Posaconazole
Posaconazole Prescribing Information
Warnings and Precautions, Pseudoaldosteronism (
Posaconazole is an azole antifungal indicated as follows:
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Posaconazole is indicated for the prophylaxis of invasive
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o
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• Administer
• 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
• 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
• Do NOT administer
• 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
• 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
Table 1: Recommended Dosage in Adult Patients | ||||||||||||||||||||
Indication | Dosage Form, Dose, and Duration of Therapy | |||||||||||||||||||
| 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. (Table 1: Dosing Regimens in Adult Patients
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)
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• 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. (
Posaconazole is indicated for the prophylaxis of invasive
•
• 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
• 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
The recommended dosing regimen of posaconazole injection for pediatric patients 2 to less than 18 years of age is shown in
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. |
Greater than 40 kg (2 to less than 18 years of age) | |||
Posaconazole injection (300 mg per vial) is available as a clear, colorless to yellow sterile liquid in a single-dose vial.
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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
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.
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.
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The safety and effectiveness of
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
The safety and effectiveness of posaconazole have not been established in pediatric patients younger than 2 years of age.
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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
• Known hypersensitivity to posaconazole or other azole antifungal agents. (
Posaconazole 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 (
• 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
• CYP3A4 substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of torsades de pointes (TdP)
• HMG-CoA Reductase Inhibitors Primarily Metabolized through CYP3A4
• Ergot alkaloids
• Venetoclax: In patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp-up phase
Posaconazole is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.
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
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
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
Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism
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
Concomitant administration of posaconazole with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors
• CYP3A4 substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of torsades de pointes (TdP) (
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
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
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
• 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
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
• Ergot alkaloids (
Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism
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
• Venetoclax: In patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp-up phase (
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
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
For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering posaconazole with venetoclax