Eraksis® (Eraxis®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAnidulafunginAnidulafungin
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  • Eraksis®
    lyophilizate d / infusion 
    Pharmacy and Upjohn Campani     USA
    • Dosage form: & nbsplyophilizate for the preparation of concentrate for the preparation of a solution for infusions
    Composition:

    1 bottle contains:

    active substance: Anidulafungin fructose-stabilized 122 mg in terms of anidulafungin 100 mg

    Excipients: fructose 102.5 mg, mannitol 512.5 mg, polysorbate 80 256.3 mg, tartaric acid 11.5 mg.

    Description:

    White or almost white lyophilized mass.

    Pharmacotherapeutic group:antifungal agent for systemic use
    ATX: & nbsp

    D.01.B.A   Antifungal drugs for systemic use

    J.02.A.X.06   Anidulafungin

    Pharmacodynamics:

    Anidulafungin is a semisynthetic echinocandin, a lipopeptide synthesized from the fermentation product of Aspergillus nidulans.

    Anidulafungin selectively inhibits 1,3-B-D glycan synthetase, an important component of the fungal cell wall. In mammalian cells, 1,3-B-D glycogen synthase is absent. Determined that anidulafungin has fungicidal activity against Candida spp., and also suppresses cell growth of Aspergillus fumigatus.

    In vitro activity

    Anidulafungin is sensitive to Candida spp., including C. albicans, FROM. glabrata, FROM. krusei, FROM. parapsilosis, FROM. tropicalis, FROM. dubliniensis, FROM. lusitaniae and FROM. guiUiermondii, a also Aspergillus spp., including A. fumigatus, A. flavus, A. niger and A. terreus. Anidulafungin is active against mycosis pathogens, resistant to antifungal drugs of other classes.

    The MIC was determined according to the standard CLSI method of M27 and M38 for yeast. The relationship between the activity of anidulafungin in vitro and the clinical result is not established.

    In vivo activity

    In the experiment anidulafungin, parenterally administered was effective against Candida spp. Both with normal and with impaired immunity. Treatment with anidulafungin increased survival, and also reduced Candida spp. defeat of organs. In the experiment, a disseminated infection caused by C. albicans, fluconazole-resistant esophageal candidiasis / oral cavity caused by C. albicans, as well as a fluconazole-resistant disseminated infection caused by C. glabrata was modeled in the experiment. Anidulafungin was also effective in experimental aspergillosis caused by Aspergillus fumigatus.

    Combination with other antifungal agents

    In vitro studies have shown that anidulafungin in combination with fluconazole, itraconazole and amphotericin B, is not an antagonist of these preparations for strains of Candida spp. The clinical significance of these results is unknown.

    In-vitro studies assessed the sensitivity of Aspergillus spp. To anidulafungin in combination with itraconazole, voriconazole, and amphotericin B. When the combination of anidulafungin and amphotericin B was combined, there was no interaction between the preparations in 16 of the 26 isolates, while 18 of 26 isolates showed synergy with the combination of anidulafungin with itraconazole or voriconazole. The clinical significance of these results is unknown.

    Pharmacokinetics:

    General pharmacokinetic characteristics

    Anidulafungin with a single administration has a linear pharmacokinetics in a wide range of daily doses (from 15 mg to 130 mg).

    The coefficient of variability of the area under the pharmacokinetic concentration-time curve (AUC) for healthy volunteers, patients and in special groups of study patients was about 25%. The equilibrium state was achieved on the first day after administration of the saturating dose (twice the maintenance dose).

    Distribution

    Anidulafungin is rapidly distributed in the body tissues (the half-absorption time is about 0.5-1 hour). The volume of distribution is about 30-50 liters, which is approximately equal to the total volume of fluid in the body. Anidulafungin largely binds to blood plasma proteins (binding rate> 99%).

    Metabolism

    Metabolism of anidulafungin in the liver is not established. Because the anidulafungin is not a clinically relevant substrate, inducer or inhibitor of cytochrome P450 isoenzymes, it is unlikely that anidulafungin has a clinically significant effect on the metabolism of drugs, which occurs with the participation of the cytochrome P450 system.

    At physiological values ​​of temperature and pH anidulafungin undergoes slow chemical degradation, turning into a peptide with an open ring, devoid of antifungal activity. The half-life of anidulafungin under physiological conditions is approximately 24 hours. In vivo, the peptide with an open ring is sequentially cleaved to other peptides and is eliminated, mainly by excretion with bile.

    Excretion

    The clearance of anidulafungin is about 1 l / h. The half-life (T1 / 2) is about 24 hours, and the terminal half-life is 40-50 hours.

