Drug Safety-related Labeling Changes (SrLC)

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NOXAFIL POWDERMIX KIT (NDA-214770)

(POSACONAZOLE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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01/27/2026 (SUPPL-9)

Approved Drug Label (PDF)

6 Adverse Reactions

Additions and/or revisions underlined:

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)]

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information.

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reaction has been identified during the post-approval use of Noxafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Endocrine Disorders: Pseudoaldosteronism

7 Drug Interactions

Additions and/or revisions underlined:

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 [Clinical Pharmacology (12.3)].

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

7.1 Effects of Other Drugs on Noxafil and Noxafil PowderMix

Subsection title revised

Additions and/or revisions underlined:

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

Newly added table; please refer to label for complete information.

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

Newly added table; please refer to label for complete information.

7.2 Effects of Noxafil and Noxafil PowderMix on Other Drugs

Subsection title revised

Additions and/or revisions underlined:

Posaconazole is a strong CYP3A4 inhibitor. Therefore, concomitant use of Noxafil may increase plasma concentrations of drugs that are CYP3A4 substrates [see Clinical Pharmacology (12.3)].

Table 17: Drug Interactions Affecting Drugs Administered Concomitantly with Noxafil and Noxafil PowderMix

Newly added table; please refer to label for complete information.

7.3 Absence of Clinically Important Interaction with Noxafil and Noxafil PowderMix

Subsection title revised

Additions and/or revisions underlined:

Additional clinical studies demonstrated that no clinically important effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with Noxafil 200 mg once daily; therefore, no dose adjustments are required for these drugs when coadministered with Noxafil 200 mg once daily.

No clinically relevant effects on the pharmacokinetics of Noxafil delayed-release tablets were observed during concomitant use with antacids, H2-receptor antagonists and proton pump inhibitors, and metoclopramide [see Clinical Pharmacology (12.3)]. No dosage adjustment of Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension is required during concomitant use with these drugs.

No clinically relevant effects on the pharmacokinetics of Noxafil oral suspension were observed during concomitant use with antacids, H2-receptor antagonists (other than cimetidine), and loperamide [see Clinical Pharmacology (12.3)]. No dosage adjustment of Noxafil oral suspension is required during concomitant use with these drugs (other than cimetidine).

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The three Noxafil dosage forms (injection, delayed-release tablets, oral suspension) and one Noxafil PowderMix (for delayed-release oral suspension) dosage form are different products; are approved for different pediatric indications, age groups, and weights; have different dosing regimens; and have different preparation and administration instructions. Therefore, select the recommended dosage form based on the pediatric indication, age group, and weight [see Dosage and Administration (2.1)].

Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with HFI. Because a diagnosis of HFI may not yet be established in pediatric patients, obtain a careful history of HFI symptoms with sorbitol/fructose/sucrose exposure prior to administration of Noxafil PowderMix for delayed-release oral suspension [see Warnings and Precautions (5.9)].

Treatment of Invasive Aspergillosis

The safety and effectiveness of Noxafil (injection and delayed-release tablets) have been established for the treatment of invasive aspergillosis in pediatric patients 2 years of age and older.

The safety and effectiveness of Noxafil PowderMix have been established for the treatment of invasive aspergillosis in pediatric patients 2 years of age and older who weigh 10 kg to 40 kg.

Use of Noxafil and Noxafil PowderMix for these pediatric indications is supported by evidence from adequate and well-controlled studies of Noxafil in adults and safety and pharmacokinetic (PK) data from two pediatric studies [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. The safety of Noxafil and Noxafil PowderMix in pediatric patients for these pediatric indications was consistent with the known safety profile of Noxafil in adults [see Adverse Reactions (6.1)].

Noxafil PowderMix for delayed-release oral suspension is not recommended for use in patients who weigh greater than 40 kg because the recommended dosage cannot be achieved with this dosage form.

The safety and effectiveness of Noxafil and Noxafil PowderMix have not been established in pediatric patients less than 2 years of age.

