Posaconazole

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Posaconazole Prescribing Information

Warnings and Precautions, Pseudoaldosteronism (

5.4 Pseudoaldosteronism

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.

) 10/2024

Posaconazole is an azole antifungal indicated as follows:

•
Posaconazole injection
is 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 injection
is 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 injection:
  adults and pediatric patients 2 years of age and older
)
•
Posaconazole injection:
adults and pediatric patients 2 years of age and older

•
Posaconazole injection
must be administered through an in-line filter.
•Administer
posaconazole injection
by intravenous infusion over approximately 90 minutes via a central venous line. (
2.1 Important Administration Instructions
Posaconazole injection
•Administer via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes
[see Dosage and Administration (2.4)]
.
•If a central venous catheter is not available, posaconazole injection may be administered through a peripheral venous catheter by slow intravenous infusion over 30 minutes only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other intravenous treatment.
•When multiple dosing is required, the infusion should be done via a central venous line.
•Do
NOT
administer posaconazole injection as an intravenous bolus injection.
)
•Do NOT administer
posaconazole injection
as an intravenous bolus injection. (
2.1 Important Administration Instructions
Posaconazole injection
•Administer via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes
[see Dosage and Administration (2.4)]
.
•If a central venous catheter is not available, posaconazole injection may be administered through a peripheral venous catheter by slow intravenous infusion over 30 minutes only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other intravenous treatment.
•When multiple dosing is required, the infusion should be done via a central venous line.
•Do
NOT
administer posaconazole injection as an intravenous bolus injection.
)

Indication

Dosage Form, Dose, and Duration of Therapy

Treatment of invasive Aspergillosis

Posaconazole Injection:

Loading dose:

300 mg posaconazole injection intravenously twice a day on the first day.

Maintenance dose:

300 mg posaconazole injection intravenously once a day thereafter. Recommended total duration of therapy is 6 to 12 weeks. (

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 Injection: Loading dose: 300 mg posaconazole injection intravenously twice a day on the first day. Maintenance dose: 300 mg posaconazole injection intravenously once a day, starting on the second day.	Loading dose: 1 day Maintenance dose: Recommended total duration of therapy is 6 to 12 weeks.
Prophylaxis of invasive Aspergillus and Candida infections	Posaconazole Injection: Loading dose: 300 mg posaconazole injection intravenously twice a day on the first day. Maintenance dose: 300 mg posaconazole injection intravenously once a day thereafter.	Loading dose: 1 day Maintenance dose: Duration of therapy is based on recovery from neutropenia or immunosuppression.

)

Prophylaxis of invasive

Aspergillus

and

Candida

infections

Posaconazole Injection:

Loading dose:

300 mg posaconazole injection intravenously twice a day on the first day.

Maintenance dose:

300 mg posaconazole injection intravenously once a day thereafter. Duration of therapy is based on recovery from neutropenia or immunosuppression. (

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 Injection: Loading dose: 300 mg posaconazole injection intravenously twice a day on the first day. Maintenance dose: 300 mg posaconazole injection intravenously once a day, starting on the second day.	Loading dose: 1 day Maintenance dose: Recommended total duration of therapy is 6 to 12 weeks.
Prophylaxis of invasive Aspergillus and Candida infections	Posaconazole Injection: Loading dose: 300 mg posaconazole injection intravenously twice a day on the first day. Maintenance dose: 300 mg posaconazole injection intravenously once a day thereafter.	Loading dose: 1 day Maintenance dose: Duration of therapy is based on recovery from neutropenia or immunosuppression.

2.3 Dosing Regimen in Pediatric Patients (ages 2 to less than 18 years of age)

The recommended dosing regimen of posaconazole injection for pediatric patients 2 to less than 18 years of age is shown in Table 2

[see Clinical Pharmacology (12.3)]

Table 2: Posaconazole Injection Dosing Regimens for Pediatric Patients (ages 2 to less than 18 years of age)
		Recommended Pediatric Dosage and Formulation
Indication	Weight/Age	Injection	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)	Loading dose: 6 mg/kg up to a maximum of 300 mg twice daily on the first day Maintenance dose: 6 mg/kg up to a maximum of 300 mg once daily	Duration of therapy is based on recovery from neutropenia or immunosuppression.
Prophylaxis of invasive Aspergillus and Candida infections	Greater than 40 kg (2 to less than 18 years of age)
Treatment of invasive Aspergillosis	13 to less than 18 years of age regardless of weight.	Loading dose: 300 mg posaconazole injection intravenously twice a day on the first day. Maintenance dose: 300 mg posaconazole injection intravenously 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.

)

•For pediatric patients, see the Full Prescribing Information for dosing recommendations for

posaconazole injection

based on the age and indication associated with the dosage form. (

1.1 Treatment of Invasive Aspergillosis

Posaconazole injection

is 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 injection:
adults and pediatric patients 2 years of age and older

2.1 Important Administration Instructions

Posaconazole injection

•Administer via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes
[see Dosage and Administration (2.4)]
.
•If a central venous catheter is not available, posaconazole injection may be administered through a peripheral venous catheter by slow intravenous infusion over 30 minutes only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other intravenous treatment.
•When multiple dosing is required, the infusion should be done via a central venous line.
•Do
NOT
administer posaconazole injection as an intravenous bolus injection.

