Posaconazole - vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT POSACONAZOLE-VISTA (POSACONAZOLE-VISTA)

Composition:

Active substance: posaconazole;

1 ml of suspension contains posaconazole, calculated as 100 % dry substance, 40 mg;
Excipients: polysorbate 80; xanthan gum; sodium benzoate (E 211); citric acid monohydrate; sodium citrate; glycerol; glucose solution; titanium dioxide (E 171); simethicone emulsion 30 %; artificial cherry flavor; purified water.

Pharmaceutical form. Oral suspension.

Main physicochemical properties: homogeneous suspension, white to almost white in color, free from foreign particles, with a characteristic odor.

Pharmacotherapeutic group. Antifungal agents for systemic use. Triazole derivatives. ATC code J02A C04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Posaconazole is a potent inhibitor of the enzyme lanosterol 14α-demethylase, which catalyzes a key step in ergosterol biosynthesis. Thus, posaconazole exhibits broad-spectrum antifungal activity against both yeast and filamentous fungi.

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 remain very limited and are insufficient to assess the efficacy of posaconazole against these pathogens.

Resistance. Strains with reduced susceptibility to posaconazole have been identified. The primary mechanism of resistance involves mutations in the target enzyme CYP51. Epidemiological cutoff values for Aspergillus spp.

Epidemiological cutoff values 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).

Epidemiological cutoff values established by EUCAST:

Aspergillus flavus – 0.5 mg/L;
Aspergillus fumigatus – 0.25 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.

Breakpoints. Minimum inhibitory concentration (MIC) breakpoints for posaconazole according to the European Committee on Antimicrobial Susceptibility Testing (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.

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

Combination with other antifungal agents. Studies of posaconazole in combination with caspofungin or amphotericin B, both in vitro and in vivo, have shown no or minimal antagonism, and in some cases, additive effects have been observed. The clinical significance of these findings has not been established.

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

Clinical experience.

Invasive aspergillosis. The use of oral posaconazole at a dose of 800 mg per day administered in multiple 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 study. 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 the 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 remission) 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 at the end of treatment for invasive aspergillosis compared with the external control group

Total efficacy of therapy (mycologically confirmed)	Posaconazole		External control group
	45/107 (42 %)		22/86 (26 %)
Success by species
Aspergillus spp. 1	34/76	(45 %)	19/74	(26 %)
A. fumigatus	12/29	(41 %)	12/34	(35 %)
A. flavus	10/19	(53 %)	3/16	(19 %)
A. terreus	4/14	(29 %)	2/13	(15 %)
A. niger	3/5	(60 %)	2/7	(29 %)

1 Includes other, less common or rare species.

Fusariosis. 11 out of 24 patients with confirmed or suspected fusariosis were successfully treated with posaconazole at a dose of 800 mg per day in divided doses, for a median duration of 124 days, and up to a maximum of 212 days. Among 18 patients who had intolerance or infection refractory to amphotericin B or itraconazole, 7 patients were classified as having a therapeutic response.

Chromoblastomycosis/mycetoma. 9 out of 11 patients were successfully treated with posaconazole at a dose of 800 mg per day in divided doses, for a median duration of 268 days, and up to a maximum of 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 (complete or partial resolution of symptoms observed at baseline by end of treatment) with posaconazole at a dose of 800 mg per day in divided doses, for a median duration of 296 days, and up to a maximum of 460 days.

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

The clinical response rates from the study described above are presented in Table 2. Posaconazole was demonstrated to be non-inferior to fluconazole in terms of clinical efficacy rates on Day 14, as well as 4 weeks after the end of treatment.

Table 2

Clinical efficacy rates* for oropharyngeal candidiasis

Clinical efficacy	Posaconazole	Fluconazole
Clinical efficacy rate on day 14	91.7% (155/169)	92.5% (148/160)
Clinical efficacy rate at 4 weeks after completion of treatment	68.5% (98/143)	61.8% (84/136)

Clinical efficacy endpoint — this is the number of cases defined as those with clinical response (cure or improvement) 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 prophylactic trials were conducted in patients at high risk of developing invasive fungal infections.

