Posaconazole - Posaconazole tablet, Coated
(Posaconazole)Posaconazole - Posaconazole tablet, Coated Prescribing Information
Warnings and Precautions, Pseudoaldosteronism (
Pseudoal
Posaconazole is an azole antifungal indicated as follows:
- Posaconazoleis indicated for the prophylaxis of invasiveAspergillusandCandidainfections 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 InvasiveAspergillusandCandidaInfectionsPosaconazole delayed-release tablets are indicated for the prophylaxis of invasive
AspergillusandCandidainfections 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 (14.2)]as follows:- Posaconazole delayed-release tablets:adults and pediatric patients 2 years of age and older who weigh greater than 40 kg
oPosaconazole delayed-release tablets:adults and pediatric patients 2 years of age and older who weigh greater than 40 kg
- Noxafil® oral suspensionis not substitutable withposaconazole delayed-release tabletsorNoxafil® PowderMix for delayed-release oral suspensiondue to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations. (,
2.1 Important Administration InstructionsNon-substitutableNoxafil®oral suspensionis not substitutable withposaconazole delayed-release tabletsorNoxafil®PowderMix for delayed-release oral suspensiondue 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 (2.5)and Clinical Pharmacology (12.3)].
- For patients who cannot eat a full meal, posaconazole delayed-release tablets should be used instead of Noxafil®oral suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Noxafil®oral suspension under both fed and fasted conditions, and therefore is the preferred oral formulation for the prophylaxis indication.
,2.2 Dosing Regimen in Adult PatientsTable 1: Dosing Regimens in Adult PatientsIndicationDose and FrequencyDuration of TherapyProphylaxis of invasive AspergillusandCandidainfectionsLoadingdose: 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.Loadingdose:
1 dayMaintenance 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 for pediatric patients 2 to less than 18 years of age is shown in
Tables 2[ see Dosage and Administration (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 FormulationIndicationWeight/AgeDelayed-Release TabletDuration of therapyProphylaxis of invasive AspergillusandCandidainfectionsLess than or equal to 40 kg (2 to less than 18 years of age)
Greater than 40 kg (2 to less than 18 years of age)Not Applicable Loading dose:
300 mg twice daily on the first dayMaintenance dose:
300 mg once dailyDuration of therapy is based on recovery from neutropenia or immunosuppression. - Administer posaconazole delayed-release tabletswith or without food. ()
2.1 Important Administration InstructionsNon-substitutableNoxafil®oral suspensionis not substitutable withposaconazole delayed-release tabletsorNoxafil®PowderMix for delayed-release oral suspensiondue 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 (2.5)and Clinical Pharmacology (12.3)].
- For patients who cannot eat a full meal, posaconazole delayed-release tablets should be used instead of Noxafil®oral suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Noxafil®oral suspension under both fed and fasted conditions, and therefore is the preferred oral formulation for the prophylaxis indication.
Table 1: Recommended Dosage in Adult Patients | |||||||||||||||||||
Indication | Dosage Form, Dose, and Duration of Therapy | ||||||||||||||||||
| Prophylaxis of invasive Aspergillus and Candida infections | 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. Duration of therapy is based on recovery from neutropenia or immunosuppression. (Table 1: Dosing Regimens in Adult Patients
The recommended dosing regimen of posaconazole for pediatric patients 2 to less than 18 years of age is shown in Tables 2 [ see Dosage and Administration (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)
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- For pediatric patients, see the Full Prescribing Information for dosing recommendations for posaconazole delayed-release tablets(,
1.2 Prophylaxis of InvasiveAspergillusandCandidaInfectionsPosaconazole delayed-release tablets are indicated for the prophylaxis of invasive
AspergillusandCandidainfections 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 (14.2)]as follows:- Posaconazole delayed-release tablets:adults and pediatric patients 2 years of age and older who weigh greater than 40 kg
,2.1 Important Administration InstructionsNon-substitutableNoxafil®oral suspensionis not substitutable withposaconazole delayed-release tabletsorNoxafil®PowderMix for delayed-release oral suspensiondue 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 (2.5)and Clinical Pharmacology (12.3)].
- For patients who cannot eat a full meal, posaconazole delayed-release tablets should be used instead of Noxafil®oral suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Noxafil®oral suspension under both fed and fasted conditions, and therefore is the preferred oral formulation for the prophylaxis indication.
)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[ see Dosage and Administration (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 FormulationIndicationWeight/AgeDelayed-Release TabletDuration of therapyProphylaxis of invasive AspergillusandCandidainfectionsLess than or equal to 40 kg (2 to less than 18 years of age)
Greater than 40 kg (2 to less than 18 years of age)Not Applicable Loading dose:
300 mg twice daily on the first dayMaintenance dose:
300 mg once dailyDuration of therapy is based on recovery from neutropenia or immunosuppression.
Posaconazole delayed-release tablets are available as yellow colored, capsule shaped, textured, biconvex film-coated tablets debossed with 'MP 1' on one side and plain on other side containing 100 mg of posaconazole.
- Pregnancy: Based on animal data, may cause fetal harm. ()
8.1 PregnancyRisk 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.DataAnimal 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 UseThe safety and effectiveness of
posaconazole delayed-release tabletsfor the prophylaxis of invasiveAspergillusandCandidainfections 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.
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 ImpairmentFollowing 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 to 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 (2.9)].Similar recommendations apply to posaconazole delayed-release tablets; however, a specific study has not been conducted with the posaconazole delayed-release tablets.
- Known hypersensitivity to posaconazole or other azole antifungal agents. ()
4.1 HypersensitivityPosaconazole 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 SirolimusPosaconazole 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 ToxicityConcomitant 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 CYP3A4Sirolimus: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 Cmaxand 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 SubstratesPosaconazole 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 ProlongationSome 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 SubstratesConcomitant 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 CYP3A4Coadministration 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 CYP3A4Concomitant 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 AlkaloidsPosaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism
[ see Drug Interactions (7.4)].)7.4 Ergot AlkaloidsMost 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 VenetoclaxCoadministration 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 ToxicityConcomitant 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 VenetoclaxConcomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax Cmaxand 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.