Noxafil Drug Information

Important Administration Instructions

Noxafil injection, Noxafil delayed-release tablets, Noxafil oral suspension and Noxafil PowderMix for delayed-release oral suspension are supplied in different dose strengths of posaconazole, are approved for different indications, age groups and weights; have different dosages and duration of therapy; and have different preparation and administration instructions. Therefore, select the recommended dosage form based on the indication, age group, and weight and carefully follow the recommended dosage, preparation and administration instructions described for each product, and the following important administration instructions described below. Non-substitutable Noxafil oral suspension is not substitutable with Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation.

Therefore, follow the specific dosage recommendations for each of the formulations. Noxafil injection Administer via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes. Do NOT administer Noxafil injection as an intravenous bolus injection.

Noxafil delayed-release tablets Swallow tablets whole. Do not divide, crush, or chew. Administer with or without food.

For patients who cannot eat a full meal, Noxafil delayed-release tablets should be used instead of Noxafil oral suspension for the prophylaxis indication. Noxafil delayed-release tablets generally provide higher plasma drug exposures than Noxafil oral suspension under both fed and fasted conditions. Noxafil oral suspension Administer with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal.

Noxafil PowderMix for delayed-release oral suspension Administer with food. To ensure delivery of the correct dose, ONLY the provided notched tip syringes must be used for preparation and administration. The design of the notched tip syringe prevents aggregation of the suspension during preparation and administration.

Recommended Dosage of Noxafil in Adult Patients

The recommended dosage of Noxafil (injection, delayed-release tablets, and oral suspension) in adult patients for the treatment of invasive aspergillosis, prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, or for the treatment of oropharyngeal candidiasis (OPC) is shown in Table 1. Noxafil PowderMix for delayed-release oral suspension is not recommended for use in adults. Table 1: Recommended Dosage of Noxafil Injection, Noxafil Delayed-Release Tablets, and Noxafil Oral Suspension in Adult Patients of Noxafil for the Treatment of Invasive Aspergillosis and Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients 2 Years of Age and Older Noxafil injection and Noxafil delayed-release tablets The recommended dosage of Noxafil injection in pediatric patients 2 years of age and older who weigh 10 kg or greater, and Noxafil delayed-release tablets in pediatric patients 2 years of age and older who weigh greater than 40 kg for the treatment of invasive aspergillosis and prophylaxis of invasive Aspergillus and Candida infections is shown in Table 2.

Noxafil delayed-release tablets are not recommended for use in pediatric patients who weigh 40 kg or less because the recommended dosage cannot be achieved with this dosage form. Table 2: Recommended Dosage of Noxafil Injection and Noxafil Delayed-Release Tablets for the Treatment of Invasive Aspergillosis Switching between the intravenous and delayed-release tablets is acceptable. A loading dose is not required when switching between formulations. and Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients (2 Years of Age and Older) Noxafil Oral Suspension The recommended dosage of Noxafil oral suspension in pediatric patients 13 years of age and older for the prophylaxis of invasive Aspergillus and Candida Infections is shown in Table 3.

Table 3: Recommended Dosage of Noxafil Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients (13 Years of Age and Older) Recommended Pediatric Dosage of Noxafil Oral Suspension Duration of Therapy 200 mg (5 mL) three times a day Duration of therapy is based on recovery from neutropenia or immunosuppression. Noxafil PowderMix The recommended dosage of Noxafil PowderMix for delayed-release oral suspension in pediatric patients 2 years of age and older who weigh 10 kg to 40 kg, for the treatment of invasive aspergillosis, and the prophylaxis of invasive Aspergillus and Candida infections, is shown in Table 4 and Table 5. The dosing for these indications is the same, except for patients weighing 10 to less than 12 kg.

