Posotero

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

Composition:

Active substance: posaconazole;

1 tablet contains 100 mg of posaconazole;

Excipients: hypromellose acetate succinate, microcrystalline cellulose, hydroxypropylcellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, film coating: Opadry® II Orange 85F530145 (polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc, yellow iron oxide (E 172), and red iron oxide (E 172)).

Pharmaceutical form. Gastro-resistant tablets.

Main physicochemical properties: light orange, oblong-shaped tablets with a film coating, marked with "H" on one side and "P11" on the other.

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

Resistance

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

Epidemiological cut-off values (ECOFF) for Aspergillus spp.

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).

Epidemiological cut-off values established by EUCAST:

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

Currently, there are insufficient data to establish clinical breakpoints for Aspergillus spp. Epidemiological cut-off values are not equivalent to 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.

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 either posaconazole or other therapies; however, there are currently no clinical data demonstrating that combination therapy provides additional benefit.

Electrocardiogram (ECG) assessment

No clinically significant changes in mean QTc interval values were observed compared to baseline.

Pharmacokinetics.

Pharmacokinetic/pharmacodynamic relationship

A correlation was observed between the total area under the drug 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 aim for achieving maximum drug concentration (Cmax) in plasma of patients infected with Aspergillus (see section "Dosage and administration" for recommended dosing regimens).

Absorption

The median time to peak concentration (Tmax) of posaconazole tablets is 4 to 5 hours, and dose-proportional pharmacokinetics were demonstrated after single and multiple doses up to 300 mg.

Following a single 300 mg dose of posaconazole tablets administered with a high-fat meal to healthy volunteers, AUC0–72 hours and Cmax were higher compared to fasting conditions (51% and 16% higher for AUC0–72 hours and Cmax, respectively). According to population pharmacokinetic modeling, Cav values of posaconazole increase by 20% when administered with food compared to fasting.

In some patients, plasma concentrations of posaconazole may increase over time after tablet administration. The reason for this time dependency is not fully understood.

Distribution

After administration of tablets, posaconazole has a mean apparent volume of distribution of 394 L (42%), ranging from 294 to 583 L in studies conducted in healthy volunteers. Posaconazole is highly bound to plasma proteins (>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 account for approximately 17% of the administered radiolabeled dose.

Elimination

Posaconazole is slowly eliminated, with a mean elimination half-life (t½) of 29 hours (ranging from 26 to 31 hours) and a mean apparent clearance of 7.5 to 11 L/h. After administration of 14C-posaconazole, radioactivity was predominantly recovered in feces (77% of the radiolabeled dose), with the main component being unchanged drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 14% of the radiolabeled dose excreted in urine (<0.2% of the radiolabeled dose as unchanged drug). Steady-state plasma concentrations were achieved by day 6 with a 300 mg once-daily dose (after a loading dose of 300 mg twice daily on the first day of treatment).

Pharmacokinetics in special patient populations

Based on population pharmacokinetic modeling, the pharmacokinetics of posaconazole for the treatment of invasive aspergillosis and prevention of invasive fungal infections have been evaluated.

Population pharmacokinetic analysis of posaconazole in patients suggests that race, gender, renal impairment, and disease condition (prophylaxis or treatment) do not have a clinically significant impact on posaconazole pharmacokinetics.

Gender

The pharmacokinetics of posaconazole tablets in males and females are not different.

Elderly patients

No overall differences in safety between elderly patients and younger patients have been observed.

Population pharmacokinetic modeling of posaconazole concentrate for infusion solution and tablets indicates that posaconazole clearance is age-dependent. Overall, Cav of posaconazole is comparable in younger and elderly patients (≥65 years); however, in patients aged ≥80 years, Cav increases by 11%. Therefore, careful monitoring for adverse reactions is recommended in elderly patients (≥80 years).

The pharmacokinetics of posaconazole tablets are comparable in younger and elderly patients (≥65 years). Pharmacokinetic differences based on age are not considered clinically significant, and dose adjustment is not required.

Race

There are insufficient data on the use of posaconazole tablets in different racial groups.

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

Body weight

Population pharmacokinetic modeling of posaconazole concentrate for infusion solution and tablets indicates that posaconazole clearance is body weight-dependent. In patients >120 kg, Cav decreases by 25%, and in patients <50 kg, Cav increases by 19%. Therefore, careful monitoring for breakthrough fungal infections is recommended in patients with body weight >120 kg.

Renal impairment

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

Similar recommendations apply to posaconazole tablets, although no specific study with posaconazole tablets has been conducted.

