product. Administration Instructions Administer Noxafil PowderMix for delayed-release oral suspension with food. Choose the correct syringe based on the prescribed dose: Use 3 mL (GREEN) syringe if dose is 3 mL or less. Use 10 mL (BLUE) syringe if dose is more than 3 mL. Measure the prescribed dose volume with the notched tip syringe provided with the kit and administer the dose orally. Administer the dose orally within 1 hour of mixing. Not all of the Noxafil PowderMix in the mixing cup will be used. There will be some left over in the mixing cup. The maximum dose that can be accurately withdrawn from the mixing cup after reconstitution is 240 mg (8 mL). To ensure delivery of the correct dose, ONLY the provided notched tip syringes must be used for preparation and administration. The design of the notched tip syringe prevents aggregation of the suspension during preparation and administration. Discard any remaining suspension. The mixing cup may be hand washed and reused. Alternatively, the mixing cup may be discarded, and a similar mixing cup with a lid may be used for subsequent doses. The notched tip syringes may also be hand washed and reused. For additional supply, a separate box of notched tip syringes is provided with the Noxafil PowderMix kit. 2.9 Dosage Adjustments in Patients with Renal Impairment The pharmacokinetics of Noxafil oral suspension and Noxafil delayed-release tablets are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment. Noxafil 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 Noxafil injection. In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <50 mL/min), receiving the Noxafil 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 Noxafil therapy.

Known hypersensitivity to posaconazole or other azole antifungal agents. ( 4.1 ) Coadministration of Noxafil with the following drugs is contraindicated; Noxafil 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 ) Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with known or suspected Hereditary Fructose Intolerance (HFI). ( 4.7 , 5.9 , 8.4 ) 4.1 Hypersensitivity Noxafil is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents. 4.2 Use with Sirolimus Noxafil is contraindicated with sirolimus. Concomitant administration of Noxafil 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 Noxafil is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of Noxafil 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 Noxafil 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 Noxafil 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) ]. 4.7 Use of Noxafil PowderMix for Delayed-Release Oral Suspension in Patients with Hereditary Fructose Intolerance Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with known or suspected hereditary fructose intolerance (HFI) [see Warnings and Precautions (5.9) and Use in Specific Populations (8.4) ] .

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 Noxafil in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. ( 6.1 ) Pediatric Patients: Common adverse reactions (incidence >20% receiving 6 mg/kg Noxafil injection and Noxafil PowderMix for delayed-release oral suspension) 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 Merck Sharp & Dohme LLC at 1-877-888-4231 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 Noxafil 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 Noxafil Injection and Noxafil Delayed-Release Tablets for the Treatment of Invasive Aspergillosis The safety of Noxafil injection and Noxafil delayed-release tablet was assessed in a randomized, double-blind, active-controlled clinical study of Noxafil injection and Noxafil delayed-release tablets versus voriconazole for treatment of invasive aspergillosis (Aspergillosis Treatment Study). A total of 575 (288 in Noxafil 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 Noxafil 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 Noxafil arm, and septic shock and acute myeloid leukemia in the voriconazole arm. Table 7: Noxafil Invasive Aspergillosis Treatment Study: Adverse Reactions in at Least 10% of Subjects Treated with Noxafil Injection or Noxafil Delayed-Release Tablets System Organ Class Noxafil injection or tablet (N = 288), n (%) Voriconazole injection or oral (N = 287), n (%) Blood and lymphatic system disorders Anemia 25 (8.7) 29 (10.1) Febrile