DOSAGE & ADMINISTRATION SECTION.

2DOSAGE AND ADMINISTRATION. 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 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 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 PatientsIndicationDosage Form, Dose, and Duration of TherapyTreatment of invasive AspergillosisNoxafil Injection:Loading dose: 300 mg Noxafil injection intravenously twice day on the first day.Maintenance dose: 300 mg Noxafil injection intravenously once day thereafter. Recommended total duration of therapy is to 12 weeks. (2.2)Noxafil Delayed-Release Tablets:Loading dose: 300 mg (three 100 mg delayed-release tablets) twice day on the first day. Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once day thereafter. Recommended total duration of therapy is to 12 weeks. (2.2)Switching between the intravenous and delayed-release tablets is acceptable. loading dose is not required when switching between formulations. (2.2)Prophylaxis of invasive Aspergillus and Candida infectionsNoxafil Injection:Loading dose: 300 mg Noxafil injection intravenously twice day on the first day.Maintenance dose: 300 mg Noxafil injection intravenously once 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 day on the first day.Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once 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 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 day on the first day.Maintenance dose: 100 mg (2.5 mL) once day for 13 days. (2.2, 2.3)OPC Refractory (rOPC) to Itraconazole and/or FluconazoleNoxafil Oral Suspension: 400 mg (10 mL) twice day. Duration of therapy is based on the severity of the patients 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). 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 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 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). 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). 2.1Important Administration Instructions. Non-substitutableNoxafil 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 injectionAdminister via central venous line, including central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes [see Dosage and Administration (2.4)].If central venous catheter is not available, Noxafil injection may be administered through peripheral venous catheter by slow intravenous infusion over 30 minutes only as single dose in advance of central venous line placement or to bridge the period during which central venous line is replaced or is in use for other intravenous treatment.When multiple dosing is required, the infusion should be done via central venous line.Do NOT administer Noxafil injection as an intravenous bolus injection.Noxafil delayed-release tabletsSwallow 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 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 suspensionAdminister with full meal or with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat 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 suspensionAdminister 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)].. Administer via central venous line, including central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes [see Dosage and Administration (2.4)].. If central venous catheter is not available, Noxafil injection may be administered through peripheral venous catheter by slow intravenous infusion over 30 minutes only as single dose in advance of central venous line placement or to bridge the period during which central venous line is replaced or is in use for other intravenous treatment.. When multiple dosing is required, the infusion should be done via central venous line.. Do NOT administer Noxafil injection as an intravenous bolus injection.. 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 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)]. Administer with full meal or with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat 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)]. 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 PatientsIndicationDose and FrequencyDuration of TherapyTreatment of invasive AspergillosisNoxafil Injection:Loading dose: 300 mg Noxafil injection intravenously twice day on the first day.Maintenance dose: 300 mg Noxafil injection intravenously once day, starting on the second day. Noxafil Delayed-Release Tablets: Loading dose: 300 mg (three 100 mg delayed-release tablets) twice day on the first day. Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once day, starting on the second day.Switching between the intravenous and delayed-release tablets is acceptable. loading dose is not required when switching between formulations.Loading dose:1 dayMaintenance dose:Recommended total duration of therapy is to 12 weeks.Prophylaxis of invasive Aspergillus and Candida infectionsNoxafil Injection: Loading dose: 300 mg Noxafil injection intravenously twice day on the first day.Maintenance dose: 300 mg Noxafil injection intravenously once day thereafter. Noxafil Delayed-Release Tablets: Loading dose: 300 mg (three 100 mg delayed-release tablets) twice day on the first day.Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once day, starting on the second day. Noxafil Oral Suspension: 200 mg (5 mL) three times day. Loading dose:1 dayMaintenance 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 day on the first day. Maintenance dose: 100 mg (2.5 mL) once day thereafter.Loading dose:1 dayMaintenance dose: 13 daysOPC Refractory (rOPC) to Itraconazole and/or FluconazoleNoxafil Oral Suspension: 400 mg (10 mL) twice day. Duration of therapy is based on the severity of the patients underlying disease and clinical response.. 2.3Dosing Regimen in Pediatric Patients (ages to less than 18 years of age). The recommended dosing regimen of Noxafil for pediatric patients to less than 18 years of age is shown in Tables 2, 3, and [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 to less than 18 years of age)Recommended Pediatric Dosage and FormulationIndicationWeight/Age Delayed-Release TabletInjectionDuration of therapyProphylaxis of invasive Aspergillus and Candida infectionsLess than or equal to 40 kg (2 to less than 18 years of age)Not ApplicableLoading dose:6 mg/kg up to maximum of 300 mg twice daily on the first dayDuration 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 dailyMaintenance dose:6 mg/kg up to maximum of 300 mg once dailyTreatment of invasive Aspergillosis13 to less than 18 years of age regardless of weight.Loading dose:300 mg (three 100 mg delayed-release tablets) twice day on the first day.Loading dose:300 mg Noxafil injection intravenously twice day on the first day.Loading dose:1 dayMaintenance dose:300 mg (three 100 mg delayed-release tablets) once day, starting on the second day.Maintenance dose: 300 mg Noxafil injection intravenously once day, starting on the second day.Maintenance dose:Recommended total duration of therapy is to 12 weeks.Switching between the intravenous and delayed-release tablets is acceptable. loading dose is not required when switching between formulations.Switching between the intravenous and delayed-release tablets is acceptable. 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)IndicationLoading Dose (volume) and frequencyMaintenance Dose (volume) and frequencyDuration of therapyProphylaxis of invasive Aspergillus and Candida infections200 mg (5 mL) three times day200 mg (5 mL) three times dayDuration of therapy is based on recovery from neutropenia or immunosuppression.Oropharyngeal Candidiasis (OPC)100 mg (2.5 mL) twice daily on the first day100 mg (2.5 mL) once daily13 daysOPC Refractory (rOPC) to Itraconazole and/or Fluconazole400 mg (10 mL) twice daily400 mg (10 mL) twice dailyDuration of therapy is based on the severity of the patients underlying disease and clinical response.Table 4: Noxafil PowderMix for Delayed-Release Oral Suspension Dosing Regimen in Pediatric Patients (ages to less than 18 years of age, weighing 10 to 40 kg)IndicationWeight (kg)Loading Dose (volume)Maintenance Dose (volume)Prophylaxis of invasive Aspergillus and Candida infections10 to less than 1290 mg (3 mL) twice daily on the first day90 mg (3 mL) once daily12 to less than 17120 mg (4 mL) twice daily on the first day120 mg (4 mL) once daily17 to less than 21150 mg (5 mL) twice daily on the first day150 mg (5 mL) once daily21 to less than 26180 mg (6 mL) twice daily on the first day180 mg (6 mL) once daily26 to less than 36210 mg (7 mL) twice daily on the first day210 mg (7 mL) once daily36 to 40240 mg (8 mL) twice daily on the first day240 mg (8 mL) once daily. 2.4Preparation, 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 compatible admixture diluent (as described in Table 5), to achieve final concentration of posaconazole that is between mg/mL and mg/mL. Use of other diluents is not recommended because they may result in particulate formation.Noxafil injection is 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 to 8C (36 to 46F). 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 and 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 Diluents0.45% sodium chloride0.9% sodium chloride5% dextrose in water5% dextrose and 0.45% sodium chloride5% dextrose and 0.9% sodium chloride5% dextrose and 20 mEq potassium chlorideNoxafil 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 DrugsAmikacin sulfateCaspofunginCiprofloxacinDaptomycinDobutamine hydrochlorideFamotidineFilgrastimGentamicin sulfateHydromorphone hydrochlorideLevofloxacinLorazepamMeropenemMicafunginMorphine sulfateNorepinephrine bitartratePotassium chlorideVancomycin hydrochlorideIncompatible Diluents:Noxafil injection must not be diluted with the following diluents:Lactated Ringers solution5% dextrose with Lactated Ringers solution4.2% sodium bicarbonateAdministration:Noxafil injection must be administered through 0.22-micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter.Administer via central venous line, including central venous catheter or PICC by slow infusion over approximately 90 minutes. Noxafil injection is not for bolus administration.If central venous catheter is not available, Noxafil injection may be administered through peripheral venous catheter only as single dose in advance of central venous line placement or to bridge the period during which central venous line is replaced or is in use for other treatment.When multiple dosing is required, the infusion should be done via central venous line. When administered through 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)].. 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 compatible admixture diluent (as described in Table 5), to achieve final concentration of posaconazole that is between mg/mL and mg/mL. Use of other diluents is not recommended because they may result in particulate formation.. Noxafil injection is 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 to 8C (36 to 46F). 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.. Noxafil injection can be infused at the same time through the same intravenous line (or cannula) with the following compatible diluents:. 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.. Noxafil injection must be administered through 0.22-micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter.. Administer via central venous line, including central venous catheter or PICC by slow infusion over approximately 90 minutes. Noxafil injection is not for bolus administration.. If central venous catheter is not available, Noxafil injection may be administered through peripheral venous catheter only as single dose in advance of central venous line placement or to bridge the period during which central venous line is replaced or is in use for other treatment.. When multiple dosing is required, the infusion should be done via central venous line. When administered through 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)].. 2.5Administration 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)]. Swallow tablets whole. Do not divide, crush, or chew.. Administer Noxafil delayed-release tablets with or without food [see Clinical Pharmacology (12.3)]. 2.6Administration Instructions for Noxafil Oral Suspension. Shake Noxafil oral suspension well before use. Administer with measured dosing spoon (see Figure 1) provided.Figure 1: measured dosing spoon is provided, marked for doses of 2.5 mL and 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 full meal [see Clinical Pharmacology (12.3)]. For patients who cannot eat 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 full meal and for whom Noxafil delayed-release tablets or Noxafil injection are not options, administer each dose of Noxafil oral suspension with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).For patients who cannot eat 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.. Shake Noxafil oral suspension well before use. Administer with measured dosing spoon (see Figure 1) provided.. 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 full meal [see Clinical Pharmacology (12.3)]. For patients who cannot eat 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 full meal and for whom Noxafil delayed-release tablets or Noxafil injection are not options, administer each dose of Noxafil oral suspension with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).. For patients who cannot eat 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. 2.7Non-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)]. 2.8Preparation and Administration Instructions for Noxafil PowderMix for Delayed-Release Oral Suspension (pediatric patients ages 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 InstructionsDo 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 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 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 mL of mixing liquid giving 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 hour. Discard unused portion of the prepared drug product.Administration InstructionsAdminister Noxafil PowderMix for delayed-release oral suspension with food.Choose the correct syringe based on the prescribed dose:Use mL (GREEN) syringe if dose is mL or less.Use 10 mL (BLUE) syringe if dose is more than 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 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 similar mixing cup with lid may be used for subsequent doses.The notched tip syringes may also be hand washed and reused. For additional supply, separate box of notched tip syringes is provided with the Noxafil PowderMix kit. 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 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 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 mL of mixing liquid giving 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 hour. Discard unused portion of the prepared drug product.. Administer Noxafil PowderMix for delayed-release oral suspension with food.. Choose the correct syringe based on the prescribed dose:Use mL (GREEN) syringe if dose is mL or less.Use 10 mL (BLUE) syringe if dose is more than mL.. Use mL (GREEN) syringe if dose is mL or less.. Use 10 mL (BLUE) syringe if dose is more than 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 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 similar mixing cup with lid may be used for subsequent doses.. The notched tip syringes may also be hand washed and reused. For additional supply, separate box of notched tip syringes is provided with the Noxafil PowderMix kit. 2.9Dosage 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.. 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.

ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS. The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling:Hypersensitivity [see Contraindications (4.1)] Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)] Hepatic Toxicity [see Warnings and Precautions (5.4)] Hypersensitivity [see Contraindications (4.1)] Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)] Hepatic Toxicity [see Warnings and Precautions (5.4)] Adult Patients: Common adverse reactions in studies with Noxafil in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. (6.1)Pediatric Patients: Common adverse reactions (incidence >20% receiving mg/kg Noxafil injection and Noxafil PowderMix for delayed-release oral suspension) in 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 Corp., subsidiary of Merck Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 mg/kg Noxafil injection and Noxafil PowderMix for delayed-release oral suspension) in study in pediatric patients are pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis. (6.1). 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 AdultsClinical Trial Experience with Noxafil Injection and Noxafil Delayed-Release Tablets for the Treatment of Invasive AspergillosisThe safety of Noxafil injection and Noxafil delayed-release tablet was assessed in 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). 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 days for both groups. Table 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 TabletsSystem Organ ClassNoxafil injection or tablet(N 288), (%)Voriconazole injection or oral(N 287), (%)Blood and lymphatic system disorders Anemia25 (8.7)29 (10.1) Febrile neutropenia42 (14.6)38 (13.2)Gastrointestinal disorders Abdominal pain29 (10.1)24 (8.4) Constipation32 (11.1)23 (8.0) Diarrhea52 (18.1)52 (18.1) Nausea65 (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) Pyrexia81 (28.1)72 (25.1)Infections and infestations Pneumonia36 (12.5)26 (9.1)Investigations Alanine aminotransferase increased42 (14.6)37 (12.9) Aspartate aminotransferase increased38 (13.2)36 (12.5) Blood alkaline phosphatase increased21 (7.3)29 (10.1)Metabolism and nutrition disorders Hypokalemia82 (28.5)49 (17.1) Hypomagnesemia29 (10.1)18 (6.3)Nervous system disorders Headache35 (12.2)25 (8.7)Respiratory, thoracic and mediastinal disorders Cough30 (10.4)24 (8.4) Epistaxis32 (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 ProphylaxisMultiple doses of Noxafil injection administered via 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 clinical trial. Patients were enrolled in 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 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 single dose of 200 mg Noxafil injection, 21 patients received 200 mg daily dose for median of 14 days, and 237 patients received 300 mg daily dose for median of days. Table presents adverse reactions observed in patients treated with Noxafil injection 300 mg daily dose in the Noxafil Injection Study. Each patient received 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 SystemNoxafil Injection Treatment Phasen=237 (%)Adverse reactions reported in patients with an onset during the Noxafil intravenous dosing phase of the study. Noxafil InjectionTreatment Phase or Subsequent Noxafil Oral Suspension Treatment Phasen=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 Reaction220(93)235(99)Blood and Lymphatic System Disorder Anemia16(7)23(10) Thrombocytopenia17(7)25(11)Gastrointestinal Disorders Abdominal Pain Upper15(6)25(11) Abdominal Pain30(13)41(17) Constipation18(8)31(13) Diarrhea75(32)93(39) Nausea46(19)70(30) Vomiting29(12)45(19)General Disorders and Administration Site Conditions Fatigue19(8)24(10) Chills28(12)38(16) Edema Peripheral28(12)35(15) Pyrexia49(21)73(31)Metabolism and Nutrition Disorders Decreased appetite23(10)29(12) Hypokalemia51(22)67(28) Hypomagnesemia25(11)30(13)Nervous System Disorders Headache33(14)49(21)Respiratory, Thoracic and Mediastinal Disorders Cough21(9)31(13) Dyspnea16(7)24(10) Epistaxis34(14)40(17)Skin and Subcutaneous Tissue Disorders Petechiae20(8)24(10) Rash35(15)56(24)Vascular Disorders Hypertension20(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 ProphylaxisThe safety of Noxafil delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in 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 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 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 in each cohort). Table 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 DoseBody SystemNoxafil delayed-release tablet (300 mg)n=210 (%)Subjects Reporting any Adverse Reaction207(99)Blood and Lymphatic System Disorder Anemia22(10) Thrombocytopenia29(14)Gastrointestinal Disorders Abdominal Pain23(11) Constipation20(10) Diarrhea61(29) Nausea56(27) Vomiting28(13)General Disorders and Administration Site Conditions Asthenia20(10) Chills22(10) Mucosal Inflammation29(14) Edema Peripheral33(16) Pyrexia59(28)Metabolism and Nutrition Disorders Hypokalemia46(22) Hypomagnesemia20(10)Nervous System Disorders Headache30(14)Respiratory, Thoracic and Mediastinal Disorders Cough35(17) Epistaxis30(14)Skin and Subcutaneous Tissue Disorders Rash34(16)Vascular Disorders Hypertension23(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 SuspensionThe 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 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 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 randomized, comparative prophylaxis studies (Noxafil Oral Suspension Study and 2), the safety of Noxafil oral suspension 200 mg three times day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice 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 and Study 2. Adverse Reactions in at Least 10% of the Noxafil Oral Suspension or Fluconazole Treatment Groups (Pooled Prophylaxis Safety Analysis)Body SystemNoxafil Oral Suspensionn=605 (%)Fluconazolen=539 (%)Itraconazolen=58 (%)Subjects Reporting any Adverse Reaction595(98)531(99)58(100)Body as Whole General Disorders Fever274(45)254(47)32(55) Headache171(28)141(26)23(40) Rigors122(20)87(16)17(29) Fatigue101(17)98(18)5(9) Edema Legs93(15)67(12)11(19) Anorexia92(15)94(17)16(28) Dizziness64(11)56(10)5(9) Edema54(9)68(13)8(14) Weakness51(8)52(10)2(3)Cardiovascular Disorders, General Hypertension106(18)88(16)3(5) Hypotension83(14)79(15)10(17)Disorders of Blood and Lymphatic System Anemia149(25)124(23)16(28) Neutropenia141(23)122(23)23(40)Disorders of the Reproductive System and Breast Vaginal HemorrhagePercentages of sex-specific adverse reactions are based on the number of males/females. 24(10)20(9)3(12)Gastrointestinal System Disorders Diarrhea256(42)212(39)35(60) Nausea232(38)198(37)30(52) Vomiting174(29)173(32)24(41) Abdominal Pain161(27)147(27)21(36) Constipation126(21)94(17)10(17) Dyspepsia61(10)50(9)6(10)Heart Rate and Rhythm Disorders Tachycardia72(12)75(14)3(5)Infection and Infestations Pharyngitis71(12)60(11)12(21)Liver and Biliary System Disorders Bilirubinemia59(10)51(9)11(19)Metabolic and Nutritional Disorders Hypokalemia181(30)142(26)30(52) Hypomagnesemia110(18)84(16)11(19) Hyperglycemia68(11)76(14)2(3) Hypocalcemia56(9)55(10)5(9)Musculoskeletal System Disorders Musculoskeletal Pain95(16)82(15)9(16) Arthralgia69(11)67(12)5(9) Back Pain63(10)66(12)4(7)Platelet, Bleeding and Clotting Disorders Thrombocytopenia175(29)146(27)20(34) Petechiae64(11)54(10)9(16)Psychiatric Disorders Insomnia103(17)92(17)11(19)Respiratory System Disorders Coughing146(24)130(24)14(24) Dyspnea121(20)116(22)15(26) Epistaxis82(14)73(14)12(21)Skin and Subcutaneous Tissue Disorders Rash113(19)96(18)25(43) Pruritus69(11)62(12)11(19). HIV Infected Subjects with OPC: In randomized comparative studies in OPC, the safety of Noxafil oral suspension at 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 dose of 100 mg once daily.An additional 239 HIV-infected patients with refractory OPC received Noxafil oral suspension in 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 SuspensionBody SystemNumber (%) of SubjectsControlled OPC PoolRefractory OPC PoolNoxafil Oral SuspensionFluconazoleNoxafil OralSuspensionn=557n=262n=239OPC=oropharyngeal candidiasisSubjects Reporting any Adverse ReactionNumber of subjects reporting adverse reactions at least once during the study, without regard to relationship to treatment. Subjects may have reported more than event. 356 (64)175 (67)221 (92)Body as Whole General Disorders Fever34 (6)22 (8)82 (34) Headache44 (8)23 (9)47 (20) Anorexia10 (2)4 (2)46 (19) Fatigue18 (3)12 (5)31 (13) Asthenia9 (2)5 (2)31 (13) Rigors2 (<1)4 (2)29 (12) Pain4 (1)2 (1)27 (11)Disorders of Blood and Lymphatic System Neutropenia21 (4)8 (3)39 (16) Anemia11 (2)5 (2)34 (14)Gastrointestinal System Disorders Diarrhea58 (10)34 (13)70 (29) Nausea48 (9)30 (11)70 (29) Vomiting37 (7)18 (7)67 (28) Abdominal Pain27 (5)17 (6)43 (18)Infection and Infestations Candidiasis, Oral3 (1)1 (<1)28 (12) Herpes Simplex16 (3)8 (3)26 (11) Pneumonia17 (3)6 (2)25 (10)Metabolic and Nutritional Disorders Weight Decrease4 (1)2 (1)33 (14) Dehydration4 (1)7 (3)27 (11)Psychiatric Disorders Insomnia8 (1)3 (1)39 (16)Respiratory System Disorders Coughing18 (3)11 (4)60 (25) Dyspnea8 (1)8 (3)28 (12)Skin and Subcutaneous Tissue Disorders Rash15 (3)10 (4)36 (15) Sweating Increased13 (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 aggravatedEndocrine disorders: adrenal insufficiencyNervous system disorders: paresthesiaImmune system disorders: allergic reaction [see Contraindications (4.1)] Cardiac disorders: torsades de pointes [see Warnings and Precautions (5.2)] Vascular disorders: pulmonary embolismGastrointestinal disorders: pancreatitisLiver and Biliary System Disorders: hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundiceRenal Urinary System Disorders: renal failure acute. 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 at baseline to Grade or during the study is presented in Table 12. Table 12: Noxafil Oral Suspension Study and Study 2. Changes in Liver Test Results from CTC Grade 0, 1, or at Baseline to Grade or 4Number (%) of Patients with ChangeChange from Grade to at baseline to Grade or during the study. These data are presented in the form X/Y, where represents the number of patients who met the criterion as indicated, and represents the number of patients who had baseline observation and at least one post-baseline observation. Noxafil Oral Suspension Study 1CTC Common Toxicity Criteria; AST= Aspartate Aminotransferase;ALT= Alanine Aminotransferase.Laboratory ParameterNoxafil Oral Suspensionn=301Fluconazolen=299 AST11/266 (4)13/266 (5) ALT47/271 (17)39/272 (14) Bilirubin24/271 (9)20/275 (7) Alkaline Phosphatase9/271 (3)8/271 (3)Noxafil Oral Suspension Study 2Laboratory ParameterNoxafil Oral Suspension(n=304)Fluconazole/Itraconazole(n=298) AST9/286 (3)5/280 (2) ALT18/289 (6)13/284 (5) Bilirubin20/290 (7)25/285 (9) Alkaline Phosphatase4/281 (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 ValueLaboratory TestControlledRefractoryNoxafil Oral SuspensionFluconazoleNoxafil Oral Suspensionn=557 (%)n=262 (%)n=239 (%)ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase.ALT 3.0 ULN16/537 (3)13/254 (5) 25/226 (11)AST 3.0 ULN33/537 (6)26/254 (10)39/223 (17)Total Bilirubin 1.5 ULN15/536 (3)5/254 (2)9/197 (5)Alkaline Phosphatase 3.0 ULN17/535 (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 at Baseline to Grade or 4Number (%) of Patients with ChangeChange from Grade to at baseline to Grade or during the study. These data are presented in the form n/N, where represents the number of patients who met the criterion as indicated, and represents the number of patients who had baseline observation and at least one post-baseline observation. Laboratory ParameterNoxafiln/N (%)Voriconazolen/N (%)N=Number of subjects for given laboratory test with baseline value of CTC Grade 0, 1, or and at least one post-baseline value.CTC Common Toxicity Criteria; AST= Aspartate Aminotransferase;ALT= Alanine Aminotransferase. AST22/281 (8)21/285 (7) ALT29/281(10)23/282 (8) Bilirubin26/280 (9)25/284 (9) Alkaline Phosphatase12/282 (4)20/284 (7)Clinical Trial Experience in PediatricsClinical 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 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 mg/kg (twice daily on day 1) in three dose cohorts. All 115 subjects initially received Noxafil injection for at least 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: to 28 days) on Noxafil injection and 11.6 days (range: 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 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 SuspensionAdverse ReactionNoxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension mg/kg Dose Cohort n=49 (%)Noxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension All Dose Cohorts n=115 (%)Pyrexia16 (33)50 (43)Febrile neutropenia15 (31)25 (22)Vomiting12 (24)30 (26)Mucosal inflammation11 (22)32 (28)Pruritus11 (22)18 (16)Hypertension10 (20)20 (17)Hypokalemia10 (20)16 (14)Stomatitis10 (20)13 (11)Diarrhea9 (18)25 (22)Nausea9 (18)18 (16)Abdominal pain8 (16)20 (17)Decreased appetite7 (14)17 (15)Rash7 (14)18 (16)Alanine aminotransferase increased6 (12)8 (7)Headache6 (12)16 (14)Aspartate aminotransferase increased5 (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 at baseline to Grade or is presented in Table 16.Table 16: Noxafil Pediatric Study: Changes in Liver Tests from CTC Grade 0, 1, or at Baseline to Grade or 4Number (%) of Patients with ChangeChange from Grade to at baseline to Grade or during the study. These data are presented in the form X/Y, where represents the number of patients who met the criterion as indicated, and represents the number of patients who had baseline observation and at least one post-baseline observation. Pediatric Study 1Laboratory ParameterNoxafil 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 AST2/49 (4) ALT3/49 (6) Bilirubin0/48 (0) Alkaline Phosphatase0/48 (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 population of uncertain size, it is not always possible to reliably estimate their frequency.. Endocrine Disorders: Pseudoaldosteronism.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. In nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from to 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 similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to months of age). There were no drug-related increases in the incidence of brain ventricle enlargement when treated and control animals were compared in separate study of 10-week old dogs dosed with intravenous posaconazole for 13 weeks with 9-week recovery period or follow-up study of 31-week old dogs dosed for months.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4)].. 12.2 Pharmacodynamics. Exposure Response Relationship Prophylaxis: In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), wide range of plasma exposures to posaconazole was noted following administration of Noxafil oral suspension. pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 17). lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.Table 17: Noxafil Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials Prophylaxis in AML/MDSNeutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS Prophylaxis in GVHDHSCT recipients with GVHD Cavg Range (ng/mL)Treatment FailureDefined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections (%)Cavg Range (ng/mL)Treatment Failure (%)Cavg the average posaconazole concentration when measured at steady stateQuartile 190-32254.722-55744.4Quartile 2322-49037.0557-91520.6Quartile 3490-73446.8915-156317.5Quartile 4734-220027.81563-365017.5Exposure Response Relationship Treatment of Invasive Aspergillosis:Across range of posaconazole plasma minimum concentrations (Cmin, range: 244 to 5663 ng/mL) following administration of Noxafil injection and Noxafil delayed-release tablets in patients treated for invasive aspergillosis in Aspergillosis Treatment Study, there was no association between posaconazole Cmin and treatment efficacy [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)]. Similarly, across range of population pharmacokinetic model-predicted steady-state plasma average concentrations (Cavg, range: 589 to 6315 ng/mL), there was no association between posaconazole Cavg and treatment efficacy.. 12.3 Pharmacokinetics. General Pharmacokinetic Characteristics. Noxafil InjectionNoxafil 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 Noxafil 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 Noxafil Injection on Day 1Dose (mg)nAUC0- (nghr/mL)AUC0-12 (nghr/mL)Cmax (ng/mL)t1/2 (hr)CL(L/hr)AUC0- Area under the plasma concentration-time curve from time zero to infinity; AUC0-12 Area under the plasma concentration-time curve from time zero to 12 hr after the first dose on Day 1; Cmax maximum observed concentration; 1/2 terminal phase half-life; CL total body clearance; N/D Not DeterminedHealthy Volunteers200935400 (50)8840 (20)2250 (29)23.6 (23)6.5 (32)300946400 (26)13000 (13)2840 (30)24.6 (20)6.9 (27)Patients20030N/D5570 (32)954 (44)N/DN/D30022N/D8240 (26)1590 (62)N/DN/DTable 19 displays the pharmacokinetic parameters of posaconazole in patients following administration of Noxafil injection 300 mg taken once 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 Noxafil Injection (300 mg)300 mg dose administered over 90 minutes once day following twice daily dosing on Day DayNCmax (ng/mL)Tmax Median (minimum-maximum) (hr)AUC0-24 (nghr/mL)Cav(ng/mL)Cmin (ng/mL)AUC0-24 area under the concentration-time curve over the dosing interval (i.e. 24 hours); Cav= time-averaged concentrations (i.e., AUC0-24h/24hr);Cmin POS trough level immediately before subject received the dose of POS on the day specified in the protocol; Cmax observed maximum plasma concentration; CV coefficient of variation, expressed as percent (%); Day study day on treatment; Tmax time of observed maximum plasma concentration.10/14493280 (74)1.5 (0.98-4.0)36100 (35)1500 (35)1090 (44). Noxafil Delayed-Release TabletsNoxafil delayed-release tablets exhibit dose proportional pharmacokinetics after single and multiple dosing up to 300 mg. The mean pharmacokinetic parameters of posaconazole at steady state following administration of Noxafil delayed-release tablets 300 mg twice daily on Day 1, then 300 mg once daily thereafter in healthy volunteers and in neutropenic patients who are receiving cytotoxic chemotherapy for AML or MDS or HSCT recipients with GVHD are shown in Table 20.Table 20: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Noxafil Delayed-Release Tablets (300 mg)300 mg twice daily on Day 1, then 300 mg once daily thereafter NAUC0-24 hr (nghr/mL)CavCav time-averaged concentrations (i.e., AUC0-24 hr/24hr) (ng/mL)Cmax (ng/mL)Cmin (ng/mL)Tmax Median (minimum-maximum) (hr)t1/2 (hr)CL/F(L/hr)CV coefficient of variation expressed as percentage (%CV); AUC0-T Area under the plasma concentration-time curve from time zero to 24 hr; Cmax maximum observed concentration; Cmin minimum observed plasma concentration; Tmax time of maximum observed concentration; 1/2 terminal phase half-life; CL/F Apparent total body clearanceHealthy Volunteers1251618(25)2151(25)2764(21)1785(29)4(3-6)31(40)7.5(26)Patients5037900(42)1580(42)2090(38)1310(50)4 (1.3-8.3)-9.39(45). Noxafil Oral SuspensionDose-proportional increases in plasma exposure (AUC) to Noxafil oral suspension were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg twice daily to 400 mg twice daily in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg twice daily to 600 mg twice daily in febrile neutropenic patients or those with refractory invasive fungal infections.The mean (%CV) [min-max] Noxafil oral suspension average steady-state plasma concentrations (Cavg) and steady-state pharmacokinetic parameters in patients following administration of 200 mg three times day and 400 mg twice daily of the oral suspension are provided in Table 21. Table 21: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Noxafil Oral Suspension 200 mg Three Times Day and 400 mg Twice DailyDoseOral suspension administration Cavg (ng/mL)AUCAUC (0-24 hr) for 200 mg three times day and AUC (0-12 hr) for 400 mg twice daily (nghr/mL)CL/F (L/hr)V/F (L)t 1/2 (hr)Cavg the average posaconazole concentration when measured at steady stateThe variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.200 mg three times dayHSCT recipients with GVHD (n=252)1103 (67)[21.5-3650]NDNot done ND ND ND 200 mg three times dayNeutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes (n=215)583 (65)[89.7-2200]15,900 (62)[4100-56,100]51.2 (54)[10.7-146]2425 (39)[828-5702]37.2 (39)[19.1-148]400 mg twice dailyFebrile neutropenic patients or patients with refractory invasive fungal infections, Cavg n=24 (n=23)723 (86)[6.70-2256]9093 (80)[1564-26,794]76.1 (78)[14.9-256]3088 (84)[407-13,140]31.7 (42)[12.4-67.3]. Absorption: Noxafil Delayed-Release TabletsWhen given orally in healthy volunteers, Noxafil delayed-release tablets are absorbed with median Tmax of to hours. Steady-state plasma concentrations are attained by Day at the 300 mg dose (once daily after twice daily loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. The Cmax and AUC of posaconazole following administration of Noxafil delayed-release tablets is increased 16% and 51%, respectively, when given with high fat meal compared to fasted state (see Table 22).Table 22: Statistical Comparison of Plasma Pharmacokinetics of Posaconazole Following Single Oral Dose Administration of 300 mg Noxafil Delayed-Release Tablet to Healthy Subjects under Fasting and Fed ConditionsFasting ConditionsFed Conditions (High Fat Meal)48.5 fat Fed/FastingPharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)GMR=Geometric least-squares mean ratio; CI=Confidence intervalCmax (ng/mL)14935 (34)161060 (25)1.16 (0.96, 1.41)AUC0-72hr (hrng/mL)1426200 (28)1638400 (18)1.51 (1.33, 1.72)Tmax Median (Min, Max) reported for Tmax (hr)145.00 (3.00, 8.00)166.00 (5.00, 24.00)N/AConcomitant administration of Noxafil delayed-release tablets with drugs affecting gastric pH or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see Table 23).Table 23: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Delayed-Release Tablets in Healthy VolunteersCoadministered DrugAdministration ArmsChange in Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to Noxafil alone for Cmax or AUC0-last.;90% CI of the ratio estimate)Change in AUC0-last (ratio estimate;90% CI of the ratio estimate)Mylanta(R) Ultimate strength liquid (Increase in gastric pH)25.4 meq/5 mL, 20 mL6%(1.06; 0.90 -1.26)4%(1.04; 0.90 -1.20)Ranitidine (Zantac(R)) (Alteration in gastric pH)150 mg (morning dose of 150 mg Ranitidine twice daily)4%(1.04; 0.88 -1.23)3%(0.97; 0.84 -1.12)Esomeprazole (Nexium(R)) (Increase in gastric pH)40 mg (every morning for days, Day -4 to 1)2%(1.02; 0.88-1.17)5%(1.05; 0.89 -1.24)Metoclopramide (Reglan(R)) (Increase in gastric motility)15 mg four times daily for days (Day -1 and 1)14%(0.86, 0.73,1.02)7%(0.93, 0.803,1.07)Noxafil PowderMix for Delayed-Release Oral SuspensionThe absolute bioavailability of the Noxafil PowderMix for delayed-release oral suspension is approximately 70-80%. The effect of food on the pharmacokinetics of the Noxafil PowderMix for delayed-release oral suspension has not been determined.Concomitant administration of Noxafil PowderMix for delayed-release oral suspension with drugs affecting gastric pH or gastric motility would not be expected to demonstrate any significant effects on posaconazole pharmacokinetic exposure based on similarity to the delayed-release tablets.An in vitro dissolution study was conducted to evaluate the impact of alcohol (5, 10, 20, and 40%) on the dissolution of Noxafil PowderMix delayed-release oral suspension. The