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.

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)].

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.

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.

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.

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.

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.

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 m2, 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 m2, 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 m2 is the same as those with normal renal function.

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)].

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 m2), 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 m2), 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.

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.

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.

7.1 Effects of Other Drugs on Noxafil and Noxafil PowderMix

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)].

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, H2-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, H2-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).

8.1 Pregnancy

8.2 Lactation

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 m2 or higher.
Due to variability in posaconazole exposure, closely monitor patients with eGFR less than 20 mL/minute/1.73 m2 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 m2 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 m2.

If treatment with Noxafil injection is unavoidable in patients with eGFR less than 50 mL/minute/1.73 m2, 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)].

12.1 Mechanism of Action

Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4)].

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

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).

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).

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).

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.

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.

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).

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).

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)].