neutropenia 42 (14.6) 38 (13.2) Gastrointestinal disorders Abdominal pain 29 (10.1) 24 (8.4) Constipation 32 (11.1) 23 (8.0) Diarrhea 52 (18.1) 52 (18.1) Nausea 65 (22.6) 51 (17.8) Vomiting 52 (18.1) 39 (13.6) General disorders and administration site conditions Edema peripheral 32 (11.1) 24 (8.4) Pyrexia 81 (28.1) 72 (25.1) Infections and infestations Pneumonia 36 (12.5) 26 (9.1) Investigations Alanine aminotransferase increased 42 (14.6) 37 (12.9) Aspartate aminotransferase increased 38 (13.2) 36 (12.5) Blood alkaline phosphatase increased 21 (7.3) 29 (10.1) Metabolism and nutrition disorders Hypokalemia 82 (28.5) 49 (17.1) Hypomagnesemia 29 (10.1) 18 (6.3) Nervous system disorders Headache 35 (12.2) 25 (8.7) Respiratory, thoracic and mediastinal disorders Cough 30 (10.4) 24 (8.4) Epistaxis 32 (11.1) 17 (5.9) The most frequently reported adverse reactions in the Noxafil-treated group were pyrexia (28%), hypokalemia (28%), and nausea (23%). Clinical Trial Experience with Noxafil Injection for Prophylaxis Multiple doses of Noxafil injection administered via a peripheral venous catheter were associated with thrombophlebitis (60% incidence). Therefore, in subsequent studies, Noxafil injection was administered via central venous catheter. The safety of Noxafil injection has been assessed in 268 patients in a clinical trial. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of Noxafil injection when given as antifungal prophylaxis (Noxafil Injection Study). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 55% male, had a mean age of 51 years (range 18-82 years, 19% of patients were ≥65 years of age), and were 95% white and 8% Hispanic. Ten patients received a single dose of 200 mg Noxafil 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 Noxafil injection 300 mg daily dose in the Noxafil Injection Study. Each patient received a loading dose, 300 mg twice on Day 1. Following Noxafil intravenous therapy, patients received Noxafil oral suspension to complete 28 days of total Noxafil therapy. Table 8: Noxafil Injection Study: Adverse Reactions in at Least 10% of Subjects Treated with Noxafil Injection 300 mg Daily Dose Body System Noxafil Injection Treatment Phase n=237 (%) Adverse reactions reported in patients with an onset during the Noxafil intravenous dosing phase of the study. Noxafil 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 Noxafil 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 Noxafil intravenous phase of dosing with 300 mg once daily were diarrhea (32%), hypokalemia (22%), pyrexia (21%), and nausea (19%). These adverse reactions were consistent with those seen in studies with Noxafil oral suspension. Clinical Trial Experience with Noxafil Delayed-Release Tablets for Prophylaxis The safety of Noxafil delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of Noxafil delayed-release tablets when given as antifungal prophylaxis (Noxafil Delayed-Release Tablet Study). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 62% male, had a mean age of 51 years (range 19-78 years, 17% of patients were ≥65 years of age), and were 93% white and 16% Hispanic. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received 200 mg daily dose and 210 patients received 300 mg daily dose (following twice daily dosing on Day 1 in each cohort). Table 9 presents adverse reactions observed in patients treated with 300 mg daily dose at an incidence of ≥10% in Noxafil Delayed-Release Tablet Study. Table 9: Noxafil Delayed-Release Tablet Study: Adverse Reactions in at Least 10% of Subjects Treated with 300 mg Daily Dose Body System Noxafil delayed-release tablet (300 mg) n=210 (%) Subjects Reporting any Adverse Reaction 207 (99) Blood and Lymphatic System Disorder Anemia 22 (10) Thrombocytopenia 29 (14) Gastrointestinal Disorders Abdominal Pain 23 (11) Constipation 20 (10) Diarrhea 61 (29) Nausea 56 (27) Vomiting 28 (13) General Disorders and Administration Site Conditions Asthenia 20 (10) Chills 22 (10) Mucosal Inflammation 29 (14) Edema Peripheral 33 (16) Pyrexia 59 (28) Metabolism and Nutrition Disorders Hypokalemia 46 (22) Hypomagnesemia 20 (10) Nervous System Disorders Headache 30 (14) Respiratory, Thoracic and Mediastinal Disorders Cough 35 (17) Epistaxis 30 (14) Skin and Subcutaneous Tissue Disorders Rash 34 (16) Vascular Disorders Hypertension 23 (11) The most frequently reported adverse reactions (>25%) with Noxafil delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea. The most common adverse reaction leading to discontinuation of Noxafil delayed-release tablets 300 mg once daily was nausea (2%). Clinical Trial Safety Experience with Noxafil Oral Suspension The safety of Noxafil oral suspension has been assessed in 1844 patients. This includes 605 patients in the active-controlled prophylaxis studies, 557 patients in the active-controlled OPC studies, 239 patients in refractory OPC studies, and 443 patients from other indications. