Posaconazole 300 Mg Solution

POSACONAZOLE concentrate for solution for infusion is indicated for prophylaxis of invasive fungal infections, including both yeasts and molds, in patients, 18 years of age and older, who are at high risk of developing these infections, such as patients with prolonged neutropenia or hematopoietic stem cell transplant (HSCT) recipients. POSACONAZOLE concentrate for solution for infusion is indicated for use in the treatment of the following fungal infections in patients 18 years of age or older:

• Invasive aspergillosis in patients with disease that is refractory to amphotericin B, itraconazole or voriconazole, or in patients who are intolerant of these medicine. 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.
• Candidaemia in patients with disease that is refractory to amphotericin B, fluconazole or itraconazole, or in patients who are intolerant of these medicines. Refractoriness is defined as progression of infection or failure to improve after a minimum treatment period (persistent fungaemia: 3 days; non-fungaemic infections: 7 days.
• Fusariosis, zygomycosis, cryptococcosis, chromoblastomycosis, and mycetoma in patients with disease refractory to other therapy, or patients who are intolerant of other therapy.
• Coccidioidomycosis. In patients with disease that is refractory to amphotericin B, fluconazole or itraconazole, or in patients who are intolerant of these medicines.

Treatment should be initiated by a medical practitioner experienced in the management of fungal infections or in the supportive care in the high-risk patients for which posaconazole is indicated as prophylaxis.

Posology

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 patientsu2019 condition allows (see section 4.4).

Table 1: Recommended Dose According to Indication

Indication Dose and Duration of therapy

• Prophylaxis of Invasive Fungal Infections: Loading dose of 300 mg POSACONAZOLE 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 acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS), prophylaxis with POSACONAZOLE should start several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 500 cells per mm 3.
• Refractory Invasive Fungal Infections (IFI)/Patients with IFI intolerant to 1st line therapy: Loading dose of 300 mg POSACONAZOLE 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.
• Coccidioidomycosis: Special populations
• Renal impairment: In patients with moderate or severe renal impairment (eGFR < 50 mL/min/1,73m 2), 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 POSACONAZOLE concentrate for solution for infusion. Serum creatinine levels should be closely monitored in these patients (see section 4.4).
• Use in hepatic impairment: There are limited pharmacokinetic data in patients with hepatic impairment; therefore, no recommendation for dose adjustment can be made. In the small number of subjects studied who had hepatic impairment (including Child-Pugh C classification of chronic liver disease), there was an increase in half-life with a decrease in hepatic function.
• Use in paediatrics: The safety and effectiveness of POSACONAZOLE concentrate for solution for infusion in adolescents and children below the age of 18 years of age has not been established. The use of POSACONAZOLE concentrate for solution for infusion to patients under 18 years of age is not recommended.

Method of administration

POSACONAZOLE concentrate for solution for infusion requires dilution (see section 6.6) prior to administration. POSACONAZOLE 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 (see sections 4.2, 4.4, and 4.8). POSACONAZOLE 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 section 4.8).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with ergot alkaloids (see section 4.5).

Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, or quinidine since this may result in increased plasma concentrations of these medicines, leading to QTc prolongation and occurrences of Torsadeu2019s de pointes (see sections 4.4 and 4.5).

Co-administration with the HMG-CoA reductase inhibitors that are primarily metabolised through CYP3A4 is contraindicated since increased plasma concentration of these medicines can lead to rhabdomyolysis (see section 4.5).

Pregnancy and lactation (see section 4.6).

Hypersensitivity: There is no information regarding cross-sensitivity between POSACONAZOLE and other azole antifungal medicines. Caution should be used when prescribing POSACONAZOLE to patients with hypersensitivity to other azoles.

Hepatic toxicity: In clinical trials, there were infrequent cases of hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis). The elevations in liver function tests were generally reversible on discontinuation of therapy and in some instances these tests normalised without interruption of the medicine and rarely required medicine discontinuation. Rarely, more severe hepatic reactions including cholestasis or hepatic failure were reported in patients with serious underlying medical conditions (e.g. haematologic malignancy) during treatment with POSACONAZOLE.

Renal Impairment: In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) < 50 mL/min/1,73m 2), receiving the POSACONAZOLE concentrate for solution for infusion, accumulation of the intravenous vehicle, Betadex Sulfobutyl Ether Sodium (SBECD), is expected to occur. POSACONAZOLE concentrate for solution for infusion should be used with caution in patients with moderate or severe renal impairment (eGFR < 50 mL/min/1,73m 2), when an assessment of the benefit/risk to the patient justifies the use of POSACONAZOLE concentrate for solution for infusion. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to NOXAFIL oral suspension therapy. Due to the variability in exposure, patients with renal impairment should be monitored closely for breakthrough fungal infections.

QT prolongation: Some azoles have been associated with prolongation of QT interval. Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Nevertheless, POSACONAZOLE should not be administered with medications that are known to prolong QTc interval and are metabolised through CYP3A4.

