Noxafil

Noxafil is an azole antifungal indicated as follows: 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 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: 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

1.1Treatment 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

1.2Prophylaxis 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

1.3Treatment of Oropharyngeal Candidiasis Including Oropharyngeal

Candidiasis Refractory to Itraconazole and/or Fluconazole Noxafil oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole in adults and pediatric patients 13 years of age and older.

Noxafil 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. 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. 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. Administer Noxafil delayed-release tablets with or without food. Administer Noxafil oral suspension with a full meal. Administer Noxafil PowderMix for delayed-release oral suspension with food. Administer Noxafil PowderMix for delayed-release oral suspension with the provided notched tip syringes only. 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 )

2.1Important 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 , 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 . 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 . 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 . 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 . 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 . Noxafil PowderMix for delayed-release oral suspension Administer with food . 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 .

2.2Recommended 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 . Noxafil PowderMix for delayed-release oral suspension is not recommended for use in adults . 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.

2.3Recommended 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 Noxafil injection in pediatric patients 2 years of age and older who weigh 10 kg or greater, and 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 . 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 . 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

2.4Recommended 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.

2.5Preparation 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

2.6Administration of Diluted Noxafil Infusion Solution

See Dosage and Administration 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 . 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 . 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

2.7Administration 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 .

2.8Administration 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 . For those patients using the Noxafil oral suspension: Shake Noxafil oral suspension well before use.

Administer with measured dosing spoon provided in the package . 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 . 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

2.9Non-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 .

2.10Preparation 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 . 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.

2.11Dosage 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.

Calcineurin-Inhibitor Toxicity : Noxafil increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. 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. Pseudoaldosteronism : Manifested by the onset or worsening of hypertension, and abnormal laboratory findings. Monitor blood pressure and potassium levels, and manage as necessary. 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. 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. 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 )

5.1Calcineurin-Inhibitor Toxicity Concomitant

administration of Noxafil with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors . 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.

5.2Arrhythmias 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 .

5.3Electrolyte Disturbances Electrolyte

disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during Noxafil therapy.

5.4Pseudoaldosteronism 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.

5.5Hepatic 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.

5.6Renal 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 . 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 .

5.7Midazolam 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 .

5.8Vincristine 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 .

5.9Risk 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 .

5.10Breakthrough 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.

5.11Venetoclax 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 . 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 . Refer to the venetoclax prescribing information for dosing instructions.

Known hypersensitivity to posaconazole or other azole antifungal agents. 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 )

4.1Hypersensitivity Noxafil

is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.

4.2Use 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 .

4.3QT 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 .

4.4HMG-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 .

4.5Use with Ergot Alkaloids Noxafil

may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism .

4.6Use 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 .

4.7Use of Noxafil PowderMix for Delayed-Release Oral

Suspension in Patients with Hereditary Fructose Intolerance Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with known or suspected hereditary fructose intolerance (HFI) .

8.1Pregnancy 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 . 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.

The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling: Arrhythmias and QT Prolongation Electrolyte Disturbances Pseudoaldosteronism Hepatic Toxicity Adult Patients: Common adverse reactions in studies with Noxafil in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. 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. 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 .

6.1Clinical 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

97.6Hypokalemia

28.5

17.1Pyrexia

28.1

25.1Nausea

22.6

17.8Diarrhea

18.1

18.1Vomiting

18.1

13.6Alanine

aminotransferase increased 14.6

12.9Febrile

neutropenia 14.6

13.2Aspartate

aminotransferase increased 13.2

12.5Pneumonia

12.5

9.1Headache

12.2

8.7Constipation

11.1

8.0Edema

peripheral 11.1

8.4Epistaxis

11.1

5.9Cough

10.4

8.4Abdominal

pain 10.1

8.4Hypomagnesemia

10.1

6.3Clinical 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 . 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 . 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 ) 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 Cardiac disorders: torsades de pointes 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 13/266 ALT 47/271 39/272 Bilirubin 24/271 20/275 Alkaline Phosphatase 9/271 8/271 Noxafil Oral Suspension Study 2 Laboratory Parameter Noxafil Oral Suspension (n=304) Fluconazole/Itraconazole (n=298) AST 9/286 5/280 ALT 18/289 13/284 Bilirubin 20/290 25/285 Alkaline Phosphatase 4/281 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 13/254 25/226 AST > 3.0 x ULN 33/537 26/254 39/223 Total Bilirubin > 1.5 x ULN 15/536 5/254 9/197 Alkaline Phosphatase > 3.0 x ULN 17/535 15/253 24/190 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 21/285 ALT 29/281 23/282 Bilirubin 26/280 25/284 Alkaline Phosphatase 12/282 20/284 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 . 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 . 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.

6.2Postmarketing 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