Presentation and Status in Health Basket
1 X 300 mg
Treatment should be initiated by a physician experienced in the management of fungal infections or in the supportive care in the high risk patients for which posaconazole is indicated as prophylaxis.
Noxafil is also available for oral administration (Noxafil 100 mg gastro-resistant tablets and 40 mg/mL oral suspension). A switch to oral administration is recommended as soon as the patients’ condition allows.
Refractory invasive fungal infections (IFI)/patients with IFI intolerant to 1st line therapy: Loading dose of 300 mg Noxafil twice a day on the first day, then 300 mg once a day thereafter. Duration of therapy should be based on the severity of the underlying disease, recovery from immunosuppression, and clinical response.
Prophylaxis of invasive fungal infections: Loading dose of 300 mg Noxafil twice a day on the first day, then 300 mg once a day thereafter. Duration of therapy is based on recovery from neutropenia or immunosuppression. For patients with AML or MDS, prophylaxis with Noxafil should start several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 500 cells per mm³.
Noxafil should be administered via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC) by slow intravenous infusion over approximately 90 minutes. Noxafil concentrate for solution for infusion should not be given by bolus administration.
If a central venous catheter is not available, a single infusion may be administered through a peripheral venous catheter. When administered through a peripheral venous catheter, the infusion should be administered over approximately 30 minutes.
Renal impairment: In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, Betadex Sulfobutyl Ether Sodium (SBECD), is expected to occur. Oral formulations of Noxafil should be used in these patients unless an assessment of the benefit/risk to the patient justifies the use of Noxafil concentrate for solution for infusion. Serum creatinine levels should be closely monitored in these patients.
Hepatic impairment: Limited data on the effect of hepatic impairment (including Child-Pugh C classification of chronic liver disease) on the pharmacokinetics of posaconazole demonstrate an increase in plasma exposure
compared to subjects with normal hepatic function, but do not suggest that dose adjustment is necessary. It is recommended to exercise caution due to the potential for higher plasma exposure.
Paediatric population: The safety and efficacy of Noxafil concentrate for solution for infusion in children aged below 18 years have not been established.
No data are available.
Noxafil concentrate for solution for infusion should not be used in children aged below 18 years because of pre-clinical safety concerns.
Method of administration: Noxafil concentrate for solution for infusion requires dilution prior to administration.
Noxafil should be administered via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC) by slow intravenous (IV) infusion over approximately 90 minutes.
Noxafil concentrate for solution for infusion should not be given by bolus administration.
If a central venous catheter is not available, a single infusion may be administered through a peripheral venous catheter. When administered through a peripheral venous catheter, the infusion should be administered over approximately 30 minutes to reduce the likelihood of infusion site reactions.
See prescribing information for full details
Noxafil concentrate for solution for infusion is indicated for use in the treatment of the following fungal infections in adults:
– Invasive aspergillosis in patients with disease that is refractory to amphotericin B or itraconazole or in patients who are intolerant of these medicinal products;
– Fusariosis in patients with disease that is refractory to amphotericin B or in patients who are intolerant of amphotericin B;
– Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole or in patients who are intolerant of itraconazole;
– Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole or fluconazole or in patients who are intolerant of these medicinal products.
– Zygomycosis, in patients intolerant of, or with disease that is refractory to, alternative therapy.
Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy.
Noxafil concentrate for solution for infusion is also indicated for prophylaxis of invasive fungal infections in the following patients:
– Patients receiving remission-induction chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high risk of developing invasive fungal infections;
– Hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease (GVHD) and who are at high risk of developing invasive fungal infections.
Please refer to the Summary of Product Characteristics of Noxafil oral suspension for use in oropharyngeal candidiasis.
Hypersensitivity to the active substance or to any of the excipients.
Co-administration with ergot alkaloids.
Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes.
Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin.
Hypersensitivity: There is no information regarding cross-sensitivity between posaconazole and other azole antifungal agents. Caution should be used when prescribing Noxafil to patients with hypersensitivity to other azoles.
Hepatic toxicity: Hepatic reactions (e.g. elevations in ALT, AST, alkaline phosphatase, total bilirubin and/or clinical hepatitis) have been reported during treatment with posaconazole. Elevated liver function tests were generally reversible on discontinuation of therapy and in some instances these tests normalised without interruption of therapy. Rarely, more severe hepatic reactions with fatal outcomes have been reported.
Posaconazole should be used with caution in patients with hepatic impairment due to limited clinical experience and the possibility that posaconazole plasma levels may be higher in these patients.
Monitoring of patients with severe renal impairment: Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections.
Monitoring of hepatic function: Liver function tests should be evaluated at the start of and during the course of posaconazole therapy.
Patients who develop abnormal liver function tests during Noxafil therapy must be routinely monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin).
Discontinuation of Noxafil should be considered if clinical signs and symptoms are consistent with development of liver disease.
