Posaconazole - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Antifungal means

Included in the formulation

Noxafil®

suspension inwards

Schering-Plau S.A. France

АТХ:

J.02.A.C Triazole derivatives

J.02.A.C.04 Posaconazole

Pharmacodynamics:

Antifungal agent. The triazole derivative exhibits an antifungal effect by blocking the biosynthesis of the ergosterol of the fungal cell membrane. "Target" for the action of the drug is the enzyme 14-α-demethylase.

14-α-demethylase is part of a group of enzymes known collectively cytochrome P450. All enzymes of the cytochrome P450 group contain a hematinic iron-containing pigment. Posaconazole binds to the iron atom of the hematinic group and inactivates 14-α-demethylase, which leads to a disruption in the synthesis of ergosterol and the accumulation of lanosterol and other sterols. Their incorporation into the membrane instead of ergosterol significantly disrupts the structure and function of the fungal cell membrane.

The decrease in the synthesis of ergosterol, as well as the accumulation of 14α-methylsterols, destroys the densely packed acyl chains of the phospholipids of the fungal membranes. Destabilization of the fungal membrane leads to dysfunction of membrane enzymes, including those involved in the electron transport chain, and ultimately to cell death.

Used in systemic mycosis: candidosis, cryptococcosis, blastomycosis, histoplasmosis, coccidioidomycosis, as well as dermatomycosis. The drug is active against Candida (FROM. albicans, FROM. glabrata, FROM. krusei, FROM. parapsilosis, FROM. lusitaniae), Aspergillus (A. fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus, A. ochraceus), Absida 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:

The drug is absorbed within 3-5 hours. The change in pH of gastric contents does not affect the absorption of posaconazole. Compared to fasting, the AUC of posaconazole when taken with low-fat food or food additives (14 grams of fat) is increased by about 2.6 times, and when taken with fatty foods (about 50 grams of fat), 4 times. Metabolized in the liver, half-life is 35 hours, excreted by the kidneys and gastrointestinal tract.

Indications:

Treatment and prevention of fungal infections that are caused by susceptible to the species of fungi: andnasal candidiasis, esophageal candidiasis, resistant to amphotericin B, itraconazole, fluconazole or with their intolerance; invasive aspergillosis, resistant to amphotericin B, itraconazole or when intolerant; zygomycosis (mukormikoz), cryptococcosis, resistant to other antifungal agents or with their intolerance; Fusarium, resistant to amphotericin B or with its intolerance; Chromomycosis and mycetoma, resistant to itraconazole or with its intolerance; coccidioidosis resistant to amphotericin B, itraconazole, fluconazole or when intolerant.Severe oropharyngeal candidiasis (first-line therapy), including in patients with reduced immunity, with possible ineffectiveness of topical agents. Prevention of invasive fungal infections (with a decrease in immunity in hematological patients with prolonged neutropenia due to chemotherapy, as well as in transplant recipients of hematopoietic stem cells receiving high doses of immunosuppressants).

ICD-10

I.B35-B49.B37.0 Candidiasis stomatitis

I.B35-B49.B37.1 Pulmonary Candidiasis

I.B35-B49.B37.2 Candidiasis of skin and nails

I.B35-B49.B37.3 Candidiasis of the vulva and vagina (N77.1 *)

I.B35-B49.B37.4 Candidiasis of other urogenital localizations

I.B35-B49.B37.6 Candidiasis endocarditis (I39.8 *)

I.B35-B49.B37.7 Candida septicemia

I.B35-B49.B37.8 Candidiasis of other localizations

I.B35-B49.B38 Coccidioidomycosis

I.B35-B49.B43 Chromomycosis and pheomycotic abscess

I.B35-B49.B44 Aspergillosis

I.B35-B49.B45 Cryptococcosis

I.B35-B49.B46 Zygomycosis

I.B35-B49.B47 Mycetoma

I.B35-B49.B49 Mycosis, unspecified

XXI.Z40-Z54.Z51.1 Chemotherapy for neoplasm

XXI.Z80-Z99.Z94.8 Presence of other transplanted organs and tissues

Contraindications:

Pregnancy and lactation

Joint application with ergot alkaloids (in connection with the risk of increasing the concentration of ergot alkaloids in the blood and the development of ergotism)

Co-administration with substrates CYP3A4-terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine (due to the risk of increasing the concentration of active substances in the blood, the subsequent prolongation of the QTc interval, and in rare cases, the development of ventricular arrhythmia such as "pirouette"

Joint use with inhibitors of HMG-CoA reductase - simvastatin, lovastatin and atorvastatin (due to the risk of increasing concentrations of these drugs in the blood and the development of rhabdomyolysis.