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy, neutropenia post-chemotherapy, GVHD post HSCT, and HIV infection, as well as non-neutropenic patients. This patient population was 71% male, had a mean age of 42 years (range 8-84 years, 6% of patients were ≥65 years of age and 1% was <18 years of age), and were 64% white, 16% Hispanic, and 36% non-white (including 14% black). Noxafil therapy was given to 171 patients for ≥6 months, with 58 patients receiving Noxafil therapy for ≥12 months. Table 10 presents adverse reactions observed at an incidence of >10% in Noxafil prophylaxis studies. Table 11 presents adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies. Prophylaxis of Aspergillus and Candida: In the 2 randomized, comparative prophylaxis studies (Noxafil Oral Suspension Study 1 and 2), the safety of Noxafil oral suspension 200 mg three times a day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely immunocompromised patients. The most frequently reported adverse reactions (>30%) in the prophylaxis clinical trials were fever, diarrhea, and nausea. The most common adverse reactions leading to discontinuation of Noxafil in the prophylaxis studies were associated with GI disorders, specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%). Table 10: Noxafil Oral Suspension Study 1 and Study 2. Adverse Reactions in at Least 10% of the Noxafil Oral Suspension or Fluconazole Treatment Groups (Pooled Prophylaxis Safety Analysis) Body System Noxafil Oral Suspension n=605 (%) Fluconazole n=539 (%) Itraconazole n=58 (%) Subjects Reporting any Adverse Reaction 595 (98) 531 (99) 58 (100) Body as a Whole - General Disorders Fever 274 (45) 254 (47) 32 (55) Headache 171 (28) 141 (26) 23 (40) Rigors 122 (20) 87 (16) 17 (29) Fatigue 101 (17) 98 (18) 5 (9) Edema Legs 93 (15) 67 (12) 11 (19) Anorexia 92 (15) 94 (17) 16 (28) Dizziness 64 (11) 56 (10) 5 (9) Edema 54 (9) 68 (13) 8 (14) Weakness 51 (8) 52 (10) 2 (3) Cardiovascular Disorders, General Hypertension 106 (18) 88 (16) 3 (5) Hypotension 83 (14) 79 (15) 10 (17) Disorders of Blood and Lymphatic System Anemia 149 (25) 124 (23) 16 (28) Neutropenia 141 (23) 122 (23) 23 (40) Disorders of the Reproductive System and Breast Vaginal Hemorrhage Percentages of sex-specific adverse reactions are based on the number of males/females. 24 (10) 20 (9) 3 (12) Gastrointestinal System Disorders Diarrhea 256 (42) 212 (39) 35 (60) Nausea 232 (38) 198 (37) 30 (52) Vomiting 174 (29) 173 (32) 24 (41) Abdominal Pain 161 (27) 147 (27) 21 (36) Constipation 126 (21) 94 (17) 10 (17) Dyspepsia 61 (10) 50 (9) 6 (10) Heart Rate and Rhythm Disorders Tachycardia 72 (12) 75 (14) 3 (5) Infection and Infestations Pharyngitis 71 (12) 60 (11) 12 (21) Liver and Biliary System Disorders Bilirubinemia 59 (10) 51 (9) 11 (19) Metabolic and Nutritional Disorders Hypokalemia 181 (30) 142 (26) 30 (52) Hypomagnesemia 110 (18) 84 (16) 11 (19) Hyperglycemia 68 (11) 76 (14) 2 (3) Hypocalcemia 56 (9) 55 (10) 5 (9) Musculoskeletal System Disorders Musculoskeletal Pain 95 (16) 82 (15) 9 (16) Arthralgia 69 (11) 67 (12) 5 (9) Back Pain 63 (10) 66 (12) 4 (7) Platelet, Bleeding and Clotting Disorders Thrombocytopenia 175 (29) 146 (27) 20 (34) Petechiae 64 (11) 54 (10) 9 (16) Psychiatric Disorders Insomnia 103 (17) 92 (17) 11 (19) Respiratory System Disorders Coughing 146 (24) 130 (24) 14 (24) Dyspnea 121 (20) 116 (22) 15 (26) Epistaxis 82 (14) 73 (14) 12 (21) Skin and Subcutaneous Tissue Disorders Rash 113 (19) 96 (18) 25 (43) Pruritus 69 (11) 62 (12) 11 (19) HIV Infected Subjects with OPC : In 2 randomized comparative studies in OPC, the safety of Noxafil oral suspension at a dose of less than or equal to 400 mg once daily in 557 HIV-infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at