Hepatic impairment

After a single 400 mg dose of posaconazole oral suspension administered to 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 impairment. Unbound drug concentrations were not measured, and an increase in unbound posaconazole concentration greater than the observed 60% increase in total AUC cannot be excluded. The mean elimination half-life (t½) increased from approximately 27 hours to approximately 43 hours in the respective groups. Dose adjustment is not required for patients with mild to severe hepatic impairment, but caution is advised due to the potential for increased plasma concentrations.

Similar recommendations apply to posaconazole tablets, although no specific study with posaconazole tablets has been conducted.

Clinical characteristics.

Indications.

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

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

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

The medicinal product is indicated for prophylaxis of invasive fungal infections in the following patients:

• patients receiving chemotherapy for induction of remission in the treatment of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), which may lead to prolonged neutropenia and who are at high risk of developing invasive fungal infections (IFI);
• recipients of hematopoietic stem cell transplantation (HSCT) who are receiving high doses of immunosuppressants to prevent graft-versus-host disease and who are at high risk of developing IFI.

For oropharyngeal candidiasis, refer to the prescribing information for posaconazole oral suspension.

Contraindications.

• Hypersensitivity to posaconazole or to any other component of the medicinal product listed in the section "Composition".
• Concomitant use with:
  • ergot alkaloids (see section "Interaction with other medicinal products and other types of interactions");
  • CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine, since elevated plasma concentrations of these medicinal products may cause QT interval prolongation and very rarely ventricular tachycardia torsades de pointes (see sections "Special precautions for use" and "Interaction with other medicinal products and other types of interactions");
  • HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin (see section "Interaction with other medicinal products and other types of interactions").
• Concomitant use at the beginning of treatment and during the dose titration phase of venetoclax in patients with chronic lymphocytic leukemia (see sections "Special precautions for use" and "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

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 excretion by P-glycoprotein (P-gp) in vitro. Therefore, inhibitors (e.g., verapamil, cyclosporine, quinidine, clarithromycin, erythromycin) or inducers (e.g., rifampicin, rifabutin, anticonvulsants) of this metabolic pathway may increase or decrease posaconazole plasma concentrations, 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 unless the benefit of their use outweighs the risk to the patient.

Flucloxacillin. (CYP450 inducer) may reduce posaconazole plasma concentrations. Concomitant use of posaconazole and flucloxacillin should be avoided unless the benefit to the patient outweighs the risk (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 of their use outweighs the risk to the patient.

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

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

H2-receptor antagonists, proton pump inhibitors and antacids. No clinically significant effects were observed when posaconazole was co-administered with antacids, H2-receptor antagonists or proton pump inhibitors. Dose adjustment of posaconazole tablets is not required when co-administered with antacids, H2-receptor antagonists or proton pump inhibitors.

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 posaconazole is co-administered with intravenous CYP3A4 substrates. It may also be necessary to reduce the dose of the CYP3A4 substrate. If posaconazole is administered concomitantly with oral CYP3A4 substrates whose 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 dose adjusted as necessary. 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 administration of posaconazole on plasma levels of CYP3A4 substrates may also vary among different patients.

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), which may cause 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. Use of these HMG-CoA reductase inhibitors should be discontinued during posaconazole therapy, as their elevated levels may lead to rhabdomyolysis (see section "Contraindications").

Vinca alkaloids. Most vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of vincristine and azole antifungal agents, including posaconazole, has been associated with serious adverse reactions (see section "Special precautions for use"). Posaconazole may increase plasma concentrations of vinca alkaloids, which may lead to neurotoxicity and other serious adverse reactions. Therefore, treatment with azole antifungal agents, including posaconazole, is recommended in patients receiving vinca alkaloids, including vincristine, 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 of their use outweighs the risk to the patient. When these medicinal products are used concomitantly, careful monitoring of blood counts and adverse reactions related to increased rifabutin concentrations (e.g., uveitis) is recommended.

Sirolimus. In healthy volunteers, repeated dosing 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 interaction effect between posaconazole and sirolimus in patients is unknown but is expected to vary due to changes in posaconazole exposure in patients. Concomitant administration of posaconazole and sirolimus is not recommended and should be avoided. If concomitant use cannot be avoided, a significant reduction in sirolimus dose is recommended at the start of posaconazole therapy, followed by frequent monitoring of sirolimus trough concentrations in whole blood. Sirolimus concentrations should be measured at initiation, during concomitant use, and after discontinuation of posaconazole, with appropriate dose adjustments. The relationship between trough concentration and AUC of sirolimus changes when co-administered with posaconazole. As a result, trough concentrations corresponding to usual therapeutic ranges may lead to subtherapeutic levels. Therefore, trough concentrations should aim for the upper end of the usual therapeutic range, with close monitoring of clinical symptoms, laboratory parameters, and tissue biopsy findings.

