NOKSAFIL

Active material: Posaconazole
When ATH: J02AC04
CCF: Antifungal agent
ICD-10 codes (testimony): B37.0, B37.1, B37.2, B37.3, B37.4, B37.6, B37.7, B37.8, B38, B43, B44, B45, B46, B53
When CSF: 08.01.01
Manufacturer: SCHERING-PLOUGH S.A. (France)

Pharmaceutical form, composition and packaging

Oral suspension white; There can be translucent or opaque semi-hard white colored particles.

Excipients: polysorbate 80, simethicone, Sodium benzoate, sodium citrate dihydrate, citric acid monohydrate, glycerol, xanthan gum, Dextrose liquid, Titanium dioxide, cherry flavor (#13174), Purified water.

105 ml – vials of dark glass (1) complete with a dosing spoon – packs cardboard.

Pharmacological action

Antifungal agent. Posaconazole ingibiruet enzyme lanosterol 14α-demetilazu (SYP51), which catalyzes an important stage in the biosynthesis of ergosterol, main component of the cytoplasmic membrane of fungi. Consequently, a wide range of different anti-fungal posaconazole activity. Active against pathogens of yeast and fungal Mycosis, including strains, resistant to other antifungal drugs.

Posaconazole is active against fungi of the genus Candida (t. h. strains of Candida albicans, resistant to fluconazole, itrakonazolu and vorikonazolu, Candida glabrata and Candida kruseiy, resistant or less sensitive to fluconazole, Candida Lusitania, resistant or less sensitive to amfotericinu in), Aspergillus spp. (t. h. isolates of Aspergillus spp., resistant to fluconazole, vorikonazolu, itraconazole and amphotericin B). Posaconazole, Unlike other azole antifungals, active against pathogens zigomikoza (Absida spp., Mucor spp., Rhizopus spp., Rhizomucor spp.).

In experiments in vitro and in clinical studies posaconazole has demonstrated activity against microorganisms: Aspergillus spp. (Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Aspergillus nidulans, Aspergillus niger, Aspergillus burns, Aspergillus ochraceus), Candida spp. (Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis), Cryptococcus neoformans, Merciless coccidioides, Fonsecaea pedrosoi, Histoplasma capsulatum, Pseudallescheria boydii, Alternaria spp., Exophiala spp., Fusarium spp., Ramichloridium spp., Rhizomucor spp., Mucor spp., Rhizopus spp.

In experiments in vitro posaconazole activity has also demonstrated against the following microorganisms: Candida spp. (Candida of Dublin, Candida Famata, Candida guiltiermondii, Candida Lusitania, Candida kefyr, candida rugosa, Candida tropicalis, Candida zeylanoides, White invisible, Candida lipolytica, Candida norvegensis, Candida pseudotropicalis), Cryptococcus Lawrence, Kluyveromyces marxianus, Saccharomyces cerevisiae, Yarrowiali polytica, Pichia spp., Trichosporon spp., Aspergillus sydowii, Bjerkandera crackle, Blastomyces dermatitidis, Epidermophyton floccosum, P. brasiliensis, Scedosporium apiospermum injection, 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, not investigated.

Under laboratory conditions failed to get strains of Candida albicans, resistant to posaconazole. Spontaneously mutated strains of Aspergillus fumigatus laboratory, showed a decrease in sensitivity to posaconazole, met with a frequency of 1 x 10-8 to 1×10-9. Clinical isolates of Candida albicans and Aspergillus fumigatus with reduced susceptibility to posaconazole rare. In these rare cases it is not established a distinct relationship between reduced susceptibility to posaconazole and clinical failure. There are cases of clinical efficacy of posaconazole in mycosis, due to resistant to anti-fungal substances azol′nym or amfotericinu in pathogens, against which posaconazole was active in vitro. The criteria for clinical significance of in vitro susceptibility of any fungi to posaconazole is not installed.

In the study of posaconazole combinations with amphotericin B or caspofungin in vitro and in vivo, there was little or no antagonism was detected antifungals, In some cases, there is an additive effect. The clinical significance of these findings is not defined.

