Noxafil suspension for vn. receiving 40mg ml 105ml N1
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Active ingredients
Posaconazole
Release form
Suspension
Composition
In 1 ml - posaconazole (micronized) 40 mg. Adjuvants: polysorbate 80 - 10 mg, simethicone - 3 mg, sodium benzoate - 2 mg, sodium citrate dihydrate - 600 μg, citric acid monohydrate - 1.5 mg, glycerol - 100 mg, xanthan gum - 3 mg, dextrose liquid (liquid glucose) - 350 mg, titanium dioxide - 4 mg, cherry flavoring (# 13174) - 5 mg, purified water - qs to 1 ml.
Pharmacological effect
Antifungal medication. Posaconazole inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyzes an important step in the biosynthesis of ergosterol, the main component of the cytoplasmic membrane of fungi. Because of this, posaconazole has a wide spectrum of antifungal action. It is active against pathogens of yeast and mold mycoses, including strains resistant to other antifungal drugs. Posonazol is active against Candida spp. (Including Candida albicans strains resistant to fluconazole, itraconazole and voriconazole, Candida glabrata and Candida kruse i). sensitive to fluconazole, Candida lusitaniae, resistant or less sensitive to amphotericin B), Aspergillus spp. (including isolates of Aspergillus spp. resistant to fluconazole, voriconazole, itraconazole and amphotericin B). Posaconazole, unlike other azole antifungal drugs, is active against zygomycosis pathogens (Absida spp., Mucor spp., Rhizopus spp., Rhizomucor spp.). In vitro experiments and in clinical studies, posaconazole showed activity against the following microorganisms: Aspergillus spp . (Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Aspergillus nidulans, Aspergillus niger, Aspergillus ustus, Aspergillus ochraceus), Candida spp. (Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis), Cryptococcus neoformans, Coccidioides immitis, Fonsecaea pedrosoi, Histoplasma capsulatum, Pseudallescheria boydii, Alternaria spp., Exophiala spp. spp., Rhizopus spp. In in vitro experiments, posaconazole also showed activity against the following microorganisms: Candida spp. (Candida dubliniensis, Candida famata, Candida guiltiermondii, Candida lusitaniae, Candida kefyr, Candida rugosa, Candida tropicalis, Candida zeylanoides, Candida inconspicua lawyers, Candida lipolytica, Candy lipora, Candida pizza, Candida tropical districts; Pichia sp ., Paecilomyces spp., Penicillium spp., Trichophyton spp. However, in clinical studies, the efficacy and safety of posaconazole in the treatment of infections caused by these microorganisms have not been studied. Posoconazole-resistant strains of Candida albicans could not be obtained under laboratory conditions. Spontaneously mutated laboratory strains of Aspergillus fumigatus, which showed a decrease in posaconazole sensitivity, were found with a frequency from 1x10-8 to 1x10-9.Clinical isolates of Candida albicans and Aspergillus fumigatus with reduced posaconazole sensitivity are rare. In these rare cases, a clear relationship has not been established between the reduced sensitivity to posaconazole and its clinical ineffectiveness. There are cases of the clinical efficacy of posaconazole in mycoses caused by azole-resistant antifungal agents or amphotericin B pathogens against which posaconazole was active in vitro. The criteria for the in vitro sensitivity of any fungi to posaconazole have not been established. When studying combinations of posaconazole with caspofungin or amphotericinin, antagonism of antifungal drugs was found in vitro and in vivo, and in some cases an additive effect was noted. The clinical significance of the results of these studies is not defined.