Cyclosporine. In patients who underwent heart transplantation and were on a stable dose of cyclosporine, administration of posaconazole oral suspension at 200 mg once daily increased blood cyclosporine concentrations, necessitating dose reduction. In clinical efficacy studies, interactions resulted in increased cyclosporine levels causing serious adverse reactions, including nephrotoxicity, and one fatal case of leukoencephalopathy has been 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 necessary.

Tacrolimus. Posaconazole increased Cmax and AUC of tacrolimus (single 0.05 mg/kg dose) by 121% and 358%, respectively. In clinical efficacy studies, clinically significant drug interactions were recorded, requiring hospitalization and/or discontinuation of posaconazole. 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 necessary.

HIV protease inhibitors. Since HIV protease inhibitors are CYP3A4 substrates, there is a potential for posaconazole to increase plasma levels of these antiretroviral drugs. In healthy volunteers, administration of posaconazole oral suspension (400 mg twice daily) 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. 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 a mean of 1.5-fold and 2.5-fold (range 0.9- to 4.1-fold), respectively. Addition of posaconazole to atazanavir 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 early detection of possible adverse and toxic reactions.

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

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

Calcium channel blockers metabolized by CYP3A4 (e.g., diltiazem, verapamil, nifedipine, nicardipine). Monitoring for adverse and/or toxic reactions associated with calcium channel blocker use is recommended when co-administered with posaconazole, with dose adjustment if necessary.

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 when used concomitantly with posaconazole and after treatment completion.

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

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

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

Pediatric population.

Studies have been conducted only in adult patients.

Special precautions for use.

Hypersensitivity.

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

Hepatotoxicity.

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

Liver function monitoring.

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

QT interval prolongation.

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

Caution is advised when administering posaconazole to patients at risk of developing cardiac arrhythmias, particularly:

• 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 arrhythmias;
• 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 be used only under special conditions when co-administered with other medicinal products metabolized by CYP3A4 (see section "Interaction with other medicinal products and other forms of interaction").

Midazolam and other benzodiazepines metabolized by CYP3A4.

Due to the risk of prolonged sedative effects and possible respiratory depression, concomitant use of posaconazole with any benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam) should be considered only if necessary. Dose adjustment of benzodiazepines metabolized by CYP3A4 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 other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and paralytic ileus. If patients are receiving vinca alkaloids, including vincristine, antifungal therapy 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 the risk of tumor lysis syndrome (TLS) and neutropenia (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Plasma levels.

Plasma concentrations of posaconazole after administration of posaconazole tablets are generally higher than those achieved with the oral suspension formulation. Plasma concentrations of posaconazole after tablet administration may increase over time in some patients (see section "Pharmacological properties. Pharmacokinetics").

Gastrointestinal disorders.

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 infections.

Photosensitivity reaction.

Posaconazole may increase the risk of photosensitivity reactions. Patients should be advised to avoid exposure to sunlight during treatment unless adequately protected, e.g., by wearing protective clothing and using sunscreen with a high sun protection factor (SPF).

Excipients.

Sodium. This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, 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 pregnant woman clearly 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 therapy.

Fertility

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

Ability to drive and use machines.

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

Method of administration and dosage.

Treatment should be initiated by a physician experienced in the treatment of fungal infections (FI) or in managing prophylactic therapy in patients at high risk of fungal infections.

Non-interchangeability of posaconazole tablets and posaconazole oral suspension

Tablets and oral suspension are not interchangeable due to differences between these two formulations in dosing frequency, food effects, and achieved drug plasma concentrations. Therefore, specific dosage recommendations must be strictly followed for each dosage form.

Dosage

Posaconazole tablets generally provide higher drug exposure in plasma compared to posaconazole oral suspension, both when administered with food and in the fasting state. Therefore, tablets represent the preferred dosage form for optimizing drug plasma concentrations. Posaconazole is also available as an oral suspension 40 mg/mL.

Recommended doses are shown in Table 1.

