Usual Adult Dose for Aspergillosis - Invasive

PROPHYLAXIS OF INVASIVE ASPERGILLUS AND CANDIDA INFECTIONS:
IV:

• Loading dose: 300 mg IV twice a day on the first day
• Maintenance dose: 300 mg IV once a day thereafter

ORAL:
Delayed-Release Tablets:

• Loading dose: 300 mg orally twice a day on the first day
• Maintenance dose: 300 mg orally once a day, starting on the second day

Oral Suspension: 200 mg orally 3 times a day

Duration of Therapy:

• Loading dose: 1 day
• Maintenance dose: Should be based on recovery from immunosuppression or neutropenia

TREATMENT OF INVASIVE ASPERGILLOSIS:
IV:

• Loading dose: 300 mg IV twice a day on the first day
• Maintenance dose: 300 mg IV once a day, starting on the second day

ORAL:
Delayed-Release Tablets:

• Loading dose: 300 mg orally twice a day on the first day
• Maintenance dose: 300 mg orally once a day, starting on the second day

Duration of Therapy:

• Loading dose: 1 day
• Maintenance dose: 6 to 12 weeks (total)

Comments:

• Switching between the IV and delayed-release tablets is acceptable for the treatment of invasive aspergillosis; a loading dose is not needed when switching between formulations.

Uses:

• For the prophylaxis of invasive Aspergillus and Candida infections in high-risk, severely immunocompromised patients, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or patients with hematologic malignancies with prolonged neutropenia from chemotherapy
• For the treatment of invasive aspergillosis

Usual Adult Dose for Candidemia

PROPHYLAXIS OF INVASIVE ASPERGILLUS AND CANDIDA INFECTIONS:
IV:

• Loading dose: 300 mg IV twice a day on the first day
• Maintenance dose: 300 mg IV once a day thereafter

ORAL:
Delayed-Release Tablets:

• Loading dose: 300 mg orally twice a day on the first day
• Maintenance dose: 300 mg orally once a day, starting on the second day

Oral Suspension: 200 mg orally 3 times a day

Duration of Therapy:

• Loading dose: 1 day
• Maintenance dose: Should be based on recovery from immunosuppression or neutropenia

TREATMENT OF INVASIVE ASPERGILLOSIS:
IV:

• Loading dose: 300 mg IV twice a day on the first day
• Maintenance dose: 300 mg IV once a day, starting on the second day

ORAL:
Delayed-Release Tablets:

• Loading dose: 300 mg orally twice a day on the first day
• Maintenance dose: 300 mg orally once a day, starting on the second day

Duration of Therapy:

• Loading dose: 1 day
• Maintenance dose: 6 to 12 weeks (total)

Comments:

• Switching between the IV and delayed-release tablets is acceptable for the treatment of invasive aspergillosis; a loading dose is not needed when switching between formulations.

Uses:

• For the prophylaxis of invasive Aspergillus and Candida infections in high-risk, severely immunocompromised patients, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or patients with hematologic malignancies with prolonged neutropenia from chemotherapy
• For the treatment of invasive aspergillosis

Usual Adult Dose for Oral Thrush

Oral Suspension:
Oropharyngeal candidiasis:

• Loading dose: 100 mg orally twice a day on the first day
• Maintenance dose: 100 mg orally once a day thereafter
• Duration of therapy:
• Loading dose: 1 day
• Maintenance dose: 13 days

Oropharyngeal candidiasis refractory to itraconazole and/or fluconazole: 400 mg orally twice a day

• Duration of therapy: Should be based on the severity of the patient's underlying disease and clinical response

Use: For the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole

Usual Pediatric Dose for Aspergillosis - Invasive

PROPHYLAXIS OF INVASIVE ASPERGILLUS AND CANDIDA INFECTIONS:
IV:
2 to less than 18 years:

• Loading dose: 6 mg/kg IV twice a day on the first day
• Maximum dose: 300 mg/dose
• Maintenance dose: 6 mg/kg IV once a day thereafter
• Maximum dose: 300 mg/dose

ORAL:
Delayed-Release Tablets:
2 to less than 18 years, weighing greater than 40 kg:

• Loading dose: 300 mg orally twice a day on the first day
• Maintenance dose: 300 mg orally once a day, starting on the second day

Oral Suspension:
13 to less than 18 years: 200 mg orally 3 times a day

Powder for Delayed-Release Oral Suspension:
2 to less than 18 years, weighing 10 to 40 kg:

• Weight 10 to less than 12 kg:
• Loading dose: 90 mg orally twice a day on the first day
• Maintenance dose: 90 mg orally once a day thereafter
• Weight 12 to less than 17 kg:
• Loading dose: 120 mg orally twice a day on the first day
• Maintenance dose: 120 mg orally once a day thereafter
• Weight 17 to less than 21 kg:
• Loading dose: 150 mg orally twice a day on the first day
• Maintenance dose: 150 mg orally once a day thereafter
• Weight 21 to less than 26 kg:
• Loading dose: 180 mg orally twice a day on the first day
• Maintenance dose: 180 mg orally once a day thereafter
• Weight 26 to less than 36 kg:
• Loading dose: 210 mg orally twice a day on the first day
• Maintenance dose: 210 mg orally once a day thereafter
• Weight 36 to 40 kg:
• Loading dose: 240 mg orally twice a day on the first day
• Maintenance dose: 240 mg orally once a day thereafter

Duration of Therapy: Should be based on recovery from immunosuppression or neutropenia

TREATMENT OF INVASIVE ASPERGILLOSIS:
13 to less than 18 years (regardless of weight):
IV:

• Loading dose: 300 mg IV twice a day on the first day
• Maintenance dose: 300 mg IV once a day, starting on the second day

ORAL:
Delayed-Release Tablets:

• Loading dose: 300 mg orally twice a day on the first day
• Maintenance dose: 300 mg orally once a day, starting on the second day

Duration of Therapy:

• Loading dose: 1 day
• Maintenance dose: 6 to 12 weeks (total)

Comments:

• The powder for delayed-release oral suspension is not recommended for use in patients weighing greater than 40 kg as the recommended dosage cannot be achieved.
• Switching between the IV and delayed-release tablets is acceptable for the treatment of invasive aspergillosis; a loading dose is not needed when switching between formulations.

Uses:

• For the prophylaxis of invasive Aspergillus and Candida infections in high-risk, severely immunocompromised patients, such as HSCT recipients with GVHD or patients with hematologic malignancies with prolonged neutropenia from chemotherapy
• For the treatment of invasive aspergillosis in pediatric patients at least 13 years of age

Usual Pediatric Dose for Candidemia

PROPHYLAXIS OF INVASIVE ASPERGILLUS AND CANDIDA INFECTIONS:
IV:
2 to less than 18 years:

• Loading dose: 6 mg/kg IV twice a day on the first day
• Maximum dose: 300 mg/dose
• Maintenance dose: 6 mg/kg IV once a day thereafter
• Maximum dose: 300 mg/dose

ORAL:
Delayed-Release Tablets:
2 to less than 18 years, weighing greater than 40 kg:

• Loading dose: 300 mg orally twice a day on the first day
• Maintenance dose: 300 mg orally once a day, starting on the second day

Oral Suspension:
13 to less than 18 years: 200 mg orally 3 times a day

Powder for Delayed-Release Oral Suspension:
2 to less than 18 years, weighing 10 to 40 kg:

• Weight 10 to less than 12 kg:
• Loading dose: 90 mg orally twice a day on the first day
• Maintenance dose: 90 mg orally once a day thereafter
• Weight 12 to less than 17 kg:
• Loading dose: 120 mg orally twice a day on the first day
• Maintenance dose: 120 mg orally once a day thereafter
• Weight 17 to less than 21 kg:
• Loading dose: 150 mg orally twice a day on the first day
• Maintenance dose: 150 mg orally once a day thereafter
• Weight 21 to less than 26 kg:
• Loading dose: 180 mg orally twice a day on the first day
• Maintenance dose: 180 mg orally once a day thereafter
• Weight 26 to less than 36 kg:
• Loading dose: 210 mg orally twice a day on the first day
• Maintenance dose: 210 mg orally once a day thereafter
• Weight 36 to 40 kg:
• Loading dose: 240 mg orally twice a day on the first day
• Maintenance dose: 240 mg orally once a day thereafter

Duration of Therapy: Should be based on recovery from immunosuppression or neutropenia

TREATMENT OF INVASIVE ASPERGILLOSIS:
13 to less than 18 years (regardless of weight):
IV:

• Loading dose: 300 mg IV twice a day on the first day
• Maintenance dose: 300 mg IV once a day, starting on the second day

ORAL:
Delayed-Release Tablets:

• Loading dose: 300 mg orally twice a day on the first day
• Maintenance dose: 300 mg orally once a day, starting on the second day

Duration of Therapy:

• Loading dose: 1 day
• Maintenance dose: 6 to 12 weeks (total)

Comments:

• The powder for delayed-release oral suspension is not recommended for use in patients weighing greater than 40 kg as the recommended dosage cannot be achieved.
• Switching between the IV and delayed-release tablets is acceptable for the treatment of invasive aspergillosis; a loading dose is not needed when switching between formulations.