Pharmacokinetics

Absorption

Duration of absorption is pozakonazola, average, from 3 to 5 no. Posaconazole different linear pharmacokinetics in single or multiple doses prior to admission 800 mg. When using pozakonazola in doses more 800 mg / increase the pharmacokinetic parameters there is no. Changing the pH of gastric contents will not affect the absorption of posaconazole. Separation of admission daily dose pozakonazola (by 400 mg 2) It leads to increased pharmacokinetic parameters for 184% compared to the single administration 800 mg.

As compared with the fasted, Posaconazole AUC when taken with a low-fat diet or supplementation (14 g fat) increases about 2.6 times, and when taken with fatty foods (about 50 g fat) – in 4 times.

Distribution

Posaconazole is very Vd (1114 l), reflecting on distributed the drug in tissue penetration. More 98% the drug binds to proteins, mostly with albuminom blood plasma.

The equilibrium state is achieved after 7-10 days repeated use of the drug.

Metabolism

Posaconazole does not constitute active circulating metabolites, unlikely, that its concentration changes under the influence of inhibitors of P450 isoenzymes. The number of circulating metabolites accounted for the bulk of glûkuronidnye conjugates and pozakonazola a small proportion of oxidized (through the P450) metabolites.

Deduction

Excretion of metabolites through the kidneys and the intestine is approximately 17% of the administered dose.

Posaconazole is slowly eliminated from the body, average T1 / 2 is 35 no (from 20 to 66 no), and the total clearance – 32 l /. The drug is excreted primarily through the intestines (77%), the main part of the (66%) falls on the active substance. Kidney klirens is a small part of the Elimination – about 14% (the active substance is less than 0.2%).

Pharmacokinetics in special clinical situations

After applying a daily dose of posaconazole 800 mg, divided into several times, the concentration of the drug in plasma in patients aged 8-17 years was comparable to the levels in patients aged 18-64 years (average, 776 ng / ml 817 ng / ml, respectively). Pharmacokinetic data for children under 8 years not available.

In elderly people (senior 65 years) increases in Cmax 26% and AUC of 29% compared to people aged 18-45 years. However, in clinical studies, the safety performance of posaconazole in young and elderly were similar. Therefore, adjusting the dose depending on age is not required.

Pharmacokinetics pozakonazola in men and women does not differ. It is not necessary to modify the dosage depending on gender.

There was a slight (on 16%) reduction in AUC and Cmax pozakonazola at blacks. Adjusting the dose depending on race is not required.

The one-time use of pozakonazola renal failure mild (n=18, CC >20 mL/min per 1.73 m2) do not have influence on drug farmakokinetiku, Therefore, dose adjustment is this category of patients have not needed. Patients with severe renal insufficiency (n=6, CC<20 mL/min per 1.73 m2) AUC pozakonazola strongly varied (coefficient of variation 96%) in comparison with other patients with renal insufficiency (coefficient of variation <40%). But, since the renal clearance is negligible posaconazole, unlikely, that renal failure severe affect the farmakokinetiku drug, Therefore, dose adjustment is not required in this case.

In patients with hepatic insufficiency was an increase in T1 / 2 (26.6 no, 35.3 and h 46.1 no – for easy, moderate and severe hepatic insufficiency on Child-Pugh, respectively), compared to patients with normal liver function (22.1 no). In view of the limited pharmacokinetic data recommendations on dose adjustment in patients with hepatic insufficiency have not been developed.

Indications for use of the preparation NOKSAFIL

Prophylaxis of invasive fungal infections while lowering of immunity and increased risk of such infections, eg, at the hematological patients with prolonged neutropenia due to chemotherapy, as well as recipients of transplants of hematopoietic stem cells, receiving high doses of immunosupressorov.