QTc prolongation: Some azoles have been associated with prolongation of the QTc interval. Noxafil must not be administered with medicinal products that are substrates for CYP3A4 and are known to prolong the QTc interval. Noxafil should be administered with caution to patients with pro-arrhythmic conditions such as:
• Congenital or acquired QTc prolongation
• Cardiomyopathy, especially in the presence of cardiac failure
• Sinus bradycardia
• Existing symptomatic arrhythmias
• Concomitant use with medicinal products known to prolong the QTc interval (See prescribing information for full details).
Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.
In patients, mean maximum plasma concentrations (Cmax) after posaconazole concentrate for solution for infusion are 4-fold increased compared to administration of oral suspension. An increased effect on the QTc interval cannot be ruled out. Particular caution is advised in such cases where posaconazole is administered peripherally, as the recommended infusion time of 30 minutes may further increase Cmax.
Drug Interactions: Posaconazole is an inhibitor of CYP3A4 and should only be used under specific circumstances during treatment with other medicinal products that are metabolised by CYP3A4.
Midazolam and other benzodiazepines: Due to the risk of prolonged sedation and possible respiratory depression co-administration of posaconazole with any benzodiazepines metabolised by CYP3A4 (e.g. midazolam, triazolam, alprazolam) should only be considered if clearly necessary. Dose adjustment of benzodiazepines metabolised by CYP3A4 should be considered.
Vincristine 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 vincristine, who have no alternative antifungal treatment options.
Rifamycin antibacterials (rifampicin, rifabutin), certain anticonvulsants (phenytoin, carbamazepine, phenobarbital, primidone), and efavirenz
Posaconazole concentrations may be significantly lowered in combination; therefore, concomitant use with posaconazole should be avoided unless the benefit to the patient outweighs the risk.
Plasma exposure: Plasma concentrations following administration of posaconazole intravenous concentrate for solution for infusion are generally higher than those obtained with posaconazole oral suspension.
Posaconazole plasma concentrations following administration of posaconazole may increase over time in some patients. Safety data at higher exposure levels achieved with posaconazole concentrate for solution for infusion are at present limited.
Thromboembolic events: Thromboembolic events have been identified as a potential risk for posaconazole intravenous concentrate for solution for infusion but were not observed in the clinical studies. Thrombophlebitis was observed in clinical trials. Caution is warranted on any sign or symptom of thromboembolic
Sodium content: Each vial of Noxafil contains 462 mg (20 mmol) of sodium. This should be taken into consideration for patients on a controlled sodium diet.
The most frequently reported adverse reaction (>25 %) with an onset during the posaconazole intravenous phase of dosing with 300 mg once daily was diarrhoea (32 %).
The most common adverse reaction (>1 %) leading to discontinuation of posaconazole concentrate for solution for infusion 300 mg once daily was AML (1 %).
See prescribing information for full details.
Effects of other medicinal products on posaconazole: Posaconazole is metabolised via UDP glucuronidation (phase 2 enzymes) and is a substrate for pglycoprotein (P-gp) efflux in vitro. Therefore, inhibitors (e.g. verapamil, ciclosporin, quinidine, clarithromycin, erythromycin, etc.) or inducers (e.g. rifampicin, rifabutin, certain anticonvulsants, etc.) of these clearance pathways may increase or decrease posaconazole plasma concentrations, respectively.
Effects of posaconazole on other medicinal products: Posaconazole is a potent inhibitor of CYP3A4. Co-administration of posaconazole with CYP3A4
substrates may result in large increases in exposure to CYP3A4 substrates as exemplified by the effects on tacrolimus, sirolimus, atazanavir and midazolam below. Caution is advised during coadministration of posaconazole with CYP3A4 substrates administered intravenously and the dose of the CYP3A4 substrate may need to be reduced. If posaconazole is used concomitantly with CYP3A4
substrates that are administered orally, and for which an increase in plasma concentrations may be associated with unacceptable adverse reactions, plasma concentrations of the CYP3A4 substrate and/or adverse reactions should be closely monitored and the dose adjusted as needed.
See prescribing information for full details.
Pregnancy and Lactation
Pregnancy: There is insufficient information on the use of posaconazole in pregnant women. Women of childbearing potential have to use effective contraception during treatment. Posaconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential
risk to the foetus.
Lactation: The excretion of posaconazole in human breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with posaconazole.
See prescribing information for full details.
There is no experience with overdose of posaconazole concentrate for solution for infusion.
During clinical trials, patients who received posaconazole oral suspension doses up to 1,600 mg/day experienced no different adverse reactions from those reported with patients at the lower doses.
Accidental overdose was noted in one patient who took posaconazole oral suspension 1,200 mg twice a day for 3 days. No adverse reactions were noted by the investigator.
Posaconazole is not removed by haemodialysis. There is no special treatment available in the case of overdose with posaconazole. Supportive care may be considered.
Incompatibilities: Noxafil must not be diluted with: Lactated Ringer’s solution, 5 % dextrose with Lactated Ringer’s solution, 4.2% sodium bicarbonate.
Shelf life: 3 years.
Storage: Store in a refrigerator at 2°C-8°C.