Zinforo® (Zinforo®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceTseftarolina fosamilTseftarolina fosamil
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  • Zinforo®
    concentratepowder d / infusion 
    AstraZeneca UK Ltd     United Kingdom
    • Dosage form: & nbsp
    Powder for the preparation of concentrate for the preparation of solution for infusion.
    Composition:
    1 bottle contains:

    Active substance: ceftaroline fosamyl acetate monohydrate 668.4 mg equivalent to ceftaroline fosamyl 600.0 mg.
    Excipient: L-arginine 395.0 mg
    Description:Powder from yellowish-white to light yellow color.
    Pharmacotherapeutic group:Antibiotic-cephalosporin.
    ATX: & nbsp

    J.01.D.I.02   Tseftarolina fosamil

    Pharmacodynamics:
    After intravenous administration, a prodrug ceftaroline fosamil quickly turns into active ceftaroline.
    Mechanism of action
    Ceftarolin is an antibiotic of the class of cephalosporins with activity against gram-positive and gram-negative microorganisms. In vitro studies have shown the bactericidal effect of ceftaroline, due to inhibition of the biosynthesis of the bacterial cell wall by binding with penicillin-binding proteins (PSB). Ceftaroline is showing
    bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and for penicillin-insensitive Streptococcus pneumoniae (PNSP) due to its high affinity to the altered PSB of these microorganisms.

    Communication_pharmacokinetics_and pharmacodynamics
    The antimicrobial activity of ceftaroline, as well as of other beta-lactam antibiotics, is best correlated with the time interval during which the drug concentration remains above the minimum inhibitory concentration (MIC) of the infecting microorganism (% T> IPC).

    The mechanism of resistance

    Tseftarolin is not active against strains Enterobacteriaceae, producing beta-lactamases Extended spectrum (BLBR) of TEM families, SHV or CTX-M, serine carbapenemases (such as CRS), Class B or class C metal-beta-lactamase (cephalosporinase AmpFROM). Resistance can also be associated with impaired permeability of the bacterial cell wall or with active excretion of the antibiotic (efflux). A microorganism may have one or more resistance mechanisms.

    Cross-resistance

    Despite the possible development of cross-resistance, some strains resistant to other cephalosporins may be are sensitive to ceftarolin. Microorganisms possessing natural resistance:

    Chlamydophila spp.

    Legionella spp.

    Mycoplasma spp.

    Proteus spp.

    Pseudomonas aeruginosa

    Interaction with other antimicrobial agents

    Research in vitro did not reveal antagonism in the use of ceftaroline in combination with other commonly prescribed antimicrobial agents (such as amikacin, azithromycin, aztreonam, daptomycin, levofloxacin, linezolid, meropenem, tigecycline and vancomycin). Sensitivity

    The sensitivity of antibiotics in vitro varies depending on the geographical region and over time, so when choosing antibacterial therapy, it is necessary to take into account local information on resistance.

    If the local resistance is such that the effectiveness of the drug for some infections becomes questionable, you need to seek the advice of an expert. Sensitivity to ceftarolin should be determined using standard methods. Interpretation of results should be carried out in accordance with local guidelines. Clinical efficacy against individual pathogenic microorganisms The following pathogenic microorganisms (according to indications for use), sensitive to ceftarolin in vitro, for which the effectiveness of ceftaroline has been shown in clinical studies.

