Noxafil^® (Tablets, Concentrate, Suspension) Instructions for Use

ATC Code

J02AC04 (Posaconazole)

Active Substance

Posaconazole (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Antifungal drugs for systemic use, triazole derivatives

Pharmacological Action

An antifungal agent with a broad spectrum of antifungal activity. It inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyzes an important step in the biosynthesis of ergosterol, the main component of the fungal cytoplasmic membrane.

It is active against pathogens of yeast and mold mycoses, including strains resistant to fluconazole, voriconazole, itraconazole, and amphotericin B.

Active against fungi of the genus Candida (C. albicans, C. glabrata, C. krusei, C. parapsilosis, C. lusitaniae), fungi of the genus Aspergillus (A. fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus, A. ochraceus), Absidia spp., Cryptococcus neoformans, Coccidioides immitis, Fonsecaea pedrosoi, Histoplasma capsulatum, Pseudallescheria boydii, Alternaria spp., Exophiala spp., Fusarium spp, Ramichloridium spp., Rhizomucor spp., Mucor spp, Rhizopus spp.

Pharmacokinetics

Absorption

After oral administration, the absorption time of posaconazole is 3-5 hours. Posaconazole exhibits linear pharmacokinetics after single or multiple doses up to 800 mg. At doses above 800 mg/day, no increase in pharmacokinetic parameters occurs. Changes in gastric pH do not affect the absorption of posaconazole. Compared to fasting, the AUC of posaconazole increases approximately 2.6-fold when taken with a non-fatty meal or nutritional supplements (14 g fat), and 4-fold when taken with a high-fat meal (approximately 50 g fat).

Dividing the daily dose into two administrations (400 mg each) leads to a 184% increase in pharmacokinetic parameters compared to a single 800 mg dose.

Distribution

Posaconazole has a high V_d (1774 L), indicating significant distribution into tissues. Plasma protein binding (primarily to albumin) is more than 98%. Steady-state is reached after 7-10 days of multiple dosing.

Metabolism

Posaconazole does not form active circulating metabolites, and it is unlikely that its concentration is altered by the action of CYP450 isoenzyme inhibitors. Among the circulating metabolites, the majority are glucuronide conjugates of posaconazole and a small fraction of metabolites oxidized by CYP450 isoenzymes.

Excretion

Posaconazole is slowly eliminated from the body, with a mean T_1/2 of 35 hours (20-66 hours), and a total clearance of 32 L/h. It is excreted primarily via the intestine (77%), with 66% as unchanged substance. Renal clearance accounts for approximately 14% (the parent substance is less than 0.2%). Excretion via the kidneys and intestine as metabolites accounts for approximately 17% of the administered dose.

Pharmacokinetics in special clinical cases

After administration of posaconazole at a daily dose of 800 mg, divided into several doses, the plasma concentration in patients aged 8-17 years was comparable to that in patients aged 18-64 years (on average, 776 ng/mL and 817 ng/mL, respectively). There are no pharmacokinetic data for children under 8 years of age.

In elderly individuals, an increase in C_max by 26% and AUC by 29% was noted compared to individuals aged 18-45 years. However, in clinical studies, the safety profile of posaconazole was similar in young and elderly individuals. Therefore, no dose adjustment based on age is required.

The pharmacokinetics of posaconazole are not dependent on gender.

A slight (16%) decrease in the AUC and C_max of posaconazole was noted in individuals of Black race compared to Caucasians. No dose adjustment based on race is required.

In single-dose use, mild to moderate renal impairment did not affect the pharmacokinetics of the drug, so no dose adjustment is required for this category of patients. In patients with severe renal impairment, the AUC of posaconazole varied widely (coefficient of variation 96%) compared to other patients with renal impairment (coefficient of variation <40%). However, since the renal clearance of posaconazole is insignificant, it is unlikely that severe renal impairment affects the pharmacokinetics of the drug, so no dose adjustment is required in this case either.

In patients with hepatic impairment, an increase in T_1/2 was noted (26.6, 35.3, and 46.1 hours for mild, moderate, and severe hepatic impairment according to Child-Pugh classification, respectively), compared to patients with normal liver function. Due to limited pharmacokinetic data, recommendations for dose adjustment in patients with hepatic impairment have not been established.

