{ "meta": { "disclaimer": "Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service.", "terms": "https://open.fda.gov/terms/", "license": "https://open.fda.gov/license/", "last_updated": "2026-04-25", "results": { "skip": 0, "limit": 1, "total": 1 } }, "results": [ { "spl_product_data_elements": [ "NOXAFIL posaconazole posaconazole posaconazole polysorbate 80 sodium benzoate trisodium citrate dihydrate citric acid monohydrate glycerin xanthan gum anhydrous dextrose titanium dioxide water NOXAFIL posaconazole posaconazole posaconazole HYPROMELLOSE ACETATE SUCCINATE 06081224 (3 MM2/S) MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) SILICON DIOXIDE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE POLYVINYL ALCOHOL, UNSPECIFIED POLYETHYLENE GLYCOL 3350 TITANIUM DIOXIDE TALC FERRIC OXIDE YELLOW oblong 100 NOXAFIL posaconazole posaconazole posaconazole BETADEX SULFOBUTYL ETHER SODIUM EDETATE DISODIUM HYDROCHLORIC ACID SODIUM HYDROXIDE WATER NOXAFIL posaconazole POSACONAZOLE POSACONAZOLE HYPROMELLOSE ACETATE SUCCINATE 06081224 (3 MM2/S) ANHYDROUS CITRIC ACID DIMETHICONE CARBOXYMETHYLCELLULOSE SODIUM, UNSPECIFIED CARRAGEENAN GLYCERIN METHYLPARABEN MICROCRYSTALLINE CELLULOSE POTASSIUM SORBATE PROPYLPARABEN WATER SODIUM CITRATE, UNSPECIFIED FORM SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE SACCHARIN SODIUM SORBITOL SOLUTION XANTHAN GUM CALCIUM SULFATE, UNSPECIFIED FORM SODIUM PHOSPHATE, TRIBASIC, ANHYDROUS berry citrus sweet flavor" ], "recent_major_changes": [ "Indications and Usage ( 1.1 , 1.2 ) 1/2026 Dosage and Administration ( 2 ) 1/2026" ], "recent_major_changes_table": [ "
Indications and Usage (1.1, 1.2) 1/2026
Dosage and Administration (2) 1/2026
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Noxafil is an azole antifungal indicated as follows: Noxafil is indicated for the treatment of invasive aspergillosis as follows: ( 1.1 ) Noxafil injection: adults and pediatric patients 2 years of age and older who weigh 10 kg or greater Noxafil delayed-release tablets: adults and pediatric patients 2 years of age and older who weigh greater than 40 kg Noxafil PowderMix for delayed-release oral suspension: pediatric patients 2 years of age and older who weigh 10 kg to 40 kg Noxafil is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy as follows: ( 1.2 ) Noxafil injection: adults and pediatric patients 2 years of age and older who weigh 10 kg or greater. Noxafil delayed-release tablets: adults and pediatric patients 2 years of age and older who weigh greater than 40 kg Noxafil oral suspension: adults and pediatric patients 13 years of age and older Noxafil PowderMix for delayed-release oral suspension: pediatric patients 2 years of age and older who weigh 10 kg to 40 kg Noxafil oral suspension is indicated for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in adults and pediatric patients 13 years of age and older ( 1.3 ) 1.1 Treatment of Invasive Aspergillosis Noxafil is indicated for the treatment of invasive aspergillosis as follows: Noxafil injection: adults and pediatric patients 2 years of age and older who weigh 10 kg or greater Noxafil delayed-release tablets: adults and pediatric patients 2 years of age and older who weigh greater than 40 kg Noxafil PowderMix for delayed-release oral suspension: pediatric patients 2 years of age and older who weigh 10 to 40 kg 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 as follows: Noxafil injection: adults and pediatric patients 2 years of age and older who weigh 10 kg or greater Noxafil delayed-release tablets: adults and pediatric patients 2 years of age and older who weigh greater than 40 kg Noxafil oral suspension: adults and pediatric patients 13 years of age and older Noxafil PowderMix for delayed-release oral suspension: pediatric patients 2 years of age and older who weigh 10 kg to 40 kg 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." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Noxafil formulations are supplied in different dose strengths of posaconazole, are approved for different indications, age groups, and weights, have different dosages and duration of therapy; and have different preparation and administration instructions. ( 2.1 ) 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 ) Noxafil injection must be administered through an in-line filter. ( 2.6 ) Administer Noxafil injection by intravenous infusion over approximately 90 minutes via a central venous line. ( 2.1 , 2.6 ) Do NOT administer Noxafil injection as an intravenous bolus injection. ( 2.1 ) Administer Noxafil delayed-release tablets with or without food. ( 2.1 ) Administer Noxafil oral suspension with a full meal. ( 2.1 ) Administer Noxafil PowderMix for delayed-release oral suspension with food. ( 2.1 ) Administer Noxafil PowderMix for delayed-release oral suspension with the provided notched tip syringes only. ( 2.1 ) See the full prescribing information for important administration instructions and preparation instructions for Noxafil (injection, delayed-release tablets, and oral suspension) and Noxafil PowderMix delayed-release oral suspension ( 2.5 , 2.6 , 2.7 , 2.8 , 2.9 , 2.10 ) For adult and pediatric patients aged 2 years of age and older, see the Full Prescribing Information for dosing recommendations for Noxafil injection, Noxafil delayed-release tablets, Noxafil oral suspension, and/or Noxafil PowderMix for delayed-release oral suspension based on the indication, age, and weight associated with the dosage form ( 1.1 , 1.2 , 1.3 , 2.1 , 2.2 , 2.3 , 2.4 ) 2.1 Important Administration Instructions Noxafil injection, Noxafil delayed-release tablets, Noxafil oral suspension and Noxafil PowderMix for delayed-release oral suspension are supplied in different dose strengths of posaconazole, are approved for different indications, age groups and weights; have different dosages and duration of therapy; and have different preparation and administration instructions. Therefore, select the recommended dosage form based on the indication, age group, and weight and carefully follow the recommended dosage, preparation and administration instructions described for each product [see Dosage and Administration (2.2 to 2.11) ] , and the following important administration instructions described below. Non-substitutable Noxafil oral suspension is not substitutable with Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration (2.2 , 2.3) ]. Noxafil injection Administer via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes [see Dosage and Administration (2.6) ] . Do NOT administer Noxafil injection as an intravenous bolus injection. Noxafil delayed-release tablets Swallow tablets whole. Do not divide, crush, or chew. Administer with or without food [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3) ] . For patients who cannot eat a full meal, Noxafil delayed-release tablets should be used instead of Noxafil oral suspension for the prophylaxis indication. Noxafil delayed-release tablets generally provide higher plasma drug exposures than Noxafil oral suspension under both fed and fasted conditions [see Dosage and Administration (2.8) ] . Noxafil oral suspension Administer with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal [see Dosage and Administration (2.8) ]. Noxafil PowderMix for delayed-release oral suspension Administer with food [see Clinical Pharmacology (12.3) ] . 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 (2.10) ] . 2.2 Recommended Dosage of Noxafil in Adult Patients The recommended dosage of Noxafil (injection, delayed-release tablets, and oral suspension) in adult patients for the treatment of invasive aspergillosis, prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, or for the treatment of oropharyngeal candidiasis (OPC) is shown in Table 1 [see Dosage and Administration (2.5 , 2.6 , 2.7 , 2.8 , 2.9) and Clinical Pharmacology (12.3) ]. Noxafil PowderMix for delayed-release oral suspension is not recommended for use in adults [see Indications and Usage (1.1 , 1.2) ]. Table 1: Recommended Dosage of Noxafil Injection, Noxafil Delayed-Release Tablets, and Noxafil Oral Suspension in Adult Patients Dosage Duration of Therapy Treatment of Invasive Aspergillosis Switching between the Noxafil injection and delayed-release tablets is acceptable. A loading dose is not required when switching between dosage forms. Noxafil Injection: Loading dose : 300 mg Noxafil injection intravenously twice a day on the first day. Maintenance dose : 300 mg Noxafil injection intravenously once a day, starting on the second day. Noxafil Delayed-Release Tablets: Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose : 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Loading dose: 1 day Maintenance dose: Recommended total duration of therapy is 6 to 12 weeks. Prophylaxis of Invasive Aspergillus and Candida Infections Noxafil Injection: Loading dose : 300 mg Noxafil injection intravenously twice a day on the first day. Maintenance dose : 300 mg Noxafil injection intravenously once a day thereafter. Noxafil Delayed-Release Tablets: Loading dose : 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose : 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Noxafil Oral Suspension: 200 mg (5 mL) three times a day. Loading dose : 1 day Maintenance dose : Duration of therapy is based on recovery from neutropenia or immunosuppression Oropharyngeal Candidiasis (OPC) Noxafil Oral Suspension: Loading dose : 100 mg (2.5 mL) twice a day on the first day. Maintenance dose : 100 mg (2.5 mL) once a day thereafter. Loading dose : 1 day Maintenance dose : 13 days OPC Refractory (rOPC) to Itraconazole and/or Fluconazole Noxafil Oral Suspension: 400 mg (10 mL) twice a day. Duration of therapy is based on the severity of the patient’s underlying disease and clinical response. 2.3 Recommended Dosage of Noxafil for the Treatment of Invasive Aspergillosis and Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients 2 Years of Age and Older Noxafil injection and Noxafil delayed-release tablets The recommended dosage of (1) Noxafil injection in pediatric patients 2 years of age and older who weigh 10 kg or greater, and (2) Noxafil delayed-release tablets in pediatric patients 2 years of age and older who weigh greater than 40 kg for the treatment of invasive aspergillosis and prophylaxis of invasive Aspergillus and Candida infections is shown in Table 2 [see Dosage and Administration (2.5 , 2.6 , 2.7 , 2.9 ) and Clinical Pharmacology (12.3) ]. Noxafil delayed-release tablets are not recommended for use in pediatric patients who weigh 40 kg or less because the recommended dosage cannot be achieved with this dosage form. Table 2: Recommended Dosage of Noxafil Injection and Noxafil Delayed-Release Tablets for the Treatment of Invasive Aspergillosis Switching between the intravenous and delayed-release tablets is acceptable. A loading dose is not required when switching between formulations. and Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients (2 Years of Age and Older) Recommended Pediatric Dosage by Formulation Duration of Therapy Noxafil Injection (patients weighing 10 kg or greater): Loading dose : 6 mg/kg up to a maximum of 300 mg twice daily on the first day Maintenance dose : 6 mg/kg up to a maximum of 300 mg once daily, starting on the second day. Noxafil Delayed-Release Tablets (patients weighing greater than 40 kg): Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose : 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Treatment of invasive aspergillosis: Recommended total duration of therapy is 6 to 12 weeks Prophylaxis of invasive Aspergillus and Candida infections: Duration of therapy is based on recovery from neutropenia or immunosuppression. Noxafil Oral Suspension The recommended dosage of Noxafil oral suspension in pediatric patients 13 years of age and older for the prophylaxis of invasive Aspergillus and Candida Infections is shown in Table 3. Table 3: Recommended Dosage of Noxafil Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients (13 Years of Age and Older) Recommended Pediatric Dosage of Noxafil Oral Suspension Duration of Therapy 200 mg (5 mL) three times a day Duration of therapy is based on recovery from neutropenia or immunosuppression. Noxafil PowderMix The recommended dosage of Noxafil PowderMix for delayed-release oral suspension in pediatric patients 2 years of age and older who weigh 10 kg to 40 kg, for the treatment of invasive aspergillosis, and the prophylaxis of invasive Aspergillus and Candida infections, is shown in Table 4 and Table 5 . The dosing for these indications is the same, except for patients weighing 10 to less than 12 kg [see Dosage and Administration (2.9 , 2.10 ) and Clinical Pharmacology (12.3) ]. Noxafil PowderMix for delayed-release oral suspension is not recommended for use in pediatric patients who weigh greater than 40 kg because the recommended dosage cannot be achieved with this dosage form. Table 4: Recommended Dosage for Noxafil PowderMix for Delayed-Release Oral Suspension for the Treatment of Invasive Aspergillosis in Pediatric Patients (2 Years of Age and Older) Weight (kg) Recommended Pediatric Dosage of Noxafil PowderMix for Delayed-Release Oral Suspension Duration of Therapy 10 to less than 17 Loading Dose: 120 mg (4 mL) twice daily on the first day Maintenance Dose: 120 mg (4 mL) once daily Recommended total duration of therapy is 6 to 12 weeks. 17 to less than 21 Loading Dose: 150 mg (5 mL) twice daily on the first day Maintenance Dose: 150 mg (5 mL) once daily 21 to less than 26 Loading Dose: 180 mg (6 mL) twice daily on the first day Maintenance Dose: 180 mg (6 mL) once daily 26 to less than 36 Loading Dose: 210 mg (7 mL) twice daily on the first day Maintenance Dose: 210 mg (7 mL) once daily 36 to 40 Loading Dose: 240 mg (8 mL) twice daily on the first day Maintenance Dose: 240 mg (8 mL) once daily Table 5: Recommended Dosage for Noxafil PowderMix for Delayed-Release Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida infections in Pediatric Patients (2 Years of Age and Older ) Weight (kg) Recommended Pediatric Dosage of Noxafil PowderMix for Delayed-Release Oral Suspension Duration of Therapy 10 to less than 12 Loading Dose: 90 mg (3 mL) twice daily on the first day Maintenance Dose: 90 mg (3 mL) once daily Duration of therapy is based on recovery from neutropenia or immunosuppression . 12 to less than 17 Loading Dose: 120 mg (4 mL) twice daily on the first day Maintenance Dose: 120 mg (4 mL) once daily 17 to less than 21 Loading Dose: 150 mg (5 mL) twice daily on the first day Maintenance Dose: 150 mg (5 mL) once daily 21 to less than 26 Loading Dose: 180 mg (6 mL) twice daily on the first day Maintenance Dose: 180 mg (6 mL) once daily 26 to less than 36 Loading Dose: 210 mg (7 mL) twice daily on the first day Maintenance Dose: 210 mg (7 mL) once daily 36 to 40 Loading Dose: 240 mg (8 mL) twice daily on the first day Maintenance Dose: 240 mg (8 mL) once daily 2.4 Recommended Dosage of Noxafil Oral Suspension for the Treatment of Oropharyngeal Candidiasis in Pediatric Patients 13 Years of Age and Older The recommended dosage of Noxafil oral suspension for the treatment of oropharyngeal candidiasis (OPC) and OPC refractory (rOPC) to itraconazole and/or fluconazole in pediatric patients 13 years of age and older is shown in Table 6. The Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix for delayed-release oral suspension products are not approved for the treatment of oropharyngeal candidiasis in pediatric patients. Table 6: Recommended Dosage of Noxafil Oral Suspension for the Treatment of OPC and rOPC in Pediatric Patients (13 Years of Age and Older) Recommended Pediatric Dosage of Noxafil Oral Suspension Duration of Therapy Oropharyngeal Candidiasis (OPC) Loading Dose: 100 mg (2.5 mL) twice daily on the first day Maintenance Dose: 100 mg (2.5 mL) once daily Loading dose: 1 day Maintenance dose: 13 days OPC Refractory (rOPC) to Itraconazole and/or Fluconazole 400 mg (10 mL) twice daily Duration of therapy is based on the severity of the patient’s underlying disease and clinical response. 2.5 Preparation of Noxafil Injection Preparation of Noxafil Injection: Remove the vial of Noxafil injection from the refrigerator and allow to equilibrate to room temperature prior to use. To prepare the required dose, aseptically transfer one vial of Noxafil injection (containing 300 mg of posaconazole in 16.7 mL of solution) to an intravenous bag or bottle of one of the following compatible diluents to achieve a final posaconazole concentration between 1 mg/mL and 2 mg/mL: 0.45% Sodium Chloride Injection 0.9% Sodium Chloride Injection 5% Dextrose Injection 5% Dextrose and 0.45% Sodium Chloride Injection 5% Dextrose and 0.9% Sodium Chloride Injection 5% Dextrose and 20 mEq Potassium Chloride Injection Use of other diluents is not recommended because they may result in particulate formation. Discard any unused Noxafil injection from the vial. Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Once admixed, the diluted Noxafil infusion solution ranges from colorless to yellow (variations of color within this range do not affect the quality of the product). Immediately use the diluted Noxafil infusion solution, once admixed. If not used immediately, refrigerate (2 to 8°C (36 to 46°F)) the diluted Noxafil infusion solution up to 24 hours. Discard any unused portion. Incompatible Diluents Co-administration of drug products besides the infusion solutions or products stated above are not recommended because this may result in particulate formation. The following diluents were determined to be incompatible with Noxafil injection; thus, do not dilute Noxafil injection with them: Lactated Ringer’s Injection Lactated Ringer's and 5% Dextrose Injection 4.2% Sodium Bicarbonate Injection 2.6 Administration of Diluted Noxafil Infusion Solution See Dosage and Administration (2.5) for the preparation instructions for the diluted Noxafil Solution. Important Administration Instructions for the Diluted Noxafil Infusion Solution Must administer diluted Noxafil Infusion Solution through a 0.22-micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter. Administer diluted Noxafil infusion solution via a central venous line, including a central venous catheter (CVC) or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes [see Adverse Reactions (6.1) ] . If a CVC or PICC are not available, may administer diluted Noxafil solution once through a peripheral venous catheter by intravenous infusion over approximately 30 minutes to bridge the period during which a CVC or PICC are replaced, inserted, or unavailable for use (e.g., the CVC is being used for intravenous treatment with another product). However, do not administer diluted Noxafil infusion solution more than once via peripheral venous catheter because in clinical trials, multiple peripheral infusions given through the same vein resulted in infusion site reactions [see Adverse Reactions (6.1) ]. When multiple dosing is required, the infusion should be done via a central venous line. Additional Administration Instructions for the Diluted Noxafil Infusion Solution Administer diluted Noxafil infusion solution intravenously through the same intravenous line (or cannula) with the following compatible infusion solutions: 0.45% Sodium Chloride Injection 0.9% Sodium Chloride Injection 5% Dextrose Injection 5% Dextrose and 0.45% Sodium Chloride Injection 5% Dextrose and 0.9% Sodium Chloride Injection 5% Dextrose and 20 mEq potassium chloride Injection Administer diluted Noxafil infusion solution intravenously at the same time through the same intravenous line (or cannula) with the following intravenous drug products prepared in 5% Dextrose Injection or 0.9% Sodium Chloride Injection: Amikacin Sulfate Injection Caspofungin Acetate for Injection Ciprofloxacin Injection Daptomycin for Injection Dobutamine Injection Famotidine Injection Filgrastim Injection Gentamicin Injection Hydromorphone Hydrochloride Injection Levofloxacin Injection Lorazepam Injection Meropenem for Injection Micafungin for Injection Morphine Sulfate Injection Norepinephrine Bitartrate Injection Potassium Chloride Injection Vancomycin Hydrochloride for Injection 2.7 Administration Instructions for Noxafil Delayed-Release Tablets Swallow the Noxafil delayed-release tablets whole. Do not divide, crush, or chew. Administer Noxafil delayed-release tablets orally with or without food [see Clinical Pharmacology (12.3) ]. 2.8 Administration Instructions for Noxafil Oral Suspension Administer Noxafil oral suspension with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal. For patients who cannot eat a full meal, use Noxafil delayed-release tablets instead of the Noxafil oral suspension for the prophylaxis of invasive Aspergillus and Candida infections in those who are at high risk of developing these infections due to being severely immunocompromised. This is because Noxafil delayed-release tablets provide higher plasma drug exposures than Noxafil oral suspension under fasted condition [see Dosage and Administration (2.1) ]. For those patients using the Noxafil oral suspension: Shake Noxafil oral suspension well before use. Administer with measured dosing spoon provided in the package (see Figure 1 ). Figure 1: Measured dosing spoon provided in the package marked for doses of 2.5 mL and 5 mL. Administer each dose of Noxafil oral suspension during or immediately (i.e., within 20 minutes) following a full meal [see Clinical Pharmacology (12.3) ]. In patients who cannot eat a full meal and for whom Noxafil delayed-release tablets or Noxafil injection are not options, administer each dose of Noxafil oral suspension with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale). If these patients cannot tolerate an oral nutritional supplement or an acidic carbonated beverage either use: An alternative antifungal therapy, or Noxafil oral suspension and closely monitor patients for breakthrough fungal infections. Rinse the spoon with water after each administration and before storage. Figure 1 2.9 Non-substitutability between Noxafil Oral Suspension and Other Formulations Noxafil oral suspension is not substitutable with Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration (2.2 , 2.3) ]. 2.10 Preparation and Administration Instructions for Noxafil PowderMix for Delayed-Release Oral Suspension For details on preparation and administration of Noxafil PowderMix for delayed-release oral suspension, see Instructions for Use . Preparation Instructions for Noxafil PowderMix for Delayed-Release Oral Suspension Do not open the Noxafil PowderMix packet until ready to prepare the drug. Remove cap from the mixing liquid and push the bottle adapter into the neck of the bottle. Once in place, the bottle adapter stays in the bottle. Remove 9 mL of mixing liquid using the provided blue syringe. Put the cap back on the bottle. Only use the mixing liquid in the kit to prepare Noxafil PowderMix. Using the provided mixing cup, combine 9 mL of mixing liquid and the entire contents of one packet in the Noxafil PowderMix kit and mix (containing 300 mg of posaconazole). Shake the mixing cup vigorously for 45 seconds to mix the powder and mixing liquid from the Noxafil PowderMix kit. The final concentration of the reconstituted Noxafil PowderMix delayed-release suspension is approximately 30 mg/mL of posaconazole. Check to make sure the powder is mixed (the mixture should look cloudy and free of clumps). Must use the reconstituted Noxafil PowderMix delayed-release suspension within 1 hour of reconstitution. Discard unused portion of the reconstituted Noxafil PowderMix delayed-release suspension. Administration Instructions for Noxafil PowderMix Delayed-Release Reconstituted Suspension To ensure delivery of the correct reconstituted Noxafil PowderMix Delayed-release dose, only use the provided notched tip syringes for preparation and administration because its design reduces the risk of aggregation of the product during preparation and administration. Choose the correct syringe based on the prescribed Noxafil PowderMix dose: Use 3 mL ( green ) notched tip syringe (provided with the kit) if dose is 3 mL or less. Use 10 mL ( blue ) notched tip syringe (provided with the kit) if dose is more than 3 mL. Administer reconstituted Noxafil PowderMix suspension orally with food within 1 hour of reconstitution [see Clinical Pharmacology (12.3) ]. The maximum dose that can be accurately withdrawn from the mixing cup after reconstitution is 240 mg (8 mL). Discarding Unused Reconstituted Noxafil PowderMix Suspension and Reuse of Syringes Not all the reconstituted Noxafil PowderMix suspension in the mixing cup will be used; there will be some left over in the mixing cup. Discard any remaining reconstituted Noxafil PowderMix suspension. The mixing cup may be hand washed and reused. Alternatively, the mixing cup may be discarded, and a similar mixing cup with a lid may be used for subsequent doses. The notched tip syringes may be hand washed and reused. 2.11 Dosage Modifications in Patients with Renal Impairment The recommended dosage of Noxafil oral suspension, Noxafil delayed-release tablets, and Noxafil PowderMix for delayed-release oral suspension is the same in patients with renal impairment compared to those with normal renal function. Avoid the use of Noxafil injection in patients with eGFR less than 50 mL/minute/1.73 m 2 , unless an assessment of the benefit/risk to the patient justifies its use. If the decision is made to use Noxafil injection in patients with eGFR less than 50 mL/minute/1.73 m 2 , closely monitor serum creatinine levels, and, if increases occur, consider changing to oral Noxafil therapy. The recommended dosage of Noxafil injection in patients with eGFR 50 to 90 mL/minute/1.73 m 2 is the same as those with normal renal function." ], "dosage_and_administration_table": [ "
Table 1: Recommended Dosage of Noxafil Injection, Noxafil Delayed-Release Tablets, and Noxafil Oral Suspension in Adult Patients
DosageDuration of Therapy
Treatment of Invasive AspergillosisSwitching between the Noxafil injection and delayed-release tablets is acceptable. A loading dose is not required when switching between dosage forms.
