Noxafil®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NOXAFIL® (NOXAFIL®)

Composition:

Active substance: posaconazole;

1 ml of suspension contains posaconazole (micronized) 40 mg;

Excipients: polysorbate 80; simethicone; sodium benzoate (E 211); sodium citrate, dihydrate; citric acid, monohydrate; glycerin; xanthan gum; glucose solution; titanium dioxide (E 171); artificial cherry flavor containing benzyl alcohol and propylene glycol (E 1520); purified water.

Pharmaceutical form. Oral suspension.

Main physicochemical properties: white or almost white suspension; semi-solid particles ranging from translucent to white may be observed.

Pharmacotherapeutic group. Antifungal agents for systemic use. Triazole derivatives. ATC Code J02AC04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Posaconazole is a potent inhibitor of the enzyme lanosterol 14α-demethylase (CYP51), which catalyzes a key step in the biosynthesis of ergosterol.

Microbiology

In vitro studies have demonstrated that posaconazole is active against the following microorganisms: Aspergillus species (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus), Candida species (Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. famata, C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis), Coccidioides immitis, Fonsecaea pedrosoi, as well as Fusarium, Rhizomucor, Mucor, and Rhizopus. Microbiological data indicate that posaconazole is active against Rhizomucor, Mucor, and Rhizopus; however, clinical data are currently very limited and do not allow assessment of the efficacy of posaconazole against these pathogens.

The following in vitro data are available, although their clinical significance is unknown. In an observational study involving >3000 clinical isolates of molds collected between 2010 and 2018, the following in vitro minimum inhibitory concentrations (MICs) were determined for 90% of non-Aspergillus fungi: Mucorales spp (n = 81) – 2 mg/L; Scedosporium apiospermum/S. boydii (n = 65) – 2 mg/L; Exophiala dermatitidis (n = 15) – 0.5 mg/L; and Purpureocillium lilacinum (n = 21) – 1 mg/L.

Resistance

Strains with reduced susceptibility to posaconazole have been identified. The primary mechanism of resistance involves mutations in the target protein, CYP51.

Epidemiological cutoff values for Aspergillus spp.

Epidemiological cutoff values (ECOFFs) for posaconazole, used to differentiate wild-type populations from isolates with acquired resistance, have been defined according to the methodology of the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

EUCAST-established epidemiological cutoff values:

• Aspergillus flavus – 0.5 mg/L;
• Aspergillus fumigatus – 0.5 mg/L;
• Aspergillus nidulans – 0.5 mg/L;
• Aspergillus niger – 0.5 mg/L;
• Aspergillus terreus – 0.25 mg/L.

Currently, there are insufficient data to establish clinical breakpoints for Aspergillus spp. Epidemiological cutoff values should not be equated with clinical breakpoints.

Clinical breakpoints

Minimum inhibitory concentration (MIC) clinical breakpoints for posaconazole according to EUCAST (susceptible – S; resistant – R):

• Candida albicans: S ≤ 0.06 mg/L, R > 0.06 mg/L;
• Candida tropicalis: S ≤ 0.06 mg/L, R > 0.06 mg/L;
• Candida parapsilosis: S ≤ 0.06 mg/L, R > 0.06 mg/L;
• Candida dubliniensis: S ≤ 0.06 mg/L, R > 0.06 mg/L.

Currently, there are insufficient data to establish clinical breakpoints for other Candida species.

Combination with other antifungal agents

Combination antifungal therapy should not reduce the efficacy of posaconazole or other therapies; however, there are currently no clinical data demonstrating that combination therapy provides additional benefit.

Pharmacokinetic/pharmacodynamic relationships

A correlation has been observed between the total area under the plasma concentration-time curve divided by the MIC (AUC/MIC) and clinical outcome. The AUC/MIC threshold value in patients infected with Aspergillus was approximately 200. It is particularly important to ensure maximum plasma drug concentrations in patients infected with Aspergillus (see section "Posology and method of administration" for recommended dosing regimens and the effect of food on absorption).

Clinical experience

Invasive aspergillosis

The use of posaconazole oral suspension at a dose of 800 mg/day administered in divided doses was evaluated for the treatment of invasive aspergillosis in patients with disease refractory to amphotericin B (including liposomal formulations) or itraconazole, or in patients intolerant to these agents, in a non-comparative salvage therapy trial (Study 0041). Clinical outcomes were compared with data from an external control group derived from a retrospective review of medical records. The external control group included 86 patients who received available therapy (as described above), mostly during the same period and at the same institution as patients receiving posaconazole. Most cases of aspergillosis were considered refractory to prior therapy in both the posaconazole group (88%) and the external control group (79%).

As shown in Table 1, a favorable response (complete or partial recovery) at the end of treatment was achieved in 42% of patients receiving posaconazole compared to 26% in the external control group. However, this was not a prospective, randomized, controlled trial; therefore, all comparisons with the external control group should be interpreted with caution.

Table 1

Overall efficacy of posaconazole oral suspension at the end of treatment for invasive aspergillosis compared to the external control group

1 Includes other, less common or rare species.

Fusarium spp.