Prophylaxis of Invasive Aspergillus and Candida Infections

The safety and effectiveness of Noxafil (injection and delayed-release tablets) have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 2 years of age and older who are at high risk of developing these infections due to being severely immunocompromised.

The safety and effectiveness of Noxafil oral suspension have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 13 years of age and older who are at high risk of developing these infections due to being severely immunocompromised.

The safety and effectiveness of Noxafil PowderMix have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 2 years of age and older who weigh 10 kg to 40 kg who are at high risk of developing these infections due to being severely immunocompromised.

Use of Noxafil and Noxafil PowderMix for these pediatric indications is supported by adequate and well controlled studies of Noxafil in adults and pediatric patients aged 13 years of age and older and additional PK and safety data in pediatric patients 2 years of age and older [see Clinical Pharmacology (12.3) and Clinical studies (14)].

Noxafil PowderMix is not recommended for use in patients who weigh greater than 40 kg because the recommended dosage cannot be achieved with this dosage form.

The safety and effectiveness of Noxafil and Noxafil PowderMix have not been established in pediatric patients less than 2 years of age.

Treatment of Oropharyngeal Candidiasis, including Refractory to Itraconazole and/or Fluconazole

The safety and effectiveness of Noxafil oral suspension have been established for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in pediatric patients 13 years of age and older.

Use of Noxafil oral suspension for this pediatric indication is supported by adequate and well controlled studies in adults and pediatric patients 13 years of age and older [see Clinical studies (14.4)].

The Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix products are not approved for the treatment of oropharyngeal candidiasis in pediatric patients. Noxafil Oral Suspension is the only dosage form approved for the treatment of OPC and rOPC in pediatric patients [see Dosage and Administration (2.4)].

The safety and effectiveness of Noxafil oral suspension for the treatment of OPC and rOPC have not been established in pediatric patients less than 13 years of age.

8.5 Geriatric Use

Additions and/or revisions underlined:

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 greater than or equal to 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 greater than or equal to 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 greater than or equal to 65 years of age.

8.6 Renal Impairment

Additions and/or revisions underlined:

Noxafil Oral Suspension and Noxafil Delayed-Release Tablets

No dosage adjustment is required for patients with eGFR 20 mL/minute/1.73 m2 or higher.

Due to variability in posaconazole exposure, closely monitor patients with eGFR less than 20 mL/minute/1.73 m2 for breakthrough fungal infections. [see Clinical Pharmacology (12.3)].

Noxafil Injection

Avoid use of Noxafil injection in patients with eGFR less than 50 mL/minute/1.73 m2 unless the benefit/risk to the patient justifies its use. The inactive ingredient in Noxafil injection, Betadex Sulfobutyl Ether Sodium (SBECD) is expected to accumulate in patients with reduced renal function. Safety and effectiveness of Noxafil injection have not been established in patients with less than 50 mL/minute/1.73 m2.

If treatment with Noxafil injection is unavoidable in patients with eGFR less than 50 mL/minute/1.73 m2, monitor serum creatinine levels. If serum creatinine increases, consider changing to oral Noxafil therapy.

8.7 Hepatic Impairment

Additions and/or revisions underlined:

No dosage adjustment is recommended for Noxafil oral suspension, Noxafil delayed-release tablets, Noxafil PowderMix for delayed-release oral suspension, and Noxafil injection in patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C, respectively) [see Clinical Pharmacology (12.3)].

However, a specific hepatic impairment study has not been conducted with the Noxafil delayed- release tablets, Noxafil PowderMix for delayed-release oral suspension, or Noxafil injection.

8.10 Weight

Additions and/or revisions underlined:

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)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

. . .

Noxafil injection is used for:

• prevention of fungal infections in adults and children 2 years of age and older who weigh 22 lbs (10 kg) or greater.
• treatment of fungal infections in adults and children 2 years of age and older who weigh 22 lbs (10 kg) or greater.

Noxafil delayed-release tablets are used for:

• prevention of fungal infections in adults and children 2 years of age and older who weigh greater than 88 lbs (40 kg).
• treatment of fungal infections in adults and children 2 years of age and older who weigh greater than 88 lbs (40 kg).