Malabsorption syndrome (for LF-containing glucose).

Hypersensitivity to posaconazole.

Carefully:

Hypersensitivity to azole compounds in the anamnesis
Severe liver dysfunction
Interval lengthening QT or simultaneous use of drugs that extend QT interval (except those listed above) in connection with an increased risk of heart rhythm disturbances.
Sinus bradycardia
Symptomatic arrhythmia

Pregnancy and lactation:

Category by FDA - C. Do not use when pregnant and breast-feeding.

The use of the drug during pregnancy is possible only if the intended benefit to the mother exceeds the potential risk to the fetus.If you need to use the drug during lactation, you should decide whether to stop breastfeeding.

Dosing and Administration:

Inside 400 mg 2 times a day or 200 mg 4 times a day. The dosage regimen and the duration of the course of treatment are determined individually by the attending physician in accordance with the diagnosis and individual characteristics of the patient.

For treatment invasive fungal infections appoint 400 mg twice a day. Patients who can not take the drug with food or food additives, it is recommended to appoint 200 mg 4 times a day. The duration of therapy depends on the severity of the patient's underlying illness, the severity of immunodeficiency, and the effectiveness of the treatment.

For treatment of oropharyngeal candidiasis on the first day of treatment, 200 mg once a day (initial dose), then 100 mg once a day for the next 13 days.

For treatment of oropharyngeal candidiasis, refractory to itraconazole and / or fluconazole appoint 400 mg twice a day. The duration of therapy depends on the severity of the patient's underlying illness and the effectiveness of the treatment.

An increase in the dose of posaconazole over 800 mg per day does not lead to an increase in the effectiveness of treatment.

For prevention of invasive fungal infections appoint 200 mg 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. Patients with acute myeloid leukemia or myelodysplastic syndrome should receive prophylactic treatment several days before the expected onset of neutropenia and continue for 7 days after an increase in the number of neutrophils to a level of more than 500 / μl.

Side effects:

From the side blood: thrombocytopenia, neutropenia, eosinophilia, anemia, bleeding, thrombocytopenic purpura, pancytopenia, impaired blood clotting.

From the side nervous system: paresthesia, fainting, convulsions, neuropathy, blindness of sight, hearing impairment, scotoma, diplopia, encephalopathy, tremor, hypoesthesia, depression, psychosis.

From the side gastrointestinal tract: vomiting, abdominal pain, dyspepsia, dry mouth, anorexia, pancreatitis, ulceration of the oral mucosa, intestinal obstruction, cholestatic hepatitis, hepatosplenomegaly, liver soreness, nausea, diarrhea, flatulence, bloating, increased bilirubin content in the blood, damage to hepatocytes, gastrointestinal bleeding, hepatic insufficiency, cholestasis, asterixis (hepatic tremor).

From the side musculoskeletal system: back pain.

From the side respiratory system: pneumonitis, pulmonary hypertension, interstitial pneumonia.

From the side of cardio-vascular system: interval lengthening QTc/QT, palpitation, ventricular arrhythmia such as "pirouette", ventricular tachycardia, heart failure, cerebral circulation disorder, ECG changes, increase or decrease in blood pressure, sudden death, cardiac and respiratory arrest, myocardial infarction, pulmonary embolism, deep vein thrombosis (unspecified).

From the side genitourinary system: renal failure, interstitial nephritis, menstrual irregularities, acute renal failure, increased serum creatinine, renal tubular acidosis, tenderness of the mammary glands.

Other: fever, fatigue, weakness, chills, tongue edema, allergic reactions, hyperglycemia, asthenia, swelling, pain, malaise, face swelling,violation of electrolyte balance.

Overdose:

Not described.

Interaction:

Cimetidine reduces the concentration of the drug in the blood.

Do not use simultaneously with efavirenz, everolimus, pimozide, halofantrine.

