Composition, form of production and packaging
Solution for infusions is transparent, colorless or yellow.
1 ml
linezolid 2 mg
Excipients: sodium citrate dihydrate, citric acid, dextrose hydrate, water d / u.
100 ml - disposable infusion packs, made of Excel film, sealed inside a laminated foil (1, 2, 5, 10 or 25) - cardboard boxes.
200 ml - disposable infusion packs, made of Excel film, sealed inside a laminated foil (1, 2, 5, 10 or 25) - cardboard boxes.
300 ml - disposable infusion packs, made of Excel film, sealed inside a laminated foil (1, 2, 5, 10 or 25) - cardboard boxes.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2010.
PHARMACHOLOGIC EFFECT
Antimicrobial drug belongs to the class of oxazolidinones. The mechanism of action of the drug is due to selective inhibition of protein synthesis in bacteria. By binding to bacterial ribosomes, linezolid prevents the formation of a functional initiating complex 70S, which is a component of the translation process in protein synthesis.
The drug is active against aerobic Gram-positive bacteria: Corynebacterium jeikeium, Enterococcus faecalis (including glycopeptide-resistant strains), Enterococcus faecium (including glycopeptide-resistant strains), Enterococcus casseliflavus, Enterococcus gallinarum, Listeria monocytogenes, Staphylococcus aureus (including methicillin-resistant strains), Staphylococcus aureus (strains with intermediate sensitivity to glycopeptides), Staphylococcus epidermidis (including methicillin-resistant strains), Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus intermedius, Streptococcus pneumoniae (including strains with intermediate sensitivity to neoplasm nitsillinu and penicillin-resistant strains), Streptococcus spp. (group C and G streptococci), Streptococcus pyrogenes, Streptococcus viridans; aerobic gram-negative bacteria: Pasteurella canis, Pasteurella multocida; anaerobic Gram-positive bacteria: Clostridium perfringens, Peptostreptococcus spp. (including Peptostreptococcus anaerobius); anaerobic gram-negative bacteria: Bacteroides fragilis, Prevotella spp .; Chlamydia pneumoniae.
The drug is moderately sensitive to Legionella spp., Moraxella catarrhalis, Mycoplasma spp.
The drug is resistant to Haemophilus influenzae, Neisseria spp., Enterobacteriaceae, Pseudomonas spp.
There was no cross-resistance between Zyvox and aminoglycosides, beta-lactam antibiotics, folic acid antagonists, glycopeptides, lincosamides, quinolones, rifamycins, streptograms, tetracyclines, chloramphenicol. The mechanism of action of linezolid differs from the mechanisms of action of these antibacterial drugs.
Resistance to Zyvoksu develops slowly through a multistage mutation of 23S ribosomal RNA and occurs at a frequency of less than 1x10 -9 -1x10 -11 .
In vitro, the post-antibiotic effect of Zyvox is about 2 h for Staphylococcus aureus, in vivo (in experimental animal studies) - 3.6 h and 3.9 h for Staphylococcus aureus and Staphylococcus pneumoniae, respectively.
PHARMACOKINETICS
The active substance of Zivox В® is (s) -lenezolid, which is biologically active and metabolized in the body with the formation of inactive derivatives. The solubility of linezolid in water is about 3 mg / ml and does not depend on pH in the range of 3-9.
The average pharmacokinetic parameters (standard deviation) of linezolid in healthy volunteers after a single and multiple (before the achievement of C ss linezolid in the blood) in / in the administration are given in the tables.
