Noxafil Solution
FDA Label NDC 0085-4331

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

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, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole in adults and pediatric patients 13 years of age and older.

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)].

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)].

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.

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.

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

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

• 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)].

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 (Noxafil 01)

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.

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)].

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.

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.

Noxafil injection

300 mg/16.7 mL (18 mg/mL) of posaconazole: Clear, colorless to yellow sterile liquid in a single-dose vial.

Noxafil Delayed-Release Tablets

100 mg of posaconazole: Yellow, coated, oblong tablets, debossed with "100" on one side.

Noxafil Oral Suspension

4,200 mg/105 mL (40 mg/mL) of posaconazole: White, cherry-flavored suspension in amber glass bottles with child-resistant closures.

Noxafil PowderMix for Delayed-Release Oral Suspension

300 mg: Off-white to yellowish powder for delayed-release oral suspension and a mixing liquid in a kit. The kit contains (1) Package A that contains single-use packets of Noxafil PowderMix, green notched tip syringes, blue notched tip syringes, mixing cups, mixing liquid bottle, and one bottle adapter for the mixing liquid bottle; and (2) Package B that contains green and blue notched tip syringes for additional supply [see How Supplied/Storage and Handling (16.1)].

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

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)].

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)].

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)].

Noxafil may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [see Drug Interactions (7.2)].

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)].

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)].

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.

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)].

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

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.

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.

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)].

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)].

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)].

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)].

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.

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.

The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling:

• Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)]
• Electrolyte Disturbances [see Warnings and Precautions (5.3)]
• Pseudoaldosteronism [see Warnings and Precautions (5.4)]
• Hepatic Toxicity [see Warnings and Precautions (5.5)]

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%).

Clinical Trial Experience with Noxafil Injection for Prophylaxis of Invasive Aspergillus and Candida Infections

Administration of multiple doses of Noxafil injection via a peripheral venous catheter were associated with thrombophlebitis (60% incidence). Therefore, in subsequent studies, Noxafil injection was administered via central venous catheter [see Dosage and Administration (2.6)].

The safety of Noxafil injection has been assessed in 268 patients in a clinical trial. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of Noxafil injection when given as antifungal prophylaxis (Noxafil Injection Study). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 55% male, had a mean age of 51 years (range: 18-82 years, 19% of patients were ≥65 years of age), and were 95% White and 8% Hispanic. In this study, 10 patients received a single dose of 200 mg Noxafil injection, 21 patients received 200 mg daily dosage for a median of 14 days, and 237 patients received 300 mg daily dosage for a median of 9 days (the 200 mg dosage is not a recommended dosage for prophylaxis of invasive Aspergillus and Candida infections in adults [see Dosage and Administration (2.2)]. In the 300 mg daily dosage group each patient received a loading intravenous dose of Noxafil injection 300 mg twice on Day 1, then intravenous Noxafil injection therapy, and finally Noxafil oral suspension to complete 28 days of total Noxafil therapy.

Table 8 presents adverse reactions observed in patients treated with the Noxafil injection 300 mg daily dosage group in the Noxafil Injection Study.

The most frequently reported adverse reactions with an onset during the intravenous Noxafil injection phase of dosing with 300 mg once daily were diarrhea (32%), hypokalemia (22%), pyrexia (21%), and nausea (19%). These adverse reactions were consistent with those seen in studies with Noxafil oral suspension.

Clinical Trial Experience with Noxafil Delayed-Release Tablets for Prophylaxis of Invasive Aspergillus and Candida Infections

The safety of Noxafil delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of Noxafil delayed-release tablets when given as antifungal prophylaxis (Noxafil Delayed-Release Tablet Study). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 62% male, had a mean age of 51 years (range: 19-78 years, 17% of patients were ≥65 years of age), and were 93% White and 16% Hispanic. Noxafil delayed-release tablets were given for a median duration of 28 days. In this study, 20 adult patients received 200 mg daily dosage (this is not a recommended dosage [see Dosage and Administration (2.2)]) and 210 adult patients received 300 mg daily dosage (following twice daily dosing on Day 1 in each cohort). Table 9 presents adverse reactions (incidence of ≥ 10%) observed in patients treated with the Noxafil delayed-release tablets 300 mg daily dosage in the Noxafil Delayed-Release Tablet Study.

The most frequently reported adverse reactions (>25%) in patients treated with Noxafil delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea. The most common adverse reaction leading to discontinuation of Noxafil delayed-release tablets 300 mg once daily was nausea (2%).

Clinical Trials Safety Experience with Noxafil Oral Suspension

The safety of Noxafil oral suspension has been assessed in 1,844 patients, including:

• 605 patients in the active-controlled studies for the prophylaxis of invasive Aspergillus and Candida infections
• 557 patients in the active-controlled OPC studies (not refractory to itraconazole or fluconazole)
• 239 patients in refractory OPC studies (refractory to itraconazole or fluconazole) (rOPC), and
• 443 patients in other patient populations

These studies included immunocompromised patients (e.g., patients with hematological malignancy, neutropenia post-chemotherapy, GVHD post HSCT, and HIV infection), as well as non-neutropenic patients. This patient population was 71% male, had a mean age of 42 years (range: 8-84 years, 6% of patients were ≥65 years of age and 1% was <18 years of age), and were 64% White, 14% Black, 16% Hispanic. Noxafil oral suspension therapy was given to 171 patients for ≥6 months, including 58 patients who received Noxafil oral suspension therapy for ≥12 months. Table 10 presents adverse reactions observed at an incidence of >10% in the studies for prophylaxis of invasive Aspergillus and Candida infections. Table 11 presents adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies.

Prophylaxis of Invasive Aspergillus and Candida Infections (Noxafil oral suspension)

In the two randomized, comparative studies for prophylaxis of invasive Aspergillus and Candida infections in those at high risk of developing these infections due to being severely immunocompromised (Noxafil Oral Suspension Study 1 and 2), the safety of Noxafil oral suspension 200 mg three times a day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely immunocompromised patients. The most frequently reported adverse reactions (>30%) in these trials were fever, diarrhea, and nausea. The most common adverse reactions leading to discontinuation of Noxafil oral suspension were GI adverse reactions, specifically, nausea (2%), vomiting (2%), and increased hepatic enzymes (2%).

Table 10: Adverse Reactions in at least 10% of Patients Receiving Noxafil Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida Infections

Adverse Reactions	Noxafil Oral Suspension n=605 (%)	Fluconazole n=539 (%)	Itraconazole n=58 (%)
Percentage of Patients Reporting any Adverse Reaction	98	99	100
Fever	45	47	55
Diarrhea	42	39	60
Nausea	38	37	52
Hypokalemia	30	26	52
Thrombocytopenia	29	27	34
Vomiting	29	32	41
Headache	28	26	40
Abdominal Pain	27	27	36
Anemia	25	23	28
Coughing	24	24	24
Neutropenia	23	23	40
Constipation	21	17	17
Dyspnea	20	22	26
Rigors	20	16	29
Rash	19	18	43
Hypertension	18	16	5
Hypomagnesemia	18	16	19
Fatigue	17	18	9
Insomnia	17	17	19
Musculoskeletal Pain	16	15	16
Anorexia	15	17	28
Edema Legs	15	12	19
Epistaxis	14	14	21
Hypotension	14	15	17
Pharyngitis	12	11	21
Tachycardia	12	14	5
Arthralgia	11	12	9
Dizziness	11	10	9
Hyperglycemia	11	14	3
Petechiae	11	10	16
Pruritus	11	12	19
Back Pain	10	12	7
Bilirubinemia	10	9	19
Dyspepsia	10	9	10
Vaginal Hemorrhage Percentages of sex-specific adverse reactions are based on the number of males/females.	10	9	12

Treatment of Nonrefractory OPC and Refractory OPC (Noxafil oral suspension)

In two randomized comparative studies for the treatment of nonrefractory OPC, the safety of Noxafil oral suspension (less than or equal to 400 mg once daily) in 557 HIV-infected patients was compared to the safety of fluconazole (100 mg once daily) in 262 HIV-infected patients.

An additional 239 HIV-infected patients with refractory OPC (rOPC) received Noxafil oral suspension in two non-comparative trials for rOPC. Of these patients, 149 received the 800 mg/day dosage and the remainder received the less than or equal to 400 mg once daily dosage.

In the nonrefractory OPC and rOPC studies, the most common adverse reactions in patients treated with Noxafil oral suspension were fever, diarrhea, nausea, headache, vomiting, and coughing.

Adverse reactions were reported more frequently in the studies of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions were reported in 55% (132/239) of Noxafil oral suspension-treated patients. The most commonly reported serious adverse reactions were fever (13%) and neutropenia (10%).