Pharmacokinetics
Absorption Posaconazole absorption lasts, on average, from 3 to 5 hours. Posaconazole differs by linear pharmacokinetics when taken once or several times in doses up to 800 mg. When using posaconazole in doses of more than 800 mg / day, there is no increase in pharmacokinetic parameters. A change in the pH of the gastric contents does not affect the absorption of posaconazole. Separation of posaconazole daily dose (400 mg 2 times / day) leads to an increase in pharmacokinetic parameters by 184% compared with a single dose of 800 mg. Compared with fasting, posaconazole AUC when taken with a low-fat food or food additives (14 g fat ) increases about 2.6 times, and when taken with fatty foods (about 50 g of fat) - 4 times. Distribution Posaconazole has a large Vd (1114 l), which indicates the widespread penetration of the drug into the tissue. More than 98% of the drug binds to proteins, mainly plasma albumin. The equilibrium state is reached after 7-10 days of repeated use of the drug. Metabolism Posaconazole does not form active circulating metabolites, and it is unlikely that its concentration is altered by the action of P450 isoenzyme inhibitors. Of the circulating metabolites, the bulk of the posaconazole glucuronide conjugates and a small proportion of oxidized (through P450) metabolites. Excretion Excretion of metabolites through the kidneys and through the intestine makes up about 17% of the administered dose. Posaconazole is slowly excreted, the average T1 / 2 is 35 h from 20 to 66 h), and the total clearance - 32 l / h.The drug is excreted mainly through the intestines (77%), while the main part (66%) falls on the active substance. Renal clearance is an insignificant part of the elimination — approximately 14% (the active substance is less than 0.2%). Pharmacokinetics in special clinical situationsAfter applying posaconazole at a daily dose of 800 mg divided into several doses, the plasma concentration in patients aged 8–17 years was compared with this indicator in patients aged 18-64 years (on average, 776 ng / ml and 817 ng / ml, respectively). Pharmacokinetic data for children younger than 8 years old are not available. In elderly people (over 65 years old), Cmax increased by 26% and AUC by 29% compared with people aged 18-45 years. However, in clinical studies, the safety record for posaconazole in younger and older people was similar. Therefore, dose adjustment depending on age is not required. Posaconazole pharmacokinetics in men and women does not differ. There is no need to change the dose of the drug depending on gender. A slight (by 16%) decrease in AUC and Cmax of posaconazole in people of the Negroid race has been observed. Dose adjustments based on race are not required. When using posaconazole once, the renal failure of mild and moderate severity (n = 18, QC greater than 20 ml / min / 1.73 m2) did not affect the pharmacokinetics of the drug, therefore dose adjustments in this category of patients did not required. In patients with severe renal insufficiency (n = 6, KK less than 20 ml / min / 1.73 m2), posonacazole AUC varied greatly (coefficient of variation 96%) compared with other patients with renal insufficiency (coefficient of variation less than 40%). However, since the renal clearance of posaconazole is insignificant, it is unlikely that severe renal insufficiency affects the pharmacokinetics of the drug, therefore dose adjustment is not required in this case. An increase in T1 / 2 is observed in patients with hepatic insufficiency (26.6 h, 35.3 h and 46.1 h - for mild, moderate, and severe hepatic failure for Child-Puff, respectively), compared with patients with normal liver function (22.1 h). Due to the limited pharmacokinetic data, recommendations for dose adjustment in patients with hepatic insufficiency have not been developed.
Indications
Prevention of invasive fungal infections with reduced immunity and an increased risk of developing such infections, for example, in hematological patients with long-term neutropenia due to chemotherapy, as well as in recipients of hematopoietic stem cell transplants receiving high doses of immunosuppressors. , refractory to amphotericin B, itraconazole or fluconazole, or in case of intolerance to these drugs; - invasive aspergillosis, re antioxidant for amphotericin B or itraconazole, or for intolerance to these drugs; - zygomycosis (mucormycosis), cryptococcosis, refractory to other antifungal drugs, or when they are intolerable; - Fusarium, refractory to amphotericin B, or inoperable, or unperfluent; mycetoma refractory to itraconazole, or if it is intolerable; - coccidioidosis, refractory to amphotericin B, itraconazole or fluconazole, or to the intolerance of these medicines. Refractoriness is considered to be ogresirovanie infection or the lack of improvement of the patient after treatment for 7 days (with candidemia - within 3 days, with esophageal candidiasis - within 14 days, with other forms of invasive candidiasis - 7 days). Treatment of oropharyngeal candidiasis is the first-line therapy for patients with severe disease or with reduced immunity, in which no significant effect is expected from the use of topical preparations.
Contraindications
- combined use with ergot alkaloids (due to the risk of increasing the concentration of ergot alkaloids in the blood and the development of ergotism); - combined use of CYP3A4 isoenzyme terfenadine, astemizole, cisapride, pimozide, halofantrin or quinidine with substrates (due to the risk of increasing the concentration of drugs. blood, subsequent lengthening of the QTc interval and, in rare cases, the development of ventricular tachycardia such as pirouette; - combined use with HMG-CoA reductase inhibitors with simvastatin, lovastatin and atorvastat SG (due to the risk of increasing the concentration in the blood and the development of these drugs rhabdomyolysis) - hypersensitivity to any component of preparata.S caution should be prescribed at elevatedsensitivity to other azole compounds in history, with severe impaired liver function, congenital or acquired prolongation of the QTc interval, with cardiomyopathy, especially in combination with heart failure, sinus bradycardia, diagnosed symptomatic arrhythmias, when taken jointly with drugs, extending the QTc interval (except listed in the Contraindications section), due to an increased risk of developing heart rhythm disorders.