Table 1
Zyvox dosage regimen Pharmacokinetic parameters
C max (SD) Ојg / ml C min (SD) Ојg / ml T max (SD) h
Solution for infusions 600 mg once 12.9 (1.6) - 0.5 (0.1)
Solution for infusions 600 mg 2 times / day 15.1 (2.52) 3.68 (2.36) 0.51 (0.03)
table 2
Zyvox dosage regimen Pharmacokinetic parameters
AUC (SD) Ојg x h / ml T 1/2 (SD) h Cl (SD) ml / min
Solution for infusion 600 mg once 80.2 (33.3) 4.4 (2.4) 138 (39)
Solution for infusions 600 mg 2 times / day 89.7 (31) 4.8 (1.7) 123 (40)
SD is the standard deviation
The average values ​​of C min achieved at the dosing regimen of 600 mg 2 times / day are approximately equal to the highest values ​​of the MIC of 90 for the least sensitive microorganisms.
Distribution
Linezolid is rapidly distributed in tissues with good perfusion. V d at achievement C ss at healthy volunteers makes on the average 40-50 l. Binding to plasma proteins is 31% and does not depend on the concentration of linezolid in the blood.
Metabolism
It is established that cytochrome P450 isoenzymes do not participate in the metabolism of linezolid in vitro. Linezolid also does not inhibit the activity of clinically important cytochrome P450 isoenzymes (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Metabolic oxidation leads to the formation of 2 inactive metabolites - hydroxyethylglycine (which is the main metabolite in humans and is formed as a result of a non-enzymatic process) and aminoethoxyacetic acid (formed in smaller amounts). Other inactive metabolites are also described.
Excretion
Linezolid is excreted mainly with urine in the form of hydroxyethyl glycine (40%), aminoethoxyacetic acid (10%) and unchanged drug (30-35%). It is excreted in the form of hydroxyethyl glycine (6%) and aminoethoxyacetic acid (3%). The unchanged drug is practically not excreted with feces.
Pharmacokinetics in special clinical cases
The pharmacokinetics of linezolid was studied after a single intravenous administration at a dose of 10 mg / kg or 600 mg in children from birth to 17 years (including both full-term and premature newborns), in healthy adolescents (12-17 years) and in children from 1 week to 12 years.
Pharmacokinetic parameters - mean value (correlation coefficient,%) [minimum value; maximum value]) are shown in the table.
Table 3
Age group C max Ојg / ml V d l / kg AUC Ојg x h / ml T 1/2 h Cl ml / min / kg
Newborn preterm infants * <1 week f 12.7 (30%) [9.6; 22.2] 0.81 (24%) [0.43; 1.05] 108 (47%) [41; 191] 5.6 (46%) [2.4; 9.8] 2.0 (52%) [0.9; 4.0]
Newborn donors ** <1 week f 11.5 (24%) [8.0; 18.3] 0.78 (20%) [0.45; 0.96] 55 (47%) [19; 103] 3.0 (55%) [1.3; 6.1] 3.8 (55%) [1.5; 8.8]
Newborn donors ** from 1 to 4 weeks f 12.9 (28%) [7.7; 21.6] 0.66 (29%) [0.35; 1.06] 34 (21%) [23; 50] 1.5 (17%) [1.2; 1.9] 5.1 (22%) [3.3; 7.2]
Newborns from 4 weeks to 3 months f 11.0 (27%) [7.2; 18.0] 0.79 (26%) [0.42; 1.08] 33 (26%) [17; 48] 1.8 (28%) [1.2; 2.8] 5.4 (32%) [3.5; 9.9]
Children from 3 months to 11 years f 15.1 (30%) [6.8; 36.7] 0.69 (28%) [0.31; 1.5] 58 (54%) [19; 153] 2.9 (53%) [0.9; 8.0] 3.8 (53%) [1.0; 8.5]
Adolescents 11 to 17 years of age J 16.7 (24%) [9.9; 28.9] 0.61 (15%) [0.44; 0.79] 95 (44%) [32; 178] 4.1 (46%) [1.3; 8.1] 2.1 (53%) [0.9; 5.2]
Adults В§ 12.5 (21%) [8.2; 19.3] 0.65 (16%) [0.45; 0.84] 91 (33%) [53; 155] 4.9 (35%) [1.8; 8.3] 1.7 (34%) [0.9; 3.3]
* - pregnancy <34 weeks (1 premature infant aged 1 to 4 weeks included.
