ZEFTERA

Active material: Tseftobyprol
When ATH: J01DI01
CCF: IV generation cephalosporin
ICD-10 codes (testimony): L01, L02, L03, L08.0
When CSF: 06.02.04
Manufacturer: JANSSEN PHARMACEUTICA N.V. (Belgium)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Valium for solution for infusion in the form of compact, the fractured or powder of a white or slightly yellowish to brownish color.

Excipients: citric acid monohydrate, Sodium hydroxide, nitrogen (inert gas lyophilization).

Glass Bottles capacity 20 ml (1) – packs cardboard.
Glass Bottles capacity 20 ml (10) – packs cardboard.

Pharmacological action

The antibiotic of cephalosporin group. Ceftobiprole is a water soluble prodrug medokaril ceftobiprole, cephalosporin, having bactericidal activity against a broad spectrum of gram-positive bacteria, including methicillin-resistant Staphylococcus species, penicillin-resistant Streptococcus pneumoniae, and ampicillin-sensitive Enterococcus faecalis. Ceftobiprole also active against many gram-negative bacteria, including many strains of Enterobacter spp family. и Pseudomonas aeruginosa.

Ceftobiprole is closely associated with many important penicillin-binding proteins (RVR) both Gram positive, and Gram-negative bacteria. Ceftobiprole has a pronounced bactericidal activity against Staphylococcus spp., resistant to methicillin, thanks to strong binding to staphylococci PBP2a, including methicillin-resistant Staphylococcus aureus.

Tseftobyprol active against most isolates of the following organisms both in vitro, and in 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 man , Staphylococcus lugdunensis and Staphylococcus saprophyticus), Streptococcus pneumoniae (isolates, penicillin-sensitive, moderately resistant to penicillin and penicillin resistance), Streptococcus viridans group; Gram-negative aerobic – Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus is wonderful, Pseudomonas aeruginosa, Citrobacter spp. (including Citrobacter freundii, Citrobacter koseri), Enterobacter aerogenes, Klebsiella oxytoca, Moraxella catarrhalis, Morganella morganii, Neisseria spp., Providencia spp., Serratia wilting.

Ceftobiprole is resistant to hydrolysis by Staphylococcus aureus penicillinases, as well as to hydrolysis by many β-lactamases of class C and class A, produced by Gram-negative bacteria. Like most cephalosporins, ceftobiprole hydrolyses beta-lactamases spread spectrum, carbapenemases and metallo-beta-lactamases. In vitro was observed breeding high-level resistance in staphylococci, streptococci and Haemophilus influenzae .

Resistance to ceftobiprole, caused by a spontaneous mutation in vitro, rarely observed. Described cross-resistance between ceftobiprole and some other latest generation cephalosporins. At the same time, Enterobacteriaceae, resistant to other cephalosporins, may be sensitive to ceftobiprole.

Pharmacokinetics

Mean pharmacokinetic parameters ceftobiprole in adults after administration in a single dose 500 mg as an infusion for 60 min and administration in multiple doses 500 mg as infusion for 120 every min 8 no, are given in Table. 1. Pharmacokinetic characteristics similar after administration of a single dose and after administration of multiple doses.

Table 1. Average (standard deviation) pharmacokinetic parameters of ceftobiprole in adults

C_max ceftobiprole and AUC increased proportionally with dose in the dose range 125 mg – 1 g. C_ss concentrations are achieved on the first day of treatment; in people with normal kidney function every introduction of ceftobiprole 8 hours and every 12 h did not cause its accumulation.

Distribution

Binding ceftobiprole plasma protein is 16% and does not depend on its concentration. V_d at steady state 18 L, approaching the extracellular fluid volume in humans.

Metabolism

Biotransformation through Ceftobiprole Medocaril, which is a prodrug of, the active substance ceftobiprole occurs rapidly and is catalyzed by plasma esterases. The concentrations of prodrug are negligible, and it can be detected in plasma and urine only during infusion.

Ceftobiprole undergoes minimal metabolism to non-cyclic metabolite, which is microbiologically inactive. The concentration of this metabolite concentrations below of ceftobiprole and is about 4 % from the last.

Deduction

Ceftobiprole is derived mainly unchanged through the renal excretion. T_1/2 is about 3 no. The main mechanism of renal excretion is glomerular filtration, a small fraction of the dose undergoes tubular reabsorption. In preclinical studies, probenecid does not affect the pharmacokinetics of ceftobiprole, indicating no active tubular secretion of last. After a single dose of approximately 89% detected in the urine as active ceftobiprole (83%), metabolite with an open ring (5%) and ceftobiprole medokarila (<1%).

Pharmacokinetics in special clinical situations

The pharmacokinetics of ceftobiprole is similar in healthy volunteers and in patients with renal insufficiency, mild (CC 50-80 ml / min). Compared with the AUC in healthy volunteers with normal renal function, AUC was ceftobiprole 2.5 and 3.3 times greater in patients with renal failure secondary to the (KK from 30 ml / min and ≤50 ml / min) and severe (CC < 30 ml / min) respectively. In patients with renal failure secondary to severe recommended to reduce the dose of ceftobiprole. AUC ceftobiprole and its microbiologically inactive metabolite with the structure of the open ring increases patients, who require hemodialysis, compared to the AUC in healthy volunteers.