Use during pregnancy and lactation
Information on the use of posaconazole in pregnant women is not enough. In animal studies revealed a toxic effect of the drug on the fetus. The potential risk to humans is unknown. Women of reproductive age are recommended to use effective contraception during posaconazole treatment. Posonazonol use during pregnancy is contraindicated unless the potential benefit to the mother exceeds the risk to the fetus. Posaconazole is excreted in milk in lactating rats. Excretion of posaconazole with breast milk in humans has not been studied. In the appointment of posaconazole, breastfeeding should be discontinued.
Dosage and administration
The drug should be taken orally during meals. Patients who cannot combine the drug with regular food, to improve the absorption of posaconazole should take the drug at the same time as taking liquid food additives. Before use, the suspension should be thoroughly shaken. To prevent invasive fungal infections, the drug is prescribed 200 mg (5 ml) 3 times / day. The duration of prophylactic treatment depends on the duration of neutropenia in hematological patients or the severity of immunosuppression in recipients of hematopoietic stem cell transplants. Patients with acute myeloid leukemia or myelodysplastic syndrome prophylactic treatment with Noxafil should begin several days before the expected onset of neutropenia and continue for 7 days after increasing the number of neutrophils to more than 500 / ml. For the treatment of invasive fungal infections refractory to other antifungal drugs , or in case of intolerance to other antifungal drugs prescribed 400 mg (10 ml), 2 times / day.Patients who cannot take the drug with food or nutritional supplements are recommended to take Noxafil 200 mg (5 ml) 4 times / day. The duration of therapy depends on the severity of the underlying disease of the patient, the severity of immunodeficiency and the effectiveness of the treatment. For the treatment of oropharyngeal candidiasis, 200 mg (5 ml) is prescribed 1 time / day - on the first day of treatment (introductory dose), then 100 mg (2.5 ml) 1 time / day for the next 13 days. For the treatment of oropharyngeal candidiasis, refractory to itraconazole and / or fluconazole, 400 mg (10 ml) is prescribed 2 times / day. The duration of therapy depends on the severity of the underlying disease of the patient and the effectiveness of the treatment. Increasing Noxafil's dose over 800 mg / day does not lead to an increase in the effectiveness of the treatment. There are no changes in pharmacokinetic parameters in renal dysfunction, therefore dose adjustment in renal dysfunction is not required. liver function relevant pharmacokinetic data is limited, therefore, recommendations for dose adjustment in this group of patients have not been developed. In a small number of patients with reduced liver function, an increase in T1 / 2 of posaconazole was observed.
Side effects
The following are all treatment-related adverse events reported in studies involving 2,400 patients; of these, 172 patients received posaconazole for at least 6 months, and 58 patients received posaconazole for at least 12 months. The most common adverse events were nausea (6%) and headache (6%). Serious adverse events were recorded (with a frequency of 1% each ) in patients with invasive mycoses, included a change in the concentration of other drugs, increased liver enzymes, nausea, rash and vomiting. Serious adverse events reported (with a frequency of 1% each) in patients who received posaconazole for the prevention of inva Mycosis included hyperbilirubinemia, elevated liver enzymes, hepatocyte damage, nausea and vomiting. A single case of ventricular tachycardia of pirouette was registered in a patient who was in serious condition and had multiple risk factors that could lead to this complication, such as arythma. , recent cardiotoxic chemotherapy,history of hypokalemia and hypomagnesemia. Rare cases of hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura were noted mainly in patients who, in addition to treating the underlying disease, received cyclosporine or tacrolimus in order to prevent transplant rejection. (more than 1/100, but less than 1/10), infrequently (more than 1/1000, but less than 1/100), rarely (more than 1/10 000, but less than 1/1000) and in descending gravity within each frequency group. on the side of the hematopoietic system: often - neutropenia; infrequently - thrombocytopenia, leukopenia, anemia, eosinophilia, lymphadenopathy; rarely - hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, pancytopenia, bleeding disorder, bleeding (unspecified). On the immune system: infrequently - allergic reactions; rarely - Stevens-Johnson syndrome, hypersensitivity reactions. For the endocrine system: rarely - adrenal insufficiency, decreased gonadotropin levels. For the central nervous system: often - paresthesia, dizziness, drowsiness, headache; infrequently - convulsions, neuropathy, hypoesthesia, tremor; rarely - psychosis, depression, syncope, encephalopathy, peripheral neuropathy. On the part of the organ of vision: infrequently - blurry vision; rarely - diplopia, scotoma. On the part of the organ of hearing: rarely - hearing impairment. On the part of the cardiovascular system: rarely - prolongation of the QTc / QT interval, abnormalities in ECG, heartbeat, increase or decrease in blood pressure; rarely - ventricular tachycardia (including pirouette type), sudden death, cardiac and respiratory arrest, heart failure, myocardial infarction, cerebrovascular accident, pulmonary embolism, deep vein thrombosis (unspecified). Respiratory system: rarely - pulmonary hypertension, interstitial pneumonia, pneumonitis. From the digestive system: often - anorexia, vomiting, nausea, abdominal pain, diarrhea, dyspepsia, flatulence, dry mouth, bloating, increased liver function (including Single ALT, ACT, bilirubin, alkaline phosphatase, GGT); infrequently - ulceration of the oral mucosa, pancreatitis, damage to hepatocytes; rarely - gastrointestinal bleeding, intestinal obstruction, liver failure,cholestatic hepatitis, cholestasis, hepatosplenomegaly, liver pain, asteriksis (hepatic tremor), severe lesion of the liver with a fatal outcome. Dermatological reactions: often - rash; infrequently - alopecia; rarely - vesicular rash. From the musculoskeletal system: infrequently - back pain. From the urinary system: infrequently - renal failure (including acute), an increase in the level of creatinine in the blood; rarely, interstitial nephritis, renal canalicular acidosis. On the part of the reproductive system: infrequently, menstrual disorders; rarely - pain in the mammary gland. From the laboratory parameters: infrequently - changes in serum concentrations of other drugs. Others: often - fever, asthenia, fatigue, electrolyte imbalance; infrequently - hyperglycemia, swelling, weakness, pain, chills, malaise; rarely - swelling of the tongue, swelling of the face.
Overdose
In patients treated with posaconazole in doses up to 1600 mg / day, no additional adverse events were detected compared with those who received lower doses. Accidental overdose was registered in one patient who took the drug 1200 mg 2 times / day for 3 days. There were no adverse events associated with overdose in this patient. Posaconazole is not eliminated by hemodialysis.
Interaction with other drugs
Posaconazole is metabolized by glucururisation of UDP (phase II enzymatic reaction) and is the substrate for the production of p-glycoprotein in vitro. Thus, inhibitors (for example, verapamil, cyclosporine, quinidine, clarithromycin, erythromycin) or inducers (for example, rifampicin, rifabutin, certain anticonvulsants) of this metabolic pathway can increase or decrease, respectively, the concentration of posaconazole in plasma. Efavirenz (400 mg 1 times / day) reduces Cmax in plasma and AUC for posaconazole by 45% and 50%, respectively. The combined use of posaconazole and efavirenz should be avoided if the benefits of such use do not exceed its risk for the patient. Rifabutin (300 mg 1 time / day) reduces Cmax and AUC for posaconazole by 57% and 51%, respectively. The combined use of posaconazole and rifabutin or similar inducers (for example, rifampicin) should be avoided if the advantages of combined use do not exceed its risk for the patient. Phenytoin (200 mg 1 time / day) reduces Cmax and AUC for posaconazole by 41% and 50%, respectively.The combined use of posaconazole and phenytoin or similar inducers (for example, carbamazepine, phenobarbital, primidone) should be avoided if the advantages of combined use do not exceed its risk for the patient. The concentration of posaconazole in plasma (Cmax and AUC) may decrease by 39% if posaconazole is administered together with cimetidine (400 mg 2 times / day). The effect is associated with a decrease in absorption, probably secondary to a decrease in gastric acidity. The combined use of posaconazole and cimetidine should be avoided if the advantages of combined use do not exceed its risk for the patient. The effect of other histamine H2 receptor blockers or proton pump inhibitors capable of reducing the acidity of gastric juice for several hours on posaconazole levels in plasma has not been studied, but because of the likely decrease in the bioavailability of posaconazole, it should be avoided if possible in conjunction with these drugs. Posaconazole is a CYP3A4 inhibitor. The introduction of posaconazole in a dose of 200 mg 1 time / day increases the content (AUC) of midazolam - CYP3A4 substrate - by 83% after it is administered intravenously. Care should be taken when co-prescribing posaconazole and substrates of CYP3A4 isoenzyme administered IV, it may be necessary to reduce the dose of substrates of