Posaconazole-teva

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

Composition:

Active substance: posaconazole;

1 ml of oral suspension contains 40 mg of posaconazole;

Excipients: citric acid monohydrate; sodium dihydrogen citrate anhydrous; sodium benzoate (E 211); sodium lauryl sulfate; simethicone emulsion 30%: simethicone, methylcellulose, sorbic acid, water; xanthan gum; glycerin; glucose solution; titanium dioxide (E 171); cherry flavor PHL 142-355; purified water.

Pharmaceutical form. Oral suspension.

Main physicochemical properties: oral suspension of white to yellowish color with a cherry odor, in amber-colored glass bottles.

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, posaconazole has been shown to be active against the following microorganisms: fungi of the genus Aspergillus (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus), fungi of the genus Candida (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. Clinical isolates with reduced susceptibility to posaconazole have been identified. The primary mechanism of resistance is the occurrence of substitutions in the target protein, CYP51.

Epidemiological cutoff values (ECOFF) for Aspergillus species. Epidemiological cutoff values for posaconazole, which differentiate the wild-type population from isolates with acquired resistance, according to the methodology of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Epidemiological cutoff values (ECOFF) by EUCAST methodology: 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 species. Epidemiological cutoff values should not be equated with clinical breakpoints.

Breakpoints (cutoff values). Minimum inhibitory concentration (MIC) breakpoints according to EUCAST data for posaconazole [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. Combined antifungal therapy does not lead to a reduction in the efficacy of posaconazole or other agents; however, there are currently no clinical data demonstrating that combination therapy provides an additive effect.

Pharmacokinetic/pharmacodynamic relationship. A correlation has been observed between the total area under the plasma concentration-time curve divided by the MIC (AUC/MIC) and clinical outcome. The threshold AUC/MIC ratio for patients infected with Aspergillus was approximately 200. It is particularly important to ensure achievement of maximum drug concentration in plasma in patients infected with Aspergillus.

Clinical experience. Invasive aspergillosis. In a non-comparative salvage therapy study, the use of posaconazole oral suspension at a dose of 800 mg/day in divided doses was evaluated for the treatment of patients with invasive aspergillosis refractory to amphotericin B (including liposomal formulations) or itraconazole, or in patients intolerant to these agents. Clinical outcomes were compared with data from an external control group collected from a retrospective medical chart review. The external control group included 86 patients who received standard therapy (as described above), primarily during the same time period and at the same institutions as the patients treated with posaconazole. Most cases of aspergillosis were considered refractory to prior therapy in both the posaconazole-treated group (88%) and the external control group (79%).

Data in Table 1 indicate that a favorable response (complete or partial recovery) at the end of treatment was achieved in 42% of patients treated with posaconazole, compared to 26% of patients in the external control group. However, this study 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 with the external control group

	Posaconazole, oral suspension	External control group
Overall treatment efficacy (mycologically confirmed)	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 given in multiple doses for a mean duration of 124 days, with a maximum of 212 days. Among 18 patients who were intolerant to amphotericin B or itraconazole, or had infection refractory to treatment with amphotericin B or itraconazole, 7 patients were categorized as having therapeutic benefit.

Chromoblastomycosis/mycetoma. 9 out of 11 patients were successfully treated with posaconazole at a dose of 800 mg/day given in multiple doses for a mean duration of 268 days, with a maximum of 377 days. Five of these patients had chromoblastomycosis caused by Fonsecaea pedrosoi, and 4 had mycetoma, primarily caused by fungi of the genus Madurella.

Coccidioidomycosis. 11 out of 16 patients were successfully treated (complete or partial resolution at the end of treatment of signs and symptoms present at baseline) with posaconazole oral suspension at a dose of 800 mg/day given in multiple doses over a mean period of 296 days, with a maximum of 460 days.