Noxafil oral suspension is used for:

• prevention of fungal infections in adults and children 13 years of age and older.

Noxafil PowderMix for delayed-release oral suspension is used for:

• prevention of fungal infections in children 2 years of age and older who weigh 22 lbs to 88 lbs (10 kg to 40 kg).
• treatment of fungal infections in children 2 years of age and older who weigh 22 lbs to 88 lbs (10 kg to 40 kg).

Noxafil oral suspension is also used to treat a fungal infection called “thrush” caused by Candida in your mouth or throat area. Noxafil oral suspension can be used as the first treatment for thrush, or as another treatment for thrush after itraconazole or fluconazole treatment has not worked.

Noxafil oral suspension is for adults and children 13 years of age and older.

It is not known if Noxafil oral suspension is safe and effective in children under 13 years of age for the treatment of thrush as the first treatment for thrush, or as another treatment for thrush after itraconazole or fluconazole treatment has not worked.

It is not known if Noxafil or Noxafil PowderMix is safe and effective in children under 2 years of age.

Do not take Noxafil or Noxafil PowderMix if you:

• are allergic to posaconazole, any of the ingredients in Noxafil or Noxafil PowderMix, or other azole antifungal medicines. See the end of this Patient Information leaflet for a complete list of ingredients in Noxafil and Noxafil PowderMix.

. . .

Before you take Noxafil or Noxafil PowderMix, tell your healthcare provider about all of your medical conditions, including if you:

• are taking certain medicines that lower your immune system like cyclosporine or tacrolimus.

. . .

How should I take Noxafil or Noxafil PowderMix?

. . .

• Noxafil oral suspension:

. . .

• If you miss a dose, take it as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not take a double dose to make up for the missed dose or take more than your prescribed dose.

. . .

How should I store Noxafil or Noxafil PowderMix?

Noxafil injection

• Store Noxafil injection refrigerated between 36 degrees F to 46 degrees F (2 degrees C to 8 degrees C).

. . .

10/25/2024 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Pseudoaldosteronism

Newly added subsection:

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

…

What are the possible side effects of Noxafil or Noxafil PowderMix?

Noxafil or Noxafil PowderMix may cause serious side effects, including:

…

• new or worsening high blood pressure and low potassium levels in your blood (pseudoaldosteronism). Your healthcare provider should check your blood pressure and potassium levels.

…

01/13/2022 (SUPPL-2)

Approved Drug Label (PDF)

4 Contraindications

Newly added subsections:

4.6 Use with Venetoclax

Coadministration of Noxafil with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Warnings and Precautions (5.10) and Drug Interactions (7.16)].

4.7 Use of Noxafil PowderMix for Delayed-Release Oral Suspension in Patients with Hereditary Fructose Intolerance

Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with known or suspected hereditary fructose intolerance (HFI) [see Warnings and Precautions (5.8) and Use in Specific Populations (8.4)].

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Calcineurin-Inhibitor Toxicity

5.6 Midazolam Toxicity

Newly added subsections:

5.8 Risk in Patients with Hereditary Fructose Intolerance (HFI)

Noxafil PowderMix for delayed-release oral suspension contains sorbitol, an inactive ingredient, and may precipitate a metabolic crisis that may include, but is not limited to life-threatening hypoglycemia, hypophosphatemia, lactic acidosis, and hepatic failure in patients with HFI. Obtain careful history of HFI symptoms (nausea, vomiting, abdominal pain) with sorbitol/fructose/sucrose exposure prior to Noxafil PowderMix for delayed-release oral suspension administration because a diagnosis of HFI may not yet be established in pediatric patients [see Contraindications (4), Use in Specific Populations (8.4)].

5.9 Breakthrough Fungal Infections

Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving Noxafil delayed-release tablets, Noxafil oral suspension, or Noxafil PowderMix for delayed-release oral suspension.

