Posaconazole

Posaconazole is an azole antifungal indicated as follows:

• Posaconazole delayed-release tablets
  are indicated for the treatment of invasive aspergillosis in adults and pediatric patients 13 years of age and older. (
  1.1 Treatment of Invasive Aspergillosis

  Posaconazole delayed-release tablets

  are indicated for the treatment of invasive aspergillosis in adults and pediatric patients 13 years of age and older.
  )
• Posaconazole
  is indicated for the prophylaxis of invasive
  Aspergillus
  and
  Candida
  infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy as follows: (
  1.2 Prophylaxis of Invasive

  Aspergillus

  and

  Candida

  Infections

  Posaconazole is indicated for the prophylaxis of invasive

  Aspergillus

  and

  Candida

  infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy

  [see Clinical Studies (14.1)]

  as follows:

  • Posaconazole delayed-release tablets
    : adults and pediatric patients 2 years of age and older who weigh greater than 40 kg
  • Posaconazole oral suspension:
    adults and pediatric patients 13 years of age and older
  )
  
  • Posaconazole delayed-release tablets:
    adults and pediatric patients 2 years of age and older who weigh greater than 40 kg
  • Posaconazole oral suspension:
    adults and pediatric patients 13 years of age and older
• Posaconazole oral suspension
  is indicated for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in adult and pediatric patients aged 13 years and older. (
  1.3 Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole

  Posaconazole oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole in adults and pediatric patients 13 years of age and older.
  )

• Posaconazole oral suspension
  is not substitutable with
  Posaconazole 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. (
  2.1 Important Administration Instructions

  Non-substitutable

  Posaconazole oral suspension

  is not substitutable with

  Posaconazole delayed-release tablets

  or

  Noxafil PowderMix for delayed-release oral suspension

  due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations

  [see Dosage and Administration (2.2, 2.3)].

  Posaconazole delayed-release tablets

  • Swallow tablets whole. Do not divide, crush, or chew.
  • Administer with or without food
    [see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)]
    .
  • For patients who cannot eat a full meal, Posaconazole delayed-release tablets should be used instead of Posaconazole oral suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Posaconazole oral suspension under both fed and fasted conditions
    [see Dosage and Administration (2.5)]
    .

  Posaconazole oral suspension

  • Administer with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal
    [see Dosage and Administration (2.5)].
  • Co-administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections
    [see Drug Interactions (7.6, 7.7, 7.8, 7.9, 7.13)].
  ,
  2.2 Dosing Regimen in Adult Patients

  Table 1: Dosing Regimens in Adult Patients

  Indication	Dose and Frequency	Duration of Therapy
  Treatment of invasive Aspergillosis	Posaconazole Delayed-Release Tablets: Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose : 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Switching between the intravenous and delayed-release tablets is acceptable. A loading dose is not required when switching between formulations.	Loading dose: 1 day Maintenance dose: Recommended total duration of therapy is 6 to 12 weeks.
  Prophylaxis of invasive Aspergillus and Candida infections	Posaconazole Delayed-Release Tablets: Loading dose : 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose : 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Posaconazole Oral Suspension: 200 mg (5 mL) three times a day.	Loading dose : 1 day Maintenance dose : Duration of therapy is based on recovery from neutropenia or immunosuppression.
  Oropharyngeal Candidiasis (OPC)	Posaconazole Oral Suspension: Loading dose : 100 mg (2.5 mL) twice a day on the first day. Maintenance dose : 100 mg (2.5 mL) once a day thereafter.	Loading dose : 1 day Maintenance dose : 13 days
  OPC Refractory (rOPC) to Itraconazole and/or Fluconazole	Posaconazole Oral Suspension: 400 mg (10 mL) twice a day.	Duration of therapy is based on the severity of the patient’s underlying disease and clinical response.
  ,
  2.3 Dosing Regimen in Pediatric Patients (ages 2 to less than 18 years of age)

  • The recommended dosing regimen of posaconazole for pediatric patients 2 to less than 18 years of age is shown in
    Tables 2 and 3
    [see Dosage and Administration (2.4, 2.5)and Clinical Pharmacology (12.3)].

  Table 2: Posaconazole Delayed-Release Tablet Dosing Regimens for Pediatric Patients (ages 2 to less than 18 years of age)

  		Recommended Pediatric Dosage and Formulation
  Indication	Weight/Age	Delayed-Release Tablet	Duration of therapy
  Prophylaxis of invasive Aspergillus and Candida infections	Less than or equal to 40 kg (2 to less than 18 years of age)	Not Applicable	Duration of therapy is based on recovery from neutropenia or immunosuppression.
  	Greater than 40 kg (2 to less than 18 years of age)	Loading dose: 300 mg twice daily on the first day Maintenance dose: 300 mg once daily
  Treatment of invasive Aspergillosis	13 to less than 18 years of age regardless of weight.	Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Switching between the intravenous and delayed-release tablets is acceptable. A loading dose is not required when switching between formulations.	Loading dose: 1 day Maintenance dose: Recommended total duration of therapy is 6 to 12 weeks.