The drug slows the excretion of other drugs,which are metabolized by the enzyme CYP3A47 (increases their maximum concentration in plasma): atazanavir, atorvastatin (risk of rhabdomyolysis), Bosutinib, vemurafenib, vinblastine (can cause neurotoxic reactions), vincristine (can cause neurotoxic reactions), vismodegib, dihydroergotamine (risk of ergotism development), digoxin, diltiazem, Lachinimod, lovastatin (risk of rhabdomyolysis), midazolam, nifedipine, ranolazine, rilpivirine, simvastatin (risk of rhabdomyolysis), sirolimus, tacrolimus, ergotamine (risk of development of ergotism), etravirine.

Joint use of astemizole, quinidine, cisapride or terfenadine (isoenzyme substrates CYP3A4) with pozakonazolom contraindicated, since it can lead to an increase in the concentration of astemizole, quinidine, cisapride or terfenadine in plasma with subsequent lengthening of the interval QT and in rare cases, the development of pirouette ventricular tachycardia.

In some healthy volunteers, when glipizide and postazonazole were combined, there was a decrease in glucose concentration. It is recommended to monitor the concentration of glucose in the blood in diabetic patients receiving glipizide and posaconazole.

The combined use of posaconazole and carbamazepine should be avoided - inductor P450, if the benefits of joint application do not exceed its risk for a particular patient.

Posaconazole is metabolized by glucuronidation of uridine-5'-diphosphate (enzymatic phase II reaction) and is a substrate for excretion by P-glycoprotein in vitro. Thus, clarithromycin , erythromycin - an inhibitor of P-glycoprotein - may increase the concentration of posaconazole in plasma.

The combined use of posaconazole and primidone, the P450 inducer, should be avoided if the benefits of joint application do not exceed its risk for a particular patient.

Posaconazole is metabolized by glucuronidation of uridine-5'-diphosphate (enzymatic reaction of the II phase) and is a substrate for excretion by P-glycoprotein in vitro. In this way, rifabutin - inducer of P-glycoprotein - can reduce the concentration of posaconazole in plasma. Rifabutin (300 mg once a day) reduces C_max and AUC pozanazol by 57 and 51% respectively. Posaconazole enhances C_max and AUC rifabutin by 31 and 72%, respectively. The combined use of posaconazole and rifabutin should be avoided if the benefits of combination therapy do not exceed its risk for the patient. When these drugs it is recommended to carefully monitor the cellular composition of the blood and the presence of side effects associated with an increased concentration of rifabutin (eg, uveitis).

Phenytoin (200 mg once a day) reduces C_max and AUC pozakozol by 41 and 50% respectively.The combined use of posaconazole and phenytoin - the P450 inducer should be avoided if the benefits of joint application do not exceed its risk for a particular patient.

The combined use of posaconazole and phenobarbital, the P450 inducer, should be avoided if the benefits of joint application do not exceed its risk for a particular patient.

The combined use of fosamprenavir and posaconazole may lead to a decrease in the concentration of posaconazole in the blood plasma. If joint use is required, it is recommended that the possible development of a fungal infection be carefully monitored. Repeated use of fosamprenavir (700 mg twice a day × 10 days) reduces C_max and AUC pozakonazola.

In the case of pozaconazole, together with cimetidine (400 mg twice daily), C_max and AUC Posaconazole may be reduced by 39%. The effect is associated with a decrease in absorption, probably secondary to a decrease in the acidity of gastric juice. Joint use of posaconazole and cimetidine should be avoided if the benefits of sharing do not exceed its risk for a particular patient.

Efavirenz (400 mg once a day) reduces C_max and AUC pozakonazola by 45 and 50% respectively. Joint use of posaconazole and efavirenz should be avoided if the benefits of such use do not exceed its risk for a particular patient.

Special instructions:

Treatment can begin without waiting for the results of a microbiological study, but after receiving them, an adequate correction of antifungal therapy should be made.

It is necessary to control the electrolyte balance, especially the content of potassium, magnesium and calcium, and if necessary, make an appropriate correction before and during therapy with posaconazole.

Data on the pharmacokinetics in patients with severe dysfunction of the digestive tract, which may lead to lower concentration of posaconazole blood (e.g., severe diarrhea or vomiting) are limited. These patients should be carefully monitored for the timely detection of possible activation of fungal infection.

Impact on the ability to drive vehicles and manage mechanisms not found.

Instructions

Posaconazole (Posaconazolum)