5.10 Venetoclax Toxicity

Concomitant administration of Noxafil, a strong CYP3A4 inhibitor, with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS), neutropenia, and serious infections. In patients with CLL/SLL, administration of Noxafil during initiation and the ramp-up phase of venetoclax is contraindicated [see Contraindications (4.6)]. Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients.

For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering Noxafil with venetoclax [see Drug Interactions (7.16)]. Refer to the venetoclax prescribing information for dosing instructions.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Clinical Trial Experience in Adults

Clinical Trial Experience with Noxafil Injection and Noxafil Delayed-Release Tablets for the Treatment of Invasive Aspergillosis

The safety of Noxafil injection and Noxafil delayed-release tablet 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 (288 in Noxafil arm, 287 in voriconazole arm) adult and pediatric patients 13 years of age and older with proven, probable or possible invasive aspergillosis were included. The median duration of treatment was 67 days for Noxafil injection or Noxafil delayed-release tablet and 64 days for voriconazole, with 55% to 60% of subjects starting treatment with the IV formulation of either drug. The median duration of the first instance of IV treatment (before switching to oral treatment or discontinuing or completing study treatment) was 9 days for both groups. Table 7 presents adverse reactions reported at an incidence of greater than or equal to10% in either one of the groups in Aspergillosis Treatment Study.

Adverse reactions leading to treatment discontinuation were reported for 33.9% of subjects. The most commonly reported adverse reactions (>2% of subjects) leading to treatment discontinuation were septic shock, respiratory failure, and bronchopulmonary aspergillosis in the Noxafil arm, and septic shock and acute myeloid leukemia in the voriconazole arm.

Table 7: Noxafil Invasive Aspergillosis Treatment Study: Adverse Reactions in at Least 10% of Subjects Treated with Noxafil Injection or Noxafil Delayed-Release Tablets (Newly added table; please refer to label for complete information)

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 (INECTION)

Table 8: Noxafil Injection Study: Adverse Reactions in at Least 10% of Subjects Treated with Noxafil Injection 300 mg Daily Dose (Table renamed from original Table 6; data remains the same).

Clinical Trial Experience with Noxafil Delayed-Release Tablets for Prophylaxis

Table 9: Noxafil Delayed-Release Tablet Study: Adverse Reactions in at Least 10% of Subjects

Treated with 300 mg Daily Dose (Previously Table 7; Line item ‘Subjects Reporting any Adverse Reaction’ data has changed; please refer to label for complete information)

Table 10: Noxafil Oral Suspension Study 1 and Study 2. Adverse Reactions in at Least 10% of the Noxafil Oral Suspension or Fluconazole Treatment Groups (Pooled Prophylaxis Safety Analysis) (Previously Table 8; data remains the same)

Table 11: Adverse Reactions in at Least 10% of the Treated Population in OPC Studies with Noxafil Oral Suspension (Previously Table 9; data remains the same)

Additions and/or revisions underlined:

Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions (SARs) were reported in 55% (132/239). The most commonly reported SARs were fever (13%) and neutropenia (10%).

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

Table 12: Noxafil Oral Suspension Study 1 and Study 2. Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 (Previously Table 10; data remains the same)

Table 13: Noxafil Oral Suspension Studies: Clinically Significant Laboratory Test Abnormalities without Regard to Baseline Value

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

Table 14: Aspergillosis Treatment Study: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 (Newly added table; please refer to label for complete information)

Newly added information:

Clinical Trial Experience in Pediatrics

Clinical Trial Experience in Pediatric Patients (2 to less than 18 Years of Age)

The safety of Noxafil injection and Noxafil PowderMix for delayed-release oral suspension for prophylaxis of invasive fungal infections has been assessed in an open label uncontrolled dose-ranging PK and safety study (Noxafil injection/ Noxafil PowderMix for delayed-release oral suspension Pediatric Study 1, NCT02452034); hereinafter referred to as Noxafil Pediatric Study) in 115 immunocompromised pediatric patients 2 to less than 18 years of age with known or expected neutropenia. Noxafil injection and Noxafil PowderMix for delayed-release oral suspension was administered at daily doses of up to 6 mg/kg (twice daily on day 1) in three dose cohorts. All 115 subjects initially received Noxafil injection for at least 7 days, and 63 subjects were transitioned to Noxafil PowderMix for delayed-release oral suspension. The mean overall treatment duration for all treated subjects was 20.6 days with 14.3 days (range: 1 to 28 days) on Noxafil injection and 11.6 days (range: 2 to 18 days) on Noxafil PowderMix for delayed-release oral suspension [see Clinical Pharmacology (12.3)].

