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Non-Interchangeability between Noxafil Tablets and Noxafil Oral Suspension
The tablet and oral suspension are not to be used interchangeably due to the differences between these two formulations in frequency of dosing, administration with food and plasma drug concentration achieved. Substitution of the tablets for the oral suspension, or vice versa, can result in inadvertent overdosing or underdosing and adverse drug reactions. Therefore, follow the specific dosage recommendations for each formulation.
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 as 100 mg gastro-resistant tablet. Noxafil tablets are the preferred formulation to optimize plasma concentrations and generally provide higher plasma drug exposures than Noxafil oral suspension.
Refractory invasive fungal infections (IFI)/patients with IFI intolerant to 1st line therapy: 200 mg (5 mL) four times a day. Alternatively, patients who can tolerate food or a nutritional supplement may take 400 mg (10 mL) twice a day during or immediately following a meal or nutritional supplement. Duration of therapy should be based on the severity of the underlying disease, recovery from immunosuppression, and clinical response.
Oropharyngeal candidiasis: Loading dose of 200 mg (5 mL) once a day on the first day, then 100 mg (2.5 mL) once a day for 13 days.
Each dose of Noxafil should be administered during or immediately after a meal, or a nutritional supplement in patients who cannot tolerate food to enhance the oral absorption and to ensure adequate exposure.
Prophylaxis of invasive fungal infections: 200 mg (5 mL) three times a day. Each dose of Noxafil should be administered during or immediately after a meal, or a nutritional supplement in patients who cannot tolerate food to enhance the oral absorption and to ensure adequate exposure.
The duration of therapy is based on recovery from neutropenia or immunosuppression. For patients with acute myelogenous leukemia or myelodysplastic syndromes, 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.
Renal impairment: An effect of renal impairment on the pharmacokinetics of posaconazole is not expected and no dose adjustment is recommended.
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 in children aged below 18 years have not been established.
Method of administration: For oral use. The oral suspension must be shaken well before use.
Noxafil oral suspension 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;
– Oropharyngeal candidiasis: as first-line therapy in patients who have severe disease or are immunocompromised, in whom response to topical therapy is expected to be poor.
– 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 oral suspension 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 and who are at high risk of developing invasive fungal infections.
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. mild to moderate 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 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.
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), efavirenz and cimetidine: 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.
Gastrointestinal dysfunction: There are limited pharmacokinetic data in patients with severe gastrointestinal dysfunction (such as severe diarrhoea). Patients who have severe diarrhoea or vomiting should be monitored closely for breakthrough fungal infections.
Excipients: This medicinal product contains approximately 1.75 g of glucose per 5 mL of suspension. Patients with glucose-galactose malabsorption should not take this medicine.
The most frequently reported serious related adverse reactions included nausea, vomiting, diarrhoea, pyrexia, and increased bilirubin.
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 p-glycoprotein (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 co-administration 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. Several of the interaction studies were conducted in healthy volunteers in whom a higher exposure to posaconazole occurs compared to patients administered the same dose. The effect of posaconazole on CYP3A4 substrates in patients might be somewhat lower than that observed in healthy volunteers, and is expected to be
variable between patients due to the variable posaconazole exposure in patients. The effect of co-administration with posaconazole on plasma levels of CYP3A4 substrates may also be variable within a patient, unless posaconazole is administered in a strictly standardised way with food, given the large food effect on posaconazole exposure.
See prescribing information for full details
Pregnancy and Lactation
Pregnancy: There is insufficient information on the use of posaconazole in pregnant women. The potential risk for humans is unknown.
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
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.
Shelf life: Unopened container: 2 years. After first opening the container: 4 weeks.
Storage: Store below 25˚C. Do not freeze.