In patients with hepatic impairment has not been studied pharmacokinetics of ceftobiprole. Ceftobiprole undergoes minimal hepatic metabolism and is mainly excreted by the kidneys unchanged, so there is no reason to believe, that the clearance of ceftobiprole in patients with hepatic impairment to be reduced.

Population pharmacokinetic studies ceftobiprole showed no independent effect of age on its pharmacokinetic parameters. Elderly patients with normal renal function to reduce the dose of the drug is not required.

The values ​​of the pharmacokinetic parameters of system ceftobiprole were higher in women, than men (C_max on 21 % and AUC of 15 %); at the same time % t>MIK (where t – time, during which the drug concentration exceeds the MIC) It was similar in men and women. Hence, no need to adjust the dose depending on Zeftera sex of the patient.

Population pharmacokinetic studies (which included a small number of Caucasians and Negroid and other races) We found no effect of race on the pharmacokinetic parameters of ceftobiprole. It does not require correction dose, depending on the race of the patient.

Testimony

- The treatment of complicated infections of the skin and its appendages, including infected diabetic foot without concomitant osteomyelitis.

Dosage regimen

At infections, presumed or proven caused by Gram-negative bacteria, Gram-positive and Gram-negative bacteria in the infected diabetic foot without concomitant osteomyelitis, the recommended dose is Zeftera 500 mg every 8 hours in a 120-min / in infusion.

At infections, presumed or proven caused by Gram-positive bacteria, dose is 500 mg every 12 h in a 60-min / in infusion. This dosing regimen (at 12 hour intervals) not studied in patients with infected diabetic foot.

In elderly patients dose adjustment is not required.

In patients minor impairment of renal function (CC 50-80 ml / min) dose adjustment is not required. At moderately severe renal failure (KK from 30 ml / min to <50 ml / min) dose of Zeftera 500 mg every 12 hours in a 120-min / in infusion. At severe renal insufficiency (CC <30 ml / min) dose is 250 mg every 12 hours in a 120-min / in infusion. Due to limited clinical data and the anticipated increase in the concentration of ceftobiprole and its metabolites Zeftera drug should be prescribed with caution in patients with severe renal insufficiency.

Ceftobiprole appear in hemodialysis, but currently not enough information to change dosage regimen in patients, dialysis. Thus, Zeftera drug is not recommended for patients, We are on any form of hemodialysis.

Currently, there is no experience in the use of ceftobiprole Patients with liver failure. However, given the, that ceftobiprole undergoes minimal metabolism in the liver and is eliminated primarily by the kidneys, it could be considered, In patients with hepatic failure dose of ceftobiprole reduce not required.

Rules of drug infusion solution

The lyophilized powder can be dissolved in 10 ml 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 10 m. Before dilution in the infusion solution should be given to settle the resulting foam.

Dilution 10 ml of this solution should be removed from the bottle and put in an appropriate container (eg, bags made of polyvinyl chloride or polyethylene, glass bottles), containing 250 ml 0.9% sodium chloride, 5% glucose solution or Ringer's lactate solution for infusion. Capacity with infusion solution should be gently turned upside-down 5-10 time to obtain a uniform solution ceftobiprole. In order to avoid the formation of foam can not shake vigorously solution.

To patients with severe renal insufficiency 5 ml final solution is diluted in ceftobiprole 125 ml 0.9% sodium chloride, 5% glucose solution or Ringer's lactate solution for infusion.

Before the introduction of the infusion solution is visually checked for the absence of mechanical impurities and, if found a solution last cull.

Side effect

Adverse effects, It occurs with a frequency ≥1 % patients, which was prepared 500 ceftobiprole mg every 8-12 h in a 60-minute or 120-minute infusion, are listed in Table 2.

Cancel ceftobiprole was required during the development of the following undesirable effects: skin rash (0.6%), nausea (0.5 %), vomiting (0.4 %), hypersensitivity reactions (0.3%), giponatriemiya (0.3%).

Table 2. Frequency (%) adverse effects, observed in two clinical trials of phase 3 a frequency ≥1%

In most cases, mild nausea was, held their own, removal of the drug is not required. Nausea was observed in patients less, receiving the drug in the form of 120-minute infusion (10%), than in the case of 60-minute infusion (14%).

The incidence of seizures, anaphylaxis and pseudomembranous colitis, caused by Clostridium difficile, the application of ceftobiprole, was less than 1%.

Contraindications

- Specifying a history of allergic reaction to beta-lactam antibiotics;

- Up to 18 years;

- Hypersensitivity to the drug;

- Hypersensitivity to other cephalosporins.