Noxafil Injection:Loading dose: 300 mg Noxafil injection intravenously twice a day on the first day. Maintenance dose: 300 mg Noxafil injection intravenously once a day, starting on the second day. Noxafil Delayed-Release Tablets: Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Loading dose: 1 day Maintenance dose: Recommended total duration of therapy is 6 to 12 weeks.
Prophylaxis of Invasive Aspergillus and Candida Infections
Noxafil Injection: Loading dose: 300 mg Noxafil injection intravenously twice a day on the first day. Maintenance dose: 300 mg Noxafil injection intravenously once a day thereafter. Noxafil Delayed-Release Tablets: Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Noxafil Oral Suspension: 200 mg (5 mL) three times a day. Loading dose: 1 day Maintenance dose: Duration of therapy is based on recovery from neutropenia or immunosuppression
Oropharyngeal Candidiasis (OPC)
Noxafil Oral Suspension: Loading dose: 100 mg (2.5 mL) twice a day on the first day. Maintenance dose: 100 mg (2.5 mL) once a day thereafter.Loading dose: 1 day Maintenance dose: 13 days
OPC Refractory (rOPC) to Itraconazole and/or Fluconazole
Noxafil Oral Suspension: 400 mg (10 mL) twice a day. Duration of therapy is based on the severity of the patient’s underlying disease and clinical response.
", "
Table 2: Recommended Dosage of Noxafil Injection and Noxafil Delayed-Release Tablets for the Treatment of Invasive AspergillosisSwitching between the intravenous and delayed-release tablets is acceptable. A loading dose is not required when switching between formulations. and Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients (2 Years of Age and Older)
Recommended Pediatric Dosage by FormulationDuration of Therapy
Noxafil Injection (patients weighing 10 kg or greater):Loading dose: 6 mg/kg up to a maximum of 300 mg twice daily on the first day Maintenance dose: 6 mg/kg up to a maximum of 300 mg once daily, starting on the second day. Noxafil Delayed-Release Tablets (patients weighing greater than 40 kg): Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Treatment of invasive aspergillosis: Recommended total duration of therapy is 6 to 12 weeks Prophylaxis of invasive Aspergillus and Candida infections: Duration of therapy is based on recovery from neutropenia or immunosuppression.
", "
Table 3: Recommended Dosage of Noxafil Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients (13 Years of Age and Older)
Recommended Pediatric Dosage of Noxafil Oral SuspensionDuration of Therapy
200 mg (5 mL) three times a dayDuration of therapy is based on recovery from neutropenia or immunosuppression.
", "
Table 4: Recommended Dosage for Noxafil PowderMix for Delayed-Release Oral Suspension for the Treatment of Invasive Aspergillosis in Pediatric Patients (2 Years of Age and Older)
Weight (kg)Recommended Pediatric Dosage of Noxafil PowderMix for Delayed-Release Oral SuspensionDuration of Therapy
10 to less than 17Loading Dose: 120 mg (4 mL) twice daily on the first day Maintenance Dose: 120 mg (4 mL) once daily Recommended total duration of therapy is 6 to 12 weeks.
17 to less than 21Loading Dose: 150 mg (5 mL) twice daily on the first day Maintenance Dose: 150 mg (5 mL) once daily
21 to less than 26Loading Dose: 180 mg (6 mL) twice daily on the first day Maintenance Dose: 180 mg (6 mL) once daily
26 to less than 36Loading Dose: 210 mg (7 mL) twice daily on the first day Maintenance Dose: 210 mg (7 mL) once daily
36 to 40Loading Dose: 240 mg (8 mL) twice daily on the first day Maintenance Dose: 240 mg (8 mL) once daily
", "
Table 5: Recommended Dosage for Noxafil PowderMix for Delayed-Release Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida infections in Pediatric Patients (2 Years of Age and Older )
Weight (kg)Recommended Pediatric Dosage of Noxafil PowderMix for Delayed-Release Oral SuspensionDuration of Therapy
10 to less than 12Loading Dose: 90 mg (3 mL) twice daily on the first day Maintenance Dose: 90 mg (3 mL) once daily Duration of therapy is based on recovery from neutropenia or immunosuppression.
12 to less than 17Loading Dose: 120 mg (4 mL) twice daily on the first day Maintenance Dose: 120 mg (4 mL) once daily
17 to less than 21Loading Dose: 150 mg (5 mL) twice daily on the first day Maintenance Dose: 150 mg (5 mL) once daily
21 to less than 26Loading Dose: 180 mg (6 mL) twice daily on the first day Maintenance Dose: 180 mg (6 mL) once daily
26 to less than 36Loading Dose: 210 mg (7 mL) twice daily on the first day Maintenance Dose: 210 mg (7 mL) once daily
36 to 40Loading Dose: 240 mg (8 mL) twice daily on the first day Maintenance Dose: 240 mg (8 mL) once daily
", "
Table 6: Recommended Dosage of Noxafil Oral Suspension for the Treatment of OPC and rOPC in Pediatric Patients (13 Years of Age and Older)
Recommended Pediatric Dosage of Noxafil Oral SuspensionDuration of Therapy
Oropharyngeal Candidiasis (OPC)
Loading Dose: 100 mg (2.5 mL) twice daily on the first day Maintenance Dose: 100 mg (2.5 mL) once daily Loading dose: 1 day Maintenance dose: 13 days
OPC Refractory (rOPC) to Itraconazole and/or Fluconazole
400 mg (10 mL) twice daily Duration of therapy is based on the severity of the patient’s underlying disease and clinical response.
", "
Figure 1: Measured dosing spoon provided in the package marked for doses of 2.5 mL and 5 mL.
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Noxafil injection 300 mg/16.7 mL (18 mg/mL) of posaconazole: Clear, colorless to yellow sterile liquid in a single-dose vial. Noxafil Delayed-Release Tablets 100 mg of posaconazole: Yellow, coated, oblong tablets, debossed with \"100\" on one side. Noxafil Oral Suspension 4,200 mg/105 mL (40 mg/mL) of posaconazole: White, cherry-flavored suspension in amber glass bottles with child-resistant closures. Noxafil PowderMix for Delayed-Release Oral Suspension 300 mg: Off-white to yellowish powder for delayed-release oral suspension and a mixing liquid in a kit. The kit contains (1) Package A that contains single-use packets of Noxafil PowderMix, green notched tip syringes, blue notched tip syringes, mixing cups, mixing liquid bottle, and one bottle adapter for the mixing liquid bottle; and (2) Package B that contains green and blue notched tip syringes for additional supply [see How Supplied/Storage and Handling (16.1) ]. Noxafil injection: 300 mg per vial (18 mg per mL) in a 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 )" ], "contraindications": [ "4 CONTRAINDICATIONS 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 , 7.2 ) 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 , 7.2 ) Ergot alkaloids ( 4.5 , 7.2 ) Venetoclax: In patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp-up phase ( 4.6 , 5.11 , 7.2 ) Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with known or suspected Hereditary Fructose Intolerance (HFI). ( 4.7 , 5.9 , 8.4 ) 4.1 Hypersensitivity Noxafil is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents. 4.2 Use with Sirolimus Noxafil is contraindicated with sirolimus. Concomitant administration of Noxafil with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity [see Drug Interactions (7.2) 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 (7.2) 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 (7.2) ]. 4.6 Use with Venetoclax Coadministration of Noxafil with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Warnings and Precautions (5.11) and Drug Interactions (7.2) ]. 4.7 Use of Noxafil PowderMix for Delayed-Release Oral Suspension in Patients with Hereditary Fructose Intolerance Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with known or suspected hereditary fructose intolerance (HFI) [see Warnings and Precautions (5.9) and Use in Specific Populations (8.4) ] ." ], "warnings_and_cautions": [ "5 WARNINGS 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 , 7.2 ) Electrolyte Disturbances : Monitor and correct, especially those involving potassium (K + ), magnesium (Mg ++ ), and calcium (Ca ++ ), before and during Noxafil therapy. ( 5.3 ) Pseudoaldosteronism : Manifested by the onset or worsening of hypertension, and abnormal laboratory findings. Monitor blood pressure and potassium levels, and manage as necessary. ( 5.4 ) 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. ( 5.5 ) Renal Impairment : Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR less than 50 mL/min/1.73 m 2 ), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. ( 5.6 , 8.6 ) Concomitant Use with Midazolam : Noxafil can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available. ( 5.7 , 7.2 ) 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 a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. ( 5.8 , 7.2 ) 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. ( 5.9 , 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. ( 5.10 ) 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 , 5.11 , 7.2 ) 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 (7.2) 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 a 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 a 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 a 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. A decrease in the QTc(F) interval (–3 msec) was also observed in a 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 a 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 Pseudoaldosteronism Pseudoaldosteronism, manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevated 11-deoxycortisol), has been reported with posaconazole use in the postmarket setting. Monitor blood pressure and potassium levels and manage as necessary. Management of pseudoaldosteronism may include discontinuation of Noxafil, substitution with an appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone receptor antagonists. 5.5 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 a 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. 5.6 Renal 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 (2.11) and Use in Specific Populations (8.6) ]. Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m 2 ), 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/1.73 m 2 ), 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 (2.11) and Use in Specific Populations (8.6) ] . 5.7 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 (7.2) and Clinical Pharmacology (12.3) ] . 5.8 Vincristine 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 a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Drug Interactions (7.2) ] . 5.9 Risk in Patients with Hereditary Fructose Intolerance (HFI) Noxafil PowderMix for delayed-release oral suspension contains sorbitol, an inactive ingredient, and may precipitate a 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 a diagnosis of HFI may not yet be established in pediatric patients [see Contraindications (4) and Use in Specific Populations (8.4) ] . 5.10 Breakthrough 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. 5.11 Venetoclax Toxicity Concomitant administration of Noxafil, a 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 (7.2) ]. Refer to the venetoclax prescribing information for dosing instructions." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling: Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2) ] Electrolyte Disturbances [see Warnings and Precautions (5.3) ] Pseudoaldosteronism [see Warnings and Precautions (5.4) ] Hepatic Toxicity [see Warnings and Precautions (5.5) ] Adult Patients: Common adverse reactions in studies with Noxafil in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. ( 6.1 ) Pediatric Patients: Common adverse reactions (incidence >20% receiving 6 mg/kg Noxafil injection and Noxafil PowderMix for delayed-release oral suspension) in a study in pediatric patients are pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of Noxafil cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment of Invasive Aspergillosis in Adults and Adolescents (Noxafil injection and Noxafil Delayed-Release Tablets) The safety of Noxafil injection and Noxafil delayed-release tablets was assessed in a randomized, double-blind, active-controlled clinical study of Noxafil injection and Noxafil delayed-release tablets versus voriconazole for treatment of invasive aspergillosis (Aspergillosis Treatment Study). A total of 575 adult and pediatric patients 14 years of age and older (288 in the Noxafil group, 287 in voriconazole group (voriconazole for injection or voriconazole tablets)) with proven, probable or possible invasive aspergillosis were included. The median duration of treatment was 67 days for Noxafil injection or Noxafil delayed-release tablets and 64 days for voriconazole. In this study, 55% to 60% of patients started intravenous treatment with Noxafil (Noxafil injection) or voriconazole (voriconazole for injection). The median duration of the first instance of intravenous treatment (before switching to oral treatment or discontinuing or completing study treatment) was 9 days for both groups. Table 7 presents adverse reactions reported at an incidence of ≥10% in either one of the treatment groups in the Aspergillosis Treatment Study. Adverse reactions leading to treatment discontinuation were reported for 34% of patients. The most commonly reported adverse reactions (>2% of patients) leading to treatment discontinuation were septic shock, respiratory failure, and bronchopulmonary aspergillosis in the Noxafil group, and septic shock and acute myeloid leukemia in the voriconazole group. The most frequently reported adverse reactions in the Noxafil-treated group were pyrexia (28%), hypokalemia (28%), and nausea (23%). Table 7: Adverse Reactions in at least 10% of Adults and Adolescents Receiving Noxafil Injection or Noxafil Delayed-Release Tablets for the Treatment of Invasive Aspergillosis Adverse Reactions Noxafil injection or Noxafil delayed-release tablets n=288 (%) Voriconazole for injection or Voriconazole tablets n=287 (%) Percentage of Patients Reporting any Adverse Reaction 97.6 97.6 Hypokalemia 28.5 17.1 Pyrexia 28.1 25.1 Nausea 22.6 17.8 Diarrhea 18.1 18.1 Vomiting 18.1 13.6 Alanine aminotransferase increased 14.6 12.9 Febrile neutropenia 14.6 13.2 Aspartate aminotransferase increased 13.2 12.5 Pneumonia 12.5 9.1 Headache 12.2 8.7 Constipation 11.1 8.0 Edema peripheral 11.1 8.4 Epistaxis 11.1 5.9 Cough 10.4 8.4 Abdominal pain 10.1 8.4 Hypomagnesemia 10.1 6.3 Clinical Trial Experience with Noxafil Injection for Prophylaxis of Invasive Aspergillus and Candida Infections Administration of multiple doses of Noxafil injection via a peripheral venous catheter were associated with thrombophlebitis (60% incidence). Therefore, in subsequent studies, Noxafil injection was administered via central venous catheter [see Dosage and Administration (2.6) ]. The safety of Noxafil injection has been assessed in 268 patients in a clinical trial. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of Noxafil injection when given as antifungal prophylaxis (Noxafil Injection Study). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 55% male, had a mean age of 51 years (range: 18-82 years, 19% of patients were ≥65 years of age), and were 95% White and 8% Hispanic. In this study, 10 patients received a single dose of 200 mg Noxafil injection, 21 patients received 200 mg daily dosage for a median of 14 days, and 237 patients received 300 mg daily dosage for a median of 9 days (the 200 mg dosage is not a recommended dosage for prophylaxis of invasive Aspergillus and Candida infections in adults [see Dosage and Administration (2.2) ]. In the 300 mg daily dosage group each patient received a loading intravenous dose of Noxafil injection 300 mg twice on Day 1, then intravenous Noxafil injection therapy, and finally Noxafil oral suspension to complete 28 days of total Noxafil therapy. Table 8 presents adverse reactions observed in patients treated with the Noxafil injection 300 mg daily dosage group in the Noxafil Injection Study. The most frequently reported adverse reactions with an onset during the intravenous Noxafil injection 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. Table 8: Adverse Reactions in at least 10% of Adults Receiving Noxafil Injection for the Prophylaxis of Invasive Aspergillus and Candida infections Adverse Reactions Noxafil Injection Treatment Phase n=237 Adverse reactions reported in patients with an onset during the Noxafil intravenous dosing phase of the study. (%) Noxafil Injection Treatment Phase or Subsequent Noxafil Oral Suspension Treatment Phase n=237 Adverse reactions reported with an onset at any time during the study in patients who were treated for up to 28 days of Noxafil therapy. (%) Percentage of Patients Reporting any Adverse Reaction 93 99 Diarrhea 32 39 Hypokalemia 22 28 Pyrexia 21 31 Nausea 19 30 Rash 15 24 Headache 14 21 Epistaxis 14 17 Abdominal Pain 13 17 Chills 12 16 Edema Peripheral 12 15 Vomiting 12 19 Hypomagnesemia 11 13 Decreased appetite 10 12 Cough 9 13 Constipation 8 13 Fatigue 8 10 Hypertension 8 11 Petechiae 8 10 Anemia 7 10 Dyspnea 7 10 Thrombocytopenia 7 11 Abdominal Pain Upper 6 11 Clinical Trial Experience with Noxafil Delayed-Release Tablets for Prophylaxis of Invasive Aspergillus and Candida Infections The safety of Noxafil delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of Noxafil delayed-release tablets when given as antifungal prophylaxis (Noxafil Delayed-Release Tablet Study). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 62% male, had a mean age of 51 years (range: 19-78 years, 17% of patients were ≥65 years of age), and were 93% White and 16% Hispanic. Noxafil delayed-release tablets were given for a median duration of 28 days. In this study, 20 adult patients received 200 mg daily dosage (this is not a recommended dosage [see Dosage and Administration (2.2) ] ) and 210 adult patients received 300 mg daily dosage (following twice daily dosing on Day 1 in each cohort). Table 9 presents adverse reactions (incidence of ≥ 10%) observed in patients treated with the Noxafil delayed-release tablets 300 mg daily dosage in the Noxafil Delayed-Release Tablet Study. The most frequently reported adverse reactions (>25%) in patients treated 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%). Table 9: Adverse Reactions in at least 10% of Adults Receiving Noxafil Delayed-Release Tablets (300 mg Daily Dosage) for the Prophylaxis of Invasive Aspergillus and Candida infections Adverse Reactions Noxafil delayed-release tablet (300 mg) n=210 (%) Percentage of Patients Reporting any Adverse Reaction 99 Diarrhea 29 Pyrexia 28 Nausea 27 Hypokalemia 22 Cough 17 Edema Peripheral 16 Rash 16 Epistaxis 14 Headache 14 Mucosal Inflammation 14 Thrombocytopenia 14 Vomiting 13 Abdominal Pain 11 Hypertension 11 Anemia 10 Asthenia 10 Chills 10 Constipation 10 Hypomagnesemia 10 Clinical Trials Safety Experience with Noxafil Oral Suspension The safety of Noxafil oral suspension has been assessed in 1,844 patients, including: 605 patients in the active-controlled studies for the prophylaxis of invasive Aspergillus and Candida infections 557 patients in the active-controlled OPC studies (not refractory to itraconazole or fluconazole) 239 patients in refractory OPC studies (refractory to itraconazole or fluconazole) (rOPC), and 443 patients in other patient populations These studies included immunocompromised patients (e.g., patients with hematological malignancy, neutropenia post-chemotherapy, GVHD post HSCT, and HIV infection), as well as non-neutropenic patients. This patient population was 71% male, had a mean age of 42 years (range: 8-84 years, 6% of patients were ≥65 years of age and 1% was <18 years of age), and were 64% White, 14% Black, 16% Hispanic. Noxafil oral suspension therapy was given to 171 patients for ≥6 months, including 58 patients who received Noxafil oral suspension therapy for ≥12 months. Table 10 presents adverse reactions observed at an incidence of >10% in the studies for prophylaxis of invasive Aspergillus and Candida infections. Table 11 presents adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies. Prophylaxis of Invasive Aspergillus and Candida Infections (Noxafil oral suspension) In the two randomized, comparative studies for prophylaxis of invasive Aspergillus and Candida infections in those at high risk of developing these infections due to being severely immunocompromised (Noxafil Oral Suspension Study 1 and 2), the safety of Noxafil oral suspension 200 mg three times a day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely immunocompromised patients. The most frequently reported adverse reactions (>30%) in these trials were fever, diarrhea, and nausea. The most common adverse reactions leading to discontinuation of Noxafil oral suspension were GI adverse reactions, specifically, nausea (2%), vomiting (2%), and increased hepatic enzymes (2%). Table 10: Adverse Reactions in at least 10% of Patients Receiving Noxafil Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida Infections Adverse Reactions Noxafil Oral Suspension n=605 (%) Fluconazole n=539 (%) Itraconazole n=58 (%) Percentage of Patients Reporting any Adverse Reaction 98 99 100 Fever 45 47 55 Diarrhea 42 39 60 Nausea 38 37 52 Hypokalemia 30 26 52 Thrombocytopenia 29 27 34 Vomiting 29 32 41 Headache 28 26 40 Abdominal Pain 27 27 36 Anemia 25 23 28 Coughing 24 24 24 Neutropenia 23 23 40 Constipation 21 17 17 Dyspnea 20 22 26 Rigors 20 16 29 Rash 19 18 43 Hypertension 18 16 5 Hypomagnesemia 18 16 19 Fatigue 17 18 9 Insomnia 17 17 19 Musculoskeletal Pain 16 15 16 Anorexia 15 17 28 Edema Legs 15 12 19 Epistaxis 14 14 21 Hypotension 14 15 17 Pharyngitis 12 11 21 Tachycardia 12 14 5 Arthralgia 11 12 9 Dizziness 11 10 9 Hyperglycemia 11 14 3 Petechiae 11 10 16 Pruritus 11 12 19 Back Pain 10 12 7 Bilirubinemia 10 9 19 Dyspepsia 10 9 10 Vaginal Hemorrhage Percentages of sex-specific adverse reactions are based on the number of males/females. 10 9 12 Treatment of Nonrefractory OPC and Refractory OPC (Noxafil oral suspension) In two randomized comparative studies for the treatment of nonrefractory OPC, the safety of Noxafil oral suspension (less than or equal to 400 mg once daily) in 557 HIV-infected patients was compared to the safety of fluconazole (100 mg once daily) in 262 HIV-infected patients. An additional 239 HIV-infected patients with refractory OPC (rOPC) received Noxafil oral suspension in two non-comparative trials for rOPC. Of these patients, 149 received the 800 mg/day dosage and the remainder received the less than or equal to 400 mg once daily dosage. In the nonrefractory OPC and rOPC studies, the most common adverse reactions in patients treated with Noxafil oral suspension were fever, diarrhea, nausea, headache, vomiting, and coughing. Adverse reactions were reported more frequently in the studies of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions were reported in 55% (132/239) of Noxafil oral suspension-treated patients. The most commonly reported serious adverse reactions were fever (13%) and neutropenia (10%). Table 11: Adverse Reactions in at least 10% of Patients Receiving Noxafil Oral Suspension for the Treatment of Nonrefractory and Refractory OPC Adverse Reactions Controlled OPC Pool Refractory OPC Pool Noxafil Oral Suspension Fluconazole Noxafil Oral Suspension n=557 (%) n=262 (%) n=239 (%) OPC=oropharyngeal candidiasis Percentage of Patients that Reported any Adverse Reaction Based on patients reporting adverse reactions at least once during the study, without regard to relationship to treatment. Patients may have reported more than 1 adverse reaction. 