Table 4: Recommended Dosage for Noxafil PowderMix for Delayed-Release Oral Suspension for the Treatment of Invasive Aspergillosis in Pediatric Patients (2 Years of Age and Older) for Noxafil PowderMix for Delayed-Release Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida infections in Pediatric Patients (2 Years of Age and Older ) of Noxafil Oral Suspension for the Treatment of Oropharyngeal Candidiasis in Pediatric Patients 13 Years of Age and Older The recommended dosage of Noxafil oral suspension for the treatment of oropharyngeal candidiasis (OPC) and OPC refractory (rOPC) to itraconazole and/or fluconazole in pediatric patients 13 years of age and older is shown in Table 6. The Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix for delayed-release oral suspension products are not approved for the treatment of oropharyngeal candidiasis in pediatric patients.

• Preparation of Noxafil Injection Preparation of Noxafil Injection: Remove the vial of Noxafil injection from the refrigerator and allow to equilibrate to room temperature prior to use. 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

Administration of Diluted Noxafil Infusion Solution See Dosage and Administration for the preparation instructions for the diluted Noxafil Solution. Important Administration Instructions for the Diluted Noxafil Infusion Solution Must administer diluted Noxafil Infusion Solution through a 0.22-micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter. If a CVC or PICC are not available, may administer diluted Noxafil solution once through a peripheral venous catheter by intravenous infusion over approximately 30 minutes to bridge the period during which a CVC or PICC are replaced, inserted, or unavailable for use (e.g., the CVC is being used for intravenous treatment with another product).

However, do not administer diluted Noxafil infusion solution more than once via peripheral venous catheter because in clinical trials, multiple peripheral infusions given through the same vein resulted in infusion site reactions. When multiple dosing is required, the infusion should be done via a central venous line. Additional Administration Instructions for the Diluted Noxafil Infusion Solution Administer diluted Noxafil infusion solution intravenously through the same intravenous line (or cannula) with the following compatible infusion solutions: 0.45% Sodium Chloride Injection 0.9% Sodium Chloride Injection 5% Dextrose Injection 5% Dextrose and 0.45% Sodium Chloride Injection 5% Dextrose and 0.9% Sodium Chloride Injection 5% Dextrose and 20 mEq potassium chloride Injection Administer diluted Noxafil infusion solution intravenously at the same time through the same intravenous line (or cannula) with the following intravenous drug products prepared in 5% Dextrose Injection or 0.9% Sodium Chloride Injection: Amikacin Sulfate Injection Caspofungin Acetate for Injection Ciprofloxacin Injection Daptomycin for Injection Dobutamine Injection Famotidine Injection Filgrastim Injection Gentamicin Injection Hydromorphone Hydrochloride Injection Levofloxacin Injection Lorazepam Injection Meropenem for Injection Micafungin for Injection Morphine Sulfate Injection Norepinephrine Bitartrate Injection Potassium Chloride Injection Vancomycin Hydrochloride for Injection

For patients who cannot eat a full meal, use Noxafil delayed-release tablets instead of the Noxafil oral suspension for the prophylaxis of invasive Aspergillus and Candida infections in those who are at high risk of developing these infections due to being severely immunocompromised. This is because Noxafil delayed-release tablets provide higher plasma drug exposures than Noxafil oral suspension under fasted condition. For those patients using the Noxafil oral suspension: Shake Noxafil oral suspension well before use.

Administer with measured dosing spoon provided in the package (see Figure 1 ). Administer each dose of Noxafil oral suspension during or immediately (i.e., within 20 minutes) following a full meal. If these patients cannot tolerate an oral nutritional supplement or an acidic carbonated beverage either use: An alternative antifungal therapy, or Noxafil oral suspension and closely monitor patients for breakthrough fungal infections.

Rinse the spoon with water after each administration and before storage. Figure 1

Preparation and Administration Instructions for Noxafil PowderMix for Delayed-Release Oral Suspension For details on preparation and administration of Noxafil PowderMix for delayed-release oral suspension, see Instructions for Use. Preparation Instructions for Noxafil PowderMix for Delayed-Release Oral Suspension Do not open the Noxafil PowderMix packet until ready to prepare the drug. Remove cap from the mixing liquid and push the bottle adapter into the neck of the bottle.