Table 11: Adverse Reactions in at least 10% of Patients Receiving Noxafil Oral Suspension for the Treatment of Nonrefractory and Refractory OPC

Adverse Reactions
	Controlled OPC Pool		Refractory OPC Pool
	Noxafil Oral Suspension	Fluconazole	Noxafil Oral Suspension
	n=557 (%)	n=262 (%)	n=239 (%)
OPC=oropharyngeal candidiasis
Percentage of Patients that Reported any Adverse Reaction Based on patients reporting adverse reactions at least once during the study, without regard to relationship to treatment. Patients may have reported more than 1 adverse reaction.	64	67	92
Diarrhea	10	13	29
Nausea	9	11	29
Headache	8	9	20
Vomiting	7	7	28
Fever	6	8	34
Abdominal Pain	5	6	18
Neutropenia	4	3	16
Coughing	3	4	25
Fatigue	3	5	13
Herpes Simplex	3	3	11
Pneumonia	3	2	10
Rash	3	4	15
Anemia	2	2	14
Anorexia	2	2	19
Asthenia	2	2	13
Sweating Increased	2	2	10
Candidiasis, Oral	1	<1	12
Dehydration	1	3	11
Dyspnea	1	3	12
Insomnia	1	1	16
Pain	1	1	11
Weight Decrease	1	<1	14
Rigors	<1	2	12

Additional Adverse Reactions Reported in Less Than 5% of Noxafil-Treated Patients in Clinical Trials

Other clinically significant adverse reactions reported in less than 5% of patients in clinical trials of Noxafil are listed below:

• Blood and lymphatic system disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated
• Endocrine disorders: adrenal insufficiency
• Nervous system disorders: paresthesia
• Immune system disorders: allergic reaction [see Contraindications (4.1)]
• Cardiac disorders: torsades de pointes [see Warnings and Precautions (5.2)]
• Vascular disorders: pulmonary embolism
• Gastrointestinal disorders: pancreatitis
• Liver and Biliary System Disorders: hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice
• Renal & Urinary System Disorders: renal failure acute

Liver Test Abnormalities in the Clinical Trials of Noxafil Oral Suspension

Liver Test Abnormalities in the Clinical Trials with Noxafil Oral Suspension for Prophylaxis of Invasive Aspergillus and Candida Infections

In the prophylaxis of invasive Aspergillus and Candida infections studies, the number and percentage of patients with changes in liver tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 at the end of the studies is presented in Table 12.

Table 12: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 in Prophylaxis of Invasive Aspergillus and Candida Infections Studies (Noxafil Oral Suspension Studies 1 and 2)

Number (%) of Patients with Change Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation.
Noxafil Oral Suspension Study 1
	CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase;
	ALT= Alanine Aminotransferase.
Laboratory Parameter	Noxafil Oral Suspension n=301	Fluconazole n=299
AST	11/266 (4)	13/266 (5)
ALT	47/271 (17)	39/272 (14)
Bilirubin	24/271 (9)	20/275 (7)
Alkaline Phosphatase	9/271 (3)	8/271 (3)
Noxafil Oral Suspension Study 2
Laboratory Parameter	Noxafil Oral Suspension (n=304)	Fluconazole/Itraconazole (n=298)
AST	9/286 (3)	5/280 (2)
ALT	18/289 (6)	13/284 (5)
Bilirubin	20/290 (7)	25/285 (9)
Alkaline Phosphatase	4/281 (1)	1/276 (<1)

Liver Test Abnormalities in the Clinical Trials with Noxafil Oral Suspension for the Treatment of OPC

The number and percentage of patients treated for OPC with clinically significant liver test abnormalities at any time during the studies is provided in Table 13 (liver test abnormalities were present in some of these patients prior to initiation of the study drug).

Table 13: Clinically Significant Liver Test Abnormalities without Regard to Baseline Value (Noxafil Oral Suspension Studies for the Treatment of OPC)

Laboratory Test	Nonrefractory OPC		Refractory OPC
	Noxafil Oral Suspension	Fluconazole	Noxafil Oral Suspension
	n=557 (%)	n=262 (%)	n=239 (%)
ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase.
ALT > 3.0 x ULN	16/537 (3)	13/254 (5)	25/226 (11)
AST > 3.0 x ULN	33/537 (6)	26/254 (10)	39/223 (17)
Total Bilirubin > 1.5 x ULN	15/536 (3)	5/254 (2)	9/197 (5)
Alkaline Phosphatase > 3.0 x ULN	17/535 (3)	15/253 (6)	24/190 (13)

Liver Test Abnormalities in the Clinical Trials with Noxafil Oral Suspension for the Treatment of Invasive Aspergillosis

The number and percentage of patients treated for invasive aspergillosis with clinically significant liver test abnormalities at any time during the Aspergillosis Treatment Study is provided in Table 14. Liver test abnormalities present prior to the initiation of study drug included: ALT (22% of the patients), AST (13% of the patients), and bilirubin (13% of the patients).

Table 14: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 (Aspergillosis Treatment Study)

Number (%) of Patients with Change Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form n/N, where n represents the number of patients who met the criterion as indicated, and N represents the number of patients who had a baseline observation and at least one post-baseline observation.
Laboratory Parameter	Noxafil n/N (%)	Voriconazole n/N (%)
N=Number of patients for a given laboratory test with a baseline value of CTC Grade 0, 1, or 2 and at least one post-baseline value.
CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase;
ALT= Alanine Aminotransferase.
AST	22/281 (8)	21/285 (7)
ALT	29/281(10)	23/282 (8)
Bilirubin	26/280 (9)	25/284 (9)
Alkaline Phosphatase	12/282 (4)	20/284 (7)

In healthy volunteers and patients, elevation of liver test values did not appear to be associated with higher plasma posaconazole concentrations.

Clinical Trials in Pediatric Patients 2 Years of Age and Older

The safety of Noxafil injection and Noxafil PowderMix (for delayed-release oral suspension) for prophylaxis of invasive fungal infections was evaluated in an open-label uncontrolled dose-ranging pharmacokinetic and safety study of Noxafil injection and Noxafil PowderMix (Pediatric Study 1, NCT02452034). In this study, 115 immunocompromised pediatric patients 2 to less than 18 years of age with known or expected neutropenia initially received Noxafil injection (up to 6 mg/kg twice daily for the first day and then up to 6 mg/kg for at least 7 days), and then 63 patients were transitioned to Noxafil PowderMix (up to 6 mg/kg once daily). The mean overall treatment duration was 21 days including a mean duration of 14 days (range: 1 to 28 days) on Noxafil injection and a mean duration of 12 days (range: 2 to 18 days) on Noxafil PowderMix [see Clinical Pharmacology (12.3)]. In this study, the reported adverse reaction profile of Noxafil injection and Noxafil PowderMix in pediatric patients was consistent with the safety profile of Noxafil in adults. The most common adverse reactions that occurred in greater than 20% of pediatric patients who received Noxafil injection and Noxafil PowderMix were pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis.

The safety of Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix for delayed-release oral suspension for the treatment of invasive aspergillosis was evaluated in an open-label, non-comparative clinical study in 31 pediatric patients 2 to less than 18 years of age with a diagnosis of possible, probable, or proven invasive aspergillosis (Pediatric Study 2, NCT04218851). In this study, all 31 pediatric patients initially received Noxafil injection (6 mg/kg twice daily on the first day and then 6 mg/kg once daily) for the treatment of invasive aspergillosis; 12 patients were transitioned to Noxafil delayed-release tablets (300 mg once daily) if they weighed ≥40 kg, and 10 patients were transitioned to Noxafil PowderMix (based on weight) if they weighed 10 to 40 kg [see Dosage and Administration (2.3)]. The mean overall treatment duration was 50 days including 15 days (range: 2 to 78 days) on Noxafil injection, 54 days (range: 6 to 80 days) on Noxafil delayed-release tablets, and 44 days (range: 7 to 76 days) on Noxafil PowderMix. The reported adverse reaction profile of Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix in pediatric patients was consistent with the known safety profile of Noxafil in adults. The most common adverse reactions that occurred in greater than 20% of pediatric patients who received any of the three formulations of Noxafil were vomiting, pyrexia, abdominal pain, liver test abnormalities, and hypertension.