11 out of 24 patients with confirmed or suspected fusariosis were successfully treated with posaconazole oral suspension at a dose of 800 mg/day in divided doses, administered for a median duration of 124 days (maximum 212 days). Among eighteen patients who had intolerance or infection refractory to amphotericin B or itraconazole, seven patients were classified as having therapeutic success.

Chromoblastomycosis/Mycetoma

9 out of 11 patients were successfully treated with posaconazole oral suspension at a dose of 800 mg/day in divided doses, administered for a median duration of 268 days (maximum 377 days). Five of these patients had chromoblastomycosis caused by Fonsecaea pedrosoi, and four had mycetoma, primarily caused by fungi of the genus Madurella.

Coccidioidomycosis

11 out of 16 patients were successfully treated (at the end of treatment, complete or partial resolution of signs and symptoms observed at baseline) with posaconazole oral suspension at a dose of 800 mg/day in divided doses, administered for a median duration of 296 days (maximum 460 days).

Treatment of azole-susceptible oropharyngeal candidiasis

A randomized, double-blind, controlled study was conducted in HIV-infected patients with azole-susceptible oropharyngeal candidiasis (most of these patients had C. albicans isolated at baseline). The primary efficacy variable was the clinical response rate (cure or improvement) after 14 days of treatment. Patients were treated with either posaconazole or fluconazole oral suspension (both posaconazole and fluconazole were administered as follows: 100 mg twice daily on Day 1, followed by 100 mg once daily for 13 days).

The clinical response rates from the study described above are presented in Table 2.

Posaconazole was shown to be non-inferior to fluconazole in terms of clinical efficacy rates on Day 14 and at 4 weeks after completion of treatment.

Table 2

Clinical efficacy rates* for oropharyngeal candidiasis

* The clinical efficacy endpoint is defined as the number of cases determined to have a clinical response (cured or improved) divided by the total number of cases that can be included in the analysis.

Prevention of invasive fungal infections (IFI) (Studies 316 and 1899)

Two randomized, controlled studies were conducted to evaluate the prevention of IFIs in patients at high risk of developing invasive fungal infections.

Study 316 was a randomized, double-blind study comparing posaconazole oral suspension (200 mg three times daily) with fluconazole capsules (400 mg once daily) in recipients of allogeneic hematopoietic stem cell transplants who had graft-versus-host disease (GVHD). The primary efficacy endpoint was the number of proven/possible cases of IFI at 16 weeks after randomization, as determined by an independent, blinded external expert panel. A key secondary efficacy endpoint was the number of proven/possible cases of IFI during the treatment period (from first dose to last dose of investigational drug plus 7 days). At study entry, the majority (377/600 [63%]) of patients had grade 2 or 3 acute GVHD or chronic extensive GVHD (195/600 [32.5%]). The mean duration of treatment was 80 days for posaconazole and 77 days for fluconazole.

Study 1899 was a randomized, blinded study comparing posaconazole oral suspension (200 mg three times daily) with either fluconazole oral suspension (400 mg once daily) or itraconazole oral solution (200 mg twice daily) in neutropenic patients receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. The primary efficacy endpoint was the number of proven/possible cases of IFI, as determined by an independent, blinded external expert panel, during the treatment period. A key secondary efficacy endpoint was the number of proven/possible cases of IFI at 100 days after randomization. Newly diagnosed acute myelogenous leukemia was the most common underlying condition (435/602 [72%]). The mean duration of treatment was 29 days for posaconazole and 25 days for fluconazole/itraconazole.

In both IFI prevention studies, aspergillosis was the most common fungal infection (see Tables 3 and 4, which present the results of both studies). Patients receiving posaconazole had fewer Aspergillus infections compared to the control group.

Table 3

Results of clinical studies on prevention of invasive fungal infections

FLU – fluconazole; ITZ – itraconazole; POS – posaconazole.

a FLU/ITZ (1899); FLU (316).

b For study 1899, this was the period from randomization to the last dose of investigational medicinal product plus 7 days; for study 316, this was the period from first dose to last dose of investigational medicinal product plus 7 days.

c For study 1899, this was the 100-day period after randomization; for study 316, this was the 111-day period after baseline.

d All randomized.

e All received treatment.

Table 4

Results of clinical studies for the prevention of invasive fungal infections

FLU – fluconazole; ITZ – itraconazole; POS – posaconazole.

a FLU/ITZ (1899); FLU (316).

b For study 1899, this was the period from randomization to the last dose of investigational medicinal product plus 7 days; for study 316, this was the period from the first dose to the last dose of investigational medicinal product plus 7 days.

c For study 1899, this was the 100-day period after randomization; for study 316, this was the 111-day period after baseline.

d All randomized.

e All received treatment.

In study 1899, a significant reduction in all-cause mortality was observed in favor of posaconazole (POS 49/304 (16%) vs. FLU/ITZ 67/298 (22%), p = 0.048). According to Kaplan-Meier survival analysis, the probability of survival up to 100 days after randomization was significantly higher in patients receiving posaconazole. This survival benefit was demonstrated when analyzing all-cause mortality (p = 0.0354) as well as mortality related to invasive fungal infections (IFI) (p = 0.0209).