    Complicated skin and soft tissue infections
    Gram-positive microorganisms
    Staphylococcus aureus (including methicillin-resistant strains)
    Streptococcus pyogenes
    Streptococcus agalactiae
    Group Streptococcus anginosus (includes S. anginosus, S. intermedius and S. constellatus)
    Streptococcus dysgalactiae
    Gram-negative microorganisms
    Escherichia coli
    Klebsiella pneumoniae
    Klebsiella oxytoca
    Morganella morganii
    Community-acquired pneumonia
    Gram-positive microorganisms
    Streptococcus pneumoniae (including cases accompanied by bacteremia)
    Staphylococcus aureus (only methicillin-sensitive strains)
    Gram-negative microorganisms
    Escherichia coli
    Haemophilus influenzae
    Haemophilus parainfluenzae
    Klebsiella pneumoniae
    Efficacy against other significant pathogens
    The clinical efficacy of ceftaroline in relation to the pathogenic microorganisms listed below has not been established, but the results of in vitro studies suggest that they are sensitive to ceftarolin in the absence of acquired resistance mechanisms.
    Gram-positive anaerobes
    Peptostreptococcus spp.
    Gram-negative anaerobes
    Fusobacterium spp.
    Pharmacokinetics:
    The maximum concentration (Cmax) and the area under the concentration-time curve (AUC) of ceftaroline increase almost in proportion to the dose with a single administration of the drug in the dose range of 50 to 1000 mg. There was no noticeable cumulation of ceftaroline after multipleintravenous administration of the drug at a dose of 600 mg for 60 minutes every 12 hours for 14 days to healthy volunteers with normal renal function.
    Distribution
    The degree of binding of ceftaroline to plasma proteins is low (about 20%), the drug does not penetrate into the red blood cells. The median volume of distribution in the equilibrium state in healthy adult men after a single intravenous injection of 600 mg of ceftorolin of fosamil labeled with an isotope was 20.3 liters, almost like the volume of extracellular fluid.
    Metabolism
    In blood plasma under the action of phosphatases prodrug ceftaroline fosamil quickly converted to active ceftaroline; the concentrations of the prodrug are measurable in plasma, mainly during intravenous infusion. The hydrolysis of the beta-lactam ring of ceftaroline produces a microbiologically non-active metabolite, ceftorolin M-1. The ratio of the average values ​​of AUC of ceftarolin M-1 to ceftorolin in the blood plasma after a single intravenous injection of 600 mg of ceftaroline fosamil to healthy volunteers is approximately 20-30%.
    Metabolism ceftarolina occurs without the participation of isoenzymes of the cytochrome P450 system.
    Excretion
    Ceftarolin is excreted mainly by the kidneys. The renal clearance of ceftaroline is approximately equal to or slightly below the glomerular filtration rate in the kidneys. Studies of in vitro transporters show that active secretion does not promote renal elimination of ceftaroline.
    Average the half-life of ceftaroline in healthy adults is approximately 2.5 hours. After a single intravenous administration of 600 mg isotope labeled tsftarolina fosamil to healthy adult men approximately 88% of radioactivity was found in urine and 6% in feces.

    Special patient groups

    Renal insufficiency

    After a single intravenous infusion of 600 mg of ceftaroline fosamil for 60 minutes CmOh ceftaroline in plasma was 28.4 ± 6.9 μg / ml, 28.2 ± 5.4 μg / ml and 30.8 ± 4.9 μg / ml in patients with normal renal function, mild renal insufficiency and renal failure severity, respectively. FROMmOh ceftaroline was reached approximately 60 minutes after the start of the infusion. AUC ceftaroline increased in proportion to the degree of renal failure and was 75.6 ± 9.7 μg / hr / ml, 92.3 ± 25.3 μg / hr / ml and 114.8 ± 14.1 μg / hr / ml in patients with normal renal function, mild renal insufficiency and renal insufficiency of moderate severity, respectively. Correction of the dose is required only in patients with moderate renal insufficiency (creatinine clearance (CK) 30-50 ml / min) (see section "Method of administration and dose"). There is insufficient data for recommendations for dose adjustment in patients with severe renal insufficiency (QC <30 ml / min) and the terminal stage of renal failure, including patients on hemodialysis.

    Liver failure

    Pharmacokinetics studies ceftaroline in patients with hepatic insufficiency was not performed. Since ceftaroline does not undergo hepatic metabolism to a large extent, it is not expected, what hepatic Insufficiency will significantly affect the systemic clearance of ceftaroline. Therefore, it is not recommended to adjust the dose of the drug in patients with hepatic insufficiency.

    Elderly patients (> 65 years old)

    After a single intravenous injection of 600 mg of ceftaroline, fosamil, the pharmacokinetics of the drug were similar in healthy elderly (> 65 years old) and healthy young patients (18-45 years). In elderly volunteers there was a slight increase AUCo-∞, (by 33%), which is mainly due to age-related changes in kidney function. No dose adjustment is needed in elderly patients with a creatinine clearance above 50 ml / min.