Treatment of invasive fungal infections:

is invasive candidiasis or candidiasis of the esophagus, refrakternae to amfotericinu in, itraconazole or fluconazole, or intolerance of these drugs;

-invasive aspergillosis, refractory to amfotericinu in or itrakonazolu, or intolerance of these drugs;

— zigomikoz (mukormikoz), kryptokokkoz, refrakternae to other antifungal medicines, or intolerance;

-Fusarium wilt disease, refractory to amfotericinu in, or intolerance;

— hromomikoz and eumycetoma, refrakternae to itrakonazolu, or intolerance;

— kokcidioidoz, refractory to amfotericinu in, itraconazole or fluconazole, or intolerance of these drugs.

Refractivity considered progression of infection or lack of improvement of the patient after treatment for 7 days (when candidemia – during 3 days, candidiasis of the esophagus – during 14 days, other forms of invasive candidiasis – 7 days).

Orofaringealynogo treating candidiasis – first-line therapy in patients with severe disease or immunocompromised, which is not expected to effect substantial application of topical preparations.

Dosage regimen

The drug should be taken inside at the time of delivery. Patients, which can not combine the drug with a normal diet, to improve pozakonazola intake should take medication simultaneously with the acquisition of liquid nutritional supplements. Before use, the suspension must be thoroughly shaken.

For the prevention of invasive fungal infections drug appoint 200 mg (5 ml) 3 The duration of preventive treatment depends on the duration of neutropenia in hematological patients, or severity of immunosuppression in recipients of hematopoietic stem cell transplants. Patients with acute mieloidnym leukemia or mielodisplastičeskim syndrome Noksafilom preventive treatment should begin within a few days before the anticipated start of neutropenia and continue for 7 days after the increase in the number of neutrophils to the level of more than 500/ml.

For the treatment of invasive fungal infections, refractory to other antifungal medicines, or in rejecting other antifungal medicines appoint 400 mg (10 ml) 2 Patients, which can not take the drug with food or food additives, It is recommended to take Noksafil on 200 mg (5 ml) 4 The duration of therapy depends on the severity of the underlying disease of the patient, immunodeficiency and the effectiveness of the treatment.

For the treatment of oropharyngeal candidiasis appoint 200 mg (5 ml) 1 time / – on the first day of treatment (vvodnaya dose), then 100 mg (2.5 ml) 1 times / over the next 13 days.

For the treatment of oropharyngeal candidiasis, refrakternogo to itrakonazolu and/or fluconazole is administered 400 mg (10 ml) 2 The duration of therapy depends on the severity of the underlying disease of the patient and the efficiency of the treatment.

Increasing the dose of Noksafila more 800 mg / does not lead to more effective treatments.

When the kidneys no changes farmakokineticeskih indicators, Therefore, dose adjustment in violation of the kidney is not required.

If any of the liver relevant pharmacokinetic data limited, Therefore, the recommendations for dose adjustment in this group of patients not developed. A small number of patients with impaired liver function, an increase in T1 / 2 of posaconazole.

Side effect

Below are all connected with the treatment of adverse events, registered in research, involving 2400 patients; of them 172 the patient receive posaconazole not less than 6 Months, and 58 patients receive posaconazole not less than 12 Months.

The most frequent undesirable phenomena were nausea (6%) and headache (6%).

Serious adverse events, registered (a frequency 1% each) in patients with invasive Mycosis, included the change in the concentration of other drugs, increased liver enzymes, nausea, rash and vomiting.

Serious adverse events, registered (a frequency 1% each) patients, receiving posaconazole prophylaxis of invasive Mycosis, include giperbilirubinemiû, increased liver enzymes, hepatocyte damage, nausea and vomiting.

Registered a single case of ventricular tachycardia type development “pirouette” the patient, operating condition and multiple risk factors, which together could lead to this complication, such as arrhythmia, the recent holding of kardiotoksičeskoj chemotherapy, gipokaliemia and gipomagniemia history.

Rare cases of haemolytic uraemic syndrome and trombotičeskoj trombocitopeničeskoj Purpura were marked, mainly, patients, which in addition to treating the underlying disease received cyclosporin or Tacrolimus to prevent transplant rejection.

Side effects of pozakonazola are classified by frequency: often (>1/100, but <1/10), infrequently (>1/1000, but <1/100), rarely (>1/10 000, but <1/1000) and in descending order of severity within each frequency band.

