Noxafil 300 Mg Solution

NOXAFIL concentrate for solution for infusion is indicated for prophylaxis of invasive fungal infections, including both yeasts and moulds, 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. NOXAFIL 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 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 acute myelogenous leukaemia (AML) or myelodysplastic syndromes (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.

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.

Coccidioidomycosis

Special populations

Renal impairment: In patients with moderate or severe renal impairment (eGFR < 50 mL/min/1,73m2), 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 (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 NOXAFIL concentrate for solution for infusion in adolescents and children below the age of 18 years of age has not been established. The use of NOXAFIL concentrate for solution for infusion to patients under 18 years of age is not recommended.

Method of administration

NOXAFIL concentrate for solution for infusion requires dilution (see section 6.6) 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 (see sections 4.2, 4.4, and 4.8). 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 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 NOXAFIL and other azole antifungal medicines. Caution should be used when prescribing NOXAFIL 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 NOXAFIL.

Renal Impairment: In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) < 50 mL/min/1,73m2), receiving the NOXAFIL concentrate for solution for infusion, accumulation of the intravenous vehicle, Betadex Sulfobutyl Ether Sodium (SBECD), is expected to occur. NOXAFIL concentrate for solution for infusion should be used with caution in patients with moderate or severe renal impairment (eGFR < 50 mL/min/1,73m2), when 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, 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, NOXAFIL 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 NOXAFIL 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 CYP3A4 substrate) 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)

The following information was derived from data with NOXAFIL oral suspension or early tablet formulation. All drug interactions with NOXAFIL oral suspension described below, are considered relevant to NOXAFIL concentrate for solution for infusion as well.

Effects of other medicines on NOXAFIL: NOXAFIL is metabolised via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect NOXAFIL plasma concentrations.

Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area under the plasma concentration curve) of NOXAFIL by 43 % and 49 % respectively. Concomitant use of NOXAFIL and rifabutin should be avoided.

Phenytoin (200 mg once a day) decreased the Cmax and AUC of NOXAFIL by 41 % and 50 %, respectively. Concomitant use of NOXAFIL and phenytoin should be avoided.

Glipizide (10 mg single dose) had no clinically significant effect on NOXAFIL Cmax and AUC. Efavirenz (400 mg once a day) decreased the Cmax and AUC of posaconazole by 45 % and 50 %, respectively. Concomitant use of posaconazole and efavirenz should be avoided.

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. Repeat dose administration of fosamprenavir (700 mg twice daily x 10 days) decreased the Cmax and AUC of posaconazole (200 mg oral suspension daily on the 1st day, 200 mg oral suspension twice daily on the 2nd day, then 400 mg oral suspension twice daily x 8 Days) by 21 % and 23 %, respectively.

Effects of NOXAFIL on other medicines: NOXAFIL is not metabolised to a clinically significant extent through the cytochrome P450 system. However, NOXAFIL is an inhibitor of CYP3A4 and thus the plasma levels of medicines that are metabolised through this enzyme pathway may increase when administered with NOXAFIL.

Ergot alkaloids: NOXAFIL may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine), which may lead to ergotism. Co-administration of NOXAFIL and ergot alkaloids is contra-indicated. (see section 4.3).

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 section 4.4). 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.

Ciclosporin: In heart transplant patients on stable doses of ciclosporin, posaconazole 200 mg oral suspension once daily increased ciclosporin concentrations requiring dose reductions. When initiating treatment with posaconazole in patients already receiving ciclosporin, the dose of ciclosporin should be reduced (e.g. to about three-fourths of the current dose). Thereafter blood levels of ciclosporin should be monitored carefully during co-administration and upon discontinuation of posaconazole treatment, and the dose of ciclosporin should be adjusted as necessary.

Tacrolimus: NOXAFIL increased Cmax and AUC of tacrolimus (0,05 mg/kg single dose) by 121 % and 358 % respectively. When initiating NOXAFIL treatment in patients already receiving tacrolimus, the dose of tacrolimus should be reduced (e.g. to about one third of the current dose). Thereafter blood levels of tacrolimus should be monitored carefully during co-administration and upon discontinuation of NOXAFIL, and the dose of tacrolimus should be adjusted as necessary.

Sirolimus: Repeat dose administration of oral NOXAFIL (400 mg oral suspension twice daily for 16 days) increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 6,7-fold and 8,9-fold, respectively, in healthy subjects. When initiating therapy in patients already taking sirolimus, the dose of sirolimus should be reduced (e.g. to about 1/10 of the current dose) with frequent monitoring of sirolimus whole blood trough concentrations. Sirolimus concentrations should be performed upon initiation, during co-administration, and at discontinuation of NOXAFIL treatment, with sirolimus doses adjusted accordingly.

Rifabutin: NOXAFIL increased the Cmax and AUC of rifabutin by 31 % and 72 %, respectively. Concomitant use of NOXAFIL and rifabutin should be avoided unless the benefit to the patient outweighs the risk. If the medicines are co-administered, careful monitoring of full blood counts and adverse effects related to increased rifabutin levels (e.g. uveitis) is recommended.

