Noxafil, oral suspension 40mg/ml 105ml

Composition

1 ml:

– posaconazole (micronized) 40 mg

Auxiliary substances:

polysorbate 80,

simethicone,

sodium benzoate,

sodium citrate dihydrate,

citric acid monohydrate,

glycerol,

xanthan gum,

dextrose liquid,

titanium dioxide,

cherry flavor (#13174),

purified water.

Pharmacological action

of the pharmaceutical group:

An antifungal drug.

Pharmaceutical action:  

Noxafil is an antifungal drug. Posaconazole 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. As a result, 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.

Posaconazole is active against fungi of the genus Candida (including strains of Candida albicans resistant to fluconazole, itraconazole and voriconazole, Candida glabrata and Candida kruseii, resistant or less sensitive to fluconazole, Candida lusitaniae, resistant or less sensitive to amphotericin B), Aspergillus spp. (including Aspergillus isolates spp., resistant to fluconazole, voriconazole, itraconazole and amphotericin B). Posaconazole, unlike other azole antifungal drugs, is active against pathogens of zygomycosis (Absida spp., Mucor spp., Rhizopus spp., Rhizomucor spp. ).

In experiments in vitro and in clinical studies, Posaconazole has demonstrated 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. Fusarium spp. Ramichloridium spp. Rhizomucor spp., Mucor 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, Candida lipolytica, Candida norvegensis, Candida pseudotropicalis), Cryptococcus laurentii, Kluyveromyces marxianus, Saccharomyces cerevisiae, Yarrowiali polytica, Pichia spp., Trichosporon spp., Aspergillus sydowii, Bjerkandera adusta, Blastomyces dermatitidis, Epidermophyton floccosum, Paracoccidioides brasiliensis, Scedosporium apiospermum, Sporothrix schenckii, Wangiella dermatitidis, Absida spp., Apophysomyces spp., Bipolaris spp., Curvularia spp., Microsporum spp., 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.

No posaconazole-resistant Candida albicans strains were obtained in the laboratory. Spontaneously mutated laboratory strains of Aspergillus fumigatus, which showed a decrease in sensitivity to posaconazole, occurred with a frequency of 1 x 10-8 to 1 x 10-9. Clinical isolates of Candida albicans and Aspergillus fumigatus with reduced sensitivity to posaconazole are rare. In these rare cases, there is no clear correlation between reduced sensitivity to posaconazole and its clinical ineffectiveness. There are cases of clinical efficacy of posaconazole in mycoses caused by pathogens resistant to azole antifungal drugs or amphotericin B, against which posaconazole was active in vitro. Criteria for the clinical significance of in vitro sensitivity of any fungi to posaconazole have not been established. When studying combinations of posaconazole with caspofungin or amphotericin In vitro and in vivo, there was no or almost no antagonism of antifungal drugs, in some cases an additive effect was noted. The clinical significance of the results of these studies has not been determined.

Pharmacokinetics:  

Absorption The absorption time of posaconazole is, on average, from 3 to 5 hours. Posaconazole is characterized by linear pharmacokinetics with a single or multiple dose of up to 800 mg. When posaconazole is used in doses greater than 800 mg / day, there is no increase in pharmacokinetic parameters. Changes in the pH of gastric contents do not affect the absorption of posaconazole. Dividing the daily dose of posaconazole (400 mg 2 times a day) leads to an increase in pharmacokinetic parameters by 184% compared to a single dose of 800 mg.

Compared to fasting, the AUC of posaconazole increases approximately 2.6 – fold when taken with low-fat food or dietary supplements (14 g of fat), and 4-fold when taken with fatty foods (approximately 50 g of fat).

The distribution of posaconazole is characterized by a large Vd (1114 l), which indicates widespread penetration of the drug into tissues. 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.

Metabolizm Osaconazole does not form active circulating metabolites, and it is unlikely that its concentration changes under the action of inhibitors of P450 isoenzymes. Among the circulating metabolites, the bulk consists of posaconazole glucuronide conjugates and a small proportion of oxidized (via P450) metabolites.

Excretionthe elimination of metabolites through the kidneys and intestines is approximately 17% of the administered dose. Posaconazole is slowly eliminated from the body, with an average T1 / 2 of 35 hours (20 to 66 hours) and a total clearance of 32 l / h. The drug is mainly excreted through the intestines (77%), while the main part (66%) is accounted for by the Active ingredient. Renal clearance is a small part of elimination – approximately 14% (the Active ingredient is less than 0.2%).

