Polizanol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT POLIZANOL (POLIZANOL)

Composition:

Active substance: posaconazole;

1 ml of suspension contains posaconazole equivalent to 40 mg of 100 % dry substance;

Excipients: citric acid monohydrate; anhydrous sodium citrate; sodium benzoate (E 211); sodium lauryl sulfate; xanthan gum; glycerol; glucose solution; titanium dioxide; cherry flavoring; purified water; simethicone emulsion 30 %, containing: simethicone, methylcellulose, sorbic acid, water.

Pharmaceutical form. Oral suspension.

Main physicochemical properties: at the time of release — white-colored suspension with a cherry odor in a brown glass bottle; during the shelf life — suspension ranging from white to yellowish color with a cherry odor in a brown glass bottle.

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 (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 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 Cut-Off Values (ECOFFs) for Aspergillusspp.

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

The EUCAST-established epidemiological cut-off values are:

• 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 cut-off values should not be equated with clinical breakpoints.

Breakpoints

Minimum inhibitory concentration (MIC) 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

The use of 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 ratio of the total area under the 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 is approximately 200. Achieving adequate maximum plasma concentration (Cmax) is particularly important in patients infected with Aspergillus (see section "Dosage and 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 therapies (as described above), mostly during the same time 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 successful 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

Total efficacy of therapy (mycologically confirmed)	Posaconazole oral suspension		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.

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 administered in multiple doses, for an average duration of 124 days and up to 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/Myetoma

9 out of 11 patients were successfully treated with posaconazole oral suspension at a dose of 800 mg/day administered in multiple doses, for an average duration of 268 days and up to 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 administered in multiple doses, for an average duration of 296 days and up to 460 days.

Treatment of azole-susceptible oropharyngeal candidiasis

A randomized, double-blind, controlled trial 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 (cured or improved) 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, then 100 mg once daily for 13 days).

The clinical response rates from the above-mentioned study 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

Endpoint	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 is the number of cases defined as having a clinical response (cure or improvement) divided by the total number of cases that can be included in the analysis.

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

Two randomized controlled trials 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 trial 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 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 of investigational medicinal product plus 7 days). At study entry, the majority (377/600 [63%]) of patients had GVHD at grade 2 or 3 acute or chronic extensive stage (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 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, 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 post-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 prophylaxis 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 trials for prevention of invasive fungal infections

Study	Posaconazole oral suspension	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 after randomization; in study 316, this was the 111-day period after baseline.

d All randomized.

e All received treatment.

Table 4

Results of clinical trials for prevention of invasive fungal infections

Study	Posaconazole oral suspension	Control groupa
Proportion (%) of patients with proven/possible aspergillosis
Treatment periodb
1899d	2/304 (1)	20/298 (7)
316e	3/291 (1)	17/288 (6)
Established periodc
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). Based on Kaplan-Meier survival analysis, the probability of survival to day 100 after randomization was significantly higher in patients receiving posaconazole. This survival benefit was demonstrated when analyzing deaths from all causes (p = 0.0354) as well as deaths related to IFI (invasive fungal infections) (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).

Pediatric population

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 children 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% achieved pre-specified target concentrations (on day 7 of treatment, mean steady-state posaconazole concentrations 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 (ECG) assessment

Multiple time-matched ECGs recorded over 12 hours 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 food). No clinically significant changes in mean QT interval values were observed compared to baseline.

Pharmacokinetics

Absorption

The median time to peak concentration (tmax) of posaconazole after oral administration is 3 hours (when taken with food). Posaconazole pharmacokinetics are linear after single and multiple doses up to 800 mg when administered with high-fat food. No further increase in exposure was observed when patients and healthy volunteers received doses exceeding 800 mg/day. When administered in the fasted state, AUC increased less than proportionally to dose when the dose exceeded 200 mg. When healthy volunteers received the drug in the fasted state, 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 oral absorption in healthy volunteers

Absorption of posaconazole was significantly increased when a single 400 mg dose was taken with or immediately after a high-fat meal (~50 grams of fat), compared to administration before a meal, resulting in approximately 330% and 360% increases in Cmax and AUC, respectively. The AUC of posaconazole increased approximately 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 (see sections "Interaction with other medicinal products and other forms of interaction" and "Posology and method of administration").