Endocrine Disorders: Pseudoaldosteronism

Posaconazole is primarily metabolized via UDP-glucuronosyltransferase and is a substrate of p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Concomitant use of Noxafil with drugs that can decrease the plasma posaconazole concentrations should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

Table 15: Drug Interactions Affecting Noxafil and Noxafil PowderMix When Administered Concomitantly with Other Drugs

UDP-Glucuronidase Inducers
Mechanism and Clinical Effect(s)	Posaconazole is a UDP-glucuronosyltransferase substrate. Concomitant use of Noxafil with UDP-glucuronidase inducers may decrease posaconazole exposure [see Clinical Pharmacology (12.3)], which may reduce the effectiveness of posaconazole.
Prevention or Management	Efavirenz	Avoid concomitant use of posaconazole with efavirenz, unless the benefit outweighs the risks.
	Rifabutin	Avoid concomitant use of posaconazole with rifabutin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor closely for breakthrough fungal infections. See Table 17 for rifabutin monitoring considerations when posaconazole affects rifabutin via CYP3A4 inhibition.
	Phenytoin	Avoid concomitant use of posaconazole with phenytoin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor for breakthrough fungal infections. See Table 17 for phenytoin monitoring considerations when posaconazole affects phenytoin via CYP3A4 inhibition.
Fosamprenavir
Mechanism and Clinical Effect(s)	Concomitant use of Noxafil with fosamprenavir may lead to decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce effectiveness of posaconazole.
Prevention or Management	If concomitant use of posaconazole with fosamprenavir is needed, monitor closely for breakthrough fungal infections.

Table 16: Drug Interactions Affecting Noxafil Oral Suspension and Noxafil PowderMix Absorption When Administered Concomitantly with Other Drugs

Noxafil Oral Suspension
Cimetidine and Esomeprazole
Mechanism and Clinical Effect(s)	Concomitant use of Noxafil oral suspension with cimetidine or esomeprazole resulted in decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce effectiveness of Noxafil.
Prevention or Management	Avoid concomitant use of Noxafil oral suspension with cimetidine or esomeprazole unless the benefit outweighs the risks. If concomitant use is needed, monitor closely for breakthrough fungal infections.
Metoclopramide
Mechanism and Clinical Effect(s)	Concomitant use of Noxafil oral suspension with metoclopramide decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce effectiveness of Noxafil oral suspension.
Prevention or Management	If Noxafil oral suspension is concomitantly administered with metoclopramide, closely monitor for breakthrough fungal infections.
Noxafil Oral PowderMix
Alcohol
Mechanism and Clinical Effect(s)	Posaconazole releases faster from Noxafil PowderMix in the presence of alcohol, which may interfere with Noxafil PowderMix’s delayed-release characteristics [see Clinical Pharmacology (12.3)].
Prevention or Management	Administration of Noxafil PowderMix with alcohol is not recommended.

Risk Summary

Based on findings from animal data, Noxafil may cause fetal harm when administered to pregnant women. Available data for use of Noxafil in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, skeletal malformations were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses ≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of Noxafil in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, doses of ≥ 3 times the clinical exposure caused an increase in resorptions (see Data). Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data: Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen.

Risk Summary

There are no data on the presence of posaconazole in human milk, the effects on the breastfed infant, or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Noxafil and any potential adverse effects on the breastfed child from Noxafil or from the underlying maternal condition.

Exposure Response Relationship: Prophylaxis of invasive Aspergillus and Candida Infections in Adults Who Are at High Risk of Developing These Infections Due to Being Severely Immunocompromised

In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), a wide range of plasma posaconazole exposures was noted following administration of Noxafil oral suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 18). A lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.

Table 18: Noxafil Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials

Cavg = the average posaconazole concentration when measured at steady state
	Prophylaxis in AML/MDS Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS		Prophylaxis in GVHD HSCT recipients with GVHD
	Cavg Range (ng/mL)	Treatment Failure Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections (%)	Cavg Range (ng/mL)	Treatment Failure (%)
Quartile 1	90-322	54.7	22-557	44.4
Quartile 2	322-490	37.0	557-915	20.6
Quartile 3	490-734	46.8	915-1563	17.5
Quartile 4	734-2200	27.8	1563-3650	17.5

Exposure Response Relationship: Treatment of Invasive Aspergillosis in Adult and Adolescent Patients:

Across a range of posaconazole plasma minimum concentrations (C_min, range: 244 to 5663 ng/mL) following administration of Noxafil injection and Noxafil delayed-release tablets in adult and pediatric patients aged 14 years and older treated for invasive aspergillosis in Aspergillosis Treatment Study, there was no association between posaconazole C_min and treatment efficacy [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)]. Similarly, across a range of population pharmacokinetic model-predicted steady-state plasma average concentrations (Cavg, range: 589 to 6315 ng/mL), there was no association between posaconazole Cavg and treatment efficacy.

General Pharmacokinetic Characteristics

General Pharmacokinetic Characteristics of Noxafil Injection

Noxafil injection exhibits dose proportional pharmacokinetics after single doses between 200 and 300 mg in healthy volunteers and patients. The mean pharmacokinetic parameters after single doses with Noxafil injection in healthy volunteers and patients are shown in Table 19.

Table 19: Summary of Mean Pharmacokinetic Parameters (%CV) in Healthy Volunteers (30 minute infusion via peripheral venous line) and Patients (90 minute infusion via central venous line) after Dosing with Noxafil Injection on Day 1

	Dose (mg)	n	AUC0-∞ (ng∙hr/mL)	AUC0-12 (ng∙hr/mL)	Cmax (ng/mL)	t1/2 (hr)	CL (L/hr)
AUC0-∞ = Area under the plasma concentration-time curve from time zero to infinity; AUC0-12 = Area under the plasma concentration-time curve from time zero to 12 hr after the first dose on Day 1; Cmax = maximum observed concentration; t½ = terminal phase half-life; CL = total body clearance; N/D = Not Determined
Healthy Volunteers	200	9	35400 (50)	8840 (20)	2250 (29)	23.6 (23)	6.5 (32)
	300	9	46400 (26)	13000 (13)	2840 (30)	24.6 (20)	6.9 (27)
Patients	200	30	N/D	5570 (32)	954 (44)	N/D	N/D
	300	22	N/D	8240 (26)	1590 (62)	N/D	N/D

Table 20 displays the pharmacokinetic parameters of posaconazole in patients following administration of Noxafil injection 300 mg taken once a day for 10 or 14 days following twice daily dosing on Day 1.

Table 20: Arithmetic Mean (%CV) of PK Parameters in Serial PK-Evaluable Patients Following Dosing of Noxafil Injection (300 mg)

300 mg dose administered over 90 minutes once a day following twice daily dosing on Day 1

Day	N	Cmax (ng/mL)	Tmax Median (minimum-maximum) (hr)	AUC0-24 (ng*hr/mL)	Cav (ng/mL)	Cmin (ng/mL)
AUC0-24 = area under the concentration-time curve over the dosing interval (i.e., 24 hours); Cav= time-averaged concentrations (i.e., AUC0-24h/24hr);
Cmin = POS trough level immediately before a subject received the dose of POS on the day specified in the protocol; Cmax = observed maximum plasma concentration; CV = coefficient of variation, expressed as a percent (%); Day = study day on treatment; Tmax = time of observed maximum plasma concentration.
10/14	49	3280 (74)	1.5 (0.98-4.0)	36100 (35)	1500 (35)	1090 (44)

General Pharmacokinetic Characteristics of Noxafil Delayed-Release Tablets

Noxafil delayed-release tablets exhibit dose proportional pharmacokinetics after single and multiple dosing up to 300 mg. The mean pharmacokinetic parameters of posaconazole at steady state following administration of Noxafil delayed-release tablets 300 mg twice daily on Day 1, then 300 mg once daily thereafter in healthy volunteers and in neutropenic patients who are receiving cytotoxic chemotherapy for AML or MDS or HSCT recipients with GVHD are shown in Table 21.

Table 21: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Noxafil Delayed-Release Tablets (300 mg)

300 mg twice daily on Day 1, then 300 mg once daily thereafter

	N	AUC0-24 hr (ng∙hr/mL)	Cav Cav = time-averaged concentrations (i.e., AUC0-24 hr/24 hr) (ng/mL)	Cmax (ng/mL)	Cmin (ng/mL)	Tmax Median (minimum-maximum) (hr)	t1/2 (hr)	CL/F (L/hr)
CV = coefficient of variation expressed as a percentage (%CV); AUC0-T = Area under the plasma concentration-time curve from time zero to 24 hr; Cmax = maximum observed concentration; Cmin = minimum observed plasma concentration; Tmax = time of maximum observed concentration; t½ = terminal phase half-life; CL/F = Apparent total body clearance
Healthy Volunteers	12	51618 (25)	2151 (25)	2764 (21)	1785 (29)	4 (3-6)	31 (40)	7.5 (26)
Patients	50	37900 (42)	1580 (42)	2090 (38)	1310 (50)	4 (1.3-8.3)	-	9.39 (45)

General Pharmacokinetic Characteristics of Noxafil Oral Suspension

Dose-proportional increases in plasma exposure (AUC) to Noxafil oral suspension were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg twice daily to 400 mg twice daily in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg twice daily to 600 mg twice daily in febrile neutropenic patients or those with refractory invasive fungal infections.