Pharmacokinetics in special clinical cases

After use of posaconazole in a daily dose of 800 mg divided into several doses, the plasma concentration of the drug in patients aged 8-17 years was comparable with this indicator in patients aged 18-64 years (on average,776 ng / ml and 817 ng/ml, respectively). Pharmacokinetic data for children under 8 years of age are not available.

For the elderly (over 65 years of age) There was a 26% increase in Cmax and a 29% increase in AUC compared to people aged 18-45 years. However, in clinical studies, the safety indicators of posaconazole in young and elderly people were similar. Therefore, dose adjustments based on age are not required.

The pharmacokinetics of posaconazole in men and women do not differ. There is no need to change the dose of the drug depending on gender.

There was a slight (16%) decrease in posaconazole AUC and Cmax in black people. No dose adjustment based on race is required.

With a single dose of posaconazole, mild to moderate renal insufficiency (n=18, creatinine clearance >20 ml/min/1.73 m2) did not affect the pharmacokinetics of the drug, so no dose adjustment is required in this category of patients. Patients with severe renal insufficiency (n=6, CCU of patients with hepatic insufficiency showed an increase in T1 / 2 (26.6 hours,35.3 hours and 46.1 hours for mild, moderate and severe Child-Pugh hepatic insufficiency, respectively), compared with patients with normal liver function (22.1 hours). Due to 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 prolonged neutropenia due to chemotherapy, as well as in recipients of hematopoietic stem cell transplants receiving high doses of immunosuppressants. Treatment of invasive fungal infections: – invasive candidiasis or esophageal candidiasis that is refractory to amphotericin B, itraconazole or fluconazole, or if you are intolerant to these drugs;— invasive aspergillosis that is refractory to amphotericin B or itraconazole, or is intolerant to these drugs;— zygomycosis (mucormycosis), cryptococcosis that is refractory to other antifungal drugs, or is intolerant to them;- fusariasis that is refractory to amphotericin B, or if it is intolerant;- chromomycosis and mycetoma that are refractory to itraconazole or are intolerant to it;- coccidioidosis, refractory to amphotericin B, itraconazole or fluconazole, or with intolerance to these drugs.

Refractoriness is considered to be the progression of infection or the lack of improvement in the patient’s condition after treatment for 7 days (for candidemia – for 3 days, for esophageal candidiasis – for 14 days, for other forms of invasive candidiasis-7 days). Treatment of oropharyngeal candidiasis is first-line therapy in patients with severe disease or with reduced immunity, who are not expected to have a significant effect from the use of topical drugs.

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);— co— use with substrates of the CYP3A4 isoenzyme terfenadine, astemizole, cisapride, pimozideWhen ritonavir is added to this combination (100 mg of ritonavir once a day for 7 days), the cmax and AUC of atazanavir increase 1.5-fold and 2.5-fold, respectively. Patients taking these medications together with posaconazole should be closely monitored for possible toxic reactions. The use of posaconazole (200 mg 2 times a day for 7 days) together with midazolam (0.4 mg IV 1 time a day) increases the Cmax and AUC of midazolam by 1.3 times and 4.6 times, respectively.

The use of posaconazole (400 mg 2 times a day for 7 days) together with midazolam (0.4 mg IV 1 time a day) increases the Cmax and AUC of midazolam by 1.6 times and 6.2 times, respectively.

Both posaconazole dosage regimens increase the Cmax and AUC of midazolam administered orally at a dose of 2 mg once a day by 2.2 times and 4.5 times, respectively.

The use of posaconazole in doses of 200 mg and 400 mg increases the T1/2 of midazolam from 3-4 hours to 8-10 hours when used together. Caution should be exercised when prescribing other benzodiazepines that are metabolized by the CYP3A4 isoenzyme to patients receiving posaconazole.

When posaconazole is co-administered with BMCC (diltiazem, verapamil, nifedipine, nisoldipine), it is necessary to monitor adverse and toxic reactions associated with the action of BMCC and, if necessary, adjust their dose. When posaconazole is co-administered with digoxin, the concentration of digoxin may increase, which should be monitored during and after concomitant therapy.

When glipizide and posaconazole were used together, a decrease in glucose concentration was noted. It is recommended to monitor the blood glucose concentration in patients with diabetes mellitus who are simultaneously receiving sulfonylureas and posaconazole. In combinations of posaconazole with caspofungin or amphotericin, no antagonism was detected in vitro and in vivo, and in some cases an additive effect was noted.

How to take, course of use and dosage

The drug should be taken orally with a meal. Patients who cannot combine the use of Noxafil with regular food, to improve the absorption of posaconazole, should take the drug simultaneously with taking liquid food supplements. The suspension must be shaken thoroughly before use.