Midazolam: Repeat dose administration of oral NOXAFIL (200 mg oral suspension twice daily for 7 days) increased the Cmax and AUC of IV midazolam (0,4 mg single dose) an average of 1,3 and 4,6-fold, respectively; NOXAFIL 400 mg oral suspension twice daily for 7 days increased the IV midazolam Cmax and AUC by 1,6 and 6,2-fold, respectively. Both doses of posaconazole increased Cmax and AUC of oral midazolam (2 mg single oral dose) by 2,2 and 4,5-fold, respectively. In addition, oral NOXAFIL (200 mg or 400 mg oral suspension) prolonged the mean terminal half-life of midazolam from approximately 3-4 hours to 8-10 hours during co-administration. It is recommended that dose adjustments of benzodiazepines metabolised by CYP3A4, be considered during co-administration with NOXAFIL.

Zidovudine (AZT), lamivudine (3TC), indinavir: Clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir were observed when administered with NOXAFIL; therefore, no dose adjustments are required for these co-administered medicines.

HIV Protease Inhibitors: As HIV protease inhibitors are CYP3A4 substrates, it is expected that NOXAFIL will increase plasma levels of these antiretroviral medicines. Repeat dose administration of oral NOXAFIL (400 mg oral suspension twice daily for 7 days) increased the Cmax and AUC of atazanavir (300 mg once a day for 7 days) an average of 2,6-fold and 3,7-fold, respectively, in healthy subjects. Repeat dose administration of NOXAFIL (400 mg oral suspension twice daily for 7 days) increased the Cmax and AUC of atazanavir to a lesser extent when administered as a boosted regimen with ritonavir (300 mg atazanavir plus ritonavir 100 mg once a day for 7 days) with an average of 1,5-fold and 2,5-fold, respectively, in healthy subjects. Frequent monitoring for adverse events and toxicity related to antiretroviral medicines that are substrates of CYP3A4 is recommended during co-administration with NOXAFIL.

HMG-CoA reductase inhibitors primarily metabolised through CYP3A4: Repeat dose administration of oral NOXAFIL (50, 100, and 200 mg oral suspension once daily for 13 days) increased the Cmax and AUC of simvastatin (40 mg single dose) an average of 7,4- to 11,4-fold, and 5,7- to 10,6-fold, respectively. Increased HMG-CoA reductase inhibitor concentrations in plasma can be associated with rhabdomyolysis. Co-administration of posaconazole and HMG-CoA reductase inhibitors primarily metabolised through CYP3A4 is contraindicated. (see section 4.3)

Calcium channel blockers metabolised through CYP3A4: Frequent monitoring for adverse events and toxicity related to calcium channel blockers is recommended during co-administration with NOXAFIL. Dose adjustment of calcium channel blockers may be required.

Digoxin: Administration of other azoles has been associated with increases in digoxin levels. Therefore, NOXAFIL may increase plasma concentration of digoxin and digoxin levels need to be monitored when initiating or discontinuing NOXAFIL treatment.

Venetoclax: Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax Cmax and AUC0-INF, which may increase venetoclax toxicities (see section 4.4).

Pregnancy

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

Breastfeeding

NOXAFIL is excreted into the milk of lactating rats. The excretion of NOXAFIL in human breast milk has not been investigated. NOXAFIL 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 NOXAFIL infused over 30 minutes via a peripheral venous catheter was well tolerated. However, multiple doses of NOXAFIL administered via a peripheral venous catheter were associated with thrombophlebitis (60 % incidence). Therefore, in subsequent studies, NOXAFIL 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 NOXAFIL 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 NOXAFIL 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 NOXAFIL 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 NOXAFIL 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

Common febrile neutropenia

Gastrointestinal disorders

Common abdominal pain, anorectal discomfort, constipation, diarrhoea, dyspepsia, nausea, vomiting, dry mouth, flatulence

General disorders and administration site conditions

Common chest discomfort, chills, infusion site pain, infusion site thrombosis, mucosal inflammation, peripheral oedema, asthenia, fatigue, pyrexia (fever)

Hepatobiliary disorders

Common cholestasis, elevated liver function tests (including AST, ALT, alkaline phosphate, GGT, and bilirubin)

Infections and infestations

Common pulmonary mycosis

Investigations

Common electrocardiogram QT prolonged

Metabolism and nutrition disorders

Common Anorexia, decreased appetite, fluid overload, electrolyte imbalance (including hypokalaemia, hypomagnesaemia, hypophosphataemia)

Nervous system disorders

Common dizziness, dysgeusia, headache, paraesthesia, somnolence

Renal and urinary disorders

Common Acute renal failure

Skin and subcutaneous tissue disorders

Common petechiae, pruritus, rash

Vascular disorders

Common 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 NOXAFIL 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 1200 mg NOXAFIL oral suspension twice a day for 3 days. No adverse events were noted by the investigator.

NOXAFIL is not removed by haemodialysis.