a dose of 100 mg once daily. An additional 239 HIV-infected patients with refractory OPC received Noxafil oral suspension in 2 non-comparative trials for refractory OPC (rOPC). Of these subjects, 149 received the 800-mg/day dose and the remainder received the less than or equal to 400-mg once daily dose. In the OPC/rOPC studies, the most common adverse reactions were fever, diarrhea, nausea, headache, vomiting, and coughing. The most common adverse reactions that led to treatment discontinuation of Noxafil in the Controlled OPC Pool included respiratory impairment (1%) and pneumonia (1%). In the refractory OPC pool, the most common adverse reactions that led to treatment discontinuation of Noxafil were AIDS (7%) and respiratory impairment (3%). Table 11: Adverse Reactions in at Least 10% of the Treated Population in OPC Studies with Noxafil Oral Suspension Body System Number (%) of Subjects Controlled OPC Pool Refractory OPC Pool Noxafil Oral Suspension Fluconazole Noxafil Oral Suspension n=557 n=262 n=239 OPC=oropharyngeal candidiasis Subjects Reporting any Adverse Reaction Number of subjects reporting adverse reactions at least once during the study, without regard to relationship to treatment. Subjects may have reported more than 1 event. 356 (64) 175 (67) 221 (92) Body as a Whole – General Disorders Fever 34 (6) 22 (8) 82 (34) Headache 44 (8) 23 (9) 47 (20) Anorexia 10 (2) 4 (2) 46 (19) Fatigue 18 (3) 12 (5) 31 (13) Asthenia 9 (2) 5 (2) 31 (13) Rigors 2 (<1) 4 (2) 29 (12) Pain 4 (1) 2 (1) 27 (11) Disorders of Blood and Lymphatic System Neutropenia 21 (4) 8 (3) 39 (16) Anemia 11 (2) 5 (2) 34 (14) Gastrointestinal System Disorders Diarrhea 58 (10) 34 (13) 70 (29) Nausea 48 (9) 30 (11) 70 (29) Vomiting 37 (7) 18 (7) 67 (28) Abdominal Pain 27 (5) 17 (6) 43 (18) Infection and Infestations Candidiasis, Oral 3 (1) 1 (<1) 28 (12) Herpes Simplex 16 (3) 8 (3) 26 (11) Pneumonia 17 (3) 6 (2) 25 (10) Metabolic and Nutritional Disorders Weight Decrease 4 (1) 2 (1) 33 (14) Dehydration 4 (1) 7 (3) 27 (11) Psychiatric Disorders Insomnia 8 (1) 3 (1) 39 (16) Respiratory System Disorders Coughing 18 (3) 11 (4) 60 (25) Dyspnea 8 (1) 8 (3) 28 (12) Skin and Subcutaneous Tissue Disorders Rash 15 (3) 10 (4) 36 (15) Sweating Increased 13 (2) 5 (2) 23 (10) Adverse reactions were reported more frequently in the pool of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions (SARs) were reported in 55% (132/239). The most commonly reported SARs were fever (13%) and neutropenia (10%). Other clinically significant adverse reactions reported in less than 5% of patients in clinical trials of Noxafil 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. For the prophylaxis studies, the number of patients with changes in liver tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 during the study is presented in Table 12 . Table 12: Noxafil Oral Suspension Study 1 and Study 2. Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 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. Noxafil Oral Suspension Study 1 CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase. Laboratory Parameter Noxafil Oral Suspension n=301 Fluconazole n=299 AST 11/266 (4) 13/266 (5) ALT 47/271 (17) 39/272 (14) Bilirubin 24/271 (9) 20/275 (7) Alkaline Phosphatase 9/271 (3) 8/271 (3) Noxafil Oral Suspension Study 2 Laboratory Parameter Noxafil Oral Suspension (n=304) Fluconazole/Itraconazole (n=298) AST 9/286 (3) 5/280 (2) ALT 18/289 (6) 13/284 (5) Bilirubin 20/290 (7) 25/285 (9) Alkaline Phosphatase 4/281 (1) 1/276 (<1) The number of patients treated for OPC with clinically significant liver test abnormalities at any time during the studies is provided in Table 13 (liver test abnormalities were present in some of these patients prior to initiation of the study drug). Table 13: Noxafil Oral Suspension Studies: Clinically Significant Laboratory Test Abnormalities without Regard to Baseline Value Laboratory Test Controlled Refractory Noxafil Oral Suspension Fluconazole Noxafil Oral Suspension n=557 (%) n=262 (%) n=239 (%) ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase. ALT > 3.0 × ULN 16/537 (3) 13/254 (5) 25/226 (11) AST > 3.0 × ULN 33/537 (6) 26/254 (10) 39/223 (17) Total Bilirubin > 1.5 × ULN 15/536 (3) 5/254 (2) 9/197 (5) Alkaline Phosphatase > 3.0 × ULN 17/535 (3) 15/253 (6) 24/190 (13) 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 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 Noxafil n/N (%) Voriconazole n/N (%) 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. 