The mean (%CV) [min-max] Noxafil oral suspension average steady-state plasma concentrations (Cavg) and steady-state pharmacokinetic parameters in patients following administration of 200 mg three times a day and 400 mg twice daily of the oral suspension are provided in Table 22.

Table 22: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Noxafil Oral Suspension 200 mg Three Times a Day and 400 mg Twice Daily

Dose Oral suspension administration	Cavg (ng/mL)	AUC AUC (0-24 hr) for 200 mg three times a day and AUC (0-12 hr) for 400 mg twice daily (ng∙hr/mL)	CL/F (L/hr)	V/F (L)	t½ (hr)
Cavg = the average posaconazole concentration when measured at steady state
The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.
200 mg three times a day HSCT recipients with GVHD (n=252)	1103 (67) [21.5-3650]	ND Not done	ND	ND	ND
200 mg three times a day Neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes (n=215)	583 (65) [89.7-2200]	15,900 (62) [4100-56,100]	51.2 (54) [10.7-146]	2425 (39) [828-5702]	37.2 (39) [19.1-148]
400 mg twice daily Febrile neutropenic patients or patients with refractory invasive fungal infections, Cavg n=24 (n=23)	723 (86) [6.70-2256]	9093 (80) [1564-26,794]	76.1 (78) [14.9-256]	3088 (84) [407-13,140]	31.7 (42) [12.4-67.3]

Absorption:

Absorption of Noxafil Delayed-Release Tablets

When given orally in healthy volunteers, Noxafil delayed-release tablets are absorbed with a median T_max of 4 to 5 hours. Steady-state plasma concentrations are attained by Day 6 at the 300 mg dose (once daily after twice daily loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. The C_max and AUC of posaconazole following administration of Noxafil delayed-release tablets are increased 16% and 51%, respectively, when given with a high fat meal compared to a fasted state (see Table 23).

Table 23: Statistical Comparison of Plasma Pharmacokinetics of Posaconazole Following Single Oral Dose Administration of 300 mg Noxafil Delayed-Release Tablet to Healthy Subjects under Fasting and Fed Conditions

	Fasting Conditions		Fed Conditions (High Fat Meal) 48.5 g fat		Fed/Fasting
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
GMR=Geometric least-squares mean ratio; CI=Confidence interval
Cmax (ng/mL)	14	935 (34)	16	1060 (25)	1.16 (0.96, 1.41)
AUC0-72hr (hr∙ng/mL)	14	26200 (28)	16	38400 (18)	1.51 (1.33, 1.72)
Tmax Median (Min, Max) reported for Tmax (hr)	14	5.00 (3.00, 8.00)	16	6.00 (5.00, 24.00)	N/A

Absorption of Noxafil PowderMix for Delayed-Release Oral Suspension

The absolute bioavailability of the Noxafil PowderMix for delayed-release oral suspension is approximately 70-80%. The effect of food on the pharmacokinetics of the Noxafil PowderMix for delayed-release oral suspension has not been determined.

Absorption of Noxafil Oral Suspension

Noxafil oral suspension is absorbed with a median T_max of ~3 to 5 hours. Steady-state plasma concentrations are attained at 7 to 10 days following multiple-dose administration.

Following single-dose administration of 200 mg, the mean AUC and C_max of posaconazole are approximately 3 times higher when the oral suspension is administered with a nonfat meal and approximately 4 times higher when administered with a high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of Noxafil oral suspension 400 mg, the mean AUC and C_max of posaconazole are approximately 3 times higher when administered with a liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 24). In addition, the effects of varying gastric administration conditions on the C_max and AUC of Noxafil oral suspension in healthy volunteers have been investigated and are shown in Table 25.

To assure attainment of adequate plasma concentrations, it is recommended to administer Noxafil oral suspension during or immediately following a full meal. In patients who cannot eat a full meal, Noxafil oral suspension should be taken with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).

Table 24: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-Dose Noxafil Oral Suspension Administration of 200 mg and 400 mg Under Fed and Fasted Conditions

Dose (mg)	Cmax (ng/mL)	Tmax Median [min-max]. (hr)	AUC (I) (ng∙hr/mL)	CL/F (L/hr)	t½ (hr)
200 mg fasted (n=20) n=15 for AUC (I), CL/F, and t½	132 (50) [45-267]	3.50 [1.5-36 The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between 4 hrs and 36 hrs). ]	4179 (31) [2705-7269]	51 (25) [28-74]	23.5 (25) [15.3-33.7]
200 mg nonfat (n=20)	378 (43) [131-834]	4 [3-5]	10,753 (35) [4579-17,092]	21 (39) [12-44]	22.2 (18) [17.4-28.7]
200 mg high fat (54 gm fat) (n=20)	512 (34) [241-1016]	5 [4-5]	15,059 (26) [10,341-24,476]	14 (24) [8.2-19]	23.0 (19) [17.2-33.4]
400 mg fasted (n=23) n=10 for AUC (I), CL/F, and t½	121 (75) [27-366]	4 [2-12]	5258 (48) [2834-9567]	91 (40) [42-141]	27.3 (26) [16.8-38.9]
400 mg with liquid nutritional supplement (14 gm fat) (n=23)	355 (43) [145-720]	5 [4-8]	11,295 (40) [3865-20,592]	43 (56) [19-103]	26.0 (19) [18.2-35.0]

Table 25: The Effect of Varying Gastric Administration Conditions on the C_max and AUC of Noxafil Oral Suspension in Healthy Volunteers

In 5 subjects, the C_max and AUC decreased substantially (range: -27% to -53% and -33% to -51%, respectively) when Noxafil was administered via an NG tube compared to when Noxafil was administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when Noxafil is administered via an NG tube because a lower plasma exposure may be associated with an increased risk of treatment failure.

Study Description	Administration Arms	Change in Cmax (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for Cmax or AUC. ; 90% CI of the ratio estimate)	Change in AUC (ratio estimate; 90% CI of the ratio estimate)
400 mg single dose with a high-fat meal relative to fasted state (n=12)	5 minutes before high-fat meal	↑96% (1.96; 1.48-2.59)	↑111% (2.11; 1.60-2.78)
	During high-fat meal	↑339% (4.39; 3.32-5.80)	↑382% (4.82; 3.66-6.35)
	20 minutes after high-fat meal	↑333% (4.33; 3.28-5.73)	↑387% (4.87; 3.70-6.42)
400 mg twice daily and 200 mg four times daily for 7 days in fasted state and with liquid nutritional supplement (BOOST®) (n=12)	400 mg twice daily with BOOST	↑65% (1.65; 1.29-2.11)	↑66% (1.66; 1.30-2.13)
	200 mg four times daily with BOOST	No Effect	No Effect
Divided daily dose from 400 mg twice daily to 200 mg four times daily for 7 days regardless of fasted conditions or with BOOST (n=12)	Fasted state	↑136% (2.36; 1.84-3.02)	↑161% (2.61; 2.04-3.35)
	With BOOST	↑137% (2.37; 1.86-3.04)	↑157% (2.57; 2.00-3.30)
400 mg single dose with carbonated acidic beverage (ginger ale) and/or proton pump inhibitor (esomeprazole) (n=12)	Ginger ale	↑92% (1.92; 1.51-2.44)	↑70% (1.70; 1.43-2.03)
	Esomeprazole	↓32% (0.68; 0.53-0.86)	↓30% (0.70; 0.59-0.83)
400 mg single dose with a prokinetic agent (metoclopramide 10 mg three times a day for 2 days) + BOOST or an antikinetic agent (loperamide 4 mg single dose) + BOOST (n=12)	With metoclopramide + BOOST	↓21% (0.79; 0.72-0.87)	↓19% (0.81; 0.72-0.91)
	With loperamide + BOOST	↓3% (0.97; 0.88-1.07)	↑11% (1.11; 0.99-1.25)
400 mg single dose either orally with BOOST or via an NG tube with BOOST (n=16)	Via NG tube NG = nasogastric	↓19% (0.81; 0.71-0.91)	↓23% (0.77; 0.69-0.86)

Distribution:

The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226-295 L between studies and dose levels.

Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin.

Metabolism:

Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. Posaconazole is a substrate for p-glycoprotein (P-gp) efflux.

In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4.

Excretion:

Following administration of Noxafil oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).

Noxafil injection is eliminated with a mean terminal half-life (t_½) of 27 hours and a total body clearance (CL) of 7.3 L/h.