In study 316, overall mortality was similar (POS – 25%; FLU – 28%). However, the proportion of deaths related to IFI was significantly lower in the POS group (4/301) compared to the FLU group (12/299; p = 0.0413).

Children

In study (0041) of invasive fungal infections, 16 patients aged 8–17 years received an oral suspension dose of posaconazole 800 mg/day. Based on available data from these 16 patients, safety profiles were similar to those observed in patients aged ≥18 years.

Additionally, 12 patients aged 13–17 years received an oral suspension dose of posaconazole 600 mg/day for prophylaxis of invasive fungal infections (studies 316 and 1899). Safety profiles in these patients under 18 years of age were similar to those observed in adults. Based on pharmacokinetic data from 10 of these patients, the pharmacokinetic profile was comparable to that observed in patients aged ≥18 years.

In a study (Study 03579) involving 136 neutropenic children aged 11 months to 17 years who received posaconazole oral suspension at doses up to 18 mg/kg/day divided into three doses, approximately 50% achieved predefined target concentrations (on day 7, mean steady-state concentration of posaconazole ranged between 500 ng/mL and 2500 ng/mL).

The efficacy and safety of posaconazole oral suspension in children under 13 years of age have not been established.

Electrocardiogram assessment

Multiple 12-hour serial ECGs were obtained from 173 healthy male and female volunteers aged 18 to 85 years before and during administration of posaconazole oral suspension (400 mg twice daily with high-fat meal). No clinically significant changes in mean QT interval values were observed compared to baseline.

Pharmacokinetics.

Absorption

The mean time to peak concentration (tmax) of posaconazole is 3 hours (after food intake). The pharmacokinetics of posaconazole are linear after single and multiple doses up to 800 mg when administered with a high-fat meal. No further increase in concentration was observed when patients and healthy volunteers received doses exceeding 800 mg/day. When administered in the fasting state, AUC increased less than proportionally to dose when the dose exceeded 200 mg. When healthy volunteers received the drug fasting, dividing the total daily dose (800 mg) into four 200 mg doses per day, posaconazole concentrations increased 2.6-fold compared to administration of 400 mg twice daily.

Effect of food on oral absorption in healthy volunteers

Absorption of posaconazole was significantly increased when 400 mg posaconazole (once daily) was administered during or immediately after a high-fat meal (~50 grams of fat), compared to administration before a meal, with Cmax and AUC increasing by approximately 330% and 360%, respectively. The AUC of posaconazole increased 4-fold when the drug was taken with a high-fat meal (~50 grams of fat) and approximately 2.6-fold when taken with a low-fat meal or nutritional supplement (14 grams of fat), compared to fasting (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Distribution

Posaconazole is slowly absorbed and slowly eliminated with a large apparent volume of distribution (1774 liters) and has a high degree of protein binding (>98%), primarily to serum albumin.

Biotransformation

Posaconazole has no significant circulating metabolites, and it is unlikely that its concentrations are altered by CYP450 enzyme inhibitors. Among circulating metabolites, most are glucuronide conjugates of posaconazole, with a small amount of oxidative metabolites (mediated by CYP450). Metabolites excreted in urine and feces accounted for approximately 17% of the administered radiolabeled dose.

Elimination

Posaconazole is slowly eliminated, with a mean elimination half-life (t½) of 35 hours (ranging from 20 to 66 hours). After administration of 14C-posaconazole, radioactivity was predominantly recovered in feces (77% of radiolabeled dose), with the main component being unchanged drug (66% of radiolabeled dose). Renal clearance is a minor elimination pathway, with 14% of the radiolabeled dose excreted in urine (<0.2% of radiolabeled dose as unchanged drug). Steady-state concentrations were achieved after 7–10 days of multiple dosing.

Pharmacokinetics in special patient populations

Children (<18 years)

After administration of 800 mg/day posaconazole in divided doses for treatment of invasive fungal infections, mean trough plasma concentrations in 12 patients aged 8–17 years (776 ng/mL) were similar to those in 194 patients aged 18–64 years (817 ng/mL). Similarly, in prophylaxis studies, mean steady-state concentrations (Cav) of posaconazole in 10 children (13–17 years) were comparable to Cav in adults (≥18 years).

In a study involving 136 neutropenic patients aged 11 months to 17 years receiving posaconazole oral suspension at doses up to 18 mg/kg/day divided into three doses, approximately 50% achieved predefined target concentrations (on day 7, mean steady-state concentration of posaconazole ranged between 500 ng/mL and 2500 ng/mL). Overall, posaconazole concentrations were generally higher in older children (7 to <18 years) than in younger children (2 to <7 years).

Gender

Pharmacokinetics of posaconazole in males and females are not different.

Elderly patients

In elderly patients, Cmax (26%) and AUC (29%) were increased (24 patients aged ≥65 years) compared to younger individuals (24 patients aged 18–45 years). However, in clinical efficacy studies, safety profiles of posaconazole in younger and older patients were similar.

