Composition, form of production and packaging
Powder for the preparation of concentrate for the preparation of a solution for infusions from yellowish white to light yellow color.
1 f.
tsftarolina fosamyl acetate monohydrate 668.4 mg,
which corresponds to the content of ceftorroline fosamil 600 mg
Excipients: L-arginine - 395 mg.
Vials of glass capacity 20 ml (1) - packs cardboard with the control of the first opening.
Vials of glass capacity 20 ml (10) - packs cardboard with the control of the first opening.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
Antibiotic group of cephalosporins of the V generation. After iv introduction, the prodrug of ceftaroline fosamil rapidly turns into active ceftaroline.
Ceftarolin is an antibiotic of the class of cephalosporins with activity against gram-positive and gram-negative microorganisms. In vitro studies, the bactericidal effect of ceftaroline, due to the inhibition of the biosynthesis of the bacterial cell wall by binding to penicillin-binding proteins (PSB), is shown. Ceftaroline exhibits bactericidal activity against Staphylococcus aureus (MRSA) and for penicillin-insensitive Streptococcus pneumoniae (PNSP) due to its high affinity to the altered PSB of these microorganisms.
The antimicrobial activity of ceftaroline, as well as of other beta-lactam antibiotics, is best correlated with the time interval during which drug concentrations remain above the minimum inhibitory concentration (MIC) of the infecting microorganism (% T> MIC).
Tseftarolin is not active against Enterobacteriaceae strains producing extended-spectrum ОІ-lactamase (BLBR) of the TEM, SHV, or CTX-M families, serine carbapenemases (such as CRS), Class B or Class C metal-Оі-lactamase (cephalosporinase AmpC). 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.
Despite the possible development of cross-resistance, some strains resistant to other cephalosporins may be sensitive to ceftarolin. Microorganisms possessing natural resistance: Chlamydophila spp., Legionella spp., Mycoplasma spp., Proteus spp., Pseudomonas aeruginosa.
In vitro studies have not revealed 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).
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 selected 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, Streptococcus anginosus group (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 (including methicillin-sensitive strains); Gram-negative microorganisms - Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae.
The clinical efficacy of ceftaroline in relation to the pathogens listed below has not been established, but 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
Suction
C max and 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 appreciable cumulation of ceftaroline after repeated iv administration of the drug at a dose of 600 mg for 60 min 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. Median V d in the equilibrium state in healthy adult men after a single intravenous injection of 600 mg of the phthalomol of fosamil labeled with the isotope was 20.3 liters, almost like the volume of the extracellular fluid.
Metabolism
In plasma of blood under the influence of phosphatases, the prodrug of ceftaroline fosamil is rapidly transformed into active ceftaroline; the concentrations of the prodrug are measurable in plasma, mainly during intravenous infusion. In the hydrolysis of the beta-lactam ring of ceftaroline, a microbiologically inactive metabolite, ceftorolin M-1, is formed. The ratio of the average values ​​of AUC of ceftorolin M-1 to ceftorolin in the blood plasma after a single IV injection of 600 mg of ceftaroline fosamil to healthy volunteers is approximately 20-30%.
Metabolism ceftarolina occurs without the participation of enzymes of the cytochrome P450 system.
Excretion
Ceftarolin is excreted mainly by the kidneys. Renal clearance of ceftarolin is approximately equal to or slightly lower than the glomerular filtration rate in the kidneys, studies of in vitro transporters show that active secretion does not promote renal elimination of ceftaroline. The average T 1/2 ceftaroline in healthy adults is approximately 2.5 hours. After a single IV administration of 600 mg isotope-labeled ceftaroline fosamil, in healthy adults, approximately 88% of radioactivity was detected in urine and 6% in feces.
Pharmacokinetics in specific patient groups
After a single IV infusion of 600 mg of ceftorolin of fosamil for 60 min, C max of ceftaroline in plasma was 28.4 В± 6.9 Ојg / ml, 28.2 В± 5.4 Ојg / ml and 30.8 В± 4.9 Ојg / ml in patients with normal renal function, renal insufficiency of the lung and moderate severity, respectively. C max of ceftaroline was reached approximately 60 minutes after the start of the infusion. AUC of ceftaroline increased in proportion to the degree of renal failure and was 75.6 В± 9.7 Ојg / hr, 92.3 В± 25.3 Ојg h / ml and 114.8 В± 14.1 Ојg h / ml in patients with normal kidney function, renal failure of mild to moderate severity, respectively. Correction of the dose is required only in patients with moderate renal insufficiency (KK 30-50 ml / min). There is insufficient data for recommendations for dose adjustment in patients with severe renal insufficiency (QC-30 mL / min) and terminal stage of renal failure, including patients on hemodialysis.
Studies of the pharmacokinetics of ceftaroline in patients with hepatic insufficiency have not been conducted. Because ceftaroline does not undergo hepatic metabolism to a large extent, it is not expected that 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.
After a single IV dose of 600 mg of ceftaroline, fosamil, the pharmacokinetics of the drug were similar in healthy elderly (? 65 years) and healthy young patients (18-45 years). In elderly volunteers, a slight increase in AUC 0-? (by 33%), which is mainly due to age-related changes in kidney function. It is not necessary to adjust the dose of the drug in elderly patients with CK> 50 ml / min.