64 67 92 Diarrhea 10 13 29 Nausea 9 11 29 Headache 8 9 20 Vomiting 7 7 28 Fever 6 8 34 Abdominal Pain 5 6 18 Neutropenia 4 3 16 Coughing 3 4 25 Fatigue 3 5 13 Herpes Simplex 3 3 11 Pneumonia 3 2 10 Rash 3 4 15 Anemia 2 2 14 Anorexia 2 2 19 Asthenia 2 2 13 Sweating Increased 2 2 10 Candidiasis, Oral 1 <1 12 Dehydration 1 3 11 Dyspnea 1 3 12 Insomnia 1 1 16 Pain 1 1 11 Weight Decrease 1 <1 14 Rigors <1 2 12 Additional Adverse Reactions Reported in Less Than 5% of Noxafil-Treated Patients in Clinical Trials Other clinically significant adverse reactions reported in less than 5% of patients in clinical trials of Noxafil are listed below: Blood and lymphatic system disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated Endocrine disorders: adrenal insufficiency Nervous system disorders: paresthesia Immune system disorders: allergic reaction [see Contraindications (4.1) ] Cardiac disorders: torsades de pointes [see Warnings and Precautions (5.2) ] Vascular disorders: pulmonary embolism Gastrointestinal disorders: pancreatitis Liver and Biliary System Disorders: hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice Renal & Urinary System Disorders: renal failure acute Liver Test Abnormalities in the Clinical Trials of Noxafil Oral Suspension Liver Test Abnormalities in the Clinical Trials with Noxafil Oral Suspension for Prophylaxis of Invasive Aspergillus and Candida Infections In the prophylaxis of invasive Aspergillus and Candida infections studies, the number and percentage of patients with changes in liver tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 at the end of the studies is presented in Table 12 . Table 12: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 in Prophylaxis of Invasive Aspergillus and Candida Infections Studies (Noxafil Oral Suspension Studies 1 and 2) Number (%) of Patients with Change Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation. Noxafil Oral Suspension Study 1 CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase. Laboratory Parameter Noxafil Oral Suspension n=301 Fluconazole n=299 AST 11/266 (4) 13/266 (5) ALT 47/271 (17) 39/272 (14) Bilirubin 24/271 (9) 20/275 (7) Alkaline Phosphatase 9/271 (3) 8/271 (3) Noxafil Oral Suspension Study 2 Laboratory Parameter Noxafil Oral Suspension (n=304) Fluconazole/Itraconazole (n=298) AST 9/286 (3) 5/280 (2) ALT 18/289 (6) 13/284 (5) Bilirubin 20/290 (7) 25/285 (9) Alkaline Phosphatase 4/281 (1) 1/276 (<1) Liver Test Abnormalities in the Clinical Trials with Noxafil Oral Suspension for the Treatment of OPC The number and percentage 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: Clinically Significant Liver Test Abnormalities without Regard to Baseline Value (Noxafil Oral Suspension Studies for the Treatment of OPC) Laboratory Test Nonrefractory OPC Refractory OPC Noxafil Oral Suspension Fluconazole Noxafil Oral Suspension n=557 (%) n=262 (%) n=239 (%) ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase. ALT > 3.0 x ULN 16/537 (3) 13/254 (5) 25/226 (11) AST > 3.0 x ULN 33/537 (6) 26/254 (10) 39/223 (17) Total Bilirubin > 1.5 x ULN 15/536 (3) 5/254 (2) 9/197 (5) Alkaline Phosphatase > 3.0 x ULN 17/535 (3) 15/253 (6) 24/190 (13) Liver Test Abnormalities in the Clinical Trials with Noxafil Oral Suspension for the Treatment of Invasive Aspergillosis The number and percentage 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% of the patients), AST (13% of the patients), and bilirubin (13% of the patients). Table 14: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 (Aspergillosis Treatment Study) Number (%) of Patients with Change Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form n/N, where n represents the number of patients who met the criterion as indicated, and N represents the number of patients who had a baseline observation and at least one post-baseline observation. Laboratory Parameter Noxafil n/N (%) Voriconazole n/N (%) N=Number of patients for a given laboratory test with a baseline value of CTC Grade 0, 1, or 2 and at least one post-baseline value. CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase. AST 22/281 (8) 21/285 (7) ALT 29/281(10) 23/282 (8) Bilirubin 26/280 (9) 25/284 (9) Alkaline Phosphatase 12/282 (4) 20/284 (7) In healthy volunteers and patients, elevation of liver test values did not appear to be associated with higher plasma posaconazole concentrations. Clinical Trials in Pediatric Patients 2 Years of Age and Older The safety of Noxafil injection and Noxafil PowderMix (for delayed-release oral suspension) for prophylaxis of invasive fungal infections was evaluated in an open-label uncontrolled dose-ranging pharmacokinetic and safety study of Noxafil injection and Noxafil PowderMix (Pediatric Study 1, NCT02452034). In this study, 115 immunocompromised pediatric patients 2 to less than 18 years of age with known or expected neutropenia initially received Noxafil injection (up to 6 mg/kg twice daily for the first day and then up to 6 mg/kg for at least 7 days), and then 63 patients were transitioned to Noxafil PowderMix (up to 6 mg/kg once daily). The mean overall treatment duration was 21 days including a mean duration of 14 days (range: 1 to 28 days) on Noxafil injection and a mean duration of 12 days (range: 2 to 18 days) on Noxafil PowderMix [see Clinical Pharmacology (12.3) ]. In this study, the reported adverse reaction profile of Noxafil injection and Noxafil PowderMix in pediatric patients was consistent with the safety profile of Noxafil in adults. The most common adverse reactions that occurred in greater than 20% of pediatric patients who received Noxafil injection and Noxafil PowderMix were pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis. The safety of Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix for delayed-release oral suspension for the treatment of invasive aspergillosis was evaluated in an open-label, non-comparative clinical study in 31 pediatric patients 2 to less than 18 years of age with a diagnosis of possible, probable, or proven invasive aspergillosis (Pediatric Study 2, NCT04218851). In this study, all 31 pediatric patients initially received Noxafil injection (6 mg/kg twice daily on the first day and then 6 mg/kg once daily) for the treatment of invasive aspergillosis; 12 patients were transitioned to Noxafil delayed-release tablets (300 mg once daily) if they weighed ≥40 kg, and 10 patients were transitioned to Noxafil PowderMix (based on weight) if they weighed 10 to 40 kg [see Dosage and Administration (2.3) ] . The mean overall treatment duration was 50 days including 15 days (range: 2 to 78 days) on Noxafil injection, 54 days (range: 6 to 80 days) on Noxafil delayed-release tablets, and 44 days (range: 7 to 76 days) on Noxafil PowderMix. The reported adverse reaction profile of Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix in pediatric patients was consistent with the known safety profile of Noxafil in adults. The most common adverse reactions that occurred in greater than 20% of pediatric patients who received any of the three formulations of Noxafil were vomiting, pyrexia, abdominal pain, liver test abnormalities, and hypertension. 6.2 Postmarketing Experience The following adverse reaction has been identified during the post-approval use of Noxafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Endocrine Disorders: Pseudoaldosteronism" ], "adverse_reactions_table": [ "
Table 7: Adverse Reactions in at least 10% of Adults and Adolescents Receiving Noxafil Injection or Noxafil Delayed-Release Tablets for the Treatment of Invasive Aspergillosis
Adverse ReactionsNoxafil injection or Noxafil delayed-release tablets n=288 (%)Voriconazole for injection or Voriconazole tablets n=287 (%)
Percentage of Patients Reporting any Adverse Reaction97.697.6
Hypokalemia28.517.1
Pyrexia28.125.1
Nausea22.617.8
Diarrhea18.118.1
Vomiting18.113.6
Alanine aminotransferase increased14.612.9
Febrile neutropenia14.613.2
Aspartate aminotransferase increased13.212.5
Pneumonia12.59.1
Headache12.28.7
Constipation11.18.0
Edema peripheral11.18.4
Epistaxis11.15.9
Cough10.48.4
Abdominal pain10.18.4
Hypomagnesemia10.16.3
", "
Table 8: Adverse Reactions in at least 10% of Adults Receiving Noxafil Injection for the Prophylaxis of Invasive Aspergillus and Candida infections
Adverse ReactionsNoxafil Injection Treatment Phase n=237Adverse reactions reported in patients with an onset during the Noxafil intravenous dosing phase of the study. (%)Noxafil Injection Treatment Phase or Subsequent Noxafil Oral Suspension Treatment Phase n=237Adverse reactions reported with an onset at any time during the study in patients who were treated for up to 28 days of Noxafil therapy. (%)
Percentage of Patients Reporting any Adverse Reaction9399
Diarrhea3239
Hypokalemia2228
Pyrexia2131
Nausea1930
Rash1524
Headache1421
Epistaxis1417
Abdominal Pain1317
Chills1216
Edema Peripheral1215
Vomiting1219
Hypomagnesemia1113
Decreased appetite1012
Cough913
Constipation813
Fatigue810
Hypertension811
Petechiae810
Anemia710
Dyspnea710
Thrombocytopenia711
Abdominal Pain Upper611
", "
Table 9: Adverse Reactions in at least 10% of Adults Receiving Noxafil Delayed-Release Tablets (300 mg Daily Dosage) for the Prophylaxis of Invasive Aspergillus and Candida infections
Adverse ReactionsNoxafil delayed-release tablet (300 mg) n=210 (%)
Percentage of Patients Reporting any Adverse Reaction99
Diarrhea29
Pyrexia28
Nausea27
Hypokalemia22
Cough17
Edema Peripheral16
Rash16
Epistaxis14
Headache14
Mucosal Inflammation14
Thrombocytopenia14
Vomiting13
Abdominal Pain11
Hypertension11
Anemia10
Asthenia10
Chills10
Constipation10
Hypomagnesemia10
", "
Table 10: Adverse Reactions in at least 10% of Patients Receiving Noxafil Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida Infections
Adverse ReactionsNoxafil Oral Suspension n=605 (%)Fluconazole n=539 (%)Itraconazole n=58 (%)
Percentage of Patients Reporting any Adverse Reaction9899100
Fever454755
Diarrhea423960
Nausea383752
Hypokalemia302652
Thrombocytopenia292734
Vomiting293241
Headache282640
Abdominal Pain272736
Anemia252328
Coughing242424
Neutropenia232340
Constipation211717
Dyspnea202226
Rigors201629
Rash191843
Hypertension18165
Hypomagnesemia181619
Fatigue17189
Insomnia171719
Musculoskeletal Pain161516
Anorexia151728
Edema Legs151219
Epistaxis141421
Hypotension141517
Pharyngitis121121
Tachycardia12145
Arthralgia11129
Dizziness11109
Hyperglycemia11143
Petechiae111016
Pruritus111219
Back Pain10127
Bilirubinemia10919
Dyspepsia10910
Vaginal HemorrhagePercentages of sex-specific adverse reactions are based on the number of males/females.10912
", "
Table 11: Adverse Reactions in at least 10% of Patients Receiving Noxafil Oral Suspension for the Treatment of Nonrefractory and Refractory OPC
Adverse Reactions
Controlled OPC PoolRefractory OPC Pool
Noxafil Oral SuspensionFluconazoleNoxafil Oral Suspension
n=557 (%)n=262 (%)n=239 (%)
OPC=oropharyngeal candidiasis
Percentage of Patients that Reported any Adverse ReactionBased on patients reporting adverse reactions at least once during the study, without regard to relationship to treatment. Patients may have reported more than 1 adverse reaction.646792
Diarrhea101329
Nausea91129
Headache8920
Vomiting7728
Fever6834
Abdominal Pain5618
Neutropenia4316
Coughing3425
Fatigue3513
Herpes Simplex3311
Pneumonia3210
Rash3415
Anemia2214
Anorexia2219
Asthenia2213
Sweating Increased2210
Candidiasis, Oral1<112
Dehydration1311
Dyspnea1312
Insomnia1116
Pain1111
Weight Decrease1<114
Rigors<1212
", "
Table 12: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 in Prophylaxis of Invasive Aspergillus and Candida Infections Studies (Noxafil Oral Suspension Studies 1 and 2)
Number (%) of Patients with ChangeChange from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation.
Noxafil Oral Suspension Study 1
CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase;
ALT= Alanine Aminotransferase.
Laboratory ParameterNoxafil Oral Suspension n=301Fluconazole n=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 2
Laboratory 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)
", "
Table 13: Clinically Significant Liver Test Abnormalities without Regard to Baseline Value (Noxafil Oral Suspension Studies for the Treatment of OPC)
Laboratory TestNonrefractory OPCRefractory OPC
Noxafil Oral SuspensionFluconazoleNoxafil Oral Suspension
n=557 (%)n=262 (%)n=239 (%)
ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase.
ALT > 3.0 x ULN16/537 (3)13/254 (5) 25/226 (11)
AST > 3.0 x ULN33/537 (6)26/254 (10)39/223 (17)
Total Bilirubin > 1.5 x ULN15/536 (3)5/254 (2)9/197 (5)
Alkaline Phosphatase > 3.0 x ULN17/535 (3)15/253 (6) 24/190 (13)
", "
Table 14: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 (Aspergillosis Treatment Study)
Number (%) of Patients with ChangeChange from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form n/N, where n represents the number of patients who met the criterion as indicated, and N represents the number of patients who had a baseline observation and at least one post-baseline observation.
Laboratory ParameterNoxafil n/N (%)Voriconazole n/N (%)
N=Number of patients for a given laboratory test with a baseline value of CTC Grade 0, 1, or 2 and at least one post-baseline value.
CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase;
ALT= Alanine Aminotransferase.
AST 22/281 (8) 21/285 (7)
ALT 29/281(10) 23/282 (8)
Bilirubin26/280 (9) 25/284 (9)
Alkaline Phosphatase 12/282 (4) 20/284 (7)
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Table 15 and Table 17 include drugs with clinically important drug interactions when administered concomitantly with Noxafil and Noxafil PowderMix and instructions for preventing or managing them. Table 16 includes important drug interactions specific to the absorption of posaconazole administered as either Noxafil oral suspension or Noxafil PowderMix. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse reactions or loss of efficacy [see Clinical Pharmacology (12.3) ] . The following information was derived from data with Noxafil oral suspension or another posaconazole tablet formulation unless otherwise noted. All clinically important drug interactions with Noxafil oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility), are considered relevant to clinically important drug interactions with Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix for delayed-release oral suspension [see Clinical Pharmacology (12.3) ] . Consult the labeling of concomitantly used drugs to obtain further information about interactions with posaconazole. Interaction Drug Interaction Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazole The drug interactions with esomeprazole and metoclopramide do not apply to Noxafil tablets or Noxafil PowderMix ( 7.3 , 12.3 ). Avoid coadministration unless the benefit outweighs the risks ( 7.1 , 7.2 ) Other drugs metabolized by CYP3A4 Consider dosage adjustment and monitor for adverse effects and toxicity ( 7.2 ) Digoxin Monitor digoxin plasma concentrations ( 7.2 ) Fosamprenavir, metoclopramide Monitor for breakthrough fungal infections ( 7.1 ) 7.1 Effects of Other Drugs on Noxafil and Noxafil PowderMix Posaconazole is primarily metabolized via UDP-glucuronosyltransferase and is a substrate of p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Concomitant use of Noxafil with drugs that can decrease the plasma posaconazole concentrations should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections. Table 15: Drug Interactions Affecting Noxafil and Noxafil PowderMix When Administered Concomitantly with Other Drugs UDP-Glucuronidase Inducers Mechanism and Clinical Effect(s) Posaconazole is a UDP-glucuronosyltransferase substrate. Concomitant use of Noxafil with UDP-glucuronidase inducers may decrease posaconazole exposure [see Clinical Pharmacology (12.3) ], which may reduce the effectiveness of posaconazole. Prevention or Management Efavirenz Avoid concomitant use of posaconazole with efavirenz, unless the benefit outweighs the risks. Rifabutin Avoid concomitant use of posaconazole with rifabutin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor closely for breakthrough fungal infections. See Table 17 for rifabutin monitoring considerations when posaconazole affects rifabutin via CYP3A4 inhibition. Phenytoin Avoid concomitant use of posaconazole with phenytoin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor for breakthrough fungal infections. See Table 17 for phenytoin monitoring considerations when posaconazole affects phenytoin via CYP3A4 inhibition. Fosamprenavir Mechanism and Clinical Effect(s) Concomitant use of Noxafil with fosamprenavir may lead to decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3) ], which may reduce effectiveness of posaconazole. Prevention or Management If concomitant use of posaconazole with fosamprenavir is needed, monitor closely for breakthrough fungal infections. Table 16: Drug Interactions Affecting Noxafil Oral Suspension and Noxafil PowderMix Absorption When Administered Concomitantly with Other Drugs Noxafil Oral Suspension Cimetidine and Esomeprazole Mechanism and Clinical Effect(s) Concomitant use of Noxafil oral suspension with cimetidine or esomeprazole resulted in decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3) ], which may reduce effectiveness of Noxafil. Prevention or Management Avoid concomitant use of Noxafil oral suspension with cimetidine or esomeprazole unless the benefit outweighs the risks. If concomitant use is needed, monitor closely for breakthrough fungal infections. Metoclopramide Mechanism and Clinical Effect(s) Concomitant use of Noxafil oral suspension with metoclopramide decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3) ], which may reduce effectiveness of Noxafil oral suspension. Prevention or Management If Noxafil oral suspension is concomitantly administered with metoclopramide, closely monitor for breakthrough fungal infections. Noxafil Oral PowderMix Alcohol Mechanism and Clinical Effect(s) Posaconazole releases faster from Noxafil PowderMix in the presence of alcohol, which may interfere with Noxafil PowderMix’s delayed-release characteristics [see Clinical Pharmacology (12.3) ]. Prevention or Management Administration of Noxafil PowderMix with alcohol is not recommended. 7.2 Effects of Noxafil and Noxafil PowderMix on Other Drugs Posaconazole is a strong CYP3A4 inhibitor. Therefore, concomitant use of Noxafil may increase plasma concentrations of drugs that are CYP3A4 substrates [see Clinical Pharmacology (12.3) ] . Table 17: Drug Interactions Affecting Drugs Administered Concomitantly with Noxafil and Noxafil PowderMix Digoxin Clinical Effect(s) Increased digoxin plasma concentrations have been reported in patients who received concomitant posaconazole and digoxin. Prevention or Management Monitor digoxin plasma concentrations during concomitant use of posaconazole. Glipizide Clinical Effect(s) No dosage modification of glipizide is needed when used concomitantly with Noxafil. However, glucose concentrations decrease in some patients concomitantly administered posaconazole and glipizide. Prevention or Management Increase monitoring of glucose concentrations when used concomitantly. CYP3A Substrates Immunosuppressants that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Posaconazole is a strong CYP3A4 inhibitor. Therefore, plasma concentrations of CYP3A4 substrates may be increased by posaconazole use [see Clinical Pharmacology (12.3) ]. Prevention or Management Sirolimus Posaconazole is contraindicated with sirolimus [see Clinical Pharmacology (12.3) ] . Tacrolimus • At initiation of posaconazole treatment, reduce the tacrolimus dosage to approximately one-third of the original tacrolimus dosage. • Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dosage should be modified accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . Cyclosporine • At initiation of posaconazole treatment reduce the cyclosporine dosage to approximately three-fourths of the original dosage. • Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dosage should be modified accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . CYP3A4 Substrates that Prolong QTc Interval Mechanism and Clinical Effect(s) Concomitant use of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of the CYP3A4 substrates leading to QTc interval prolongation and torsades de pointes [see Warnings and Precautions (5.2) ]. Prevention or Management Pimozide Concomitant use with posaconazole is contraindicated. Quinidine HMG-CoA Reductase Inhibitors (Statins) that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Concomitant use of posaconazole with simvastatin increased simvastatin plasma concentrations which can lead to rhabdomyolysis [see Clinical Pharmacology (12.3) ]. Prevention or Management Atorvastatin, Lovastatin, Simvastatin Concomitant use with posaconazole is contraindicated. Benzodiazepines that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Concomitant use of posaconazole with midazolam increased midazolam plasma concentrations which could potentiate and prolong hypnotic and sedative effects [see Clinical Pharmacology (12.3) ] . Prevention or Management Midazolam, Alprazolam, Triazolam Closely monitor for adverse reactions associated with high plasma concentrations of benzodiazepines that are CYP3A4 substrates during concomitant use, and a benzodiazepine receptor antagonist should be available to reverse effects [see Warnings and Precautions (5.7) ]. Calcium Channel Blockers that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Posaconazole may increase the plasma concentrations of calcium channel blockers that are substrates of CYP3A4. Prevention or Management Verapamil, Diltiazem, Nifedipine, Nicardipine, Felodipine Monitor frequently for adverse reactions and toxicity with concomitant use of posaconazole with calcium channel blockers that are CYP3A4 substrates. Dosage reduction of the calcium channel blocker may be needed. Anti-HIV Drugs that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Ritonavir and atazanavir are CYP3A4 substrates and posaconazole increased plasma concentrations of these drugs [see Clinical Pharmacology (12.3) ]. Prevention or Management Ritonavir and Atazanavir Monitor frequently for adverse reactions and toxicity of ritonavir and atazanavir during concomitant use. Antineoplastic Drugs that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Posaconazole may increase plasma concentrations of oncology drugs that are CYP3A4 substrates, which may increase the risk of serious adverse reactions. Prevention or Management Venetoclax CLL/SLL patients : Concomitant use of posaconazole with venetoclax during initiation and ramp-up phase is contraindicated. AML patients : With concomitant use, venetoclax dosage reduction and safety monitoring is recommended across all dosing phases [see Warnings and Precautions (5.11) ] . Vinca alkaloids (e.g., vincristine, vinblastine) Reserve concomitant use for patients with no alternative antifungal treatment options [see Warnings and Precautions (5.8) ]. Ergot Alkaloids Mechanism and Clinical Effect(s) Most of the ergot alkaloids are CYP3A4 substrates. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Prevention or Management Ergotamine, Dihydroergotamine Concomitant use with posaconazole is contraindicated. Phenytoin Mechanism and Clinical Effect(s) Phenytoin is a CYP3A4 substrate. Concomitant use of posaconazole with phenytoin increased phenytoin plasma concentrations [see Clinical Pharmacology (12.3) ]. Prevention or Management Avoid concomitant use of posaconazole with phenytoin unless the benefit outweighs the risk. frequently monitor phenytoin concentrations and consider a dosage reduction of phenytoin. See Table 15 for additional monitoring considerations when phenytoin affects posaconazole via UDP-glucuronosyltransferase inhibition. Rifabutin Mechanism and Clinical Effect(s) Rifabutin is a CYP3A4 substrate. Concomitant use of posaconazole with rifabutin increased rifabutin plasma concentrations [see Clinical Pharmacology (12.3) ]. Prevention or Management Avoid concomitant use of posaconazole with rifabutin unless the benefit outweighs the risk. Frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) during concomitant use are recommended. See Table 15 for additional monitoring considerations when rifabutin affects posaconazole via UDP-glucuronosyltransferase inhibition. 7.3 Absence of Clinically Important Interaction with Noxafil and Noxafil PowderMix Additional clinical studies demonstrated that no clinically important 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 drugs when coadministered with Noxafil 200 mg once daily. No clinically relevant effects on the pharmacokinetics of Noxafil delayed-release tablets were observed during concomitant use with antacids, H 2 -receptor antagonists and proton pump inhibitors, and metoclopramide [see Clinical Pharmacology (12.3) ] . No dosage adjustment of Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension is required during concomitant use with these drugs. No clinically relevant effects on the pharmacokinetics of Noxafil oral suspension were observed during concomitant use with antacids, H 2 -receptor antagonists (other than cimetidine), and loperamide [see Clinical Pharmacology (12.3) ] . No dosage adjustment of Noxafil oral suspension is required during concomitant use with these drugs (other than cimetidine)." ], "drug_interactions_table": [ "
Interaction DrugInteraction
Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazoleThe drug interactions with esomeprazole and metoclopramide do not apply to Noxafil tablets or Noxafil PowderMix (7.3, 12.3).Avoid coadministration unless the benefit outweighs the risks (7.1, 7.2)
Other drugs metabolized by CYP3A4Consider dosage adjustment and monitor for adverse effects and toxicity (7.2)
DigoxinMonitor digoxin plasma concentrations (7.2)
Fosamprenavir, metoclopramideMonitor for breakthrough fungal infections (7.1)
", "
Table 15: Drug Interactions Affecting Noxafil and Noxafil PowderMix When Administered Concomitantly with Other Drugs
UDP-Glucuronidase Inducers
Mechanism and Clinical Effect(s)Posaconazole is a UDP-glucuronosyltransferase substrate. Concomitant use of Noxafil with UDP-glucuronidase inducers may decrease posaconazole exposure [see Clinical Pharmacology (12.3)], which may reduce the effectiveness of posaconazole.
Prevention or ManagementEfavirenzAvoid concomitant use of posaconazole with efavirenz, unless the benefit outweighs the risks.
RifabutinAvoid concomitant use of posaconazole with rifabutin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor closely for breakthrough fungal infections. See Table 17 for rifabutin monitoring considerations when posaconazole affects rifabutin via CYP3A4 inhibition.
PhenytoinAvoid concomitant use of posaconazole with phenytoin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor for breakthrough fungal infections. See Table 17 for phenytoin monitoring considerations when posaconazole affects phenytoin via CYP3A4 inhibition.
Fosamprenavir
Mechanism and Clinical Effect(s)Concomitant use of Noxafil with fosamprenavir may lead to decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce effectiveness of posaconazole.
Prevention or ManagementIf concomitant use of posaconazole with fosamprenavir is needed, monitor closely for breakthrough fungal infections.