Once in place, the bottle adapter stays in the bottle. Remove 9 mL of mixing liquid using the provided blue syringe. Put the cap back on the bottle.

Only use the mixing liquid in the kit to prepare Noxafil PowderMix. Using the provided mixing cup, combine 9 mL of mixing liquid and the entire contents of one packet in the Noxafil PowderMix kit and mix (containing 300 mg of posaconazole). Shake the mixing cup vigorously for 45 seconds to mix the powder and mixing liquid from the Noxafil PowderMix kit.

The final concentration of the reconstituted Noxafil PowderMix delayed-release suspension is approximately 30 mg/mL of posaconazole. Check to make sure the powder is mixed (the mixture should look cloudy and free of clumps). Must use the reconstituted Noxafil PowderMix delayed-release suspension within 1 hour of reconstitution.

Discard unused portion of the reconstituted Noxafil PowderMix delayed-release suspension. Administration Instructions for Noxafil PowderMix Delayed-Release Reconstituted Suspension To ensure delivery of the correct reconstituted Noxafil PowderMix Delayed-release dose, only use the provided notched tip syringes for preparation and administration because its design reduces the risk of aggregation of the product during preparation and administration. Choose the correct syringe based on the prescribed Noxafil PowderMix dose: Use 3 mL ( green ) notched tip syringe (provided with the kit) if dose is 3 mL or less.

Use 10 mL ( blue ) notched tip syringe (provided with the kit) if dose is more than 3 mL. Administer reconstituted Noxafil PowderMix suspension orally with food within 1 hour of reconstitution. 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.

Dosage Modifications in Patients with Renal Impairment

The recommended dosage of Noxafil oral suspension, Noxafil delayed-release tablets, and Noxafil PowderMix for delayed-release oral suspension is the same in patients with renal impairment compared to those with normal renal function. Avoid the use of Noxafil injection in patients with eGFR less than 50 mL/minute/1.73 m 2, unless an assessment of the benefit/risk to the patient justifies its use. If the decision is made to use Noxafil injection in patients with eGFR less than 50 mL/minute/1.73 m 2, closely monitor serum creatinine levels, and, if increases occur, consider changing to oral Noxafil therapy.

The recommended dosage of Noxafil injection in patients with eGFR 50 to 90 mL/minute/1.73 m 2 is the same as those with normal renal function.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of Noxafil cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment of Invasive Aspergillosis in Adults and Adolescents (Noxafil injection and Noxafil Delayed-Release Tablets) The safety of Noxafil injection and Noxafil delayed-release tablets was assessed in a randomized, double-blind, active-controlled clinical study of Noxafil injection and Noxafil delayed-release tablets versus voriconazole for treatment of invasive aspergillosis (Aspergillosis Treatment Study). A total of 575 adult and pediatric patients 14 years of age and older (288 in the Noxafil group, 287 in voriconazole group (voriconazole for injection or voriconazole tablets)) with proven, probable or possible invasive aspergillosis were included.

The median duration of treatment was 67 days for Noxafil injection or Noxafil delayed-release tablets and 64 days for voriconazole. In this study, 55% to 60% of patients started intravenous treatment with Noxafil (Noxafil injection) or voriconazole (voriconazole for injection). The median duration of the first instance of intravenous treatment (before switching to oral treatment or discontinuing or completing study treatment) was 9 days for both groups.

Table 7 presents adverse reactions reported at an incidence of ≥10% in either one of the treatment groups in the Aspergillosis Treatment Study. Adverse reactions leading to treatment discontinuation were reported for 34% of patients. The most commonly reported adverse reactions (>2% of patients) leading to treatment discontinuation were septic shock, respiratory failure, and bronchopulmonary aspergillosis in the Noxafil group, and septic shock and acute myeloid leukemia in the voriconazole group.