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

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

Table 2

Clinical efficacy rates* in oropharyngeal candidiasis

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

*The clinical efficacy endpoint is defined as the number of cases determined to have clinical response (recovery 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 evaluated the prevention of IFIs in patients at high risk for developing IFIs. 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 transplantation who had graft-versus-host disease (GVHD). The primary efficacy endpoint (EPE) was the number of proven/possible cases of IFI at 16 weeks after randomization, as determined by an independent, blinded external expert panel. A key secondary EPE was the number of proven/possible cases of IFI during the treatment period (from first dose to last dose of investigational drug plus 7 days). At study entry, the majority (377/600 [63%]) of patients had acute GVHD of grade II or III severity or chronic extensive GVHD (195/600 [32.5%]). The mean duration of treatment was 80 days for posaconazole and 77 days for fluconazole.

Study 1899 was a randomized, blinded 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 EPE 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 EPE was the number of proven/possible cases of IFI at 100 days after randomization. Newly diagnosed acute myelogenous leukemia was the most common underlying condition (435/602 [72%]). The mean duration of treatment was 29 days for posaconazole and 25 days for fluconazole/itraconazole. In both IFI prophylaxis studies, aspergillosis was the most common breakthrough infection (see Tables 3 and 4 for 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, oral suspension	Control group a	p-value
Proportion (%) of patients with proven/possible IFI
Treatment period b
1899d	7/304 (2)	25/298 (8)	0.0009
316e	7/291 (2)	22/288 (8)	0.0038
Established period c
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 For study 1899, this was the period from randomization to the last dose of investigational medicinal product plus 7 days; for study 316, this was the period from first dose to last dose of investigational medicinal product plus 7 days.

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

d All randomized.

e All received treatment. Table 4

Results of clinical studies on the prevention of IFIs

Study	Posaconazole, oral suspension	Control group a
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 For study 1899, this was the period from randomization to the administration of the last dose of investigational medicinal product plus 7 days; for study 316, this was the period from the first dose to the last dose of investigational medicinal product plus 7 days.

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

d All randomized.

e All received treatment.

In study 1899, a significant reduction in all-cause mortality was observed in favor of posaconazole (POS 49/304 [16%] vs. FLU/ITZ 67/298 [22%], p=0.048). Kaplan-Meier survival analysis showed significantly higher probability of survival 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 IFI-related deaths was significantly lower in the POS group (4/301) compared to the FLU group (12/299, p=0.0413).

Children. In a study (0041), 16 patients aged 8–17 years with IFI received 800 mg/day of posaconazole oral suspension. Based on available data from these 16 patients, the safety profile was similar to that observed in patients aged ≥18 years.

Twelve patients aged 13–17 years received a posaconazole dose of 600 mg/day for IFI prophylaxis (studies 316 and 1899). The safety profile in these patients aged <18 years was similar to that 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 (03579) involving 136 neutropenic children aged 11 months to 17 years who received posaconazole oral suspension up to 18 mg/kg/day divided into three doses, approximately 50% of patients achieved pre-defined target concentrations (mean steady-state posaconazole concentration on day 7 within 500–2500 ng/mL).

Electrocardiogram (ECG) assessment. Serial baseline ECGs recorded over 12 hours were obtained from 173 healthy male and female volunteers aged 18–85 years before and during administration of posaconazole (400 mg twice daily with high-fat food). No clinically significant changes in mean corrected (Fridericia method) QT interval were observed compared to baseline.

Pharmacokinetics.

Absorption. The mean time to peak concentration (tmax) of posaconazole is 3 hours (after food intake). The pharmacokinetics of posaconazole are linear after single and multiple doses up to 800 mg when administered with high-fat food. Increased exposure with doses exceeding 800 mg/day was not observed in patients or healthy volunteers. 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 in the fasting state, dividing the total daily dose (800 mg) into four 200 mg doses, posaconazole concentrations increased 2.6-fold compared to administration of 400 mg twice daily.

Effect of food on absorption following oral administration in healthy volunteers. Absorption of posaconazole was significantly increased when a single 400 mg dose (once daily) was taken during or immediately after a high-fat meal (~50 g fat), compared to administration before a meal, with Cmax and AUC increasing by approximately 330% and 360%, respectively. AUC of posaconazole increased approximately 4-fold when the drug was taken with a high-fat meal (~50 g fat) and approximately 2.6-fold when taken with a low-fat meal or nutritional supplement (14 g fat), compared to fasting.