Table 15 presents adverse reactions observed in greater than or equal to 10% of pediatric patients treated with Noxafil in the Noxafil Pediatric Study.

Reported adverse reaction profile of Noxafil in pediatric patients was consistent with the safety profile of Noxafil in adults. The most common adverse reactions (occurring in greater than 20% of pediatric patients receiving 6 mg/kg Noxafil injection and Noxafil PowderMix for delayed-release oral suspension daily dose) were pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis.

Table 15: Adverse Reactions in at Least 10% of Pediatric Patients Treated with Noxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension (Newly added table; please refer to label for complete information)

The number of patients receiving Noxafil in the Noxafil Pediatric Study who had changes in liver tests from Grade 0, 1, or 2 at baseline to Grade 3 or 4 is presented in Table 16.

Table 16: Noxafil Pediatric Study: Changes in Liver Tests from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 (Newly added table; please refer to label for complete information)

7 Drug Interactions

Additions and/or revisions underlined:

… The following information was derived from data with Noxafil oral suspension or early tablet formulation unless otherwise noted. All drug interactions with Noxafil oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility), are considered relevant to Noxafil injection, Noxafil delayed-release tablet, and Noxafil PowderMix for delayed-release oral suspension as well [see Drug Interactions (7.9) and (7.13)].

7.9 Gastric Acid Suppressors/Neutralizers

Noxafil Delayed-Release Tablet and Noxafil PowderMix for Delayed-Release Oral Suspension:

… No dosage adjustment of Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension is required when concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors.

7.13 Gastrointestinal Motility Agents

Noxafil Delayed-Release Tablet and Noxafil PowderMix for Delayed-Release Oral Suspension:

… No dosage adjustment of Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension is required when given concomitantly with metoclopramide.

Noxafil Oral Suspension:

… No dosage adjustment of Noxafil oral suspension is required when loperamide and Noxafil oral suspension are used concomitantly.

Newly added subsections:

7.15 Alcohol

Posaconazole was found to release faster from Noxafil PowderMix for delayed-release oral suspension in the presence of alcohol in vitro, which may interfere with its delayed release characteristics. Administration of Noxafil PowderMix for delayed-release oral suspension with alcohol is not recommended [see Clinical Pharmacology (12.3)].

7.16 Venetoclax

Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax Cmax and AUC0-INF, which may increase venetoclax toxicities [see Contraindications (4.6), Warnings and Precautions (5.10)]. Refer to the venetoclax prescribing information for more information on the dosing instructions and the extent of increase in venetoclax exposure.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of Noxafil injection, Noxafil delayed-release tablets, Noxafil PowderMix for delayed-release oral suspension, and Noxafil oral suspension for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged 2 and older who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy.

The safety and effectiveness of Noxafil injection and Noxafil delayed-release tablets for the treatment of invasive aspergillosis have been established in pediatric patients aged 13 years and older.

The safety and effectiveness of Noxafil oral suspension have been established for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in pediatric patients aged 13 years and older.

Use of Noxafil in these age groups is supported by evidence from adequate and well-controlled studies of Noxafil in adult and pediatric patients and additional pharmacokinetic and safety data in pediatric patients 2 years of age and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)].

The safety and effectiveness of Noxafil have not been established in pediatric patients younger than 2 years of age.

Noxafil PowderMix for delayed-release oral suspension is not recommended for use in patients who weigh greater than 40 kg because the recommended dosage cannot be achieved with this formulation.

Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with HFI. Because 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 (5.8)].