    In a clinical study on healthy volunteers using a single dose (about 88 mg) of radiolabelled carbon (14C) anidulafungin,that about 30% of the administered dose was eliminated by the intestine within 9 days, the share of unchanged product being less than 10%. Less than 1% of the administered labeled drug was excreted by the kidneys. After 6 days after taking the drug, the concentrations of anidulafungin decreased below the detection limit. After 8 weeks after taking the drug, its concentrations in blood, urine and feces were negligible.

    Special patient groups

    Patients with fungal infections

    According to the population pharmacokinetic analysis of the pharmacokinetics of anidulafungin in patients with fungal infections is similar to that in healthy individuals. In the range of daily doses from 100 mg to 200 mg and at an infusion rate of 1 mg / min, the maximum equilibrium concentration (Cmah) and the minimum concentration (Cmin) constitute about 7 mg / l and 3 mg / l, respectively, and average equilibrium AUC - about 110 mg-hr / L.

    The weight

    The patient's weight practically does not affect the pharmacokinetics of anidulafungin.

    Floor

    The concentrations of anidulafungin in the plasma of healthy men and women were similar. In studies using several doses of anidulafungin, it was shown that in men the clearance of anidulafungin is somewhat accelerated (approximately 22%).

    Elderly patients

    In elderly people (patients> 65 years old, average clearance 1.07 l / h), according to the population pharmacokinetic analysis, the average clearance of anidulafungin differs somewhat from that in other age groups (patients <65 years, average clearance 1.22 L / hour), while the variations in the values ​​of the clearance of anidulafungin were similar.

    HIV-infected patients

    Correction of the dose in HIV-infected patients with different types of antiretroviral therapy is not required.

    Lack of liver function

    Anidulafungin is not metabolized in the liver. The concentration of anidulafungin in blood plasma in patients with hepatic insufficiency of any degree (classes A, B and C according to the Child-Pugh classification) did not increase. Although a slight decrease in AUC was observed in patients with severe hepatic insufficiency (class C according to the Child-Pugh classification), it did not go beyond the limits of values ​​in healthy volunteers.

    Lack of kidney function

    Anidulafungin is practically not excreted by the kidneys (clearance <1%). In clinical studies in patients with mild, moderate, severe, or terminal stage of renal failure, the pharmacokinetics of anidulafungin were similar to those in patients with normal renal function. Anidulafungin It is not excreted during hemodialysis and it can be used regardless of the time of hemodialysis.

    Children

    The pharmacokinetics of anidulafungin were studied in 24 immunocompromised children (2 to 11 years) and adolescents (12 to 17 years old) with symptoms of neutropenia. The equilibrium state was achieved on the first day after administration of the saturating dose (or twice the maintenance dose), and the equilibrium Cmah and AUCss increased in a dose-dependent manner. After administration of the drug in daily maintenance doses of 0.75 mg / kg / day and 1.5 mg / kg / day for children aged 2 to 17 years, the systemic indicators were comparable to those in adults when administered at doses of 50 mg / day and 100 mg / day, respectively.

    Indications:

    Invasive candidiasis, including candidemia

    Candidiasis of the esophagus

    Contraindications:

    Hypersensitivity to anidulafungin or other components of the drug

    Hypersensitivity to other drugs of the class of echinocandins (for example, to aspofungin)

    Carefully:

    Action on the liver

    Laboratory signs of liver dysfunction were observed in healthy individuals and patients taking anidulafungin. Significant abnormalities of liver function were observed in patients with serious diseases that received along with anidulafungin concomitant therapy with other drugs.Individual cases of severe hepatic insufficiency, hepatitis or exacerbation of liver failure have been described, but the association of these disorders with the intake of anidulafungin has not been established. Patients who developed liver failure during the treatment with anidulafungin should be carefully monitored and the decision to continue therapy with anidulafungin should be taken after an assessment of the risk-benefit ratio.

    Pregnancy and lactation:

    In experimental studies, the reproductive toxicity of anidulafungin was not detected. The possible risk to man is unknown. There are no data of controlled studies on the use of anidulafungin in pregnant women.

    Therefore, in pregnancy anidulafungin It should be used only if the expected benefit for the mother clearly exceeds the potential risk to the fetus.

    On experimental models it is shown that anidulafungin is excreted with milk. It is not known whether anidulafungin with breast milk in women. The decision to continue / stop therapy with anidulafungin should be taken in consideration of the benefits of breastfeeding for the baby and the benefits of ani- dulafungin treatment for the mother.

    Dosing and Administration:

    Prior to the initiation of therapy, a material for sowing and other laboratory tests (including histological examination) should be obtained to isolate and identify the causative agent of the disease. Treatment can begin before obtaining the results of laboratory studies. However, after receiving these results, it is necessary to adjust the antifungal therapy.

    The drug Eraksis® is administered intravenously.

    The infusion rate should not exceed 1.1 mg / min, which is equivalent to 1.4 ml / min for a dosage of 100 mg.

    The minimum duration of infusion is 90 minutes.

