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 )
Posaconazole injection 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 ) o Posaconazole injection: adults and pediatric patients 2 years of age and older.
1.1Treatment of Invasive Aspergillosis
Posaconazole injection is indicated for the treatment of invasive aspergillosis in adults and pediatric patients 13 years of age and older.
1.2Prophylaxis of Invasive Aspergillus and Candida Infections
Posaconazole injection 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
Contraindications
Known hypersensitivity to posaconazole or other azole antifungal agents. ( 4.1 )
Coadministration of posaconazole with the following drugs is contraindicated; posaconazole increases concentrations and toxicities of:
Sirolimus ( 4.2 , 5.1 , 7.1 )
CYP3A4 substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of torsades de pointes (TdP) ( 4.3, 5.2 , 7.2 )
Venetoclax: In patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp-up phase ( 4.6, 5.11 , 7.16 )
4.1Hypersensitivity
Posaconazole is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.
4.2Use 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 ) ].
4.3QT 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 ) ].
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 ) ].
4.5Use 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 ) ].
4.6Use 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 ) ].
Warnings and precautions
Calcineurin-Inhibitor Toxicity : Posaconazole increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. ( 5.1 )
Arrhythmias and QTc Prolongation : Posaconazole has been shown to prolong the QTc interval and cause cases of TdP. Administer with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs known to prolong QTc interval and metabolized through CYP3A4. ( 5.2)
Electrolyte Disturbances : Monitor and correct, especially those involving potassium (K + ), magnesium (Mg ++ ), and calcium (Ca ++ ), before and during posaconazole therapy. ( 5.3 )
Pseudoaldosteronism : Manifested by the onset or worsening of hypertension, and abnormal laboratory findings. Monitor blood pressure and potassium levels, and manage as necessary. ( 5.4 )
Hepatic Toxicity : Elevations in liver tests may occur. Discontinuation should be considered in patients who develop abnormal liver tests or monitor liver tests during treatment. ( 5.5 )
Renal Impairmen t: Posaconazole injection should be avoided in patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole injection. ( 5.6 , 8.6 )
Concomitant Use with Midazolam : Posaconazole can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available. ( 5.7 , 7.5 )
Vincristine Toxicity : Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions; reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. ( 5.8 , 7.10 )
Venetoclax Toxicity : Concomitant administration of posaconazole with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome, neutropenia, and serious infections; monitor for toxicity and reduce venetoclax dose. ( 4.6 , 5.11 , 7.16 )
5.1Calcineurin-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.
5.2Arrhythmias 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 (18-85 years of age) administered Noxafil ® (posaconazole) 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 ) ].
5.3Electrolyte Disturbances
Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.
5.4Pseudoaldosteronism
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.
5.5Hepatic Toxicity
Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole.
These severe hepatic reactions were seen primarily in subjects receiving the Noxafil ® (posaconazole) oral suspension 800 mg daily (400 mg twice daily or 200 mg four times a day) in clinical trials. Liver tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver tests during posaconazole therapy should be monitored for the development of more severe hepatic injury.
Patient management should include laboratory evaluation of hepatic function (particularly liver tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.
5.6Renal 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 Use in Specific Populations ( 8.6 ) ].
5.7Midazolam Toxicity
Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [ see Drug Interactions ( 7.5 ) and Clinical Pharmacology ( 12.3 ) ].
5.8Vincristine Toxicity
Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including Posaconazole, for patients receiving a vinca alkaloid, including
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Interactions
Posaconazole is primarily metabolized via UDP glucuronosyltransferase and is a substrate of p- glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Coadministration 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.
Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole [ see Clinical Pharmacology ( 12.3 ) ]. The following information was derived from data with Noxafil ® (posaconazole) oral suspension or early tablet formulation unless otherwise noted. All drug interactions with Noxafil ® (posaconazole) oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility), are considered relevant to posaconazole injection as well.
Interaction Drug Interaction Rifabutin, phenytoin, efavirenz Avoid coadministration unless the benefit outweighs the risks ( 7.6 , 7.7, 7.8 ) Other drugs metabolized by CYP3A4 Consider dosage adjustment and monitor for adverse effects and toxicity ( 7.1, 7.10 , 7.11 ) Digoxin Monitor digoxin plasma concentrations ( 7.12 ) Fosamprenavir Monitor for breakthrough fungal infections ( 7.6 )
7.1Immunosuppressants 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 C max 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 ) ].
7.2CYP3A4 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 ) ].
7.3HMG-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 ) ].
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 ) ].
7.5Benzodiazepines Metabolized by CYP3A4
Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects [ see Warnings and Precautions ( 5.7 ) and Clinical Pharmacology ( 12.3 ) ].
7.6Anti-HIV Drugs Efavirenz:
Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations [ see Clinical Pharmacology ( 12.3 ) ]. It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks. Ritonavir and Atazanavir : Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs [ see Clinical Pharmacology ( 12.3 ) ].
Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole. Fosamprenavir : Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended [ see Clinical Pharmacology ( 12.3 ) ].
7.7Rifabutin
Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, coadministration of rifabutin with posaconazole increases rifabutin plasma concentrations [ see Clinical Pharmacology ( 12.3 ) ]. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended.
7.8Phenytoin
Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations [ see Clinical Pharmacology ( 12.3 ) ]. Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered.
7.10 Vinca Alkaloids Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with serious adverse reactions [ see Warnings and Precautions ( 5.8 ) ]. Posaconazole may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions.
Therefore, reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.
7.11Calcium Channel Blockers Metabolized by CYP3A4
Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. Dose reduction of calcium channel blockers may be needed.
7.12Digoxin
Increased plasma concentr
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Pregnancy and breastfeeding
8.1Pregnancy 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.
Adverse reactions
The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling:
Hypersensitivity [see Contraindications ( 4.1 )]
Arrhythmias and QT Prolongation [see Warnings and Precautions ( 5.2 )]
Hepatic Toxicity [see Warnings and Precautions ( 5.5 )]
Adult Patients: Common adverse reactions in studies with posaconazole in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. ( 6.1 )
Pediatric Patients: Common adverse reactions (incidence >20% receiving 6 mg/kg posaconazole injection) in a study in pediatric patients are pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience Table 16: Posaconazole Pediatric Study: Changes in Liver Tests from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 Number (%) of Patients with Change* Pediatric Study 1 Laboratory Parameter Posaconazole Injection and Noxafil ® PowderMix (posaconazole) for delayed-release oral suspension (6 mg/kg daily) n=49 (%) AST 2/49 (4) ALT 3/49 (6) Bilirubin 0/48 (0) Alkaline Phosphatase 0/48 (0) *Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study.
These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation. CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase
6.2Postmarketing Experience
The following adverse reaction has been identified during the post-approval use of posaconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency. Endocrine Disorders: Pseudoaldosteronism
Composition
Active ingredients
POSACONAZOLE 300MG/16.7ML (18MG/ML)
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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