", "
Table 16: Drug Interactions Affecting Noxafil Oral Suspension and Noxafil PowderMix Absorption When Administered Concomitantly with Other Drugs
Noxafil Oral Suspension
Cimetidine and Esomeprazole
Mechanism and Clinical Effect(s)Concomitant use of Noxafil oral suspension with cimetidine or esomeprazole resulted in decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce effectiveness of Noxafil.
Prevention or ManagementAvoid concomitant use of Noxafil oral suspension with cimetidine or esomeprazole unless the benefit outweighs the risks. If concomitant use is needed, monitor closely for breakthrough fungal infections.
Metoclopramide
Mechanism and Clinical Effect(s)Concomitant use of Noxafil oral suspension with metoclopramide decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce effectiveness of Noxafil oral suspension.
Prevention or ManagementIf Noxafil oral suspension is concomitantly administered with metoclopramide, closely monitor for breakthrough fungal infections.
Noxafil Oral PowderMix
Alcohol
Mechanism and Clinical Effect(s)Posaconazole releases faster from Noxafil PowderMix in the presence of alcohol, which may interfere with Noxafil PowderMix’s delayed-release characteristics [see Clinical Pharmacology (12.3)].
Prevention or ManagementAdministration of Noxafil PowderMix with alcohol is not recommended.
", "
Table 17: Drug Interactions Affecting Drugs Administered Concomitantly with Noxafil and Noxafil PowderMix
Digoxin
Clinical Effect(s)Increased digoxin plasma concentrations have been reported in patients who received concomitant posaconazole and digoxin.
Prevention or ManagementMonitor digoxin plasma concentrations during concomitant use of posaconazole.
Glipizide
Clinical Effect(s)No dosage modification of glipizide is needed when used concomitantly with Noxafil. However, glucose concentrations decrease in some patients concomitantly administered posaconazole and glipizide.
Prevention or ManagementIncrease monitoring of glucose concentrations when used concomitantly.
CYP3A Substrates
Immunosuppressants that are CYP3A4 Substrates
Mechanism and Clinical Effect(s)Posaconazole is a strong CYP3A4 inhibitor. Therefore, plasma concentrations of CYP3A4 substrates may be increased by posaconazole use [see Clinical Pharmacology (12.3)].
Prevention or ManagementSirolimusPosaconazole is contraindicated with sirolimus [see Clinical Pharmacology (12.3)].
Tacrolimus• At initiation of posaconazole treatment, reduce the tacrolimus dosage to approximately one-third of the original tacrolimus dosage. • Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dosage should be modified accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Cyclosporine• At initiation of posaconazole treatment reduce the cyclosporine dosage to approximately three-fourths of the original dosage. • Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dosage should be modified accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
CYP3A4 Substrates that Prolong QTc Interval
Mechanism and Clinical Effect(s)Concomitant use of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of the CYP3A4 substrates leading to QTc interval prolongation and torsades de pointes [see Warnings and Precautions (5.2)].
Prevention or ManagementPimozideConcomitant use with posaconazole is contraindicated.
Quinidine
HMG-CoA Reductase Inhibitors (Statins) that are CYP3A4 Substrates
Mechanism and Clinical Effect(s)Concomitant use of posaconazole with simvastatin increased simvastatin plasma concentrations which can lead to rhabdomyolysis [see Clinical Pharmacology (12.3)].
Prevention or ManagementAtorvastatin, Lovastatin, SimvastatinConcomitant use with posaconazole is contraindicated.
Benzodiazepines that are CYP3A4 Substrates
Mechanism and Clinical Effect(s)Concomitant use of posaconazole with midazolam increased midazolam plasma concentrations which could potentiate and prolong hypnotic and sedative effects [see Clinical Pharmacology (12.3)].
Prevention or ManagementMidazolam, Alprazolam, TriazolamClosely monitor for adverse reactions associated with high plasma concentrations of benzodiazepines that are CYP3A4 substrates during concomitant use, and a benzodiazepine receptor antagonist should be available to reverse effects [see Warnings and Precautions (5.7)].
Calcium Channel Blockers that are CYP3A4 Substrates
Mechanism and Clinical Effect(s)Posaconazole may increase the plasma concentrations of calcium channel blockers that are substrates of CYP3A4.
Prevention or ManagementVerapamil, Diltiazem, Nifedipine, Nicardipine, FelodipineMonitor frequently for adverse reactions and toxicity with concomitant use of posaconazole with calcium channel blockers that are CYP3A4 substrates. Dosage reduction of the calcium channel blocker may be needed.
Anti-HIV Drugs that are CYP3A4 Substrates
Mechanism and Clinical Effect(s)Ritonavir and atazanavir are CYP3A4 substrates and posaconazole increased plasma concentrations of these drugs [see Clinical Pharmacology (12.3)].
Prevention or ManagementRitonavir and AtazanavirMonitor frequently for adverse reactions and toxicity of ritonavir and atazanavir during concomitant use.
Antineoplastic Drugs that are CYP3A4 Substrates
Mechanism and Clinical Effect(s)Posaconazole may increase plasma concentrations of oncology drugs that are CYP3A4 substrates, which may increase the risk of serious adverse reactions.
Prevention or ManagementVenetoclaxCLL/SLL patients: Concomitant use of posaconazole with venetoclax during initiation and ramp-up phase is contraindicated. AML patients: With concomitant use, venetoclax dosage reduction and safety monitoring is recommended across all dosing phases [see Warnings and Precautions (5.11)].
Vinca alkaloids (e.g., vincristine, vinblastine)Reserve concomitant use for patients with no alternative antifungal treatment options [see Warnings and Precautions (5.8)].
Ergot Alkaloids
Mechanism and Clinical Effect(s)Most of the ergot alkaloids are CYP3A4 substrates. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism.
Prevention or ManagementErgotamine, DihydroergotamineConcomitant use with posaconazole is contraindicated.
Phenytoin
Mechanism and Clinical Effect(s)Phenytoin is a CYP3A4 substrate. Concomitant use of posaconazole with phenytoin increased phenytoin plasma concentrations [see Clinical Pharmacology (12.3)].
Prevention or ManagementAvoid concomitant use of posaconazole with phenytoin unless the benefit outweighs the risk. frequently monitor phenytoin concentrations and consider a dosage reduction of phenytoin. See Table 15 for additional monitoring considerations when phenytoin affects posaconazole via UDP-glucuronosyltransferase inhibition.
Rifabutin
Mechanism and Clinical Effect(s)Rifabutin is a CYP3A4 substrate. Concomitant use of posaconazole with rifabutin increased rifabutin plasma concentrations [see Clinical Pharmacology (12.3)].
Prevention or ManagementAvoid concomitant use of posaconazole with rifabutin unless the benefit outweighs the risk. Frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) during concomitant use are recommended. See Table 15 for additional monitoring considerations when rifabutin affects posaconazole via UDP-glucuronosyltransferase inhibition.
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) Pediatrics: Safety and effectiveness in patients younger than 2 years of age have not been established. ( 8.4 ) Severe Renal Impairment: Monitor closely for breakthrough fungal infections. ( 8.6 ) 8.1 Pregnancy Risk Summary Based on findings from animal data, Noxafil may cause fetal harm when administered to pregnant women. Available data for use of Noxafil in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, skeletal malformations were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses ≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of Noxafil in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, doses of ≥ 3 times the clinical exposure caused an increase in resorptions (see Data ) . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data : Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen. 8.2 Lactation Risk Summary There are no data on the presence of posaconazole in human milk, the effects on the breastfed infant, or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Noxafil and any potential adverse effects on the breastfed child from Noxafil or from the underlying maternal condition. 8.4 Pediatric Use The three Noxafil dosage forms (injection, delayed-release tablets, oral suspension) and one Noxafil PowderMix (for delayed-release oral suspension) dosage form are different products; are approved for different pediatric indications, age groups, and weights; have different dosing regimens; and have different preparation and administration instructions. Therefore, select the recommended dosage form based on the pediatric indication, age group, and weight [see Dosage and Administration (2.1) ]. Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with HFI. Because a diagnosis of HFI may not yet be established in pediatric patients, obtain a 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 (5.9) ]. Treatment of Invasive Aspergillosis The safety and effectiveness of Noxafil (injection and delayed-release tablets) have been established for the treatment of invasive aspergillosis in pediatric patients 2 years of age and older . The safety and effectiveness of Noxafil PowderMix have been established for the treatment of invasive aspergillosis in pediatric patients 2 years of age and older who weigh 10 kg to 40 kg. Use of Noxafil and Noxafil PowderMix for these pediatric indications is supported by evidence from adequate and well-controlled studies of Noxafil in adults and safety and pharmacokinetic (PK) data from two pediatric studies [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] . The safety of Noxafil and Noxafil PowderMix in pediatric patients for these pediatric indications was consistent with the known safety profile of Noxafil in adults [see Adverse Reactions (6.1) ]. 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 dosage form. The safety and effectiveness of Noxafil and Noxafil PowderMix have not been established in pediatric patients less than 2 years of age . Prophylaxis of Invasive Aspergillus and Candida Infections The safety and effectiveness of Noxafil (injection and delayed-release tablets) have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 2 years of age and older who are at high risk of developing these infections due to being severely immunocompromised. The safety and effectiveness of Noxafil oral suspension have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 13 years of age and older who are at high risk of developing these infections due to being severely immunocompromised. The safety and effectiveness of Noxafil PowderMix have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 2 years of age and older who weigh 10 kg to 40 kg who are at high risk of developing these infections due to being severely immunocompromised. Use of Noxafil and Noxafil PowderMix for these pediatric indications is supported by adequate and well controlled studies of Noxafil in adults and pediatric patients aged 13 years of age and older and additional PK and safety data in pediatric patients 2 years of age and older [see Clinical Pharmacology (12.3) and Clinical studies (14) ]. Noxafil PowderMix is not recommended for use in patients who weigh greater than 40 kg because the recommended dosage cannot be achieved with this dosage form. The safety and effectiveness of Noxafil and Noxafil PowderMix have not been established in pediatric patients less than 2 years of age. Treatment of Oropharyngeal Candidiasis, including Refractory to Itraconazole and/or Fluconazole 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 13 years of age and older. Use of Noxafil oral suspension for this pediatric indication is supported by adequate and well controlled studies in adults and pediatric patients 13 years of age and older [see Clinical studies (14.4) ]. The Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix products are not approved for the treatment of oropharyngeal candidiasis in pediatric patients. Noxafil Oral Suspension is the only dosage form approved for the treatment of OPC and rOPC in pediatric patients [see Dosage and Administration (2.4) ]. The safety and effectiveness of Noxafil oral suspension for the treatment of OPC and rOPC have not been established in pediatric patients less than 13 years of age. 8.5 Geriatric Use No overall differences in the safety or effectiveness of Noxafil injection, Noxafil delayed-release tablets, and Noxafil oral suspension have been observed between geriatric patients and younger adult patients in the clinical trials; therefore, the recommended dosage in geriatric patients is the same as that for younger adult patients. No clinically meaningful differences in posaconazole pharmacokinetics were observed in Noxafil-treated geriatric patients compared to Noxafil-treated younger adult patients during clinical trials [see Clinical Pharmacology (12.3) ] . Of the 279 patients treated with Noxafil injection in the Noxafil Injection Study (prophylaxis of invasive Aspergillus and Candida infections in those at high risk of developing these infections due to being severely immunocompromised), 52 (19%) patients were >65 years of age. Of the 230 patients treated with Noxafil delayed-release tablets, 38 (17%) patients were >65 years of age. Of the 605 patients treated with Noxafil oral suspension in Noxafil Oral Suspension Study 1 and Study 2 (prophylaxis of invasive Aspergillus and Candida infections in those at high risk of developing these infections due to being severely immunocompromised), 63 (10%) patients were ≥65 years of age. In studies of Noxafil for an unapproved indication, 48 patients treated with Noxafil oral suspension (greater than or equal to 800 mg/day (eight times the maximum recommended maintenance dosage for the treatment of OPC)) were ≥65 years of age. Of the 288 patients treated with Noxafil injection or Noxafil delayed-release tablets in the Aspergillosis Treatment Study, 85 (29%) patients were ≥65 years of age. 8.6 Renal Impairment Noxafil Oral Suspension and Noxafil Delayed-Release Tablets No dosage adjustment is required for patients with eGFR 20 mL/minute/1.73 m 2 or higher. Due to variability in posaconazole exposure, closely monitor patients with eGFR less than 20 mL/minute/1.73 m 2 for breakthrough fungal infections. [see Clinical Pharmacology (12.3) ] . Noxafil Injection Avoid use of Noxafil injection in patients with eGFR less than 50 mL/minute/1.73 m 2 unless the benefit/risk to the patient justifies its use. The inactive ingredient in Noxafil injection, Betadex Sulfobutyl Ether Sodium (SBECD) is expected to accumulate in patients with reduced renal function. Safety and effectiveness of Noxafil injection have not been established in patients with less than 50 mL/minute/1.73 m 2 . If treatment with Noxafil injection is unavoidable in patients with eGFR less than 50 mL/minute/1.73 m 2 , monitor serum creatinine levels. If serum creatinine increases, consider changing to oral Noxafil therapy. 8.7 Hepatic Impairment No dosage adjustment is recommended for Noxafil oral suspension, Noxafil delayed-release tablets, Noxafil PowderMix for delayed-release oral suspension, and Noxafil injection in patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C, respectively) [see Clinical Pharmacology (12.3) ] . However, a specific hepatic impairment study has not been conducted with the Noxafil delayed-release tablets, Noxafil PowderMix for delayed-release oral suspension, or Noxafil injection. 8.8 Sex No adjustment in the dosage of Noxafil is necessary based on sex. 8.9 Race No adjustment in the dosage of Noxafil is necessary based on race. 8.10 Weight Pharmacokinetic modeling suggests that patients who weigh greater than 120 kg may have lower posaconazole plasma drug exposure. Therefore, consider closely monitoring for breakthrough fungal infections particularly when using Noxafil oral suspension in patients weighing greater than 120 kg [see Clinical Pharmacology (12.3) ] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Based 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 a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, skeletal malformations were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses ≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of Noxafil in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, doses of ≥ 3 times the clinical exposure caused an increase in resorptions (see Data ) . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data : Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen." ], "pediatric_use": [ "8.4 Pediatric Use The three Noxafil dosage forms (injection, delayed-release tablets, oral suspension) and one Noxafil PowderMix (for delayed-release oral suspension) dosage form are different products; are approved for different pediatric indications, age groups, and weights; have different dosing regimens; and have different preparation and administration instructions. Therefore, select the recommended dosage form based on the pediatric indication, age group, and weight [see Dosage and Administration (2.1) ]. Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with HFI. Because a diagnosis of HFI may not yet be established in pediatric patients, obtain a 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 (5.9) ]. Treatment of Invasive Aspergillosis The safety and effectiveness of Noxafil (injection and delayed-release tablets) have been established for the treatment of invasive aspergillosis in pediatric patients 2 years of age and older . The safety and effectiveness of Noxafil PowderMix have been established for the treatment of invasive aspergillosis in pediatric patients 2 years of age and older who weigh 10 kg to 40 kg. Use of Noxafil and Noxafil PowderMix for these pediatric indications is supported by evidence from adequate and well-controlled studies of Noxafil in adults and safety and pharmacokinetic (PK) data from two pediatric studies [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] . The safety of Noxafil and Noxafil PowderMix in pediatric patients for these pediatric indications was consistent with the known safety profile of Noxafil in adults [see Adverse Reactions (6.1) ]. 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 dosage form. The safety and effectiveness of Noxafil and Noxafil PowderMix have not been established in pediatric patients less than 2 years of age . Prophylaxis of Invasive Aspergillus and Candida Infections The safety and effectiveness of Noxafil (injection and delayed-release tablets) have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 2 years of age and older who are at high risk of developing these infections due to being severely immunocompromised. The safety and effectiveness of Noxafil oral suspension have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 13 years of age and older who are at high risk of developing these infections due to being severely immunocompromised. The safety and effectiveness of Noxafil PowderMix have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 2 years of age and older who weigh 10 kg to 40 kg who are at high risk of developing these infections due to being severely immunocompromised. Use of Noxafil and Noxafil PowderMix for these pediatric indications is supported by adequate and well controlled studies of Noxafil in adults and pediatric patients aged 13 years of age and older and additional PK and safety data in pediatric patients 2 years of age and older [see Clinical Pharmacology (12.3) and Clinical studies (14) ]. Noxafil PowderMix is not recommended for use in patients who weigh greater than 40 kg because the recommended dosage cannot be achieved with this dosage form. The safety and effectiveness of Noxafil and Noxafil PowderMix have not been established in pediatric patients less than 2 years of age. Treatment of Oropharyngeal Candidiasis, including Refractory to Itraconazole and/or Fluconazole 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 13 years of age and older. Use of Noxafil oral suspension for this pediatric indication is supported by adequate and well controlled studies in adults and pediatric patients 13 years of age and older [see Clinical studies (14.4) ]. The Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix products are not approved for the treatment of oropharyngeal candidiasis in pediatric patients. Noxafil Oral Suspension is the only dosage form approved for the treatment of OPC and rOPC in pediatric patients [see Dosage and Administration (2.4) ]. The safety and effectiveness of Noxafil oral suspension for the treatment of OPC and rOPC have not been established in pediatric patients less than 13 years of age." ], "geriatric_use": [ "8.5 Geriatric Use No overall differences in the safety or effectiveness of Noxafil injection, Noxafil delayed-release tablets, and Noxafil oral suspension have been observed between geriatric patients and younger adult patients in the clinical trials; therefore, the recommended dosage in geriatric patients is the same as that for younger adult patients. No clinically meaningful differences in posaconazole pharmacokinetics were observed in Noxafil-treated geriatric patients compared to Noxafil-treated younger adult patients during clinical trials [see Clinical Pharmacology (12.3) ] . Of the 279 patients treated with Noxafil injection in the Noxafil Injection Study (prophylaxis of invasive Aspergillus and Candida infections in those at high risk of developing these infections due to being severely immunocompromised), 52 (19%) patients were >65 years of age. Of the 230 patients treated with Noxafil delayed-release tablets, 38 (17%) patients were >65 years of age. Of the 605 patients treated with Noxafil oral suspension in Noxafil Oral Suspension Study 1 and Study 2 (prophylaxis of invasive Aspergillus and Candida infections in those at high risk of developing these infections due to being severely immunocompromised), 63 (10%) patients were ≥65 years of age. In studies of Noxafil for an unapproved indication, 48 patients treated with Noxafil oral suspension (greater than or equal to 800 mg/day (eight times the maximum recommended maintenance dosage for the treatment of OPC)) were ≥65 years of age. Of the 288 patients treated with Noxafil injection or Noxafil delayed-release tablets in the Aspergillosis Treatment Study, 85 (29%) patients were ≥65 years of age." ], "overdosage": [ "10 OVERDOSAGE 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 1,600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg twice daily Noxafil oral suspension for 3 days. No related adverse reactions were noted by the investigator. Posaconazole is not removed by hemodialysis." ], "description": [ "11 DESCRIPTION Noxafil and Noxafil PowderMix contain posaconazole, an azole antifungal agent. Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3 R ,5 R )-5- (2,4-difluorophenyl)tetrahydro-5- (1 H -1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1 S ,2 S )-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3 H -1,2,4-triazol-3-one with an empirical formula of C 37 H 42 F 2 N 8 O 4 and a molecular weight of 700.8. The chemical structure is: Posaconazole is a white powder with a low aqueous solubility. Noxafil (posaconazole) Injection Noxafil injection, for intravenous use, is a clear colorless to yellow, without preservatives sterile liquid essentially free of foreign matter. Each vial contains 300 mg of posaconazole and the following inactive ingredients: 6.68 g Betadex Sulfobutyl Ether Sodium (SBECD), 0.0033 g edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6, and water for injection. Noxafil (posaconazole) Delayed-Release Tablets Noxafil delayed-release tablet, for oral use, is yellow, coated, and oblong and contains 100 mg of posaconazole. Each delayed-release tablet contains the following 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 (posaconazole) Oral Suspension Noxafil oral suspension is a white, cherry-flavored immediate-release suspension that contains 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 (posaconazole) for Delayed-Release Oral Suspension Noxafil PowderMix for delayed-release oral suspension is supplied as a component of a kit. Each kit contains Noxafil as an off-white to yellowish powder for delayed-release oral suspension, a bottle of mixing liquid, two 3 mL (green) notched tip syringes, two 10 mL (blue) notched tip syringes, two mixing cups, and one bottle adapter for the mixing liquid bottle. Noxafil PowderMix for delayed-release oral suspension contains 300 mg of posaconazole and the following inactive ingredient: hypromellose acetate succinate. The mixing liquid contains: anhydrous citric acid, antifoam Af emulsion, berry citrus sweet flavor, carboxymethylcellulose sodium, carrageenan calcium sulfate trisodium phosphate, glycerin, methylparaben, microcrystalline cellulose, potassium sorbate, propylparaben, purified water, sodium citrate, sodium phosphate monobasic monohydrate, sodium saccharin, sorbitol solution, and xanthan gum. Chemical Structure" ], "description_table": [ "
" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4) ] . 12.2 Pharmacodynamics Exposure Response Relationship: Prophylaxis of invasive Aspergillus and Candida Infections in Adults Who Are at High Risk of Developing These Infections Due to Being Severely Immunocompromised 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), a wide range of plasma posaconazole exposures was noted following administration of Noxafil oral suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 18). A 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 18: Noxafil Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials Cavg = the average posaconazole concentration when measured at steady state Prophylaxis in AML/MDS Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS Prophylaxis in GVHD HSCT recipients with GVHD Cavg Range (ng/mL) Treatment Failure Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections (%) Cavg Range (ng/mL) Treatment Failure (%) Quartile 1 90-322 54.7 22-557 44.4 Quartile 2 322-490 37.0 557-915 20.6 Quartile 3 490-734 46.8 915-1563 17.5 Quartile 4 734-2200 27.8 1563-3650 17.5 Exposure Response Relationship: Treatment of Invasive Aspergillosis in Adult and Adolescent Patients: Across a range of posaconazole plasma minimum concentrations (C min , range: 244 to 5663 ng/mL) following administration of Noxafil injection and Noxafil delayed-release tablets in adult and pediatric patients aged 14 years and older treated for invasive aspergillosis in Aspergillosis Treatment Study, there was no association between posaconazole C min and treatment efficacy [see Clinical Pharmacology (12.3) and Clinical Studies (14.1) ] . Similarly, across a range of population pharmacokinetic model-predicted steady-state plasma average concentrations (Cavg, range: 589 to 6315 ng/mL), there was no association between posaconazole Cavg and treatment efficacy. 12.3 Pharmacokinetics General Pharmacokinetic Characteristics General Pharmacokinetic Characteristics of Noxafil Injection Noxafil 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 19. Table 19: 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 1 Dose (mg) n AUC 0-∞ (ng∙hr/mL) AUC 0-12 (ng∙hr/mL) C max (ng/mL) t 1/2 (hr) CL (L/hr) AUC 0-∞ = Area under the plasma concentration-time curve from time zero to infinity; AUC 0-12 = Area under the plasma concentration-time curve from time zero to 12 hr after the first dose on Day 1; C max = maximum observed concentration; t ½ = terminal phase half-life; CL = total body clearance; N/D = Not Determined Healthy Volunteers 200 9 35400 (50) 8840 (20) 2250 (29) 23.6 (23) 6.5 (32) 300 9 46400 (26) 13000 (13) 2840 (30) 24.6 (20) 6.9 (27) Patients 200 30 N/D 5570 (32) 954 (44) N/D N/D 300 22 N/D 8240 (26) 1590 (62) N/D N/D Table 20 displays the pharmacokinetic parameters of posaconazole in patients following administration of Noxafil injection 300 mg taken once a day for 10 or 14 days following twice daily dosing on Day 1. Table 20: 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 a day following twice daily dosing on Day 1 Day N C max (ng/mL) T max Median (minimum-maximum) (hr) AUC 0-24 (ng*hr/mL) Cav (ng/mL) C min (ng/mL) AUC 0-24 = area under the concentration-time curve over the dosing interval (i.e., 24 hours); Cav= time-averaged concentrations (i.e., AUC 0-24h /24hr); C min = POS trough level immediately before a subject received the dose of POS on the day specified in the protocol; C max = observed maximum plasma concentration; CV = coefficient of variation, expressed as a percent (%); Day = study day on treatment; T max = time of observed maximum plasma concentration. 10/14 49 3280 (74) 1.5 (0.98-4.0) 36100 (35) 1500 (35) 1090 (44) General Pharmacokinetic Characteristics of Noxafil Delayed-Release Tablets Noxafil 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 21. Table 21: 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 N AUC 0-24 hr (ng∙hr/mL) Cav Cav = time-averaged concentrations (i.e., AUC 0-24 hr/24 hr ) (ng/mL) C max (ng/mL) C min (ng/mL) T max Median (minimum-maximum) (hr) t 1/2 (hr) CL/F (L/hr) CV = coefficient of variation expressed as a percentage (%CV); AUC 0-T = Area under the plasma concentration-time curve from time zero to 24 hr; C max = maximum observed concentration; C min = minimum observed plasma concentration; T max = time of maximum observed concentration; t ½ = terminal phase half-life; CL/F = Apparent total body clearance Healthy Volunteers 12 51618 (25) 2151 (25) 2764 (21) 1785 (29) 4 (3-6) 31 (40) 7.5 (26) Patients 50 37900 (42) 1580 (42) 2090 (38) 1310 (50) 4 (1.3-8.3) - 9.39 (45) General Pharmacokinetic Characteristics of Noxafil Oral Suspension Dose-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 a day and 400 mg twice daily of the oral suspension are provided in Table 22. Table 22: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Noxafil Oral Suspension 200 mg Three Times a Day and 400 mg Twice Daily Dose Oral suspension administration Cavg (ng/mL) AUC AUC (0-24 hr) for 200 mg three times a day and AUC (0-12 hr) for 400 mg twice daily (ng∙hr/mL) CL/F (L/hr) V/F (L) t ½ (hr) Cavg = the average posaconazole concentration when measured at steady state The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects. 200 mg three times a day HSCT recipients with GVHD (n=252) 1103 (67) [21.5-3650] ND Not done ND ND ND 200 mg three times a day Neutropenic 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 daily Febrile 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: Absorption of Noxafil Delayed-Release Tablets When given orally in healthy volunteers, Noxafil delayed-release tablets are absorbed with a median T max of 4 to 5 hours. Steady-state plasma concentrations are attained by Day 6 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 C max and AUC of posaconazole following administration of Noxafil delayed-release tablets are increased 16% and 51%, respectively, when given with a high fat meal compared to a fasted state (see Table 23 ). Table 23: 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 Conditions Fasting Conditions Fed Conditions (High Fat Meal) 48.5 g fat Fed/Fasting Pharmacokinetic Parameter N Mean (%CV) N Mean (%CV) GMR (90% CI) GMR=Geometric least-squares mean ratio; CI=Confidence interval C max (ng/mL) 14 935 (34) 16 1060 (25) 1.16 (0.96, 1.41) AUC 0-72hr (hr∙ng/mL) 14 26200 (28) 16 38400 (18) 1.51 (1.33, 1.72) T max Median (Min, Max) reported for T max (hr) 14 5.00 (3.00, 8.00) 16 6.00 (5.00, 24.00) N/A Absorption of Noxafil PowderMix for Delayed-Release Oral Suspension The 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. Absorption of Noxafil Oral Suspension Noxafil oral suspension is absorbed with a median T max of ~3 to 5 hours. Steady-state plasma concentrations are attained at 7 to 10 days following multiple-dose administration. Following single-dose administration of 200 mg, the mean AUC and C max of posaconazole are approximately 3 times higher when the oral suspension is administered with a nonfat meal and approximately 4 times higher when administered with a 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 C max of posaconazole are approximately 3 times higher when administered with a 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 C max and AUC of Noxafil oral suspension in healthy volunteers have been investigated and are shown in Table 25. To assure attainment of adequate plasma concentrations, it is recommended to administer Noxafil oral suspension during or immediately following a full meal. In patients who cannot eat a full meal, Noxafil oral suspension should be taken with a 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 Conditions Dose (mg) C max (ng/mL) T max Median [min-max]. (hr) AUC (I) (ng∙hr/mL) CL/F (L/hr) t ½ (hr) 200 mg fasted (n=20) n=15 for AUC (I), CL/F, and t ½ 132 (50) [45-267] 3.50 [1.5-36 The subject with T max of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between 4 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 t ½ 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 C max and AUC of Noxafil Oral Suspension in Healthy Volunteers In 5 subjects, the C max 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 a lower plasma exposure may be associated with an increased risk of treatment failure. Study Description Administration Arms Change in C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for C max or AUC. ; 90% CI of the ratio estimate) Change in AUC (ratio estimate ; 90% CI of the ratio estimate) 400 mg single dose with a high-fat meal relative to fasted state (n=12) 5 minutes before high-fat meal ↑96% (1.96; 1.48-2.59) ↑111% (2.11; 1.60-2.78) During high-fat meal ↑339% (4.39; 3.32-5.80) ↑382% (4.82; 3.66-6.35) 20 minutes after high-fat meal ↑333% (4.33; 3.28-5.73) ↑387% (4.87; 3.70-6.42) 400 mg twice daily and 200 mg four times daily for 7 days in fasted state and with liquid nutritional supplement (BOOST ® ) (n=12) 400 mg twice daily with BOOST ↑65% (1.65; 1.29-2.11) ↑66% (1.66; 1.30-2.13) 200 mg four times daily with BOOST No Effect No Effect Divided daily dose from 400 mg twice daily to 200 mg four times daily for 7 days regardless of fasted conditions or with BOOST (n=12) Fasted state ↑136% (2.36; 1.84-3.02) ↑161% (2.61; 2.04-3.35) With BOOST ↑137% (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 ale ↑92% (1.92; 1.51-2.44) ↑70% (1.70; 1.43-2.03) Esomeprazole ↓32% (0.68; 0.53-0.86) ↓30% (0.70; 0.59-0.83) 400 mg single dose with a prokinetic agent (metoclopramide 10 mg three times a day for 2 days) + BOOST or an antikinetic agent (loperamide 4 mg single dose) + BOOST (n=12) With metoclopramide + BOOST ↓21% (0.79; 0.72-0.87) ↓19% (0.81; 0.72-0.91) With loperamide + BOOST ↓3% (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 tube NG = nasogastric ↓19% (0.81; 0.71-0.91) ↓23% (0.77; 0.69-0.86) Distribution: The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226-295 L between studies and dose levels. Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin. Metabolism: Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. Posaconazole is a substrate for p-glycoprotein (P-gp) efflux. In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. 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 a 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 a mean terminal half-life (t ½ ) of 27 hours and a total body clearance (CL) of 7.3 L/h. Noxafil delayed-release tablet is eliminated with a mean half-life (t ½ ) ranging between 26 to 31 hours. Noxafil oral suspension is eliminated with a mean half-life (t ½ ) of 35 hours (range: 20-66 hours). Specific Populations: No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment). Patients with Renal Impairment: After Noxafil oral administration, there were no significant differences in the posaconazole pharmacokinetics in patients with eGFR 20 mL/minute/1.73 m 2 or higher compared to those with eGFR >80 mL/minute/1.73 m 2 . Although the mean posaconazole plasma exposure (AUC) was similar in patients with eGFR less than 20 mL/minute/1.73 m 2 treated with Noxafil oral suspension to those with eGFR >80 mL/minute/1.73 m 2 treated with Noxafil oral suspension, the range of the AUC estimates was highly variable (CV=96%) in patients with eGFR less than 20 mL/minute/1.73 m 2 compared to those with eGFR >80 mL/minute/1.73 m 2 (CV<40%).Similar posaconazole pharmacokinetic results are expected after administration of Noxafil delayed-release tablets [see Use in Specific Populations (8.6) ]. Patients with Hepatic Impairment: After a 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 C max was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively [see Use in Specific Populations (8.7) ]. Race/Ethnicity: In a population pharmacokinetic analysis of posaconazole, AUC was found to be 25% higher in Chinese patients relative to patients from other races/ethnicities. This higher exposure is not expected to be clinically relevant given the expected variability in posaconazole exposure [see Use in Specific Populations (8.9) ] . Patients Weighing More Than 120 kg: Weight has a clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered 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 Patients: Prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 2 years of age and older: A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a 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 a 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. The mean pharmacokinetic parameters after multiple-dose administration of Noxafil injection and Noxafil PowderMix for delayed-release oral suspension in neutropenic pediatric patients 2 to less than 18 years of age (Pediatric Study 1) are shown in Table 26. Patients were enrolled into 2 age groups and received Noxafil injection and Noxafil PowderMix for delayed-release oral suspension doses at 6 mg/kg (0.6 to 1 times the recommended dose) with a maximum 300 mg dose once daily (twice daily on Day 1) [see Adverse Reactions (6.1) ] . Table 26: Summary of Steady-State Geometric Mean Pharmacokinetic Parameters (% Geometric CV) After Multiple Dosing with Noxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension 6 mg/kg 0.6 to 1 times the recommended dose in Pediatric Patients with Neutropenia or Expected Neutropenia Age Group Dose Type N AUC 0-24 hr (ng·hr/mL) Cav Cav = time-averaged concentrations (i.e., AUC 0-24 hr/24 hr ) (ng/mL) C max (ng/mL) C min (ng/mL) T max Median (minimum-maximum) (hr) CL/F Clearance (CL for IV and CL/F for PFS) (L/hr) IV= Noxafil injection; PFS= Noxafil PowderMix for delayed-release oral suspension; AUC 0-24 = Area under the plasma concentration-time curve from time zero to 24 hr; C max = maximum observed concentration; C min = minimum observed plasma concentration; T max = time of maximum observed concentration; CL/F = apparent total body clearance 2 to <7 years IV 17 31100 (48.9) 1300 (48.9) 3060 (54.1) 626 (104.8) 1.75 (1.57-1.83) 3.27 (49.3) PFS 7 23000 (47.3) 960 (47.3) 1510 (43.4) 542 (68.8) 4.00 (2.17-7.92) 4.60 (35.2) 7 to 17 years IV 24 44200 (41.5) 1840 (41.5) 3340 (39.4) 1160 (60.4) 1.77 (1.33-6.00) 4.76 (55.7) PFS 12 25000 (184.3) 1040 (184.3) 1370 (178.5) 713 (300.6) 2.78 (0.00-4.00) 8.39 (190.3) Based on a population pharmacokinetic model evaluating posaconazole pharmacokinetics and predicting exposures in pediatric patients, the exposure of steady-state posaconazole average concentration greater than or equal to 700 ng/mL in approximately 90% of patients is attained with the recommended dose of Noxafil injection and Noxafil PowderMix for delayed-release oral suspension. The population pharmacokinetic analysis of posaconazole in pediatric patients from Pediatric Study 1 suggests that age, sex, renal impairment and ethnicity have no clinically meaningful effect on the pharmacokinetics of posaconazole. Treatment of invasive aspergillosis in pediatric patients 2 years of age and older: A total of 31 patients 2 to less than 18 years of age (body weight of ≥12 kg) received pediatric dosing based on body weight of Noxafil delayed-release tablets, Noxafil Injection, and Noxafil PowderMix for delayed-release oral suspension [see Dosage and Administration (2.3 ]. The mean population pharmacokinetic model parameters after multiple dose administration of Noxafil delayed-release tablets, Noxafil Injection, and Noxafil PowderMix for delayed-release oral suspension in pediatric patients 2 to less than 18 years of age for the treatment of invasive aspergillosis (Pediatric Study 2) are shown in Table 27. [see Adverse Reactions (6.1) ] . Table 27: Summary of Steady-State Geometric Mean Pharmacokinetic Parameters Parameter estimates reported only for N>2 (excludes a single patient ≥2 to <12 receiving tablet and 2 patients ≥12 to <18 years receiving PFS) (% Geometric CV) After Multiple Dosing with Noxafil Injection, Noxafil PowderMix for Delayed-Release Oral Suspension, and Noxafil Delayed-Release Tablets in Pediatric Patients being Treated for Invasive Aspergillosis Age Group Dose Type N Some patients had 2 values (1 for IV dosing and 1 for oral dosing) AUC 0-24 hours (ng·hr/mL) C av Cav = time-averaged concentrations (i.e., AUC 0-24 hours /24hr) (ng/mL) C max (ng/mL) C min (ng/mL) T max Median (minimum-maximum) (hr) CL/F Clearance (CL for IV and CL/F for PFS or Tablet) (L/hr) IV = Noxafil injection; PFS = Noxafil PowderMix for delayed-release oral suspension; Tablet = Noxafil delayed-release tablets; AUC 0-24 hours = Area under the plasma concentration-time curve from time zero to 24 hr; C max = maximum observed concentration; C min = minimum observed plasma concentration; T max = time of maximum observed concentration; CL/F = apparent total body clearance 2 to <12 years IV 9 61900 (49.8) 2580 (49.8) 3630 (30.8) 1710 (82.2) 1.50 (1.25-1.77) 2.56 (47.8) PFS 6 45200 (30.2) 1880 (30.2) 2220 (26.5) 1370 (41.8) 7.00 (6.40-7.20) 3.25 (34.6) 12 to <18 years IV 13 60800 (35.6) 2530 (35.6) 3510 (26.8) 1740 (48.5) 1.50 (1.30-1.63) 4.41 (41.8) Tablet 10 47800 (52.7) 1990 (52.7) 2250 (48.3) 1580 (62.6) 7.15 (6.70-7.30) 6.27 (52.7) The population pharmacokinetic analysis of posaconazole in pediatric patients, including Pediatric Study 2, suggests that age, sex, ethnicity, and disease status have no clinically meaningful effect on the pharmacokinetics of posaconazole Drug Interaction Studies: Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically with the oral suspension or another tablet formulation, which affect posaconazole concentrations, is provided in Table 28. Table 29 and Table 30 include a summary of the drug effects of concomitant medications that may impact the absorption of posaconazole when administered as either the oral suspension or delayed-release tablets. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 31 [see Contraindications (4) and Drug Interactions (7.2) including recommendations ] . Effects of Other Drugs on Noxafil and Noxafil PowderMix: Table 28: Summary of the Effects of Coadministered Drugs on Noxafil in Healthy Volunteers Coadministered Drug (Postulated Mechanism of Interaction) Coadministered Drug Dose/Schedule Noxafil Dose/Schedule Effect on Bioavailability of Posaconazole Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to Noxafil alone for C max 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 days 400 mg (oral suspension) twice daily × 10 and 20 days ↓45% (0.55; 0.47-0.66) ↓ 50% (0.50; 0.43-0.60) Fosamprenavir (unknown mechanism) 700 mg twice daily × 10 days 200 mg once daily on the 1 st day, 200 mg twice daily on the 2 nd day, then 400 mg twice daily × 8 Days ↓21% 0.79 (0.71-0.89) ↓23% 0.77 (0.68-0.87) Rifabutin (UDP-G Induction) 300 mg once daily × 17 days 200 mg (tablets) once daily × 10 days The tablet refers to a 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 days 200 mg (tablets) once daily × 10 days ↓ 41% (0.59; 0.44-0.79) ↓ 50% (0.50; 0.36-0.71) Noxafil Oral Suspension: Concomitant administration of Noxafil oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (see Table 29 .) Table 29: The Effects of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Oral Suspension in Healthy Volunteers Coadministered Drug (Postulated Mechanism of Interaction) Coadministered Drug Dose/Schedule Noxafil Dose/Schedule Effect on Bioavailability of Posaconazole Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for C max 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 days 200 mg (tablets) once daily × 10 days The tablet refers to a 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 days 400 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 a day × 2 days 400 mg (oral suspension) single dose ↓ 21% (0.79; 0.72-0.87) ↓ 19% (0.81; 0.72-0.91) Noxafil Delayed-Release Tablets: Concomitant 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 30 ). Table 30: The Effects of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Delayed-Release Tablets in Healthy Volunteers Coadministered Drug Administration Arms Change in C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to Noxafil alone for C max or AUC 0-last . ; 90% CI of the ratio estimate) Change in AUC 0-last (ratio estimate ; 90% CI of the ratio estimate) Mylanta ® Ultimate strength liquid (Increase in gastric pH) 25.4 mEq/5 mL, 20 mL ↑6% (1.06; 0.90 -1.26)↑ ↑4% (1.04; 0.90 -1.20) Ranitidine (Zantac ® ) (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 ® ) (Increase in gastric pH) 40 mg (every morning for 5 days, Day -4 to 1) ↑2% (1.02; 0.88-1.17)↑ ↑5% (1.05; 0.89 -1.24) Metoclopramide (Reglan ® ) (Increase in gastric motility) 15 mg four times daily for 2 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 Suspension: 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 Drug Interactions (7.1) ] . Effects of Noxafil and Noxafil PowderMix on Other Drugs: Table 31: Summary of the Effects of Noxafil on Coadministered Drugs in Healthy Adult Volunteers and Patients Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole) Coadministered Drug Dose/Schedule Noxafil Dose/ Schedule Effect on Bioavailability of Coadministered Drugs Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for C max or AUC. ; 90% CI of the ratio estimate) Change in Mean AUC (ratio estimate ; 90% CI of the ratio estimate) Sirolimus 2-mg single oral dose 400 mg (oral suspension) twice daily x 16 days ↑ 572% (6.72; 5.62-8.03) ↑ 788% (8.88; 7.26-10.9) Cyclosporine Stable maintenance dose in heart transplant recipients 200 mg (tablets) once daily x 10 days The tablet refers to a non-commercial tablet formulation without polymer. ↑ Cyclosporine whole blood trough concentrations Cyclosporine dose reductions of up to 29% were required Tacrolimus 0.05-mg/kg single oral dose 400 mg (oral suspension) twice daily x 7 days ↑ 121% (2.21; 2.01-2.42) ↑ 358% (4.58; 4.03-5.19) Simvastatin 40-mg single oral dose 100 mg (oral suspension) once daily x 13 days Simvastatin ↑ 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 Acid ↑634% (7.34, 5.82-9.25) 200 mg (oral suspension) once daily x 13 days Simvastatin ↑ 1041% (11.41, 7.99-16.29) Simvastatin Acid ↑851% (9.51, 8.15-11.10) Simvastatin ↑ 960% (10.60, 8.63-13.02) Simvastatin Acid ↑ 748% (8.48, 7.04-10.23) Midazolam 0.4-mg single intravenous dose The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with Noxafil. 200 mg (oral suspension) twice daily x 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 x 7 days ↑62% (1.62; 1.41-1.86) ↑524% (6.24; 5.43-7.16) 2-mg single oral dose 200 mg (oral suspension) once daily x 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 x 7 days ↑ 138% (2.38; 2.13-2.66) ↑ 397% (4.97; 4.46-5.54) Rifabutin 300 mg once daily x 17 days 200 mg (tablets) once daily x 10 days ↑ 31% (1.31; 1.10-1.57) ↑ 72% (1.72;1.51-1.95) Phenytoin 200 mg once daily PO x 10 days 200 mg (tablets) once daily x 10 days ↑ 16% (1.16; 0.85-1.57) ↑ 16% (1.16; 0.84-1.59) Ritonavir 100 mg once daily x 14 days 400 mg (oral suspension) twice daily x 7 days ↑ 49% (1.49; 1.04-2.15) ↑ 80% (1.8;1.39-2.31) Atazanavir 300 mg once daily x 14 days 400 mg (oral suspension) twice daily x 7 days ↑ 155% (2.55; 1.89-3.45) ↑ 268% (3.68; 2.89-4.70) Atazanavir/ritonavir boosted regimen 300 mg/100 mg once daily x 14 days 400 mg (oral suspension) twice daily x 7 days ↑ 53% (1.53; 1.13-2.07) ↑ 146% (2.46; 1.93-3.13) 12.4 Microbiology Mechanism of Action Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole. Resistance Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known. Antimicrobial Activity Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1) ] . Microorganisms Aspergillus spp. and Candida spp. Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC ." ], "clinical_pharmacology_table": [ "
Table 18: Noxafil Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials
Cavg = the average posaconazole concentration when measured at steady state
Prophylaxis in AML/MDSNeutropenic patients who were receiving cytotoxic chemotherapy for AML or MDSProphylaxis 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 (%)
Quartile 190-32254.722-55744.4
Quartile 2322-49037.0557-91520.6
Quartile 3490-73446.8915-156317.5
Quartile 4734-220027.81563-365017.5
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Table 19: 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 1
Dose (mg)nAUC0-∞ (ng∙hr/mL)AUC0-12 (ng∙hr/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; t½ = terminal phase half-life; CL = total body clearance; N/D = Not Determined
Healthy 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/D
30022N/D8240 (26)1590 (62)N/DN/D
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Table 20: 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 a day following twice daily dosing on Day 1
DayNCmax (ng/mL)TmaxMedian (minimum-maximum) (hr)AUC0-24 (ng*hr/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 a subject received the dose of POS on the day specified in the protocol; Cmax = observed maximum plasma concentration; CV = coefficient of variation, expressed as a 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)
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Table 21: 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 (ng∙hr/mL)CavCav = time-averaged concentrations (i.e., AUC0-24 hr/24 hr) (ng/mL)Cmax (ng/mL)Cmin (ng/mL)TmaxMedian (minimum-maximum) (hr)t1/2 (hr)CL/F (L/hr)
CV = coefficient of variation expressed as a 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; t½ = terminal phase half-life; CL/F = Apparent total body clearance
Healthy 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)
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Table 22: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Noxafil Oral Suspension 200 mg Three Times a Day and 400 mg Twice Daily
DoseOral suspension administrationCavg (ng/mL)AUCAUC (0-24 hr) for 200 mg three times a day and AUC (0-12 hr) for 400 mg twice daily (ng∙hr/mL)CL/F (L/hr)V/F (L)t½ (hr)
Cavg = the average posaconazole concentration when measured at steady state
The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.