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

Biotransformation. Posaconazole has no significant circulating metabolites and is unlikely to have its concentrations 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 of 35 hours (range 20–66 hours). After administration of 14C-posaconazole, radioactivity was predominantly recovered in feces (77% of radiolabeled dose), with the main component being unchanged drug (66% of radiolabeled dose). Renal clearance is a minor elimination pathway, with 14% of the radiolabeled dose excreted in urine (<0.2% of radiolabeled dose as unchanged drug). Steady-state concentrations were achieved after 7–10 days of multiple dosing.

Pharmacokinetics in special patient populations. Children (<18 years). After administration of 800 mg/day posaconazole in divided doses for treatment of IFI, mean residual plasma concentrations in 12 patients aged 8–17 years (776 ng/mL) were comparable to those in 194 patients aged 18–64 years (817 ng/mL). Similarly, in prophylaxis studies, mean steady-state concentration (Cav) of posaconazole in 10 children (13–17 years) was comparable to Cav in adults (≥18 years). In a study involving 136 neutropenic patients aged 11 months to 17 years receiving posaconazole oral suspension up to 18 mg/kg/day divided into three doses, approximately 50% of patients achieved pre-defined target concentrations (mean steady-state posaconazole concentration on day 7 within 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).

Gender. Posaconazole pharmacokinetics are not different between males and females.

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

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

Body weight. Pharmacokinetic modeling using the tablet formulation suggests that lower posaconazole levels may occur in patients with body weight >120 kg. Therefore, breakthrough fungal infections should be closely monitored in patients with body weight >120 kg. In patients with low body weight (≤60 kg), there is a high likelihood of increased posaconazole plasma concentrations; therefore, careful monitoring for adverse reactions is required.

After a single dose of posaconazole oral suspension in patients with mild or moderate renal impairment (n=18, ClCr ≥20 mL/min/1.73 m²), no effect on pharmacokinetic parameters of posaconazole 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 varied widely (coefficient of variation [CV] >96%) compared to other patient groups with renal impairment (CV <40%). However, since only a small fraction of posaconazole is eliminated 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.

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

Clinical characteristics.

Indications.

Posaconazole-Teva oral suspension is indicated for the treatment of the following fungal infections in adults:

− invasive aspergillosis in patients with resistance to amphotericin B or itraconazole, or in patients with intolerance to these medicinal products;

− fusariosis in patients with resistance to amphotericin B or in patients with intolerance to amphotericin B;

− chromoblastomycosis and mycetoma in patients with resistance to itraconazole or in patients with intolerance to itraconazole;

− coccidioidomycosis in patients with resistance to amphotericin B, itraconazole or fluconazole, or in patients with intolerance to these medicinal products;

− oropharyngeal candidiasis: as first-line therapy in immunocompromised patients, where topical agents may have limited efficacy.

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

Posaconazole-Teva 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 myelogenous 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.

Posaconazole-Teva 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 of the excipients. Concomitant use with CYP3A4 substrates: terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine (since increased plasma concentrations of these drugs may cause QT interval prolongation and very rarely ventricular tachycardia torsades de pointes); ergot alkaloids (due to the risk of increased plasma concentrations of ergot alkaloids and development of ergotism); HMG-CoA reductase inhibitors: simvastatin, lovastatin, and atorvastatin. Concomitant use at the beginning of treatment and during the dose titration phase of venetoclax in patients with chronic lymphocytic leukemia.

Interaction with other medicinal products and other forms of interaction.

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

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, except when 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, except when the benefit outweighs the risk to the patient.

Combination of fosamprenavir with posaconazole may lead to decreased plasma concentrations of posaconazole. If concomitant administration is necessary, close monitoring for possible reactivation of HIV 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 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, except when the benefit outweighs the risk to the patient.

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

H2-receptor antagonists and proton pump inhibitors. Cmax and AUC of posaconazole were reduced by 39% when administered (200 mg daily) with cimetidine (400 mg twice daily) due to reduced absorption, possibly due to decreased 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 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. There are no data on interactions of alcohol, herbal medicinal products, smoking with posaconazole.