Indications

Treatment of invasive fungal infections refractory* to amphotericin B, itraconazole, or fluconazole, or in cases of intolerance to these drugs: invasive candidiasis, esophageal candidiasis, invasive aspergillosis, zygomycosis (mucormycosis), cryptococcosis, fusariosis, chromomycosis, mycetoma, coccidioidomycosis.

Treatment of oropharyngeal candidiasis – first-line therapy in patients with severe disease or immunocompromised status, where a significant effect from topical agents is not expected.

Prophylaxis of invasive fungal infections in immunocompromised states and increased risk of developing such infections in hematological patients with prolonged neutropenia due to chemotherapy; in recipients of hematopoietic stem cell transplants receiving high doses of immunosuppressants.

* Refractoriness is defined as progression of the infection or lack of improvement in the patient’s condition after 7 days of treatment (for candidemia – within 3 days, for esophageal candidiasis – within 14 days, for other forms of invasive candidiasis – 7 days).

ICD codes

Dosage Regimen

Tablets, Suspension, Concentrate

For treatment of invasive fungal infections, 400 mg twice daily is prescribed. For patients who cannot take the drug with food or nutritional supplements, 200 mg four times daily is recommended. The duration of therapy depends on the severity of the patient’s underlying disease, the degree of immunodeficiency, and the effectiveness of the treatment.

For treatment of oropharyngeal candidiasis, on the first day of treatment, 200 mg once daily (loading dose) is prescribed, then 100 mg once daily for the subsequent 13 days.

For treatment of oropharyngeal candidiasis refractory to itraconazole and/or fluconazole, 400 mg twice daily is prescribed. The duration of therapy depends on the severity of the patient’s underlying disease and the effectiveness of the treatment.

Increasing the posaconazole dose above 800 mg/day does not lead to an increase in treatment efficacy.

For prophylaxis of invasive fungal infections, 200 mg three times daily is prescribed. The duration of prophylactic treatment depends on the duration of neutropenia in hematological patients or the degree of immunosuppression in recipients of hematopoietic stem cell transplants. For patients with acute myeloid leukemia or myelodysplastic syndrome, prophylactic treatment should be started several days before the expected onset of neutropenia and continued for 7 days after the neutrophil count increases to above 500/µL.

No dose adjustment is required in renal impairment.

Pharmacokinetic data on the use of posaconazole in hepatic impairment are limited, therefore recommendations for dose adjustment in this group of patients have not been established. In a small number of patients with impaired liver function, an increase in the T_1/2 of posaconazole was observed.

The drug should be taken with meals. Patients who cannot combine drug intake with regular food should take the drug simultaneously with liquid nutritional supplements to improve the absorption of posaconazole.

Adverse Reactions

From the hematopoietic system common – neutropenia; uncommon – thrombocytopenia, leukopenia, anemia, eosinophilia, lymphadenopathy; rare – hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, pancytopenia, bleeding (unspecified).

From the blood coagulation system rare – coagulation disorders (unspecified).

From the endocrine system rare – adrenal insufficiency, decreased gonadotropin levels.

From the central and peripheral nervous system common – paresthesia, dizziness, drowsiness, headache; uncommon – convulsions, neuropathy, hypesthesia, tremor; rare – syncope, encephalopathy, peripheral neuropathy, psychosis, depression.

From the sensory organs uncommon – blurred vision; rare – diplopia, scotoma (visual field defect), hearing impairment.

From the cardiovascular system uncommon – QTc/QT interval prolongation, ECG changes, palpitation, increased or decreased blood pressure; rare – torsades de pointes, sudden death, ventricular tachycardia, cardiac and respiratory arrest, heart failure, myocardial infarction, cerebrovascular accident, pulmonary embolism, deep vein thrombosis (unspecified).

From the respiratory system rare – pulmonary hypertension, interstitial pneumonia, pneumonitis.