CYP3A4 isoenzyme. The effect of posaconazole on the concentration of substrates of CYP3A4 isoenzyme in plasma upon their oral administration has not been studied, but it can be expected that it will be much more pronounced than with a / in the introduction of substrates. If posaconazole is used in conjunction with oral substrates of CYP3A4 isoenzyme, which, if elevated in plasma, can cause serious adverse events, then the level of CYP3A4 isoenzyme in the blood should be carefully monitored and the possible development of adverse events should be monitored and the dose of terfenadine should be reduced. , astemizole, cisapride, pimozide, halofantrine or quinidine with posaconazole is contraindicated, because can lead to an increase in plasma concentrations of these drugs, with a subsequent lengthening of the QT interval and, in rare cases, the development of ventricular tachycardia such as pirouette. Posaconazole can increase the ergot alkaloids concentration in the blood (ergotamine and dihydroergotamine), which can lead to poisoning - ergotism.The combined use of ergot alkaloids and posaconazole is contraindicated. Posaconazole can significantly increase the concentration in the blood of HMG-CoA reductase inhibitors (for example, simvastatin, lovastatin and atorvastatin), which are metabolized by CYP3A4 isoenzyme. During treatment with posaconazole, the use of HMG-CoA reductase inhibitors should be discontinued, since an increase in the concentration of these substances in the blood is associated with the development of rhabdomyolysis. Therefore, the combined use of posaconazole and vinca alkaloids should be avoided if the benefits of the combination therapy do not exceed its risk for the patient. If necessary, the joint use of these drugs is recommended to adjust the dose of the Vinca alkaloid. Posaconazole increases Cmax and AUC of rifabutin by 31% and 72%, respectively. The combined use of posaconazole and rifabutin should be avoided if the benefits of the combination therapy do not exceed its risk for the patient. When using these drugs together, it is recommended to carefully monitor the blood formula and the presence of side effects associated with elevated concentrations of rifabutin (for example, uveitis). In patients undergoing heart transplants and taking a stable dose of cyclosporine, posaconazole in a dose of 200 mg 1 time / day increases the concentration of cyclosporine in the bloodstream, which requires a lower dosage. In clinical efficacy studies, there were reported cases of serious side effects caused by an increase in the concentration of cyclosporine in the blood, including nephrotoxic reactions and one case of the development of fatal leukoencephalopathy. It is recommended to control the level of cyclosporine in the blood before starting with posaconazole, during treatment and after it, adapting, if necessary, the dose of cyclosporine. Posaconazole increases Cmax and AUC of tacrolimus (single dose - 50 µg / kg body weight) by 121% and 358% , respectively. In clinical efficacy studies, cases of the development of clinically significant drug interactions have been reported, requiring hospitalization and / or discontinuation of posaconazole.When prescribing posaconazole to patients taking tacrolimus, the dose of the latter should be reduced (for example, to 1/3 of the current dose). After starting the joint use of drugs and after the application of posaconazole, the level of tacrolimus in the blood should be carefully monitored and, if necessary, its dose should be adjusted. In healthy volunteers, the use of posaconazole (400 mg 2 times / day for 16 days) increases Cmax and AUC of sirolimus (2 mg 1 time / day) on average 6.7 times and 8.9 times respectively. When prescribing treatment with posaconazole to patients taking sirolimus, the dose of the latter should be reduced (for example, to 1/10 of the dose taken). It is often necessary to monitor the concentration of sirolimus in the blood. It is recommended to control the level of sirolimus in the blood before starting posaconazole treatment, during and after treatment, adjusting, if necessary, the dose of sirolimus. a dosing regimen is not required. Anti-retroviral drugs (non-nucleoside reverse transcriptase inhibitors) are substrates of the CYP3A4 isoenzyme, and posaconazole can be expected to increase flushes the contents of these antiretrovirals in the blood. Patients taking these drugs together with posaconazole should be carefully monitored to detect possible toxic reactions. Since HIV protease inhibitors are substrates of the CYP3A4 isoenzyme, posaconazole can be expected to increase blood levels of these antiretroviral drugs. In healthy volunteers, posaconazole (400 mg, 2 times / day for 7 days) increases the Cmax and AUC of atazanavir (300 mg 1 time / day for 7 days), on average, 2.6 times and 3.7 times, respectively. The use of posaconazole