Effect of posaconazole on other medicinal products. Posaconazole is a potent inhibitor of CYP3A4; its concomitant use with CYP3A4 substrates may lead to a significant increase in their effects (as evidenced by effects on tacrolimus, sirolimus, atazanavir, and midazolam described below). Caution is recommended when administering posaconazole concomitantly with CYP3A4 substrates administered intravenously, and the dose of the CYP3A4 substrate may need to be reduced. When posaconazole is administered concomitantly with orally administered CYP3A4 substrates for which increased plasma concentrations may be associated with unacceptable adverse reactions, plasma concentrations of the CYP3A4 substrate and/or adverse reactions should be closely monitored and the dose adjusted as necessary. In several interaction studies involving healthy volunteers, posaconazole levels were higher than those observed in patients receiving the same doses. The effect of posaconazole on CYP3A4 substrates may be somewhat less in patients than in healthy volunteers and may vary due to variability in posaconazole exposure among patients. The effect of concomitant posaconazole administration on plasma levels of CYP3A4 substrates may also vary within a single patient unless posaconazole is administered in a strictly standardized form with food, since food significantly affects posaconazole absorption.

All-trans retinoic acid (ATRA) or tretinoin. Since ATRA is metabolized by hepatic CYP450 enzymes, particularly CYP3A4, concomitant use with posaconazole, a potent CYP3A4 inhibitor, may lead to increased tretinoin exposure and increased toxicity (especially hypercalcemia). Serum calcium levels should be monitored and, if necessary, dose adjustment of tretinoin should be considered during and for several days after posaconazole treatment.

Concomitant administration of posaconazole with terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine is contraindicated, as it may lead to increased plasma concentrations of these drugs, resulting in QTc interval prolongation and, in rare cases, ventricular tachycardia torsades de pointes.

Posaconazole may increase plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine), which may cause ergotism. Concomitant use of ergot alkaloids and posaconazole is contraindicated. Posaconazole may significantly increase plasma concentrations of HMG-CoA reductase inhibitors (simvastatin, lovastatin, and atorvastatin) metabolized via CYP3A4. Treatment with these HMG-CoA reductase inhibitors must be discontinued during posaconazole therapy, as increased levels have been associated with rhabdomyolysis.

Most vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant use of vincristine and azole antifungal agents, including posaconazole, has been associated with the development of serious adverse reactions. Posaconazole may increase plasma concentrations of vinca alkaloids, which may lead 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 alternative antifungal therapy is available.

Posaconazole increased Cmax and AUC of rifabutin by 31% and 72%, respectively. Their concomitant use should be avoided, except when benefit outweighs risk to the patient. When used concomitantly, blood counts and adverse effects related to increased rifabutin concentrations (e.g., uveitis) should be closely monitored.

In healthy volunteers, administration of posaconazole oral suspension (400 mg twice daily for 16 days) increased Cmax and AUC of sirolimus (single 2 mg dose) by a mean 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 in patients. Concomitant administration 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 start of posaconazole treatment, and frequent monitoring of sirolimus trough concentrations in whole blood is required thereafter. Sirolimus concentrations should be measured at the beginning, during concomitant administration, and after completion of posaconazole treatment, with appropriate dose adjustments. It should be noted that the relationship between trough concentration and AUC of sirolimus changes during concomitant administration with posaconazole. As a result, trough concentrations corresponding to normal therapeutic ranges may lead to subtherapeutic levels. Therefore, trough concentrations should aim for the upper end of the normal therapeutic range, and clinical signs and symptoms, laboratory parameters, and biopsy data should be closely monitored.

In heart transplant recipients receiving a stable dose of cyclosporine, posaconazole oral suspension at 200 mg once daily increased cyclosporine concentrations, necessitating dose reduction. In clinical efficacy studies, cases of elevated cyclosporine levels causing serious adverse reactions, including nephrotoxicity, 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). Therefore, cyclosporine blood levels should be closely monitored during and after posaconazole treatment, with dose adjustments as necessary.

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 recorded. Before initiating posaconazole in patients already receiving tacrolimus, the tacrolimus dose should be reduced (e.g., to 1/3 of the current dose). Therefore, tacrolimus blood concentrations should be closely monitored during and after posaconazole treatment, with dose adjustments as necessary.

