Zinforo

General characteristics. Structure:

Active agent: the tseftarolina fosamit acetate the monohydrate of 668,4 mg equivalent to a tseftarolin to a fosamil of 600,0 mg.
Excipient: L-arginine of 395,0 mg

ОПИСАНИЕ:Порошок from yellow-white till light yellow color.

Pharmacological properties:

Pharmacodynamics. After intravenous administration fosamit pro-medicine of a tseftarolin quickly turns into an active tseftarolin.
Action mechanism
Tseftarolin – an antibiotic of a class of cephalosporins with in vitro activity concerning gram-positive and gram-negative microorganisms. Bactericidal action of a tseftarolin leads to inhibition of biosynthesis of a cell wall of bacteria, due to linkng with penitsillinsvyazyvayushchy proteins (PSB). Tseftarolin shows bactericidal activity concerning Staphylococcus aureus due to high affinity to PSB2A and concerning Streptococcus pneumoniae because of the high affinity to PSB2h.
Communication of pharmacokinetics and pharmacodynamics
Antimicrobic activity of a tseftarolin, also as well as others beta лактамных antibiotics, well correlates with a span during which concentration of drug remain above the minimum inhibiting concentration (MIC) for the infecting microorganism (%T> of MIK).
Resistance mechanism
Tseftarolin is not active concerning strains of Enterobacteriaceae producing beta lactamelements of an expanded action spectrum (ESBLs) of the TEM, SHV or CTX-M families, serinovy karbapenemaza (such as KPC), metal - beta lactamelements of a class B or a class C (AmpC tsefalosporinaza).
Cross resistance
Despite possible development of cross resistance, some strains, resistant to other cephalosporins, can be sensitive to a tseftarolin.
Sensitivity
Prevalence of the acquired resistance to antibiotics at certain microorganisms can vary depending on the region and time. It is recommended to consider local data on resistance, especially at treatment of heavy infections. If local resistance such is that efficiency of drug concerning some infections becomes doubtful, it is necessary to address for consultation the expert.
Sensitivity to a tseftarolin has to decide on the help of standard methods. Interpretation of results should be carried out according to the local managements.
Usually sensitive microorganisms
Gram-positive microorganisms
Staphylococcus aureus * (Methicillinum - sensitive and Methicillinum - resistant)
Streptococcus agalactiae *
The Streptococcus anginosus group (includes S. anginosus, S. intermedius and S. constellatus) *
Streptococcus dysgalactiae *
Streptococcus pneumoniae *
Streptococcus pyogenes *
Gram-negative microorganisms
Haemophilus influenzae *
Haemophilus parainfluenzae *
Anaerobe bacterias
Fusobacterium spp.
Peptostreptococcus spp.
Prevotella spp.
Propionibacterium acnes
Microorganisms for which the problem of the acquired resistance is urgent
Gram-negative microorganisms
Citrobacter freundii
Citrobacter koseri
Enterobacter aerogenes
Enterobacter cloacae
Escherichia coli *
Klebsiella oxytoca *
Klebsiella pneumoniae *
Morganella morganii *
The microorganisms having natural resistance
Chlamydophila spp.
Legionella spp.
Mycoplasma spp.
Pseudomonas aeruginosa
* activators concerning which in clinical trials satisfactory efficiency was shown.