** - pregnancy? 34 weeks
f - dose of linezolid 10 mg / kg
J - dose of linezolid 600 mg or 10 mg / kg to a maximum of 600 mg
В§ - dose of linezolid 600 mg
C max and V d of linezolid do not depend on the age of the patients, while the linezolid clearance varies with age. In children from 1 week to 11 years of age, the clearance is greatest, with AUC and T 1/2 being less than in adults. As the age increases, the linezolid clearance gradually decreases, while in adolescence the average clearance values ​​approach those of adults.
In children under 11 years of age, who received the drug every 8 hours, and in adults and adolescents who received the drug every 12 hours, the average daily AUC values ​​were noted. The clearance of linezolid is higher in children and decreases with age.
The pharmacokinetics of linezolid does not change significantly in the group of patients aged 65 years and older.
Some pharmacokinetic differences in women, expressed in slightly more reduced V d , decrease in clearance by approximately 20%, sometimes in higher concentrations in the blood plasma, are noted. Since T 1/2 of linezolid is not significantly different in women and men, there is no need to adjust the dose of the drug.
In patients with mild, moderate and severe renal insufficiency, dose adjustment is not required; there is no relationship between QA and the excretion of the drug through the kidneys. Since 30% of the dose is withdrawn within 3 hours of hemodialysis, in patients receiving similar treatment, linezolid should be administered after dialysis.
The pharmacokinetics of linezolid does not change in patients with moderate or moderate hepatic impairment, so there is no need to adjust the dose of the drug.
Pharmacokinetics in patients with severe hepatic insufficiency has not been studied. However, considering that linezolid is metabolized as a result of a non-enzymatic process, it can be argued that liver function does not significantly affect the metabolism of the drug.
INDICATIONS
Treatment of infectious and inflammatory diseases caused by anaerobic and aerobic Gram-positive microorganisms sensitive to the drug (including infections accompanied by bacteremia):
- community-acquired pneumonia;
- hospital pneumonia;
- skin and soft tissue infections;
- infections caused by Enterococcus spp. (including Enterococcus faecalis and Enterococcus faecium strains resistant to vancomycin).
Infections caused by gram-negative microorganisms, confirmed or suspected (as part of combination therapy).
DOSING MODE
Solution for infusions should be administered within 30-120 minutes.
The dosage regimen and duration of treatment depends on the pathogen, the location and severity of the infection, and also on clinical effectiveness.
The recommended dosing regimen for adults and children over 12 years is indicated in the table:
Indications (including infections accompanied by bacteremia) Single dose and multiplicity of administration Recommended duration of treatment
Community-acquired pneumonia 600 mg every 12 hours 10-14 days
Hospital pneumonia 600 mg every 12 hours 10-14 days
Infections of the skin and soft tissues 600 mg every 12 h 10-14 days
Enterococcal infections 600 mg every 12 hours 14-28 days
The recommended dosing regimen for children under the age of 12 years is indicated in the table:
Indications (including infections accompanied by bacteremia) Single dose and multiplicity of administration Recommended duration of treatment
Community-acquired pneumonia 10 mg / kg every 8 hours 10-14 days
Hospital pneumonia 10 mg / kg every 8 hours 10-14 days
Infections of the skin and soft tissues 10 mg / kg every 8 h 10-14 days
Enterococcal infections 10 mg / kg every 8 hours 14-28 days
Patients who at the beginning of the therapy the drug was assigned IV, in the future can be transferred to any dosage form for oral administration. At the same time, dose selection is not required, because bioavailability with oral administration is almost 100%.
Rules for administering the solution
It is necessary to remove the protective membrane from the foil immediately before the infusion and for about 1 minute compress the infusion bag to make sure there are no leaks. If the bag is leaking, the solution is not sterile.
