Composition, form of production and packaging
Lyophilizate for the preparation of a solution for infusions in the form of a compact, broken or pulverulent mass of white or from yellowish to slightly brownish in color.
1 f.
cetofibrol sodium medocaryl 666.6 mg,
which corresponds to the content of ceftobiprol 500 mg
Excipients: citric acid monohydrate, sodium hydroxide, nitrogen (inert gas during lyophilization).
Glass bottles with a capacity of 20 ml (1) - packs cardboard.
Glass bottles with a capacity of 20 ml (10) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2010.
PHARMACHOLOGIC EFFECT
Antibiotic group cephalosporins. Cetobiprol medocaryl is a water soluble prodrug of ceftobiprol, cephalosporin, which has bactericidal activity against a wide range of Gram-positive bacteria, including methicillin-resistant Staphylococcus species, penicillin-resistant Streptococcus pneumoniae, and ampicillin-sensitive Enterococcus faecalis. Cetofibiprol is also active against many Gram-negative bacteria, including many strains of the Enterobacter spp. Family. and Pseudomonas aeruginosa.
Ceftobiprol binds strongly to many important penicillin-binding proteins (PBPs) of both Gram-positive and Gram-negative bacteria. Cetofibiprol has a pronounced bactericidal activity against Staphylococcus spp., Resistant to methicillin, due to strong binding to PBP2a of staphylococci, including methicillin-resistant Staphylococcus aureus.
Cetobiprol is active against most isolates of the following microorganisms, both in vitro and nosocomial infections: gram-positive aerobes -Enterococcus faecalis (isolates sensitive and resistant to vancomycin), Staphylococcus aureus (isolates sensitive and resistant to methicillin), Staphylococcus epidermidis, Streptococcus agalactiae , Streptococcus pyogenes, coagulase-negative strains of Staphylococcus spp. (isolates sensitive and resistant to methicillin, including Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus lugdunensis and Staphylococcus saprophyticus), Streptococcus pneumoniae (penicillin sensitive isolates, moderately resistant to penicillin and resistant to penicillin), Streptococcus group of viridans; gram-negative aerobes - Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Citrobacter spp. (including Citrobacter freundii, Citrobacter koseri), Enterobacter aerogenes, Klebsiella oxytoca, Moraxella catarrhalis, Morganella morganii, Neisseria spp., Providencia spp., Serratia marcescens.
Ceftobiprol is resistant to hydrolysis by penicillinases Staphylococcus aureus, and also to hydrolysis by many ОІ-lactamases of class C and class A produced by Gram-negative bacteria. Like most cephalosporins, ceftobiprol is hydrolyzed by extended-spectrum beta-lactamases, carbapenemases and metal-beta-lactamases. In vitro, no selection of high-level resistance in staphylococci, streptococci and Haemophilus influenzae was observed.
Resistance to ceftobiprole caused by spontaneous mutation in vitro is rare. Cross-resistance between ceftobiprol and some other cephalosporins of the last generation has been described. However, some microorganisms resistant to other cephalosporins may be sensitive to ceftobiprole.
PHARMACOKINETICS
The average pharmacokinetic parameters of ceftobiprol in adults after administration in a single dose of 500 mg in the form of infusion over 60 minutes and administration in multiple doses of 500 mg in the form of infusions for 120 min every 8 hours are shown in Table. 1. Pharmacokinetic characteristics are similar after the administration of a single dose and after the administration of multiple doses.
Table 1. Mean (standard deviation) pharmacokinetic parameters of ceftobiprole in adults
Parameters One dose of 500 mg in the form of infusion over 60 min. Multiple doses of 500 mg in the form of infusions 120 min every 8 h
Cmax (Ојg / ml) 34.2 (6.05) 33.0 (4.83)
AUC (Ојg / hr / ml) 116 (20.2) 102 (11.9)
T 1/2 (h) 2.85 (0.55) 3.3 (0.3)
clearance (l / h) 4.46 (0.84) 4.98 (0.58)
Cmax and AUC of ceftobiprol increase in proportion to the dose in the dose range of 125 mg - 1 g. C ss concentrations are achieved on the first day of treatment; in people with normal renal function, the administration of ceftobiprol every 8 hours and every 12 hours does not cause it to accumulate.
Distribution
The binding of ceftobiprol with plasma proteins is 16% and does not depend on its concentration. V d in the equilibrium state is 18 liters and approaches the volume of extracellular fluid in humans.
Metabolism
Biotransformation from ceftobiprole medocaryl, which is a prodrug, into the active substance ceftobiprol occurs rapidly and is catalyzed by plasma esterases.Concentrations of the prodrug are negligible, and it can be detected in plasma and urine only during infusion.