Pharmacokinetics. The maximum concentration (Cmax) and the area under a curve "concentration time" (AUC) of a tseftarolin increase almost in proportion to a dosage at single administration of drug in the range of doses from 50 to 1000 mg. Noticeable cumulation of a tseftarolin after repeated intravenous administration of drug in a dose of 600 mg within 60 minutes each 12 hours within 14 days to healthy volunteers with normal function of kidneys was not observed.
Distribution
Extent of linkng of a tseftarolin with proteins of plasma low (about 20%), drug does not get into erythrocytes. The distribution volume median in an equilibrium state at healthy adult men after single intravenous administration of 600 mg of a tseftarolin fosamit, marked isotope, made 20,3 l, almost like and the volume of extracellular liquid.
Metabolism
In a blood plasma under the influence of phosphatases fosamit pro-medicine of a tseftarolin quickly it will be transformed to an active tseftarolin, concentration of pro-medicine give in to measurement in plasma, preferential, during intravenous infusion. At hydrolysis beta лактамного rings of a tseftarolin microbiological inactive metabolite, цефтаролин is formed by M-1. The ratio of average AUC values of a tseftarolin of M-1 to a tseftarolin in a blood plasma after single intravenous administration of 600 mg of a tseftarolin of a fosamil to healthy volunteers makes about 20-30%.
Metabolism of a tseftarolin proceeds without participation of enzymes of system of P450 cytochrome.
Excretion
Tseftarolin is brought, preferential, by kidneys. The renal clearance of a tseftarolin is approximately equal or glomerular filtration rates in kidneys are a little lower, researches of in vitro conveyors show that active secretion does not promote renal elimination of a tseftarolin. The average elimination half-life of a tseftarolin at healthy adults makes about 2,5 hours. After single intravenous administration of 600 mg marked isotope of a tseftarolin fosamit to healthy adult men, about 88% of radioactivity were found in urine and 6% - in excrements.
Special groups of patients
Renal failure
After single intravenous infusion of 600 mg of a tseftarolin of a fosamil within 60 minutes of Cmax of a tseftarolin in plasma made 28,4 ± 6,9 mkg/ml, 28,2 ± 5,4 mkg/ml and 30,8 ± 4,9 mkg/ml at patients with normal function of kidneys, a slight and moderate renal failure, respectively. Cmax of a tseftarolin was reached approximately in 60 minutes after the beginning of infusion. AUC of a tseftarolin increased in proportion to degree of a renal failure and made 75,6 ± 9,7 мкг×ч/мл, 92,3 ± 25,3 мкг×ч/мл and 114,8 ± 14,1 мкг×ч/мл at patients with normal function of kidneys, a slight and moderate renal failure, respectively.
Dose adjustment is required only from patients with a moderate renal failure (the clearance of creatinine (CC) 30 <to KK ≤ 50 ml/min.) (see the section "Route of Administration and Doses").
There are not enough data for recommendations about dose adjustment at patients with a heavy renal failure (KK ≤ 30 ml/min.) and an end-stage of a renal failure, including the patients who are on a hemodialysis.
Liver failure
The research of pharmacokinetics of a tseftarolin at patients with a liver failure was not conducted. As цефтаролин is not exposed to hepatic metabolism substantially, it is not expected that the liver failure will significantly influence system clearance of a tseftarolin. Therefore, it is not recommended to adjust a drug dose at patients with a liver failure.
Elderly patients (≥ 65 years)
After single intravenous administration of 600 mg of a tseftarolin of a fosamil healthy elderly people had similar parameters of pharmacokinetics of drug (≥ 65 years) and healthy young patients (18-45 years). At elderly volunteers small increase in AUC0-∞ is noted (for 33%) that is caused, mainly, by age changes of function of kidneys. Dose adjustment of drug is not required from elderly patients with clearance of creatinine higher than 50 ml/min.
Children
Safety and efficiency of the drug Zinforo™ at children aged up to 18 years are not established.
Floor
Men and women had similar parameters of pharmacokinetics of a tseftarolin. Dose adjustment depending on a sex of the patient is not required.
Race
Essential distinctions of parameters of pharmacokinetics of a tseftarolin at the patients belonging to different ethnic groups were not observed. It is not required to adjust a drug dose depending on race of the patient.

Indications to use:

The drug Zinforo™ is shown for treatment at adult following infections:
- the complicated infections of skin and soft tissues caused by sensitive strains of the following gram-positive and gram-negative microorganisms: Staphylococcus aureus (including Methicillinum - sensitive and Methicillinum - resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca and Morganella morganii;
- the community-acquired pneumonia caused by sensitive strains of the following gram-positive and gram-negative microorganisms: Streptococcus pneumoniae (including the cases which are followed by bacteremia), Staphylococcus aureus (only Methicillinum - sensitive strains), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Klebsiella oxytoca and Escherichia coli.

Route of administration and doses:

Зинфоро™ it is entered intravenously in the form of infusion within 60 minutes (see. "Preparation of solution for infusions").
Duration of therapy has to be established depending on type and weight of an infection, the response of the patient to therapy.
The following mode of dosing is recommended:
                                 Dose      introduction Frequency     infusion Time  therapy Duration
Complicated          
infections of skin      of 600 mg     each 12                           hours 60 minutes 5-14 days
and soft tissues
Extra hospital      600 mg     each 12                           hours 60 minutes 5-14 days
pneumonia