study showed alcohol-induced dose-dumping potential with the Noxafil PowderMix delayed-release oral suspension [see Dosage and Administration (2.1) and Drug Interactions (7.15)].. Noxafil Oral SuspensionNoxafil oral suspension is absorbed with median Tmax of ~3 to hours. Steady-state plasma concentrations are attained at to 10 days following multiple-dose administration.Following single-dose administration of 200 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when the oral suspension is administered with nonfat meal and approximately 4-times higher when administered with high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of Noxafil oral suspension 400 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when administered with liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 24). In addition, the effects of varying gastric administration conditions on the Cmax and AUC of Noxafil oral suspension in healthy volunteers have been investigated and are shown in Table 25.In order to assure attainment of adequate plasma concentrations, it is recommended to administer Noxafil oral suspension during or immediately following full meal. In patients who cannot eat full meal, Noxafil oral suspension should be taken with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).Table 24: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-Dose Noxafil Oral Suspension Administration of 200 mg and 400 mg Under Fed and Fasted ConditionsDose (mg)Cmax (ng/mL)Tmax Median [min-max]. (hr)AUC (I)(nghr/mL)CL/F(L/hr)t 1/2 (hr)200 mg fasted(n=20)n=15 for AUC (I), CL/F, and 1/2 132 (50)[45-267]3.50[1.5-36The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between hrs and 36 hrs).]4179 (31)[2705-7269]51 (25)[28-74]23.5 (25)[15.3-33.7]200 mg nonfat(n=20) 378 (43)[131-834]4 [3-5]10,753 (35)[4579-17,092]21 (39)[12-44]22.2 (18)[17.4-28.7]200 mg high fat(54 gm fat)(n=20) 512 (34)[241-1016]5 [4-5]15,059 (26)[10,341-24,476]14 (24)[8.2-19]23.0 (19)[17.2-33.4]400 mg fasted(n=23)n=10 for AUC (I), CL/F, and 1/2 121 (75)[27-366]4 [2-12]5258 (48)[2834-9567]91 (40)[42-141]27.3 (26)[16.8-38.9]400 mg with liquid nutritional supplement(14 gm fat)(n=23) 355 (43)[145-720]5 [4-8]11,295 (40)[3865-20,592]43 (56)[19-103]26.0 (19)[18.2-35.0]Table 25: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of Noxafil Oral Suspension in Healthy VolunteersIn subjects, the Cmax and AUC decreased substantially (range: -27% to -53% and -33% to -51%, respectively) when Noxafil was administered via an NG tube compared to when Noxafil was administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when Noxafil is administered via an NG tube because lower plasma exposure may be associated with an increased risk of treatment failure. Study DescriptionAdministration ArmsChange in Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for Cmax or AUC.;90% CI of the ratio estimate)Change in AUC(ratio estimate;90% CI of the ratio estimate)400-mg single dose with high-fat meal relative to fasted state (n=12) minutes before high-fat meal96%(1.96; 1.48-2.59)111%(2.11; 1.60-2.78)During high-fat meal339%(4.39; 3.32-5.80)382%(4.82; 3.66-6.35)20 minutes after high-fat meal333%(4.33; 3.28-5.73)387%(4.87; 3.70-6.42)400 mg twice daily and 200 mg four times daily for days in fasted state and with liquid nutritional supplement (BOOST(R)) (n=12)400 mg twice daily with BOOST65%(1.65; 1.29-2.11)66%(1.66; 1.30-2.13)200 mg four times daily with BOOSTNo EffectNo EffectDivided daily dose from 400 mg twice daily to 200 mg four times daily for days regardless of fasted conditions or with BOOST (n=12)Fasted state136%(2.36; 1.84-3.02)161%(2.61; 2.04-3.35)With BOOST137%(2.37; 1.86-3.04)157%(2.57; 2.00-3.30)400-mg single dose with carbonated acidic beverage (ginger ale) and/or proton pump inhibitor (esomeprazole) (n=12)Ginger ale92%(1.92; 1.51-2.44)70%(1.70; 1.43-2.03)Esomeprazole32%(0.68; 0.53-0.86)30%(0.70; 0.59-0.83)400-mg single dose with prokinetic agent (metoclopramide 10 mg three times day for days) BOOST or an antikinetic agent (loperamide 4-mg single dose) BOOST (n=12)With metoclopramide BOOST21%(0.79; 0.72-0.87)19%(0.81; 0.72-0.91)With loperamide BOOST3%(0.97; 0.88-1.07)11%(1.11; 0.99-1.25)400-mg single dose either orally with BOOST or via an NG tube with BOOST (n=16)Via NG tubeNG nasogastric 19%(0.81; 0.71-0.91)23%(0.77; 0.69-0.86)Concomitant administration of Noxafil oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (See Table 26.)Table 26: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Oral Suspension in Healthy VolunteersCoadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in MeanCmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Cimetidine(Alteration of gastric pH)400 mg twice daily 10 days200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. 39%(0.61; 0.53-0.70) 39%(0.61; 0.54-0.69)Esomeprazole (Increase in gastric pH)The drug interactions associated with the oral suspension are also relevant for the delayed-release tablet with the exception of Esomeprazole and Metoclopramide. 40 mg every morning 3 days400 mg (oral suspension) single dose 46%(0.54; 0.43-0.69) 32%(0.68; 0.57-0.81)Metoclopramide (Increase in gastric motility) 10 mg three times day 2 days400 mg (oral suspension) single dose 21%(0.79; 0.72-0.87) 19%(0.81; 0.72-0.91). Distribution:The mean volume of distribution of posaconazole after intravenous solution administration was 261 and ranged from 226-295 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 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 enzymes) and is substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. summary of drugs studied clinically with the oral suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in Table 27. Table 27: Summary of the Effect of Coadministered Drugs on Noxafil in Healthy VolunteersCoadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in MeanCmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to Noxafil alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Efavirenz(UDP-G Induction)400 mg once daily 10 and 20 days400 mg (oral suspension) twice daily 10 and 20 days45%(0.55; 0.47-0.66) 50%(0.50; 0.43-0.60)Fosamprenavir (unknown mechanism)700 mg twice daily 10 days200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily 8 Days21%0.79 (0.71-0.89)23%0.77 (0.68-0.87)Rifabutin(UDP-G Induction)300 mg once daily 17 days200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. 43%(0.57; 0.43-0.75) 49%(0.51; 0.37-0.71)Phenytoin(UDP-G Induction)200 mg once daily 10 days200 mg (tablets) once daily 10 days 41%(0.59; 0.44-0.79) 50%(0.50; 0.36-0.71)In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. clinical study in healthy volunteers also indicates that posaconazole is strong CYP3A4 inhibitor as evidenced by >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 28 [see Contraindications (4) and Drug Interactions (7.1) including recommendations].Table 28: Summary of the Effect of Noxafil on Coadministered Drugs in Healthy Adult Volunteers and PatientsCoadministered Drug(Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of Coadministered DrugsChange in Mean Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Sirolimus2-mg single oral dose400 mg (oral suspension) twice daily 16 days 572%(6.72; 5.62-8.03) 788%(8.88; 7.26-10.9)CyclosporineStable maintenance dose in heart transplant recipients200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. cyclosporine whole blood trough concentrationsCyclosporine dose reductions of up to 29% were requiredTacrolimus0.05-mg/kg single oral dose400 mg (oral suspension) twice daily 7 days 121%(2.21; 2.01-2.42) 358%(4.58; 4.03-5.19)Simvastatin40-mg single oral dose100 mg (oral suspension) once daily 13 daysSimvastatin 841%(9.41, 7.13-12.44)Simvastatin Acid 817%(9.17, 7.36-11.43)Simvastatin 931%(10.31, 8.40-12.67)Simvastatin Acid634%(7.34, 5.82-9.25)200 mg (oral suspension) once daily 13 daysSimvastatin 1041%(11.41, 7.99-16.29)Simvastatin Acid851%(9.51, 8.15-11.10)Simvastatin 960%(10.60, 8.63-13.02)Simvastatin Acid 748%(8.48, 7.04-10.23)Midazolam0.4-mg single intravenous doseThe mean terminal half-life of midazolam was increased from hours to to 11 hours during coadministration with Noxafil. 200 mg (oral suspension) twice daily 7 days 30%(1.3; 1.13-1.48) 362%(4.62; 4.02-5.3)0.4-mg single intravenous dose 400 mg (oral suspension) twice daily 7 days62%(1.62; 1.41-1.86)524%(6.24; 5.43-7.16)2-mg single oral dose 200 mg (oral suspension) once daily 7 days 169%(2.69; 2.46-2.93) 470%(5.70; 4.82-6.74)2-mg single oral dose 400 mg (oral suspension) twice daily 7 days 138%(2.38; 2.13-2.66) 397%(4.97; 4.46-5.54)Rifabutin300 mg once daily 17 days200 mg (tablets) once daily 10 days 31%(1.31; 1.10-1.57) 72%(1.72;1.51-1.95)Phenytoin200 mg once daily PO 10 days200 mg (tablets) once daily 10 days 16%(1.16; 0.85-1.57) 16%(1.16; 0.84-1.59)Ritonavir100 mg once daily 14 days400 mg (oral suspension)twice daily 7 days 49%(1.49; 1.04-2.15) 80%(1.8;1.39-2.31)Atazanavir300 mg once daily 14 days400 mg (oral suspension) twice daily 7 days 155%(2.55; 1.89-3.45) 268%(3.68; 2.89-4.70)Atazanavir/ ritonavir boosted regimen300 mg/100 mg once daily 14 days 400 mg (oral suspension) twice daily 7 days 53%(1.53; 1.13-2.07) 146%(2.46; 1.93-3.13)Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with Noxafil 200 mg once daily; therefore, no dose adjustments are required for these coadministered drugs when coadministered with Noxafil 200 mg once daily.. Excretion:Following administration of Noxafil oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).Noxafil injection is eliminated with mean terminal half-life (t 1/2 of 27 hours and total body clearance (CL) of 7.3 L/h.Noxafil delayed-release tablet is eliminated with mean half-life (t 1/2 ranging between 26 to 31 hours.Noxafil oral suspension is eliminated with mean half-life (t 1/2 of 35 hours (range: 20-66 hours).Specific PopulationsNo clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment). Race/Ethnicity:In 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 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 Noxafil 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 PatientsThe mean pharmacokinetic parameters after multiple-dose administration of Noxafil injection and Noxafil PowderMix for delayed-release oral suspension in neutropenic pediatric patients to less than 18 years of age are shown in Table 29. Patients were enrolled into age groups and received Noxafil injection and Noxafil PowderMix for delayed-release oral suspension doses at mg/kg (0.6 to times the recommended dose) with 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 Noxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension mg/kg0.6 to times the recommended dose in Pediatric Patients with Neutropenia or Expected NeutropeniaAge GroupDoseTypeNAUC0-24 hr (ng.hr/mL)CavCav time-averaged concentrations (i.e., AUC0-24 hr/24hr) (ng/mL)Cmax (ng/mL)Cmin (ng/mL)Tmax Median (minimum-maximum) (hr)CL/FClearance (CL for IV and CL/F for PFS) (L/hr)IV= Noxafil injection; PFS= Noxafil PowderMix for delayed-release oral suspension; AUC0-24 Area under the plasma concentration-time curve from time zero to 24 hr; Cmax maximum observed concentration; Cmin minimum observed plasma concentration; Tmax time of maximum observed concentration; CL /F apparent total body clearance2 to <7 yearsIV1731100 (48.9)1300 (48.9)3060 (54.1)626 (104.8)1.75 (1.57-1.83)3.27 (49.3)PFS723000 (47.3)960 (47.3)1510 (43.4)542 (68.8)4.00 (2.17-7.92)4.60 (35.2)7 to 17 yearsIV2444200 (41.5)1840 (41.5)3340 (39.4)1160 (60.4)1.77 (1.33-6.00)4.76 (55.7)PFS1225000 (184.3)1040 (184.3)1370 (178.5)713 (300.6)2.78 (0.00-4.00)8.39 (190.3)Based on 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 Noxafil injection and Noxafil PowderMix for delayed-release oral suspension. 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.A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times day) of Noxafil oral suspension for prophylaxis of invasive fungal infections. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state Cav was similar between these patients and adults (>=18 years of age). In study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with Noxafil oral suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients.. 12.4 Microbiology. Mechanism of Action:Posaconazole blocks the synthesis of ergosterol, key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and 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 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Treatment of Invasive Aspergillosis with Noxafil Injection and Noxafil Delayed-Release Tablets. Aspergillosis Treatment Study (NCT01782131) was randomized, double-blind, controlled trial which evaluated the safety and efficacy of Noxafil 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 history of allogeneic bone marrow transplant, liver transplant, or relapsed leukemia undergoing salvage chemotherapy. The median age of patients was 57 years (range 14-91 years), with 27.8% of patients aged >=65 years; patients were pediatric patients 14-16 years of age, of whom were treated with Noxafil and 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 recent history of neutropenia, while approximately 20% with 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 Noxafil were given dose of 300 mg once daily (twice daily on Day 1) IV or tablet. Patients randomized to receive voriconazole were given dose of mg/kg twice daily Day followed by mg/kg twice daily IV, or oral 300 mg twice daily Day 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 maximum allowed duration of 98 days. Median treatment duration was 67 days for Noxafil patients and 64 days for voriconazole patients. Overall, 55% to 60% of patients began treatment with the IV formulation with median duration of 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 Noxafil patients compared to 20.6% for voriconazole patients for an adjusted treatment difference of -5.3% with 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: Noxafil Injection and Noxafil Delayed-Release Tablets Invasive Aspergillosis Treatment Study: All-Cause Mortality Through Day 42Noxafil Injection and Delayed-Release TabletsVoriconazolePopulationNn (%)Nn (%)DifferenceAdjusted treatment difference based on Miettinen and Nurminens method stratified by randomization factor (risk for mortality/poor outcome), using Cochran-Mantel-Haenszel weighting scheme. (95% CI)Intent to Treat28844 (15.3)28759 (20.6)-5.3 (-11.6, 1.0)Proven/Probable Invasive Aspergillosis16331 (19.0)17132 (18.7)0.3 (-8.2, 8.8)Global clinical response at Week was assessed by 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 was seen in 44.8% for Noxafil-treated patients compared to 45.6% for voriconazole-treated patients (see Table 31).Table 31: Noxafil Injection and Noxafil Delayed-Release Tablets Invasive Aspergillosis Treatment Study: Successful Global Clinical ResponseSuccessful Global Clinical Response was defined as survival with partial or complete response. at Week 6PosaconazoleVoriconazolePopulationNSuccessNSuccessDifferenceAdjusted treatment difference based on Miettinen and Nurminens method stratified by randomization factor (risk for mortality/poor outcome), using Cochran-Mantel-Haenszel weighting scheme. (95% CI)Proven/Probable Invasive Aspergillosis 16373 (44.8)17178 (45.6)-0.6 (-11.2, 10.1). 14.2 Prophylaxis of Aspergillus and Candida Infections with Noxafil Oral Suspension. Two randomized, controlled studies were conducted using Noxafil as prophylaxis for the prevention of invasive fungal infections (IFIs) among patients at high risk due to severely compromised immune systems.The first study (Noxafil Oral Suspension Study 1) was randomized, double-blind trial that compared Noxafil oral suspension (200 mg three times day) with fluconazole capsules (400 mg once daily) as prophylaxis against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD). Efficacy of prophylaxis was evaluated using composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (patients may have met more than one of these criteria). This assessed all patients while on study therapy plus days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the treatment groups (80 days, Noxafil oral suspension; 77 days, fluconazole). Table 32 contains the results from Noxafil Oral Suspension Study 1.Table 32: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD): Noxafil Oral Suspension Study 1Posaconazolen=301Fluconazolen=299On therapy plus daysClinical FailurePatients may have met more than one criterion defining failure. 50 (17%)55 (18%)Failure due to: Proven/Probable IFI7 (2%)22 (7%)(Aspergillus)3 (1%)17 (6%)(Candida)1 (<1%)3 (1%)(Other)3 (1%)2 (1%) All Deaths22 (7%)24 (8%)Proven/probable fungal infection prior to death2 (<1%)6 (2%) SAFUse of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >4 consecutive days). 27 (9%)25 (8%)Through 16 weeksClinical Failure 95% confidence interval (posaconazole-fluconazole) (-11.5%, +3.7%). 99 (33%)110 (37%)Failure due to: Proven/Probable IFI16 (5%)27 (9%)(Aspergillus)7 (2%)21 (7%)(Candida)4 (1%)4 (1%)(Other)5 (2%)2 (1%) All Deaths58 (19%)59 (20%)Proven/probable fungal infection prior to death10 (3%)16 (5%) SAF 26 (9%)30 (10%) Event free lost to follow-upPatients who are lost to follow-up (not observed for 112 days), and who did not meet another clinical failure endpoint. These patients were considered failures. 24 (8%)30 (10%)The second study (Noxafil Oral Suspension Study 2) was randomized, open-label study that compared Noxafil oral suspension (200 mg times day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice day) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS. As in Noxafil Oral Suspension Study 1, efficacy of prophylaxis was evaluated using composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (Patients might have met more than one of these criteria). This study assessed patients while on treatment plus days and 100 days postrandomization. The mean duration of therapy was comparable between the treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 33 contains the results from Noxafil Oral Suspension Study 2.Table 33: Results from Open-Label Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Noxafil Oral Suspension Study 2Posaconazolen=304Fluconazole/Itraconazolen=298On therapy plus daysClinical Failure95% confidence interval (posaconazole-fluconazole/itraconazole) (-22.9%, -7.8%). Patients may have met more than one criterion defining failure. 82 (27%)126 (42%) Failure due to: Proven/Probable IFI7 (2%)25 (8%)(Aspergillus)2 (1%)20 (7%)(Candida)3 (1%)2 (1%)(Other)2 (1%)3 (1%) All Deaths17 (6%)25 (8%)Proven/probable fungal infection prior to death1 (<1%)2 (1%) SAFUse of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >3 consecutive days). 67 (22%)98 (33%)Through 100 days postrandomizationClinical Failure 158 (52%)191 (64%) Failure due to: Proven/Probable IFI14 (5%)33 (11%)(Aspergillus)2 (1%)26 (9%)(Candida)10 (3%)4 (1%)(Other)2 (1%)3 (1%) All Deaths44 (14%)64 (21%)Proven/probable fungal infection prior to death2 (1%)16 (5%) SAF 98 (32%)125 (42%) Event free lost to follow-upPatients who are lost to follow-up (not observed for 100 days), and who did not meet another clinical failure endpoint. These patients were considered failures. 34 (11%)24 (8%)In summary, clinical studies of prophylaxis were conducted with the Noxafil oral suspension. As seen in the accompanying tables (Tables 32 and 33 ), clinical failure represented composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Noxafil Oral Suspension Study (Table 32), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% CI for the difference posaconazole-comparator -11.5% to 3.7%) while in Noxafil Oral Suspension Study (Table 33) clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% CI for the difference posaconazole-comparator -22.9% to -7.8%).All-cause mortality was similar at 16 weeks for both treatment arms in Noxafil Oral Suspension Study [POS 58/301 (19%) vs. FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for Noxafil-treated patients in Noxafil Oral Suspension Study [POS 44/304 (14%) vs. FLU/ITZ 64/298 (21%)]. Both studies demonstrated fewer breakthrough infections caused by Aspergillus species in patients receiving Noxafil prophylaxis when compared to patients receiving fluconazole or itraconazole.. 14.3Treatment of Oropharyngeal Candidiasis with Noxafil Oral Suspension. Noxafil Oral Suspension Study was randomized, controlled, evaluator-blinded study in HIV-infected patients with oropharyngeal candidiasis. Patients were treated with Noxafil or fluconazole oral suspension (both Noxafil and fluconazole were given as follows: 100 mg twice day for day followed by 100 mg once day for 13 days).Clinical and mycological outcomes were assessed after 14 days of treatment and at weeks after the end of treatment. Patients who received at least dose of study medication and had positive oral swish culture of Candida species at baseline were included in the analyses (see Table 34). The majority of the subjects had C. albicans as the baseline pathogen.Clinical success at Day 14 (complete or partial resolution of all ulcers and/or plaques and symptoms) and clinical relapse rates (recurrence of signs or symptoms after initial cure or improvement) weeks after the end of treatment were similar between the treatment arms (see Table 34).Mycologic eradication rates (absence of colony forming units in quantitative culture at the end of therapy, Day 14), as well as mycologic relapse rates (4 weeks after the end of treatment) were also similar between the treatment arms (see Table 34).Table 34: Noxafil Oral Suspension Clinical Success, Mycological Eradication, and Relapse Rates in Oropharyngeal CandidiasisNoxafilFluconazoleClinical Success at End of Therapy (Day 14)155/169 (91.7%)148/160 (92.5%)Clinical Relapse (4 Weeks after End of Therapy)45/155 (29.0%)52/148 (35.1%)Mycological Eradication (absence of CFU) at End of Therapy (Day 14)88/169 (52.1%)80/160 (50.0%)Mycological Relapse (4 Weeks after End of Treatment)49/88 (55.6%)51/80 (63.7%)Mycologic response rates, using criterion for success as posttreatment quantitative culture with <=20 colony forming units (CFU/mL) were also similar between the two groups (Noxafil 68.0%, fluconazole 68.1%). The clinical significance of this finding is unknown.. 14.4Noxafil Oral Suspension Treatment of Oropharyngeal Candidiasis Refractory to Treatment with Fluconazole or Itraconazole. Noxafil Oral Suspension Study was noncomparative study of Noxafil oral suspension in HIV-infected subjects with OPC that was refractory to treatment with fluconazole or itraconazole. An episode of OPC was considered refractory if there was failure to improve or worsening of OPC after standard course of therapy with fluconazole greater than or equal to 100 mg/day for at least 10 consecutive days or itraconazole 200 mg/day for at least 10 consecutive days and treatment with either fluconazole or itraconazole had not been discontinued for more than 14 days prior to treatment with Noxafil. Of the 199 subjects enrolled in this study, 89 subjects met these strict criteria for refractory infection.Forty-five subjects with refractory OPC were treated with Noxafil oral suspension 400 mg twice daily for days, followed by 400 mg once daily for 25 days with an option for further treatment during 3-month maintenance period. Following dosing amendment, further 44 subjects were treated with posaconazole 400 mg twice daily for 28 days. The efficacy of Noxafil was assessed by the clinical success (cure or improvement) rate after weeks of treatment. The clinical success rate was 74.2% (66/89). The clinical success rates for both the original and the amended dosing regimens were similar (73.3% and 75.0%, respectively).