Race

A slight decrease (16%) in AUC and Cmax of posaconazole oral suspension was observed in Black patients compared to Caucasian patients. However, safety profiles of posaconazole in Black and Caucasian patients were similar.

Body weight

Pharmacokinetic modeling using the oral tablet formulation suggests that patients with body weight over 120 kg may have lower posaconazole exposure. Therefore, careful monitoring for breakthrough fungal infections is recommended in patients with body weight over 120 kg. Patients with low body weight (<60 kg) are more likely to have higher posaconazole plasma concentrations, and they should be closely monitored for adverse reactions.

Renal impairment

After single-dose administration of posaconazole oral suspension, mild to moderate renal impairment (n = 18, Clcr ≥20 mL/min/1.73 m²) had no effect on posaconazole pharmacokinetics, so dose adjustment is not required. In patients with severe renal impairment (n = 6, Clcr <20 mL/min/1.73 m²), AUC of posaconazole showed high variability (coefficient of variation (CV) >96%) compared to other renal impairment groups (CV <40%). However, since only a small fraction of posaconazole is excreted renally, significant impact of severe renal impairment on posaconazole pharmacokinetics is not expected, and dose adjustment is not required. Posaconazole is not removed by hemodialysis.

Hepatic impairment

After a single 400 mg dose of posaconazole oral suspension in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment (6 patients per group), mean AUC was 1.3–1.6 times higher compared to control patients without hepatic impairment. Unbound drug concentrations were not measured, and a greater increase in unbound posaconazole concentration than the observed 60% increase in total AUC cannot be excluded. The mean elimination half-life (t½) was prolonged from approximately 27 hours to approximately 43 hours in the respective groups. Dose adjustment is not required in patients with mild to severe hepatic impairment, but caution should be exercised due to the potential for increased plasma concentrations.

Clinical characteristics.

Indications.

Noksafile® is indicated for the treatment of the following fungal infections in adults:

• invasive aspergillosis in patients with resistance to amphotericin B or itraconazole, or in patients intolerant to these medicinal products;
• fusariosis in patients with resistance to amphotericin B or in patients intolerant to amphotericin B;
• chromoblastomycosis and mycetoma in patients with resistance to itraconazole or in patients intolerant to itraconazole;
• coccidioidomycosis in patients with resistance to amphotericin B, itraconazole, or fluconazole, or in patients intolerant to these medicinal products;
• oropharyngeal candidiasis: as first-line therapy in immunocompromised patients, where topical agents may have limited efficacy.

Resistance is defined as progression of infection or lack of improvement after at least 7 days of prior effective antifungal therapy.

Noksafile® is indicated for the prevention of invasive fungal infections in the following patients:

• patients receiving chemotherapy for induction of remission in the treatment of acute myeloid leukemia or myelodysplastic syndrome, which may lead to prolonged neutropenia, and who are at high risk of developing invasive fungal infections;
• hematopoietic stem cell transplant recipients receiving high-dose immunosuppressants to prevent graft-versus-host reaction, and who are at high risk of developing invasive fungal infections.

Noksafile® is indicated for the prevention of invasive fungal infections caused by yeast or mould fungi in adults and children aged 13 years and older who are at increased risk of such infections (e.g., patients with prolonged neutropenia or hematopoietic stem cell transplant recipients).

Contraindications.

• Hypersensitivity to posaconazole or to any other component of the medicinal product listed in the section "Composition".

• Concomitant use with:

  • CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine, since increased plasma concentrations of these medicinal products may cause QT interval prolongation and very rarely ventricular tachycardia torsades de pointes (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction");
  • ergot alkaloids (see section "Interaction with other medicinal products and other forms of interaction");
  • HMG-CoA reductase inhibitors (statins) simvastatin, lovastatin, and atorvastatin (see section "Interaction with other medicinal products and other forms of interaction").

• Concomitant use at the beginning of treatment and during the dose titration phase of venetoclax in patients with chronic lymphocytic leukemia (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on posaconazole

Posaconazole is metabolized via glucuronidation (UGT, phase II enzymatic reaction) and is a substrate for P-glycoprotein (P-gp) efflux in vitro. Thus, inhibitors (e.g., verapamil, cyclosporine, quinidine, clarithromycin, erythromycin, etc.) or inducers (e.g., rifampicin, rifabutin, certain anticonvulsants, etc.) of this metabolic pathway may increase or decrease posaconazole plasma concentrations, respectively.

Rifabutin (300 mg once daily) reduced the Cmax (maximum plasma concentration) and AUC (area under the concentration-time curve) of posaconazole by 57% and 51%, respectively. Concomitant use of posaconazole and rifabutin or similar inducers (e.g., rifampicin) should be avoided unless the benefit outweighs the risk to the patient. See also information below regarding the effect of posaconazole on rifabutin plasma levels.

Flucloxacillin. Flucloxacillin (a CYP450 inducer) may reduce posaconazole plasma concentrations. Concomitant use of posaconazole and flucloxacillin should be avoided unless the benefit outweighs the risk to the patient (see section "Special precautions for use").