Use for special groups of patients
Renal failure
At patients with a heavy renal failure (KK ≤ 30) or an end-stage of a renal failure use of drug is contraindicated.
If the clearance of creatinine makes 30 <KK ≤ 50 ml/min., the dose has to be corrected as follows:
Clearance of creatinine     Dose       introduction Frequency    infusion Time
(ml/min.)                  
30 <KK ≤                   50 400 mg     each 12      hours 60 minutes
Liver failure
There is no need to adjust a drug dose at patients with a liver failure.
Elderly patients (≥ 65 years)
There is no need to adjust a drug dose at elderly patients with KK> 50 ml/min.
Children
Safety and efficiency of the drug Zinforo™ at children aged up to 18 years are not established.
Preparation of solution for infusions
At preparation and administration of drug it is necessary to follow standard rules of an asepsis. Each bottle is intended only for single use.
Зинфоро™ powder for preparation of a concentrate for preparation of solution for infusions should be dissolved in 20 ml of sterile water for injections. One ml of a concentrate contains 30 mg of a tseftarolin of a fosamil. The received concentrate needs to use, be not to stored immediately (time from the beginning of dissolution of powder before full preparation of solution for intravenous infusions should not exceed 30 minutes).
For preparation of solution for infusions the received concentrate is stirred up and transferred to the infusional bottle containing one of the listed below compatible infusional liquids:
- solution of sodium of chloride of 9 mg/ml (0,9%) for injections,
- solution of a dextrose of 50 mg/ml (5%) for injections,
- solution of sodium of chloride of 4,5 mg/ml and solution of a dextrose of 25 mg/ml for injections (0,45% solution of sodium of chloride and 2,5% dextrose solution),
- Ringer's solution of a lactate.
At use of a dose of drug of 600 mg with compatible infusional liquid transfer all received concentrate (20 ml) to a bottle, at use of a dose of 400 mg – 14 ml of a concentrate.
Solution for infusions can be prepared by addition of a concentrate in a bottle with infusional liquid of 50 ml, 100 ml or 250 ml.
After preparation of solution for infusions, it should be used within 6 hours from the moment of preparation. The prepared solution for infusions keeps stability within 24 hours at storage in the refrigerator (2-8 °C). After extraction from the refrigerator solution for infusions needs to be used within 6 hours at the room temperature.
Unused drug or waste need to be utilized according to local requirements.

Features of use:

At use of drug it is necessary to be guided by official recommendations about appropriate use of antibacterial drugs.
Hypersensitivity reactions
As well as at use of all beta лактамных antibiotics development of serious reactions of hypersensitivity is possible (sometimes with a lethal outcome).
At patients with hypersensitivity to cephalosporins, penicillin or another beta лактамным to antibiotics in the anamnesis, allergic reaction to a tseftarolin can also develop. Before therapy by the drug Zinforo™ antibiotics should conduct careful examination of the patient regarding identification of reactions of hypersensitivity to a beta laktamnym.
At development of heavy allergic reaction it is necessary to stop administration of medicine and to take the appropriate measures.
The diarrhea associated with Clostridium difficile
At use of almost all antibacterial drugs, including the drug Zinforo™, it was reported about development of antibiotikoassotsiirovanny colitis and pseudomembranous colitis which can vary on weight from lungs to life-threatening forms. It is necessary to take into account a possibility of development of colitis when developing diarrhea against the background of use of a tseftarolin of a fosamil. In this case it is necessary to stop therapy by the drug Zinforo™, to hold the supporting events and to appoint specific treatment of Clostridium difficile.
Patients with a convulsive syndrome in the anamnesis
As well as at use of other cephalosporins, in researches of toxicity of a tseftarolin development of spasms at administration of drug in the doses exceeding Smakh at 7-25 times was observed. Experience of use of a tseftarolin for patients with a convulsive syndrome in the anamnesis is limited in this connection it is necessary to be careful at use of the drug Zinforo™ for this group of patients.
Renal failure
Experience of use of a tseftarolin for patients with a heavy renal failure and an end-stage of a renal failure is limited. Therefore use of the drug Zinforo™ for this population of patients is contraindicated.
Direct antiglobulinovy test (Koombs's test)
The positive direct antiglobulinovy test (DAT) can be received against the background of use of cephalosporins. Frequency positive the STALEMATE at the patients receiving цефтаролин made 10,7% in the integrated researches of a phase 3. At one patient with positive the STALEMATE against the background of use of a tseftarolin hemolysis signs are not revealed.