    Invasive candidiasis, including candidemia

    In the first day the preparation Eraksis® is administered once in a dose of 200 mg, then in a dose

    100 mg / day. The duration of treatment depends on the patient's clinical response. Antifungal therapy should be continued at least 14 days after the disappearance of symptoms of infection and eradication of the pathogen.

    Candidiasis of the esophagus

    On the first day, Eraksis® is administered once in a dose of 100 mg, then in a dose of 50 mg / day. The duration of treatment depends on the clinical response of the patient and is at least 14 days, and at least 7 days after the disappearance of the symptoms of infection.At a risk of recurrence of esophageal candidiasis in patients with HIV infection, it should be determined the need for anti-relapse antifungal therapy after the course of treatment with anidulafungin.

    Instructions for preparing a solution for infusions

    Eraksis® is available in single-use vials.

    Eraxis® should be reconstituted with water for injection and then diluted ONLY with 0.9% sodium chloride solution for infusion or 5% dextrose solution for infusion.

    ATTENTION: the compatibility of the reconstituted anidulafungin with other drugs for intravenous administration, as well as solutions, is unknown.

    Recovery

    Under aseptic conditions, 30 ml of water for injection is added to the vial and a solution is obtained containing anidulafungin in a concentration of about 3.33 mg / ml. Recovery may take about 5 minutes.

    The reconstituted solution can be stored at 25 ° C for 24 hours.

    When detecting visible particles and / or visible staining, the solution should be destroyed.

    Breeding and infusion

    In aseptic conditions, the reconstituted solution is transferred from the vial into the infusion bag (or vial) containing 0.9% sodium chloride solution for infusion or 5% dextrose solution for infusion to achieve the required concentration of anidulafungin.The table below shows the required volumes of solution and solvent, as well as the infusion rate and the minimum duration of infusion.

    The ready-made infusion solution should be stored at 25 ° C and used within 48 hours.

    Preparation of a solution for infusions

    Doziro

    the

    The required volume was restored

    The required volume of diluent A

    Full

    amount

    infusion

    of the

    solution

    at

    Skor

    awn

    infu

    the

    Min and small prodolzhitel

    100 mg

    30 ml

    100 ml

    130 ml

    1,4

    ml / mi

    90

    mines

    A 0.9% solution of sodium chloride for infusion or 5% solution of dextrose for infusions

    at The concentration of the solution for infusion is about 0.77 mg / ml.

    Lack of liver function

    In patients with mild, moderate and severe hepatic insufficiency (classes A, B and C according to the Child-Pugh classification), correction of the dose of Eraxis® is not required.

    Lack of kidney function

    In patients with any degree of renal failure, including patients receiving hemodialysis, correction of the dose of Eraxis® is not required. The drug can be used regardless of the time of hemodialysis.

    Special patient groups

    Depending on their age, sex, weight, race, and presence of HIV infection, correction of the Eraxis® dose is not required in adults.

    Application in children and adolescents

    The experience of using Eraksis ® in children is limited. Use in children under 18 years of age is not recommended except when the potential benefit of the application exceeds the possible risk.

    Side effects:

    According to clinical studies, adverse events observed with the use of Eraksis ® were mild or moderate and rarely led to withdrawal of the drug.

    Influenza-related adverse events included rashes, urticaria, "hot flashes", itching, shortness of breath, bronchospasm and arterial hypotension.

    The following undesirable phenomena associated with the use of the drug were classified according to frequency: frequent (> 1/100, <1/10); infrequent (> 1/1000, <1/100), the frequency is unknown (data from postmarketing studies).

    Infections Infrequent: fungemia, colitis associated with Clostridium difficile, candidiasis of the oral cavity.

    Metabolic disorders Frequent: hyperkalemia, hypokalemia, hypomagnesemia.Infrequently: hyperglycemia, hypercalcemia, hypernatremia.

    From the side of the cardiovascular system Frequent: "tides" of blood to the skin of the face. Infrequent: atrial fibrillation, sinus arrhythmia, ventricular extrasystole, right bundle branch blockade; thrombosis, arterial hypertension, sensation of fever.

    From the gastrointestinal tract Frequent: diarrhea, increased bilirubin concentration, increased activity of gamma-glutamyltransferase, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase. Infrequent: pain in the upper abdomen, vomiting, involuntary defecation, nausea, constipation, cholestasis.

    On the part of the system of hematopoiesis and lymphatic system Frequent: thrombocytopenia, coagulopathy. Infrequent: thrombocytosis.

    From the side of the nervous system Frequent: convulsions, headache.

    From the side of the musculoskeletal system and connective tissue: Infrequent: pain in the back.

    From the skin and subcutaneous tissues Frequent: rash, hives. Infrequent: itching, generalized urticaria.

    From the side of the organ of sight Infrequent: pain in the eyes, visual impairment, blurred vision.