Study 316 was a randomized, double-blind trial comparing posaconazole oral suspension (200 mg three times daily) with fluconazole capsules (400 mg once daily) in hematopoietic stem cell transplant recipients with graft-versus-host disease (GVHD). The primary efficacy endpoint was the number of proven/possible cases of IFI at 16 weeks post-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 plus 7 days). At study entry, the majority (377/600 [63%]) of patients had GVHD in stage 2 or 3 acute flare or chronic extensive form (195/600 [32.5%]). The mean duration of treatment was 80 days for posaconazole and 77 days for fluconazole.

Study 1899 was a randomized, blind trial comparing posaconazole oral suspension (200 mg three times daily) with 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 during the treatment period as determined by an independent, blinded external expert panel. A key secondary efficacy endpoint was the number of proven/possible cases of IFI at 100 days post-randomization. Newly diagnosed acute myelogenous leukemia was the most common underlying disease (435/602 [72%]). The mean duration of treatment was 29 days for posaconazole and 25 days for fluconazole/itraconazole.

In both prophylactic studies, aspergillosis was the most common breakthrough infection during prophylactic therapy (see Tables 3 and 4, which present results from both studies). Patients receiving posaconazole had fewer Aspergillus infections compared to the control group.

Table 3

Results of clinical trials for prevention of invasive fungal infections

Study	Posaconazole	Control groupa	p-value
Proportion (%) of patients with proven/possible IFI
Treatment periodb
1899d	7/304 (2)	25/298 (8)	0.0009
316e	7/291 (2)	22/288 (8)	0.0038
Established periodc
1899d	14/304 (5)	33/298 (11)	0.0031
316d	16/301 (5)	27/299 (9)	0.0740

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

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

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

c In study 1899, this was the 100-day period following randomization; in study 316, this was the 111-day period following the baseline period.

d All randomized.

e All received treatment.

Table 4

Results of clinical studies on the prevention of invasive fungal infections

Study	Posaconazole	Control groupa
Proportion (%) of patients with proven/possible aspergillosis
Treatment period b
1899d	2/304 (1)	20/298 (7)
316e	3/291 (1)	17/288 (6)
Established period c
1899d	4/304 (1)	26/298 (9)
316d	7/301 (2)	21/299 (7)

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

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

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

c In study 1899, this was the 100-day period after randomization; in 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). Kaplan-Meier survival analysis showed significantly higher survival probability up to 100 days after randomization 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 a study (0041) of invasive fungal infections, 16 patients aged 8–17 years received a posaconazole dose of 800 mg per day. Based on available data from these 16 patients, the safety profile was similar to that observed in patients aged ≥18 years. Additionally, 12 patients aged 13–17 years received a posaconazole dose of 600 mg per day for prophylaxis of invasive fungal infections (studies 316 and 1899). The safety profile in these patients under 18 years of age was similar to that observed in adults. Based on pharmacokinetic data from 10 of these patients, the pharmacokinetic profile was comparable to that in patients aged ≥18 years.

In a study (03579) involving 136 patients with neutropenia 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% of patients achieved pre-defined target concentrations (on day 7 of treatment, mean steady-state posaconazole concentrations ranged between 500 ng/mL and 2500 ng/mL).

Electrocardiogram (ECG) assessment. Multiple 12-hour ECG recordings were obtained from 173 healthy male and female volunteers aged 18 to 85 years before and during administration of posaconazole (400 mg twice daily with a 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). Posaconazole pharmacokinetics 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 per 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 daily dose (800 mg) into four 200 mg doses, posaconazole concentrations increased 2.6-fold compared to administration as 400 mg twice daily.

Effect of food on absorption following oral administration in healthy volunteers. Absorption of posaconazole was significantly increased when 400 mg posaconazole (once daily) was taken 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 fourfold 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.

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

Biotransformation. Posaconazole has no significant circulating metabolites, and its concentrations are unlikely to be 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 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 the radiolabeled dose), with the parent compound being the main component (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 14% of the radiolabeled dose excreted in urine (<0.2% of the radiolabeled dose as unchanged compound). Steady-state concentrations were achieved after 7–10 days of multiple dosing.

Pharmacokinetics in special patient populations.