    Children

    The safety and efficacy of Zinforo® in children under the age of 18 years are not installed.

    Floor

    Parameters of the pharmacokinetics of ceftaroline were similar in men and women. Not dose adjustment in relation to from the patient's floor.

    Race

    There were no significant differences parameters of the pharmacokinetics of ceftaroline in patients belonging to different ethnic groups. Not required adjust the dose of the drug in depending on the race of the patient.



    Indications:
    Zinforo ® is indicated for the treatment of adults with the following infections:
    - complicated skin and soft tissue infections caused by sensitive strains
    the following gram-positive and gram-negative microorganisms:
    Staphylococcus aureus (including methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus, Streptococcus dysgalactiae, Escherichia coli,
    Klebsiella pneumoniae, Klebsiella oxytoca and Morganella morganii;
    - Community-acquired pneumonia caused by susceptible strains of the following Gram-positive and
    Gram-negative microorganisms: Streptococcus pneumoniae (including cases accompanied by bacteremia), Staphylococcus aureus (only methicillin-sensitive strains), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae and Escherichia coli.
    Contraindications:
    - Hypersensitivity to ceftarolina fosamyl or L-arginine.

    - Hypersensitivity to cephalosporins.

    - Severe immediate-type hypersensitivity reactions (eg, anaphylactic reaction) to any other antibacterial agent having a beta-lactam structure (eg, penicillins or carbapenems).

    - Severe renal insufficiency (creatinine clearance (CC) < 30 ml / min), terminal stage of renal failure and patients on hemodialysis.

    - Children under 18 years.
    Carefully:
    A convulsive syndrome in the anamnesis.

    Pregnancy and lactation:
    Pregnancy
    Clinical data on the use of ceftaroline fosamil in pregnant women are absent. Animal studies did not reveal the adverse effects of ceftaroline fosamil on fertility, pregnancy, childbirth or post-natal development. Zinforo® should not be used during pregnancy, unless the potential benefit to the mother exceeds the potential risk to the fetus.
    Breastfeeding period
    Data on the penetration of ceftaroline into breast milk are not available.However, due to the fact that many beta-lactam antibiotics are excreted in breast milk, it is recommended that breastfeeding be discontinued if Zinforo® is needed.
    Dosing and Administration:
    Zinforo® is administered intravenously in the form of infusion for 60 minutes (see "Preparation of a solution for infusions"). The duration of therapy should be determined depending on the type and severity of the infection, the patient's response to therapy.

    The following dosing regimen is recommended:

    Dose

    Frequency

    introduction of

    Infusion time

    Duration of therapy

    Obstruction

    the

    infection

    the

    skin and

    600 mg

    every 12 hours

    60 minutes

    5-14 days

    soft

    fabrics

    Outpatient pneumonia

    600 mg

    every 12 hours

    60 minutes

    5-7 days

    the


    Use in special patient groups

    Renal insufficiency In patients with severe renal failure (CK <30 ml / min), terminal stage of renal failure and patients,

    on the hemodialysis, the use of the drug is contraindicated. If the creatinine clearance is 30-50 ml / min, the dose should be adjusted as follows:

    Creatinine clearance at

    (ml / min)

    Dose

    Frequency of administration

    Infusion time

    30-50

    400 mg

    every 12 hours

    60 minutes

    Liver failure

    There is no need to adjust the dose drug in patients with hepatic insufficiency.

    Elderly patients (> 65 years old)

    There is no need to adjust the dose in elderly patients with QC > 50 ml / min.

    Children

    The safety and efficacy of Zinforo ® in children under the age of 18 years have not been established.

    Preparation of a solution for infusions

    When preparing and administering the drug, you must follow the standard rules of asepsis. Each bottle is for single use only.

    Zinforo® powder for the preparation of concentrate for solution for infusion should be dissolved in 20 ml of sterile water for injection. One ml of concentrate contains 30 mg of ceftorolin of fosamil. The resulting concentrate is a solution of pale yellow color, free from visible particles. Concentrate must be used immediately, do not store (the time from the beginning of the dissolution of the powder to the complete preparation of the solution for intravenous infusion should not exceed 30 minutes). To prepare a solution for infusions, the resulting concentrate is shaken and transferred to an infusion bottle,containing one of the following compatible infusion liquids:

    - 0.9% solution of sodium chloride,

    - 5% dextrose solution,

    - 0.45% sodium chloride solution and 2.5% dextrose solution,

    - Ringer's lactate solution.