Since HIV protease inhibitors are substrates of CYP3A4, there is a possibility that posaconazole will increase plasma concentrations of these antiretroviral drugs. In healthy volunteers, administration of posaconazole (400 mg twice daily for 7 days) with atazanavir (300 mg once daily for 7 days) increased Cmax and AUC of atazanavir by a mean of 2.6-fold and 3.7-fold (range 1.2- to 26-fold), respectively. When posaconazole (400 mg twice daily for 7 days) was administered concomitantly with atazanavir and ritonavir (300 mg atazanavir + 100 mg ritonavir once daily for 7 days) in healthy volunteers, Cmax and AUC of atazanavir increased by a mean of 1.5-fold and 2.5-fold (range 0.9–4.1-fold), respectively. Adding posaconazole to atazanavir therapy or atazanavir and ritonavir therapy was associated with increased plasma bilirubin levels. Patients receiving antiretroviral drugs 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 the effect (AUC) of intravenously administered midazolam (0.05 mg/kg) by 83%. In another study involving healthy volunteers, repeated doses of posaconazole suspension (200 mg twice daily for 7 days) increased Cmax and AUC of intravenously administered midazolam (0.4 mg single dose) by a mean of 1.3-fold and 4.6-fold (range 1.7–6.4-fold), respectively; posaconazole 400 mg twice daily for 7 days increased Cmax and AUC of intravenously administered midazolam by 1.6-fold and 6.2-fold (range 1.6–7.6-fold), respectively. Both doses of posaconazole increased Cmax and AUC of orally administered midazolam (2 mg single dose) by 2.2-fold and 4.5-fold, respectively. In addition, orally administered posaconazole (200 mg or 400 mg) prolonged the mean terminal half-life of midazolam from approximately 3–4 hours to 8–10 hours during concomitant administration. Due to the risk of prolonged sedative effect, dose adjustment of benzodiazepines is recommended when posaconazole is used concomitantly with any benzodiazepine metabolized by CYP3A4 isoenzyme (e.g., midazolam, triazolam, alprazolam).

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

Use of other azole antifungal medicinal products has been associated with increased digoxin blood levels. Therefore, posaconazole may increase digoxin blood concentrations, and digoxin levels should be monitored at the start of posaconazole therapy and upon discontinuation of treatment.

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.

Venetoclax. Concomitant administration of 300 mg posaconazole, a potent 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 brief product characteristics of venetoclax).

Children. Studies were conducted only in adult patients.

Special precautions for use.

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

Hepatotoxicity. Rare hepatic reactions have been reported during posaconazole therapy (e.g., mild to moderate increases in ALT, AST, ALP, total bilirubin levels, and/or clinical hepatitis). Elevations in liver function tests were usually reversible upon discontinuation of therapy; in some cases normalization occurred without stopping treatment. Very rare, more severe hepatic reactions (including fatal cases) have been reported in patients with serious underlying conditions (such as hematologic 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 concentrations in these patients. Liver function tests should be monitored before and during posaconazole therapy. Patients who develop abnormalities in liver function tests during treatment should be closely monitored for more severe liver injury. Laboratory assessment of liver function (particularly liver function tests and bilirubin levels) should be part of patient management. Consideration should be given to discontinuing posaconazole therapy if clinical signs and symptoms suggest development of liver disease.

Some azole compounds may cause QTc interval prolongation. ECG analysis in healthy volunteers did not reveal QTc interval prolongation. Posaconazole should not be used concomitantly with drugs that prolong the QTc interval and/or are CYP3A4 substrates. Caution is advised when administering posaconazole to patients at risk of cardiac arrhythmias: those with congenital or acquired QTc prolongation; cardiomyopathy, especially with heart failure; sinus bradycardia; diagnosed symptomatic arrhythmia; or concomitant use of drugs that prolong the QTc interval. Electrolyte imbalances, particularly serum potassium, magnesium, and calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy. Posaconazole is a CYP3A4 inhibitor and should only be co-administered with other drugs metabolized by CYP3A4 under specific circumstances.

Midazolam and other benzodiazepines. Due to the risk of prolonged sedative effects and possible respiratory depression, concomitant use of posaconazole with any benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam) should only be considered if absolutely necessary. Dose adjustment of CYP3A4-metabolized benzodiazepines is required.