From the hematopoietic system: often – neutropenia; infrequently – thrombocytopenia, leukopenia, anemia, eozinofilija, lymphadenopathy; rarely – hemolytic uremic syndrome, tromboticheskaya trombotsitopenicheskaya purpura, pancytopenia, coagulation failure, bleeding (unspecified).

On the part of the immune system: infrequently – allergic reactions; rarely – Stevens-Johnson syndrome, hypersensitivity reactions.

On the part of the endocrine system: rarely – adrenal insufficiency, reduction of gonadotropins.

CNS: often – paraesthesia, dizziness, drowsiness, headache; infrequently – convulsions, Neuropathy, gipesteziya, tremor; rarely – psychosis, depression, fainting, encephalopathy, perifericheskaya neuropathy.

On the part of the organ of vision: infrequently – blurred vision; rarely – diplopia, scotoma.

On the part of the organ of hearing: rarely – hearing disorder.

Cardio-vascular system: infrequently – lengthening the interval QTc / QT, abnormalities in the ECG, heartbeat, increase or decrease in blood pressure; rarely – ventricular tachycardia (incl. type “pirouette”), sudden death, cardiac arrest and respiratory, heart failure, myocardial infarction, cerebrovascular accident, pulmonary embolism, deep vein thrombosis (unspecified).

The respiratory system: rarely – pulmonary hypertension, interstitial pneumonia, pneumonitis.

From the digestive system: often – anorexia, vomiting, nausea, abdominal pain, diarrhea, dyspepsia, flatulence, dry mouth, abdominal distention, improving the performance of the liver (including ALT, ACT, bilirubin, Alkaline phosphatase, GGT); infrequently – ulceration of the mucous membrane of the mouth, pancreatitis, hepatocyte damage; rarely – gastrointestinal bleeding, bowel obstruction, hepatic failure, cholestatic hepatitis, cholestasis, hepatosplenomegaly, liver tenderness, asteriksis (liver tremor), heavy defeat liver fatal.

Dermatological reactions: often – rash; infrequently – alopecia; rarely – vesicular rash.

On the part of the musculoskeletal system: infrequently – backache.

From the urinary system: infrequently – renal failure (incl. acute), increased creatinine in the blood; rarely – interstitial nephritis, renal tubular acidosis.

On the part of the reproductive system: infrequently – menstrual irregularities; rarely – pain in the breast.

From the laboratory parameters: infrequently – change of serum concentrations of other drugs.

Other: often – fever, asthenia, fatigue, electrolyte imbalance; infrequently – giperglikemiâ, edema, weakness, pain, chills, malaise; rarely – swelling of the tongue, swelling of the face.

Contraindications for drug NOKSAFIL

-the combined use of ergot alkaloids (due to the risk of increasing the concentration of ergot alkaloids in the blood and the development ergotism);

-combined use with izofermenta CYP3A4 substrates terfenadine, astemizolom, cizapridom, pimozidom, halofantrine or quinidine (in connection with the risk of increasing concentrations of these drugs in the blood, subsequent lengthening of the interval and QTs, rarely, development of ventricular tachycardia type “pirouette”;

-combined use with inhibitors g-KOA-reduktaza simvastatinom, lovastatin, atorvastatin (in connection with the risk of increasing concentrations of these drugs in the blood and rabdomioliza);

- Hypersensitivity to any component of the drug.

The caution should appoint drug in case of hypersensitivity to other azol′nym compounds in history, with severe liver dysfunction, congenital or acquired QTc prolongation, when cardiomyopathy, especially in conjunction with heart failure, sinus bradycardia, diagnosed symptomatic arrhythmia, When coupled with drugs, prolonging the QTc interval (than those listed in section “Contraindications”), due to increased risk of heart rhythm disorders.

Application of NOKSAFIL in pregnancy and lactation

Information about the application of pozakonazola in pregnant women is not enough. Studies on animals revealed a toxic effect of the drug on fruit. The potential risk for humans is unknown.