From the digestive system common – vomiting, nausea, abdominal pain, diarrhea, dyspepsia, flatulence, dry mouth, abdominal distension, anorexia, increased ALT, AST, ALP, GGT activity, increased blood bilirubin levels; uncommon – pancreatitis, hepatocellular damage, oral mucosa ulceration; rare – gastrointestinal bleeding, intestinal obstruction, hepatic failure, cholestatic hepatitis, cholestasis, hepatosplenomegaly, liver tenderness, asterixis (liver flap).

Dermatological reactions : common – skin rash; uncommon – alopecia; rare – vesicular rash.

From the musculoskeletal system uncommon – back pain.

From the urinary system uncommon – acute renal failure, renal failure, increased serum creatinine; rare – interstitial nephritis, renal tubular acidosis.

From the reproductive system uncommon – menstrual cycle disorders; rare – breast tenderness.

Other common – fever, asthenia, fatigue; uncommon – edema, weakness, pain, chills, malaise; rare – tongue edema, facial edema.

Allergic reactions uncommon – anaphylactic reactions; rare – Stevens-Johnson syndrome, hypersensitivity reactions.

From laboratory parameters common – electrolyte imbalance; uncommon – hyperglycemia.

Contraindications

Concomitant use with ergot alkaloids (due to the risk of increased blood concentrations of ergot alkaloids and development of ergotism); concomitant use with CYP3A4 substrates – terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine (due to the risk of increased blood concentrations of active substances, subsequent QT_c interval prolongation, and, in rare cases, development of torsades de pointes); concomitant use with HMG-CoA reductase inhibitors – simvastatin, lovastatin, and atorvastatin (due to the risk of increased blood concentrations of these drugs and development of rhabdomyolysis); hypersensitivity to posaconazole.

Use with caution in cases of hypersensitivity to other azole compounds in the medical history, in severe hepatic impairment, congenital or acquired QT_c interval prolongation, in cardiomyopathy (especially in combination with heart failure), in sinus bradycardia, in diagnosed symptomatic arrhythmia, concomitant use with drugs that prolong the QT_c interval (other than those listed above), due to an increased risk of developing cardiac arrhythmias.

Use in Pregnancy and Lactation

Information on the safety of posaconazole use during pregnancy and lactation is insufficient. Use of the drug during pregnancy is possible only if the anticipated benefit for the mother outweighs the potential risk to the fetus. If it is necessary to use the drug during lactation, the issue of discontinuing breastfeeding should be considered.

In experimental studies in animals, the drug revealed toxic effects on the fetus. Posaconazole is excreted in the milk of lactating rats.

Use in Hepatic Impairment

Use with caution in severe hepatic impairment. Patients who develop impaired liver function according to laboratory tests during posaconazole therapy should be under clinical supervision to prevent the development of more serious liver damage. Monitoring should include laboratory control of liver function (specifically, determination of ALT, AST, ALP, and total bilirubin levels in blood serum).

Use in Renal Impairment

No dose adjustment is required in renal impairment.

Pediatric Use

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

Special Precautions

Treatment can be initiated without waiting for the results of microbiological testing; however, after receiving them, appropriate adjustment of antifungal therapy should be made.

There is no information on cross-sensitivity between posaconazole and other antifungal azole compounds, but caution should be exercised when prescribing posaconazole to patients with hypersensitivity to other azoles.

Clinical studies have reported cases of altered liver function (e.g., mild to moderate increases in serum ALT, AST, ALP, and total bilirubin activity) during treatment with posaconazole. These reactions were observed mainly in patients with severe underlying diseases (e.g., oncohematological) and were not grounds for discontinuing therapy. The increases in liver function test parameters were reversible and resolved after discontinuation of therapy, and in some cases, normalization of functional parameters was observed prior to discontinuation of therapy.

Caution is advised when prescribing posaconazole to patients with severe hepatic impairment. In such patients, the prolonged T_1/2 of posaconazole may lead to an enhanced effect. Patients who develop impaired liver function according to laboratory tests during posaconazole therapy should be under clinical supervision to prevent the development of more serious liver damage. Monitoring should include laboratory control of liver function (specifically, determination of ALT, AST, ALP, and total bilirubin levels in blood serum).