Vincristine toxicity. Concomitant administration of vincristine and azole antifungal agents, including posaconazole, has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and paralytic ileus. In patients receiving vinca alkaloids, such as vincristine, treatment with azole antifungals, including posaconazole, is recommended only when no alternative antifungal therapy is available.

Antibacterial agents of the rifamycin class (rifampicin, rifabutin), flucloxacillin, certain anticonvulsants (phenytoin, carbamazepine, phenobarbital, primidone), efavirenz, and cimetidine. Posaconazole concentrations may be significantly reduced when co-administered with these drugs. Therefore, concomitant use with posaconazole should be avoided, except when the benefit to the patient outweighs the risk.

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

Gastrointestinal (GI) tract dysfunction. There are limited pharmacokinetic data in patients with severe gastrointestinal dysfunction (e.g., severe diarrhea). Patients with severe diarrhea or vomiting should be closely monitored for possible reactivation of GI disease.

Venetoclax toxicity. Concomitant administration 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. For detailed information, refer to the summary of product characteristics for venetoclax.

Excipients. This medicinal product contains approximately 2.11 g of glucose syrup per 5 mL of suspension. Patients with rare hereditary fructose intolerance 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 potential risk to the fetus.

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

Fertility. There is no clinical experience regarding the effect of posaconazole on human fertility. Posaconazole did not affect fertility in male or female rats at doses up to 180 mg/kg and 45 mg/kg, respectively.

Ability to affect reaction speed when driving vehicles or operating machinery.

Caution should be exercised when driving or operating machinery, as the use of the drug may occasionally cause dizziness and somnolence.

Method of Administration and Dosage

Treatment should be initiated by a physician experienced in the management of gastrointestinal infections (GI) or in providing supportive care for high-risk patients for whom posaconazole is prescribed for prophylaxis. Tablets and oral suspension are not interchangeable due to differences in dosing frequency, food intake requirements, and achieved plasma drug concentrations. Therefore, specific dosage instructions for each dosage form must be strictly followed. Administer orally to adults and children aged 13 years and older during meals or with 240 mL of liquid nutritional supplements (enteral feeding). The suspension bottle must be shaken well (5–10 seconds) before use.

Recommended Dosages by Indication

• Resistant fungal infections (FI)/patients with fungal infections intolerant to first-line agents: 200 mg (5 mL) four times daily. Additionally, patients able to consume food or liquid nutritional supplements may take 400 mg (10 mL) twice daily during or immediately after a meal or liquid nutritional supplement intake. Duration of therapy depends on the severity of the underlying disease, recovery period following immunosuppressive therapy, and clinical response to treatment.
• Oropharyngeal candidiasis: 200 mg (5 mL) once on the first day of treatment, followed by 100 mg (2.5 mL) once daily for 13 days. Posaconazole-Teva should be taken during or immediately after a meal or liquid nutritional supplement intake (for patients unable to tolerate food) to enhance oral absorption and ensure adequate effect.
• Prophylaxis of invasive fungal infections: 200 mg (5 mL) three times daily. Posaconazole-Teva should be taken during or immediately after a meal or liquid nutritional supplement intake (for patients unable to tolerate food) to enhance oral absorption and ensure adequate effect. 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 Posaconazole-Teva should begin several days prior to anticipated neutropenia and continue for 7 days after neutrophil counts recover to above 500 cells/mm³.

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

Hepatic impairment. Limited data are available on the effect of hepatic insufficiency (including Child–Pugh class C chronic liver disease) on the pharmacokinetics of posaconazole, showing increased plasma concentrations of posaconazole in patients with impaired liver function compared to those with normal hepatic function, but not indicating a need for dose adjustment. Caution is recommended due to the potential for increased plasma levels.

Pediatric use.

The efficacy and safety of posaconazole in children under 13 years of age have not been established; therefore, the drug should not be used in this age group. Data on pediatric dosing are limited.

Overdose.

During clinical trials, no adverse reactions different from those observed in patients receiving lower doses were reported in patients who received posaconazole (oral suspension) at doses up to 1600 mg/day. One case of accidental overdose was reported in a patient who received 1200 mg twice daily for 3 days. No adverse events were observed in this patient. Posaconazole is not eliminated by hemodialysis. There are no specific guidelines for the treatment of posaconazole overdose. Supportive therapy is recommended.