Children (< 18 years). When 800 mg per day of posaconazole was administered 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). In prophylaxis studies, mean steady-state posaconazole concentrations (Cav) in children (13–17 years) were comparable to those in adults (≥18 years). In study (03579), 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 had concentrations in approximately 50% of patients meeting pre-defined targets (on day 7 of treatment, mean steady-state posaconazole concentrations ranged between 500–2500 ng/mL). Overall, posaconazole concentrations are generally higher in older children (7 to <18 years) than in younger children (2 to <7 years).

Sex. Posaconazole pharmacokinetics do not differ between men and women. Elderly patients (≥65 years). Elderly patients showed increased Cmax (26%) and AUC (29%) (24 patients aged ≥65 years) compared to younger patients (24 patients aged 18–45 years). However, in clinical efficacy studies, the safety profiles of posaconazole in younger and older patients were similar. Race. A slight decrease (16%) in AUC and Cmax of posaconazole was observed in non-Caucasian patients compared to Caucasian patients. However, the safety profiles of posaconazole in non-Caucasian and Caucasian patients were similar.

Body weight.

Pharmacokinetic modeling using the oral tablet formulation suggests that exposure to posaconazole may be lower in patients with body weight over 120 kg. 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 should be closely monitored for adverse reactions. Renal impairment. After single-dose administration, no effect of mild to moderate renal impairment (n = 18, Clcr ≥20 mL/min/1.73 m²) on posaconazole pharmacokinetics was observed; therefore, 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 renally excreted, 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 insufficiency. After administration of a single 400 mg dose of posaconazole in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic insufficiency (6 patients per group), mean AUC values were 1.3–1.6 times higher than in control subjects without hepatic impairment. The concentration of unbound drug was not measured, and an increase in unbound posaconazole concentration greater than the observed 60% increase in total AUC cannot be excluded. Mean t½ was prolonged from approximately 27 hours to about 43 hours in the respective groups. Dose adjustment is not required in patients with mild to severe hepatic insufficiency, but caution should be exercised due to the potential for increased plasma concentrations.

Clinical characteristics.

Indications.

The medicinal product is indicated for the treatment of the following fungal infections in adults:

• invasive aspergillosis in patients resistant to amphotericin B or itraconazole, or in patients intolerant to these medicinal products;
• fusariosis in patients resistant to amphotericin B and in patients intolerant to amphotericin B;
• chromoblastomycosis and mycetoma in patients resistant to itraconazole and in patients intolerant to itraconazole;
• coccidioidomycosis in patients resistant to amphotericin B, itraconazole, or fluconazole, and in patients intolerant to these medicinal products;
• oropharyngeal candidiasis: as first-line therapy in immunocompromised patients when 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. The medicinal product is indicated for prophylaxis of invasive fungal infections (IFIs) 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 IFIs;
• hematopoietic stem cell transplant recipients receiving high-dose immunosuppressants to prevent graft-versus-host disease, and who are at high risk of developing IFIs.

The medicinal product is indicated for prophylaxis of IFIs caused by yeast or mould fungi in adults and children aged 13 years and older who are at increased risk of developing 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, as 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: 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 pharmacokinetics.

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

Rifabutin (300 mg once daily) reduced Cmax and AUC 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.

Efavirenz (400 mg once daily) reduced Cmax and AUC 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. Co-administration of fosamprenavir with posaconazole may lead to decreased plasma concentrations of posaconazole. If concomitant use is necessary, close monitoring for possible fungal infection breakthrough is recommended. Repeated doses of fosamprenavir (700 mg twice daily for 10 days) reduced Cmax and AUC of posaconazole (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 plasma levels of fosamprenavir when fosamprenavir is co-administered with ritonavir is unknown.

Phenytoin (200 mg once daily) reduced 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, proton pump inhibitors, and antacids. Cimetidine (400 mg twice daily) reduced posaconazole plasma concentrations (Cmax and AUC of 200 mg posaconazole daily) by 39% due to decreased absorption, possibly due to reduced gastric acid secretion. Concomitant use of posaconazole and cimetidine should be avoided.

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

Food. Absorption of posaconazole is significantly increased when taken with food.

Alcohol. Data on interaction with posaconazole are not available.