Electrolyte balance, especially potassium, magnesium, and calcium levels, should be monitored and, if necessary, appropriate correction should be made before starting and during posaconazole therapy.

Data on the pharmacokinetics of the drug in patients with significant gastrointestinal dysfunction, which may lead to decreased blood concentrations of posaconazole (e.g., severe diarrhea or vomiting), are limited. Such patients should be closely monitored for timely detection of possible activation of fungal infection.

Use in pediatrics.

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

Effect on ability to drive vehicles and operate machinery

There are no data on the effect of posaconazole on the ability to drive a car and operate other machinery.

Drug Interactions

Posaconazole is metabolized by UDP glucuronidation (a phase II enzymatic reaction) and is a substrate for P-glycoprotein efflux in vitro. Thus, inhibitors (including verapamil, cyclosporine, quinidine, clarithromycin, erythromycin, etc.) or inducers (including rifampicin, rifabutin, some anticonvulsants.) of this metabolic pathway may increase or decrease, respectively, the plasma concentration of posaconazole.

Efavirenz (400 mg once daily) reduces the C_max and AUC of posaconazole by 45% and 50%, respectively, therefore concomitant use of these drugs should be avoided.

Rifabutin (300 mg once daily) reduces the C_max and AUC of posaconazole by 57% and 51%, respectively. Posaconazole increases the C_max and AUC of rifabutin by 31% and 72%, respectively. Concomitant use of posaconazole and rifabutin or similar inducers (e.g., rifampicin) should be avoided unless the benefits of concomitant use outweigh the risk for the given patient. If these drugs are used concomitantly, it is recommended to carefully monitor blood counts and the presence of side effects associated with increased rifabutin concentrations (e.g., uveitis).

Phenytoin (200 mg once daily) reduces the C_max and AUC of posaconazole by 41% and 50%, respectively. The concomitant use of posaconazole and phenytoin or similar inducers (e.g., carbamazepine, phenobarbital, primidone) should be avoided unless the benefits outweigh the risks for the specific patient.

A reduction in the C_max and AUC of posaconazole by 39% is possible with the concomitant use of posaconazole and cimetidine (400 mg twice daily). This is due to reduced absorption, likely associated with decreased gastric acidity. The effect of other H₂-receptor antagonists or proton pump inhibitors, which can reduce gastric acidity for several hours, on the plasma concentration of posaconazole has not been studied; however, due to the potential reduction in posaconazole bioavailability, its concomitant use with these drugs should be avoided whenever possible.

Posaconazole is an inhibitor of CYP3A4. If a patient is already taking drugs metabolized by this isoenzyme, Posaconazole should be used only when the benefits of combination therapy outweigh the risks for the specific patient.

Administration of posaconazole at a dose of 200 mg once daily increases the exposure of midazolam, a CYP3A4 substrate, by 83% following its intravenous administration. Caution should be exercised when co-administering posaconazole and drugs that are substrates of the CYP3A4 isoenzyme administered intravenously, as a dose reduction of the latter may be required. The effect of posaconazole on the plasma concentration of orally administered CYP3A4 substrates has not been studied, but it can be expected to be much more pronounced than with intravenous administration of substrates. If Posaconazole is used with oral CYP3A4 substrates that can cause serious adverse events when their plasma concentrations are increased, their blood levels should be carefully monitored and the possible development of adverse events should be tracked, reducing their doses if necessary.

Caution should be exercised with the concomitant use of benzodiazepines that are metabolized by the CYP3A4 isoenzyme.

The concomitant use of terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine with posaconazole is contraindicated, as it may lead to increased plasma concentrations of these drugs, subsequent QT interval prolongation, and, in rare cases, the development of torsades de pointes ventricular arrhythmia.

Posaconazole may significantly increase the blood concentrations of HMG-CoA reductase inhibitors (e.g., simvastatin, lovastatin, and atorvastatin) that are metabolized by the CYP3A4 isoenzyme. During treatment with posaconazole, the use of HMG-CoA reductase inhibitors should be discontinued, as increased blood concentrations of these substances are associated with the development of rhabdomyolysis.