  Table 3: Posaconazole Oral Suspension Dosing Regimens for Pediatric Patients (ages 13 to less than 18 years of age)

  Indication	Loading Dose (volume) and frequency	Maintenance Dose (volume) and frequency	Duration of therapy
  Prophylaxis of invasive Aspergillus and Candida infections	200 mg (5 mL) three times a day	200 mg (5 mL) three times a day	Duration of therapy is based on recovery from neutropenia or immunosuppression.
  Oropharyngeal Candidiasis (OPC)	100 mg (2.5 mL) twice daily on the first day	100 mg (2.5 mL) once daily	13 days
  OPC Refractory (rOPC) to Itraconazole and/or Fluconazole	400 mg (10 mL) twice daily	400 mg (10 mL) twice daily	Duration of therapy is based on the severity of the patient’s underlying disease and clinical response.
  )
• Administer
  Posaconazole delayed-release tablets
  with or without food. (
  2.1 Important Administration Instructions

  Non-substitutable

  Posaconazole oral suspension

  is not substitutable with

  Posaconazole delayed-release tablets

  or

  Noxafil PowderMix for delayed-release oral suspension

  due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations

  [see Dosage and Administration (2.2, 2.3)].

  Posaconazole delayed-release tablets

  • Swallow tablets whole. Do not divide, crush, or chew.
  • Administer with or without food
    [see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)]
    .
  • For patients who cannot eat a full meal, Posaconazole delayed-release tablets should be used instead of Posaconazole oral suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Posaconazole oral suspension under both fed and fasted conditions
    [see Dosage and Administration (2.5)]
    .

  Posaconazole oral suspension

  • Administer with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal
    [see Dosage and Administration (2.5)].
  • Co-administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections
    [see Drug Interactions (7.6, 7.7, 7.8, 7.9, 7.13)].
  )
• Administer
  Posaconazole oral suspension
  with a full meal. (
  2.1 Important Administration Instructions

  Non-substitutable

  Posaconazole oral suspension

  is not substitutable with

  Posaconazole delayed-release tablets

  or

  Noxafil PowderMix for delayed-release oral suspension

  due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations

  [see Dosage and Administration (2.2, 2.3)].

  Posaconazole delayed-release tablets

  • Swallow tablets whole. Do not divide, crush, or chew.
  • Administer with or without food
    [see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)]
    .
  • For patients who cannot eat a full meal, Posaconazole delayed-release tablets should be used instead of Posaconazole oral suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Posaconazole oral suspension under both fed and fasted conditions
    [see Dosage and Administration (2.5)]
    .

  Posaconazole oral suspension

  • Administer with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal
    [see Dosage and Administration (2.5)].
  • Co-administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections
    [see Drug Interactions (7.6, 7.7, 7.8, 7.9, 7.13)].
  )

• For pediatric patients, see the Full Prescribing Information for dosing recommendations for
  Posaconazole delayed-release tablets
  and
  Posaconazole oral suspension
  based on the age and indication associated with the dosage form. (
  1.1 Treatment of Invasive Aspergillosis

  Posaconazole delayed-release tablets

  are indicated for the treatment of invasive aspergillosis in adults and pediatric patients 13 years of age and older.
  ,
  1.2 Prophylaxis of Invasive

  Aspergillus

  and

  Candida

  Infections

  Posaconazole is indicated for the prophylaxis of invasive

  Aspergillus

  and

  Candida

  infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy

  [see Clinical Studies (14.1)]

  as follows:

  • Posaconazole delayed-release tablets
    : adults and pediatric patients 2 years of age and older who weigh greater than 40 kg
  • Posaconazole oral suspension:
    adults and pediatric patients 13 years of age and older
  ,
  1.3 Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole

  Posaconazole oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole in adults and pediatric patients 13 years of age and older.
  ,
  2.1 Important Administration Instructions

  Non-substitutable

  Posaconazole oral suspension

  is not substitutable with

  Posaconazole delayed-release tablets

  or

  Noxafil PowderMix for delayed-release oral suspension

  due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations

  [see Dosage and Administration (2.2, 2.3)].