Efavirenz (400 mg once daily) reduced the Cmax and A游戏副本 of posaconazole by 45% and 50%, respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit outweighs the risk to the patient.

Fosamprenavir. Combination of fosamprenavir with posaconazole may lead to decreased plasma concentrations of posaconazole. If concomitant use is necessary, close monitoring for possible reactivation of fungal infections is recommended. Repeated doses of fosamprenavir (700 mg twice daily for 10 days) reduced the Cmax and AUC of posaconazole oral suspension (200 mg once daily on Day 1, 200 mg twice daily on Day 2, then 400 mg twice daily for 8 days) by 21% and 23%, respectively. The effect of posaconazole on fosamprenavir levels when fosamprenavir is co-administered with ritonavir is unknown.

Phenytoin (200 mg once daily) reduced the Cmax and AUC of posaconazole by 41% and 50%, respectively. Concomitant use of posaconazole and phenytoin or similar inducers (e.g., carbamazepine, phenobarbital, primidone) should be avoided unless the benefit outweighs the risk to the patient.

H2-receptor antagonists and proton pump inhibitors. Posaconazole plasma concentrations (Cmax and AUC) were reduced by 39% when posaconazole was administered with cimetidine (400 mg twice daily), likely due to reduced absorption resulting from decreased gastric acid secretion. If possible, concomitant use of posaconazole and H2-receptor antagonists should be avoided.

Similarly, administration of 400 mg posaconazole with esomeprazole (40 mg daily) reduced mean Cmax and AUC values by 46% and 32%, respectively, compared to administration of 400 mg posaconazole alone. Concomitant use of posaconazole and proton pump inhibitors should be avoided whenever possible.

Food. Absorption of posaconazole is significantly increased when taken with food (see sections "Dosage and administration" and "Pharmacological properties. Pharmacokinetics").

Effect of posaconazole on other medicinal products

Posaconazole is a potent inhibitor of CYP3A4. Concomitant administration of posaconazole and CYP3A4 substrates may lead to a significant increase in exposure to CYP3A4 substrates, as demonstrated by effects on tacrolimus, sirolimus, atazanavir, and midazolam described below. Caution is recommended when co-administering posaconazole with intravenous CYP3A4 substrates, and dose reduction of the CYP3A4 substrate may be necessary. When posaconazole is administered concomitantly with orally administered CYP3A4 substrates for which increased plasma concentrations may lead to unacceptable adverse reactions, plasma concentrations of the CYP3A4 substrate and/or adverse reactions should be closely monitored and the dose adjusted as needed. Several interaction studies were conducted in healthy volunteers, who had higher posaconazole exposure compared to patients receiving the same doses. The effect of posaconazole on CYP3A4 substrates in patients may be somewhat less than that observed in healthy volunteers and is expected to vary among patients due to variable posaconazole exposure. The effect of concomitant posaconazole administration on plasma levels of CYP3A4 substrates may also vary within a single patient unless posaconazole is administered in a strictly standardized manner with food, since food significantly affects posaconazole absorption.

Terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine (CYP3A4 substrates).
Concomitant administration of posaconazole with terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine is contraindicated. Concomitant use may lead to increased plasma concentrations of these medicinal products, resulting in QTc interval prolongation and, in rare cases, ventricular tachycardia torsades de pointes (see section "Contraindications").

Ergot alkaloids. Posaconazole may increase plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine), potentially causing ergotism. Concomitant use of ergot alkaloids and posaconazole is contraindicated (see section "Contraindications").

HMG-CoA reductase inhibitors metabolized by CYP3A4 (e.g., simvastatin, lovastatin, and atorvastatin). Posaconazole may significantly increase plasma levels of HMG-CoA reductase inhibitors metabolized by CYP3A4. Treatment with these HMG-CoA reductase inhibitors should be discontinued during posaconazole therapy, as elevated levels may lead to rhabdomyolysis (see section "Contraindications").

Vinca alkaloids. Most vinca alkaloids (e.g., vincristine and vinblastine) are CYP3A4 substrates. Concomitant administration of vincristine and azole antifungal agents, including posaconazole, has been associated with serious adverse reactions (see section "Special precautions for use"). Posaconazole may increase plasma concentrations of vinca alkaloids, potentially leading to neurotoxicity and other serious adverse reactions. Therefore, patients receiving vinca alkaloids, including vincristine, should only be treated with azole antifungal agents, including posaconazole, when no other antifungal treatment options are available.

Rifabutin. Posaconazole increased the Cmax and AUC of rifabutin by 31% and 72%, respectively. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit outweighs the risk to the patient (see also information above regarding the effect of rifabutin on posaconazole plasma levels). When these agents are used concomitantly, careful monitoring of blood counts and adverse effects related to increased rifabutin concentrations (e.g., uveitis) is recommended.