    On the part of the respiratory system Frequency is unknown: bronchospasm.

    From the side of the immune system Frequency is unknown: anaphylactic shock, anaphylactic reactions.

    General and local reactions Infrequent: pain in place of infusion.

    Laboratory indicators Frequent: decrease in the number of platelets, increased serum creatinine concentration, prolongation of the QT interval on the ECG. Infrequent: a decrease in the concentration of magnesium and potassium in the serum, an increase in the number of platelets, an increase in the concentration of urea in the blood serum, increased activity of amylase, lipase in the blood serum, changes in the ECG.

    In the safety report, based on a complete clinical study (Phase II and Phase III, 669 patients), the following adverse events (all of them infrequent,> 1/1000, <1/100): neutropenia, leukopenia, anemia, hyperuricemia, hypocalcemia, hyponatremia hypoalbuminemia, hypophosphatemia, agitation, delirium, confusion, auditory hallucinations, dizziness, paresthesia, demyelination of the central sections of the variolium bridge, taste change, Guillain-Barre syndrome, tremor, visual impairment, deafness in one ear, phlebitis, n superficial thrombophlebitis, arterial hypotension, lymphangitis, dyspepsia, dry mouth,ulcer of the esophagus, hepatic necrosis, angioedema, hyperhidrosis, myalgia, monoarthritis, renal failure, hematuria, hyperthermia, chills, peripheral edema, reaction at the injection site, increased activity of serum creatinophosphinase, increased lactate dehydrogenase activity in the blood serum, decreased lymphocyte count.

    Overdose:

    In case of an overdose of anidulafungin, symptomatic therapy should be used.

    With the occasional single administration of anidulafungin at a dose of 400 mg, no clinically significant adverse events were observed as a saturating dose. When anidulafungin 10 was administered to healthy volunteers at a saturating dose of 260 mg followed by dosing at 130 mg per day, the drug was well tolerated. Dose-dependent toxicity was not detected. In 3 out of 10 subjects observed a transient asymptomatic increase in the level of transaminases (less than 3-fold excess of the norm).

    Anidulafungin is not excreted in hemodialysis.

    Interaction:

    Solution Eraksis ® should not be mixed or administered together with other drugs or electrolytes except for 0.9% sodium chloride solution for infusions (9 mg / ml) or 5% dextrose solution for infusions (50mg / ml).

    Special instructions:

    Data on the use of anidulafungin in patients with neutropenia are limited. Infusion-related preparations of Eraksis® are less likely to occur if the infusion rate does not exceed 1.1 mg / min. With the development of any anaphylactic reactions, anidulafungin therapy should be discontinued and appropriate treatment should be prescribed. Lyophilizate Lyophilizate can be stored for 96 hours at a temperature of 25 ° C, then it can again be placed in the refrigerator.

    The reconstituted solution

    The reconstituted solution can be stored at 25 ° C for 24 hours. The chemical and physical stability of the reconstituted solution is 24 hours at a temperature of 25 ° C. From the microbiological point of view, when reconstituted and stored under aseptic conditions, the reconstituted solution can be used for 24 hours at a temperature of 25 ° C.

    Solution for infusions

    The solution for infusions can be stored for 48 hours at a temperature of 25 ° C or stored frozen for 72 hours. The chemical and physical stability of the infusion solution is 48 hours at 25 ° C. From a microbiological point of view, when preparing and storing in aseptic conditions, the solutionfor infusions can be used within 48 hours after preparation at a temperature of 25 ° C.

    Effect on the ability to drive transp. cf. and fur:

    Data on the effect of anidulafungin on the ability to drive vehicles and control mechanisms do not. In connection with the danger of developing neurological disorders (dizziness, convulsions, visual impairment), Eraksis® should be carefully prescribed to persons managing transport and engaged in activities requiring increased concentration of attention and rapid motor reaction.

    Form release / dosage:

    Liofilizate for the preparation of concentrate for the preparation of a solution for infusions of 100 mg.

    Packaging:

    100 mg of lyophilizate in a vial of clear, colorless glass (type I), sealed with a rubber stopper and a sealed aluminum cap with plastic cap type "flip-off."

    1 bottle together with the instruction for use is placed in a cardboard box.
    Storage conditions:

    Lyophilizate - at a temperature of 2 to 8 ° C.

    The reconstituted solution is at a temperature of 25 ° C.

    Solution for infusions - at a temperature of 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    Lyophilizate - 3 years.

    The reconstituted solution is no more than 24 hours.

    Solution for infusions - no more than 48 hours.

    Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-001066
    Date of registration:27.10.2011
    The owner of the registration certificate:Pharmacy and Upjohn CampaniPharmacy and Upjohn Campani USA
    Manufacturer: & nbsp
    Information update date: & nbsp24.12.2013
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