  Posaconazole delayed-release tablets

  • Swallow tablets whole. Do not divide, crush, or chew.
  • Administer with or without food
    [see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)]
    .
  • For patients who cannot eat a full meal, Posaconazole delayed-release tablets should be used instead of Posaconazole oral suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Posaconazole oral suspension under both fed and fasted conditions
    [see Dosage and Administration (2.5)]
    .

  Posaconazole oral suspension

  • Administer with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal
    [see Dosage and Administration (2.5)].
  • Co-administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections
    [see Drug Interactions (7.6, 7.7, 7.8, 7.9, 7.13)].
  ,
  2.3 Dosing Regimen in Pediatric Patients (ages 2 to less than 18 years of age)

  • The recommended dosing regimen of posaconazole for pediatric patients 2 to less than 18 years of age is shown in
    Tables 2 and 3
    [see Dosage and Administration (2.4, 2.5)and Clinical Pharmacology (12.3)].

  Table 2: Posaconazole Delayed-Release Tablet Dosing Regimens for Pediatric Patients (ages 2 to less than 18 years of age)

  		Recommended Pediatric Dosage and Formulation
  Indication	Weight/Age	Delayed-Release Tablet	Duration of therapy
  Prophylaxis of invasive Aspergillus and Candida infections	Less than or equal to 40 kg (2 to less than 18 years of age)	Not Applicable	Duration of therapy is based on recovery from neutropenia or immunosuppression.
  	Greater than 40 kg (2 to less than 18 years of age)	Loading dose: 300 mg twice daily on the first day Maintenance dose: 300 mg once daily
  Treatment of invasive Aspergillosis	13 to less than 18 years of age regardless of weight.	Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Switching between the intravenous and delayed-release tablets is acceptable. A loading dose is not required when switching between formulations.	Loading dose: 1 day Maintenance dose: Recommended total duration of therapy is 6 to 12 weeks.

  Table 3: Posaconazole Oral Suspension Dosing Regimens for Pediatric Patients (ages 13 to less than 18 years of age)

  Indication	Loading Dose (volume) and frequency	Maintenance Dose (volume) and frequency	Duration of therapy
  Prophylaxis of invasive Aspergillus and Candida infections	200 mg (5 mL) three times a day	200 mg (5 mL) three times a day	Duration of therapy is based on recovery from neutropenia or immunosuppression.
  Oropharyngeal Candidiasis (OPC)	100 mg (2.5 mL) twice daily on the first day	100 mg (2.5 mL) once daily	13 days
  OPC Refractory (rOPC) to Itraconazole and/or Fluconazole	400 mg (10 mL) twice daily	400 mg (10 mL) twice daily	Duration of therapy is based on the severity of the patient’s underlying disease and clinical response.
  )

Posaconazole delayed-release tablets are available as yellow, coated, oblong tablets, debossed with "100" on one side containing 100 mg of posaconazole.

Posaconazole oral suspension is available as a white, cherry-flavored suspension in 4-ounce (123 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of posaconazole per mL).

• Pregnancy:
  Based on animal data, may cause fetal harm. (
  8.1 Pregnancy

  Risk Summary

  Based on findings from animal data, posaconazole 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 (cranial malformations and missing ribs) and maternal toxicity (reduced food consumption and reduced body weight gain) 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, increased resorptions, reduced litter size, and reduced body weight gain of females were seen at doses 5 times the exposure achieved with the 400 mg twice daily oral suspension regimen. Doses of ≥ 3 times the clinical exposure caused an increase in resorptions in these rabbits

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

  Data

  Animal Data

  Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen.
  )
• Pediatrics:
  Safety and effectiveness in patients younger than 2 years of age have not been established. (
  8.4 Pediatric Use

  The safety and effectiveness of

  Posaconazole oral suspension

  and

  Posaconazole delayed-release tablets

  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

  Posaconazole injection

  and

  Posaconazole 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

  Posaconazole 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 posaconazole 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 posaconazole have not been established in pediatric patients younger than 2 years of age.
  )
• Severe Renal Impairment
  : Monitor closely for breakthrough fungal infections. (
  8.6 Renal Impairment

  Following single-dose administration of 400 mg of the Noxafil oral suspension, there was no significant effect of mild (eGFR: 50-80 mL/min/1.73 m², n=6) or moderate (eGFR: 20-49 mL/min/1.73 m², n=6) renal impairment on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal impairment (eGFR: <20 mL/min/1.73 m²), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (eGFR: >80 mL/min/1.73 m²); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal impairment as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections

  [see Dosage and Administration (2)]

  . Similar recommendations apply to Posaconazole delayed-release tablets; however, a specific study has not been conducted with the Posaconazole delayed-release tablets.
  )