Sirolimus. In healthy volunteers, repeated doses of posaconazole oral suspension (400 mg twice daily for 16 days) increased the Cmax and AUC of sirolimus (single 2 mg dose) by an average of 6.7-fold and 8.9-fold (range 3.1 to 17.5-fold), respectively. The effect of posaconazole on sirolimus in patients is unknown but is expected to vary due to variable posaconazole exposure. Concomitant administration of posaconazole and sirolimus is not recommended and should be avoided whenever possible. If concomitant use cannot be avoided, a substantial reduction in sirolimus dose is recommended at the initiation of posaconazole therapy, followed by frequent monitoring of sirolimus trough concentrations in whole blood. Sirolimus concentrations should be measured at baseline, during concomitant therapy, and after discontinuation of posaconazole, with appropriate dose adjustments. It should be noted that the relationship between trough concentration and AUC of sirolimus changes during concomitant administration with posaconazole. As a result, trough concentrations corresponding to normal therapeutic ranges may lead to subtherapeutic levels. Therefore, target trough concentrations should approach the upper end of the normal therapeutic range, and clinical signs and symptoms, laboratory parameters, and biopsy findings should be closely monitored.

Cyclosporine. In heart transplant recipients receiving stable doses of cyclosporine, posaconazole oral suspension at 200 mg once daily increased cyclosporine concentrations, necessitating dose reduction. In clinical efficacy studies, cases of elevated cyclosporine levels causing serious adverse reactions, including nephrotoxicity, have been reported, including one fatal case of leukoencephalopathy. Prior to initiating posaconazole in patients already receiving cyclosporine, the cyclosporine dose should be reduced (e.g., to 3/4 of the current dose). Cyclosporine blood levels should be closely monitored during and after posaconazole therapy, with dose adjustments as needed.

Tacrolimus. Posaconazole increased the Cmax and AUC of tacrolimus (single dose 0.05 mg/kg body weight) by 121% and 358%, respectively. In clinical efficacy studies, cases of clinically significant drug interactions requiring hospitalization and/or discontinuation of posaconazole have been reported. Prior to initiating posaconazole in patients already receiving tacrolimus, the tacrolimus dose should be reduced (e.g., to 1/3 of the current dose). Tacrolimus blood concentrations should be closely monitored during and after posaconazole therapy, with dose adjustments as needed.

HIV protease inhibitors. Since HIV protease inhibitors are CYP3A4 substrates, there is a potential for posaconazole to increase plasma concentrations of these antiretroviral agents. In healthy volunteers, administration of posaconazole oral suspension (400 mg twice daily) and atazanavir (300 mg once daily) for 7 days increased the Cmax and AUC of atazanavir by an average of 2.6-fold and 3.7-fold (range 1.2 to 26-fold), respectively. Concomitant administration of posaconazole oral suspension (400 mg twice daily) with atazanavir and ritonavir (300 mg/100 mg once daily) for 7 days in healthy volunteers increased the Cmax and AUC of atazanavir by an average of 1.5-fold and 2.5-fold (range 0.9 to 4.1-fold), respectively. Adding posaconazole to atazanavir or atazanavir and ritonavir therapy was associated with increased plasma bilirubin levels. Patients receiving antiretroviral agents that are CYP3A4 substrates concomitantly with posaconazole should be monitored for early detection of possible adverse and toxic reactions.

Midazolam and other benzodiazepines metabolized by CYP3A4. In a study involving healthy volunteers, posaconazole oral suspension (200 mg once daily for 10 days) increased the effect (AUC) of intravenous midazolam (0.05 mg/kg) by 83%. In another study involving healthy volunteers, repeated oral doses of posaconazole oral suspension (200 mg twice daily for 7 days) increased the Cmax and AUC of intravenous midazolam (0.4 mg single dose) by an average of 1.3-fold and 4.6-fold (range 1.7 to 6.4-fold), respectively; posaconazole oral suspension 400 mg twice daily for 7 days increased the Cmax and AUC of intravenous midazolam by 1.6-fold and 6.2-fold (range 1.6 to 7.6-fold), respectively. Both posaconazole doses increased the Cmax and AUC of orally administered midazolam (2 mg single dose) by 2.2-fold and 4.5-fold, respectively. Additionally, posaconazole oral suspension (200 mg or 400 mg) prolonged the mean terminal half-life of midazolam from approximately 3–4 hours to 8–10 hours during concomitant administration.

Due to the risk of prolonged sedative effect, dose adjustment is recommended when posaconazole is used concomitantly with any benzodiazepine metabolized by CYP3A4 isoenzyme (e.g., midazolam, triazolam, alprazolam) (see section "Special precautions for use").

Calcium channel blockers metabolized by CYP3A4 isoenzyme (e.g., diltiazem, verapamil, nifedipine, nicardipine). Frequent monitoring for adverse and toxic reactions associated with calcium channel blocker use is recommended when used concomitantly with posaconazole. Dose adjustment of calcium channel blockers may be necessary.

Digoxin. Increased digoxin blood levels have been observed with other azoles. Therefore, posaconazole may increase digoxin blood concentrations; thus, digoxin levels should be monitored at the beginning and after completion of posaconazole therapy.