200 mg three times a dayHSCT recipients with GVHD (n=252)1103 (67) [21.5-3650]NDNot doneNDNDND
200 mg three times a 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]
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Table 23: 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 Conditions
Fasting ConditionsFed Conditions (High Fat Meal)48.5 g fatFed/Fasting
Pharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)
GMR=Geometric least-squares mean ratio; CI=Confidence interval
Cmax (ng/mL)14935 (34)161060 (25)1.16 (0.96, 1.41)
AUC0-72hr (hr∙ng/mL)1426200 (28)1638400 (18)1.51 (1.33, 1.72)
TmaxMedian (Min, Max) reported for Tmax (hr)145.00 (3.00, 8.00)166.00 (5.00, 24.00)N/A
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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 Conditions
Dose (mg)Cmax (ng/mL)TmaxMedian [min-max]. (hr)AUC (I) (ng∙hr/mL)CL/F (L/hr)t½ (hr)
200 mg fasted (n=20)n=15 for AUC (I), CL/F, and t½132 (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 4 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 t½121 (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]
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Table 25: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of Noxafil Oral Suspension in Healthy VolunteersIn 5 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 a 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 a high-fat meal relative to fasted state (n=12) 5 minutes before high-fat meal↑96% (1.96; 1.48-2.59)↑111% (2.11; 1.60-2.78)
During high-fat meal↑339% (4.39; 3.32-5.80)↑382% (4.82; 3.66-6.35)
20 minutes after high-fat meal↑333% (4.33; 3.28-5.73)↑387% (4.87; 3.70-6.42)
400 mg twice daily and 200 mg four times daily for 7 days in fasted state and with liquid nutritional supplement (BOOST®) (n=12)400 mg twice daily with BOOST↑65% (1.65; 1.29-2.11)↑66% (1.66; 1.30-2.13)
200 mg four times daily with BOOSTNo EffectNo Effect
Divided daily dose from 400 mg twice daily to 200 mg four times daily for 7 days regardless of fasted conditions or with BOOST (n=12)Fasted state↑136% (2.36; 1.84-3.02)↑161% (2.61; 2.04-3.35)
With BOOST↑137% (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 ale↑92% (1.92; 1.51-2.44)↑70% (1.70; 1.43-2.03)
Esomeprazole↓32% (0.68; 0.53-0.86)↓30% (0.70; 0.59-0.83)
400 mg single dose with a prokinetic agent (metoclopramide 10 mg three times a day for 2 days) + BOOST or an antikinetic agent (loperamide 4 mg single dose) + BOOST (n=12)With metoclopramide + BOOST↓21% (0.79; 0.72-0.87)↓19% (0.81; 0.72-0.91)
With loperamide + BOOST↓3% (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)
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Table 26: Summary of Steady-State Geometric Mean Pharmacokinetic Parameters (% Geometric CV) After Multiple Dosing with Noxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension 6 mg/kg0.6 to 1 times the recommended dose in Pediatric Patients with Neutropenia or Expected Neutropenia
Age GroupDose TypeNAUC0-24 hr (ng·hr/mL)CavCav = time-averaged concentrations (i.e., AUC0-24 hr/24 hr) (ng/mL)Cmax (ng/mL)Cmin (ng/mL)TmaxMedian (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 clearance
2 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)
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Table 27: Summary of Steady-State Geometric Mean Pharmacokinetic ParametersParameter estimates reported only for N>2 (excludes a single patient ≥2 to <12 receiving tablet and 2 patients ≥12 to <18 years receiving PFS) (% Geometric CV) After Multiple Dosing with Noxafil Injection, Noxafil PowderMix for Delayed-Release Oral Suspension, and Noxafil Delayed-Release Tablets in Pediatric Patients being Treated for Invasive Aspergillosis
Age GroupDose TypeNSome patients had 2 values (1 for IV dosing and 1 for oral dosing)AUC0-24 hours (ng·hr/mL)CavCav = time-averaged concentrations (i.e., AUC0-24 hours/24hr) (ng/mL)Cmax (ng/mL)Cmin (ng/mL)TmaxMedian (minimum-maximum) (hr)CL/FClearance (CL for IV and CL/F for PFS or Tablet) (L/hr)
IV = Noxafil injection; PFS = Noxafil PowderMix for delayed-release oral suspension; Tablet = Noxafil delayed-release tablets; AUC0-24 hours = 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 clearance
2 to <12 yearsIV961900 (49.8)2580 (49.8)3630 (30.8)1710 (82.2)1.50 (1.25-1.77)2.56 (47.8)
PFS645200 (30.2)1880 (30.2)2220 (26.5)1370 (41.8)7.00 (6.40-7.20)3.25 (34.6)
12 to <18 yearsIV1360800 (35.6)2530 (35.6)3510 (26.8)1740 (48.5)1.50 (1.30-1.63)4.41 (41.8)
Tablet1047800 (52.7)1990 (52.7)2250 (48.3)1580 (62.6)7.15 (6.70-7.30)6.27 (52.7)
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Table 28: Summary of the Effects of Coadministered Drugs on Noxafil in Healthy Volunteers
Coadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of Posaconazole
Change in Mean Cmax (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 days↓45% (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 Days↓21% 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 a 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)
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Table 29: The Effects of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Oral Suspension in Healthy Volunteers
Coadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of Posaconazole
Change 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)
Cimetidine (Alteration of gastric pH)400 mg twice daily × 10 days200 mg (tablets) once daily × 10 daysThe tablet refers to a 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 a day × 2 days400 mg (oral suspension) single dose↓ 21% (0.79; 0.72-0.87)↓ 19% (0.81; 0.72-0.91)
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Table 30: The Effects of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Delayed-Release Tablets in Healthy Volunteers
Coadministered 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® Ultimate strength liquid (Increase in gastric pH)25.4 mEq/5 mL, 20 mL↑6% (1.06; 0.90 -1.26)↑↑4% (1.04; 0.90 -1.20)
Ranitidine (Zantac®) (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®) (Increase in gastric pH)40 mg (every morning for 5 days, Day -4 to 1)↑2% (1.02; 0.88-1.17)↑↑5% (1.05; 0.89 -1.24)
Metoclopramide (Reglan®) (Increase in gastric motility)15 mg four times daily for 2 days (Day -1 and 1)↓14% (0.86, 0.73,1.02)↓7% (0.93, 0.803,1.07)
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Table 31: Summary of the Effects of Noxafil on Coadministered Drugs in Healthy Adult Volunteers and Patients
Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)Coadministered Drug Dose/ScheduleNoxafil Dose/ ScheduleEffect on Bioavailability of Coadministered Drugs
Change 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 x 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 x 10 daysThe tablet refers to a non-commercial tablet formulation without polymer.↑ Cyclosporine whole blood trough concentrations Cyclosporine dose reductions of up to 29% were required
Tacrolimus0.05-mg/kg single oral dose400 mg (oral suspension) twice daily x 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 x 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 Acid ↑634% (7.34, 5.82-9.25)
200 mg (oral suspension) once daily x 13 daysSimvastatin ↑ 1041% (11.41, 7.99-16.29) Simvastatin Acid ↑851% (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 3 hours to 7 to 11 hours during coadministration with Noxafil.200 mg (oral suspension) twice daily x 7 days↑ 30% (1.3; 1.13-1.48)↑ 362% (4.62; 4.02-5.3)
0.4-mg single intravenous dose400 mg (oral suspension) twice daily x 7 days↑62% (1.62; 1.41-1.86)↑524% (6.24; 5.43-7.16)
2-mg single oral dose200 mg (oral suspension) once daily x 7 days↑ 169% (2.69; 2.46-2.93)↑ 470% (5.70; 4.82-6.74)
2-mg single oral dose400 mg (oral suspension) twice daily x 7 days↑ 138% (2.38; 2.13-2.66)↑ 397% (4.97; 4.46-5.54)
Rifabutin300 mg once daily x 17 days200 mg (tablets) once daily x 10 days↑ 31% (1.31; 1.10-1.57)↑ 72% (1.72;1.51-1.95)
Phenytoin200 mg once daily PO x 10 days200 mg (tablets) once daily x 10 days↑ 16% (1.16; 0.85-1.57)↑ 16% (1.16; 0.84-1.59)
Ritonavir100 mg once daily x 14 days400 mg (oral suspension) twice daily x 7 days↑ 49% (1.49; 1.04-2.15)↑ 80% (1.8;1.39-2.31)
Atazanavir300 mg once daily x 14 days400 mg (oral suspension) twice daily x 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 x 14 days 400 mg (oral suspension) twice daily x 7 days↑ 53% (1.53; 1.13-2.07)↑ 146% (2.46; 1.93-3.13)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4) ] ." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Exposure Response Relationship: Prophylaxis of invasive Aspergillus and Candida Infections in Adults Who Are at High Risk of Developing These Infections Due to Being Severely Immunocompromised 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), a wide range of plasma posaconazole exposures was noted following administration of Noxafil oral suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 18). A 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 18: Noxafil Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials Cavg = the average posaconazole concentration when measured at steady state Prophylaxis in AML/MDS Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS Prophylaxis in GVHD HSCT recipients with GVHD Cavg Range (ng/mL) Treatment Failure Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections (%) Cavg Range (ng/mL) Treatment Failure (%) Quartile 1 90-322 54.7 22-557 44.4 Quartile 2 322-490 37.0 557-915 20.6 Quartile 3 490-734 46.8 915-1563 17.5 Quartile 4 734-2200 27.8 1563-3650 17.5 Exposure Response Relationship: Treatment of Invasive Aspergillosis in Adult and Adolescent Patients: Across a range of posaconazole plasma minimum concentrations (C min , range: 244 to 5663 ng/mL) following administration of Noxafil injection and Noxafil delayed-release tablets in adult and pediatric patients aged 14 years and older treated for invasive aspergillosis in Aspergillosis Treatment Study, there was no association between posaconazole C min and treatment efficacy [see Clinical Pharmacology (12.3) and Clinical Studies (14.1) ] . Similarly, across a range of population pharmacokinetic model-predicted steady-state plasma average concentrations (Cavg, range: 589 to 6315 ng/mL), there was no association between posaconazole Cavg and treatment efficacy." ], "pharmacodynamics_table": [ "
Table 18: Noxafil Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials
Cavg = the average posaconazole concentration when measured at steady state
Prophylaxis in AML/MDSNeutropenic patients who were receiving cytotoxic chemotherapy for AML or MDSProphylaxis 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 (%)
Quartile 190-32254.722-55744.4
Quartile 2322-49037.0557-91520.6
Quartile 3490-73446.8915-156317.5
Quartile 4734-220027.81563-365017.5
" ], "pharmacokinetics": [ "12.3 Pharmacokinetics General Pharmacokinetic Characteristics General Pharmacokinetic Characteristics of Noxafil Injection Noxafil 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 19. Table 19: 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 1 Dose (mg) n AUC 0-∞ (ng∙hr/mL) AUC 0-12 (ng∙hr/mL) C max (ng/mL) t 1/2 (hr) CL (L/hr) AUC 0-∞ = Area under the plasma concentration-time curve from time zero to infinity; AUC 0-12 = Area under the plasma concentration-time curve from time zero to 12 hr after the first dose on Day 1; C max = maximum observed concentration; t ½ = terminal phase half-life; CL = total body clearance; N/D = Not Determined Healthy Volunteers 200 9 35400 (50) 8840 (20) 2250 (29) 23.6 (23) 6.5 (32) 300 9 46400 (26) 13000 (13) 2840 (30) 24.6 (20) 6.9 (27) Patients 200 30 N/D 5570 (32) 954 (44) N/D N/D 300 22 N/D 8240 (26) 1590 (62) N/D N/D Table 20 displays the pharmacokinetic parameters of posaconazole in patients following administration of Noxafil injection 300 mg taken once a day for 10 or 14 days following twice daily dosing on Day 1. Table 20: 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 a day following twice daily dosing on Day 1 Day N C max (ng/mL) T max Median (minimum-maximum) (hr) AUC 0-24 (ng*hr/mL) Cav (ng/mL) C min (ng/mL) AUC 0-24 = area under the concentration-time curve over the dosing interval (i.e., 24 hours); Cav= time-averaged concentrations (i.e., AUC 0-24h /24hr); C min = POS trough level immediately before a subject received the dose of POS on the day specified in the protocol; C max = observed maximum plasma concentration; CV = coefficient of variation, expressed as a percent (%); Day = study day on treatment; T max = time of observed maximum plasma concentration. 10/14 49 3280 (74) 1.5 (0.98-4.0) 36100 (35) 1500 (35) 1090 (44) General Pharmacokinetic Characteristics of Noxafil Delayed-Release Tablets Noxafil 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 21. Table 21: 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 N AUC 0-24 hr (ng∙hr/mL) Cav Cav = time-averaged concentrations (i.e., AUC 0-24 hr/24 hr ) (ng/mL) C max (ng/mL) C min (ng/mL) T max Median (minimum-maximum) (hr) t 1/2 (hr) CL/F (L/hr) CV = coefficient of variation expressed as a percentage (%CV); AUC 0-T = Area under the plasma concentration-time curve from time zero to 24 hr; C max = maximum observed concentration; C min = minimum observed plasma concentration; T max = time of maximum observed concentration; t ½ = terminal phase half-life; CL/F = Apparent total body clearance Healthy Volunteers 12 51618 (25) 2151 (25) 2764 (21) 1785 (29) 4 (3-6) 31 (40) 7.5 (26) Patients 50 37900 (42) 1580 (42) 2090 (38) 1310 (50) 4 (1.3-8.3) - 9.39 (45) General Pharmacokinetic Characteristics of Noxafil Oral Suspension Dose-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 a day and 400 mg twice daily of the oral suspension are provided in Table 22. Table 22: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Noxafil Oral Suspension 200 mg Three Times a Day and 400 mg Twice Daily Dose Oral suspension administration Cavg (ng/mL) AUC AUC (0-24 hr) for 200 mg three times a day and AUC (0-12 hr) for 400 mg twice daily (ng∙hr/mL) CL/F (L/hr) V/F (L) t ½ (hr) Cavg = the average posaconazole concentration when measured at steady state The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects. 200 mg three times a day HSCT recipients with GVHD (n=252) 1103 (67) [21.5-3650] ND Not done ND ND ND 200 mg three times a day Neutropenic 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 daily Febrile 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: Absorption of Noxafil Delayed-Release Tablets When given orally in healthy volunteers, Noxafil delayed-release tablets are absorbed with a median T max of 4 to 5 hours. Steady-state plasma concentrations are attained by Day 6 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 C max and AUC of posaconazole following administration of Noxafil delayed-release tablets are increased 16% and 51%, respectively, when given with a high fat meal compared to a fasted state (see Table 23 ). Table 23: 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 Conditions Fasting Conditions Fed Conditions (High Fat Meal) 48.5 g fat Fed/Fasting Pharmacokinetic Parameter N Mean (%CV) N Mean (%CV) GMR (90% CI) GMR=Geometric least-squares mean ratio; CI=Confidence interval C max (ng/mL) 14 935 (34) 16 1060 (25) 1.16 (0.96, 1.41) AUC 0-72hr (hr∙ng/mL) 14 26200 (28) 16 38400 (18) 1.51 (1.33, 1.72) T max Median (Min, Max) reported for T max (hr) 14 5.00 (3.00, 8.00) 16 6.00 (5.00, 24.00) N/A Absorption of Noxafil PowderMix for Delayed-Release Oral Suspension The 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. Absorption of Noxafil Oral Suspension Noxafil oral suspension is absorbed with a median T max of ~3 to 5 hours. Steady-state plasma concentrations are attained at 7 to 10 days following multiple-dose administration. Following single-dose administration of 200 mg, the mean AUC and C max of posaconazole are approximately 3 times higher when the oral suspension is administered with a nonfat meal and approximately 4 times higher when administered with a 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 C max of posaconazole are approximately 3 times higher when administered with a 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 C max and AUC of Noxafil oral suspension in healthy volunteers have been investigated and are shown in Table 25. To assure attainment of adequate plasma concentrations, it is recommended to administer Noxafil oral suspension during or immediately following a full meal. In patients who cannot eat a full meal, Noxafil oral suspension should be taken with a 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 Conditions Dose (mg) C max (ng/mL) T max Median [min-max]. (hr) AUC (I) (ng∙hr/mL) CL/F (L/hr) t ½ (hr) 200 mg fasted (n=20) n=15 for AUC (I), CL/F, and t ½ 132 (50) [45-267] 3.50 [1.5-36 The subject with T max of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between 4 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 t ½ 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 C max and AUC of Noxafil Oral Suspension in Healthy Volunteers In 5 subjects, the C max 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 a lower plasma exposure may be associated with an increased risk of treatment failure. Study Description Administration Arms Change in C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for C max or AUC. ; 90% CI of the ratio estimate) Change in AUC (ratio estimate ; 90% CI of the ratio estimate) 400 mg single dose with a high-fat meal relative to fasted state (n=12) 5 minutes before high-fat meal ↑96% (1.96; 1.48-2.59) ↑111% (2.11; 1.60-2.78) During high-fat meal ↑339% (4.39; 3.32-5.80) ↑382% (4.82; 3.66-6.35) 20 minutes after high-fat meal ↑333% (4.33; 3.28-5.73) ↑387% (4.87; 3.70-6.42) 400 mg twice daily and 200 mg four times daily for 7 days in fasted state and with liquid nutritional supplement (BOOST ® ) (n=12) 400 mg twice daily with BOOST ↑65% (1.65; 1.29-2.11) ↑66% (1.66; 1.30-2.13) 200 mg four times daily with BOOST No Effect No Effect Divided daily dose from 400 mg twice daily to 200 mg four times daily for 7 days regardless of fasted conditions or with BOOST (n=12) Fasted state ↑136% (2.36; 1.84-3.02) ↑161% (2.61; 2.04-3.35) With BOOST ↑137% (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 ale ↑92% (1.92; 1.51-2.44) ↑70% (1.70; 1.43-2.03) Esomeprazole ↓32% (0.68; 0.53-0.86) ↓30% (0.70; 0.59-0.83) 400 mg single dose with a prokinetic agent (metoclopramide 10 mg three times a day for 2 days) + BOOST or an antikinetic agent (loperamide 4 mg single dose) + BOOST (n=12) With metoclopramide + BOOST ↓21% (0.79; 0.72-0.87) ↓19% (0.81; 0.72-0.91) With loperamide + BOOST ↓3% (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 tube NG = nasogastric ↓19% (0.81; 0.71-0.91) ↓23% (0.77; 0.69-0.86) Distribution: The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226-295 L between studies and dose levels. Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin. Metabolism: Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. Posaconazole is a substrate for p-glycoprotein (P-gp) efflux. In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. 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 a 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 a mean terminal half-life (t ½ ) of 27 hours and a total body clearance (CL) of 7.3 L/h. Noxafil delayed-release tablet is eliminated with a mean half-life (t ½ ) ranging between 26 to 31 hours. Noxafil oral suspension is eliminated with a mean half-life (t ½ ) of 35 hours (range: 20-66 hours). Specific Populations: No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment). Patients with Renal Impairment: After Noxafil oral administration, there were no significant differences in the posaconazole pharmacokinetics in patients with eGFR 20 mL/minute/1.73 m 2 or higher compared to those with eGFR >80 mL/minute/1.73 m 2 . Although the mean posaconazole plasma exposure (AUC) was similar in patients with eGFR less than 20 mL/minute/1.73 m 2 treated with Noxafil oral suspension to those with eGFR >80 mL/minute/1.73 m 2 treated with Noxafil oral suspension, the range of the AUC estimates was highly variable (CV=96%) in patients with eGFR less than 20 mL/minute/1.73 m 2 compared to those with eGFR >80 mL/minute/1.73 m 2 (CV<40%).Similar posaconazole pharmacokinetic results are expected after administration of Noxafil delayed-release tablets [see Use in Specific Populations (8.6) ]. Patients with Hepatic Impairment: After a 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 C max was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively [see Use in Specific Populations (8.7) ]. Race/Ethnicity: In a population pharmacokinetic analysis of posaconazole, AUC was found to be 25% higher in Chinese patients relative to patients from other races/ethnicities. This higher exposure is not expected to be clinically relevant given the expected variability in posaconazole exposure [see Use in Specific Populations (8.9) ] . Patients Weighing More Than 120 kg: Weight has a clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered 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 Patients: Prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 2 years of age and older: A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a 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 a 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. The mean pharmacokinetic parameters after multiple-dose administration of Noxafil injection and Noxafil PowderMix for delayed-release oral suspension in neutropenic pediatric patients 2 to less than 18 years of age (Pediatric Study 1) are shown in Table 26. Patients were enrolled into 2 age groups and received Noxafil injection and Noxafil PowderMix for delayed-release oral suspension doses at 6 mg/kg (0.6 to 1 times the recommended dose) with a maximum 300 mg dose once daily (twice daily on Day 1) [see Adverse Reactions (6.1) ] . Table 26: Summary of Steady-State Geometric Mean Pharmacokinetic Parameters (% Geometric CV) After Multiple Dosing with Noxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension 6 mg/kg 0.6 to 1 times the recommended dose in Pediatric Patients with Neutropenia or Expected Neutropenia Age Group Dose Type N AUC 0-24 hr (ng·hr/mL) Cav Cav = time-averaged concentrations (i.e., AUC 0-24 hr/24 hr ) (ng/mL) C max (ng/mL) C min (ng/mL) T max Median (minimum-maximum) (hr) CL/F Clearance (CL for IV and CL/F for PFS) (L/hr) IV= Noxafil injection; PFS= Noxafil PowderMix for delayed-release oral suspension; AUC 0-24 = Area under the plasma concentration-time curve from time zero to 24 hr; C max = maximum observed concentration; C min = minimum observed plasma concentration; T max = time of maximum observed concentration; CL/F = apparent total body clearance 2 to <7 years IV 17 31100 (48.9) 1300 (48.9) 3060 (54.1) 626 (104.8) 1.75 (1.57-1.83) 3.27 (49.3) PFS 7 23000 (47.3) 960 (47.3) 1510 (43.4) 542 (68.8) 4.00 (2.17-7.92) 4.60 (35.2) 7 to 17 years IV 24 44200 (41.5) 1840 (41.5) 3340 (39.4) 1160 (60.4) 1.77 (1.33-6.00) 4.76 (55.7) PFS 12 25000 (184.3) 1040 (184.3) 1370 (178.5) 713 (300.6) 2.78 (0.00-4.00) 8.39 (190.3) Based on a population pharmacokinetic model evaluating posaconazole pharmacokinetics and predicting exposures in pediatric patients, the exposure of steady-state posaconazole average concentration greater than or equal to 700 ng/mL in approximately 90% of patients is attained with the recommended dose of Noxafil injection and Noxafil PowderMix for delayed-release oral suspension. The population pharmacokinetic analysis of posaconazole in pediatric patients from Pediatric Study 1 suggests that age, sex, renal impairment and ethnicity have no clinically meaningful effect on the pharmacokinetics of posaconazole. Treatment of invasive aspergillosis in pediatric patients 2 years of age and older: A total of 31 patients 2 to less than 18 years of age (body weight of ≥12 kg) received pediatric dosing based on body weight of Noxafil delayed-release tablets, Noxafil Injection, and Noxafil PowderMix for delayed-release oral suspension [see Dosage and Administration (2.3 ]. The mean population pharmacokinetic model parameters after multiple dose administration of Noxafil delayed-release tablets, Noxafil Injection, and Noxafil PowderMix for delayed-release oral suspension in pediatric patients 2 to less than 18 years of age for the treatment of invasive aspergillosis (Pediatric Study 2) are shown in Table 27. [see Adverse Reactions (6.1) ] . Table 27: Summary of Steady-State Geometric Mean Pharmacokinetic Parameters Parameter estimates reported only for N>2 (excludes a single patient ≥2 to <12 receiving tablet and 2 patients ≥12 to <18 years receiving PFS) (% Geometric CV) After Multiple Dosing with Noxafil Injection, Noxafil PowderMix for Delayed-Release Oral Suspension, and Noxafil Delayed-Release Tablets in Pediatric Patients being Treated for Invasive Aspergillosis Age Group Dose Type N Some patients had 2 values (1 for IV dosing and 1 for oral dosing) AUC 0-24 hours (ng·hr/mL) C av Cav = time-averaged concentrations (i.e., AUC 0-24 hours /24hr) (ng/mL) C max (ng/mL) C min (ng/mL) T max Median (minimum-maximum) (hr) CL/F Clearance (CL for IV and CL/F for PFS or Tablet) (L/hr) IV = Noxafil injection; PFS = Noxafil PowderMix for delayed-release oral suspension; Tablet = Noxafil delayed-release tablets; AUC 0-24 hours = Area under the plasma concentration-time curve from time zero to 24 hr; C max = maximum observed concentration; C min = minimum observed plasma concentration; T max = time of maximum observed concentration; CL/F = apparent total body clearance 2 to <12 years IV 9 61900 (49.8) 2580 (49.8) 3630 (30.8) 1710 (82.2) 1.50 (1.25-1.77) 2.56 (47.8) PFS 6 45200 (30.2) 1880 (30.2) 2220 (26.5) 1370 (41.8) 7.00 (6.40-7.20) 3.25 (34.6) 12 to <18 years IV 13 60800 (35.6) 2530 (35.6) 3510 (26.8) 1740 (48.5) 1.50 (1.30-1.63) 4.41 (41.8) Tablet 10 47800 (52.7) 1990 (52.7) 2250 (48.3) 1580 (62.6) 7.15 (6.70-7.30) 6.27 (52.7) The population pharmacokinetic analysis of posaconazole in pediatric patients, including Pediatric Study 2, suggests that age, sex, ethnicity, and disease status have no clinically meaningful effect on the pharmacokinetics of posaconazole Drug Interaction Studies: Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically with the oral suspension or another tablet formulation, which affect posaconazole concentrations, is provided in Table 28. Table 29 and Table 30 include a summary of the drug effects of concomitant medications that may impact the absorption of posaconazole when administered as either the oral suspension or delayed-release tablets. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 31 [see Contraindications (4) and Drug Interactions (7.2) including recommendations ] . Effects of Other Drugs on Noxafil and Noxafil PowderMix: Table 28: Summary of the Effects of Coadministered Drugs on Noxafil in Healthy Volunteers Coadministered Drug (Postulated Mechanism of Interaction) Coadministered Drug Dose/Schedule Noxafil Dose/Schedule Effect on Bioavailability of Posaconazole Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to Noxafil alone for C max 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 days 400 mg (oral suspension) twice daily × 10 and 20 days ↓45% (0.55; 0.47-0.66) ↓ 50% (0.50; 0.43-0.60) Fosamprenavir (unknown mechanism) 700 mg twice daily × 10 days 200 mg once daily on the 1 st day, 200 mg twice daily on the 2 nd day, then 400 mg twice daily × 8 Days ↓21% 0.79 (0.71-0.89) ↓23% 0.77 (0.68-0.87) Rifabutin (UDP-G Induction) 300 mg once daily × 17 days 200 mg (tablets) once daily × 10 days The tablet refers to a 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 days 200 mg (tablets) once daily × 10 days ↓ 41% (0.59; 0.44-0.79) ↓ 50% (0.50; 0.36-0.71) Noxafil Oral Suspension: Concomitant administration of Noxafil oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (see Table 29 .) Table 29: The Effects of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Oral Suspension in Healthy Volunteers Coadministered Drug (Postulated Mechanism of Interaction) Coadministered Drug Dose/Schedule Noxafil Dose/Schedule Effect on Bioavailability of Posaconazole Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for C max 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 days 200 mg (tablets) once daily × 10 days The tablet refers to a 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 days 400 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 a day × 2 days 400 mg (oral suspension) single dose ↓ 21% (0.79; 0.72-0.87) ↓ 19% (0.81; 0.72-0.91) Noxafil Delayed-Release Tablets: Concomitant 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 30 ). Table 30: The Effects of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Delayed-Release Tablets in Healthy Volunteers Coadministered Drug Administration Arms Change in C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to Noxafil alone for C max or AUC 0-last . ; 90% CI of the ratio estimate) Change in AUC 0-last (ratio estimate ; 90% CI of the ratio estimate) Mylanta ® Ultimate strength liquid (Increase in gastric pH) 25.4 mEq/5 mL, 20 mL ↑6% (1.06; 0.90 -1.26)↑ ↑4% (1.04; 0.90 -1.20) Ranitidine (Zantac ® ) (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 ® ) (Increase in gastric pH) 40 mg (every morning for 5 days, Day -4 to 1) ↑2% (1.02; 0.88-1.17)↑ ↑5% (1.05; 0.89 -1.24) Metoclopramide (Reglan ® ) (Increase in gastric motility) 15 mg four times daily for 2 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 Suspension: 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 Drug Interactions (7.1) ] . Effects of Noxafil and Noxafil PowderMix on Other Drugs: Table 31: Summary of the Effects of Noxafil on Coadministered Drugs in Healthy Adult Volunteers and Patients Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole) Coadministered Drug Dose/Schedule Noxafil Dose/ Schedule Effect on Bioavailability of Coadministered Drugs Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for C max or AUC. ; 90% CI of the ratio estimate) Change in Mean AUC (ratio estimate ; 90% CI of the ratio estimate) Sirolimus 2-mg single oral dose 400 mg (oral suspension) twice daily x 16 days ↑ 572% (6.72; 5.62-8.03) ↑ 788% (8.88; 7.26-10.9) Cyclosporine Stable maintenance dose in heart transplant recipients 200 mg (tablets) once daily x 10 days The tablet refers to a non-commercial tablet formulation without polymer. ↑ Cyclosporine whole blood trough concentrations Cyclosporine dose reductions of up to 29% were required Tacrolimus 0.05-mg/kg single oral dose 400 mg (oral suspension) twice daily x 7 days ↑ 121% (2.21; 2.01-2.42) ↑ 358% (4.58; 4.03-5.19) Simvastatin 40-mg single oral dose 100 mg (oral suspension) once daily x 13 days Simvastatin ↑ 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 Acid ↑634% (7.34, 5.82-9.25) 200 mg (oral suspension) once daily x 13 days Simvastatin ↑ 1041% (11.41, 7.99-16.29) Simvastatin Acid ↑851% (9.51, 8.15-11.10) Simvastatin ↑ 960% (10.60, 8.63-13.02) Simvastatin Acid ↑ 748% (8.48, 7.04-10.23) Midazolam 0.4-mg single intravenous dose The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with Noxafil. 200 mg (oral suspension) twice daily x 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 x 7 days ↑62% (1.62; 1.41-1.86) ↑524% (6.24; 5.43-7.16) 2-mg single oral dose 200 mg (oral suspension) once daily x 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 x 7 days ↑ 138% (2.38; 2.13-2.66) ↑ 397% (4.97; 4.46-5.54) Rifabutin 300 mg once daily x 17 days 200 mg (tablets) once daily x 10 days ↑ 31% (1.31; 1.10-1.57) ↑ 72% (1.72;1.51-1.95) Phenytoin 200 mg once daily PO x 10 days 200 mg (tablets) once daily x 10 days ↑ 16% (1.16; 0.85-1.57) ↑ 16% (1.16; 0.84-1.59) Ritonavir 100 mg once daily x 14 days 400 mg (oral suspension) twice daily x 7 days ↑ 49% (1.49; 1.04-2.15) ↑ 80% (1.8;1.39-2.31) Atazanavir 300 mg once daily x 14 days 400 mg (oral suspension) twice daily x 7 days ↑ 155% (2.55; 1.89-3.45) ↑ 268% (3.68; 2.89-4.70) Atazanavir/ritonavir boosted regimen 300 mg/100 mg once daily x 14 days 400 mg (oral suspension) twice daily x 7 days ↑ 53% (1.53; 1.13-2.07) ↑ 146% (2.46; 1.93-3.13)" ], "pharmacokinetics_table": [ "
Table 19: 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 1
Dose (mg)nAUC0-∞ (ng∙hr/mL)AUC0-12 (ng∙hr/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; t½ = terminal phase half-life; CL = total body clearance; N/D = Not Determined
Healthy 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/D
30022N/D8240 (26)1590 (62)N/DN/D
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Table 20: 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 a day following twice daily dosing on Day 1
DayNCmax (ng/mL)TmaxMedian (minimum-maximum) (hr)AUC0-24 (ng*hr/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 a subject received the dose of POS on the day specified in the protocol; Cmax = observed maximum plasma concentration; CV = coefficient of variation, expressed as a 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)
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Table 21: 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 (ng∙hr/mL)CavCav = time-averaged concentrations (i.e., AUC0-24 hr/24 hr) (ng/mL)Cmax (ng/mL)Cmin (ng/mL)TmaxMedian (minimum-maximum) (hr)t1/2 (hr)CL/F (L/hr)
CV = coefficient of variation expressed as a 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; t½ = terminal phase half-life; CL/F = Apparent total body clearance
Healthy 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)
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Table 22: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Noxafil Oral Suspension 200 mg Three Times a Day and 400 mg Twice Daily
DoseOral suspension administrationCavg (ng/mL)AUCAUC (0-24 hr) for 200 mg three times a day and AUC (0-12 hr) for 400 mg twice daily (ng∙hr/mL)CL/F (L/hr)V/F (L)t½ (hr)
Cavg = the average posaconazole concentration when measured at steady state
The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.
200 mg three times a dayHSCT recipients with GVHD (n=252)1103 (67) [21.5-3650]NDNot doneNDNDND
200 mg three times a 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]
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Table 23: 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 Conditions
Fasting ConditionsFed Conditions (High Fat Meal)48.5 g fatFed/Fasting
Pharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)
GMR=Geometric least-squares mean ratio; CI=Confidence interval
Cmax (ng/mL)14935 (34)161060 (25)1.16 (0.96, 1.41)
AUC0-72hr (hr∙ng/mL)1426200 (28)1638400 (18)1.51 (1.33, 1.72)
TmaxMedian (Min, Max) reported for Tmax (hr)145.00 (3.00, 8.00)166.00 (5.00, 24.00)N/A
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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 Conditions
Dose (mg)Cmax (ng/mL)TmaxMedian [min-max]. (hr)AUC (I) (ng∙hr/mL)CL/F (L/hr)t½ (hr)
200 mg fasted (n=20)n=15 for AUC (I), CL/F, and t½132 (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 4 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 t½121 (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]
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Table 25: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of Noxafil Oral Suspension in Healthy VolunteersIn 5 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 a 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 a high-fat meal relative to fasted state (n=12) 5 minutes before high-fat meal↑96% (1.96; 1.48-2.59)↑111% (2.11; 1.60-2.78)
During high-fat meal↑339% (4.39; 3.32-5.80)↑382% (4.82; 3.66-6.35)
20 minutes after high-fat meal↑333% (4.33; 3.28-5.73)↑387% (4.87; 3.70-6.42)
400 mg twice daily and 200 mg four times daily for 7 days in fasted state and with liquid nutritional supplement (BOOST®) (n=12)400 mg twice daily with BOOST↑65% (1.65; 1.29-2.11)↑66% (1.66; 1.30-2.13)
200 mg four times daily with BOOSTNo EffectNo Effect
Divided daily dose from 400 mg twice daily to 200 mg four times daily for 7 days regardless of fasted conditions or with BOOST (n=12)Fasted state↑136% (2.36; 1.84-3.02)↑161% (2.61; 2.04-3.35)
With BOOST↑137% (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 ale↑92% (1.92; 1.51-2.44)↑70% (1.70; 1.43-2.03)
Esomeprazole↓32% (0.68; 0.53-0.86)↓30% (0.70; 0.59-0.83)
400 mg single dose with a prokinetic agent (metoclopramide 10 mg three times a day for 2 days) + BOOST or an antikinetic agent (loperamide 4 mg single dose) + BOOST (n=12)With metoclopramide + BOOST↓21% (0.79; 0.72-0.87)↓19% (0.81; 0.72-0.91)
With loperamide + BOOST↓3% (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)
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Table 26: Summary of Steady-State Geometric Mean Pharmacokinetic Parameters (% Geometric CV) After Multiple Dosing with Noxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension 6 mg/kg0.6 to 1 times the recommended dose in Pediatric Patients with Neutropenia or Expected Neutropenia
Age GroupDose TypeNAUC0-24 hr (ng·hr/mL)CavCav = time-averaged concentrations (i.e., AUC0-24 hr/24 hr) (ng/mL)Cmax (ng/mL)Cmin (ng/mL)TmaxMedian (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 clearance
2 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)
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Table 27: Summary of Steady-State Geometric Mean Pharmacokinetic ParametersParameter estimates reported only for N>2 (excludes a single patient ≥2 to <12 receiving tablet and 2 patients ≥12 to <18 years receiving PFS) (% Geometric CV) After Multiple Dosing with Noxafil Injection, Noxafil PowderMix for Delayed-Release Oral Suspension, and Noxafil Delayed-Release Tablets in Pediatric Patients being Treated for Invasive Aspergillosis
Age GroupDose TypeNSome patients had 2 values (1 for IV dosing and 1 for oral dosing)AUC0-24 hours (ng·hr/mL)CavCav = time-averaged concentrations (i.e., AUC0-24 hours/24hr) (ng/mL)Cmax (ng/mL)Cmin (ng/mL)TmaxMedian (minimum-maximum) (hr)CL/FClearance (CL for IV and CL/F for PFS or Tablet) (L/hr)
IV = Noxafil injection; PFS = Noxafil PowderMix for delayed-release oral suspension; Tablet = Noxafil delayed-release tablets; AUC0-24 hours = 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 clearance
2 to <12 yearsIV961900 (49.8)2580 (49.8)3630 (30.8)1710 (82.2)1.50 (1.25-1.77)2.56 (47.8)
PFS645200 (30.2)1880 (30.2)2220 (26.5)1370 (41.8)7.00 (6.40-7.20)3.25 (34.6)
12 to <18 yearsIV1360800 (35.6)2530 (35.6)3510 (26.8)1740 (48.5)1.50 (1.30-1.63)4.41 (41.8)
Tablet1047800 (52.7)1990 (52.7)2250 (48.3)1580 (62.6)7.15 (6.70-7.30)6.27 (52.7)
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Table 28: Summary of the Effects of Coadministered Drugs on Noxafil in Healthy Volunteers
Coadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of Posaconazole
Change in Mean Cmax (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 days↓45% (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 Days↓21% 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 a 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)
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Table 29: The Effects of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Oral Suspension in Healthy Volunteers
Coadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of Posaconazole
Change 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)
Cimetidine (Alteration of gastric pH)400 mg twice daily × 10 days200 mg (tablets) once daily × 10 daysThe tablet refers to a 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 a day × 2 days400 mg (oral suspension) single dose↓ 21% (0.79; 0.72-0.87)↓ 19% (0.81; 0.72-0.91)
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Table 30: The Effects of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Delayed-Release Tablets in Healthy Volunteers
Coadministered 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® Ultimate strength liquid (Increase in gastric pH)25.4 mEq/5 mL, 20 mL↑6% (1.06; 0.90 -1.26)↑↑4% (1.04; 0.90 -1.20)
Ranitidine (Zantac®) (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®) (Increase in gastric pH)40 mg (every morning for 5 days, Day -4 to 1)↑2% (1.02; 0.88-1.17)↑↑5% (1.05; 0.89 -1.24)
Metoclopramide (Reglan®) (Increase in gastric motility)15 mg four times daily for 2 days (Day -1 and 1)↓14% (0.86, 0.73,1.02)↓7% (0.93, 0.803,1.07)
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Table 31: Summary of the Effects of Noxafil on Coadministered Drugs in Healthy Adult Volunteers and Patients
Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)Coadministered Drug Dose/ScheduleNoxafil Dose/ ScheduleEffect on Bioavailability of Coadministered Drugs
Change 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 x 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 x 10 daysThe tablet refers to a non-commercial tablet formulation without polymer.↑ Cyclosporine whole blood trough concentrations Cyclosporine dose reductions of up to 29% were required
Tacrolimus0.05-mg/kg single oral dose400 mg (oral suspension) twice daily x 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 x 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 Acid ↑634% (7.34, 5.82-9.25)
200 mg (oral suspension) once daily x 13 daysSimvastatin ↑ 1041% (11.41, 7.99-16.29) Simvastatin Acid ↑851% (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 3 hours to 7 to 11 hours during coadministration with Noxafil.200 mg (oral suspension) twice daily x 7 days↑ 30% (1.3; 1.13-1.48)↑ 362% (4.62; 4.02-5.3)
0.4-mg single intravenous dose400 mg (oral suspension) twice daily x 7 days↑62% (1.62; 1.41-1.86)↑524% (6.24; 5.43-7.16)
2-mg single oral dose200 mg (oral suspension) once daily x 7 days↑ 169% (2.69; 2.46-2.93)↑ 470% (5.70; 4.82-6.74)
2-mg single oral dose400 mg (oral suspension) twice daily x 7 days↑ 138% (2.38; 2.13-2.66)↑ 397% (4.97; 4.46-5.54)
Rifabutin300 mg once daily x 17 days200 mg (tablets) once daily x 10 days↑ 31% (1.31; 1.10-1.57)↑ 72% (1.72;1.51-1.95)
Phenytoin200 mg once daily PO x 10 days200 mg (tablets) once daily x 10 days↑ 16% (1.16; 0.85-1.57)↑ 16% (1.16; 0.84-1.59)
Ritonavir100 mg once daily x 14 days400 mg (oral suspension) twice daily x 7 days↑ 49% (1.49; 1.04-2.15)↑ 80% (1.8;1.39-2.31)
Atazanavir300 mg once daily x 14 days400 mg (oral suspension) twice daily x 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 x 14 days 400 mg (oral suspension) twice daily x 7 days↑ 53% (1.53; 1.13-2.07)↑ 146% (2.46; 1.93-3.13)
" ], "microbiology": [ "12.4 Microbiology Mechanism of Action Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole. Resistance Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known. Antimicrobial Activity Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1) ] . Microorganisms Aspergillus spp. and Candida spp. Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC ." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2 year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9- or 3.5 times the exposure achieved with a 400 mg twice daily oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400 mg twice daily oral suspension regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8 times the exposure achieved with a 400 mg twice daily oral suspension regimen. Mutagenesis Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study. Impairment of Fertility Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 x the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 x the 400 mg twice daily oral suspension regimen)." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2 year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9- or 3.5 times the exposure achieved with a 400 mg twice daily oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400 mg twice daily oral suspension regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8 times the exposure achieved with a 400 mg twice daily oral suspension regimen. Mutagenesis Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study. Impairment of Fertility Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 x the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 x the 400 mg twice daily oral suspension regimen)." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Treatment of Invasive Aspergillosis with Noxafil Injection and Noxafil Delayed-Release Tablets Aspergillosis Treatment Study (NCT01782131) was a 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 a history of allogeneic bone marrow transplant, liver transplant, or relapsed leukemia undergoing salvage chemotherapy. The median age of patients was 57 years (range: 14-91 years), with 27.8% of patients aged ≥65 years; 5 patients were pediatric patients 14-16 years of age, of whom 3 were treated with Noxafil and 2 with voriconazole. The majority of patients were male (59.8%) and white (67.1%). With regard to risk factors for invasive aspergillosis, approximately two-thirds of the patients in the study had a recent history of neutropenia, while approximately 20% with a history of an allogeneic stem cell transplant. Over 80% of subjects in each treatment group had infection limited to the lower respiratory tract (primarily lung), while approximately 11% to 13% also had infection in another organ. Invasive aspergillosis was proven or probable in 58.1% of patients as classified by independent adjudicators blinded to study treatment assignment. At least one Aspergillus species was identified in 21% of the patients; A. fumigatus and A. flavus were the most common pathogens identified. Patients randomized to receive Noxafil were given a dose of 300 mg once daily (twice daily on Day 1) IV or tablet. Patients randomized to receive voriconazole were given a dose of 6 mg/kg twice daily Day 1 followed by 4 mg/kg twice daily IV, or oral 300 mg twice daily Day 1 followed by 200 mg twice daily. The recommended initial route of administration was IV; however, patients could begin oral therapy if clinically stable and able to tolerate oral dosing. The transition from IV to oral therapy occurred when the patient was clinically stable. The protocol recommended duration of therapy was 84 days with a maximum allowed duration of 98 days. Median treatment duration was 67 days for Noxafil patients and 64 days for voriconazole patients. Overall, 55% to 60% of patients began treatment with the IV formulation with a median duration of 9 days for the initial IV dosing. The Intent to Treat (ITT) population included all patients randomized and receiving at least one dose of study treatment. All-cause mortality through Day 42 in the overall population (ITT) was 15.3% for Noxafil patients compared to 20.6% for voriconazole patients for an adjusted treatment difference of -5.3% with a 95% confidence interval of -11.6 to 1.0%. Consistent results were seen in patients with proven or probable invasive aspergillosis per EORTC criteria (see Table 32 ). Table 32: Noxafil Injection and Noxafil Delayed-Release Tablets Invasive Aspergillosis Treatment Study: All-Cause Mortality Through Day 42 Noxafil Injection and Delayed-Release Tablets Voriconazole Population N n (%) N n (%) Difference Adjusted treatment difference based on Miettinen and Nurminen’s method stratified by randomization factor (risk for mortality/poor outcome), using Cochran-Mantel-Haenszel weighting scheme. (95% CI) Intent to Treat 288 44 (15.3) 287 59 (20.6) -5.3 (-11.6, 1.0) Proven/Probable Invasive Aspergillosis 163 31 (19.0) 171 32 (18.7) 0.3 (-8.2, 8.8) Global clinical response at Week 6 was assessed by a blinded, independent adjudication committee based upon prespecified clinical, radiologic, and mycologic criteria. In the subgroup of patients with proven or probable invasive aspergillosis per EORTC criteria, the global clinical response of success (complete or partial response) at Week 6 was seen in 44.8% for Noxafil-treated patients compared to 45.6% for voriconazole-treated patients (see Table 33 ). Table 33: Noxafil Injection and Noxafil Delayed-Release Tablets Invasive Aspergillosis Treatment Study: Successful Global Clinical Response Successful Global Clinical Response was defined as survival with a partial or complete response. at Week 6 Posaconazole Voriconazole Population N Success N Success Difference Adjusted treatment difference based on Miettinen and Nurminen’s method stratified by randomization factor (risk for mortality/poor outcome), using Cochran-Mantel-Haenszel weighting scheme. (95% CI) Proven/Probable Invasive Aspergillosis 163 73 (44.8) 171 78 (45.6) -0.6 (-11.2, 10.1) 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 a randomized, double-blind trial that compared Noxafil oral suspension (200 mg three times a 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 a 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 7 days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the 2 treatment groups (80 days, Noxafil oral suspension; 77 days, fluconazole). Table 34 contains the results from Noxafil Oral Suspension Study 1. Table 34: 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 1 Posaconazole n=301 Fluconazole n=299 On therapy plus 7 days Clinical Failure Patients may have met more than one criterion defining failure. 50 (17%) 55 (18%) Failure due to: Proven/Probable IFI 7 (2%) 22 (7%) ( Aspergillus ) 3 (1%) 17 (6%) ( Candida ) 1 (<1%) 3 (1%) (Other) 3 (1%) 2 (1%) All Deaths 22 (7%) 24 (8%) Proven/probable fungal infection prior to death 2 (<1%) 6 (2%) SAF Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >4 consecutive days). 27 (9%) 25 (8%) Through 16 weeks Clinical Failure , 95% confidence interval (posaconazole-fluconazole) = (-11.5%, + 3.7%). 99 (33%) 110 (37%) Failure due to: Proven/Probable IFI 16 (5%) 27 (9%) ( Aspergillus ) 7 (2%) 21 (7%) ( Candida ) 4 (1%) 4 (1%) (Other) 5 (2%) 2 (1%) All Deaths 58 (19%) 59 (20%) Proven/probable fungal infection prior to death 10 (3%) 16 (5%) SAF 26 (9%) 30 (10%) Event free lost to follow-up Patients 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 a randomized, open-label study that compared Noxafil oral suspension (200 mg 3 times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a 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 a 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 7 days and 100 days post-randomization. The mean duration of therapy was comparable between the 2 treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 35 contains the results from Noxafil Oral Suspension Study 2. Table 35: Results from Open-Label Clinical Study 2 in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Noxafil Oral Suspension Study 2 Posaconazole n=304 Fluconazole/Itraconazole n=298 On therapy plus 7 days Clinical Failure 95% 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 IFI 7 (2%) 25 (8%) ( Aspergillus ) 2 (1%) 20 (7%) ( Candida ) 3 (1%) 2 (1%) (Other) 2 (1%) 3 (1%) All Deaths 17 (6%) 25 (8%) Proven/probable fungal infection prior to death 1 (<1%) 2 (1%) SAF Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >3 consecutive days). 67 (22%) 98 (33%) Through 100 days post-randomization Clinical Failure 158 (52%) 191 (64%) Failure due to: Proven/Probable IFI 14 (5%) 33 (11%) ( Aspergillus ) 2 (1%) 26 (9%) ( Candida ) 10 (3%) 4 (1%) (Other) 2 (1%) 3 (1%) All Deaths 44 (14%) 64 (21%) Proven/probable fungal infection prior to death 2 (1%) 16 (5%) SAF 98 (32%) 125 (42%) Event free lost to follow-up Patients 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, 2 clinical studies of prophylaxis were conducted with the Noxafil oral suspension. As seen in the accompanying tables (Table 34 and Table 35), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Noxafil Oral Suspension Study 1 (Table 34), 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 2 (Table 35) 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 1 [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 2 [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. 14.3 Treatment of Oropharyngeal Candidiasis with Noxafil Oral Suspension Noxafil Oral Suspension Study 3 was a 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 a day for 1 day followed by 100 mg once a day for 13 days). Clinical and mycological outcomes were assessed after 14 days of treatment and at 4 weeks after the end of treatment. Patients who received at least 1 dose of study medication and had a positive oral swish culture of Candida species at baseline were included in the analyses (see Table 36 ). 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) 4 weeks after the end of treatment were similar between the treatment arms (see Table 36 ). 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 36 ). Table 36: Noxafil Oral Suspension Clinical Success, Mycological Eradication, and Relapse Rates in Oropharyngeal Candidiasis Noxafil Fluconazole Clinical 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 a criterion for success as a 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. 14.4 Noxafil Oral Suspension Treatment of Oropharyngeal Candidiasis Refractory to Treatment with Fluconazole or Itraconazole Noxafil Oral Suspension Study 4 was a 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 a 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 3 days, followed by 400 mg once daily for 25 days with an option for further treatment during a 3 month maintenance period. Following a dosing amendment, a 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 4 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)." ], "clinical_studies_table": [ "
Table 32: Noxafil Injection and Noxafil Delayed-Release Tablets Invasive Aspergillosis Treatment Study: All-Cause Mortality Through Day 42
Noxafil Injection and Delayed-Release TabletsVoriconazole
PopulationNn (%)Nn (%)DifferenceAdjusted treatment difference based on Miettinen and Nurminen’s method stratified by randomization factor (risk for mortality/poor outcome), using Cochran-Mantel-Haenszel weighting scheme. (95% CI)
Intent to Treat 288 44 (15.3)287 59 (20.6)-5.3 (-11.6, 1.0)
Proven/Probable Invasive Aspergillosis163 31 (19.0)171 32 (18.7)0.3 (-8.2, 8.8)
", "
Table 33: Noxafil Injection and Noxafil Delayed-Release Tablets Invasive Aspergillosis Treatment Study: Successful Global Clinical ResponseSuccessful Global Clinical Response was defined as survival with a partial or complete response. at Week 6
PosaconazoleVoriconazole
PopulationNSuccessNSuccessDifferenceAdjusted treatment difference based on Miettinen and Nurminen’s method stratified by randomization factor (risk for mortality/poor outcome), using Cochran-Mantel-Haenszel weighting scheme. (95% CI)
Proven/Probable Invasive Aspergillosis 163 73 (44.8)17178 (45.6)-0.6 (-11.2, 10.1)
", "
Table 34: 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 1
Posaconazole n=301Fluconazole n=299
On therapy plus 7 days
Clinical 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 weeks
Clinical 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%)
SAF26 (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%)
", "