CONTRAINDICATIONS SECTION.

4CONTRAINDICATIONS. 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, 5.10, 7.16) Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with known or suspected Hereditary Fructose Intolerance (HFI). (4.7, 5.8, 8.4). 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, 5.10, 7.16) 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, 5.10, 7.16). Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with known or suspected Hereditary Fructose Intolerance (HFI). (4.7, 5.8, 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 (5.10) and Drug Interactions (7.16)]. 4.7Use 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 (5.8) and Use in Specific Populations (8.4)].

DESCRIPTION SECTION.

11 DESCRIPTION. 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-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and molecular weight of 700.8. The chemical structure is:Posaconazole is white powder with low aqueous solubility.Noxafil InjectionNoxafil injection is available as 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 Betadex Sulfobutyl Ether Sodium (SBECD), 0.0033 edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6, and water for injection.Noxafil Delayed-Release TabletsNoxafil delayed-release tablet is 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 SuspensionNoxafil oral suspension is 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 SuspensionNoxafil PowderMix for delayed-release oral suspension is supplied as component of kit. Each kit contains Noxafil as an off-white to yellowish powder for delayed-release oral suspension, bottle of mixing liquid, two 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.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 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 mothers clinical need for Noxafil and any potential adverse effects on the breastfed child from Noxafil or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

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

DOSAGE FORMS & STRENGTHS SECTION.

3DOSAGE FORMS AND STRENGTHS. Noxafil injectionNoxafil injection (300 mg per vial) is available as clear, colorless to yellow sterile liquid in single-dose vial.Noxafil Delayed-Release TabletsNoxafil delayed-release tablets are available as yellow, coated, oblong tablets, debossed with 100 on one side containing 100 mg of posaconazole.Noxafil Oral SuspensionNoxafil oral suspension is available as white, cherry-flavored suspension in 4-ounce (123 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of posaconazole per mL).Noxafil PowderMix for Delayed-Release Oral SuspensionEach Noxafil PowderMix kit contains posaconazole, 300 mg, as an off-white to yellowish powder for delayed-release oral suspension and mixing liquid. Noxafil injection: 300 mg per vial (18 mg per mL) in single dose vial (3)Noxafil delayed-release tablet: 100 mg (3)Noxafil oral suspension: 40 mg per mL (3)Noxafil PowderMix for delayed-release oral suspension: 300 mg (3). Noxafil injection: 300 mg per vial (18 mg per mL) in single dose vial (3). Noxafil delayed-release tablet: 100 mg (3). Noxafil oral suspension: 40 mg per mL (3). Noxafil PowderMix for delayed-release oral suspension: 300 mg (3).

DRUG INTERACTIONS SECTION.

7DRUG INTERACTIONS. Posaconazole is primarily metabolized via UDP glucuronosyltransferase and is 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 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 DrugInteractionRifabutin, phenytoin, efavirenz, cimetidine, esomeprazoleThe 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 CYP3A4Consider dosage adjustment and monitor for adverse effects and toxicity (7.1, 7.10, 7.11)DigoxinMonitor 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 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 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 (5.6) 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, H2-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, H2-receptor antagonists and proton pump inhibitors.. Noxafil Oral Suspension:Cimetidine (an H2-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 H2-receptor antagonists other than cimetidine. No dosage adjustment of Noxafil oral suspension is required when Noxafil oral suspension is concomitantly used with antacids and H2-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 (5.7)]. 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 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.. 7.15Alcohol. 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 Cmax and AUC0-INF, which may increase venetoclax toxicities [see Contraindications (4.6), Warnings and Precautions (5.10)]. Refer to the venetoclax prescribing information for more information on the dosing instructions and the extent of increase in venetoclax exposure.

GERIATRIC USE SECTION.

8.5Geriatric Use. No overall differences in the safety of Noxafil injection, Noxafil delayed-release tablets, and Noxafil oral suspension were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for any formulation of Noxafil in geriatric patients. No clinically meaningful differences in the pharmacokinetics of Noxafil were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology (12.3)].Of the 279 patients treated with Noxafil injection in the Noxafil Injection Study, 52 (19%) were greater than 65 years of age. Of the 230 patients treated with Noxafil delayed-release tablets, 38 (17%) were greater than 65 years of age. Of the 605 patients randomized to Noxafil oral suspension in Noxafil Oral Suspension Study and Study 2, 63 (10%) were >=65 years of age. In addition, 48 patients treated with greater than or equal to 800-mg/day Noxafil oral suspension in another indication were >=65 years of age. Of the 288 patients randomized to Noxafil injection/Noxafil delayed-release tablets 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.

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Noxafil InjectionNoxafil injection is available as clear, colorless to yellow sterile liquid in single-dose Type glass vials closed with bromobutyl rubber stopper and aluminum seal (NDC 0085-4331-01) containing 300 mg of posaconazole in 16.7 mL of solution (18 mg of posaconazole per mL). Noxafil Delayed-Release TabletsNoxafil delayed-release tablets are available as yellow, coated, oblong, debossed with 100 on one side containing 100 mg of posaconazole. Bottles with child-resistant closures of 60 delayed-release tablets (NDC 0085-4324-02). Noxafil Oral SuspensionNoxafil oral suspension is available as white, cherry-flavored suspension in 4-ounce (123 mL) amber glass bottles with child-resistant closures (NDC 0085-1328-01) containing 105 mL of suspension (40 mg of posaconazole per mL).Supplied with each oral suspension bottle is plastic dosing spoon calibrated for measuring 2.5-mL and 5-mL doses.Noxafil PowderMix for Delayed-Release Oral SuspensionNoxafil PowderMix for delayed-release oral suspension is supplied as:Package A: kit with child-resistant single-use packets of Noxafil PowderMix for delayed-release oral suspension 300 mg, two mL (green) notched tip syringes, two 10 mL (blue) notched tip syringes, two mixing cups, one mixing liquid bottle, and one bottle adapter for the mixing liquid bottle.Package B: box of six mL (green) and six 10 mL (blue) notched tip syringes.Packages and are supplied separately.NDC 0085-2224-02 unit of use carton with packets.NDC 0085-2224-01 individual packet.. Package A: kit with child-resistant single-use packets of Noxafil PowderMix for delayed-release oral suspension 300 mg, two mL (green) notched tip syringes, two 10 mL (blue) notched tip syringes, two mixing cups, one mixing liquid bottle, and one bottle adapter for the mixing liquid bottle.. Package B: box of six mL (green) and six 10 mL (blue) notched tip syringes.. Packages and are supplied separately.. 16.2Storage and Handling. Noxafil InjectionNoxafil injection vial should be stored refrigerated at to 8C (36 to 46F). Storage conditions for the diluted solution are presented in another section of the prescribing information [see Dosage and Administration (2.4)]. Noxafil Delayed-Release TabletsStore at 20 to 25C (68 to 77F), excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].Noxafil Oral SuspensionStore at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature]. DO NOT FREEZE. Noxafil PowderMix for Delayed-Release Oral SuspensionStore the entire kit at 20 to 25C (68 to 77F), excursions permitted to 15 to 30C (59 to 86F) in 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)].

INDICATIONS & USAGE SECTION.

1INDICATIONS AND USAGE. 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 years of age and olderNoxafil delayed-release tablets: adults and pediatric patients years of age and older who weigh greater than 40 kgNoxafil oral suspension: adults and pediatric patients 13 years of age and olderNoxafil PowderMix for delayed-release oral suspension: pediatric patients 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). 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 years of age and olderNoxafil delayed-release tablets: adults and pediatric patients years of age and older who weigh greater than 40 kgNoxafil oral suspension: adults and pediatric patients 13 years of age and olderNoxafil PowderMix for delayed-release oral suspension: pediatric patients years of age and older who weigh 40 kg or less Noxafil injection: adults and pediatric patients years of age and older. Noxafil delayed-release tablets: adults and pediatric patients 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 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). 1.1Treatment of Invasive Aspergillosis. Noxafil(R) 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 years of age and olderNoxafil delayed-release tablets: adults and pediatric patients years of age and older who weigh greater than 40 kgNoxafil oral suspension: adults and pediatric patients 13 years of age and olderNoxafil PowderMix for delayed-release oral suspension: pediatric patients years of age and older who weigh 40 kg or less. Noxafil injection: adults and pediatric patients years of age and older. Noxafil delayed-release tablets: adults and pediatric patients 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 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.

INFORMATION FOR PATIENTS SECTION.

17PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).Important Administration InstructionsNoxafil Delayed-Release TabletsAdvise patients that Noxafil delayed-release tablets must be swallowed whole and not divided, crushed, or chewed.Instruct patients that if they miss dose, they should take it as soon as they remember. If they do not remember until it is within 12 hours of the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.Noxafil Oral SuspensionAdvise patients to take each dose of Noxafil oral suspension during or immediately (i.e., within 20 minutes) following full meal. In patients who cannot eat full meal, each dose of Noxafil oral suspension should be administered with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in order to enhance absorption.Instruct patients that if they miss dose, they should take it as soon as they remember. However, if it is almost time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.Noxafil PowderMix for Delayed-Release Oral SuspensionInstruct parents and/or caregivers that ONLY the provided notched tip syringes can be used to administer Noxafil PowderMix for delayed-release oral suspension to pediatric patients.Advise patients to take Noxafil PowderMix for delayed-release oral suspension with food.Drug InteractionsAdvise 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 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 ReactionsAdvise patients to inform their physician immediately if they:notice change in heart rate or heart rhythm or have heart condition or circulatory disease. Noxafil 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.Hereditary Fructose Intolerance (HFI)Inform patients and caregivers that Noxafil PowderMix for delayed-release oral suspension contains sorbitol and can be life-threatening when administered to patients with hereditary fructose intolerance (HFI) [see Warnings and Precautions (5.8)]. Inquire for symptoms of sorbitol/fructose and/or sucrose intolerance before administration.. 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 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.. notice change in heart rate or heart rhythm or have heart condition or circulatory disease. Noxafil 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.

INSTRUCTIONS FOR USE SECTION.