The most frequently reported adverse reactions in the Noxafil-treated group were pyrexia (28%), hypokalemia (28%), and nausea (23%). Table 7: Adverse Reactions in at least 10% of Adults and Adolescents Receiving Noxafil Injection or Noxafil Delayed-Release Tablets for the Treatment of Invasive Aspergillosis 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.

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.

In this study, 0 mg daily dosage for a median of 9 days the 200 mg dosage is not a recommended dosage for prophylaxis of invasive Aspergillus and Candida infections in adults. In the 300 mg daily dosage group each patient received a loading intravenous dose of Noxafil injection 300 mg twice on Day 1, then intravenous Noxafil injection therapy, and finally Noxafil oral suspension to complete 28 days of total Noxafil therapy. Table 8 presents adverse reactions observed in patients treated with the Noxafil injection 300 mg daily dosage group in the Noxafil Injection Study.

These adverse reactions were consistent with those seen in studies with Noxafil oral suspension. Table 8: Adverse Reactions in at least 10% of Adults Receiving Noxafil Injection for the Prophylaxis of Invasive Aspergillus and Candida infections 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. Noxafil delayed-release tablets were given for a median duration of 28 days.

Table 9 presents adverse reactions (incidence of ≥ 10%) observed in patients treated with the Noxafil delayed-release tablets 300 mg daily dosage in the Noxafil Delayed-Release Tablet Study. The most frequently reported adverse reactions (>25%) in patients treated with Noxafil delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea. The most common adverse reaction leading to discontinuation of Noxafil delayed-release tablets 300 mg once daily was nausea (2%).

Table 9: Adverse Reactions in at least 10% of Adults Receiving Noxafil Delayed-Release Tablets (300 mg Daily Dosage) for the Prophylaxis of Invasive Aspergillus and Candida infections 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. 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 (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 Reported in Less Than 5% of Noxafil-Treated Patients in Clinical Trials Other clinically significant adverse reactions reported in less than 5% of patients in clinical trials of Noxafil are listed below: Blood and lymphatic system disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated Endocrine disorders: adrenal insufficiency Nervous system disorders: paresthesia Immune system disorders: allergic reaction Cardiac disorders: torsades de pointes Vascular disorders: pulmonary embolism Gastrointestinal disorders: pancreatitis Liver and Biliary System Disorders: hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice Renal & Urinary System Disorders: renal failure acute Liver Test Abnormalities in the Clinical Trials of Noxafil Oral Suspension Liver Test Abnormalities in the Clinical Trials with Noxafil Oral Suspension for Prophylaxis of Invasive Aspergillus and Candida Infections In the prophylaxis of invasive Aspergillus and Candida infections studies, the number and percentage of patients with changes in liver tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 at the end of the studies is presented in Table 12. Table 12: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 in Prophylaxis of Invasive Aspergillus and Candida Infections Studies 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 0 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). 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, 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). 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.

Postmarketing Experience

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

Effects of Other Drugs on Noxafil and Noxafil PowderMix Posaconazole is primarily metabolized via UDP-glucuronosyltransferase and is a substrate of p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Concomitant use of Noxafil with drugs that can decrease the plasma posaconazole concentrations should generally be avoided unless the benefit outweighs the risk.

If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections. Table 15: Drug Interactions Affecting Noxafil and Noxafil PowderMix When Administered Concomitantly with Other Drugs UDP-Glucuronidase Inducers Mechanism and Clinical Effect(s) Posaconazole is a UDP-glucuronosyltransferase substrate. Concomitant use of Noxafil with UDP-glucuronidase inducers may decrease posaconazole exposure, which may reduce the effectiveness of posaconazole.