Ceftobiprol undergoes minimal metabolism to a non-cyclic metabolite, which is microbiologically inactive. The concentration of this metabolite is below the concentration of the ceftobiprole itself and is about 4% of the latter.
Excretion
Ceftobiprol is excreted mainly unchanged through renal excretion. T 1/2 is about 3 hours. The main mechanism of renal excretion is glomerular filtration, a small part of the dose is subjected to tubular reabsorption. In pre-clinical studies, probenecid did not affect the pharmacokinetics of ceftobiprole, indicating a lack of active tubular secretion of the latter. After the administration of a single dose, approximately 89% is found in the urine as active ceftobiprol (83%), open-cell metabolite (5%) and ceftobiprol medocaryl (<1%).
Pharmacokinetics in special clinical cases
The pharmacokinetics of ceftobiprol is similar in healthy volunteers and in patients with mild renal insufficiency (KK 50-80 ml / min). Compared with AUC in healthy volunteers with normal renal function, the AUC of ceftobiprol was 2.5 and 3.3 times greater in patients with moderate renal insufficiency (QC from 30 mL / min to? 50 mL / min) and severe (QC <30 mL / min), respectively. In patients with moderate and severe renal insufficiency, it is recommended to reduce the dose of ceftobiprol. AUC of ceftobiprol and its microbiologically inactive metabolite with an open ring structure increases in patients who need hemodialysis, compared to AUC in healthy volunteers.
In patients with hepatic insufficiency, the pharmacokinetics of ceftobiprol have not been studied. Ceftobiprol undergoes minimal hepatic metabolism and is excreted mainly by the kidneys unchanged, so there is no reason to believe that the clearance of ceftobiprol in patients with hepatic insufficiency will be reduced.
Population studies of the pharmacokinetics of ceftobiprol did not reveal an independent effect of age on its pharmacokinetic parameters. In elderly patients with normal renal function, the dose of this drug is not required to be reduced.
The values ​​of systemic pharmacokinetic parameters of ceftobiprol in women were higher than in men (C max by 21% and AUC by 15%); at the same time,% t> MIC (where t is the time during which the concentration of the drug exceeds MIC) was similar in men and women. Therefore, there is no need to adjust the dose of Zefter's drug depending on the patient's sex.
Population studies of pharmacokinetics (including Caucasoids and a small number of Negroids and representatives of other races) did not reveal the influence of race on the pharmacokinetic parameters of ceftobiprole. No dosage adjustment is required depending on the race of the patient.
INDICATIONS
- treatment of complicated infections of the skin and its appendages, including an infected diabetic foot without concomitant osteomyelitis.
DOSING MODE
In infections that are suspected or proven to be caused by Gram-negative bacteria, Gram-positive and Gram-negative bacteria in an infected diabetic foot without concomitant osteomyelitis, the recommended dose of Zephter is 500 mg every 8 hours as a 120-minute IV infusion.
For infections that are suspected or proven to be caused by gram-positive bacteria, the dose is 500 mg every 12 hours as a 60-minute IV infusion. This dosing regimen (with 12-hour intervals) was not studied in patients with an infected diabetic foot.
In elderly patients, dose adjustment is not required.
In patients with minor renal dysfunction (KK 50-80 ml / min) dose adjustment is not required. For renal insufficiency of moderate severity (QC from 30 ml / min to <50 ml / min), the dose of Zephter is 500 mg every 12 h as a 120-minute IV infusion. For renal insufficiency of severe degree (CK <30 ml / min), the dose of the drug is 250 mg every 12 hours in the form of 120-minute IV infusions. Due to the limited clinical data and the expected increase in the concentration of ceftobiprole and its metabolites, Zefter preparation should be administered with caution to patients with severe renal insufficiency.
Ceftobiprole is excreted by hemodialysis, but at present there is insufficient information to change the dosage regimen in patients on dialysis. Thus, it is not recommended to prescribe the preparation of Zefter for patients on any kind of hemodialysis.
Currently, there is no experience with ceftobiprol in patients with hepatic insufficiency . However, given that ceftobiprole undergoes minimal metabolism in the liver and is eliminated mainly by the kidneys, it can be considered that in patients with hepatic insufficiency, the dose of ceftobiprol is not required to be reduced.
Rules for the preparation of an infusion solution
The lyophilized powder should be dissolved in 10 ml of water for injection or 5% glucose solution for injection. The contents of the vial should be vigorously shaken.Complete dissolution of the powder takes up to 10 minutes. Before breeding in an infusion solution, it is necessary to allow the foam to settle.