Important: Read This Booklet FirstNoxafil PowderMix (posaconazole)for delayed-release oral suspensionInstructions for Usefor caregivers and healthcare providers of toddlers and children Before You StartBefore you start, be sure that you read and understand all of these instructions. They may be different than those for medicines that you have used in the past.It is important that you make all measurements very carefully.Before you give Noxafil PowderMix, check all expiration dates. The expiration date is printed on the box, the Noxafil PowderMix packets, and the mixing liquid.Do not open the Noxafil PowderMix packets until you are ready to mix the dose.Give Noxafil PowderMix with food.Note: Put your child in safe place. You will need both hands to prepare Noxafil PowderMix. Wash your hands with soap and water before preparing Noxafil PowderMix.Before You StartThe amount of Noxafil PowderMix you give depends on yourchilds weight. Your healthcare provider will tell you the right dose to give your child. Be sure to keep your healthcare providers appointments so you get new dosing information as your child grows.This booklet tells you how to:Make the Noxafil PowderMix into liquid form.Measure the right dose using the included notched-tiporal syringe. Only use the notched-tip syringes supplied with the kit. Do not use other oral syringes.Give the Noxafil PowderMix to your child.Clean up. Note before adding Noxafil PowderMix: Make sure you and your child are ready If you do not use Noxafil PowderMix within hour, you will need to throw it away and start over.Note: If you have any questions, call your healthcare provider.Kit ContentsPrescription (on Noxafil PowderMix box)2 mixing cupsInstructions for Use (this booklet)8 packets of Noxafil PowderMixPackage insertBottle adapter4 syringes (shown below)Bottle of Mixing Liquid for use with NoxafilPowderMix2 blue (10 mL) syringes2 green (3 mL) syringesThe kit has an extra cup and set of syringes in case one is lost or damaged.Do not use any damaged cups or syringes.Get to Know the Oral SyringesBefore you prepare dose, reviewthe parts of the syringe and how touse them.If you have any questions about measuring with syringe, call your healthcare provider.Make sure the plunger is pushed all the way into the barrel before you start to measure the dose.Look for the number on the measuring scale that matchesthe amount of mixing liquid or Noxafil PowderMix that you need.Be sure to follow the directions in this booklet to remove air bubbles from the syringe. Air bubbles can affect the amount of medicine that the child gets. Step 1. Get the mixing liquid ready.Important: Noxafil PowderMix needs to be prepared using the mixing liquid. Do not mix Noxafil PowderMix with milk, juice, or water.When you use the mixing liquid for the first time:Open the bottle and remove the safety seal.Place the bottle adapter on top of the bottle with the small hole facing up.Push the bottle adapter all the way down.After it is in place, the bottle adapter stays in the bottle.Put the cap back on the bottle.Step 2. Gather all your supplies and put on clean surface.Note: Put your child in safe place. You will need both hands to prepare Noxafil PowderMix. Wash your hands with soap and water before preparing Noxafil PowderMix.1 mixing cup (Using the tab on the mixing cup, pull open the lid.)1 packet ofNoxafil PowderMixpowder Mixing liquid2 syringes (Have of each size ready, but you may only use 1, depending on the dose.)Scissors (not included with kit: use sharp household scissors or kitchen scissors)The Noxafil PowderMix box has mixing cup holder inside to help tilt the cup when you are measuring the dose.Step 3. Add Noxafil PowderMix to the mixing cup.Note before adding Noxafil PowderMix: Make sure you and your child are ready If you do not use Noxafil PowderMix within hour, you will need to throw it away and start over.Take packet of Noxafil PowderMix and shake the powder to the bottom of the packet.Cut open the packet of Noxafil PowderMix at the dotted line and add all of the Noxafil PowderMix to the mixing cup. Make sure the packet of Noxafil PowderMix is completely empty.Step 4. Shake the mixing liquid bottle.Shake the mixing liquid well before each time you prepare Noxafil PowderMix.Step 5. Fill the blue syringe with mL of mixing liquid.Push the plunger of the blue syringe into the syringe barrel as far as it goes.Remove the cap from the bottle of mixing liquid.Push the notched tip of the syringe into the bottle adapter.With the syringe attached to the bottle, turn the bottle and syringe upside down. With your other hand, pull back the plunger to draw the mixing liquid back into the syringe.Stop when you get to the mL line.Turn the bottle back over and remove the syringe to check your measurement.Step 6. Check for air bubbles.Hold the syringe with notched tip up. Tap it with your finger to move any air bubbles up.Slowly push the plunger to make the air come out.Re-check the measurement of mixing liquid in the syringe. If it is less than mL, put the notched tip back into the mixing liquid and pull the plunger back until you get to the mL mark.Step 7. Add the mL of mixing liquid to the Noxafil PowderMix.Add the mL of mixing liquid to the Noxafil PowderMix in the mixing cup by pushing all the way down on the plunger.Step 8. Mix the Noxafil PowderMix.Snap the lid of the mixing cup shut.Shake the mixing cup really hard for 45 seconds to mix the Noxafil PowderMix.Check to make sure the Noxafil PowderMix powder is mixed. If it is not mixed, shake the mixing cup some more. Noxafil PowderMix should look cloudy and freeof clumps.Step 9. Check your prescription label.Find the dose amount (look for the mL written on the prescription label on the box from your healthcare provider).Note: The dose may change each time you go to the healthcare provider, so make sure you have all the recent information. Be sure to go to all of your childs healthcare provider appointments so your child gets the right dose.Step 10. Choose the syringe you need.Note: Only use the syringes provided in the kit.Choose the correct syringe for your childs dose: For mL to mLGreen For mL to 10 mL Blue Then find the mL mark on the syringe that matches your childs dose.Step 11. Measure the Noxafil PowderMix.Push the plunger into the dosing syringe as far as it goes.Tilt the cup by hand or use the mixing cup holder inside the Noxafil PowderMix box.Put the notched tip of the dosing syringe into the lowest part of the cup with the Noxafil PowderMix and pull back the plunger.Stop when you get to the line showing the prescribed dose.Important: You will not use all of the Noxafil PowderMix. There will be some left over in the mixing cup.Step 12. Check for air bubbles.Be sure to follow the directions to remove air bubbles from the syringe. Air bubbles can affect the amount of medicine that the child gets.Hold the syringe with notched tip up. Tap it with your finger to move any air bubbles up. Check for air gaps in the tip of the syringe. Slowly push the plunger to make the air bubbles or air gaps come out.Re-check the measurement of Noxafil PowderMix in the syringe. If it is less than the prescribed dose, put the notched tip back into the mixing cup with the Noxafil PowderMix and pull the plunger back until you get to the right dose mark.Step 13. Give the Noxafil PowderMix to your child.Gently place the syringe inside your childs mouth so that the notched tip touches one of his or her cheeks.Slowly push down on the plunger to give the dose of Noxafil PowderMix. It is important that your child takes all of the dose of Noxafil PowderMix (a little left in the syringe notched tip is ok).Important:If your child does not take the whole dose or spits some of it out, call your healthcare provider to find out what to do. Only use the mixing liquid from the kit. Do not mix Noxafil PowderMix with milk, juice, or water.Step 14. Clean the cup and syringes.Note: Syringes and mixing cups should be reused. Do not throw away syringes and mixing cups provided until all the Noxafil PowderMix packets are used.Pour the leftover Noxafil PowderMix from the mixing cup into the trash. Do not pour it into the sink. Pull the plungers out of any syringes you used. Hand wash the syringes, plungers, and mixing cup with warm water and dish soap. Do not wash in the dishwasher. Rinse with water and air dry.Put everything in clean, dry place.Step 15. After all packets of Noxafil PowderMix have been used.After you have used the last Noxafil PowderMix packet in this box, you will have leftover mixing liquid in the bottle. Throw away the leftover mixing liquid and all components of the kit.How should store Noxafil PowderMixStore the entire kit at room temperature between 68F to 77F (20C to 25C) in clean, dry place. Keep the mixing liquid at room temperature.Do not open the Noxafil PowderMix packet until you are ready to mix dose.Keep NOXAFIL PowderMix and all medicines out of the reach of children.For more information go to www.NOXAFIL.com or call 1-800-622-4477.Distributed by: Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., Whitehouse Station, NJ 08889, USAFor patent information: www.merck.com/product/patent/home.htmlCopyright (C) 2021 Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc. All rights reserved.ifu-mk5592-2105r000This Instructions for Use has been approved by the U.S. Food and Drug Administration.Approved: May 2021. Before you start, be sure that you read and understand all of these instructions. They may be different than those for medicines that you have used in the past.. It is important that you make all measurements very carefully.. Before you give Noxafil PowderMix, check all expiration dates. The expiration date is printed on the box, the Noxafil PowderMix packets, and the mixing liquid.. Do not open the Noxafil PowderMix packets until you are ready to mix the dose.. Give Noxafil PowderMix with food.. The amount of Noxafil PowderMix you give depends on yourchilds weight. Your healthcare provider will tell you the right dose to give your child. Be sure to keep your healthcare providers appointments so you get new dosing information as your child grows.. This booklet tells you how to:Make the Noxafil PowderMix into liquid form.Measure the right dose using the included notched-tiporal syringe. Only use the notched-tip syringes supplied with the kit. Do not use other oral syringes.Give the Noxafil PowderMix to your child.Clean up. Make the Noxafil PowderMix into liquid form.. Measure the right dose using the included notched-tiporal syringe. Only use the notched-tip syringes supplied with the kit. Do not use other oral syringes.. Give the Noxafil PowderMix to your child.. Clean up.. Prescription (on Noxafil PowderMix box). mixing cups. Instructions for Use (this booklet). packets of Noxafil PowderMix. Package insert. Bottle adapter. syringes (shown below). Bottle of Mixing Liquid for use with NoxafilPowderMix. Before you prepare dose, reviewthe parts of the syringe and how touse them.. If you have any questions about measuring with syringe, call your healthcare provider.. Make sure the plunger is pushed all the way into the barrel before you start to measure the dose.. Look for the number on the measuring scale that matchesthe amount of mixing liquid or Noxafil PowderMix that you need.. Be sure to follow the directions in this booklet to remove air bubbles from the syringe. Air bubbles can affect the amount of medicine that the child gets. Open the bottle and remove the safety seal.. Place the bottle adapter on top of the bottle with the small hole facing up.. Push the bottle adapter all the way down.. After it is in place, the bottle adapter stays in the bottle.. Put the cap back on the bottle.. Take packet of Noxafil PowderMix and shake the powder to the bottom of the packet.. Cut open the packet of Noxafil PowderMix at the dotted line and add all of the Noxafil PowderMix to the mixing cup. Make sure the packet of Noxafil PowderMix is completely empty.. Shake the mixing liquid well before each time you prepare Noxafil PowderMix.. Push the plunger of the blue syringe into the syringe barrel as far as it goes.. Remove the cap from the bottle of mixing liquid.. Push the notched tip of the syringe into the bottle adapter.. With the syringe attached to the bottle, turn the bottle and syringe upside down. With your other hand, pull back the plunger to draw the mixing liquid back into the syringe.. Stop when you get to the mL line.. Turn the bottle back over and remove the syringe to check your measurement.. Hold the syringe with notched tip up. Tap it with your finger to move any air bubbles up.. Slowly push the plunger to make the air come out.. Re-check the measurement of mixing liquid in the syringe. If it is less than mL, put the notched tip back into the mixing liquid and pull the plunger back until you get to the mL mark.. Add the mL of mixing liquid to the Noxafil PowderMix in the mixing cup by pushing all the way down on the plunger.. Snap the lid of the mixing cup shut.. Shake the mixing cup really hard for 45 seconds to mix the Noxafil PowderMix.. Check to make sure the Noxafil PowderMix powder is mixed. If it is not mixed, shake the mixing cup some more. Noxafil PowderMix should look cloudy and freeof clumps.. Find the dose amount (look for the mL written on the prescription label on the box from your healthcare provider).. Then find the mL mark on the syringe that matches your childs dose.. Push the plunger into the dosing syringe as far as it goes.. Tilt the cup by hand or use the mixing cup holder inside the Noxafil PowderMix box.. Put the notched tip of the dosing syringe into the lowest part of the cup with the Noxafil PowderMix and pull back the plunger.. Stop when you get to the line showing the prescribed dose.. Be sure to follow the directions to remove air bubbles from the syringe. Air bubbles can affect the amount of medicine that the child gets.. Hold the syringe with notched tip up. Tap it with your finger to move any air bubbles up. Check for air gaps in the tip of the syringe. Slowly push the plunger to make the air bubbles or air gaps come out.. Re-check the measurement of Noxafil PowderMix in the syringe. If it is less than the prescribed dose, put the notched tip back into the mixing cup with the Noxafil PowderMix and pull the plunger back until you get to the right dose mark.. Gently place the syringe inside your childs mouth so that the notched tip touches one of his or her cheeks.. Slowly push down on the plunger to give the dose of Noxafil PowderMix. It is important that your child takes all of the dose of Noxafil PowderMix (a little left in the syringe notched tip is ok).. If your child does not take the whole dose or spits some of it out, call your healthcare provider to find out what to do. Only use the mixing liquid from the kit. Do not mix Noxafil PowderMix with milk, juice, or water.. Pour the leftover Noxafil PowderMix from the mixing cup into the trash. Do not pour it into the sink. Pull the plungers out of any syringes you used. Hand wash the syringes, plungers, and mixing cup with warm water and dish soap. Do not wash in the dishwasher. Rinse with water and air dry.. Put everything in clean, dry place.. After you have used the last Noxafil PowderMix packet in this box, you will have leftover mixing liquid in the bottle. Throw away the leftover mixing liquid and all components of the kit.. Store the entire kit at room temperature between 68F to 77F (20C to 25C) in clean, dry place. Keep the mixing liquid at room temperature.. Do not open the Noxafil PowderMix packet until you are ready to mix dose.. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of Action:Posaconazole blocks the synthesis of ergosterol, key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and 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 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisNo drug-related neoplasms were recorded in rats or mice treated with posaconazole for years at doses higher than the clinical dose. In 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 400-mg twice daily oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered 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 400-mg twice daily oral suspension regimen.MutagenesisPosaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), chromosome aberration study in human peripheral blood lymphocytes, Chinese hamster ovary cell mutagenicity study, and mouse bone marrow micronucleus study.Impairment of FertilityPosaconazole had no effect on fertility of male rats at 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 dose up to 45 mg/kg (2.2 the 400-mg twice daily oral suspension regimen).. 13.2 Animal Toxicology and/or Pharmacology. In nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from to 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 similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to months of age). There were no drug-related increases in the incidence of brain ventricle enlargement when treated and control animals were compared in separate study of 10-week old dogs dosed with intravenous posaconazole for 13 weeks with 9-week recovery period or follow-up study of 31-week old dogs dosed for months.

OVERDOSAGE SECTION.