Concomitant use of Noxafil with fosamprenavir may lead to decreased posaconazole plasma concentrations, 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, 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. Posaconazole releases faster from Noxafil PowderMix in the presence of alcohol, which may interfere with Noxafil PowderMix’s delayed-release characteristics. Prevention or Management Administration of Noxafil PowderMix with alcohol is not recommended.

Effects of Noxafil and Noxafil PowderMix on Other Drugs Posaconazole is a strong CYP3A4 inhibitor. Therefore, concomitant use of Noxafil may increase plasma concentrations of drugs that are CYP3A4 substrates. Table 17: Drug Interactions Affecting Drugs Administered Concomitantly with Noxafil and Noxafil PowderMix Posaconazole is a strong CYP3A4 inhibitor.

Therefore, plasma concentrations of CYP3A4 substrates may be increased by posaconazole use. Prevention or Management Sirolimus Posaconazole is contraindicated with sirolimus. Tacrolimus • At initiation of posaconazole treatment, reduce the tacrolimus dosage to approximately one-third of the original tacrolimus dosage. • Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dosage should be modified accordingly.

CYP3A4 Substrates that Prolong QTc Interval Mechanism and Clinical Effect(s) Concomitant use of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of the CYP3A4 substrates leading to QTc interval prolongation and torsades de pointes. Concomitant use of posaconazole with simvastatin increased simvastatin plasma concentrations which can lead to rhabdomyolysis. Concomitant use of posaconazole with midazolam increased midazolam plasma concentrations which could potentiate and prolong hypnotic and sedative effects.

Prevention or Management Midazolam, Alprazolam, Triazolam Closely monitor for adverse reactions associated with high plasma concentrations of benzodiazepines that are CYP3A4 substrates during concomitant use, and a benzodiazepine receptor antagonist should be available to reverse effects. Ritonavir and atazanavir are CYP3A4 substrates and posaconazole increased plasma concentrations of these drugs. AML patients: With concomitant use, venetoclax dosage reduction and safety monitoring is recommended across all dosing phases.

Vinca alkaloids (e.g., vincristine, vinblastine) Reserve concomitant use for patients with no alternative antifungal treatment options. is a CYP3A4 substrate. Concomitant use of posaconazole with phenytoin increased phenytoin plasma concentrations. is a CYP3A4 substrate. Concomitant use of posaconazole with rifabutin increased rifabutin plasma concentrations.

Prevention or Management Avoid concomitant use of posaconazole with rifabutin unless the benefit outweighs the risk. See Table 15 for additional monitoring considerations when rifabutin affects posaconazole via UDP-glucuronosyltransferase inhibition.

Absence of Clinically Important Interaction with Noxafil and Noxafil PowderMix Additional clinical studies demonstrated that no clinically important effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with Noxafil 200 mg once daily; therefore, no dose adjustments are required for these drugs when coadministered with Noxafil 200 mg once daily. No clinically relevant effects on the pharmacokinetics of Noxafil delayed-release tablets were observed during concomitant use with antacids, H 2 -receptor antagonists and proton pump inhibitors, and metoclopramide. No dosage adjustment of Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension is required during concomitant use with these drugs.

No clinically relevant effects on the pharmacokinetics of Noxafil oral suspension were observed during concomitant use with antacids, H 2 -receptor antagonists (other than cimetidine), and loperamide. No dosage adjustment of Noxafil oral suspension is required during concomitant use with these drugs (other than cimetidine).

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

In pregnant rabbits dosed orally during organogenesis, doses of ≥ 3 times the clinical exposure caused an increase in resorptions (see Data ). Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 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. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen.

Pediatric Use 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. 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. 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. 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. 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. 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. 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.

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. 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. 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.

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

Use with Sirolimus Noxafil is contraindicated with sirolimus

Concomitant administration of Noxafil with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity.

QT Prolongation with Concomitant Use with CYP3A4 Substrates Noxafil is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of Noxafil with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes.

HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4 Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis.

Use with Ergot Alkaloids Noxafil may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism.

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.

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).

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.