Noxafil delayed-release tablet is eliminated with a mean half-life (t_½) ranging between 26 to 31 hours.

Noxafil oral suspension is eliminated with a mean half-life (t_½) of 35 hours (range: 20-66 hours).

Specific Populations:

No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment).

Patients with Renal Impairment:

After Noxafil oral administration, there were no significant differences in the posaconazole pharmacokinetics in patients with eGFR 20 mL/minute/1.73 m² or higher compared to those with eGFR >80 mL/minute/1.73 m². Although the mean posaconazole plasma exposure (AUC) was similar in patients with eGFR less than 20 mL/minute/1.73 m² treated with Noxafil oral suspension to those with eGFR >80 mL/minute/1.73 m² treated with Noxafil oral suspension, the range of the AUC estimates was highly variable (CV=96%) in patients with eGFR less than 20 mL/minute/1.73 m² compared to those with eGFR >80 mL/minute/1.73 m² (CV<40%).Similar posaconazole pharmacokinetic results are expected after administration of Noxafil delayed-release tablets [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment:

After a single oral dose of Noxafil oral suspension 400 mg, the mean AUC was 43%, 27%, and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), or severe (Child-Pugh Class C, N=6) hepatic impairment, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean C_max was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively [see Use in Specific Populations (8.7)].

Race/Ethnicity:

In a population pharmacokinetic analysis of posaconazole, AUC was found to be 25% higher in Chinese patients relative to patients from other races/ethnicities. This higher exposure is not expected to be clinically relevant given the expected variability in posaconazole exposure [see Use in Specific Populations (8.9)].

Patients Weighing More Than 120 kg:

Weight has a clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered Noxafil weighing more than 120 kg may be at higher risk for lower posaconazole plasma concentrations compared to lower weight patients [see Use in Specific Populations (8.10)].

Pediatric Patients:

Prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 2 years of age and older: A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) of Noxafil oral suspension for prophylaxis of invasive fungal infections. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state Cav was similar between these patients and adults (≥18 years of age). In a study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with Noxafil oral suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients.

The mean pharmacokinetic parameters after multiple-dose administration of Noxafil injection and Noxafil PowderMix for delayed-release oral suspension in neutropenic pediatric patients 2 to less than 18 years of age (Pediatric Study 1) are shown in Table 26. Patients were enrolled into 2 age groups and received Noxafil injection and Noxafil PowderMix for delayed-release oral suspension doses at 6 mg/kg (0.6 to 1 times the recommended dose) with a maximum 300 mg dose once daily (twice daily on Day 1) [see Adverse Reactions (6.1)].

Table 26: Summary of Steady-State Geometric Mean Pharmacokinetic Parameters (% Geometric CV) After Multiple Dosing with Noxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension 6 mg/kg

0.6 to 1 times the recommended dose

in Pediatric Patients with Neutropenia or Expected Neutropenia

Age Group	Dose Type	N	AUC0-24 hr (ng·hr/mL)	Cav Cav = time-averaged concentrations (i.e., AUC0-24 hr/24 hr) (ng/mL)	Cmax (ng/mL)	Cmin (ng/mL)	Tmax Median (minimum-maximum) (hr)	CL/F Clearance (CL for IV and CL/F for PFS) (L/hr)
IV= Noxafil injection; PFS= Noxafil PowderMix for delayed-release oral suspension; AUC0-24 = Area under the plasma concentration-time curve from time zero to 24 hr; Cmax = maximum observed concentration; Cmin = minimum observed plasma concentration; Tmax = time of maximum observed concentration; CL/F = apparent total body clearance
2 to <7 years	IV	17	31100 (48.9)	1300 (48.9)	3060 (54.1)	626 (104.8)	1.75 (1.57-1.83)	3.27 (49.3)
	PFS	7	23000 (47.3)	960 (47.3)	1510 (43.4)	542 (68.8)	4.00 (2.17-7.92)	4.60 (35.2)
7 to 17 years	IV	24	44200 (41.5)	1840 (41.5)	3340 (39.4)	1160 (60.4)	1.77 (1.33-6.00)	4.76 (55.7)
	PFS	12	25000 (184.3)	1040 (184.3)	1370 (178.5)	713 (300.6)	2.78 (0.00-4.00)	8.39 (190.3)

Based on a population pharmacokinetic model evaluating posaconazole pharmacokinetics and predicting exposures in pediatric patients, the exposure of steady-state posaconazole average concentration greater than or equal to 700 ng/mL in approximately 90% of patients is attained with the recommended dose of Noxafil injection and Noxafil PowderMix for delayed-release oral suspension.

The population pharmacokinetic analysis of posaconazole in pediatric patients from Pediatric Study 1 suggests that age, sex, renal impairment and ethnicity have no clinically meaningful effect on the pharmacokinetics of posaconazole.

Treatment of invasive aspergillosis in pediatric patients 2 years of age and older: A total of 31 patients 2 to less than 18 years of age (body weight of ≥12 kg) received pediatric dosing based on body weight of Noxafil delayed-release tablets, Noxafil Injection, and Noxafil PowderMix for delayed-release oral suspension [see Dosage and Administration (2.3].

The mean population pharmacokinetic model parameters after multiple dose administration of Noxafil delayed-release tablets, Noxafil Injection, and Noxafil PowderMix for delayed-release oral suspension in pediatric patients 2 to less than 18 years of age for the treatment of invasive aspergillosis (Pediatric Study 2) are shown in Table 27. [see Adverse Reactions (6.1)].

Table 27: Summary of Steady-State Geometric Mean Pharmacokinetic Parameters

Parameter estimates reported only for N>2 (excludes a single patient ≥2 to <12 receiving tablet and 2 patients ≥12 to <18 years receiving PFS)

(% Geometric CV) After Multiple Dosing with Noxafil Injection, Noxafil PowderMix for Delayed-Release Oral Suspension, and Noxafil Delayed-Release Tablets in Pediatric Patients being Treated for Invasive Aspergillosis

Age Group	Dose Type	N Some patients had 2 values (1 for IV dosing and 1 for oral dosing)	AUC0-24 hours (ng·hr/mL)	Cav Cav = time-averaged concentrations (i.e., AUC0-24 hours/24hr) (ng/mL)	Cmax (ng/mL)	Cmin (ng/mL)	Tmax Median (minimum-maximum) (hr)	CL/F Clearance (CL for IV and CL/F for PFS or Tablet) (L/hr)
IV = Noxafil injection; PFS = Noxafil PowderMix for delayed-release oral suspension; Tablet = Noxafil delayed-release tablets; AUC0-24 hours = Area under the plasma concentration-time curve from time zero to 24 hr; Cmax = maximum observed concentration; Cmin = minimum observed plasma concentration; Tmax = time of maximum observed concentration; CL/F = apparent total body clearance
2 to <12 years	IV	9	61900 (49.8)	2580 (49.8)	3630 (30.8)	1710 (82.2)	1.50 (1.25-1.77)	2.56 (47.8)
	PFS	6	45200 (30.2)	1880 (30.2)	2220 (26.5)	1370 (41.8)	7.00 (6.40-7.20)	3.25 (34.6)
12 to <18 years	IV	13	60800 (35.6)	2530 (35.6)	3510 (26.8)	1740 (48.5)	1.50 (1.30-1.63)	4.41 (41.8)
	Tablet	10	47800 (52.7)	1990 (52.7)	2250 (48.3)	1580 (62.6)	7.15 (6.70-7.30)	6.27 (52.7)

The population pharmacokinetic analysis of posaconazole in pediatric patients, including Pediatric Study 2, suggests that age, sex, ethnicity, and disease status have no clinically meaningful effect on the pharmacokinetics of posaconazole

Drug Interaction Studies:

Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically with the oral suspension or another tablet formulation, which affect posaconazole concentrations, is provided in Table 28.

Table 29 and Table 30 include a summary of the drug effects of concomitant medications that may impact the absorption of posaconazole when administered as either the oral suspension or delayed-release tablets.

A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 31 [see Contraindications (4) and Drug Interactions (7.2) including recommendations].