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 Noxafil 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 (Noxafil injection/ Noxafil PowderMix for delayed-release oral suspension Pediatric Study 1, NCT02452034); hereinafter referred to as Noxafil Pediatric Study) in 115 immunocompromised pediatric patients 2 to less than 18 years of age with known or expected neutropenia. Noxafil 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 Noxafil 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 Noxafil 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 Noxafil in the Noxafil Pediatric Study. Reported adverse reaction profile of Noxafil in pediatric patients was consistent with the safety profile of Noxafil in adults. The most common adverse reactions (occurring in greater than 20% of pediatric patients receiving 6 mg/kg Noxafil 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 Noxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension Adverse Reaction Noxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension 6 mg/kg Dose Cohort n=49 (%) Noxafil 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 Noxafil in the Noxafil 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: Noxafil Pediatric Study: Changes in Liver Tests from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 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 Noxafil Injection and Noxafil PowderMix for Delayed- Release Oral Suspension (6 mg/kg daily) n=49 (%) CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase 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 Noxafil. 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

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 Noxafil injection, Noxafil delayed-release tablet, and Noxafil PowderMix for delayed-release oral suspension as well [see Drug Interactions (7.9) and (7.13) ] . Interaction Drug Interaction Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazole The drug interactions with esomeprazole and metoclopramide do not apply to Noxafil tablets. Avoid coadministration unless the benefit outweighs the risks ( 7.6 , 7.7 , 7.8 , 7.9 ) 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, metoclopramide Monitor for breakthrough fungal infections ( 7.6 , 7.13 ) 7.1 Immunosuppressants Metabolized by CYP3A4 Sirolimus: Concomitant administration of Noxafil 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: Noxafil has been shown to significantly increase the C max 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 Noxafil treatment and the tacrolimus dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . Cyclosporine: Noxafil has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of Noxafil treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of Noxafil treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of Noxafil 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 Noxafil 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, Noxafil 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 Noxafil with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, Noxafil 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. Noxafil may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Therefore, Noxafil is contraindicated with ergot alkaloids [see Contraindications (4.5) ] . 7.5 Benzodiazepines Metabolized by CYP3A4 Concomitant administration of Noxafil 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 Noxafil 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 Noxafil unless the benefit outweighs the risks. Ritonavir and Atazanavir: Ritonavir and atazanavir are metabolized by CYP3A4 and Noxafil 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 Noxafil. Fosamprenavir: Combining fosamprenavir with Noxafil 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, coadministration of rifabutin with Noxafil increases rifabutin plasma concentrations [see Clinical Pharmacology (12.3) ] . Concomitant use of Noxafil 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 Noxafil increases phenytoin plasma concentrations [see Clinical Pharmacology (12.3) ] . Concomitant use of Noxafil 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 Noxafil and dose reduction of phenytoin should be considered. 