Distribution

Posaconazole is slowly absorbed and slowly eliminated, with a large apparent volume of distribution (1774 liters) and high 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. The circulating metabolites are mostly 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-labeled posaconazole, radioactivity was predominantly recovered in feces (77% of the radiolabeled dose), with the parent compound being the major component (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway; 14% of the radiolabeled dose was 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

Pediatric patients (<18 years)

When administered at 800 mg/day 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 concentrations (Cav) of posaconazole in 10 children (13–17 years) were comparable to those in adults (≥18 years).

In a study of 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 pre-specified target concentrations (on day 7 of treatment, mean steady-state posaconazole concentrations ranged between 500–2500 ng/mL). Overall, posaconazole concentrations were generally higher in older children (7 to <18 years) than in younger children (2 to <7 years).

Gender

Posaconazole pharmacokinetics in males and females are not different.

Elderly patients (≥65 years)

In elderly patients, Cmax (by 26%) and AUC (by 29%) were increased (24 patients aged ≥65 years) compared to younger individuals (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 (by 16%) in AUC and Cmax of posaconazole oral suspension was observed in non-Caucasian patients compared to Caucasian patients. However, safety profiles of posaconazole in non-Caucasian 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 should be closely monitored for adverse reactions.

Renal impairment

After a single dose of posaconazole oral suspension, mild to moderate renal impairment (n = 18, Clcr ≥20 mL/min/1.73 m²) did not affect posaconazole pharmacokinetics; therefore, dose adjustment is not required. In patients with severe renal impairment (n = 6, Clcr <20 mL/min/1.73 m²), AUC values showed high variability (coefficient of variation (CV) >96%) compared to other patient groups with renal impairment (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 values were 1.3–1.6 times higher than in control subjects without hepatic dysfunction. 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. Mean elimination half-life (t½) increased 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.

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

• invasive aspergillosis in patients with resistance to amphotericin B or itraconazole and in patients intolerant to these medicinal products;
• fusariosis in patients with resistance to amphotericin B and in patients intolerant to amphotericin B;
• chromoblastomycosis and mycetoma in patients with resistance to itraconazole and in patients intolerant to itraconazole;
• coccidioidomycosis in patients with resistance 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 low 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 Polizanol 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.

The medicinal product Polizanol 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.
• 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 "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use");
  • 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 "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on posaconazole

Posaconazole is metabolized via glucuronidation by UDP (uridine diphosphate) (phase II enzymatic reaction) and is a substrate for efflux by P-glycoprotein (P-gp) 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 maximum plasma concentration (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. See also information below regarding the effect of posaconazole on rifabutin plasma levels.

Flucloxacillin (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 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. Combination of fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant use is necessary, careful monitoring for possible reactivation of fungal infection is recommended. Repeated doses of fosamprenavir (700 mg twice daily for 10 days) reduce Cmax and AUC of posaconazole in oral suspension form (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 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. Cimetidine (400 mg twice daily) reduced posaconazole plasma concentrations (Cmax and AUC) by 39% due to decreased absorption, possibly due to reduced gastric acid secretion. Concomitant use of posaconazole and H2-receptor antagonists should be avoided.

Administration of 400 mg posaconazole with esomeprazole (40 mg daily) reduces 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 if possible.

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

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 intravenous CYP3A4 substrates. 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 be associated with 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. Also, variability is expected among patients receiving different doses of posaconazole. The effect of concomitant posaconazole 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 substrates of CYP3A4. Concurrent 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 be treated with azole antifungal agents, including posaconazole, only when no other antifungal treatment options are available.

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 (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 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 changes in posaconazole exposure among patients. Concomitant use of posaconazole and sirolimus is not recommended and should be avoided if 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 the beginning, 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 usual therapeutic ranges may lead to subtherapeutic levels. Therefore, target trough concentrations should be at the upper end of the usual therapeutic range, with close monitoring of clinical signs and symptoms, laboratory parameters, and biopsy findings.

Cyclosporine. In patients who underwent heart transplantation and were on a stable dose of cyclosporine, posaconazole oral suspension 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, were observed, and one fatal case of leukoencephalopathy was reported. Before initiating posaconazole in patients already receiving cyclosporine, the cyclosporine dose should be reduced (e.g., to 3/4 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. During clinical efficacy studies, cases of clinically significant drug interactions requiring hospitalization and/or discontinuation of posaconazole were recorded. Before 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 substrates of CYP3A4, there is a likelihood that posaconazole will 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 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 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 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 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 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 when administered concomitantly.