Effects of Other Drugs on Noxafil and Noxafil PowderMix:

Table 28: Summary of the Effects of Coadministered Drugs on Noxafil in Healthy Volunteers

Coadministered Drug (Postulated Mechanism of Interaction)	Coadministered Drug Dose/Schedule	Noxafil Dose/Schedule	Effect on Bioavailability of Posaconazole
			Change in Mean Cmax (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to Noxafil alone for Cmax or AUC. ; 90% CI of the ratio estimate)	Change in Mean AUC (ratio estimate; 90% CI of the ratio estimate)
Efavirenz (UDP-G Induction)	400 mg once daily × 10 and 20 days	400 mg (oral suspension) twice daily × 10 and 20 days	↓45% (0.55; 0.47-0.66)	↓ 50% (0.50; 0.43-0.60)
Fosamprenavir (unknown mechanism)	700 mg twice daily × 10 days	200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily × 8 Days	↓21% 0.79 (0.71-0.89)	↓23% 0.77 (0.68-0.87)
Rifabutin (UDP-G Induction)	300 mg once daily × 17 days	200 mg (tablets) once daily × 10 days The tablet refers to a non-commercial tablet formulation without polymer.	↓ 43% (0.57; 0.43-0.75)	↓ 49% (0.51; 0.37-0.71)
Phenytoin (UDP-G Induction)	200 mg once daily × 10 days	200 mg (tablets) once daily × 10 days	↓ 41% (0.59; 0.44-0.79)	↓ 50% (0.50; 0.36-0.71)

Noxafil Oral Suspension: Concomitant administration of Noxafil oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (see Table 29.)

Table 29: The Effects of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Oral Suspension in Healthy Volunteers

Coadministered Drug (Postulated Mechanism of Interaction)	Coadministered Drug Dose/Schedule	Noxafil Dose/Schedule	Effect on Bioavailability of Posaconazole
			Change in Mean Cmax (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for Cmax or AUC. ; 90% CI of the ratio estimate)	Change in Mean AUC (ratio estimate; 90% CI of the ratio estimate)
Cimetidine (Alteration of gastric pH)	400 mg twice daily × 10 days	200 mg (tablets) once daily × 10 days The tablet refers to a non-commercial tablet formulation without polymer.	↓ 39% (0.61; 0.53-0.70)	↓ 39% (0.61; 0.54-0.69)
Esomeprazole (Increase in gastric pH) The drug interactions associated with the oral suspension are also relevant for the delayed-release tablet with the exception of Esomeprazole and Metoclopramide.	40 mg every morning × 3 days	400 mg (oral suspension) single dose	↓ 46% (0.54; 0.43-0.69)	↓ 32% (0.68; 0.57-0.81)
Metoclopramide (Increase in gastric motility)	10 mg three times a day × 2 days	400 mg (oral suspension) single dose	↓ 21% (0.79; 0.72-0.87)	↓ 19% (0.81; 0.72-0.91)

Noxafil Delayed-Release Tablets: Concomitant administration of Noxafil delayed-release tablets with drugs affecting gastric pH or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see Table 30).

Table 30: The Effects of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Delayed-Release Tablets in Healthy Volunteers

Coadministered Drug	Administration Arms	Change in Cmax (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to Noxafil alone for Cmax or AUC0-last. ; 90% CI of the ratio estimate)	Change in AUC0-last (ratio estimate; 90% CI of the ratio estimate)
Mylanta® Ultimate strength liquid (Increase in gastric pH)	25.4 mEq/5 mL, 20 mL	↑6% (1.06; 0.90 -1.26)↑	↑4% (1.04; 0.90 -1.20)
Ranitidine (Zantac®) (Alteration in gastric pH)	150 mg (morning dose of 150 mg Ranitidine twice daily)	↑4% (1.04; 0.88 -1.23)↑	↓3% (0.97; 0.84 -1.12)
Esomeprazole (Nexium®) (Increase in gastric pH)	40 mg (every morning for 5 days, Day -4 to 1)	↑2% (1.02; 0.88-1.17)↑	↑5% (1.05; 0.89 -1.24)
Metoclopramide (Reglan®) (Increase in gastric motility)	15 mg four times daily for 2 days (Day -1 and 1)	↓14% (0.86, 0.73,1.02)	↓7% (0.93, 0.803,1.07)

Noxafil PowderMix for Delayed-Release Oral Suspension: Concomitant administration of Noxafil PowderMix for delayed-release oral suspension with drugs affecting gastric pH or gastric motility would not be expected to demonstrate any significant effects on posaconazole pharmacokinetic exposure based on similarity to the delayed-release tablets.

An in vitro dissolution study was conducted to evaluate the impact of alcohol (5, 10, 20, and 40%) on the dissolution of Noxafil PowderMix delayed-release oral suspension. The study showed alcohol-induced dose-dumping potential with the Noxafil PowderMix delayed-release oral suspension [see Drug Interactions (7.1)].

Effects of Noxafil and Noxafil PowderMix on Other Drugs:

Table 31: Summary of the Effects of Noxafil on Coadministered Drugs in Healthy Adult Volunteers and Patients

Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)	Coadministered Drug Dose/Schedule	Noxafil Dose/ Schedule	Effect on Bioavailability of Coadministered Drugs
			Change in Mean Cmax (ratio estimate Ratio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for Cmax or AUC. ; 90% CI of the ratio estimate)	Change in Mean AUC (ratio estimate; 90% CI of the ratio estimate)
Sirolimus	2-mg single oral dose	400 mg (oral suspension) twice daily x 16 days	↑ 572% (6.72; 5.62-8.03)	↑ 788% (8.88; 7.26-10.9)
Cyclosporine	Stable maintenance dose in heart transplant recipients	200 mg (tablets) once daily x 10 days The tablet refers to a non-commercial tablet formulation without polymer.	↑ Cyclosporine whole blood trough concentrations Cyclosporine dose reductions of up to 29% were required
Tacrolimus	0.05-mg/kg single oral dose	400 mg (oral suspension) twice daily x 7 days	↑ 121% (2.21; 2.01-2.42)	↑ 358% (4.58; 4.03-5.19)
Simvastatin	40-mg single oral dose	100 mg (oral suspension) once daily x 13 days	Simvastatin ↑ 841% (9.41, 7.13-12.44) Simvastatin Acid ↑ 817% (9.17, 7.36-11.43)	Simvastatin ↑ 931% (10.31, 8.40-12.67) Simvastatin Acid ↑634% (7.34, 5.82-9.25)
		200 mg (oral suspension) once daily x 13 days	Simvastatin ↑ 1041% (11.41, 7.99-16.29) Simvastatin Acid ↑851% (9.51, 8.15-11.10)	Simvastatin ↑ 960% (10.60, 8.63-13.02) Simvastatin Acid ↑ 748% (8.48, 7.04-10.23)
Midazolam	0.4-mg single intravenous dose The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with Noxafil.	200 mg (oral suspension) twice daily x 7 days	↑ 30% (1.3; 1.13-1.48)	↑ 362% (4.62; 4.02-5.3)
	0.4-mg single intravenous dose	400 mg (oral suspension) twice daily x 7 days	↑62% (1.62; 1.41-1.86)	↑524% (6.24; 5.43-7.16)
	2-mg single oral dose	200 mg (oral suspension) once daily x 7 days	↑ 169% (2.69; 2.46-2.93)	↑ 470% (5.70; 4.82-6.74)
	2-mg single oral dose	400 mg (oral suspension) twice daily x 7 days	↑ 138% (2.38; 2.13-2.66)	↑ 397% (4.97; 4.46-5.54)
Rifabutin	300 mg once daily x 17 days	200 mg (tablets) once daily x 10 days	↑ 31% (1.31; 1.10-1.57)	↑ 72% (1.72;1.51-1.95)
Phenytoin	200 mg once daily PO x 10 days	200 mg (tablets) once daily x 10 days	↑ 16% (1.16; 0.85-1.57)	↑ 16% (1.16; 0.84-1.59)
Ritonavir	100 mg once daily x 14 days	400 mg (oral suspension) twice daily x 7 days	↑ 49% (1.49; 1.04-2.15)	↑ 80% (1.8;1.39-2.31)
Atazanavir	300 mg once daily x 14 days	400 mg (oral suspension) twice daily x 7 days	↑ 155% (2.55; 1.89-3.45)	↑ 268% (3.68; 2.89-4.70)
Atazanavir/ritonavir boosted regimen	300 mg/100 mg once daily x 14 days	400 mg (oral suspension) twice daily x 7 days	↑ 53% (1.53; 1.13-2.07)	↑ 146% (2.46; 1.93-3.13)

Mechanism of Action

Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole.

Resistance

Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known.

Antimicrobial Activity

Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].

Microorganisms

Aspergillus spp. and Candida spp.

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC .

Manuf. for: Merck Sharp & Dohme LLC
Rahway, NJ 07065, USA

For patent information: www.msd.com/research/patent

The trademarks referenced herein are owned by their respective companies.

Copyright © 2006-2026 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates.
All rights reserved.

uspi-mk5592-mf-2601r050

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.

Table 15 and Table 17 include drugs with clinically important drug interactions when administered concomitantly with Noxafil and Noxafil PowderMix and instructions for preventing or managing them. Table 16 includes important drug interactions specific to the absorption of posaconazole administered as either Noxafil oral suspension or Noxafil PowderMix.