Herbal medicinal products. Data on interaction with posaconazole are not available.

Smoking. Data on interaction with posaconazole are not available.

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 administering posaconazole concomitantly with CYP3A4 substrates administered intravenously. It may also be necessary to reduce the dose of the CYP3A4 substrate. When posaconazole is administered concomitantly with oral CYP3A4 substrates whose increased plasma concentrations may lead to unacceptable adverse reactions, careful monitoring of plasma concentrations of the CYP3A4 substrate and/or adverse reactions is recommended, with dose adjustment as needed. Several interaction studies were conducted in healthy volunteers, who had higher posaconazole levels 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. Additionally, variability is expected among patients receiving different doses of posaconazole. The effect of concomitant posaconazole administration on plasma levels of CYP3A4 substrates may also vary over time in an individual patient unless posaconazole is taken in a strictly standardized manner with food, as food 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 QT interval prolongation and, in rare cases, ventricular tachycardia torsades de pointes.

Ergot alkaloids. Posaconazole may increase plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine), potentially leading to ergotism. Concomitant use of ergot alkaloids and posaconazole is contraindicated.

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

Vinca alkaloids. Most vinca alkaloids (e.g., vincristine and vinblastine) are substrates of the CYP3A4 isoenzyme. Co-administration of vincristine with azole antifungal agents, including posaconazole, has been associated with serious adverse reactions. Posaconazole may increase plasma concentrations of vinca alkaloids, potentially leading to neurotoxicity and other serious adverse reactions. Therefore, treatment with azole antifungals, including posaconazole, is recommended in patients receiving vinca alkaloids, including vincristine, only when no alternative antifungal therapy is available (see section «Special precautions for use»).

Rifabutin. Posaconazole increased 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. When these medicinal products are used concomitantly, careful monitoring of blood counts and adverse reactions related to increased rifabutin concentrations (e.g., uveitis) is recommended.

Sirolimus. In healthy adult volunteers, administration of posaconazole oral suspension (400 mg twice daily for 16 days) increased 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 interaction effect between posaconazole and sirolimus in patients is unknown but is expected to vary due to changes in posaconazole exposure in patients. Concomitant administration of posaconazole and sirolimus is not recommended and should be avoided. 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 the start, during, and after posaconazole therapy, with appropriate dose adjustments. 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 aim for the upper end of the normal therapeutic range, with close monitoring of clinical symptoms, laboratory parameters, and biopsy findings.

Cyclosporine. In patients who underwent heart transplantation and were on a stable dose of cyclosporine, administration of posaconazole oral suspension at 200 mg once daily increased cyclosporine blood concentrations, necessitating dose reduction of the latter. In clinical efficacy studies, cases of elevated cyclosporine levels causing serious adverse reactions, including nephrotoxicity, were reported, including one fatal case due to leukoencephalopathy. Before initiating posaconazole in patients already receiving cyclosporine, the dose of cyclosporine should be reduced (e.g., to ¾ of the current dose). Cyclosporine blood concentrations should be closely monitored during and after posaconazole therapy, with dose adjustments as needed.

Tacrolimus. Posaconazole increased 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 were reported. Before initiating posaconazole in patients already receiving tacrolimus, the dose of tacrolimus 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 substrates of the CYP3A4 isoenzyme, there is a potential for posaconazole to increase plasma concentrations of these antiretroviral agents. In healthy volunteers, administration of posaconazole (400 mg twice daily for 7 days) increased Cmax and AUC of atazanavir (300 mg once daily for 7 days) by an average of 2.6-fold and 3.7-fold (range 1.2 to 26-fold), respectively. To a lesser extent, administration of posaconazole in healthy volunteers (400 mg twice daily for 7 days) increased Cmax and AUC of atazanavir when co-administered with ritonavir in a boosted regimen (300 mg atazanavir + 100 mg ritonavir once daily for 7 days) 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 timely detection of possible adverse and/or toxic reactions.