8.5 Geriatric Use

Additions and/or revisions underlined:

No overall differences in the safety of Noxafil injection, Noxafil delayed-release tablets, and Noxafil oral suspension were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for any formulation of Noxafil in geriatric patients. No clinically meaningful differences in the pharmacokinetics of Noxafil were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology (12.3)].

Of the 279 patients treated with Noxafil injection in the Noxafil Injection Study, 52 (19%) were greater than 65 years of age. Of the 230 patients treated with Noxafil delayed-release tablets, 38 (17%) were greater than 65 years of age. Of the 605 patients randomized to Noxafil oral suspension in Noxafil Oral Suspension Study 1 and Study 2, 63 (10%) were greater than or equal to65 years of age. In addition, 48 patients treated with greater than or equal to 800- mg/day Noxafil oral suspension in another indication were greater than or equal to65 years of age.

Of the 288 patients randomized to Noxafil injection/Noxafil delayed-release tablets in the Aspergillosis Treatment Study, 85 (29%) were greater than or equal to65 years of age.

No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.

8.7 Hepatic Impairment

Additions and/or revisions underlined:

… It is recommended that no dose adjustment of Noxafil oral suspension, Noxafil delayed-release tablets, Noxafil PowderMix for delayed-release oral suspension, and Noxafil injection is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2) and Warnings and Precautions (5.4)]. However, a specific study has not been conducted with Noxafil delayed- release tablets, Noxafil PowderMix for delayed-release oral suspension, and Noxafil injection.

8.8 Gender

Additions and/or revisions underlined:

The pharmacokinetics of posaconazole are comparable in males and females. No adjustment in the dosage of Noxafil is necessary based on gender.

8.10 Weight

Additions and/or revisions underlined:

… It is, therefore, suggested to closely monitor for breakthrough fungal infections particularly when using Noxafil oral suspension [see Clinical Pharmacology (12.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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

Important Administration Instructions

Noxafil Delayed-Release Tablets …

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.

Hereditary Fructose Intolerance (HFI)

Inform patients and caregivers that Noxafil PowderMix for delayed-release oral suspension contains sorbitol and can be life-threatening when administered to patients with hereditary fructose intolerance (HFI) [see Warnings and Precautions (5.8)]. Inquire for symptoms of sorbitol/fructose and/or sucrose intolerance before administration.

PATIENT INFORMATION

Additions and/or revisions underlined:

What is Noxafil and Noxafil PowderMix?

Noxafil (which refers to injection, delayed-release tablets, and oral suspension) and Noxafil PowderMix (for delayed- release oral suspension) are prescription medicines used in adults and children to help prevent or treat fungal infections that can spread throughout your body (invasive fungal infections).

Noxafil injection is used for:

• prevention of fungal infections in adults and children 2 years of age and older.

• treatment of fungal infections in adults and children 13 years of age and older.

Noxafil delayed-release tablets are used for:

• prevention of fungal infections in adults and children 2 years of age and older who weigh greater than 88 lbs (40 kg).

• treatment of fungal infections in adults and children 13 years of age and older.

Noxafil oral suspension is used for:

• prevention of fungal infections in adults and children 13 years of age and older.

Noxafil PowderMix for delayed-release oral suspension is used for:

• prevention of fungal infections in children 2 years of age and older who weigh 88 lbs (40 kg) or less.

Who should not take Noxafil or Noxafil PowderMix?

Do not take Noxafil or Noxafil PowderMix if you:

• are allergic to posaconazole, any of the ingredients in Noxafil or Noxafil PowderMix, or other azole antifungal medicines. See the end of this leaflet for a complete list of ingredients in Noxafil and Noxafil PowderMix.

• have chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and you have just started taking venetoclax or your venetoclax dose is being slowly increased.

• are taking Noxafil PowderMix for delayed-release oral suspension and have hereditary fructose intolerance.

What should I tell my healthcare provider before taking Noxafil or Noxafil PowderMix?