Sulfonylureas. Hypoglycemia has been observed in some healthy volunteers receiving glipizide concomitantly with posaconazole. Blood glucose levels should be monitored in diabetic patients receiving sulfonylureas and posaconazole.

All-trans retinoic acid (ATRA), or tretinoin. Since ATRA is metabolized by hepatic cytochrome P450 enzymes, particularly CYP3A4, concomitant use with posaconazole, a strong CYP3A4 inhibitor, may enhance the effect of tretinoin, leading to increased toxicity (especially hypercalcemia). Serum calcium levels should be monitored during and for several days after posaconazole treatment, and dose adjustment of tretinoin should be considered as needed.

Venetoclax. Concomitant administration of 300 mg posaconazole, a strong CYP3A inhibitor, with venetoclax 50 mg and 100 mg for 7 days in 12 patients, compared to venetoclax 400 mg as monotherapy, increased the Cmax of venetoclax by 1.6- and 1.9-fold and the AUC by 1.9- and 2.4-fold, respectively (see sections "Contraindications" and "Special precautions for use").

See the brief product characteristics of venetoclax.

Children.

Studies have been conducted only in adult patients.

Special precautions for use

Hypersensitivity. There is no information regarding cross-sensitivity between posaconazole and other antifungal azole compounds. Caution should be exercised when administering posaconazole to patients with hypersensitivity to other azoles.

Hepatotoxicity. Hepatic reactions have been observed during posaconazole therapy (e.g., mild or moderate increases in ALT, AST, alkaline phosphatase, total bilirubin levels, and/or clinically evident hepatitis). Elevations in liver function tests were generally reversible upon discontinuation of therapy; in some cases, normalization occurred without discontinuation of treatment. Rare cases of more severe hepatic events (including fatal outcomes) have been reported. Posaconazole should be used with caution in patients with impaired liver function due to limited clinical experience and the potential for higher plasma levels of posaconazole in these patients (see sections "Dosage and administration" and "Pharmacological properties. Pharmacokinetics").

Monitoring of liver function. Liver function test parameters should be evaluated at the beginning and during treatment with posaconazole. Patients who develop abnormalities in liver function tests during posaconazole therapy require regular monitoring to prevent progression to more severe liver injury. Patient management should include assessment of liver function (including liver function tests and bilirubin levels). The decision to discontinue posaconazole therapy should be made if clinical signs and symptoms suggest the development of liver disease.

QTc interval prolongation. Some azole compounds are known to cause QTc interval prolongation. Posaconazole should not be used concomitantly with drugs that are CYP3A4 substrates and are known to prolong the QTc interval (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Caution should be exercised when administering posaconazole to patients at risk of developing cardiac rhythm disturbances, particularly:

• in patients with congenital or acquired QT prolongation;
• in patients with cardiomyopathy, especially with heart failure;
• in patients with sinus bradycardia;
• in patients diagnosed with symptomatic arrhythmia;
• in patients receiving concomitant medications that prolong the QT interval (except those listed in the section "Contraindications").

Electrolyte imbalances, particularly serum potassium, magnesium, and calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.

Drug interactions

Posaconazole is a CYP3A4 inhibitor and should be administered concomitantly with other medicinal products metabolized by CYP3A4 only under specific circumstances (see section "Interaction with other medicinal products and other forms of interaction").

Midazolam and other benzodiazepines metabolized by CYP3A4

Due to the risk of prolonged sedative effects and possible respiratory depression, the concomitant use of posaconazole with any benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam) should be considered only if necessary. Dose adjustment of benzodiazepines metabolized by CYP3A4 may be required (see section "Interaction with other medicinal products and other forms of interaction").

Vincristine toxicity

Concomitant use of vincristine and azole antifungal agents, including posaconazole, has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and paralytic ileus. In patients receiving vinca alkaloids, including vincristine, antifungal treatment with azoles such as posaconazole is recommended only when no alternative antifungal therapy is available (see section "Interaction with other medicinal products and other forms of interaction").

Rifamycin antibiotics (rifampicin, rifabutin), flucloxacillin, certain anticonvulsants (phenytoin, carbamazepine, phenobarbital, primidone), efavirenz, and cimetidine

Posaconazole concentrations may be significantly reduced when co-administered with these medicinal products. Therefore, concomitant use with posaconazole should be avoided unless the benefit to the patient outweighs the risk (see section "Interaction with other medicinal products and other forms of interaction").

Gastrointestinal dysfunction

There is limited pharmacokinetic data in patients with severe gastrointestinal disorders (such as severe diarrhea). Patients with severe diarrhea or vomiting should be closely monitored for possible breakthrough fungal infections.

Venetoclax toxicity

Concomitant use of venetoclax (a CYP3A4 substrate) with strong CYP3A inhibitors, including posaconazole, may increase venetoclax toxicity, including the risk of tumor lysis syndrome (TLS) and neutropenia (see section "Interaction with other medicinal products and other forms of interaction"). For detailed information, refer to the summary of product characteristics for venetoclax.

Photosensitivity reaction

Posaconazole may increase the risk of photosensitivity reactions. Patients should be advised to avoid exposure to sunlight without adequate protection, such as protective clothing and sunscreen with a high sun protection factor (SPF).