Adverse Reactions

The safety of posaconazole oral suspension has been evaluated in over 2400 patients and healthy volunteers in clinical trials and during the post-marketing period. The most commonly reported adverse reactions were nausea, vomiting, diarrhea, fever, and increased bilirubin levels. Adverse reactions within each organ system class are listed below by frequency of occurrence* as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); not known (cannot be estimated from available data).

Blood and lymphatic system disorders.
Common: neutropenia.
Uncommon: thrombocytopenia, leukopenia, anemia, eosinophilia, lymphadenopathy, splenic infarction.
Rare: hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, pancytopenia, coagulopathy, hemorrhage.

Immune system disorders.
Uncommon: allergic reactions.
Rare: hypersensitivity reactions.

Endocrine system disorders.
Rare: adrenal insufficiency, decreased blood gonadotropin levels.
Not known: pseudoaldosteronism.

Metabolism and nutrition disorders.
Common: electrolyte imbalance, anorexia, decreased appetite, hypokalemia, hypomagnesemia.
Uncommon: hyperglycemia, hypoglycemia.

Psychiatric disorders.
Uncommon: abnormal dreams, confusion, sleep disorders.
Rare: psychiatric disorders, depression.

Nervous system disorders.
Common: paresthesia, dizziness, somnolence, headache, dysgeusia.
Uncommon: seizures, neuropathy, hypoesthesia, tremor, aphasia, insomnia.
Rare: cerebrovascular disorder, encephalopathy, peripheral neuropathy, loss of consciousness.

Eye disorders.
Uncommon: blurred vision, photophobia, decreased visual acuity.
Rare: diplopia, scotoma.

Ear and labyrinth disorders.
Rare: hearing disorders.

Cardiac disorders.
Uncommon: QT interval prolongation syndrome§, ECG changes§, palpitations, bradycardia, supraventricular extrasystole, tachycardia.
Rare: ventricular tachycardia torsades de pointes, ventricular tachycardia, cardiopulmonary failure, heart failure, myocardial infarction, sudden death.

Vascular disorders.
Common: arterial hypertension.
Uncommon: arterial hypotension, vasculitis.
Rare: 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, 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: increased levels of liver function tests (ALT, AST, bilirubin, alkaline phosphatase, GGT).
Uncommon: hepatocellular damage, hepatitis, jaundice, hepatomegaly, cholestasis, hepatotoxicity, liver function disorders.
Rare: liver failure, cholestatic hepatitis, 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.
Not known: photosensitivity reaction.

Musculoskeletal and connective tissue disorders.
Uncommon: back pain, neck pain, musculoskeletal pain, limb pain.

Renal and urinary disorders.
Uncommon: acute renal failure, renal failure, increased blood creatinine levels.
Rare: renal tubular acidosis, interstitial nephritis.

Reproductive system and breast disorders.
Uncommon: menstrual cycle disturbances.
Rare: breast pain.

General disorders and administration site conditions.
Common: increased body temperature (pyrexia), weakness, fatigue.
Uncommon: edema, pain, chills, malaise, chest discomfort, drug intolerance, nervousness, mucosal inflammation.
Rare: tongue swelling, facial swelling.

Investigations.
Uncommon: altered drug levels, decreased blood phosphorus levels, abnormal chest X-ray.

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

§ See section "Special Warnings and Precautions for Use".

Description of selected adverse reactions.
Disorders of the liver and biliary tract.
During the post-marketing period, cases of severe hepatic injury with fatal outcome have been reported.

Reporting suspected adverse reactions.
All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua/.

Shelf life. 3 years.
After first opening of the bottle – 30 days.

Storage conditions.
The medicinal product does not require special storage conditions. Do not refrigerate or freeze. Keep out of reach of children.

Packaging.
105 ml of oral suspension in a bottle.
1 bottle with a measuring spoon in a cardboard box.

Prescription status. Prescription only.

Manufacturers.
Generics S.A.
Rapharm S.A.

Manufacturer addresses.
18 km Marathon Avenue, Pallini, Attica, 15351, Greece.
Thesi Pousi Hatzilouka, Peania, 190 02, Greece.