Before you take Noxafil or Noxafil PowderMix, tell your healthcare provider if you:

• are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and fosamprenavir can cause a decrease in the Noxafil levels in your body. Efavirenz and fosamprenavir should not be taken with Noxafil or Noxafil PowderMix.

• are taking venetoclax, a medicine used to treat cancer.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Noxafil and Noxafil PowderMix can affect the way other medicines work, and other medicines can affect the way Noxafil and Noxafil PowderMix work, and can cause serious side effects.

Especially tell your healthcare provider if you take:

• rifabutin or phenytoin. If you are taking these medicines, you should not take Noxafil delayed-release tablets, Noxafil oral suspension, or Noxafil PowderMix for delayed-release oral suspension.

How will I take Noxafil or Noxafil PowderMix?

• Do not switch between Noxafil oral suspension and Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension.

• Take Noxafil or Noxafil PowderMix exactly as your healthcare provider tells you to take it.

• Your healthcare provider will tell you how much Noxafil or Noxafil PowderMix to take and when to take it.

• Take Noxafil or Noxafil PowderMix for as long as your healthcare provider tells you to take it.

• If you take too much Noxafil or Noxafil PowderMix, call your healthcare provider or go to the nearest hospital emergency room right away.

• Noxafil delayed-release tablets:

• Take Noxafil delayed-release tablets with or without food.

• Noxafil PowderMix for delayed-release oral suspension:

• Before giving the first dose of Noxafil PowderMix for delayed-release oral suspension, read the Instructions for Use booklet that comes with Noxafil PowderMix for delayed-release oral suspension for information about the correct way to mix and give a dose of Noxafil PowderMix for delayed-release oral suspension to your child. Keep the booklet and follow it each time you prepare the medicine. Bring this booklet to your child’s appointments.

• If you have questions about how to mix or give Noxafil PowderMix, talk with your healthcare provider or pharmacist.

• Only use the mixing liquid that comes with the kit to prepare Noxafil PowderMix.

• Once mixed, measure the prescribed dose with notched tip syringe provided with the kit. Only use the notched tip syringes that come with the kit to prepare and administer the medicine.

• Give the dose within 1 hour of mixing the suspension. Give with food.

• If your child does not take all of the prescribed dose or spits some of it out, call your healthcare provider to find out what to do.

What are the possible side effects of Noxafil or Noxafil PowderMix?

Noxafil or Noxafil PowderMix may cause serious side effects, including:

• changes in body salt (electrolytes) levels in your blood. Your healthcare provider should check your electrolytes while you are taking Noxafil or Noxafil PowderMix.

  The most common side effects of Noxafil injection and Noxafil PowderMix in children include:

• Fever

• itching

• high blood pressure

• fever with low white blood cell count (febrile neutropenia)

• low potassium levels in the blood

• vomiting

• redness and sores of the lining of the mouth, lips, throat, stomach, and genitals (mucositis or stomatitis)

If you take Noxafil delayed-release tablets, Noxafil oral suspension, or Noxafil PowderMix for delayed-release oral suspension, tell your healthcare provider right away if you have diarrhea or vomiting.

These are not all the possible side effects of Noxafil or Noxafil PowderMix. For more information, ask your healthcare provider or pharmacist.

How should I store Noxafil or Noxafil PowderMix?

Noxafil oral suspension

• Store Noxafil oral suspension at room temperature between 68 degrees F to 77 degrees F (20 degrees C to 25 degrees C).

• Do not freeze Noxafil oral suspension.

  Noxafil PowderMix for delayed-release oral suspension

• Store the entire kit at room temperature between 68°F to 77°F (20°C to 25°C) in a clean, dry place.

• Do not open the foil packet until ready for use.

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

  General information about the safe and effective use of Noxafil and Noxafil PowderMix.

  Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Noxafil or Noxafil PowderMix for a condition for which it was not prescribed. Do not give Noxafil or Noxafil PowderMix to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Noxafil or Noxafil PowderMix that is written for health professionals.

  What are the ingredients in Noxafil and Noxafil PowderMix?

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

Other

Noxafil replaces posaconazole throughout label.