When diluted, 10 ml of the prepared solution should be removed from the vial and inserted into a suitable container (for example, polyvinyl chloride or polyethylene bags, glass bottles) containing 250 ml of 0.9% sodium chloride solution, 5% glucose solution or Ringer's lactate solution for infusion. The container with the infusion solution should be gently turned upside-down 5-10 times to obtain a homogeneous solution of ceftobiprole. To avoid foam formation, do not shake vigorously.
For patients with severe renal insufficiency, 5 ml of a ready solution of ceftobiprol is diluted in 125 ml of 0.9% sodium chloride solution, 5% glucose solution or Ringer's lactate solution for infusion.
Before administration, the infusion solution is visually inspected for the absence of mechanical inclusions, and upon detection of the latter, the solution is discarded.
SIDE EFFECT
Undesirable effects that occurred with a frequency of? 1% in patients who received 500 mg of ceftobiprol every 8-12 hours as 60-minute or 120-minute infusions are listed in Table 2.
The removal of ceftobiprol was required with the development of the following undesirable effects: skin rash (0.6%), nausea (0.5%), vomiting (0.4%), hypersensitivity reactions (0.3%), hyponatremia (0.3%).
Table 2. Frequency (%) of undesirable effects observed in two phase 3 clinical trials with a frequency of 1%
Systems of Zefter organs at 500 mg every 12 hours or 8 hours (n = 932) Comparison medications (n ​​= 661) (vancomycin and vancomycin + ceftazidime in studies that included patients with infections caused by both gram-positive and gram-negative bacteria)
Infections and invasions
fungal infections of the vulva and vagina, oral cavity and skin 2 2
Allergic reactions
urticaria, itching rash, drug hypersensitivity 1 3
From the side of metabolism
hyponatremia 1 0
From the side of the central nervous system and peripheral nervous system
headache 7 6
dizziness 3 2
perversion of taste 6 1
From the digestive system
Nausea 12 7
diarrhea 7 5
vomiting 7 4
indigestion 2 1
increased activity of hepatic enzymes (including ALT and AST) 3 3
Dermatological reactions
Rash (includes macular, papular, maculopapular and generalized) 4 3
itching 3 8
Local Reactions
skin reactions at the site of infusion 8 6
In most cases, the nausea was mild, it was self-administered, the drug was not required to be withdrawn. Nausea was less common in patients who received the drug in the form of 120-minute infusions (10%) than in 60-minute infusions (14%).
The incidence of seizures, anaphylaxis and pseudomembranous colitis caused by Clostridium difficile, with the use of ceftobiprole, was less than 1%.
CONTRAINDICATIONS
- indications in the anamnesis for allergic reactions to beta-lactam antibiotics;
- age up to 18 years;
- hypersensitivity to the components of the drug;
- Hypersensitivity to other cephalosporins.
Caution should be used in patients with renal insufficiency (CC less than 50 ml / min), epilepsy, with convulsive seizures (in the anamnesis), pseudomembranous colitis (in the anamnesis).
PREGNANCY AND LACTATION
Adequate and strictly controlled clinical studies of the use of Zefter during pregnancy were not conducted.
Preclinical studies have shown that ceftobiprol does not have teratogenic activity and does not affect ossification, fetal body mass and intrauterine development. The results of the study of the effect of drugs on the reproductive function of animals can not always be extrapolated to the corresponding human function, so Zepheter can be given to pregnant women only when the expected benefit of therapy for the mother exceeds the potential risk to the fetus.
It is not known whether ceftobiprole is excreted in human milk. Studies in animals have shown that ceftobiprol is excreted in breast milk. Given this, if you need to use the drug during lactation, breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER
In patients with minor renal dysfunction (KK 50-80 ml / min) dose adjustment is not required. For renal insufficiency of moderate severity (QC from 30 ml / min to <50 ml / min), the dose of Zephter is 500 mg every 12 h as a 120-minute IV infusion. For renal insufficiency of severe degree (CK <30 ml / min), the dose of the drug is 250 mg every 12 hours in the form of 120-minute IV infusions. Due to the limited clinical data and the expected increase in the concentration of ceftobiprole and its metabolites, Zefter preparation should be administered with caution to patients with severe renal insufficiency.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Currently, there is no experience with ceftobiprol in patients with hepatic insufficiency. However, given that ceftobiprole undergoes minimal metabolism in the liver and is eliminated mainly by the kidneys, it can be considered that in patients with hepatic insufficiency, the dose of ceftobiprol is not required to be reduced.
APPLICATION FOR CHILDREN
Contraindication: age to 18 years.