Women of childbearing age are recommended to use effective contraception during treatment pozakonazolom.

Pozakonazola use during pregnancy is contraindicated, except, the potential benefit to the mother outweighs the risk to the fetus.

Posaconazole is the milk from lactating rats. Pozakonazola excretion in breast milk in humans has not been studied. In appointing pozakonazola breastfeeding should be discontinued.

Application for violations of liver function

The caution should be appointed in preparation in serious violation of the liver.

Cautions

Treatment should start doctor, has experience in the treatment of systemic fungal infections.

Prior to the start of treatment to get the patient stuff for microbiological and other laboratory studies with a view to identifying the causative agent of disease. Treatment can begin, without waiting to receive the results of the studies, However, after receiving them if necessary to make correction of antifungal therapy, if necessary.

No information is available about cross sensitivity between pozakonazolom and other antifungal azole compounds. Caution must be exercised in the appointment Noksafila patients with a heightened sensitivity to other azolam.

In the treatment of pozakonazolom were recorded messages of the liver (eg, light to moderate increase in the level of ALT, ACT, ALP and total bilirubin in serum) during treatment with posaconazole. These reactions are observed, mainly, in patients with severe underlying diseases (eg, hematological), and they were not grounds for termination of therapy. Improving indicators of liver function tests were reversible and ends after cessation of therapy, and in some cases there is a normalization of functional parameters to discontinuation of therapy. In rare cases, developed a severe reaction from the liver fatal. Care should be taken when appointing posaconazole to patients with severe hepatic impairment. In these patients the lengthening of the half-life of the drug could lead to the strengthening of its action.

Patients, with Noksafilom therapy observed liver according to laboratory studies, should be under the supervision of clinical development for the prevention of more serious damage to the liver. Monitoring should include laboratory monitoring of liver function (in particular, determination of ALT, ACT, ALP and total bilirubin in serum).

Some azol′nye compounds are causing elongation QT interval. There should be Noksafil together with drugs, non-substrate for izofermenta CYP3A4 and extension QT interval. Caution must be exercised in the appointment Noksafila patients with a high risk of cardiac arrhythmias, eg:

is congenital or acquired QT interval extension;

— If you have cardiomyopathy, especially in conjunction with heart failure;

— with sinus bradycardia;

— when diagnosed symptomatic arrhythmias;

-When taking medications, prolonging the QT interval (except as provided in section “Contraindications”).

Electrolyte balance should be monitored, especially the potassium content, magnesium and calcium, and optionally, produce correction before and during therapy, pozakonazolom.

Posaconazole is inhibitor izofermenta CYP3A4 and, if the patient is already taking drugs, metaboliziruemye izofermentom CYP3A4, the posaconazole should only apply in special circumstances.

The concentration of pozakonazola can significantly decrease when used in combination with antibacterial means, rifamicinovymi (rifampicin, rifabutin), anticonvulsants (phenytoin, Carbamazepine, phenobarbital, prymydon) and cimetidine. Therefore, you should avoid their joint application with pozakonazolom, If the benefits of joint use does not exceed the risk to the patient.

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

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

Use in Pediatrics

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

Effects on ability to drive vehicles and management mechanisms

Data on the impact of Noksafila on the ability to drive and other mechanisms are not available.

Overdose

Patients, received posaconazole doses up to 1600 mg /, not identify additional adverse events compared with those, who received lower doses. Accidental overdose was noted in one patient, who took the drug for 1200 mg 2 during 3 days. Adverse events, associated with overdose, this patient was not observed.

Posaconazole is not rendered using hemodialysis.

Drug Interactions

Posaconazole metaboliziruetsя putem glюkuronirovaniя UDF (enzymatic reaction phase II) and the substrate for removing the p-glycoprotein in vitro. Thus, inhibitors (eg, verapamil, cyclosporine, quinidine, clarithromycin, Erythromycin) or inductors (eg, rifampicin, rifabutin, certain anticonvulsants) This pathway may be increased or decreased, respectively, plasma concentrations of posaconazole.