FROM caution should use the drug in patients with renal insufficiency (CC less than 50 ml / min), epilepsy, during seizures (history), psevdomembranoznom cars (history).

Pregnancy and lactation

There are no adequate and well-controlled clinical trials of the drug Zeftera during pregnancy was conducted.

Preclinical studies have shown, that ceftobiprole has no teratogenic activity and does not affect the ossification, body mass and the fetus in utero. The results of studies of the effect of drugs on the reproductive function of animals can not always be extrapolated to the proper function of man, so the drug can be administered Zeftera pregnant women only if, when the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

Unknown, whether it is allocated ceftobiprole in breast milk in humans. Animal studies have shown, that ceftobiprole is excreted in breast milk. Considering this, If necessary, use during lactation should stop breastfeeding.

Cautions

Patients, treated with beta-lactam antibiotics, described severe, sometimes with fatal consequences, anaphylactic reactions. These reactions often occur in patients with allergies to allergens large number. Before the start of treatment should be carefully collected Zeftera history and establish the presence of hypersensitivity reactions to other cephalosporins, penicillins or other allergens. In the event of an allergic reaction to ceftobiprole it must immediately cancel. With the development of severe acute hypersensitivity reactions (anaphylaxis) require emergency treatment.

It is necessary to conduct bacteriological research to isolate and identify pathogens and to determine their susceptibility to ceftobiprole. In the absence of such data should be empirical therapy, guided by local epidemiological data and information on the local structure of the sensitivity of microorganisms.

Patients, receiving antibacterials, including ceftobiprole, pseudomembranous colitis can cause varying degrees of severity. Concerning, should be aware of the possibility of pseudomembranous colitis patients, who during treatment with ceftobiprole appears diarrhea.

Prolonged use of ceftobiprole, as well as other antibiotics, can cause excessive proliferation of non-susceptible organisms, including fungi, and so you need to periodically assess the patient's condition. If superinfection occurs during treatment with ceftobiprole is necessary to take appropriate action.

In the application of ceftobiprole, as well as other beta-lactams, may develop seizures. The occurrence of seizures, associated with the use of ceftobiprole, most often seen in patients with pre-existing diseases of the CNS. It is therefore recommended in the treatment of these patients requires caution.

Effects on ability to drive vehicles and management mechanisms

There have been no studies of the effect Zeftery the ability to drive vehicles and operate machinery. Before the drug may develop dizziness Zeftera, which affects the ability to drive vehicles and work, require high concentration and speed of psychomotor reactions. Therefore, it is not recommended to use the drug while driving vehicles and other potentially dangerous activities.

Overdose

Currently there is no information on overdose of ceftobiprole in humans. The maximum dose, which was introduced in the phase 1 Clinical Research, made 3 g / day (1 g every 8 no).

Treatment: with an overdose should be general supportive therapy with monitoring of vital signs. Decrease ceftobiprole concentration in the blood plasma by using a hemodialysis.

Drug Interactions

Ceftobiprole interaction studies with other drugs have not been conducted. Ceftobiprole has minimal ability to interact with other drugs

Displaying, that ceftobiprole has minimal ability to inhibit CYP1A2 isoenzymes, CYP2C9, CYP2C19, CYP2D6 и CYP3A4, and the lack of ability to induce these isoenzymes. Due to this and due to the, that the distribution of ceftobiprole limited extracellular fluid, it has low impact on CYP450-mediated metabolic clearance of drugs administered simultaneously. The ability to interact with other drugs is also minimal ceftobiprole, because the metabolism undergoes only a small part of the dose. Thus, no reason to expect the occurrence of clinically significant drug interactions ceftobiprole.

Ceftobiprole is not secreted by the renal tubules, reabsorbed and only a fraction of the dose, and therefore the likelihood of drug interactions at the level of the kidney is very small.

Ne The effect on the pharmacokinetics of ceftobiprole following simultaneously used drugs: Fentanyl, lidokain, paracetamol, diclofenac, acetylsalicylic acid, Heparin, difengidramin, Propofol, hydromorphone hydrochloride, methadone, gidrokodona ʙitartrat, metamizole sodium and furosemide.

Pharmaceutical interaction

Ceftobiprole Compatibility with other drugs has not been studied. Ceftobiprole should not be mixed with other drugs or added to a solution, other drugs containing.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children, in a dark place in its original packaging at a temperature of 2 ° to 8 ° C. Shelf life – 2 year.

Storage of the prepared solution and an infusion solution

The prepared solution can be stored for 1 hours at a temperature of 25 ° C and for 24 hours at a temperature of from 2 ° to 8 ° C..

Dissolution, dilution and infusion must be carried out in the course of time, specified in the table below 3.

Table 3.

The prepared solution and infusion solution should not be frozen and can not be put on the sun's rays.

After removal from the refrigerator infusion solutions should give to warm to room temperature and only then do infusion. In use, infusion solution should not be protected from light. Preparation of the infusion solution should be performed in accordance with the instructions for the preparation of the solution and the treatment of them.