Uses:

• For the prophylaxis of invasive Aspergillus and Candida infections in high-risk, severely immunocompromised patients, such as HSCT recipients with GVHD or patients with hematologic malignancies with prolonged neutropenia from chemotherapy
• For the treatment of invasive aspergillosis in pediatric patients at least 13 years of age

Usual Pediatric Dose for Oral Thrush

Oral Suspension:
13 to less than 18 years:
Oropharyngeal candidiasis:

• Loading dose: 100 mg orally twice a day on the first day
• Maintenance dose: 100 mg orally once a day thereafter
• Duration of therapy:
• Loading dose: 1 day
• Maintenance dose: 13 days

Oropharyngeal candidiasis refractory to itraconazole and/or fluconazole: 400 mg orally twice a day

• Duration of therapy: Should be based on the severity of the patient's underlying disease and clinical response

Use: For the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole

Renal Dose Adjustments

IV:

• Moderate or severe renal dysfunction (estimated glomerular filtration rate [eGFR] less than 50 mL/min): The injection should be avoided unless benefit justifies risk.

Oral:

• Mild to severe renal dysfunction (eGFR up to 80 mL/min/1.73 m2): No adjustment recommended.

Comments:

• IV: The IV vehicle, betadex sulfobutyl ether sodium (SBECD), is expected to accumulate in patients with moderate or severe renal dysfunction; serum creatinine levels should be monitored closely in these patients and if increases occur, switching to oral posaconazole therapy should be considered.
• Oral: Patients with severe renal dysfunction (eGFR less than 20 mL/min/1.73 m2) should be monitored closely for breakthrough fungal infections.

Liver Dose Adjustments

Mild to severe liver dysfunction (Child-Pugh A, B, or C): No adjustment recommended.

Precautions

CONTRAINDICATIONS:

• Known hypersensitivity to the active component or other azole antifungal agents
• Coadministration with sirolimus
• Coadministration with CYP450 3A4 substrates that prolong QT interval (e.g., pimozide, quinidine)
• Coadministration with HMG-CoA reductase inhibitors primarily metabolized through CYP450 3A4 (e.g., atorvastatin, lovastatin, simvastatin)
• Coadministration with ergot alkaloids (ergotamine, dihydroergotamine)
• Powder for delayed-release oral suspension: Known/suspected hereditary fructose intolerance

Safety and efficacy have not been established in patients younger than 2 years.

Consult WARNINGS section for additional precautions.

Dialysis

This drug is not removed by hemodialysis.

Other Comments

Administration advice:
IV:

• Administer the injection through a 0.22-micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter.
• Administer the injection via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC) by slow IV infusion over about 90 minutes; do not administer as an IV bolus injection.
• If a central venous catheter is not available, the injection may be administered through a peripheral venous catheter by slow IV infusion over about 30 minutes only as a single dose before central venous line placement or to bridge the period when a central venous line is replaced or is in use for other IV therapy; when multiple dosing is needed, infuse via a central venous line.

ORAL:

• The oral suspension is not substitutable with the delayed-release tablets or the powder for delayed-release oral suspension due to differences in dosing of each formulation; follow specific dosing recommendations for each formulation.
• Delayed-Release Tablets:
• Administer with or without food.
• Swallow tablets whole; do not divide, crush, or chew.
• In patients unable to eat a full meal, use the delayed-release tablets (instead of the oral suspension) for the prophylaxis indication; in general, the delayed-release tablets provide higher plasma drug exposures than the oral suspension (under fed and fasted conditions).
• Oral Suspension:
• Shake well before use; administer with the provided measured dosing spoon.
• Administer each dose during or within 20 minutes after a full meal.
• In patients unable to eat a full meal, use the delayed-release tablets instead of the oral suspension for the prophylaxis indication; the delayed-release tablets provide higher plasma drug exposures than the oral suspension under fasted conditions.
• In patients unable to eat a full meal, and the delayed-release tablets or injection are not options, administer each dose with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).
• For patients unable to eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage, and the delayed-release tablets or injection are not options, consider alternative antifungal therapy or monitor patients closely for breakthrough fungal infections.
• If this drug is administered via a nasogastric tube, monitor patients closely for breakthrough fungal infections.
• In general, avoid concomitant use of agents that can decrease plasma levels of this drug unless benefit outweighs risk; if such agents are needed, monitor patients closely for breakthrough fungal infections.
• Powder for Delayed-Release Oral Suspension: Consult the manufacturer product information (Instructions for Use) for details regarding administration.
• Administer with food; do not administer with alcohol.
• Administer the reconstituted suspension within 1 hour; discard the unused portion of the prepared product.
• To ensure the correct dose is delivered, only use the provided notched tip syringes for preparation and administration (design prevents aggregation of the suspension); select the correct syringe based on the prescribed dose.
• This formulation is not recommended for use in patients weighing greater than 40 kg as the recommended dosage cannot be achieved; the maximum dose that can be accurately withdrawn from the mixing cup after reconstitution is 240 mg.
• The manufacturer product information should be consulted regarding missed doses.

Storage requirements:

• Injection:
• In vial: Store refrigerated at 2C to 8C (36F to 46F); equilibrate refrigerated vial to room temperature before preparation.
• Diluted solution: Once admixed, should administer immediately; if immediate administration is not possible, may store up to 24 hours refrigerated at 2C to 8C (36F to 46F)
• Delayed-release tablets: Store at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F).
• Oral suspension: Store at 25C (77F); excursions permitted to 15C to 30C (59F to 86F); do not freeze.
• Powder for delayed-release oral suspension: Store entire kit at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) in a clean, dry place; do not open foil packet until ready for use.

Reconstitution/preparation techniques:

• IV: The manufacturer product information should be consulted; final concentration should be between 1 and 2 mg/mL.
• Powder for delayed-release oral suspension: The manufacturer product information (Instructions for Use) should be consulted for details regarding preparation; the provided notched tip syringes must be used for preparation and administration (design prevents aggregation of the suspension).

IV compatibility:

• Compatible Diluents: 0.45% sodium chloride, 0.9% sodium chloride, 5% dextrose in water, 5% dextrose and 0.45% sodium chloride, 5% dextrose and 0.9% sodium chloride, 5% dextrose and 20 mEq potassium chloride
• This drug can be infused at the same time through the same IV line (or cannula) with these compatible diluents.
• Use of other diluents is not recommended as they may cause particulate formation; any diluents not listed above should not be coadministered through the same IV line (or cannula).
• Compatible Drug Products (if prepared in 5% dextrose in water or 0.9% sodium chloride): Amikacin sulfate, caspofungin, ciprofloxacin, daptomycin, dobutamine hydrochloride (HCl), famotidine, filgrastim, gentamicin sulfate, hydromorphone HCl, levofloxacin, lorazepam, meropenem, micafungin, morphine sulfate, norepinephrine bitartrate, potassium chloride, vancomycin HCl
• This drug can be infused at the same time through the same IV line (or cannula) with the above drug products prepared in 5% dextrose in water or 0.9% sodium chloride; coadministration of drug products prepared in other diluents may cause particulate formation.
• Any drug products not listed above should not be coadministered through the same IV line (or cannula).
• Incompatible Diluents: Lactated Ringer's solution, 5% dextrose with Lactated Ringer's solution, 4.2% sodium bicarbonate

Monitoring:

• General: For breakthrough fungal infections (e.g., patients with severe diarrhea/vomiting using an oral formulation, patients weighing more than 120 kg [particularly when using the oral suspension])
• Hepatic: Liver tests (at the start of and during therapy); for more severe liver injury in patients with abnormal liver tests (during therapy); hepatic function, especially liver tests and bilirubin, for patient management (during therapy)
• Metabolic: Electrolyte disturbances, especially involving potassium, magnesium, or calcium levels (before and during therapy)
• Renal: Serum creatinine levels in patients with moderate or severe renal dysfunction using the injection

Patient advice:

• Read the US FDA-approved patient information (Patient Information and Instructions for Use).
• Notify physician at once if severe diarrhea or vomiting develops or if you notice a change in heart rate or heart rhythm.
• Inform physician immediately if signs/symptoms of liver problems (e.g., itching, nausea/vomiting, yellowing of eyes/skin, feeling more tired than usual, influenza-like symptoms) develop.