Midazolam and other benzodiazepines metabolized by CYP3A4. In a study involving healthy volunteers, posaconazole (200 mg once daily for 10 days) increased AUC of intravenous midazolam (0.05 mg/kg) by 83%. In another study involving healthy volunteers, repeated oral doses of posaconazole (200 mg twice daily for 7 days) increased 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 400 mg twice daily for 7 days increased 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 Cmax and AUC of orally administered midazolam (2 mg single oral dose) by 2.2-fold and 4.5-fold, respectively. Additionally, orally administered posaconazole (200 mg or 400 mg) prolonged the mean terminal t1/2 of midazolam from approximately 3–4 hours to 8–10 hours when administered concomitantly.

Due to the risk of prolonged sedative effect, dose adjustment of benzodiazepines metabolized by CYP3A4, such as midazolam, triazolam, and alprazolam, is recommended when used concomitantly with posaconazole.

Calcium channel blockers metabolized by CYP3A4 (e.g., diltiazem, verapamil, nifedipine, nicardipine). When used concomitantly with posaconazole, monitoring for adverse and/or toxic reactions related to calcium channel blockers is recommended, with dose adjustment as needed.

Digoxin. Administration of other azoles has been associated with increased digoxin blood levels. Therefore, posaconazole may also increase digoxin blood concentrations; thus, digoxin blood concentrations should be monitored during and after concomitant use with posaconazole.

Sulfonylureas. In some volunteers, concomitant administration of glipizide and posaconazole was associated with decreased blood glucose levels. Blood glucose levels should be monitored in diabetic patients receiving sulfonylurea agents and posaconazole.

Tretinoin (trans-retinoic acid or ATRA). Since ATRA is metabolized by hepatic CYP450 enzymes, particularly CYP3A4, concomitant use with posaconazole, a potent CYP3A4 inhibitor, may lead to increased tretinoin effects, resulting in increased toxicity (e.g., hypercalcemia). Serum calcium levels should be monitored, and dose adjustment of tretinoin should be considered as needed during and for several days after posaconazole therapy.

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

An interaction between posaconazole and flucloxacillin has been established.

Paediatric population.

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, but caution should be exercised when administering posaconazole to patients with hypersensitivity to other azoles. Photosensitivity reactions may occur (see section "Adverse reactions").

Hepatotoxicity.

During clinical trials, rare hepatic reactions were observed (e.g., mild or moderate increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin levels in serum, and/or clinically evident hepatitis). Elevations in liver function tests were usually reversible upon discontinuation of therapy; in some cases normalization occurred without discontinuation of treatment, and discontinuation was required only in isolated cases. Very rare cases of severe hepatic disorders (including fatal outcomes) have been reported in patients with severe underlying conditions (such as hematological malignancies) receiving posaconazole. Posaconazole should be used with caution in patients with hepatic impairment due to limited clinical experience and the potential for higher plasma levels of posaconazole in these patients.

Monitoring of liver function.

Liver function tests should be evaluated at the beginning and during posaconazole therapy. Patients who develop abnormalities in liver function tests during treatment with Posakonazol-Vista require 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 Posakonazol-Vista should be made if clinical signs indicate development of liver disease.

QT interval prolongation.

Some azole compounds have been associated with QT interval prolongation. Analysis of a large number of ECGs in healthy volunteers did not reveal QT interval prolongation. However, posaconazole should not be used concomitantly with medicinal products that prolong the QT interval and/or are CYP3A4 substrates.

Caution is advised when using Posakonazol-Vista in patients at risk of cardiac rhythm disturbances:

• with congenital or acquired QT prolongation;
• with cardiomyopathy, especially with heart failure;
• with sinus bradycardia;
• with diagnosed symptomatic arrhythmias;
• when co-administered with medicinal products that prolong the QT interval (except those listed in section "Contraindications").

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

Drug interactions.

Posaconazole is an inhibitor of CYP3A4; therefore, it should be used only under special conditions when co-administered with other medicinal products metabolized by CYP3A4.

Gastrointestinal disorders.

Limited pharmacokinetic data are available in patients with severe gastrointestinal disorders (such as severe diarrhea). Close monitoring is required in patients with severe diarrhea or vomiting for possible reactivation of fungal infection.

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

The concentration of posaconazole 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.

Midazolam and other benzodiazepines metabolized by CYP3A4 isoenzyme.