Electrolyte disturbances: Especially those involving potassium, magnesium or calcium levels should be monitored and corrected as necessary before and during POSACONAZOLE therapy.

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 (see section 4.5).

Venetoclax Toxicity: Concomitant administration of posaconazole with venetoclax (a CYP3A4substrate) may increase venetoclax toxicities, including the risk of tumour lysis syndrome (TLS) and neutropenia (see section 4.5). Refer to the venetoclax prescribing information for detailed guidance.

Midazolam and other benzodiazepines metabolised by CYP3A4: 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 (see section 4.5).

Pregnancy: Studies in animals have shown reproductive toxicity. POSACONAZOLE has been shown to cause skeletal malformations in rats at exposures lower than those obtained at therapeutic doses in humans. In rabbits POSACONAZOLE was embryotoxic at exposures greater than those obtained at therapeutic doses. The potential risk to humans is unknown. POSACONAZOLE should not be used during pregnancy.

Breastfeeding: POSACONAZOLE is excreted into the milk of lactating rats. The excretion of POSACONAZOLE in human breast milk has not been investigated. POSACONAZOLE should not be used by breastfeeding mothers.

Since certain adverse reactions (e.g. dizziness, somnolence, etc.) have been reported with posaconazole use, which potentially may affect driving/operating machinery, caution needs to be used.

POSACONAZOLE Concentrate for Solution for Infusion Safety: In initial studies of healthy volunteers, administration of a single dose of POSACONAZOLE infused over 30 minutes via a peripheral venous catheter was well tolerated. However, multiple doses of POSACONAZOLE administered via a peripheral venous catheter were associated with thrombophlebitis (60 % incidence). Therefore, in subsequent studies, POSACONAZOLE concentrate for solution for infusion was administered via central venous catheter. If a central venous catheter was not readily available, patients could receive a single infusion over 30 minutes via a peripheral venous catheter.

The safety of POSACONAZOLE concentrate for solution for infusion has been assessed in 268 patients in a clinical trial. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of POSACONAZOLE concentrate for solution for infusion when given as antifungal prophylaxis (Study 5520). Patients were immunocompromised with underlying conditions including haematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 55 % male, had a mean age of 51 years (range 18- 82 years, 19 % of patients were u226565 years of age), and were 95 % White and 8 % Hispanic. Ten patients received a single dose of 200 mg POSACONAZOLE concentrate for solution for infusion, 21 patients received 200 mg daily dose for a median of 14 days, and 237 patients received 300 mg daily dose for a median of 9 days.

Treatment-related Adverse Reactions (TRAEs) Reported in Posaconazole Concentrate for Solution for Infusion Studies: The most common treatment-related adverse reactions (TRAEs) for POSACONAZOLE concentrate for solution for infusion (300 mg dose) are shown in Table 2. The most frequently reported TRAEs for patients treated with in the 300-mg dose group (combined IV and oral phase data) in P05520), treated with posaconazole concentrate for solution for infusion in the clinical database with n=237 were diarrhoea (9 %), nausea (8 %), rash (6 %), hypokalaemia (5 %), and vomiting (5 %). The most frequently reported adverse reactions leading to discontinuation of posaconazole concentrate for solution for infusion 300 mg once daily were rash (2 %) and pulmonary mycosis (2 %).

Table 2: Treatment-related Adverse Reactions (TRAEs) Reported in Posaconazole Concentrate for Solution for Infusion by Body System Includes all TRAEs with incidence of 1% or higher

• Common (>1/100, < 1/10): Blood and lymphatic system disorders: febrile neutropenia
• Gastrointestinal disorders: abdominal pain, anorectal discomfort, constipation, diarrhoea, dyspepsia, nausea, vomiting, dry mouth, flatulence
• General disorders and administration site conditions: chest discomfort, chills, infusion site pain, infusion site thrombosis, mucosal inflammation, peripheral oedema, asthenia, fatigue, pyrexia (fever)
• Hepatobiliary disorders: cholestasis, elevated liver function tests (including AST, ALT, alkaline phosphate, GGT, and bilirubin)
• Infections and infestations: pulmonary mycosis
• Investigations: electrocardiogram QT prolonged
• Metabolism and nutrition disorders: Anorexia, decreased appetite, fluid overload, electrolyte imbalance (including hypokalaemia, hypomagnesaemia, hypophosphataemia)
• Nervous system disorders: dizziness, dysgeusia, headache, paraesthesia, somnolence
• Renal and urinary disorders: Acute renal failure
• Skin and subcutaneous tissue disorders: petechiae, pruritus, rash
• Vascular disorders: hypertension, orthostatic hypotension

Post-marketing experience: The following post-marketing adverse experience has been reported: Endocrine Disorders: pseudoaldosteronism

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

There is no experience with overdosage of POSACONAZOLE concentrate for solution for infusion. During the clinical trials, some patients received NOXAFIL Oral Suspension up to 1 600 mg/day with no adverse events noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1 200 mg NOXAFIL oral suspension twice a day for 3 days. No adverse events were noted by the investigator. POSACONAZOLE is not removed by haemodialysis.