Table 35: Results from Open-Label Clinical Study 2 in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Noxafil Oral Suspension Study 2
Posaconazole n=304Fluconazole/Itraconazole n=298
On therapy plus 7 days
Clinical 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 post-randomization
Clinical Failure158 (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%)
SAF98 (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%)
", "
Table 36: Noxafil Oral Suspension Clinical Success, Mycological Eradication, and Relapse Rates in Oropharyngeal Candidiasis
NoxafilFluconazole
Clinical 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%)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Noxafil Injection Noxafil injection is a clear, colorless to yellow sterile liquid in single-dose Type I glass vials closed with bromobutyl rubber stopper and aluminum seal containing 300 mg of posaconazole in 16.7 mL of solution (18 mg of posaconazole per mL) (NDC 0085-4331-01). Noxafil Delayed-Release Tablets Noxafil delayed-release tablets are 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 Suspension Noxafil oral suspension is a white, cherry-flavored oral suspension in 4-ounce (123 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of posaconazole per mL).Supplied with each oral suspension bottle is a plastic dosing spoon calibrated for measuring 2.5 mL and 5 mL doses (NDC 0085-1328-01). Noxafil PowderMix for Delayed-Release Oral Suspension Noxafil PowderMix for delayed-release oral suspension is supplied as: Package A: a kit with 8 child-resistant single-use packets of Noxafil PowderMix for delayed-release oral suspension 300 mg, two 3 mL (green) notched tip syringes, two 10 mL (blue) notched tip syringes, two mixing cups, one mixing liquid bottle, one bottle adapter for the mixing liquid bottle and Instructions for Use. Package B: a box of six 3 mL (green) and six 10 mL (blue) notched tip syringes for additional supply. Packages A and B are supplied separately. NDC 0085-2224-02 unit of use carton with 8 packets. NDC 0085-2224-01 individual packet. 16.2 Storage and Handling Noxafil Injection Store Noxafil injection vial refrigerated at 2 to 8°C (36 to 46°F). Storage conditions for the diluted Noxafil infusion solution are presented in another section of the prescribing information [see Dosage and Administration (2.5) ]. Noxafil Delayed-Release Tablets Store at 20 to 25°C (68 to 77°F), excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Noxafil Oral Suspension Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. DO NOT FREEZE. Noxafil PowderMix for Delayed-Release Oral Suspension Store the entire kit at 20 to 25°C (68 to 77°F), excursions permitted to 15 to 30°C (59 to 86°F) in a clean, dry place. Do not open foil packet containing Noxafil PowderMix for delayed-release oral suspension until ready for use. Storage conditions for the reconstituted solution are presented in another section of the prescribing information [see Dosage and Administration (2.10) ].", "16.1 How Supplied Noxafil Injection Noxafil injection is a clear, colorless to yellow sterile liquid in single-dose Type I glass vials closed with bromobutyl rubber stopper and aluminum seal containing 300 mg of posaconazole in 16.7 mL of solution (18 mg of posaconazole per mL) (NDC 0085-4331-01). Noxafil Delayed-Release Tablets Noxafil delayed-release tablets are 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 Suspension Noxafil oral suspension is a white, cherry-flavored oral suspension in 4-ounce (123 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of posaconazole per mL).Supplied with each oral suspension bottle is a plastic dosing spoon calibrated for measuring 2.5 mL and 5 mL doses (NDC 0085-1328-01). Noxafil PowderMix for Delayed-Release Oral Suspension Noxafil PowderMix for delayed-release oral suspension is supplied as: Package A: a kit with 8 child-resistant single-use packets of Noxafil PowderMix for delayed-release oral suspension 300 mg, two 3 mL (green) notched tip syringes, two 10 mL (blue) notched tip syringes, two mixing cups, one mixing liquid bottle, one bottle adapter for the mixing liquid bottle and Instructions for Use. Package B: a box of six 3 mL (green) and six 10 mL (blue) notched tip syringes for additional supply. Packages A and B are supplied separately. NDC 0085-2224-02 unit of use carton with 8 packets. NDC 0085-2224-01 individual packet." ], "storage_and_handling": [ "16.2 Storage and Handling Noxafil Injection Store Noxafil injection vial refrigerated at 2 to 8°C (36 to 46°F). Storage conditions for the diluted Noxafil infusion solution are presented in another section of the prescribing information [see Dosage and Administration (2.5) ]. Noxafil Delayed-Release Tablets Store at 20 to 25°C (68 to 77°F), excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Noxafil Oral Suspension Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. DO NOT FREEZE. Noxafil PowderMix for Delayed-Release Oral Suspension Store the entire kit at 20 to 25°C (68 to 77°F), excursions permitted to 15 to 30°C (59 to 86°F) in a clean, dry place. Do not open foil packet containing Noxafil PowderMix for delayed-release oral suspension until ready for use. Storage conditions for the reconstituted solution are presented in another section of the prescribing information [see Dosage and Administration (2.10) ]." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ). Important Administration Instructions Noxafil Delayed-Release Tablets Advise patients that Noxafil delayed-release tablets must be swallowed whole and not divided, crushed, or chewed. Instruct patients that if they miss a 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 Suspension Advise patients to take each dose of Noxafil oral suspension during or immediately (i.e., within 20 minutes) following a full meal. In patients who cannot eat a full meal, each dose of Noxafil oral suspension should be administered with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in order to enhance absorption. Instruct patients that if they miss a 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 Suspension Instruct 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 Interactions Advise patients to inform their physician immediately if they: develop severe diarrhea or vomiting. are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4. are currently taking a cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath. are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole. Serious and Potentially Serious Adverse Reactions Advise patients to inform their physician immediately if they: notice a change in heart rate or heart rhythm or have a heart condition or circulatory disease. 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 (5.9) ] . Inquire for symptoms of sorbitol/fructose and/or sucrose intolerance before administration." ], "spl_unclassified_section": [ "Manuf. for: Merck Sharp & Dohme LLC Rahway, NJ 07065, USA For patent information: www.msd.com/research/patent The trademarks referenced herein are owned by their respective companies. Copyright © 2006-2026 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. uspi-mk5592-mf-2601r050" ], "spl_patient_package_insert": [ "This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 1/2026 Patient Information NOXAFIL ® ( NOX -a-fil) (posaconazole) injection NOXAFIL ® ( NOX -a-fil) (posaconazole) delayed-release tablets NOXAFIL ® ( NOX -a-fil) (posaconazole) oral suspension NOXAFIL ® ( NOX -a-fil) POWDERMIX (posaconazole) for delayed-release oral suspension What is Noxafil and Noxafil PowderMix? Noxafil (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 a weak immune system. These include people who have had a hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease or those with a 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 2 years of age and older who weigh 22 lbs (10 kg) or greater. treatment of fungal infections in adults and children 2 years of age and older who weigh 22 lbs (10 kg) or greater. Noxafil delayed-release tablets are used for: prevention of fungal infections in adults and children 2 years of age and older who weigh greater than 88 lbs (40 kg). treatment of fungal infections in adults and children 2 years of age and older who weigh greater than 88 lbs (40 kg). 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 2 years of age and older who weigh 22 lbs to 88 lbs (10 kg to 40 kg). treatment of fungal infections in children 2 years of age and older who weigh 22 lbs to 88 lbs (10 kg to 40 kg). Noxafil oral suspension is also used to treat a 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 oral suspension is safe and effective in children under 13 years of age for the treatment of thrush as the first treatment for thrush, or as another treatment for thrush after itraconazole or fluconazole treatment has not worked. It is not known if Noxafil or Noxafil PowderMix is safe and effective in children under 2 years of age. Do 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 Patient Information leaflet for a complete list of ingredients in Noxafil and Noxafil PowderMix. are taking any of the following medicines: 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. Ask your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines. Do not start taking a new medicine without talking to your healthcare provider or pharmacist. Before you take Noxafil or Noxafil PowderMix, tell your healthcare provider about all of your medical conditions, including 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 a decrease in the Noxafil levels in your body. Efavirenz and fosamprenavir should not be taken with Noxafil or Noxafil PowderMix. are taking midazolam, a hypnotic and sedative medicine. are taking vincristine, vinblastine and other “vinca alkaloids” (medicines used to treat cancer). are taking venetoclax, a 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 a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them with you to show your healthcare provider or pharmacist when you get a new medicine. How should I take Noxafil or Noxafil PowderMix? 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 a 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 a different medicine. If you miss a 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 a full meal. If you cannot eat a full meal, take each dose of Noxafil oral suspension with a 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 5 mL . See Figure A . Figure A Rinse the spoon with water after each dose of Noxafil oral suspension and before you store it away. If you miss a 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 a double dose to make up for the missed dose or take more than your prescribed 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 a 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 child’s 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. After mixing, 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 give the medicine. Give the dose within 1 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 PowderMix? Noxafil 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 a 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. new or worsening high blood pressure and low potassium levels in your blood (pseudoaldosteronism). Your healthcare provider should check your blood pressure and potassium levels. 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 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. The most common side effects of Noxafil in adults include: diarrhea nausea fever vomiting headache coughing low potassium levels in the blood The most common side effects of Noxafil injection and Noxafil PowderMix in children include: 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 If 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 I store Noxafil or Noxafil PowderMix? Noxafil injection Store Noxafil injection refrigerated between 36°F to 46°F (2°C to 8°C). Noxafil delayed-release tablets Store Noxafil delayed-release tablets at room temperature between 68°F to 77°F (20°C to 25°C). Noxafil oral suspension Store Noxafil oral suspension at room temperature between 68°F to 77°F (20°C to 25°C). Do not freeze Noxafil oral suspension. Noxafil PowderMix for delayed-release oral suspension Store the entire kit at room temperature between 68°F to 77°F (20°C to 25°C) in a 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 a Patient Information leaflet. Do not use Noxafil or Noxafil PowderMix for a 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 PowderMix? Active 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 LLC Rahway, NJ 07065, USA For patent information: www.msd.com/research/patent The trademarks depicted in this piece are owned by their respective companies. Copyright © 2006-2026 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. usppi-mk5592-mf-2601r024 For more information, go to www.noxafil.com or call 1-800-672-6372. Figure A" ], "spl_patient_package_insert_table": [ "Rinse the spoon with water after each dose of Noxafil oral suspension and before you store it away.If you miss a 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 a double dose to make up for the missed dose or take more than your prescribed 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 a 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 child’s 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.After mixing, 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 give the medicine.Give the dose within 1 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.
This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 1/2026
Patient Information NOXAFIL® (NOX-a-fil) (posaconazole) injection NOXAFIL® (NOX-a-fil) (posaconazole) delayed-release tablets NOXAFIL® (NOX-a-fil) (posaconazole) oral suspension NOXAFIL® (NOX-a-fil) POWDERMIX (posaconazole) for delayed-release oral suspension
What is Noxafil and Noxafil PowderMix? Noxafil (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 a weak immune system. These include people who have had a hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease or those with a 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 2 years of age and older who weigh 22 lbs (10 kg) or greater.treatment of fungal infections in adults and children 2 years of age and older who weigh 22 lbs (10 kg) or greater.Noxafil delayed-release tablets are used for:prevention of fungal infections in adults and children 2 years of age and older who weigh greater than 88 lbs (40 kg).treatment of fungal infections in adults and children 2 years of age and older who weigh greater than 88 lbs (40 kg).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 2 years of age and older who weigh 22 lbs to 88 lbs (10 kg to 40 kg).treatment of fungal infections in children 2 years of age and older who weigh 22 lbs to 88 lbs (10 kg to 40 kg).Noxafil oral suspension is also used to treat a 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 oral suspension is safe and effective in children under 13 years of age for the treatment of thrush as the first treatment for thrush, or as another treatment for thrush after itraconazole or fluconazole treatment has not worked.It is not known if Noxafil or Noxafil PowderMix is safe and effective in children under 2 years of age.
Do 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 Patient Information leaflet for a 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 a new medicine without talking to your healthcare provider or pharmacist.
Before you take Noxafil or Noxafil PowderMix, tell your healthcare provider about all of your medical conditions, including 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 a decrease in the Noxafil levels in your body. Efavirenz and fosamprenavir should not be taken with Noxafil or Noxafil PowderMix. are taking midazolam, a hypnotic and sedative medicine.are taking vincristine, vinblastine and other “vinca alkaloids” (medicines used to treat cancer).are taking venetoclax, a 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 a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them with you to show your healthcare provider or pharmacist when you get a new medicine.
How should I take Noxafil or Noxafil PowderMix?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 a 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 a different medicine.If you miss a 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 a full meal. If you cannot eat a full meal, take each dose of Noxafil oral suspension with a 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 5 mL. See Figure A.
 Figure A
What are the possible side effects of Noxafil or Noxafil PowderMix?Noxafil 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 a 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.new or worsening high blood pressure and low potassium levels in your blood (pseudoaldosteronism). Your healthcare provider should check your blood pressure and potassium levels.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 blood
The 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 blood
If 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 I store Noxafil or Noxafil PowderMix?Noxafil injectionStore Noxafil injection refrigerated between 36°F to 46°F (2°C to 8°C). Noxafil delayed-release tabletsStore Noxafil delayed-release tablets at room temperature between 68°F to 77°F (20°C to 25°C). Noxafil oral suspensionStore Noxafil oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).Do not freeze Noxafil oral suspension. Noxafil PowderMix for delayed-release oral suspensionStore the entire kit at room temperature between 68°F to 77°F (20°C to 25°C) in a 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 a Patient Information leaflet. Do not use Noxafil or Noxafil PowderMix for a 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 PowderMix? Active 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 LLC Rahway, NJ 07065, USA For patent information: www.msd.com/research/patent The trademarks depicted in this piece are owned by their respective companies. Copyright © 2006-2026 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. usppi-mk5592-mf-2601r024 For more information, go to www.noxafil.com or call 1-800-672-6372.
", "
itchy skinnausea or vomitingyellowing of your eyes or skin feeling very tired flu-like symptoms
" ], "instructions_for_use": [ "Important: Read This Booklet First Noxafil PowderMix (posaconazole) for delayed-release oral suspension Instructions for Use for caregivers and healthcare providers of toddlers and children Before You Start 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 3 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 a safe place. You will need both hands to prepare Noxafil PowderMix. Wash your hands with soap and water before preparing Noxafil PowderMix. Before You Start The amount of Noxafil PowderMix you give depends on your child’s weight. Your healthcare provider will tell you the right dose to give your child. Be sure to keep your healthcare provider’s appointments so you get new dosing information as your child grows. This booklet tells you how to: Make the Noxafil PowderMix into a liquid form. Measure the right dose using the included notched-tip oral 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 1 hour , you will need to throw it away and start over. Note: If you have any questions, call your healthcare provider. Kit Contents Prescription (on Noxafil PowderMix box) 2 mixing cups Instructions for Use (this booklet) 8 packets of Noxafil PowderMix Package insert Bottle adapter 4 syringes (shown below) Bottle of Mixing Liquid for use with Noxafil PowderMix 2 blue (10 mL) syringes 2 green (3 mL) syringes The 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 Syringes Before you prepare a dose, review the parts of the syringe and how to use them. If you have any questions about measuring with a 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 matches the 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 a clean surface. Note: Put your child in a 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 of Noxafil PowderMix powder Mixing liquid 2 syringes (Have 1 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 a 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 1 hour , you will need to throw it away and start over. Take 1 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 9 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 9 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 9 mL, put the notched tip back into the mixing liquid and pull the plunger back until you get to the 9 mL mark. Step 7. Add the 9 mL of mixing liquid to the Noxafil PowderMix. Add the 9 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 free of 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 child's 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 child's dose: For 1 mL to 3 mL Green For 3 mL to 10 mL Blue Then find the mL mark on the syringe that matches your child's 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 child’s 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 a 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 I store Noxafil PowderMix? Store the entire kit at room temperature between 68°F to 77°F (20°C to 25°C) in a clean, dry place. Keep the mixing liquid at room temperature. Do not open the Noxafil PowderMix packet until you are ready to mix a 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 LLC Rahway, NJ 07065, USA For patent information: www.msd.com/research/patent Copyright © 2021-2022 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. ifu-mk5592-2209r002 This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: September 2022 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" ], "instructions_for_use_table": [ "
Important: Read This Booklet First Noxafil PowderMix (posaconazole) for delayed-release oral suspension Instructions for Use for caregivers and healthcare providers of toddlers and children
", "
", "
Before You Start
", "
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 3 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 a safe place. You will need both hands to prepare Noxafil PowderMix. Wash your hands with soap and water before preparing Noxafil PowderMix.
", "
Before You Start
", "
Note before adding Noxafil PowderMix: Make sure you and your child are ready! If you do not use Noxafil PowderMix within 1 hour, you will need to throw it away and start over.
", "
Note: If you have any questions, call your healthcare provider.
", "
Kit Contents
Prescription (on Noxafil PowderMix box)2 mixing cups
Instructions for Use (this booklet)8 packets of Noxafil PowderMix
Package insertBottle adapter
4 syringes (shown below)Bottle of Mixing Liquid for use with Noxafil PowderMix
", "
2 blue (10 mL) syringes2 green (3 mL) syringes
", "
The 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 Syringes
Before you prepare a dose, review the parts of the syringe and how to use them.If you have any questions about measuring with a syringe, call your healthcare provider.Make sure the plunger is pushed all the way into the barrel before you start to measure the dose.
", "
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.
", "
", "
Step 2. Gather all your supplies and put on a clean surface.
", "
Note: Put your child in a 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 of Noxafil PowderMix powder Mixing liquid2 syringes (Have 1 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 a 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 1 hour, you will need to throw it away and start over.
", "
Take 1 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 9 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 9 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 9 mL, put the notched tip back into the mixing liquid and pull the plunger back until you get to the 9 mL mark.
", "
Step 7. Add the 9 mL of mixing liquid to the Noxafil PowderMix.
", "
Add the 9 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 free of 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 child's 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.
", "
For 1 mL to 3 mL GreenFor 3 mL to 10 mL Blue
", "
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 child’s 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 a clean, dry place.
", "
Step 15. After all packets of Noxafil PowderMix have been used.
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 105 mL Bottle Carton NDC 0085-1328-01 105 mL NOXAFIL ® (posaconazole) Oral Suspension 200 mg/5 mL Each mL contains: 40 mg posaconazole. Attention: Noxafil Oral Suspension is NOT substitutable with Noxafil Delayed-Release Tablets or Noxafil PowderMix for Delayed-Release Oral Suspension due to differences in the dosing of each formulation. SHAKE WELL BEFORE EACH USE. Take with a meal, or a nutritional supplement, or an acidic carbonated beverage. Carton contains measured dosing spoon. Rx only PRINCIPAL DISPLAY PANEL - 105 mL Bottle Carton", "PRINCIPAL DISPLAY PANEL - 60 Tablet Bottle Label NDC 0085-4324-02 Noxafil ® (posaconazole) delayed-release tablets 100 mg Each tablet contains 100 mg posaconazole. Attention: Noxafil Oral Suspension and Delayed- Release Tablets are NOT substitutable due to differences in the dosing of each formulation. Rx only 60 Tablets Principal Display Panel - 60 Tablet Bottle Label", "PRINCIPAL DISPLAY PANEL - 16.7 mL Vial Carton NDC 0085-4331-01 Noxafil ® (posaconazole) Injection 300 mg/16.7 mL (18 mg/mL) For Intravenous Use Only Requires further dilution prior to infusion. Rx only Sterile Single-Dose Vial Discard Unused Portion Principal Display Panel - 16.7 mL Vial Carton", "PRINCIPAL DISPLAY PANEL - 300 mg Carton NDC 0085-2224-02 Noxafil ® PowderMix (posaconazole) for Delayed-Release Oral Suspension 300 mg For Pediatric Use For Oral Administration Only Each packet contains 300 mg posaconazole. Attention: Noxafil PowderMix for Delayed-Release Oral Suspension is NOT substitutable with Noxafil Oral Suspension due to differences in the dosing of each formulation. Use only the notched-tip syringes and mixing liquid provided with this kit. Rx only 8 packets Multi-Dose Kit A Additional notched-tip syringes are provided in Package B with this kit. DIRECTIONS FOR USE: See instructions for use booklet and prescribing information for additional information. Principal Display Panel - 300 mg Carton" ], "set_id": "b073b082-7b57-4423-8c06-4fd4263d6f84", "id": "56740f7d-3b29-4786-b5c7-eea6c0f14400", "effective_time": "20260213", "version": "56", "openfda": { "application_number": [ "NDA022003", "NDA214770", "NDA205053", "NDA205596" ], "brand_name": [ "NOXAFIL" ], "generic_name": [ "POSACONAZOLE" ], "manufacturer_name": [ "Merck Sharp & Dohme LLC" ], "product_ndc": [ "0085-1328", "0085-4324", "0085-4331", "0085-2224" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL", "INTRAVENOUS" ], "substance_name": [ "POSACONAZOLE" ], "rxcui": [ "665019", "665022", "1482908", "1482912", "1492043", "1492047", "2558603", "2558607" ], "spl_id": [ "56740f7d-3b29-4786-b5c7-eea6c0f14400" ], "spl_set_id": [ "b073b082-7b57-4423-8c06-4fd4263d6f84" ], "package_ndc": [ "0085-1328-01", "0085-4324-02", "0085-4331-01", "0085-2224-01", "0085-2224-02" ], "is_original_packager": [ true ], "upc": [ "0300854324025" ], "nui": [ "N0000175487", "M0002083" ], "pharm_class_epc": [ "Azole Antifungal [EPC]" ], "pharm_class_cs": [ "Azoles [CS]" ], "unii": [ "6TK1G07BHZ" ] } } ] }