INFLUENCE ON ABILITY TO DRIVE THE CAR AND OTHER MECHANISMS
Researches on studying of influence of the drug Zinforo™ on ability to driving of motor transport and control of other mechanisms were not conducted. During therapy there can be dizziness therefore it is necessary to be careful at control of vehicles and at occupations other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Diarrhea, headache, nausea and itch were the most frequent undesirable reactions which developed at ≥ 3% of the patients receiving цефтаролин, and were usually poorly or moderately expressed.
The undesirable reactions noted in the joint clinical trials of a phase 3 according to indications the complicated infections of skin and soft tissues and community-acquired pneumonia are given below (1305 adult patients in group of therapy Zinforo™). Frequency of undesirable reactions is presented in the form of the following gradation: very often (≥ 1/10), it is frequent (≥ 1/100, <1/10), infrequently (≥ 1/1000, <1/100), is rare (≥ 1/10000, <1/1000).
Frequency of development of undesirable reactions in a class of system of bodies
Bodies and systems                                        Undesirable reaction
Laboratory indicators                  Very often: positive direct test of Kumbsa1
                                                               Infrequently: lengthening of a prothrombin time,
                                                               increase in the international normalized relation
Digestive tract               Often: diarrhea, nausea, vomiting, abdominal pain, lock
Nervous system                                  Often: headache, dizziness 
                                                               Infrequently: spasms
Skin and hypodermic fabrics                   Often: rash, itch
                                                               Infrequently: small tortoiseshell
Liver and biliary tract       Often: increase in activity of transaminases
                                                               Infrequently: hepatitis
Cardiovascular system            Often: phlebitis, bradycardia
                                                               Infrequently: heart consciousness
Metabolism and food                  It is frequent: hyperglycemia, hypopotassemia
                                                               Infrequently: hyperpotassemia
The general frustration and reactions         it is frequent: fever
in an injection site                                  Infrequently: reactions in the place of infusion (an erythema, phlebitis, pain)
Blood and lymphatic system        Infrequently: anemia, thrombocytopenia
                                                               Seldom: eosinophilia, neutropenia
Immune system                               Infrequently: hypersensitivity / anafilaksiya1, 2
Infections and invasions                            Infrequently: the colitis caused by Clostridium difficile1
Kidneys and urinary tract            Infrequently: renal failure (increase
                                                                 concentration of creatinine of blood)
1. See the section "Special Instructions"
2. See the section "Contraindications"

Interaction with other medicines:

Clinical trials on studying of medicinal interaction with tseftaroliny were not conducted.
In the researches in vitro цефтаролин did not inhibit isoenzymes of P450 CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 cytochrome and did not induce isoenzymes of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5. In this regard the probability of interaction of a tseftarolin with drugs which are metabolized under the influence of isoenzymes of system of P450 cytochrome is low. Tseftarolin is not metabolized under the influence of isoenzymes of P450 in vitro cytochrome therefore, influence on parameters of pharmacokinetics of a tseftarolin at combined use with inductors or inhibitors of isoenzymes of P450 cytochrome is improbable.
In vitro цефтаролин is not transferred by efflyuksny P-gp or BCRP conveyors. Tseftarolin does not inhibit P-gp, therefore, interaction with substrates, such as digoxin, is not expected. Tseftarolin is weak BCRP inhibitor, but this effect does not imeet the clinical importance. The researches in vitro showed what цефтаролин is not substrate, and did not inhibit conveyors of organic cations (OCT2) and anions (OAT1, OAT3) in kidneys; therefore, interaction with drugs which inhibit active renal secretion (for example, пробенецид) or with drugs which are substrates of these conveyors is improbable.
Interaction with other antibacterial drugs
In vitro tests did not reveal antagonism at combined use of a tseftarolin and other often used antibacterial drugs (for example, amikacin, azithromycin, an aztreonam, a daptomitsin, a levofloksatsin, a linezolid, a meropenem, a tigetsiklin and Vancomycinum).

Contraindications:

Hypersensitivity to a tseftarolin to a fosamil or L-arginine.
Hypersensitivity to any antibacterial agent having beta лактамную structure (for example, to cephalosporins, penicillin or karbapenema).
Heavy renal failure (clearance of creatinine (CC) ≤ 30 ml/min.) or end-stage of a renal failure.
Children's age up to 18 years.

With CARE: a convulsive syndrome in the anamnesis.
PREGNANCY AND PERIOD OF BREASTFEEDING
Pregnancy
Clinical data on use of a tseftarolin for pregnant women are absent. Researches on animals did not reveal an adverse effect of a tseftarolin of a fosamil on fertility, pregnancy, childbirth or puerperal development. The drug Zinforo™ should not be used during pregnancy, except for cases when the potential advantage for mother exceeds possible risk for a fruit.
Breastfeeding period
Data on penetration of a tseftarolin into breast milk are absent. However, because many beta лактамные antibiotics are allocated with breast milk, in case of need to therapy the drug Zinforo™, recommends the breastfeeding termination.

Overdose:

Data on overdose are limited. The probability of overdose is higher at patients with a renal failure. At use of drug in doses above recommended similar undesirable reactions were observed, as well as at use of drug in the recommended doses. Treatment: symptomatic.
Tseftarolin is partially brought by means of a hemodialysis.

Storage conditions:

At a temperature not above 25 °C, in the places unavailable to children. Period of validity 2 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Powder for preparation of a concentrate for preparation of solution for infusions, 600 mg.
On 600 mg of active agent in transparent glass bottles with a capacity of 20 ml (type I Evr. Pharm.) closed by the brombutilovy rubber bung with a covering from the fluorinated polymer closed from above by an aluminum cap with a polypropylene cover ("flip-off"). On 1 or 10 bottles with the application instruction in a cardboard pack with control of the first opening.