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1. Bruggemann RJM, Alffenaar JWC, Blijlevens NMA. Clinical relevance of the pharmacokinetic Interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis. 2009;48:1441-1458.
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2. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356:348-359.
3. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host diseasea. N Engl J Med. 2007;356:335-347.
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NOXAFIL oral suspension is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age 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.
Selected Important Safety Information
- NOXAFIL is contraindicated in persons with known hypersensitivity to posaconazole, or other azole antifungal agents.
- NOXAFIL is contraindicated with sirolimus. Concomitant administration of NOXAFIL with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity.
- NOXAFIL is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of NOXAFIL with the CYP3A4 substrates, pimozide and quinidine, may result in increased plasma concentrations of these drugs, leading to QT prolongation and cases of torsades de pointes.
- NOXAFIL is contraindicated with HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (eg, atorvastatin, lovastatin, and simvastatin) as increased plasma concentration of these drugs can lead to rhabdomyolysis.
- NOXAFIL is contraindicated with ergot alkaloids. NOXAFIL may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism.
- Concomitant administration of NOXAFIL with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin inhibitors. Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of cyclosporine or tacrolimus whole blood trough concentrations should be performed during and at discontinuation of NOXAFIL treatment and the tacrolimus or cyclosporine dose adjusted accordingly.
- Some azoles, including NOXAFIL, 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 NOXAFIL. NOXAFIL should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QT interval and are metabolized through CYP3A4. Rigorous attempts to correct potassium, magnesium, and calcium should be made in these patients before starting NOXAFIL.
- Hepatic reactions (eg, mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver function 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 (eg, hematologic malignancy) during treatment with NOXAFIL. Liver function tests should be evaluated at the start of and during the course of therapy. Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Consider discontinuation of NOXAFIL if clinical signs and symptoms consistent with liver disease develop that may be attributable to NOXAFIL.
- Due to the variability in exposure with NOXAFIL oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections.
- Concomitant administration of NOXAFIL with midazolam increases the midazolam plasma concentrations by approximately 5-fold which could potentiate and prolong hypnotic and sedative effects. Concomitant use of NOXAFIL and other benzodiazepines metabolized by CYP3A4 (eg, 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 midazolam and other benzodiazepines metabolized by CYP3A4. In addition, benzodiazepine receptor antagonists must be available to reverse these effects.
- The most frequently reported adverse reactions (>30%) in the prophylaxis studies with posaconazole oral suspension were fever, diarrhea and nausea.
- In clinical studies of patients with OPC and refractory OPC (rOPC), the adverse reactions with posaconazole oral suspension were more common in the pool of patients with rOPC. Common adverse reactions (>5%) in the controlled OPC pool were diarrhea, nausea, headache, vomiting, and fever. Common adverse reactions (>20%) in the rOPC pool were fever, diarrhea, nausea, vomiting, and coughing. The most common serious adverse reactions in rOPC patients included fever (13%) and neutropenia (10%).
- 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.
- Coadministration of NOXAFIL with rifabutin, phenytoin and efavirenz should be avoided unless the benefit outweighs the risk. Monitoring for toxicity and/or adverse events is recommended when tacrolimus, cyclosporine, benzodiazepines, ritonavir, atazanavir, vinca alkaloids, calcium channel blockers, and rifabutin are coadministered with NOXAFIL. Dosage adjustments should also be considered when tacrolimus, cyclosporine, vinca alkaloids, calcium channel blockers, and phenytoin are administered with NOXAFIL. Monitor plasma concentrations when coadministering digoxin, phenytoin, tacrolimus, and cyclosporine with NOXAFIL. Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when coadministering glipizide with NOXAFIL. Monitor for breakthrough fungal infections when coadministering fosamprenavir, rifabutin, and phenytoin with NOXAFIL.
- Coadministration of NOXAFIL oral suspension with cimetidine (an H2-receptor antagonist), and esomeprazole (a proton pump inhibitor) results in lower posaconazole plasma concentrations and should be avoided unless the benefit outweighs the risk. No clinically relevant effects were observed when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine. Coadministration of NOXAFIL oral suspension with metoclopromide decreases posaconazole plasma concentrations; however loperamide does not affect posaconazole plasma concentrations. Monitor for breakthrough fungal infections when coadministering cimetidine, esomeprazole, and metoclopromide with NOXAFIL oral suspension.
- The safety and effectiveness of NOXAFIL oral suspension in pediatric patients below the age of 13 years old have not been established.
- No dosage adjustment of NOXAFIL oral suspension is required in patients with mild to moderate renal impairment. Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough invasive fungal infections.
- No dose adjustment of NOXAFIL is needed in patients with mild to severe hepatic insufficiency (Child- Pugh Class A, B, and C). Discontinuation of NOXAFIL must be considered in patients who experience clinical signs and symptoms consistent with liver disease that may be attributable to NOXAFIL.
- Patients weighing greater than 120 kg may have lower posaconazole plasma drug exposures. It is, therefore, suggested to closely monitor for breakthrough fungal infections.
Before prescribing NOXAFIL, please read the Prescribing Information. The Patient Information also is available.
aNCCN = National Comprehensive Cancer Network, IDSA= Infectious Diseases Society of America, ASBMT = American Society for Blood and Marrow Transplantation
NOXAFIL® (posaconazole) Oral Suspension