Safety and efficacy of Zinforo В® in children and adolescents under the age of 18 years have not been established.
The pharmacokinetics of ceftaroline were similar in men and women. No dosage adjustment is required depending on the patient's sex.
There were no significant differences in the parameters of the pharmacokinetics of ceftaroline in patients belonging to different ethnic groups. It is not necessary to adjust the dose of the drug depending on the patient's race.
INDICATIONS
Treatment for adults of the following infections:
- complicated skin and soft tissue infections caused by sensitive strains of the following Gram-positive and Gram-negative microorganisms: Staphylococcus aureus (including methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus angiosus, 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.
DOSING MODE
The drug Zinforo В® is administered IV in the form of infusion for 60 min.
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 of administration Time of infusion Duration of therapy
Complicated skin and soft tissue infections 600 mg every 12 hours 60 minutes 5-14 days
Community-acquired pneumonia 600 mg every 12 hours 60 minutes 5-7 days
Special patient groups
In patients with severe renal insufficiency (CK-30 ml / min), terminal stage of renal failure and patients on hemodialysis , the use of the drug is contraindicated.
With QC 30-50 ml / min , the dose should be adjusted as follows:
KK (ml / min) Dose Frequency of administration Infusion time
30-50 400 mg every 12 hours 60 minutes
There is no need to adjust the dose of the drug in patients with hepatic insufficiency .
There is no need to adjust the dose of the drug in elderly patients (? 65 years) with CK> 50 ml / min.
Safety and efficacy of Zinforo В® in children and adolescents under the age of 18 years have not been established.
Rules for the preparation of a solution for infusion
When preparing and administering the drug, you must follow the standard rules of asepsis. Each bottle is for single use only.
Zinforo В® powder for the preparation of a concentrate for the preparation of a solution for infusion should be dissolved in 20 ml of sterile water for injection. 1 ml of concentrate contains 30 mg of ceftaroline fosamil. The resulting concentrate is a pale yellow solution that is free of visible particles. Concentrate must be used immediately, do not store (the time from the beginning of dissolution of the powder to the complete preparation of the solution for intravenous infusion should not exceed 30 minutes).
To prepare the solution for infusion, the resulting concentrate is shaken and transferred to an infusion bottle containing one of the following compatible infusion liquids: 0.9% sodium chloride solution, 5% dextrose solution, 0.45% sodium chloride solution and 2.5% dextrose solution, Ringer's lactate solution.
When the drug is used in a dose of 600 mg, the whole concentrate (20 ml) is transferred to a vial of compatible infusion fluid, when applied at 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.
The solution for infusion 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 В° 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 EFFECT
The most common adverse reactions that occurred in ≥3% of patients treated with ceftaroline were diarrhea, headache, nausea and pruritus, and were usually mild or moderate.
Below are the undesirable reactions noted in the combined phase 3 clinical trials for indications of complicated skin and soft tissue infections and community-acquired pneumonia (1,305 adult patients in the Zinforo В® therapy group). The frequency of unwanted reactions is presented in the following gradation: very often (? 1/10), often (? 1/100, <1/10), infrequently (? 1/1000, <1/100), rarely (? 1/10 000, <1/1000).
Frequency of development of unwanted reactions in the class of organ system
Bodies and systems Undesirable reaction
Laboratory indicators very often: a positive direct test of Coombs 1
infrequent: prolongation of prothrombin time, prolongation of APTT, increase in INR
Gastrointestinal: often, diarrhea, nausea, vomiting, abdominal pain, constipation
Nervous system often: headache, dizziness
infrequently: convulsions
Skin and subcutaneous tissue often: rash, itching
infrequently: urticaria
Liver and bile ducts often: increased activity of transaminases
infrequently: hepatitis
Cardiovascular system often: phlebitis, bradycardia
infrequent: a feeling of heartbeat
Metabolism and nutrition often: hyperglycemia, hypokalemia
infrequently: hyperkalemia
Common disorders and reactions at the injection site are often: fever, reactions at the site of infusion (erythema, phlebitis, pain)
Blood and lymphatic system infrequently: anemia, leukopenia, thrombocytopenia
rarely: eosinophilia, neutropenia
Immune system infrequent: hypersensitivity / anaphylaxis 1,2
Infections and infestations infrequent: colitis caused by Clostridium difficile 1
Kidneys and urinary tracts infrequently: impaired renal function (increased concentration of blood creatinine)
1 see the section "Special instructions"
2 see the section "Contraindications"
CONTRAINDICATIONS
- renal failure of severe degree (QC-30 ml / min), terminal stage of renal failure and patients on hemodialysis;
- children and adolescence under 18;
- hypersensitivity to ceftaroline fosamyl or L-arginine;
- hypersensitivity to cephalosporins;
- severe reactions of hypersensitivity of immediate type (for example, anaphylactic reaction) to any other antibacterial agent having a beta-lactam structure (for example, penicillins or carbapenems).