    When using a dose of 600 mg in a bottle with a compatible infusion fluid, transfer the entire concentrate (20 ml), with a dose of 400 mg - 14 ml of concentrate. The infusion solution can be prepared by adding the concentrate to a vial of an infusion fluid of 50 ml, 100 ml or 250 ml.

    After the preparation of the solution for infusion, it should be used within 6 hours from the moment of preparation. The prepared infusion solution remains stable for 24 hours when stored in a refrigerator (2-8 ° C). After removal from the refrigerator, the infusion solution should be used for 6 hours at room temperature. Unused product or waste must be disposed of in accordance with local regulations.

    Side effects:
    The most frequent undesirable reactions developed in > 3% of patients treated with ceftaroline had diarrhea, headache, nausea and pruritus, which were usually mild or moderately severe.
    Below are the undesirable reactions noted in the combined Phase 3 clinical trials indications complicated skin and soft tissue infections and community-acquired pneumonia (1305 adult patients in the Zinforo® therapy group). The frequency of unwanted reactions is presented in the form of the following gradation: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1/10000,< 1/1000).

    Frequency of development of unwanted reactions in the class of organ system

    Organs and Systems

    Unwanted reaction

    Laboratory

    Often:

    indicators

    positive direct test of Coombs1

    Infrequently: elongation

    prothrombin

    time, elongation

    activated

    partial

    thromboplastin

    time, increase

    of international

    normalized

    relations

    Gastrointestinal

    Often: diarrhea,

    tract

    nausea, vomiting, abdominal pain, constipation

    Nervous system

    Often: headache, dizziness

    Infrequently: convulsions

    Skin and subcutaneous

    Often: rash, itching

    Infrequently: hives

    fabrics

    Liver and

    Often: rise

    bile ducts

    transaminase activity

    Infrequently: hepatitis

    Cardiovascular

    Often: phlebitis,

    bradycardia

    Infrequently: sensation

    palpitation

    system

    Metabolism and

    Often:

    food

    hyperglycemia, hypokalemia

    Infrequently: hyperkalemia

    General disorders and reactions at the site of administration

    Often: fever, reactions at the site of infusion (erythema, phlebitis, pain)

    Blood and

    lymphatic system

    Infrequently: anemia,

    leukopenia,

    thrombocytopenia

    Rarely: eosinophilia, neutropenia

    The immune system

    Infrequently:

    hypersensitivity / anaphylaxis1'2

    Infections and invasions

    Infrequently: colitis,

    caused by Clostridium difficile1

    Kidneys and

    urinary tract

    Infrequently: impaired renal function

    (increase in the concentration of the creatinine of the blood)

    1. See section "Special instructions"

    2. See section "Contraindications"

    Overdose:Data on overdose are limited. The likelihood of an overdose is higher in patients with impaired renal function. When applying the drug in doses above recommended, similar adverse reactions were observed, as with the use of the drug in the recommended doses. Treatment: symptomatic. Ceftarolin is partially excreted by hemodialysis.
    Interaction:
    Clinical studies on the study of drug interaction with ceftaroline have not been conducted.
    In in vitro studies, ceftaroline did not inhibit cytochrome P450 isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 and did not induce isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4 / 5.In this regard, the probability of interaction of ceftaroline with drugs that are metabolized by isoenzymes of the cytochrome P450 system is low. Tsftarolin is not metabolized by cytochrome P450 isoenzymes in vitro, therefore, it is unlikely that effects on the pharmacokinetics of ceftaroline will be combined with inducers or inhibitors of cytochrome P450 isoenzymes. In vitro ceftaroline is not tolerated by efflux P-gp or BCRP transporter. Ceftaroline does not inhibit P-gp, therefore, interaction with substrates, such as digoxin, is not expected. Tseftorolin is a weak inhibitor of BCRP, but this effect has no clinical significance. In vitro studies have shown that ceftaroline is not a substrate, and does not inhibit the transport of organic cations (OCT2) and anions (OAT1, OATZ) in the kidneys; therefore, interaction with drugs that inhibit active renal secretion (eg, probenecid) or with preparations that are substrates of these transports is unlikely.