Due to the risk of prolonged sedative effect and possible respiratory depression, the 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 is required.

Vincristine toxicity.

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

Venetoclax toxicity.

Concomitant use of venetoclax (a CYP3A4 substrate) and 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.

Important information on excipients.

This medicinal product contains approximately 2.1 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 is established, consult a physician before taking this medicinal product. May be harmful to teeth. This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

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 period.

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 therapy.

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 exercised, as certain adverse reactions (e.g., dizziness, somnolence, etc.) have been reported, which may potentially affect the ability to drive or operate machinery.

Administration and Dosage

For oral use in adults and children aged 13 years and older, taken during meals or together with 240 mL of liquid nutritional supplements (enteral nutrition). Before administration, the suspension vial should be shaken well.

Table 5

Recommended doses according to indications

Indications	Dosage and duration of treatment
Resistant invasive fungal infections / patients with intolerance to other medicinal products (and intolerance to first-line therapy)	200 mg (5 ml) 4 times daily. In addition, patients who can consume food or liquid nutriceuticals may take 400 mg (10 ml) twice daily with food or liquid nutriceuticals or immediately after intake. The duration of therapy depends on the severity of the underlying disease, the recovery period after immunosuppressive therapy, and the clinical response to treatment.
Oropharyngeal candidiasis	Loading dose of 200 mg (5 ml) once daily on the first day of treatment, followed by 100 mg (2.5 ml) once daily for 13 days. The medicinal product should be taken during or immediately after food or liquid nutriceuticals (for patients unable to tolerate food) to enhance oral absorption and ensure adequate effect.
Prophylaxis of invasive fungal infections	200 mg (5 ml) 3 times daily. The medicinal product should be taken during or immediately after food or liquid nutriceuticals (for patients unable to tolerate food) to enhance oral absorption and ensure adequate effect. The duration of therapy is determined based on successful management of neutropenia or immune recovery. For patients with acute myeloid leukemia or myelodysplastic syndrome, prophylactic treatment with Posaconazole-Vista should be initiated several days before anticipated neutropenia and continued for 7 days after the neutrophil count has increased to more than 500 cells per 1 mm³.

Special patient groups.

Use in patients with renal impairment.

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

Use in patients with hepatic impairment.

There is limited data on the impact of hepatic insufficiency (including Child-Pugh class C chronic liver disease) on the pharmacokinetics of posaconazole, which demonstrate increased plasma concentrations of posaconazole in patients with impaired liver function compared to those with normal liver function, but do not indicate the necessity for dose adjustment (see sections "Special instructions" and "Pharmacological properties. Pharmacokinetics"). Caution is recommended due to the potential for increased plasma levels.

Children.

The efficacy and safety of the medicinal product in children under 13 years of age have not been established; therefore, it is not administered to patients in this age group. Data regarding dosing in children are limited (see section "Pharmacological properties").

Overdose.

Symptoms. During clinical trials, in patients receiving posaconazole doses up to 1600 mg per day, no adverse reactions were observed that differed from those seen in patients receiving lower doses.

One case of accidental overdose was reported in a patient who took the medicinal product at a dose of 1200 mg twice daily for 3 days. No adverse events were observed in this patient.

Treatment. Posaconazole is not removed by hemodialysis. There are no specific recommendations for the treatment of posaconazole overdose. Therapy should be symptomatic and supportive.

Adverse reactions.

Brief description of the safety profile.

The safety of posaconazole has been evaluated in over 2400 patients and healthy volunteers during clinical studies and from post-marketing experience. The most commonly reported adverse reactions were nausea, vomiting, diarrhea, fever, and increased bilirubin levels.

The list of adverse reactions is presented in Table 6.

Adverse reactions are categorized by frequency: very common (≥ 1/10); common (from > 1/100 to < 1/10); uncommon (from > 1/1000 to < 1/100); rare (from > 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from the available data).

Table 6.