10OVERDOSAGE. There is no experience with overdosage of Noxafil injection and Noxafil delayed-release tablets.During the clinical trials, some patients received Noxafil oral suspension up to 1600 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 1200 mg twice daily Noxafil oral suspension for days. No related adverse reactions were noted by the investigator.Posaconazole is not removed by hemodialysis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 105 mL Bottle Carton. NDC 0085-1328-01 105 mL NOXAFIL(R) (posaconazole)Oral Suspension200 mg/5 mLEach mL contains: 40 mg posaconazole.Attention: Noxafil Oral Suspension andDelayed-Release Tablets are NOTinterchangeable due to differences in thedosing of each formulation.SHAKE WELL BEFORE EACH USE.Take with meal, or nutritional supplement,or an acidic carbonated beverage.Carton contains measured dosing spoon.Rx only. PRINCIPAL DISPLAY PANEL 105 mL Bottle Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Noxafil injection, Noxafil delayed-release tablets, Noxafil PowderMix for delayed-release oral suspension, and Noxafil oral suspension for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged 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 Noxafil injection and Noxafil delayed-release tablets for the treatment of invasive aspergillosis have been established in pediatric patients aged 13 years and older. The safety and effectiveness of Noxafil oral suspension have been established for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in pediatric patients aged 13 years and older. Use of Noxafil in these age groups is supported by evidence from adequate and well-controlled studies of Noxafil in adult and pediatric patients and additional pharmacokinetic and safety data in pediatric patients years of age and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)]. The safety and effectiveness of Noxafil have not been established in pediatric patients younger than years of age.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. Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with HFI. Because diagnosis of HFI may not yet be established in pediatric patients, obtain careful history of HFI symptoms with sorbitol/fructose/sucrose exposure prior to administration of Noxafil PowderMix for delayed-release oral suspension [see Warnings and Precautions (5.8)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Exposure Response Relationship Prophylaxis: In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), wide range of plasma exposures to posaconazole was noted following administration of Noxafil oral suspension. pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 17). lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.Table 17: Noxafil Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials Prophylaxis in AML/MDSNeutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS Prophylaxis in GVHDHSCT recipients with GVHD Cavg Range (ng/mL)Treatment FailureDefined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections (%)Cavg Range (ng/mL)Treatment Failure (%)Cavg the average posaconazole concentration when measured at steady stateQuartile 190-32254.722-55744.4Quartile 2322-49037.0557-91520.6Quartile 3490-73446.8915-156317.5Quartile 4734-220027.81563-365017.5Exposure Response Relationship Treatment of Invasive Aspergillosis:Across range of posaconazole plasma minimum concentrations (Cmin, range: 244 to 5663 ng/mL) following administration of Noxafil injection and Noxafil delayed-release tablets in patients treated for invasive aspergillosis in Aspergillosis Treatment Study, there was no association between posaconazole Cmin and treatment efficacy [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)]. Similarly, across range of population pharmacokinetic model-predicted steady-state plasma average concentrations (Cavg, range: 589 to 6315 ng/mL), there was no association between posaconazole Cavg and treatment efficacy.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. General Pharmacokinetic Characteristics. Noxafil InjectionNoxafil 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 Noxafil 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 Noxafil Injection on Day 1Dose (mg)nAUC0- (nghr/mL)AUC0-12 (nghr/mL)Cmax (ng/mL)t1/2 (hr)CL(L/hr)AUC0- Area under the plasma concentration-time curve from time zero to infinity; AUC0-12 Area under the plasma concentration-time curve from time zero to 12 hr after the first dose on Day 1; Cmax maximum observed concentration; 1/2 terminal phase half-life; CL total body clearance; N/D Not DeterminedHealthy Volunteers200935400 (50)8840 (20)2250 (29)23.6 (23)6.5 (32)300946400 (26)13000 (13)2840 (30)24.6 (20)6.9 (27)Patients20030N/D5570 (32)954 (44)N/DN/D30022N/D8240 (26)1590 (62)N/DN/DTable 19 displays the pharmacokinetic parameters of posaconazole in patients following administration of Noxafil injection 300 mg taken once 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 Noxafil Injection (300 mg)300 mg dose administered over 90 minutes once day following twice daily dosing on Day DayNCmax (ng/mL)Tmax Median (minimum-maximum) (hr)AUC0-24 (nghr/mL)Cav(ng/mL)Cmin (ng/mL)AUC0-24 area under the concentration-time curve over the dosing interval (i.e. 24 hours); Cav= time-averaged concentrations (i.e., AUC0-24h/24hr);Cmin POS trough level immediately before subject received the dose of POS on the day specified in the protocol; Cmax observed maximum plasma concentration; CV coefficient of variation, expressed as percent (%); Day study day on treatment; Tmax time of observed maximum plasma concentration.10/14493280 (74)1.5 (0.98-4.0)36100 (35)1500 (35)1090 (44). Noxafil Delayed-Release TabletsNoxafil delayed-release tablets exhibit dose proportional pharmacokinetics after single and multiple dosing up to 300 mg. The mean pharmacokinetic parameters of posaconazole at steady state following administration of Noxafil delayed-release tablets 300 mg twice daily on Day 1, then 300 mg once daily thereafter in healthy volunteers and in neutropenic patients who are receiving cytotoxic chemotherapy for AML or MDS or HSCT recipients with GVHD are shown in Table 20.Table 20: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Noxafil Delayed-Release Tablets (300 mg)300 mg twice daily on Day 1, then 300 mg once daily thereafter NAUC0-24 hr (nghr/mL)CavCav time-averaged concentrations (i.e., AUC0-24 hr/24hr) (ng/mL)Cmax (ng/mL)Cmin (ng/mL)Tmax Median (minimum-maximum) (hr)t1/2 (hr)CL/F(L/hr)CV coefficient of variation expressed as percentage (%CV); AUC0-T Area under the plasma concentration-time curve from time zero to 24 hr; Cmax maximum observed concentration; Cmin minimum observed plasma concentration; Tmax time of maximum observed concentration; 1/2 terminal phase half-life; CL/F Apparent total body clearanceHealthy Volunteers1251618(25)2151(25)2764(21)1785(29)4(3-6)31(40)7.5(26)Patients5037900(42)1580(42)2090(38)1310(50)4 (1.3-8.3)-9.39(45). Noxafil Oral SuspensionDose-proportional increases in plasma exposure (AUC) to Noxafil oral suspension were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg twice daily to 400 mg twice daily in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg twice daily to 600 mg twice daily in febrile neutropenic patients or those with refractory invasive fungal infections.The mean (%CV) [min-max] Noxafil oral suspension average steady-state plasma concentrations (Cavg) and steady-state pharmacokinetic parameters in patients following administration of 200 mg three times day and 400 mg twice daily of the oral suspension are provided in Table 21. Table 21: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Noxafil Oral Suspension 200 mg Three Times Day and 400 mg Twice DailyDoseOral suspension administration Cavg (ng/mL)AUCAUC (0-24 hr) for 200 mg three times day and AUC (0-12 hr) for 400 mg twice daily (nghr/mL)CL/F (L/hr)V/F (L)t 1/2 (hr)Cavg the average posaconazole concentration when measured at steady stateThe variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.200 mg three times dayHSCT recipients with GVHD (n=252)1103 (67)[21.5-3650]NDNot done ND ND ND 200 mg three times dayNeutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes (n=215)583 (65)[89.7-2200]15,900 (62)[4100-56,100]51.2 (54)[10.7-146]2425 (39)[828-5702]37.2 (39)[19.1-148]400 mg twice dailyFebrile neutropenic patients or patients with refractory invasive fungal infections, Cavg n=24 (n=23)723 (86)[6.70-2256]9093 (80)[1564-26,794]76.1 (78)[14.9-256]3088 (84)[407-13,140]31.7 (42)[12.4-67.3]. Absorption: Noxafil Delayed-Release TabletsWhen given orally in healthy volunteers, Noxafil delayed-release tablets are absorbed with median Tmax of to hours. Steady-state plasma concentrations are attained by Day at the 300 mg dose (once daily after twice daily loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. The Cmax and AUC of posaconazole following administration of Noxafil delayed-release tablets is increased 16% and 51%, respectively, when given with high fat meal compared to fasted state (see Table 22).Table 22: Statistical Comparison of Plasma Pharmacokinetics of Posaconazole Following Single Oral Dose Administration of 300 mg Noxafil Delayed-Release Tablet to Healthy Subjects under Fasting and Fed ConditionsFasting ConditionsFed Conditions (High Fat Meal)48.5 fat Fed/FastingPharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)GMR=Geometric least-squares mean ratio; CI=Confidence intervalCmax (ng/mL)14935 (34)161060 (25)1.16 (0.96, 1.41)AUC0-72hr (hrng/mL)1426200 (28)1638400 (18)1.51 (1.33, 1.72)Tmax Median (Min, Max) reported for Tmax (hr)145.00 (3.00, 8.00)166.00 (5.00, 24.00)N/AConcomitant administration of Noxafil delayed-release tablets with drugs affecting gastric pH or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see Table 23).Table 23: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Delayed-Release Tablets in Healthy VolunteersCoadministered DrugAdministration ArmsChange in Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to Noxafil alone for Cmax or AUC0-last.;90% CI of the ratio estimate)Change in AUC0-last (ratio estimate;90% CI of the ratio estimate)Mylanta(R) Ultimate strength liquid (Increase in gastric pH)25.4 meq/5 mL, 20 mL6%(1.06; 0.90 -1.26)4%(1.04; 0.90 -1.20)Ranitidine (Zantac(R)) (Alteration in gastric pH)150 mg (morning dose of 150 mg Ranitidine twice daily)4%(1.04; 0.88 -1.23)3%(0.97; 0.84 -1.12)Esomeprazole (Nexium(R)) (Increase in gastric pH)40 mg (every morning for days, Day -4 to 1)2%(1.02; 0.88-1.17)5%(1.05; 0.89 -1.24)Metoclopramide (Reglan(R)) (Increase in gastric motility)15 mg four times daily for days (Day -1 and 1)14%(0.86, 0.73,1.02)7%(0.93, 0.803,1.07)Noxafil PowderMix for Delayed-Release Oral SuspensionThe absolute bioavailability of the Noxafil PowderMix for delayed-release oral suspension is approximately 70-80%. The effect of food on the pharmacokinetics of the Noxafil PowderMix for delayed-release oral suspension has not been determined.Concomitant administration of Noxafil PowderMix for delayed-release oral suspension with drugs affecting gastric pH or gastric motility would not be expected to demonstrate any significant effects on posaconazole pharmacokinetic exposure based on similarity to the delayed-release tablets.An in vitro dissolution study was conducted to evaluate the impact of alcohol (5, 10, 20, and 40%) on the dissolution of Noxafil PowderMix delayed-release oral suspension. The study showed alcohol-induced dose-dumping potential with the Noxafil PowderMix delayed-release oral suspension [see Dosage and Administration (2.1) and Drug Interactions (7.15)].. Noxafil Oral SuspensionNoxafil oral suspension is absorbed with median Tmax of ~3 to hours. Steady-state plasma concentrations are attained at to 10 days following multiple-dose administration.Following single-dose administration of 200 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when the oral suspension is administered with nonfat meal and approximately 4-times higher when administered with high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of Noxafil oral suspension 400 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when administered with liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 24). In addition, the effects of varying gastric administration conditions on the Cmax and AUC of Noxafil oral suspension in healthy volunteers have been investigated and are shown in Table 25.In order to assure attainment of adequate plasma concentrations, it is recommended to administer Noxafil oral suspension during or immediately following full meal. In patients who cannot eat full meal, Noxafil oral suspension should be taken with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).Table 24: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-Dose Noxafil Oral Suspension Administration of 200 mg and 400 mg Under Fed and Fasted ConditionsDose (mg)Cmax (ng/mL)Tmax Median [min-max]. (hr)AUC (I)(nghr/mL)CL/F(L/hr)t 1/2 (hr)200 mg fasted(n=20)n=15 for AUC (I), CL/F, and 1/2 132 (50)[45-267]3.50[1.5-36The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between hrs and 36 hrs).]4179 (31)[2705-7269]51 (25)[28-74]23.5 (25)[15.3-33.7]200 mg nonfat(n=20) 378 (43)[131-834]4 [3-5]10,753 (35)[4579-17,092]21 (39)[12-44]22.2 (18)[17.4-28.7]200 mg high fat(54 gm fat)(n=20) 512 (34)[241-1016]5 [4-5]15,059 (26)[10,341-24,476]14 (24)[8.2-19]23.0 (19)[17.2-33.4]400 mg fasted(n=23)n=10 for AUC (I), CL/F, and 1/2 121 (75)[27-366]4 [2-12]5258 (48)[2834-9567]91 (40)[42-141]27.3 (26)[16.8-38.9]400 mg with liquid nutritional supplement(14 gm fat)(n=23) 355 (43)[145-720]5 [4-8]11,295 (40)[3865-20,592]43 (56)[19-103]26.0 (19)[18.2-35.0]Table 25: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of Noxafil Oral Suspension in Healthy VolunteersIn subjects, the Cmax and AUC decreased substantially (range: -27% to -53% and -33% to -51%, respectively) when Noxafil was administered via an NG tube compared to when Noxafil was administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when Noxafil is administered via an NG tube because lower plasma exposure may be associated with an increased risk of treatment failure. Study DescriptionAdministration ArmsChange in Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for Cmax or AUC.;90% CI of the ratio estimate)Change in AUC(ratio estimate;90% CI of the ratio estimate)400-mg single dose with high-fat meal relative to fasted state (n=12) minutes before high-fat meal96%(1.96; 1.48-2.59)111%(2.11; 1.60-2.78)During high-fat meal339%(4.39; 3.32-5.80)382%(4.82; 3.66-6.35)20 minutes after high-fat meal333%(4.33; 3.28-5.73)387%(4.87; 3.70-6.42)400 mg twice daily and 200 mg four times daily for days in fasted state and with liquid nutritional supplement (BOOST(R)) (n=12)400 mg twice daily with BOOST65%(1.65; 1.29-2.11)66%(1.66; 1.30-2.13)200 mg four times daily with BOOSTNo EffectNo EffectDivided daily dose from 400 mg twice daily to 200 mg four times daily for days regardless of fasted conditions or with BOOST (n=12)Fasted state136%(2.36; 1.84-3.02)161%(2.61; 2.04-3.35)With BOOST137%(2.37; 1.86-3.04)157%(2.57; 2.00-3.30)400-mg single dose with carbonated acidic beverage (ginger ale) and/or proton pump inhibitor (esomeprazole) (n=12)Ginger ale92%(1.92; 1.51-2.44)70%(1.70; 1.43-2.03)Esomeprazole32%(0.68; 0.53-0.86)30%(0.70; 0.59-0.83)400-mg single dose with prokinetic agent (metoclopramide 10 mg three times day for days) BOOST or an antikinetic agent (loperamide 4-mg single dose) BOOST (n=12)With metoclopramide BOOST21%(0.79; 0.72-0.87)19%(0.81; 0.72-0.91)With loperamide BOOST3%(0.97; 0.88-1.07)11%(1.11; 0.99-1.25)400-mg single dose either orally with BOOST or via an NG tube with BOOST (n=16)Via NG tubeNG nasogastric 19%(0.81; 0.71-0.91)23%(0.77; 0.69-0.86)Concomitant administration of Noxafil oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (See Table 26.)Table 26: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Oral Suspension in Healthy VolunteersCoadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in MeanCmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Cimetidine(Alteration of gastric pH)400 mg twice daily 10 days200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. 39%(0.61; 0.53-0.70) 39%(0.61; 0.54-0.69)Esomeprazole (Increase in gastric pH)The drug interactions associated with the oral suspension are also relevant for the delayed-release tablet with the exception of Esomeprazole and Metoclopramide. 40 mg every morning 3 days400 mg (oral suspension) single dose 46%(0.54; 0.43-0.69) 32%(0.68; 0.57-0.81)Metoclopramide (Increase in gastric motility) 10 mg three times day 2 days400 mg (oral suspension) single dose 21%(0.79; 0.72-0.87) 19%(0.81; 0.72-0.91). Distribution:The mean volume of distribution of posaconazole after intravenous solution administration was 261 and ranged from 226-295 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 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 enzymes) and is substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. summary of drugs studied clinically with the oral suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in Table 27. Table 27: Summary of the Effect of Coadministered Drugs on Noxafil in Healthy VolunteersCoadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in MeanCmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to Noxafil alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Efavirenz(UDP-G Induction)400 mg once daily 10 and 20 days400 mg (oral suspension) twice daily 10 and 20 days45%(0.55; 0.47-0.66) 50%(0.50; 0.43-0.60)Fosamprenavir (unknown mechanism)700 mg twice daily 10 days200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily 8 Days21%0.79 (0.71-0.89)23%0.77 (0.68-0.87)Rifabutin(UDP-G Induction)300 mg once daily 17 days200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. 43%(0.57; 0.43-0.75) 49%(0.51; 0.37-0.71)Phenytoin(UDP-G Induction)200 mg once daily 10 days200 mg (tablets) once daily 10 days 41%(0.59; 0.44-0.79) 50%(0.50; 0.36-0.71)In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. clinical study in healthy volunteers also indicates that posaconazole is strong CYP3A4 inhibitor as evidenced by >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 28 [see Contraindications (4) and Drug Interactions (7.1) including recommendations].Table 28: Summary of the Effect of Noxafil on Coadministered Drugs in Healthy Adult Volunteers and PatientsCoadministered Drug(Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of Coadministered DrugsChange in Mean Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Sirolimus2-mg single oral dose400 mg (oral suspension) twice daily 16 days 572%(6.72; 5.62-8.03) 788%(8.88; 7.26-10.9)CyclosporineStable maintenance dose in heart transplant recipients200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. cyclosporine whole blood trough concentrationsCyclosporine dose reductions of up to 29% were requiredTacrolimus0.05-mg/kg single oral dose400 mg (oral suspension) twice daily 7 days 121%(2.21; 2.01-2.42) 358%(4.58; 4.03-5.19)Simvastatin40-mg single oral dose100 mg (oral suspension) once daily 13 daysSimvastatin 841%(9.41, 7.13-12.44)Simvastatin Acid 817%(9.17, 7.36-11.43)Simvastatin 931%(10.31, 8.40-12.67)Simvastatin Acid634%(7.34, 5.82-9.25)200 mg (oral suspension) once daily 13 daysSimvastatin 1041%(11.41, 7.99-16.29)Simvastatin Acid851%(9.51, 8.15-11.10)Simvastatin 960%(10.60, 8.63-13.02)Simvastatin Acid 748%(8.48, 7.04-10.23)Midazolam0.4-mg single intravenous doseThe mean terminal half-life of midazolam was increased from hours to to 11 hours during coadministration with Noxafil. 200 mg (oral suspension) twice daily 7 days 30%(1.3; 1.13-1.48) 362%(4.62; 4.02-5.3)0.4-mg single intravenous dose 400 mg (oral suspension) twice daily 7 days62%(1.62; 1.41-1.86)524%(6.24; 5.43-7.16)2-mg single oral dose 200 mg (oral suspension) once daily 7 days 169%(2.69; 2.46-2.93) 470%(5.70; 4.82-6.74)2-mg single oral dose 400 mg (oral suspension) twice daily 7 days 138%(2.38; 2.13-2.66) 397%(4.97; 4.46-5.54)Rifabutin300 mg once daily 17 days200 mg (tablets) once daily 10 days 31%(1.31; 1.10-1.57) 72%(1.72;1.51-1.95)Phenytoin200 mg once daily PO 10 days200 mg (tablets) once daily 10 days 16%(1.16; 0.85-1.57) 16%(1.16; 0.84-1.59)Ritonavir100 mg once daily 14 days400 mg (oral suspension)twice daily 7 days 49%(1.49; 1.04-2.15) 80%(1.8;1.39-2.31)Atazanavir300 mg once daily 14 days400 mg (oral suspension) twice daily 7 days 155%(2.55; 1.89-3.45) 268%(3.68; 2.89-4.70)Atazanavir/ ritonavir boosted regimen300 mg/100 mg once daily 14 days 400 mg (oral suspension) twice daily 7 days 53%(1.53; 1.13-2.07) 146%(2.46; 1.93-3.13)Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with Noxafil 200 mg once daily; therefore, no dose adjustments are required for these coadministered drugs when coadministered with Noxafil 200 mg once daily.. Excretion:Following administration of Noxafil oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).Noxafil injection is eliminated with mean terminal half-life (t 1/2 of 27 hours and total body clearance (CL) of 7.3 L/h.Noxafil delayed-release tablet is eliminated with mean half-life (t 1/2 ranging between 26 to 31 hours.Noxafil oral suspension is eliminated with mean half-life (t 1/2 of 35 hours (range: 20-66 hours).Specific PopulationsNo clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment). Race/Ethnicity:In 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 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 Noxafil 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 PatientsThe mean pharmacokinetic parameters after multiple-dose administration of Noxafil injection and Noxafil PowderMix for delayed-release oral suspension in neutropenic pediatric patients to less than 18 years of age are shown in Table 29. Patients were enrolled into age groups and received Noxafil injection and Noxafil PowderMix for delayed-release oral suspension doses at mg/kg (0.6 to times the recommended dose) with 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 Noxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension mg/kg0.6 to times the recommended dose in Pediatric Patients with Neutropenia or Expected NeutropeniaAge GroupDoseTypeNAUC0-24 hr (ng.hr/mL)CavCav time-averaged concentrations (i.e., AUC0-24 hr/24hr) (ng/mL)Cmax (ng/mL)Cmin (ng/mL)Tmax Median (minimum-maximum) (hr)CL/FClearance (CL for IV and CL/F for PFS) (L/hr)IV= Noxafil injection; PFS= Noxafil PowderMix for delayed-release oral suspension; AUC0-24 Area under the plasma concentration-time curve from time zero to 24 hr; Cmax maximum observed concentration; Cmin minimum observed plasma concentration; Tmax time of maximum observed concentration; CL /F apparent total body clearance2 to <7 yearsIV1731100 (48.9)1300 (48.9)3060 (54.1)626 (104.8)1.75 (1.57-1.83)3.27 (49.3)PFS723000 (47.3)960 (47.3)1510 (43.4)542 (68.8)4.00 (2.17-7.92)4.60 (35.2)7 to 17 yearsIV2444200 (41.5)1840 (41.5)3340 (39.4)1160 (60.4)1.77 (1.33-6.00)4.76 (55.7)PFS1225000 (184.3)1040 (184.3)1370 (178.5)713 (300.6)2.78 (0.00-4.00)8.39 (190.3)Based on 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 Noxafil injection and Noxafil PowderMix for delayed-release oral suspension. 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.A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times day) of Noxafil oral suspension for prophylaxis of invasive fungal infections. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state Cav was similar between these patients and adults (>=18 years of age). In study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with Noxafil oral suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal data, Noxafil may cause fetal harm when administered to pregnant women. Available data for use of Noxafil in pregnant women are insufficient to establish 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 Noxafil 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 times the exposure achieved with the 400 mg twice daily oral suspension regimen. Doses of >= 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.. Data. Animal DataPosaconazole 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 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 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 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 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, reduction in body weight gain of females and reduction in litter size were seen.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1)6/2021Dosage and Administration (2)6/2021Contraindications (4)1/2022Warnings and Precautions (5) 1/2022.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 01/2022Patient Information Noxafil(R) (NOX-a-fil)(posaconazole) injectionNoxafil(R) (NOX-a-fil)(posaconazole) delayed-release tabletsNoxafil(R) (NOX-a-fil)(posaconazole) oral suspensionNoxafil(R) (NOX-a-fil) PowderMix(posaconazole) for delayed-release oral suspensionWhat is Noxafil and Noxafil PowderMixNoxafil (which refers to injection, delayed-release tablets, and oral suspension) and Noxafil PowderMix (for delayed-release oral suspension) are prescription medicines used in adults and children to help prevent or treat fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called Aspergillus or Candida. Noxafil and Noxafil PowderMix are used in people who have an increased chance of getting these infections due to weak immune system. These include people who have had hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease or those with low white blood cell count due to chemotherapy for blood cancers (hematologic malignancies). Noxafil injection is used for: prevention of fungal infections in adults and children years of age and older.treatment of fungal infections in adults and children 13 years of age and older.Noxafil delayed-release tablets are used for:prevention of fungal infections in adults and children years of age and older who weigh greater than 88 lbs (40 kg).treatment of fungal infections in adults and children 13 years of age and older.Noxafil oral suspension is used for:prevention of fungal infections in adults and children 13 years of age and older.Noxafil PowderMix for delayed-release oral suspension is used for:prevention of fungal infections in children years of age and older who weigh 88 lbs (40 kg) or less.Noxafil oral suspension is also used to treat fungal infection called thrush caused by Candida in your mouth or throat area. Noxafil oral suspension can be used as the first treatment for thrush, or as another treatment for thrush after itraconazole or fluconazole treatment has not worked.Noxafil oral suspension is for adults and children 13 years of age and older.It is not known if Noxafil or Noxafil PowderMix is safe and effective in children under years of age.Who should not take Noxafil or Noxafil PowderMixDo not take Noxafil or Noxafil PowderMix if you:are allergic to posaconazole, any of the ingredients in Noxafil or Noxafil PowderMix, or other azole antifungal medicines. See the end of this leaflet for complete list of ingredients in Noxafil and Noxafil PowderMix.are taking any of the following medicines: sirolimuspimozidequinidinecertain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)ergot alkaloids (ergotamine, dihydroergotamine) have chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and you have just started taking venetoclax or your venetoclax dose is being slowly increased.are taking Noxafil PowderMix for delayed-release oral suspension and have hereditary fructose intolerance.Ask your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines.Do not start taking new medicine without talking to your healthcare provider or pharmacist.What should tell my healthcare provider before taking Noxafil or Noxafil PowderMixBefore you take Noxafil or Noxafil PowderMix, tell your healthcare provider if you:are taking certain medicines that lower your immune system like cyclosporine or tacrolimus.are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and fosamprenavir can cause decrease in the Noxafil levels in your body. Efavirenz and fosamprenavir should not be taken with Noxafil or Noxafil PowderMix. are taking midazolam, hypnotic and sedative medicine.are taking vincristine, vinblastine and other vinca alkaloids (medicines used to treat cancer).are taking venetoclax, medicine used to treat cancer.have or had liver problems.have or had kidney problems.have or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems.are pregnant or plan to become pregnant. It is not known if Noxafil will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if Noxafil passes into your breast milk. You and your healthcare provider should decide if you will take Noxafil or breastfeed. You should not do both.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Noxafil and Noxafil PowderMix can affect the way other medicines work, and other medicines can affect the way Noxafil and Noxafil PowderMix work, and can cause serious side effects. Especially tell your healthcare provider if you take: rifabutin or phenytoin. If you are taking these medicines, you should not take Noxafil delayed-release tablets, Noxafil oral suspension, or Noxafil PowderMix for delayed-release oral suspension.cimetidine or esomeprazole. If you are taking these medicines, you should not take Noxafil oral suspension.Ask your healthcare provider or pharmacist for list of these medicines if you are not sure.Know the medicines you take. Keep list of them with you to show your healthcare provider or pharmacist when you get new medicine.How will take Noxafil or Noxafil PowderMixDo not switch between Noxafil oral suspension and Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension. Take Noxafil or Noxafil PowderMix exactly as your healthcare provider tells you to take it.Your healthcare provider will tell you how much Noxafil or Noxafil PowderMix to take and when to take it.Take Noxafil or Noxafil PowderMix for as long as your healthcare provider tells you to take it.If you take too much Noxafil or Noxafil PowderMix, call your healthcare provider or go to the nearest hospital emergency room right away.Noxafil injection is usually given over 30 to 90 minutes through plastic tube placed in your vein. Noxafil delayed-release tablets:Take Noxafil delayed-release tablets with or without food.Take Noxafil delayed-release tablets whole. Do not break, crush, or chew Noxafil delayed-release tablets before swallowing. If you cannot swallow Noxafil delayed-release tablets whole, tell your healthcare provider. You may need different medicine.If you miss dose, take it as soon as you remember and then take your next scheduled dose at its regular time. If it is within 12 hours of your next dose, do not take the missed dose. Skip the missed dose and go back to your regular schedule. Do not double your next dose or take more than your prescribed dose. Noxafil oral suspension:Shake Noxafil oral suspension well before use.Take each dose of Noxafil oral suspension during or within 20 minutes after full meal. If you cannot eat full meal, take each dose of Noxafil oral suspension with liquid nutritional supplement or an acidic carbonated beverage, like ginger ale.A measured dosing spoon comes with your Noxafil oral suspension and is marked for doses of 2.5 mL and mL. See Figure A. Figure Rinse the spoon with water after each dose of Noxafil oral suspension and before you store it away.If you miss dose, take it as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not take double dose to make up for the missed dose.Noxafil PowderMix for delayed-release oral suspension:Before giving the first dose of Noxafil PowderMix for delayed-release oral suspension, read the Instructions for Use booklet that comes with Noxafil PowderMix for delayed-release oral suspension for information about the correct way to mix and give dose of Noxafil PowderMix for delayed-release oral suspension to your child. Keep the booklet and follow it each time you prepare the medicine. Bring this booklet to your childs appointments. If you have questions about how to mix or give Noxafil PowderMix, talk with your healthcare provider or pharmacist.Only use the mixing liquid that comes with the kit to prepare Noxafil PowderMix.Once mixed, measure the prescribed dose with notched tip syringe provided with the kit. Only use the notched tip syringes that come with the kit to prepare and administer the medicine. Give the dose within hour of mixing the suspension. Give with food.If your child does not take all of the prescribed dose or spits some of it out, call your healthcare provider to find out what to do.Follow the instructions from your healthcare provider on how much Noxafil or Noxafil PowderMix you should take and when to take it.What are the possible side effects of Noxafil or Noxafil PowderMixNoxafil or Noxafil PowderMix may cause serious side effects, including:drug interactions with cyclosporine or tacrolimus. If you take Noxafil or Noxafil PowderMix with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking Noxafil or Noxafil PowderMix. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.problems with the electrical system of your heart (arrhythmias and QTc prolongation). Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in Noxafil and Noxafil PowderMix, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular.changes in body salt (electrolytes) levels in your blood. Your healthcare provider should check your electrolytes while you are taking Noxafil or Noxafil PowderMix.liver problems. Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of Noxafil or Noxafil PowderMix. Your healthcare provider should do blood tests to check your liver while you are taking Noxafil or Noxafil PowderMix. Call your healthcare provider right away if you have any of the following symptoms of liver problems: itchy skinnausea or vomitingyellowing of your eyes or skin feeling very tired flu-like symptoms increased amounts of midazolam in your blood. If you take Noxafil or Noxafil PowderMix with midazolam, Noxafil or Noxafil PowderMix increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with Noxafil or Noxafil PowderMix.The most common side effects of Noxafil in adults include:diarrheanauseafevervomitingheadachecoughinglow potassium levels in the bloodThe most common side effects of Noxafil injection and Noxafil PowderMix in children include:feverfever with low white blood cell count (febrile neutropenia)vomitingredness and sores of the lining of the mouth, lips, throat, stomach, and genitals (mucositis or stomatitis)itchinghigh blood pressurelow potassium levels in the bloodIf you take Noxafil delayed-release tablets, Noxafil oral suspension, or Noxafil PowderMix for delayed-release oral suspension, tell your healthcare provider right away if you have diarrhea or vomiting.Tell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of Noxafil or Noxafil PowderMix. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store Noxafil or Noxafil PowderMixNoxafil injectionStore Noxafil injection refrigerated at 36F to 46F (2C to 8C). Noxafil delayed-release tabletsStore Noxafil delayed-release tablets at room temperature between 68F to 77F (20C to 25C). Noxafil oral suspensionStore Noxafil oral suspension at room temperature between 68F to 77F (20C to 25C).Do not freeze Noxafil oral suspension. Noxafil PowderMix for delayed-release oral suspensionStore the entire kit at room temperature between 68F to 77F (20C to 25C) in clean, dry place. Do not open the foil packet until ready for use.Safely throw away medicine that is out of date or no longer needed.Keep Noxafil and Noxafil PowderMix and all medicines out of the reach of children. General information about the safe and effective use of Noxafil and Noxafil PowderMix. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use Noxafil or Noxafil PowderMix for condition for which it was not prescribed. Do not give Noxafil or Noxafil PowderMix to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Noxafil or Noxafil PowderMix that is written for health professionals.What are the ingredients in Noxafil and Noxafil PowderMixActive ingredient: posaconazole Inactive ingredients: Noxafil injection: Betadex Sulfobutyl Ether Sodium (SBECD), edetate sodium, hydrochloric acid, sodium hydroxide, and water for injection. Noxafil delayed-release tablets: 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: 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: 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.Manuf. for: Merck Sharp Dohme Corp., subsidiary of MERCK CO., INC., Whitehouse Station, NJ 08889, USA For patent information: www.merck.com/product/patent/home.html The trademarks depicted in this piece are owned by their respective companies. Copyright (C) 2006-2022 Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc. All rights reserved. usppi-mk5592-mf-2201r021 For more information, go to www.noxafil.com or call 1-800-672-6372.. prevention of fungal infections in adults and children years of age and older.. treatment of fungal infections in adults and children 13 years of age and older.. prevention of fungal infections in adults and children years of age and older who weigh greater than 88 lbs (40 kg).. treatment of fungal infections in adults and children 13 years of age and older.. prevention of fungal infections in adults and children 13 years of age and older.. prevention of fungal infections in children years of age and older who weigh 88 lbs (40 kg) or less.. are allergic to posaconazole, any of the ingredients in Noxafil or Noxafil PowderMix, or other azole antifungal medicines. See the end of this leaflet for complete list of ingredients in Noxafil and Noxafil PowderMix.. are taking any of the following medicines: sirolimuspimozidequinidinecertain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)ergot alkaloids (ergotamine, dihydroergotamine) sirolimus. pimozide. quinidine. certain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin). ergot alkaloids (ergotamine, dihydroergotamine). have chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and you have just started taking venetoclax or your venetoclax dose is being slowly increased.. are taking Noxafil PowderMix for delayed-release oral suspension and have hereditary fructose intolerance.. are taking certain medicines that lower your immune system like cyclosporine or tacrolimus.. are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and fosamprenavir can cause decrease in the Noxafil levels in your body. Efavirenz and fosamprenavir should not be taken with Noxafil or Noxafil PowderMix. are taking midazolam, hypnotic and sedative medicine.. are taking vincristine, vinblastine and other vinca alkaloids (medicines used to treat cancer).. are taking venetoclax, medicine used to treat cancer.. have or had liver problems.. have or had kidney problems.. have or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems.. are pregnant or plan to become pregnant. It is not known if Noxafil will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if Noxafil passes into your breast milk. You and your healthcare provider should decide if you will take Noxafil or breastfeed. You should not do both.. rifabutin or phenytoin. If you are taking these medicines, you should not take Noxafil delayed-release tablets, Noxafil oral suspension, or Noxafil PowderMix for delayed-release oral suspension.. cimetidine or esomeprazole. If you are taking these medicines, you should not take Noxafil oral suspension.. Do not switch between Noxafil oral suspension and Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension. Take Noxafil or Noxafil PowderMix exactly as your healthcare provider tells you to take it.. Your healthcare provider will tell you how much Noxafil or Noxafil PowderMix to take and when to take it.. Take Noxafil or Noxafil PowderMix for as long as your healthcare provider tells you to take it.. If you take too much Noxafil or Noxafil PowderMix, call your healthcare provider or go to the nearest hospital emergency room right away.. Noxafil injection is usually given over 30 to 90 minutes through plastic tube placed in your vein. Noxafil delayed-release tablets:Take Noxafil delayed-release tablets with or without food.Take Noxafil delayed-release tablets whole. Do not break, crush, or chew Noxafil delayed-release tablets before swallowing. If you cannot swallow Noxafil delayed-release tablets whole, tell your healthcare provider. You may need different medicine.If you miss dose, take it as soon as you remember and then take your next scheduled dose at its regular time. If it is within 12 hours of your next dose, do not take the missed dose. Skip the missed dose and go back to your regular schedule. Do not double your next dose or take more than your prescribed dose. Take Noxafil delayed-release tablets with or without food.. Take Noxafil delayed-release tablets whole. Do not break, crush, or chew Noxafil delayed-release tablets before swallowing. If you cannot swallow Noxafil delayed-release tablets whole, tell your healthcare provider. You may need different medicine.. If you miss dose, take it as soon as you remember and then take your next scheduled dose at its regular time. If it is within 12 hours of your next dose, do not take the missed dose. Skip the missed dose and go back to your regular schedule. Do not double your next dose or take more than your prescribed dose. Noxafil oral suspension:Shake Noxafil oral suspension well before use.Take each dose of Noxafil oral suspension during or within 20 minutes after full meal. If you cannot eat full meal, take each dose of Noxafil oral suspension with liquid nutritional supplement or an acidic carbonated beverage, like ginger ale.A measured dosing spoon comes with your Noxafil oral suspension and is marked for doses of 2.5 mL and mL. See Figure A. Figure Rinse the spoon with water after each dose of Noxafil oral suspension and before you store it away.If you miss dose, take it as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not take double dose to make up for the missed dose.. Shake Noxafil oral suspension well before use.. Take each dose of Noxafil oral suspension during or within 20 minutes after full meal. If you cannot eat full meal, take each dose of Noxafil oral suspension with liquid nutritional supplement or an acidic carbonated beverage, like ginger ale.. measured dosing spoon comes with your Noxafil oral suspension and is marked for doses of 2.5 mL and mL. See Figure A. Figure . Rinse the spoon with water after each dose of Noxafil oral suspension and before you store it away.. If you miss dose, take it as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not take double dose to make up for the missed dose.. Noxafil PowderMix for delayed-release oral suspension:Before giving the first dose of Noxafil PowderMix for delayed-release oral suspension, read the Instructions for Use booklet that comes with Noxafil PowderMix for delayed-release oral suspension for information about the correct way to mix and give dose of Noxafil PowderMix for delayed-release oral suspension to your child. Keep the booklet and follow it each time you prepare the medicine. Bring this booklet to your childs appointments. If you have questions about how to mix or give Noxafil PowderMix, talk with your healthcare provider or pharmacist.Only use the mixing liquid that comes with the kit to prepare Noxafil PowderMix.Once mixed, measure the prescribed dose with notched tip syringe provided with the kit. Only use the notched tip syringes that come with the kit to prepare and administer the medicine. Give the dose within hour of mixing the suspension. Give with food.If your child does not take all of the prescribed dose or spits some of it out, call your healthcare provider to find out what to do.. Before giving the first dose of Noxafil PowderMix for delayed-release oral suspension, read the Instructions for Use booklet that comes with Noxafil PowderMix for delayed-release oral suspension for information about the correct way to mix and give dose of Noxafil PowderMix for delayed-release oral suspension to your child. Keep the booklet and follow it each time you prepare the medicine. Bring this booklet to your childs appointments. If you have questions about how to mix or give Noxafil PowderMix, talk with your healthcare provider or pharmacist.. Only use the mixing liquid that comes with the kit to prepare Noxafil PowderMix.. Once mixed, measure the prescribed dose with notched tip syringe provided with the kit. Only use the notched tip syringes that come with the kit to prepare and administer the medicine. Give the dose within hour of mixing the suspension. Give with food.. If your child does not take all of the prescribed dose or spits some of it out, call your healthcare provider to find out what to do.. drug interactions with cyclosporine or tacrolimus. If you take Noxafil or Noxafil PowderMix with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking Noxafil or Noxafil PowderMix. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.. problems with the electrical system of your heart (arrhythmias and QTc prolongation). Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in Noxafil and Noxafil PowderMix, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular.. changes in body salt (electrolytes) levels in your blood. Your healthcare provider should check your electrolytes while you are taking Noxafil or Noxafil PowderMix.. liver problems. Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of Noxafil or Noxafil PowderMix. Your healthcare provider should do blood tests to check your liver while you are taking Noxafil or Noxafil PowderMix. Call your healthcare provider right away if you have any of the following symptoms of liver problems: itchy skinnausea or vomitingyellowing of your eyes or skin feeling very tired flu-like symptoms itchy skin. nausea or vomiting. yellowing of your eyes or skin feeling very tired flu-like symptoms. increased amounts of midazolam in your blood. If you take Noxafil or Noxafil PowderMix with midazolam, Noxafil or Noxafil PowderMix increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with Noxafil or Noxafil PowderMix.. diarrhea. nausea. fever. vomiting. headache. coughing. low potassium levels in the blood. fever. fever with low white blood cell count (febrile neutropenia). vomiting. redness and sores of the lining of the mouth, lips, throat, stomach, and genitals (mucositis or stomatitis). itching. high blood pressure. low potassium levels in the blood. Store Noxafil injection refrigerated at 36F to 46F (2C to 8C). Store Noxafil delayed-release tablets at room temperature between 68F to 77F (20C to 25C). Store Noxafil oral suspension at room temperature between 68F to 77F (20C to 25C).. Do not freeze Noxafil oral suspension. Store the entire kit at room temperature between 68F to 77F (20C to 25C) in clean, dry place. Do not open the foil packet until ready for use.. Figure A.