These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse reactions or loss of efficacy [see Clinical Pharmacology (12.3)].

The following information was derived from data with Noxafil oral suspension or another posaconazole tablet formulation unless otherwise noted. All clinically important drug interactions with Noxafil oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility), are considered relevant to clinically important drug interactions with Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix for delayed-release oral suspension [see Clinical Pharmacology (12.3)].

Consult the labeling of concomitantly used drugs to obtain further information about interactions with posaconazole.

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)].

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).

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.

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.

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.

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.

No adjustment in the dosage of Noxafil is necessary based on sex.

No adjustment in the dosage of Noxafil is necessary based on race.

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)].

There is no experience with overdosage of Noxafil injection and Noxafil delayed-release tablets.

During the clinical trials, some patients received Noxafil oral suspension up to 1,600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg twice daily Noxafil oral suspension for 3 days. No related adverse reactions were noted by the investigator.

Posaconazole is not removed by hemodialysis.

Noxafil and Noxafil PowderMix contain posaconazole, an azole antifungal agent.

Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C₃₇H₄₂F₂N₈O₄ and a molecular weight of 700.8. The chemical structure is:

Chemical Structure (Noxafil 02)

Posaconazole is a white powder with a low aqueous solubility.

Noxafil (posaconazole) Injection

Noxafil injection, for intravenous use, is a clear colorless to yellow, without preservatives sterile liquid essentially free of foreign matter. Each vial contains 300 mg of posaconazole and the following inactive ingredients: 6.68 g Betadex Sulfobutyl Ether Sodium (SBECD), 0.0033 g edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6, and water for injection.

Noxafil (posaconazole) Delayed-Release Tablets

Noxafil delayed-release tablet, for oral use, is yellow, coated, and oblong and contains 100 mg of posaconazole. Each delayed-release tablet contains the following inactive ingredients: croscarmellose sodium, hydroxypropylcellulose, hypromellose acetate succinate, iron oxide yellow, Macrogol/PEG 3350, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol partially hydrolyzed, silicon dioxide, talc, and titanium dioxide.

Noxafil (posaconazole) Oral Suspension

Noxafil oral suspension is a white, cherry-flavored immediate-release suspension that contains 40 mg of posaconazole per mL and the following inactive ingredients: artificial cherry flavor, citric acid monohydrate, glycerin, liquid glucose, polysorbate 80, purified water, simethicone, sodium benzoate, sodium citrate dihydrate, titanium dioxide, and xanthan gum.

Noxafil PowderMix (posaconazole) for Delayed-Release Oral Suspension

Noxafil PowderMix for delayed-release oral suspension is supplied as a component of a kit. Each kit contains Noxafil as an off-white to yellowish powder for delayed-release oral suspension, a bottle of mixing liquid, two 3 mL (green) notched tip syringes, two 10 mL (blue) notched tip syringes, two mixing cups, and one bottle adapter for the mixing liquid bottle.

• Noxafil PowderMix for delayed-release oral suspension contains 300 mg of posaconazole and the following inactive ingredient: hypromellose acetate succinate.
• The mixing liquid contains: anhydrous citric acid, antifoam Af emulsion, berry citrus sweet flavor, carboxymethylcellulose sodium, carrageenan calcium sulfate trisodium phosphate, glycerin, methylparaben, microcrystalline cellulose, potassium sorbate, propylparaben, purified water, sodium citrate, sodium phosphate monobasic monohydrate, sodium saccharin, sorbitol solution, and xanthan gum.

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

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).

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).

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.

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.

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).

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.

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)].

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Important Administration Instructions

Noxafil Delayed-Release Tablets

Advise patients that Noxafil delayed-release tablets must be swallowed whole and not divided, crushed, or chewed.

Instruct patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is within 12 hours of the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.

Noxafil Oral Suspension

Advise patients to take each dose of Noxafil oral suspension during or immediately (i.e., within 20 minutes) following a full meal. In patients who cannot eat a full meal, each dose of Noxafil oral suspension should be administered with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in order to enhance absorption.

Instruct patients that if they miss a dose, they should take it as soon as they remember. However, if it is almost time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.

Noxafil PowderMix for Delayed-Release Oral Suspension

Instruct parents and/or caregivers that ONLY the provided notched tip syringes can be used to administer Noxafil PowderMix for delayed-release oral suspension to pediatric patients.

Advise patients to take Noxafil PowderMix for delayed-release oral suspension with food.

Drug Interactions

Advise patients to inform their physician immediately if they:

• develop severe diarrhea or vomiting.
• are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.
• are currently taking a cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath.
• are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole.

Serious and Potentially Serious Adverse Reactions

Advise patients to inform their physician immediately if they:

• notice a change in heart rate or heart rhythm or have a heart condition or circulatory disease. Noxafil can be administered with caution to patients with potentially proarrhythmic conditions.
• are pregnant, plan to become pregnant, or are nursing.
• have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feel more tired than usual or feel like they have the flu.
• have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.

Hereditary Fructose Intolerance (HFI)

Inform patients and caregivers that Noxafil PowderMix for delayed-release oral suspension contains sorbitol and can be life-threatening when administered to patients with hereditary fructose intolerance (HFI) [see Warnings and Precautions (5.9)]. Inquire for symptoms of sorbitol/fructose and/or sucrose intolerance before administration.

Figure (Noxafil 06)

Before you start, be sure that you read and understand all of these instructions. They may be different than those for medicines that you have used in the past. It is important that you make all measurements very carefully. Before you give Noxafil PowderMix, check all 3 expiration dates. The expiration date is printed on the box, the Noxafil PowderMix packets, and the mixing liquid. Do not open the Noxafil PowderMix packets until you are ready to mix the dose. Give Noxafil PowderMix with food.

Figure (Noxafil 07)

• The amount of Noxafil PowderMix you give depends on your child’s weight. Your healthcare provider will tell you the right dose to give your child. Be sure to keep your healthcare provider’s appointments so you get new dosing information as your child grows.
• This booklet tells you how to:
  • Make the Noxafil PowderMix into a liquid form.
  • Measure the right dose using the included notched-tip
    oral syringe. Only use the notched-tip syringes supplied
    with the kit. Do not use other oral syringes.
  • Give the Noxafil PowderMix to your child.
  • Clean up.

  Note before adding Noxafil PowderMix: Make sure you and your child are ready! If you do not use Noxafil PowderMix within 1 hour, you will need to throw it away and start over.

  Note: If you have any questions, call your healthcare provider.

  Kit Contents

  Prescription (on Noxafil PowderMix box)	Figure (Noxafil 08)	2 mixing cups	Figure (Noxafil 09)
  Instructions for Use (this booklet)	Figure (Noxafil 10)	8 packets of Noxafil PowderMix	Figure (Noxafil 11)
  Package insert		Bottle adapter	Figure (Noxafil 12)
  4 syringes (shown below)		Bottle of Mixing Liquid for use with Noxafil PowderMix	Figure (Noxafil 13)

  Figure (Noxafil 14)	Figure (Noxafil 15)
  2 blue (10 mL) syringes	2 green (3 mL) syringes

  The kit has an extra cup and set of syringes in case one is lost or damaged. Do not use any damaged cups or syringes.

  Get to Know the Oral Syringes

  Figure (Noxafil 16)

  Before you prepare a dose, review the parts of the syringe and how to use them. If you have any questions about measuring with a syringe, call your healthcare provider. Make sure the plunger is pushed all the way into the barrel before you start to measure the dose.

  • Look for the number on the measuring scale that matches
    the amount of mixing liquid or Noxafil PowderMix that
    you need.
  • Be sure to follow the directions in this booklet to remove
    air bubbles from the syringe. Air bubbles can affect the
    amount of medicine that the child gets.

  Step 1. Get the mixing liquid ready.

  Important: Noxafil PowderMix needs to be prepared using the mixing liquid. Do not mix Noxafil PowderMix with milk, juice, or water.

  Figure (Noxafil 17)

  Figure (Noxafil 18)

  Figure (Noxafil 19)

  When you use the mixing liquid for the first time:

  • Open the bottle and remove the safety seal.
  • Place the bottle adapter on top of the bottle with
    the small hole facing up.
  • Push the bottle adapter all the way down.
  • After it is in place, the bottle adapter stays in the bottle.
  • Put the cap back on the bottle.

  Step 2. Gather all your supplies and put on a clean surface.

  Note: Put your child in a safe place. You will need both hands to prepare Noxafil PowderMix. Wash your hands with soap and water before preparing Noxafil PowderMix.