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

Calcium channel blockers metabolized by CYP3A4 (e.g., diltiazem, verapamil, nifedipine, nicardipine). Frequent monitoring for adverse and/or toxic reactions associated with calcium channel blockers is recommended when used concomitantly with posaconazole, 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 at the beginning and after completion of therapy when used concomitantly with posaconazole.

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

All-trans retinoic acid (ATRA) or tretinoin. Since ATRA is metabolized by hepatic enzymes of the cytochrome CYP450 system, particularly CYP3A4, concomitant use with posaconazole, a strong inhibitor of CYP3A4, may enhance the effect of tretinoin, leading to increased toxicity (especially hypercalcemia). During and for several days after posaconazole treatment, serum calcium levels should be monitored, and dose adjustment of tretinoin should be considered as needed.

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 brief summary of the medicinal product 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; however, 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 alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total serum bilirubin levels, 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. Rarely, more severe hepatic events (including fatal outcomes) have been reported. Posaconazole should be used with caution in patients with hepatic impairment due to limited clinical experience and the possibility that plasma levels of posaconazole may be higher in these patients (see sections "Pharmacological properties. Pharmacokinetics" and "Dosage and administration").

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

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

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

• in patients with congenital or acquired QT prolongation;
• in patients with cardiomyopathy, especially with heart failure;
• in patients with sinus bradycardia;
• in patients with diagnosed symptomatic arrhythmia;
• in patients receiving concomitant medications 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 a CYP3A4 inhibitor and should only be administered under special conditions when used concomitantly with other medicinal products metabolized by CYP3A4 (see section "Interaction with other medicinal products and other forms of interaction").

Gastrointestinal dysfunction. Limited pharmacokinetic data are available in patients with severe gastrointestinal disorders (such as severe diarrhea). Patients with severe diarrhea or vomiting should be closely monitored for possible breakthrough fungal infection.

Rifamycin antibiotics (rifampicin, rifabutin), flucloxacillin, 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 (see section "Interaction with other medicinal products and other forms of interaction").

Midasolam and other benzodiazepines metabolized by CYP3A4

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

Vincristine toxicity

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

Venetoclax toxicity

Concomitant administration of venetoclax (a CYP3A4 substrate) and strong CYP3A inhibitors, including posaconazole, may increase venetoclax toxicity, including 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 sun exposure during treatment without adequate protection, such as protective clothing and sunscreen with high sun protection factor (SPF).

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 has been diagnosed, 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

Posaconazole is excreted in the milk of lactating rats. Excretion of posaconazole into human breast milk has not been studied. Breastfeeding should be discontinued upon initiation 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) have been reported, which may potentially affect the ability to drive or operate machinery.

Dosage and Administration.

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

Administer orally to adults and children aged 13 years and older during a meal or with 240 mL of liquid nutritional supplements (enteral feeding). The suspension bottle should be shaken well before use.

Table 5

Recommended doses according to indications

Indications	Dosage and duration of treatment
Resistant invasive fungal infections / patients with IFI and intolerance to first-line therapy	200 mg (5 ml) 4 times daily. Additionally, patients who can consume food or nutraceuticals may take 400 mg (10 ml) twice daily with food or nutraceuticals 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. Each dose of Polizanol should be taken with or immediately after food or nutraceuticals (for patients who cannot tolerate food) to enhance oral absorption and ensure adequate effect.
Prophylaxis of invasive fungal infections	200 mg (5 ml) 3 times daily. Each dose of Polizanol should be taken with or immediately after food or nutraceuticals (for patients who cannot tolerate food) to enhance oral absorption and ensure adequate effect. The duration of therapy should be determined based on successful management of neutropenia or immune recovery. For patients with acute myeloid leukemia or myelodysplastic syndrome, prophylactic treatment with Polizanol should begin a few days before anticipated neutropenia and continue for 7 days after neutrophil count increases to over 500 cells per 1 mm³.

Renal function impairment

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

Hepatic function impairment

There is limited data on the effect of hepatic insufficiency (including chronic liver insufficiency, Child–Pugh class C) on the pharmacokinetics of posaconazole, demonstrating increased plasma concentrations of posaconazole in patients with impaired liver function compared to those with normal liver function. However, these data do not indicate the necessity for dose adjustment (see sections "Pharmacological properties. Pharmacokinetics" and "Special precautions"). 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

During clinical trials, no adverse reactions different from those observed in patients receiving lower doses were reported in patients treated with posaconazole oral suspension at doses up to 1600 mg/day. One accidental overdose was reported in a patient who received posaconazole oral suspension at 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 administered.