    Interaction with other antibacterial drugs
    In vitro tests have not revealed antagonism in the joint use of ceftaroline and other commonly used antibacterial drugs (for example, amikacin, azithromycin, aztreonama, daptomycin,levofloxacin, linezolid, meropenem, tigecycline and vancomycin).
    Special instructions:
    When using the drug should be guided by official recommendations for the proper use of antibacterial drugs.
    Hypersensitivity reactions
    As with all beta-lactam antibiotics, it is possible to develop serious reactions
    hypersensitivity (sometimes with a fatal outcome).
    In patients with hypersensitivity to cephalosporins, penicillins or other beta-lactam antibiotics, an allergic reaction to ceftaroline fosamil. Before starting therapy with Zinforo®, the patient's data should be carefully examined for hypersensitivity reactions to beta-lactam antibiotics. The drug is contraindicated in patients from increased sensitivity to cephalosporins in the anamnesis. Also, the drug is contraindicated in patients who have previously experienced severe immediate-type hypersensitivity reactions (eg, anaphylactic reaction) to any other antibacterial agent having a beta-lactam structure (eg, penicillins or carbapenems).
    With the development of a severe allergic reaction, it is necessary to stop the administration of the drug and take appropriate measures.

    Diarrhea associated with Clostridium difficile
    With the use of almost all antibacterial drugs, including Zinforo®, the development of antibiotic-associated colitis and pseudomembranous colitis has been reported, which can vary in severity from mild to life-threatening forms. It should be taken into account the possibility of developing colitis in the occurrence of diarrhea against the background of the use of ceftaroline fosamil. In this case, it is necessary to stop therapy with Zinforo®, carry out supportive measures and prescribe a specific treatment for Clostridium difficile.

    Patients with a history of convulsive syndrome
    As with the use of other cephalosporins, the development of seizures in the toxicity studies of ceftaroline was observed when taking the drug at doses exceeding C max in 7-25 times. Experience in the use of ceftaroline in patients with convulsive syndrome in history is limited, and therefore care should be taken when using Zinforo ® in this group of patients.

    Renal insufficiency
    The experience with ceftaroline in patients with severe renal failure, end-stage renal failure, and hemodialysis patients is limited. Therefore, the use of Zinforo ® in this population of patients is contraindicated.

    Direct antiglobulin test (Coombs test)
    A positive direct antiglobulin test (PAT) can be obtained against the background of the use of cephalosporins. The frequency of positive PAT in patients receiving ceftaroline fosamil, was 10.7% in the pooled phase 3 studies. None of the patients with positive PAT on the background of ceftaroline fosamil showed signs of hemolysis.

    Insensitive microorganisms
    With the use of ceftaroline fosamil, as well as other antibiotics, superinfection may develop.
    Effect on the ability to drive transp. cf. and fur:
    There have been no studies to study the effect of Zinforo® on the ability to drive vehicles and manage other mechanisms. During therapy, dizziness may occur, therefore, care should be taken when driving vehicles and when engaging in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.If the undesirable phenomenon described above appears, one should refrain from performing these activities.


    Form release / dosage:
    Powder for the preparation of concentrate for the preparation of a solution for infusions, 600 mg.

    Packaging:
    For 600 mg of active substance in transparent glass bottles with a capacity of 20 ml (type I Eur. Pharm.) Closed with a bromobutyl rubber stopper coated with fluorinated polymer, topped with an aluminum cap with a polypropylene cover ("flip-off"). For 1 or 10 bottles with instructions for use in a cardboard box with control of the first opening.
    Storage conditions:At temperatures not higher than 25 ° C, in places inaccessible to children.
    Shelf life:2 years. Do not use after the expiry date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-001912
    Date of registration:20.11.2012
    Date of cancellation:2017-11-20
    The owner of the registration certificate:AstraZeneca UK LtdAstraZeneca UK Ltd United Kingdom
    Manufacturer: & nbsp
    Representation: & nbspAstraZeneca Pharmaceuticals Ltd.AstraZeneca Pharmaceuticals Ltd.
    Information update date: & nbsp10.11.2015
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