With caution should prescribe the drug to patients with a convulsive syndrome in the anamnesis.
PREGNANCY AND LACTATION
Clinical data on the use of ceftaroline fosamil in pregnant women are absent. Experimental studies in animals did not reveal the adverse effects of ceftaroline fosamil on fertility, pregnancy, childbirth or postnatal development.
Zinforo В® should not be used during pregnancy, except when the potential benefit to the mother exceeds the possible risk to the fetus.
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, if necessary, Zinforo В® is recommended to stop breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER
In patients with severe renal insufficiency (CK-30 ml / min), terminal stage of renal failure and patients on hemodialysis , the use of the drug is contraindicated.
With QC 30-50 ml / min , the dose should be adjusted as follows:
KK (ml / min) Dose Frequency of administration Infusion time
30-50 400 mg every 12 hours 60 minutes
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
There is no need to adjust the dose of the drug in patients with hepatic insufficiency .
APPLICATION FOR CHILDREN
Contraindicated in the use of Zinforo В® in children and adolescents under the age of 18 , safety and efficacy not established.
APPLICATION IN ELDERLY PATIENTS
There is no need to adjust the dose of the drug in elderly patients (? 65 years) with CK> 50 ml / min.
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 hypersensitivity reactions (sometimes with a fatal outcome).
In patients with hypersensitivity to cephalosporins, penicillins or other beta-lactam antibiotics in an anamnesis, an allergic reaction to ceftaroline fosamyl can also develop. Before starting therapy with Zinforo В® , the patient's data should be carefully examined for the detection of hypersensitivity reactions to beta-lactam antibiotics. The drug is contraindicated in patients with an increased sensitivity to cephalosporins in history. 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
When using almost all antibacterial drugs, incl. preparation Zinforo В® , reported on the development of antibiotic-associated colitis and pseudomembranous colitis, which can vary in severity from mild to life-threatening forms. It should take into account the possibility of the development of colitis in the event of diarrhea during treatment with ceftaroline fosamila. In this case it is necessary to stop therapy with Zinforo В® , conduct support activities and assign specific treatment for Clostridium difficile.
Patients with a history of convulsive disorders
As with other cephalosporins, ceftaroline toxicity studies in development of seizures observed while taking the drug in doses exceeding C maxin 7-25 times. Experience of ceftaroline in patients with a history of convulsive disorders is limited, and therefore should be taken when applying the drug Zinforo В® in this group of patients.
Renal failure
Experience with ceftaroline in patients with severe renal insufficiency and end-stage renal failure and in patients on hemodialysis is limited. Therefore, the use of the drug Zinforo В® in this patient population is contraindicated.
Direct antiglobulin test (Coombs test)
A positive direct antiglobulin test (APM) can be obtained on treatment with cephalosporins. The frequency of positive PAT patients treated with ceftaroline fosamil amounted to 10.7% in the combined phase 3 studies None of the patients with a positive PAT during treatment with ceftaroline not showed signs of hemolysis.
Insensitive microorganisms
When applying ceftaroline fosamila as other antibiotics may develop superinfection.
Impact on the ability to drive vehicles and manage mechanisms
No studies on the effect of the drug Zinforo В® on the ability to drive vehicles and management of other mechanisms. During therapy, can occur dizziness, so be careful when driving and when engaging in other potentially hazardous activities that require high concentration and psychomotor speed reactions. If dizziness should refrain from carrying out these activities.
OVERDOSE
overdose data are limited. The probability of overdose is higher in patients with impaired renal function. In applying the drug at doses higher than the recommended observed same adverse reactions, as in the use of the drug at the recommended doses.
Treatment: symptomatic. Ceftaroline partially displayed via hemodialysis.
DRUG INTERACTION
Clinical studies of drug interactions with ceftaroline not conducted.
In in vitro studies ceftaroline not inhibit cytochrome P450 isozymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 isozymes and did not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4 / 5. Therefore the interaction probability ceftaroline with drugs that are metabolized by the action of cytochrome P450 isoenzymes low. Ceftaroline is not metabolized by the action of cytochrome P450 isozymes in vitro, however, it is unlikely to influence the pharmacokinetics of ceftaroline parameters when combined with inducers or inhibitors of cytochrome P450 isoenzymes.
In vitro ceftaroline not transferred efflux transporter P-gp or BCRP. Ceftaroline not inhibit P-gp, consequently, the interaction with substrates such as digoxin, is expected. Ceftaroline is a weak inhibitor of BCRP, but this effect is not clinically significant.
Studies in vitro have shown that ceftaroline not a substrate, and does not inhibit organic cation transporters (OST2) and anions (OAT1, OAT3) kidney; however, it is unlikely interactions with drugs that inhibit the active renal secretion (e.g. probenecid) or with drugs that are substrates of these transporters.
Interaction with other antibacterial drugs
in vitro tests revealed no antagonism in the combined use ceftaroline and other commonly used antibacterial agents (e.g., amikacin, azithromycin, aztreonam, daptomycin, levofloxacin, linezolid, meropenem, vancomycin and tigecycline).
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 25 В° C. Shelf life - 2 years.