Adverse Reactions

The safety of posaconazole in the form of oral suspension was evaluated in over 2400 patients and healthy volunteers during clinical studies and post-marketing experience. The most commonly reported serious 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 of occurrence: 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 the available data).

Table 6

Adverse reactions reported during clinical studies and the post-marketing period, organized by system organ class 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, hemorrhages
Immune system	Uncommon: allergic reactions Rare: hypersensitivity reactions
Endocrine system	Rare: adrenal insufficiency, decreased gonadotropin levels, pseudoaldosteronism
Metabolism and nutrition	Common: electrolyte imbalance, anorexia, decreased appetite, hypokalemia, hypomagnesemia Uncommon: hyperglycemia, hypoglycemia
Psychiatric	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 organs	Uncommon: blurred vision, photophobia, decreased visual acuity Rare: diplopia, scotoma
Ear and labyrinth disorders	Rare: hearing impairment
Cardiac	Uncommon: QT interval prolongation syndrome§, ECG changes§, palpitations, bradycardia, supraventricular extrasystole, tachycardia Rare: ventricular tachycardia torsade de pointes, ventricular tachycardia, cardiorespiratory failure, heart failure, myocardial infarction, sudden death
Vascular	Common: arterial hypertension Uncommon: arterial hypotension, vasculitis Rare: pulmonary artery thromboembolism, deep vein thrombosis
Respiratory, thoracic and mediastinal	Uncommon: cough, epistaxis, nasal congestion, hiccups, pleural pain, tachypnea Rare: pulmonary hypertension, interstitial pneumonia, pneumonitis
Gastrointestinal tract	Very common: nausea Common: vomiting, abdominal pain, diarrhea, dyspepsia, dry mouth, flatulence, constipation, anorectal discomfort Uncommon: pancreatitis, abdominal distension, enteritis, epigastric discomfort, belching, gastroesophageal reflux, mouth edema Rare: gastrointestinal hemorrhage, intestinal obstruction
Hepatobiliary system	Common: increased liver function tests (ALT, AST, bilirubin, alkaline phosphatase, gamma-glutamyl transferase) Uncommon: hepatocyte damage, hepatitis, jaundice, hepatomegaly, cholestasis, hepatotoxicity, liver function abnormalities Rare: liver failure, cholestatic hepatitis, hepatosplenomegaly, liver area pain, asterixis
Skin and subcutaneous tissue	Common: rash, pruritus Uncommon: oral ulceration, alopecia, dermatitis, erythema, petechiae Rare: Stevens-Johnson syndrome, vesicular rash Frequency not known: photosensitivity reaction§
Musculoskeletal and connective tissue	Uncommon: back pain, neck pain, musculoskeletal pain, limb pain
Renal and urinary	Uncommon: acute kidney injury, renal failure, increased blood creatinine Rare: renal tubular acidosis, interstitial nephritis
Reproductive system and breast	Uncommon: menstrual cycle disturbances Rare: breast pain
General 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 swelling, facial swelling
Laboratory findings	Uncommon: altered drug levels, decreased blood phosphorus, abnormal chest X-ray

* Based on adverse reactions observed during the use of oral suspension, delayed-release tablets, and concentrate for infusion solution.

§ See section "Special precautions".

Description of selected adverse reactions

Disorders of the hepatobiliary system

During post-marketing surveillance of posaconazole oral suspension, cases of severe hepatotoxicity with fatal outcomes have been reported (see section "Special precautions").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. Unopened bottle — 3 years. Shelf life after opening the bottle — 30 days. Do not use the medicine after the expiry date stated on the packaging.

Storage conditions. This medicine does not require special storage conditions.

Do not refrigerate or freeze. Keep out of reach of children.

Packaging. 105 ml in a bottle. 1 bottle per carton. A 5 ml dosing spoon is provided for measuring doses.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak", Ukraine (secondary packaging, quality control, batch release of bulk product manufactured by Rafarm S.A., Greece (manufacturing, primary and secondary bulk packaging, batch control, bulk batch release) or GenePharm S.A., Greece (secondary bulk packaging, batch control, bulk batch release)).

Manufacturer's address.

74 Kyrylivska Street, Kyiv, 04080, Ukraine