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

Body Systems	Adverse Reactions and their frequency†
Blood and lymphatic system	Common: neutropenia. Uncommon: thrombocytopenia, leukopenia, anemia, eosinophilia, lymphadenopathy, splenic infarction. Rare: hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, pancytopenia, coagulopathy, hemorrhage.
Immune system	Uncommon: allergic reactions. Rare: hypersensitivity reactions.
Endocrine system	Rare: adrenal insufficiency, decreased gonadotropin levels. Frequency unknown: pseudoaldosteronism.
Metabolism and nutritional disorders	Common: electrolyte imbalance, anorexia, decreased appetite, hypokalemia, hypomagnesemia. Uncommon: hyperglycemia, hypoglycemia.
Psychiatric disorders	Uncommon: pathological dreams, confusion, sleep disturbances. Rare: psychiatric disorders, depression.
Nervous system	Common: paresthesia, dizziness, somnolence, headache, dysgeusia. Uncommon: seizures, neuropathy, hypoesthesia, tremor, aphasia, insomnia. Rare: cerebrovascular disorders, encephalopathy, peripheral neuropathy, loss of consciousness.
Eye disorders	Uncommon: blurred vision, photophobia, decreased visual acuity. Rare: diplopia, scotoma.
Ear and labyrinth disorders	Rare: hearing impairment.
Cardiac disorders	Common: arterial hypertension. Uncommon: QT interval prolongation syndrome, ECG changes, palpitations, bradycardia, supraventricular extrasystoles, tachycardia, arterial hypotension, vasculitis. Rare: ventricular tachycardia torsade de pointes, ventricular tachycardia, cardiorespiratory failure, heart failure, myocardial infarction, sudden death, pulmonary artery thromboembolism, deep vein thrombosis.
Respiratory, thoracic and mediastinal disorders	Uncommon: cough, epistaxis, nasal congestion, hiccups, pleural pain, tachypnea. Rare: pulmonary hypertension, interstitial pneumonia, pneumonitis.
Gastrointestinal disorders	Very common: nausea. Common: vomiting, nausea, abdominal pain, diarrhea, dyspepsia, dry mouth, flatulence, constipation, anorectal discomfort. Uncommon: pancreatitis, abdominal distension, enteritis, epigastric discomfort, belching, gastroesophageal reflux, mouth swelling. Rare: gastrointestinal hemorrhage, intestinal obstruction.
Hepatobiliary disorders*	Common: elevated liver function tests (ALT, AST, bilirubin, alkaline phosphatase, gamma-glutamyl transferase). Uncommon: hepatocellular injury, hepatitis, jaundice, hepatomegaly, cholestasis, hepatotoxicity, liver function abnormalities. Rare: liver failure, cholestatic hepatitis, cholestasis, hepatosplenomegaly, liver area pain, asterixis.
Skin and subcutaneous tissue disorders	Common: rash, pruritus. Uncommon: oral ulceration, alopecia, dermatitis, erythema, petechiae. Rare: Stevens-Johnson syndrome, vesicular rash. Unknown: photosensitivity reaction.
Musculoskeletal and connective tissue disorders	Uncommon: back pain, limb pain, neck pain, musculoskeletal pain, extremity pain.
Renal and urinary disorders	Uncommon: acute renal failure, renal failure, increased blood creatinine levels. Rare: renal tubular acidosis, interstitial nephritis.
Reproductive system disorders	Uncommon: menstrual cycle disturbances. Rare: breast pain.
General disorders and administration site conditions	Common: increased body temperature (fever), weakness, fatigue. Uncommon: edema, pain, chills, malaise, chest discomfort, drug intolerance, feeling of nervousness, mucosal inflammation. Rare: tongue and facial swelling.
Laboratory findings:	Uncommon: altered drug levels, decreased blood phosphorus levels, abnormal chest X-ray findings.

† Based on adverse reactions observed during use of the oral suspension.

* During post-marketing surveillance, a report of severe hepatic injury with fatal outcome was received.

Description of selected adverse reactions

Hepatobiliary disorders.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

After first opening of the bottle – 28 days.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze. Keep out of the reach and sight of children.

Packaging. 105 mL of suspension in a 125 mL bottle; 1 bottle with a measuring spoon in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Deva Holding A.Ş.

Manufacturer's address and place of business.
Çerkezköy Organize Sanayi Bölgesi, Karagac Mah. Atatürk Cad. No 32, Kapaklı/Tekirdağ, TR-59510, Turkey.