2.3 Dosing Regimen in Pediatric Patients (ages 2 to less than 18 years of age)

The recommended dosing regimen of posaconazole injection for pediatric patients 2 to less than 18 years of age is shown in Table 2

[see Clinical Pharmacology (12.3)]

Table 2: Posaconazole Injection Dosing Regimens for Pediatric Patients (ages 2 to less than 18 years of age)
		Recommended Pediatric Dosage and Formulation
Indication	Weight/Age	Injection	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)	Loading dose: 6 mg/kg up to a maximum of 300 mg twice daily on the first day Maintenance dose: 6 mg/kg up to a maximum of 300 mg once daily	Duration of therapy is based on recovery from neutropenia or immunosuppression.
Prophylaxis of invasive Aspergillus and Candida infections	Greater than 40 kg (2 to less than 18 years of age)
Treatment of invasive Aspergillosis	13 to less than 18 years of age regardless of weight.	Loading dose: 300 mg posaconazole injection intravenously twice a day on the first day. Maintenance dose: 300 mg posaconazole injection intravenously 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.

)

•
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 posaconazole 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 posaconazole 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 injection
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
for the treatment of invasive aspergillosis have been established 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 posaconazole 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
Posaconazole injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the posaconazole injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral posaconazole therapy
[see Dosage and Administration (2.9)
and
Warnings and Precautions (5.6)]
.
)

•Known hypersensitivity to posaconazole or other azole antifungal agents. (
4.1 Hypersensitivity
Posaconazole injection is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.
)
•Coadministration of posaconazole with the following drugs is contraindicated; posaconazole increases concentrations and toxicities of:
- •Sirolimus: (
  4.2 Use with Sirolimus
  Posaconazole is contraindicated with sirolimus. Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity
  [see Drug Interactions (7.1)
  and
  Clinical Pharmacology (12.3)]
  .
  ,
  5.1 Calcineurin-Inhibitor Toxicity
  Concomitant administration of posaconazole with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors
  [see Drug Interactions (7.1)
  and
  Clinical Pharmacology (12.3)]
  . Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.
  ,
  7.1 Immunosuppressants Metabolized by CYP3A4
  Sirolimus
  Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus
  [see Contraindications (4.2)
  and
  Clinical Pharmacology (12.3)]
  .
  Tacrolimus
  Posaconazole has been shown to significantly increase the Cmax and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly
  [see Warnings and Precautions (5.1)
  and
  Clinical Pharmacology (12.3)]
  .
  Cyclosporine
  Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly
  [see Warnings and Precautions (5.1)
  and
  Clinical Pharmacology (12.3)]
  .
  )
- •CYP3A4 substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of torsades de pointes (TdP) (
  4.3 QT Prolongation with Concomitant Use with CYP3A4 Substrates
  Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes
  [see Warnings and Precautions (5.2)
  and
  Drug Interactions (7.2)]
  .
  ,
  5.2 Arrhythmias and QT Prolongation
  Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole.
  Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18 to 85 years of age) administered Noxafil oral suspension 400 mg twice daily with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc(F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (–8 msec). No healthy subject administered posaconazole had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline.
  Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4
  [see Contraindications (4.3)
  and
  Drug Interactions (7.2)]
  .
  ,
  7.2 CYP3A4 Substrates
  Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs
  [see Contraindications (4.3)
  and
  Warnings and Precautions (5.2)]
  .
  )
- •HMG-CoA Reductase Inhibitors Primarily Metabolized through CYP3A4 (
  4.4 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
  [see Drug Interactions (7.3)
  and
  Clinical Pharmacology (12.3)]
  .
  ,
  7.3 HMG-CoA Reductase Inhibitors (Statins) Primarily Metabolized Through CYP3A4
  Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4
  [see Contraindications (4.4)
  and
  Clinical Pharmacology (12.3)]
  .
  )
- •Ergot alkaloids (
  4.5 Use with Ergot Alkaloids
  Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism
  [see Drug Interactions (7.4)]
  .
  ,
  7.4 Ergot Alkaloids
  Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Therefore, posaconazole is contraindicated with ergot alkaloids
  [see Contraindications (4.5)]
  .
  )
- •Venetoclax: In patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp-up phase (
  4.6 Use with Venetoclax
  Coadministration of posaconazole with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome
  [see Warnings and Precautions (5.11)
  and
  Drug Interactions (7.16)]
  .
  ,
  5.11 Venetoclax Toxicity
  Concomitant administration of posaconazole, 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 posaconazole 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 posaconazole with venetoclax
  [see Drug Interactions (7.16)]
  . Refer to the venetoclax prescribing information for dosing instructions.
  ,
  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 (5.11)]
  . Refer to the venetoclax prescribing information for more information on the dosing instructions and the extent of increase in venetoclax exposure.
  )

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