  Figure (Noxafil 20)	Figure (Noxafil 21)	Figure (Noxafil 22)	Figure (Noxafil 23)	Figure (Noxafil 24)
  1 mixing cup (Using the tab on the mixing cup, pull open the lid.)	1 packet of Noxafil PowderMix powder	Mixing liquid	2 syringes (Have 1 of each size ready, but you may only use 1, depending on the dose.)	Scissors (not included with kit: use sharp household scissors or kitchen scissors)
  	Figure (Noxafil 25)	The Noxafil PowderMix box has a mixing cup holder inside to help tilt the cup when you are measuring the dose.

  Step 3. Add Noxafil PowderMix to the mixing cup.

  Note before adding Noxafil PowderMix: Make sure you and your child are ready! If you do not use Noxafil PowderMix within 1 hour, you will need to throw it away and start over.

  Take 1 packet of Noxafil PowderMix and shake the powder to the bottom of the packet.	Figure (Noxafil 26)
  Cut open the packet of Noxafil PowderMix at the dotted line and add all of the Noxafil PowderMix to the mixing cup. Make sure the packet of Noxafil PowderMix is completely empty.	Figure (Noxafil 27)

  Step 4. Shake the mixing liquid bottle.

  Figure (Noxafil 28)

  Shake the mixing liquid well before each time you prepare Noxafil PowderMix.

  Step 5. Fill the blue syringe with 9 mL of mixing liquid.

  Push the plunger of the blue syringe into the syringe barrel as far as it goes. Remove the cap from the bottle of mixing liquid. Push the notched tip of the syringe into the bottle adapter. With the syringe attached to the bottle, turn the bottle and syringe upside down. With your other hand, pull back the plunger to draw the mixing liquid back into the syringe. Stop when you get to the 9 mL line. Turn the bottle back over and remove the syringe to check your measurement.

  Figure (Noxafil 29)

  Step 6. Check for air bubbles.

  Hold the syringe with notched tip up. Tap it with your finger to move any air bubbles up. Slowly push the plunger to make the air come out.	Figure (Noxafil 30)
  Figure (Noxafil 31)	Re-check the measurement of mixing liquid in the syringe. If it is less than 9 mL, put the notched tip back into the mixing liquid and pull the plunger back until you get to the 9 mL mark.

  Step 7. Add the 9 mL of mixing liquid to the Noxafil PowderMix.

  Figure (Noxafil 32)

  Add the 9 mL of mixing liquid to the Noxafil PowderMix in the mixing cup by pushing all the way down on the plunger.

  Step 8. Mix the Noxafil PowderMix.

  Snap the lid of the mixing cup shut. Shake the mixing cup really hard for 45 seconds to mix the Noxafil PowderMix.	Figure (Noxafil 33)
  Figure (Noxafil 34)	Check to make sure the Noxafil PowderMix powder is mixed. If it is not mixed, shake the mixing cup some more. Noxafil PowderMix should look cloudy and free of clumps.

  Step 9. Check your prescription label.

  Find the dose amount (look for the 'mL' written on the prescription label on the box from your healthcare provider).

  Figure (Noxafil 35)

  Note: The dose may change each time you go to the healthcare provider, so make sure you have all the recent information. Be sure to go to all of your child's healthcare provider appointments so your child gets the right dose.

  Step 10. Choose the syringe you need.

  Note: Only use the syringes provided in the kit.

  Choose the correct syringe for your child's dose:

  For 1 mL to 3 mL Green

  Figure (Noxafil 36)

  For 3 mL to 10 mL Blue

  Figure (Noxafil 37)

  • Then find the mL mark on the syringe that matches your
    child's dose.

  Step 11. Measure the Noxafil PowderMix.

  Push the plunger into the dosing syringe as far as it goes. Tilt the cup by hand or use the mixing cup holder inside the Noxafil PowderMix box. Put the notched tip of the dosing syringe into the lowest part of the cup with the Noxafil PowderMix and pull back the plunger. Stop when you get to the line showing the prescribed dose.

  Figure (Noxafil 38)

  Important: You will not use all of the Noxafil PowderMix. There will be some left over in the mixing cup.

  Step 12. Check for air bubbles.

  Be sure to follow the directions to remove air bubbles from the syringe. Air bubbles can affect the amount of medicine that the child gets. Hold the syringe with notched tip up. Tap it with your finger to move any air bubbles up. Check for air gaps in the tip of the syringe. Slowly push the plunger to make the air bubbles or air gaps come out.	Figure (Noxafil 39)
  Figure (Noxafil 40)	Re-check the measurement of Noxafil PowderMix in the syringe. If it is less than the prescribed dose, put the notched tip back into the mixing cup with the Noxafil PowderMix and pull the plunger back until you get to the right dose mark.

  Step 13. Give the Noxafil PowderMix to your child.

  Gently place the syringe inside your child’s mouth so that the notched tip touches one of his or her cheeks. Slowly push down on the plunger to give the dose of Noxafil PowderMix. It is important that your child takes all of the dose of Noxafil PowderMix (a little left in the syringe notched tip is ok).

  Figure (Noxafil 41)

  Important: If your child does not take the whole dose or spits some of it out, call your healthcare provider to find out what to do. Only use the mixing liquid from the kit. Do not mix Noxafil PowderMix with milk, juice, or water.

  Step 14. Clean the cup and syringes.

  Note: Syringes and mixing cups should be reused. Do not throw away syringes and mixing cups provided until all the Noxafil PowderMix packets are used.

  Pour the leftover Noxafil PowderMix from the mixing cup into the trash. Do not pour it into the sink. Pull the plungers out of any syringes you used. Hand wash the syringes, plungers, and mixing cup with warm water and dish soap. Do not wash in the dishwasher. Rinse with water and air dry. Put everything in a clean, dry place.

  Figure (Noxafil 42)

  Step 15. After all packets of Noxafil PowderMix have been used.

  • After you have used the last Noxafil PowderMix packet
    in this box, you will have leftover mixing liquid in the
    bottle. Throw away the leftover mixing liquid and all
    components of the kit.

  How should I store Noxafil PowderMix?

  • Store the entire kit at room temperature between 68°F to
    77°F (20°C to 25°C) in a clean, dry place.
  • Keep the mixing liquid at room temperature.
  • Do not open the Noxafil PowderMix packet until you are
    ready to mix a dose.

  Keep NOXAFIL PowderMix and all medicines out of the reach of children.

  For more information go to www.Noxafil.com or call
  1-800-622-4477.

  Distributed by:
  Merck Sharp & Dohme LLC
  Rahway, NJ 07065, USA

  For patent information: www.msd.com/research/patent

  Copyright © 2021-2022 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates.
  All rights reserved.

  ifu-mk5592-2209r002

  This Instructions for Use has been approved by the U.S. Food and
  Drug Administration.

  Revised: September 2022

NDC 0085-1328-01
105 mL

NOXAFIL^®
(posaconazole)

Oral Suspension

200 mg/5 mL

Each mL contains: 40 mg posaconazole.

Attention: Noxafil Oral Suspension is
NOT substitutable with Noxafil
Delayed-Release Tablets or Noxafil PowderMix
for Delayed-Release Oral Suspension due to
differences in the dosing of each formulation.

SHAKE WELL BEFORE EACH USE.

Take with a meal, or a nutritional supplement,
or an acidic carbonated beverage.

Carton contains measured dosing spoon.

Rx only

Principal Display Panel (105 mL Bottle Carton)

NDC 0085-4324-02

Noxafil^®
(posaconazole)
delayed-release tablets

100 mg

Each tablet contains 100 mg posaconazole.

Attention: Noxafil Oral Suspension and Delayed-
Release Tablets are NOT substitutable due to
differences in the dosing of each formulation.

Rx only

60 Tablets

Principal Display Panel (60 Tablet Bottle Label)

NDC 0085-4331-01

Noxafil^®
(posaconazole)
Injection

300 mg/16.7 mL
(18 mg/mL)

For Intravenous Use Only

Requires further dilution prior to infusion.

Rx only
Sterile Single-Dose Vial
Discard Unused Portion

Principal Display Panel (16.7 mL Vial Carton)

NDC 0085-2224-02

Noxafil^® PowderMix
(posaconazole) for
Delayed-Release Oral Suspension

300 mg

For Pediatric Use
For Oral Administration Only

Each packet contains 300 mg posaconazole.

Attention: Noxafil PowderMix for Delayed-Release Oral Suspension is NOT
substitutable with Noxafil Oral Suspension due to differences in the
dosing of each formulation.

Use only the notched-tip syringes and mixing liquid provided with this kit.

Rx only
8 packets

Multi-Dose Kit A
Additional notched-tip syringes are provided in
Package B with this kit.
DIRECTIONS FOR USE:
See instructions for use booklet and prescribing
information for additional information.

Principal Display Panel (300 mg Carton)