SPECIAL INSTRUCTIONS
In patients who received beta-lactam antibiotics, serious, sometimes fatal, anaphylactic reactions are described. These reactions occur more often in patients with allergy to a large number of allergens. Before starting treatment with Zepheter, you should carefully collect anamnesis and establish the presence of sensitivity reactions to other cephalosporins, penicillins or other allergens. In case of an allergic reaction to ceftobiprole, it should be immediately discontinued. With the development of severe acute reactions of hypersensitivity (anaphylaxis), urgent therapy is required.
It is necessary to carry out a bacteriological study to isolate and identify pathogens of infections and determine their sensitivity to ceftobiprole. In the absence of such data, empirical therapy should be conducted, guided by local epidemiological data and information on the local structure of microorganism sensitivity.
Patients receiving antibacterial agents, including ceftobiprol, may experience pseudomembranous colitis of varying severity. In this connection, it is necessary to remember the possibility of developing pseudomembranous colitis in patients who have diarrhea on the background of ceftobiprol treatment.
Prolonged use of ceftobiprole, like other antibiotics, can cause excessive reproduction of insensitive microorganisms, including fungi, and therefore it is necessary to periodically assess the patient's condition. If superinfection occurs during treatment with ceftobiprol, appropriate measures must be taken.
With the use of ceftobiprol, as well as other beta-lactams, the development of convulsive seizures is possible. The occurrence of seizures associated with the use of ceftobiprol is most often observed in patients with already existing CNS diseases. Therefore, caution is recommended in the treatment of such patients.
Impact on the ability to drive vehicles and manage mechanisms
There have been no studies of the influence of Zeftera on the ability to drive vehicles and work with mechanisms. When taking Zefter's drug, dizziness may develop, which affects the ability to drive vehicles and work that requires a high concentration of attention and speed of psychomotor reactions. Therefore, it is not recommended to use the drug while driving vehicles and other potentially hazardous activities.
OVERDOSE
At present, there is no information about an overdose of ceftobiprole in humans. The maximum dose that was introduced in Phase 1 clinical trials was 3 g / day (1 g every 8 hours).
Treatment: an overdose should be general supportive therapy with monitoring of vital signs. Reduce the concentration of ceftobiprole in the blood plasma is possible by means of hemodialysis.
DRUG INTERACTION
Ceftobiprole interaction studies with other drugs have not been conducted. Ceftobiprole possesses minimal ability to interact with other drugs
It is shown that ceftobiprole has a minimal ability to inhibit isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, as well as the lack of ability to induce these isoenzymes. Because of this and because the allocation is limited ceftobiprole extracellular fluid, it has low ability to affect the CYP450-mediated metabolic clearance of drugs administered concurrently. The ability to interact with other drugs ceftobiprole also minimal, since metabolism undergoes only a small part of the dose. Thus, there is no reason to expect the occurrence of clinically significant drug interactions ceftobiprole.
Ceftobiprole is not secreted by the renal tubules, and is reabsorbed only a fraction of the dose, and therefore on the level of kidney likelihood of drug interactions is very small.
Ne detected ceftobiprole effect on the pharmacokinetics of the drugs at the same time the following: fentanyl, lidocaine, acetaminophen, diclofenac, acetylsalicylic acid, heparin, diphenhydramine, propofol, hydromorphone hydrochloride, methadone, hydrocodone bitartrate, metamizole sodium and furosemide.
Pharmaceutical interaction
ceftobiprole Compatibility with other drugs has not been studied. Ceftobiprole should not be confused with other drugs or added to solutions containing other drugs.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be kept out of the reach of children, in a dark place in its original packaging at a temperature of from 2 В° to 8 В° C. Shelf life - 2 years.
Storage of the prepared solution and an infusion solution
may be stored in the prepared solution for 1 hour at 25 В° C and for 24 hours at a temperature of from 2 В° to 8 В° C.
Dissolution, dilution and infusion must be carried out for a time specified below in Table 3.
Table 3
Solvent (for solution for infusion) Infusion solution storage temperature of 25 В° C Infusion solution storage temperature of 2 В° to 8 В° C (refrigerator )
Storage in dark place Storage Storage light in the dark place
of 0.9% sodium chloride solution 24 h 8 h 96 h
5% dextrose 12 h 8 h 96 h
Ringer solution 24 h 8 h not keep in the fridge
The prepared solution and infusion solution should not be frozen and can not be put on the open sunlight.
After removal from the refrigerator infusion solutions should be allowed to warm to room temperature and only then do infusion. In use, infusion solution should be protected from light. Preparation of the infusion solution should be performed in accordance with the instructions for the preparation of the solution and handling.