When used concomitantly with posaconazole, it is recommended to frequently monitor for side effects and toxic reactions associated with the action of calcium channel blockers (e.g., diltiazem, verapamil, nifedipine, nisoldipine) and, if necessary, adjust the dose of these drugs.

Since HIV protease inhibitors are substrates of the CYP3A4 isoenzyme, it can be expected that Posaconazole increases their blood concentrations. In healthy volunteers, the use of posaconazole (400 mg twice daily for 7 days) increased the C_max and AUC of atazanavir (300 mg once daily for 7 days) by an average of 2.6 times and 3.7 times, respectively. The use of posaconazole in healthy volunteers (400 mg twice daily for 7 days) increased the C_max and AUC of atazanavir to a lesser extent when co-administered with ritonavir (300 mg atazanavir and 100 mg ritonavir once daily for 7 days) – by an average of 1.5 times and 2.5 times, respectively. Patients taking these drugs concomitantly with posaconazole should be under close clinical supervision to detect possible toxic reactions.

Non-nucleoside reverse transcriptase inhibitors are substrates of the CYP3A4 isoenzyme. It can be expected that Posaconazole increases their concentrations. Patients taking these drugs concomitantly with posaconazole should be under close clinical supervision to detect possible toxic reactions.

Posaconazole may increase the blood concentrations of ergot alkaloids (ergotamine and dihydroergotamine), which can lead to poisoning – ergotism (concomitant use is contraindicated).

Posaconazole may increase the blood concentrations of vinca alkaloids (e.g., vincristine and vinblastine), which can cause neurotoxic reactions (concomitant use should be avoided). If concomitant use of these drugs is necessary, dose adjustment of the vinca alkaloid is recommended.

In heart transplant patients receiving a stable dose of cyclosporine, Posaconazole increases the blood concentration of cyclosporine, necessitating a dose reduction. In clinical efficacy studies, cases of serious adverse effects due to increased cyclosporine blood concentrations have been reported, including nephrotoxic reactions and one case of fatal leukoencephalopathy. It is recommended to monitor cyclosporine blood concentrations before starting posaconazole treatment, during treatment, and after its completion, adjusting the cyclosporine dose if necessary.

Posaconazole increases the C_max and AUC of tacrolimus (single dose of 0.05 mg/kg body weight) by 121% and 358%, respectively. In clinical efficacy studies, cases of clinically significant drug interactions requiring hospitalization and/or discontinuation of posaconazole have been reported. When prescribing posaconazole to patients taking tacrolimus, the dose of the latter should be reduced (e.g., to 1/3 of the current dose). After initiating concomitant use and after discontinuing posaconazole, tacrolimus blood levels should be carefully monitored and its dose adjusted if necessary.

In healthy volunteers, the use of posaconazole (400 mg twice daily for 16 days) increased the C_max and AUC of sirolimus (2 mg once daily) by an average of 6.7 times and 8.9 times, respectively.

When co-administered with sirolimus, the dose of the latter should be reduced (e.g., to 1/10 of the administered dose). In this case, sirolimus blood concentrations should be monitored frequently. It is recommended to monitor sirolimus blood levels before starting posaconazole treatment, during treatment, and after its completion, adjusting the sirolimus dose if necessary.

Clinical studies have shown no clinically significant interaction of zidovudine, lamivudine, ritonavir, and indinavir with posaconazole; therefore, no adjustment of their dosing regimen is required when used concomitantly.

It is known that the administration of azoles is accompanied by an increase in digoxin levels. Therefore, Posaconazole may also increase the blood concentration of digoxin; consequently, its level should be monitored during concomitant administration with posaconazole and after the end of combination therapy.

In some healthy volunteers, a decrease in glucose concentration was observed with the concomitant use of glipizide and posaconazole. It is recommended to monitor blood glucose levels in diabetic patients receiving sulfonylurea drugs and Posaconazole.

When studying combinations of posaconazole with caspofungin or amphotericin B in vitro and in vivo, no or almost no antagonism of the antifungal drugs was detected; in some cases, an additive effect was noted. The clinical significance of the results of these studies is undetermined.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.