Excipients

Glucose. This medicinal product contains approximately 1.75 g of glucose per 5 ml of suspension. Patients with glucose-galactose malabsorption syndrome should not take this medicinal product.

If intolerance to certain sugars has been diagnosed, consult a physician before taking this medicinal product. May be harmful to teeth.

Sodium. This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free."

Sodium benzoate. This medicinal product contains 10 mg of sodium benzoate (E 211) per 5 ml of suspension.

Benzyl alcohol. This medicinal product contains up to 1.25 mg of benzyl alcohol per 5 ml of suspension. Benzyl alcohol may cause anaphylactoid reactions.

Propylene glycol. This medicinal product contains up to 24.75 mg of propylene glycol (E 1520) per 5 ml of suspension.

Use during pregnancy or breastfeeding

Pregnancy

There is insufficient information on the use of posaconazole in pregnant women. Animal studies have shown reproductive toxicity. The potential risk to humans is unknown.

Women of childbearing potential should use effective contraception during treatment. Posaconazole should not be used during pregnancy unless the benefit to the mother outweighs the risk to the fetus.

Breastfeeding

Posaconazole is excreted in the milk of lactating rats. Excretion of posaconazole in human breast milk has not been studied. Breastfeeding should be discontinued from the start of posaconazole treatment.

Fertility

There is no clinical experience regarding the effect of posaconazole on human fertility.

Ability to affect reaction speed when driving or operating machinery

Caution should be observed, as certain adverse reactions (e.g., dizziness, somnolence, etc.) have been reported, which may potentially impair the ability to drive or operate machinery.

Administration and Dosage

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

Noksafile® medication should be administered orally to adults and children aged 13 years and older during meals or together with 240 mL of liquid nutritional supplements (enteral feeding). The bottle containing the suspension must be shaken well before use.

Table 5

Recommended doses according to indications

Special patient groups

Renal impairment.

Renal impairment does not lead to changes in the pharmacokinetic parameters of posaconazole; therefore, dose adjustment is not required.

Hepatic impairment.

Limited data are available on the effect of hepatic impairment (including Child–Pugh class C chronic liver disease) on the pharmacokinetics of posaconazole. These data demonstrate increased plasma concentrations of posaconazole in patients with hepatic impairment compared to those with normal liver function, but do not indicate the need for dose adjustment (see sections "Special precautions" and "Pharmacological properties. Pharmacokinetics"). Caution is recommended due to the potential for increased plasma levels.

Children.

The efficacy and safety of posaconazole oral suspension in children under 13 years of age have not been established; therefore, the drug is not recommended for patients in this age group. Data regarding dosing in children are limited (see section "Pharmacological properties").

Overdose.

During clinical trials, no adverse reactions different from those observed in patients receiving lower doses were reported in patients who received posaconazole oral suspension at doses up to 1600 mg/day. One case of accidental overdose was reported in a patient who took posaconazole oral suspension at a dose of 1200 mg twice daily for 3 days. No adverse events were observed in this patient.

Posaconazole is not removed by hemodialysis. There are no specific recommendations for the treatment of posaconazole overdose. Supportive therapy should be provided.

Adverse reactions.

Short description of safety profile

The safety of posaconazole in the form of oral suspension has been evaluated in > 2400 patients and healthy volunteers during clinical trials and post-marketing experience. The most common serious adverse reactions reported were nausea, vomiting, diarrhea, fever, and increased bilirubin levels.

The list of adverse reactions is presented in Table 6.

Within each organ system class, adverse reactions are categorized by frequency according to the following: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); not known (cannot be estimated from available data).

Table 6

Adverse reactions reported during clinical trials and the post-marketing period, classified by system organ class and frequency of occurrence*

* Based on adverse reactions observed during the use of oral suspension, enteric-coated tablets, concentrate for infusion solution, and gastro-resistant powder with solvent for oral suspension.

§ See section "Special precautions for use".

Description of selected adverse reactions

Hepatobiliary disorders

During post-marketing surveillance of posaconazole oral suspension, cases of severe hepatic injury with fatal outcome have been reported (see section "Special precautions for use").

Suspected adverse reactions reporting

Reporting of suspected adverse reactions after medicine authorization is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

After first opening of the bottle – 4 weeks.

Storage conditions.

Keep out of the reach of children. Store at a temperature not exceeding 25 °C. Do not freeze.

Packaging.

105 ml of suspension in a 123 ml amber glass bottle with child-resistant cap and measuring spoon. 1 bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Organon Heist bv, Belgium /
Organon Heist bv, Belgium.

Merck Sharp & Dohme B.V., the Netherlands /
Merck Sharp & Dohme B.V., the Netherlands.

Manufacturer's address and place of business.

Industriepark 30, 2220 Heist-op-den-Berg, Belgium /
Industriepark 30, 2220 Heist-op-den-Berg, Belgium.

Waarderweg 39, 2031 BN Haarlem, the Netherlands /
Waarderweg 39, 2031 BN Haarlem, the Netherlands.