in healthy volunteers (400 mg 2 times / day for 7 days) increases Cmax and AUC of atazanavir to a lesser extent when administered together with ritonavir (300 mg of atazanavir + 100 mg of ritonavir 1 time / day for 7 days) - on average 1.5 times and 2.5 times, respectively. Patients taking these drugs together with posaconazole should be under close clinical supervision to identify possible toxic reactions. The use of posaconazole at a dose of 200 mg 2 times / day for 7 days increases the Cmax and AUC of midazolam (400 µg i / v 1 time / day ) an average of 1.3 times and 4.6 times, respectively.The use of posaconazole in a dose of 400 mg 2 times / day for 7 days increases the Cmax and AUC of midazolam (if it is intravenously) 1.6 times and 6.2 times, respectively. Both dosage regimens of posaconazole increase the Cmax and AUC of midazolam, administered orally at a dose of 2 mg 1 time / day, 2.2 times and 4.5 times, respectively. In addition, the use of posaconazole in doses of 200 mg and 400 mg increases the T1 / 2 of midazolam from about 3-4 hours to 8-10 hours when used together. Care should be taken when prescribing benzodiazepines, which are metabolized by the CYP3A4 isoenzyme, to patients receiving posaconazole. When used together with posaconazole, it is recommended to often monitor the presence of side and toxic reactions associated with the action of calcium channel blockers metabolized by the CYP3A4 isoenzyme (for example, diltiazem, verapamone, and, for example, diltiazem, and, for treatment, you should not have to use it by using a CYP3A4 isoenzyme (for example, diltiazem, verapamone, and, for example, diltiazem, and, for treatment, you should not have to use it). nizoldipin) and, if necessary, adjust the dose of these drugs. The introduction of other azoles is accompanied by an increase in the content of digoxin. Therefore, posaconazole can also increase the concentration of digoxin in the blood, and therefore, its level should be monitored when administered jointly with posaconazole and at the end of combined therapy. A decrease in glucose concentration is noted in some healthy volunteers when used together. It is recommended to control the blood glucose level in patients with diabetes mellitus receiving sulfonylurea and posaconazole.
special instructions
Treatment should begin a doctor who has experience in treating systemic fungal infections. Before the start of treatment, it is necessary to obtain material from the patient for microbiological and other laboratory tests to identify the causative agent of the disease. Treatment can begin without waiting for the results of these studies, but after receiving them, if necessary, antifungal therapy should be corrected, if necessary. There is no information on cross-sensitivity between posaconazole and other antifungal azole compounds. Care should be taken when administering Noxafil to patients with hypersensitivity to other azoles. When treating with posaconazole, there were reports of a change in liver function (for example, from a low to moderate increase in serum ALT, ACT, alkaline phosphatase and total serum bilirubin) during treatment with posaconazole.These reactions were observed mainly in patients with severe background diseases (eg, oncohematological), and they were not grounds for discontinuing therapy. The increase in the functional hepatic tests was reversible and was completed after cessation of therapy, and in some cases normalization of functional parameters was observed until cessation of therapy. In rare cases, developed severe reactions from the liver with a fatal outcome. Care must be taken when prescribing posaconazole in patients with severely impaired liver function. In such patients, prolongation of the half-life of the drug may lead to an increase in its action. Patients who have been impaired in the liver during the treatment with Noxafil according to laboratory tests should be under clinical observation to prevent the development of more serious liver damage. Observation should include laboratory monitoring of liver function (in particular, determining the level of ALT, ACT, ALT and total serum bilirubin). Some azole compounds cause lengthening of the QT interval. Do not enter Noxafil together with drugs that are substrates for CYP3A4 isoenzyme and prolong the QT interval. Care should be taken when prescribing Noxafil to patients with a high risk of cardiac arrhythmias, for example: - with congenital or acquired prolongation of the QT interval; - with cardiomyopathy, especially in combination with heart failure; - with sinus bradycardia; - with diagnosed symptomatic arrhythmia; - with taking drugs that prolong the QT interval (except for those indicated in the section Contraindications). It is necessary to control the electrolyte balance, especially the content of potassium, magnesium and calcium, and when neo to make correction before