Recommended doses according to indications

Table 1

Indications	Dosage and duration of therapy
Treatment of invasive aspergillosis (adults only)	Loading dose: 300 mg (3 tablets of 100 mg) twice daily on the first day of treatment, then 300 mg (3 tablets of 100 mg) once daily thereafter. Each dose can be taken independently of food intake. The recommended total duration of therapy is 6–12 weeks. Switching between intravenous and oral administration is appropriate when clinically indicated.
Resistant invasive fungal infections (IFI)/patients with IFI intolerant to other first-line therapeutic agents	Loading dose: 300 mg (3 tablets of 100 mg) twice daily on the first day of treatment, then 300 mg (3 tablets of 100 mg) once daily thereafter. Each dose can be taken independently of food intake. The duration of therapy depends on the severity of the underlying disease, the period of recovery from immunosuppressive therapy, and the clinical response to treatment.
Prophylaxis of invasive fungal infections	Loading dose: 300 mg (3 tablets of 100 mg) twice daily on the first day of treatment, then 300 mg (3 tablets of 100 mg) once daily thereafter. Each dose can be taken independently of food intake. The duration of therapy should be determined based on successful management of neutropenia or immune reconstitution. For patients with acute myeloid leukemia or myelodysplastic syndrome, prophylactic treatment should be initiated several days before anticipated neutropenia and continued for 7 days after neutrophil counts increase to above 500 cells per 1 mm³.

Special patient groups

Renal impairment.

Renal impairment does not result in changes in pharmacokinetic parameters of posaconazole; therefore, dose adjustment is not required (see section "Pharmacological properties. Pharmacokinetics").

Hepatic impairment.

Limited data are available on the effect of hepatic impairment (including Child–Pugh class C chronic hepatic impairment) on the pharmacokinetics of posaconazole, showing 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 "Special warnings and precautions for use" and "Pharmacological properties. Pharmacokinetics"). Caution is recommended due to the potential for increased plasma levels.

Method of administration

Oral use.

Posaconazole gastro-resistant tablets may be taken regardless of food intake (see section "Pharmacological properties. Pharmacokinetics"). The tablets should be swallowed whole with water and must not be crushed, chewed, or broken.

Children.

The safety and efficacy of posaconazole in children under 18 years of age have not been established.

Overdose.

There is no specific experience in treating overdosage with posaconazole tablets.

During clinical trials, administration of oral suspension of posaconazole at doses up to 1600 mg/day did not reveal any adverse reactions different from those observed in patients receiving lower doses. 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 removed by hemodialysis. There are no specific recommendations for the treatment of posaconazole overdose. Supportive therapy should be applied.

Adverse Reactions

Short description of the safety profile

Safety data are primarily derived from studies of the oral suspension.

The safety of posaconazole oral suspension was evaluated in over 2400 patients and healthy volunteers in clinical trials and from 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 2.

Within each organ system class, adverse reactions are categorized by frequency according to the following: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Adverse reactions by system organ classes and frequency reported during clinical trials and/or the post-marketing period*

Table 2

System Organ Classes	Adverse Reactions and Their Frequency
Blood and Lymphatic System Disorders	Common: neutropenia Uncommon: thrombocytopenia, leukopenia, anemia, eosinophilia, lymphadenopathy, splenic infarction Rare: hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, pancytopenia, coagulopathy, hemorrhages
Immune System Disorders	Uncommon: allergic reactions Rare: hypersensitivity reactions
Endocrine System Disorders	Rare: adrenal insufficiency, decreased gonadotropin levels, pseudoaldosteronism
Metabolism and Nutrition Disorders	Common: electrolyte imbalance, anorexia, decreased appetite, hypokalemia, hypomagnesemia Uncommon: hyperglycemia, hypoglycemia
Psychiatric Disorders	Uncommon: pathological dreams, confusion, sleep disturbances Rare: psychiatric disorders, depression
Nervous System 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 impairment
Cardiac Disorders	Uncommon: QT interval prolongation syndrome§, ECG changes§, palpitations, bradycardia, supraventricular extrasystoles, tachycardia Rare: ventricular tachycardia torsade de pointes, sudden death, ventricular tachycardia, cardiorespiratory failure, heart failure, myocardial infarction
Vascular Disorders	Common: arterial hypertension Uncommon: hypotension, vasculitis Rare: pulmonary artery thromboembolism, deep vein thrombosis
Respiratory, Thoracic and Mediastinal Disorders	Uncommon: cough, epistaxis, hiccups, nasal congestion, 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 disease, mouth swelling Rare: gastrointestinal hemorrhage, intestinal obstruction
Hepatobiliary Disorders	Common: increased levels of liver function tests (ALT, AST, bilirubin, alkaline phosphatase, GGT) Uncommon: hepatocellular injury, hepatitis, jaundice, hepatomegaly, cholestasis, hepatotoxicity, liver function abnormalities 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 Frequency 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 (fever), weakness, fatigue Uncommon: edema, pain, chills, malaise, chest discomfort, drug intolerance, feeling of 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 the use of oral suspension, gastro-resistant tablets, and concentrate for infusion solution.

§ See section "Special precautions for use".

Description of selected adverse reactions

Disorders of the hepatobiliary system

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

Reporting of suspected adverse reactions

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

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

10 tablets in a blister; 10 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and location of operations.

Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.