7.9 Gastric Acid Suppressors/Neutralizers Noxafil Delayed-Release Tablet and Noxafil PowderMix for Delayed-Release Oral Suspension: No clinically relevant effects on the pharmacokinetics of posaconazole were observed when Noxafil delayed-release tablets are concomitantly used with antacids, H 2 -receptor antagonists and proton pump inhibitors [see Clinical Pharmacology (12.3) ] . No dosage adjustment of Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension is required when concomitantly used with antacids, H 2 -receptor antagonists and proton pump inhibitors. Noxafil Oral Suspension: Cimetidine (an H 2 -receptor antagonist) and esomeprazole (a proton pump inhibitor) when given with Noxafil oral suspension results in decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3) ] . It is recommended to avoid concomitant use of cimetidine and esomeprazole with Noxafil oral suspension unless the benefit outweighs the risks. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. No clinically relevant effects were observed when Noxafil oral suspension is concomitantly used with antacids and H 2 -receptor antagonists other than cimetidine. No dosage adjustment of Noxafil oral suspension is required when Noxafil oral suspension is concomitantly used with antacids and H 2 -receptor antagonists other than cimetidine. 7.10 Vinca Alkaloids Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including Noxafil, with vincristine has been associated with serious adverse reactions [see Warnings and Precautions (5.8) ]. Noxafil may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including Noxafil, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. 7.11 Calcium Channel Blockers Metabolized by CYP3A4 Noxafil 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 Noxafil. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration. 7.13 Gastrointestinal Motility Agents Noxafil Delayed-Release Tablet and Noxafil PowderMix for Delayed-Release Oral Suspension: Concomitant administration of metoclopramide with Noxafil delayed-release tablets did not affect the pharmacokinetics of posaconazole [see Clinical Pharmacology (12.3) ] . No dosage adjustment of Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension is required when given concomitantly with metoclopramide. Noxafil Oral Suspension: Metoclopramide, when given with Noxafil oral suspension, decreases posaconazole plasma concentrations [see Clinical Pharmacology (12.3) ]. If metoclopramide is concomitantly administered with Noxafil oral suspension, it is recommended to closely monitor for breakthrough fungal infections. Loperamide does not affect posaconazole plasma concentrations after Noxafil oral suspension administration [see Clinical Pharmacology (12.3) ]. No dosage adjustment of Noxafil oral suspension is required when loperamide and Noxafil oral suspension are used concomitantly. 7.14 Glipizide Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when Noxafil and glipizide are concomitantly used. 7.15 Alcohol Posaconazole was found to release faster from Noxafil PowderMix for delayed-release oral suspension in the presence of alcohol in vitro , which may interfere with its delayed release characteristics. Administration of Noxafil PowderMix for delayed-release oral suspension with alcohol is not recommended [see Clinical Pharmacology (12.3) ] . 7.16 Venetoclax Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax C max and AUC 0-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.

16.2 Storage and Handling Noxafil Injection Noxafil 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) ]. Noxafil Delayed-Release Tablets Store at 20 to 25°C (68 to 77°F), excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Noxafil Oral Suspension Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. DO NOT FREEZE. Noxafil PowderMix for Delayed-Release Oral Suspension Store the entire kit at 20 to 25°C (68 to 77°F), excursions permitted to 15 to 30°C (59 to 86°F) in a clean, dry place. Do not open foil packet containing Noxafil PowderMix for delayed-release oral suspension until ready for use. Storage conditions for the reconstituted solution are presented in another section of the prescribing information [see Dosage and Administration (2.8) ].