Efavirenz (400 mg 1 time /) reduces the plasma Cmax and AUC for pozakonazola on 45% and 50% respectively. You should avoid using pozakonazola and èfavirenza, If the benefits of such use does not exceed his risk for a given patient.

Rifabutin (300 mg 1 time /) reduces the Cmax and AUC for pozakonazola on 57% and 51%, respectively. Avoid joint use of posaconazole and rifabutin and similar inducers (eg, rifampicin), if the benefits of a joint application does not exceed its risks for the patient.

Phenytoin (200 mg 1 time /) reduces the Cmax and AUC for pozakonazola on 41% and 50%, respectively. Avoid joint use of posaconazole and phenytoin and similar inducers (eg, karʙamazepina, fenoʙarʙitala, prymydona), if the benefits of a joint application does not exceed its risks for the patient.

Pozakonazola concentration in plasma (Cmax and AUC) may decline to 39%, If posaconazole is introduced together with cimetidine (400 mg 2). The effect is associated with a decrease in removals, probably, secondary to decrease gastric acidity. You should avoid combined use of pozakonazola and cimetidine, if the benefits of a joint application does not exceed its risks for the patient. The influence of other blocking gistaminovykh H2-receptor antagonists or inhibitors protonovoj pumps, capable of reducing the acidity of gastric juice for a few hours, at pozakonazola level in plasma is not known, however, due to a possible decrease posaconazole bioavailability should be, possibly, Avoid combining it with these drugs.

Posaconazole is a CYP3A4 inhibitor. The introduction in the dose posaconazole 200 mg 1 time/increases (AUC) midazolama – the CYP3A4 substrate – on 83% after / in the. Caution must be exercised in the joint appointment and pozakonazola izofermenta CYP3A4 substrates, input / in, This might require lower doses izofermenta CYP3A4 substrates. Influence of pozakonazola on the concentration of plasma izofermenta CYP3A4 substrates in their oral not known, but can be expected, that it will be much more pronounced, than with on / in a substrate. If used in conjunction with posaconazole oral izofermenta CYP3A4 substrates, that at higher concentrations in plasma can cause serious adverse effects, You should carefully monitor the level of substrates izofermenta CYP3A4 in the blood and monitor possible adverse events and, if necessary, reduce their dose.

The combined use of terfenadine, astemizola, cisapride, pimozida, halofantrine or quinidine is contraindicated with posaconazole, tk. may lead to increased concentrations of these drugs in plasma, followed QT prolongation and, rarely, development of ventricular tachycardia type “pirouette”.

Posaconazole may increase the blood concentration of ergot (ergotamine and dihydroergotamine), which can lead to poisoning – ergotism. Joint application of alkaloids lpv and pozakonazola counter.

Posaconazole may substantially increase the blood concentration of HMG-CoA reductase (eg, simvastatin, lovastatin and atorvastatin), which are metabolized by the CYP3A4 isoenzyme. During treatment with posaconazole receiving HMG-CoA reductase inhibitors should be discontinued, because increasing the concentration of these substances in the blood is associated with the development of rhabdomyolysis.

Posaconazole may increase the blood concentration of vinca alkaloids (eg, vincristine and vinblastine), which can cause neurotoxic reaction. Therefore, you should avoid using pozakonazola and vinca alkaloids, If the benefits of combination therapy does not exceed its risk to the patient. If necessary, the joint use of these drugs is recommended to adjust the dose of vinca alkaloid.

Posaconazole increases Cmax and AUC rifabutin at 31% and 72%, respectively. You should avoid using pozakonazola and rifabutin, If the benefits of combination therapy does not exceed its risk to the patient. In a joint application of these drugs is recommended to carefully monitor the blood count and the presence of side effects, related to the high concentration of rifabutin (eg, uveitis).

Patients, heart transplant and receiving a stable dose of cyclosporine, posaconazole dose 200 mg 1 time/increases the concentration of Cyclosporine in the blood, which requires a reduction of dose. In studies on the clinical efficacy have been reported cases of serious side effects, caused an increase in the blood concentration of cyclosporin, including nephrotoxic reactions and one case of fatal leukoencephalopathy. It is recommended to monitor levels of cyclosporine in the blood before starting treatment with posaconazole, during treatment and after its termination, adaptïrwya, if necessary, dose cyclosporine.