– For the prevention of invasive fungal infections, the drug is prescribed 200 mg (5 ml) 3 times a day. The duration of preventive treatment depends on the duration of neutropenia in hematological patients or the severity of immunosuppression in recipients of hematopoietic stem cell transplants. In 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 an increase in the number of neutrophils to more than 500/ml.

– For the treatment of invasive fungal infections that are refractory to other antifungal drugs, or for intolerance to other antifungal drugs,400 mg (10 ml) is prescribed 2 times a day. Patients who cannot take the drug with food or dietary supplements are recommended to take Noxafil 200 mg (5 ml) 4 times a day. The duration of therapy depends on the severity of the patient’s underlying disease, 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 (initial 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 a day. The duration of therapy depends on the severity of the underlying disease of the patient and the effectiveness of the treatment.

Increase the dose of Noxafil more than 800 mg / day. it does not lead to an increase in the effectiveness of treatment.

With impaired renal function, there are no changes in pharmacokinetic parameters, so no dose adjustment is required for impaired renal function.

In patients with impaired liver function, the relevant pharmacokinetic data are limited, so 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.

Overdose

In patients treated with posaconazole at doses up to 1600 mg / day, no additional adverse events were detected compared to those who received lower doses. Accidental overdose was reported in one patient who took Noxafil 1200 mg 2 times a day. within 3 days. No overdose-related adverse events were observed in this patient.

Posaconazole is not eliminated by hemodialysis.

Special instructions

Treatment should be initiated by a doctor who has experience in treating systemic fungal infections.

Before starting treatment, it is necessary to obtain material from the patient for conducting microbiological and other laboratory tests in order to identify the causative agent of the disease. Treatment can be initiated without waiting for the results of these studies, but after receiving them, if necessary, you should make adjustments to antifungal therapy, if necessary.

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

When treated with posaconazole, there have been reports of changes in liver function (for example, mild to moderate increases in ALT, ACT, ALP, and total serum bilirubin) during treatment with posaconazole. These reactions were observed mainly in patients with severe background diseases (for example, oncohematological), and they were not a reason for discontinuing therapy. The increase in liver function tests was reversible and was completed after discontinuation of therapy, and in some cases, normalization of functional parameters was observed before discontinuation of therapy. In rare cases, severe liver reactions with a fatal outcome developed. Caution should be exercised when prescribing posaconazole to patients with severe hepatic impairment. In such patients, prolongation of the drug’s half-life may lead to an increase in its effect.

Patients with laboratory-tested liver function abnormalities associated with Noxafil therapy should be monitored clinically to prevent the development of more serious liver damage. Follow-up should include laboratory monitoring of liver function (in particular, determination of serum ALT, ACT, ALP, and total bilirubin).

Some azole compounds cause prolongation of the QT interval. Do not administer Noxafil together with drugs that are a substrate for the CYP3A4 isoenzyme and prolong the QT interval. Caution should be exercised when prescribing Noxafil to patients at high risk for cardiac arrhythmias, such as::

– with congenital or acquired prolongation of the QT interval— – in the presence of cardiomyopathy, especially in combination with heart failure;- for sinus bradycardia;— with diagnosed symptomatic arrhythmia;— when taking medications that prolong the QT interval (with the exception of those indicated in the section “Contraindications”). The electrolyte balance should be monitored, especially the potassium, magnesium and calcium content, and if necessary, corrected before and during posaconazole therapy.

Posaconazole is an inhibitor of the CYP3A4 isoenzyme and if the patient is already taking drugs that are metabolized by the CYP3A4 isoenzyme, then posaconazole should only be used in special circumstances.

The concentration of posaconazole can be significantly reduced when used in combination with rifamycin antibacterial agents (rifampicin, rifabutin), anticonvulsants (phenytoin, carbamazepine, phenobarbital, primidone) and cimetidine. Therefore, co-use with posaconazole should be avoided if the benefits of co-use do not outweigh the risk to the patient.

The recommended daily dose of Noxafil contains approximately 7 g of glucose. The drug should not be prescribed to patients with malabsorption syndrome (impaired glucose/galactose absorption).

Data on the pharmacokinetics of the drug in patients with severe gastrointestinal dysfunction, which may lead to a decrease in the concentration of the drug in the blood (for example, with severe diarrhea or vomiting), are limited. Such patients should be carefully monitored for timely detection of possible activation of fungal infection.

Use with Pediatrics

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

Influence on the ability to drive motor vehicles and manage mechanisms

There are no data on the effect of Noxafil on the ability to drive a car or other mechanisms.

Form of production

suspension for oral use

Active ingredient

Posaconazole

Conditions of release from pharmacies

By prescription

Dosage form

suspension for oral use

Purpose

For adults as directed by your doctor

Indications

Mushroom