SPL UNCLASSIFIED SECTION.

1.1Treatment of Invasive Aspergillosis. Noxafil(R) 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.

STORAGE AND HANDLING SECTION.

16.2Storage and Handling. Noxafil InjectionNoxafil injection vial should be stored refrigerated at to 8C (36 to 46F). Storage conditions for the diluted solution are presented in another section of the prescribing information [see Dosage and Administration (2.4)]. Noxafil Delayed-Release TabletsStore at 20 to 25C (68 to 77F), excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].Noxafil Oral SuspensionStore at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature]. DO NOT FREEZE. Noxafil PowderMix for Delayed-Release Oral SuspensionStore the entire kit at 20 to 25C (68 to 77F), excursions permitted to 15 to 30C (59 to 86F) in 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)].

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm. (8.1)Pediatrics: Safety and effectiveness in patients younger than years of age have not been established. (8.4)Severe Renal Impairment: Monitor closely for breakthrough fungal infections. (8.6). Pregnancy: Based on animal data, may cause fetal harm. (8.1). Pediatrics: Safety and effectiveness in patients younger than years of age have not been established. (8.4). Severe Renal Impairment: Monitor closely for breakthrough fungal infections. (8.6). 8.1 Pregnancy. Risk SummaryBased on findings from animal data, Noxafil may cause fetal harm when administered to pregnant women. Available data for use of Noxafil in pregnant women are insufficient to establish 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 Noxafil 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 times the exposure achieved with the 400 mg twice daily oral suspension regimen. Doses of >= 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.. Data. Animal DataPosaconazole 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 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 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 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 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, reduction in body weight gain of females and reduction in litter size were seen. 8.2 Lactation. Risk SummaryThere 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 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 mothers clinical need for Noxafil and any potential adverse effects on the breastfed child from Noxafil or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of Noxafil injection, Noxafil delayed-release tablets, Noxafil PowderMix for delayed-release oral suspension, and Noxafil oral suspension for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged 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 Noxafil injection and Noxafil delayed-release tablets for the treatment of invasive aspergillosis have been established in pediatric patients aged 13 years and older. The safety and effectiveness of Noxafil oral suspension have been established for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in pediatric patients aged 13 years and older. Use of Noxafil in these age groups is supported by evidence from adequate and well-controlled studies of Noxafil in adult and pediatric patients and additional pharmacokinetic and safety data in pediatric patients years of age and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)]. The safety and effectiveness of Noxafil have not been established in pediatric patients younger than years of age.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. Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with HFI. Because diagnosis of HFI may not yet be established in pediatric patients, obtain careful history of HFI symptoms with sorbitol/fructose/sucrose exposure prior to administration of Noxafil PowderMix for delayed-release oral suspension [see Warnings and Precautions (5.8)].. 8.5Geriatric Use. No overall differences in the safety of Noxafil injection, Noxafil delayed-release tablets, and Noxafil oral suspension were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for any formulation of Noxafil in geriatric patients. No clinically meaningful differences in the pharmacokinetics of Noxafil were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology (12.3)].Of the 279 patients treated with Noxafil injection in the Noxafil Injection Study, 52 (19%) were greater than 65 years of age. Of the 230 patients treated with Noxafil delayed-release tablets, 38 (17%) were greater than 65 years of age. Of the 605 patients randomized to Noxafil oral suspension in Noxafil Oral Suspension Study and Study 2, 63 (10%) were >=65 years of age. In addition, 48 patients treated with greater than or equal to 800-mg/day Noxafil oral suspension in another indication were >=65 years of age. Of the 288 patients randomized to Noxafil injection/Noxafil delayed-release tablets 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. Following single-dose administration of 400 mg of the Noxafil oral suspension, there was no significant effect of mild (eGFR: 50-80 mL/min/1.73 m2, n=6) or moderate (eGFR: 20-49 mL/min/1.73 m2, n=6) renal impairment on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal impairment (eGFR: <20 mL/min/1.73 m2), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (eGFR: >80 mL/min/1.73 m2); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal impairment as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2)]. Similar recommendations apply to Noxafil delayed-release tablets; however, specific study has not been conducted with the Noxafil delayed-release tablets.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 (eGFR <50 mL/min), receiving the Noxafil 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 Noxafil therapy [see Dosage and Administration (2.9) and Warnings and Precautions (5.5)].. 8.7 Hepatic Impairment. After single oral dose of Noxafil oral suspension 400 mg, the mean AUC was 43%, 27%, and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), or severe (Child-Pugh Class C, N=6) hepatic impairment, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects with normal hepatic function. The elimination half-life (t 1/2 was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, or severe hepatic impairment, respectively.It is recommended that no dose adjustment of Noxafil oral suspension, Noxafil delayed-release tablets, Noxafil PowderMix for delayed-release oral suspension, and Noxafil 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 (5.4)]. However, specific study has not been conducted with Noxafil delayed-release tablets, Noxafil PowderMix for delayed-release oral suspension, and Noxafil injection.. 8.8 Gender. The pharmacokinetics of posaconazole are comparable in males and females. No adjustment in the dosage of Noxafil 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 Noxafil 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)].

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS. Calcineurin-Inhibitor Toxicity: Noxafil increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. (5.1)Arrhythmias and QTc Prolongation: Noxafil has been shown to prolong the QTc interval and cause cases of TdP. Administer with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs known to prolong QTc interval and metabolized through CYP3A4. (5.2)Electrolyte Disturbances: Monitor and correct, especially those involving potassium (K+), magnesium (Mg++), and calcium (Ca++), before and during Noxafil therapy. (5.3)Hepatic Toxicity: Elevations in liver tests may occur. Discontinuation should be considered in patients who develop abnormal liver tests or monitor liver tests during treatment. (5.4)Renal Impairment: Noxafil injection should be avoided in patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. (5.5, 8.6)Concomitant Use with Midazolam: Noxafil can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available. (5.6, 7.5)Vincristine Toxicity: Concomitant administration of azole antifungals, including Noxafil, with vincristine has been associated with neurotoxicity and other serious adverse reactions; reserve azole antifungals, including Noxafil, for patients receiving vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. (5.7, 7.10)Risk in Patients with Hereditary Fructose Intolerance (HFI): Noxafil PowderMix for delayed-release oral suspension contains sorbitol. Risk of metabolic crisis with life-threatening hypoglycemia, hypophosphatemia, lactic acidosis, and hepatic failure. Obtain history of HFI symptoms in pediatric patients before Noxafil PowderMix for delayed-release oral suspension administration. (5.8, 8.4)Breakthrough Fungal Infections: Monitor patients with severe diarrhea or vomiting when receiving Noxafil delayed-release tablets, Noxafil oral suspension, and Noxafil PowderMix for delayed-release oral suspension. (5.9)Venetoclax Toxicity: Concomitant administration of Noxafil with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome, neutropenia, and serious infections; monitor for toxicity and reduce venetoclax dose. (4.6, 5.10, 7.16). Calcineurin-Inhibitor Toxicity: Noxafil increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. (5.1). Arrhythmias and QTc Prolongation: Noxafil has been shown to prolong the QTc interval and cause cases of TdP. Administer with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs known to prolong QTc interval and metabolized through CYP3A4. (5.2). Electrolyte Disturbances: Monitor and correct, especially those involving potassium (K+), magnesium (Mg++), and calcium (Ca++), before and during Noxafil therapy. (5.3). Hepatic Toxicity: Elevations in liver tests may occur. Discontinuation should be considered in patients who develop abnormal liver tests or monitor liver tests during treatment. (5.4). Renal Impairment: Noxafil injection should be avoided in patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. (5.5, 8.6). Concomitant Use with Midazolam: Noxafil can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available. (5.6, 7.5). Vincristine Toxicity: Concomitant administration of azole antifungals, including Noxafil, with vincristine has been associated with neurotoxicity and other serious adverse reactions; reserve azole antifungals, including Noxafil, for patients receiving vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. (5.7, 7.10). Risk in Patients with Hereditary Fructose Intolerance (HFI): Noxafil PowderMix for delayed-release oral suspension contains sorbitol. Risk of metabolic crisis with life-threatening hypoglycemia, hypophosphatemia, lactic acidosis, and hepatic failure. Obtain history of HFI symptoms in pediatric patients before Noxafil PowderMix for delayed-release oral suspension administration. (5.8, 8.4). Breakthrough Fungal Infections: Monitor patients with severe diarrhea or vomiting when receiving Noxafil delayed-release tablets, Noxafil oral suspension, and Noxafil PowderMix for delayed-release oral suspension. (5.9). Venetoclax Toxicity: Concomitant administration of Noxafil with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome, neutropenia, and serious infections; monitor for toxicity and reduce venetoclax dose. (4.6, 5.10, 7.16). 5.1 Calcineurin-Inhibitor Toxicity. Concomitant administration of Noxafil with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of Noxafil treatment and the tacrolimus or cyclosporine dose adjusted accordingly.. 5.2 Arrhythmias and QT Prolongation. Some azoles, including Noxafil, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking Noxafil.Results from multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18-85 years of age) administered Noxafil oral suspension 400 mg twice daily with high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was -5 msec following administration of the recommended clinical dose. decrease in the QTc(F) interval (-3 msec) was also observed in small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (-8 msec). No healthy subject administered Noxafil had QTc(F) interval >=500 msec or an increase >=60 msec in their QTc(F) interval from baseline.Noxafil should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 [see Contraindications (4.3) and Drug Interactions (7.2)].. 5.3 Electrolyte Disturbances. Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during Noxafil therapy.. 5.4 Hepatic Toxicity. Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with Noxafil. These severe hepatic reactions were seen primarily in subjects receiving the Noxafil oral suspension 800 mg daily (400 mg twice daily or 200 mg four times day) in clinical trials.Liver tests should be evaluated at the start of and during the course of Noxafil therapy. Patients who develop abnormal liver tests during Noxafil therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver tests and bilirubin). Discontinuation of Noxafil must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to Noxafil.. 5.5Renal Impairment. Due to the variability in exposure with Noxafil delayed-release tablets, Noxafil oral suspension, and Noxafil PowderMix for delayed-release oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2.9) and Use in Specific Populations (8.6)]. 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 (eGFR <50 mL/min), receiving the Noxafil 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 Noxafil therapy [see Dosage and Administration (2.9) and Use in Specific Populations (8.6)].. 5.6 Midazolam Toxicity. 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. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].. 5.7Vincristine Toxicity. Concomitant administration of azole antifungals, including Noxafil, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including Noxafil, for patients receiving vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Drug Interactions (7.10)].. 5.8Risk in Patients with Hereditary Fructose Intolerance (HFI). Noxafil PowderMix for delayed-release oral suspension contains sorbitol, an inactive ingredient, and may precipitate metabolic crisis that may include, but is not limited to life-threatening hypoglycemia, hypophosphatemia, lactic acidosis, and hepatic failure in patients with HFI. Obtain careful history of HFI symptoms (nausea, vomiting, abdominal pain) with sorbitol/fructose/sucrose exposure prior to Noxafil PowderMix for delayed-release oral suspension administration because diagnosis of HFI may not yet be established in pediatric patients [see Contraindications (4), Use in Specific Populations (8.4)].. 5.9Breakthrough Fungal Infections. Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving Noxafil delayed-release tablets, Noxafil oral suspension, or Noxafil PowderMix for delayed-release oral suspension.. 5.10 Venetoclax Toxicity. Concomitant administration of Noxafil, strong CYP3A4 inhibitor, with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS), neutropenia, and serious infections. In patients with CLL/SLL, administration of Noxafil during initiation and the ramp-up phase of venetoclax is contraindicated [see Contraindications (4.6)]. Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients.For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering Noxafil with venetoclax [see Drug Interactions (7.16)]. Refer to the venetoclax prescribing information for dosing instructions.