Posaconazole increases Cmax and AUC of tacrolimus (single dose – 50 ug / kg body weight) on 121% and 358%, respectively. In studies on the clinical efficacy have been reported cases of clinically significant drug interactions, require hospitalization and / or discontinuation of posaconazole. In the appointment of posaconazole to patients, receiving tacrolimus, the last dose should be reduced (eg, to 1/3 the current dose). After the start of the joint use of drugs and at the end of the use of posaconazole should carefully monitor the level of tacrolimus in the blood and, if necessary, adjust the dose.

In healthy volunteers the use of posaconazole (400 mg 2 during 16 days) increases Cmax and AUC of sirolimus (2 mg 1 time /) on average 6.7 times 8.9 times, respectively,. When prescribing treatment pozakonazolom patients, host Sirolimus, the last dose should be reduced (eg, to 1/10 from the received dose). Thus 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 treatment with posaconazole, during treatment and after its termination, korrektiruя, if necessary, the dose of sirolimus.

Clinical studies have shown no clinically significant interaction between zidovudine, lamivudine, ritonavir and indinavir with posaconazole, in connection with correcting their dosage is not required.

Antiretroviral drugs (non-nucleoside reverse transcriptase inhibitors) izofermenta CYP3A4 substrates are, can be expected, that increases these posaconazole antiretroviral drugs in the blood. Patients, taking these drugs together with posaconazole, should be under close clinical observation to identify possible toxic reactions.

Since HIV protease inhibitors are substrates of CYP3A4, can be expected, that increases these posaconazole antiretroviral drugs in the blood. In healthy volunteers the use of posaconazole (400 mg 2 during 7 days) increases Cmax and AUC of atazanavir (300 mg 1 time / within 7 days) on average 2.6 times and 3.7 fold, respectively. The use of posaconazole in healthy volunteers (400 mg 2 during 7 days) increases Cmax and AUC of atazanavir to a lesser extent when coadministered with ritonavir (300 mg atazanavir + 100 mg ritonavir 1 time / within 7 days) – on average 1.5 times and 2.5 fold, respectively. Patients, taking these drugs together with posaconazole, should be under close clinical observation to identify possible toxic reactions.

Application of pozakonazola in dose 200 mg 2 during 7 days increases the Cmax and AUC of Midazolam (400 mcg/in 1 time /) on average 1.3 times and 4.6 fold, respectively. Application of pozakonazola in dose 400 mg 2 during 7 days increases the Cmax and AUC of Midazolam (When it is on/in the introduction) in 1.6 times and 6.2 fold, respectively. Both dosage pozakonazola increase the Cmax and AUC of Midazolam, applied inside the dose 2 mg 1 time /, in 2.2 times and 4.5 fold, respectively. Besides, application of pozakonazola in doses 200 mg 400 mg increases the T1/2 of Midazolam around with 3-4 h to 8-10 h when. Caution must be exercised when prescribing benzodiazepines, which are metabolized by the CYP3A4 isoenzyme, patients, receive posaconazole.

In a joint application with posaconazole it is often recommended to control the side effects and toxic reactions, associated with the action of calcium channel blockers, metaboliziruemye izofermentom CYP3A4 (eg, diltiazem, verapamil, nifedipine, nisoldipine) and, if necessary, adjust the dose of these drugs.

The introduction of other azoles has been accompanied by increased content of Digoxin. Therefore, posaconazole may also increase the concentration of digoxin in the blood, in this connection, should control the level of co-administering with posaconazole and after combination therapy.

Some healthy volunteers in the combined use of posaconazole and glipizide decreased glucose. It is recommended to monitor blood glucose levels in diabetic patients, receiving sulfonylureas and posaconazole.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children at or above 25 ° C; Do not freeze. Shelf life – 2 year.

After opening the bottle the drug should be used within 4 weeks. Do not use beyond the expiration date.