Infusion packets can not be connected in series.
Remains of unused solution should be destroyed. Do not use partially filled packages.
SIDE EFFECT
On the part of the digestive system: often (> 1%) - perversion of taste, nausea, vomiting, diarrhea, abdominal pain (including spastic), flatulence, changes in bilirubin, ALT, AST, APF.
From the hemopoietic system: often (> 1%) - reversible anemia, thrombocytopenia, leukopenia, pancytopenia.
Other: often (> 1%) - headache, candidiasis; rarely cases of peripheral neuropathy and optic nerve neuropathy when used for more than 28 days (the relationship between Zyvox's application and the development of neuropathy has not been proved, since in most of these cases patients or concurrently received drugs that can cause neuropathy (amitriptyline, paroxetine, isoniazid) and / or had diseases that can lead to the development of neuropathy (diabetes mellitus, hypertension, chronic renal failure, osteosarcoma, brain abscess).
Adverse reactions are dose independent and, as a rule, do not require discontinuation of treatment.
CONTRAINDICATIONS
- hypersensitivity to linezolid and / or other components of the drug.
PREGNANCY AND LACTATION
Adequate and strictly controlled studies of the safety of ZyvoxВ® during pregnancy have not been conducted. Zyvox application in pregnancy is possible only in cases where the intended benefit of therapy for the mother exceeds the potential risk.
It is not known if linezolid is excreted in breast milk, therefore, breastfeeding should be stopped with the prescription of the mother during lactation.
APPLICATION FOR FUNCTIONS OF THE LIVER
In patients with mild, moderate and severe renal insufficiency, dose adjustment is not required; there is no relationship between QA and the excretion of the drug through the kidneys. Since 30% of the dose is withdrawn within 3 hours of hemodialysis, in patients receiving similar treatment, linezolid should be administered after dialysis.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
The pharmacokinetics of linezolid does not change in patients with moderate or moderate hepatic impairment, so there is no need to adjust the dose of the drug.
Pharmacokinetics in patients with severe hepatic insufficiency has not been studied. However, considering that linezolid is metabolized as a result of a non-enzymatic process, it can be argued that liver function does not significantly affect the metabolism of the drug.
APPLICATION FOR CHILDREN
The recommended dosing regimen for children under the age of 12 years is indicated in the table:
Indications (including infections accompanied by bacteremia) Single dose and multiplicity of administration Recommended duration of treatment
Community-acquired pneumonia 10 mg / kg every 8 hours 10-14 days
Hospital pneumonia 10 mg / kg every 8 hours 10-14 days
Infections of the skin and soft tissues 10 mg / kg every 8 h 10-14 days
Enterococcal infections 10 mg / kg every 8 hours 14-28 days
APPLICATION IN ELDERLY PATIENTS
The pharmacokinetics of linezolid does not change significantly in the group of patients aged 65 years and older.
SPECIAL INSTRUCTIONS
With the development of diarrhea in patients taking ZyvoxВ®, the risk of developing pseudomembranous colitis of varying severity should be considered.
Control of laboratory indicators
In the process of treatment, it is necessary to conduct a clinical blood test in patients with an increased risk of bleeding, myelosuppression in anamnesis, as well as simultaneous use of drugs that reduce hemoglobin, platelet count or their functional properties, and in patients receiving linezolid for more than 2 weeks.
Impact on the ability to drive vehicles and manage mechanisms
Reception Zivox В® does not affect the ability to drive vehicles and management mechanisms.
OVERDOSE
At present, no cases of an overdose of Zyvox В® have been reported.
Treatment: if necessary, conduct symptomatic therapy (including the need to maintain the level of glomerular filtration). Approximately 30% of the dose is excreted within 3 hours of hemodialysis.
DRUG INTERACTION
Linezolid is a weak, reversible, non-selective MAO inhibitor, so in some patients ZyvoxВ® can cause a moderate reversible increase in the pressor effect of pseudoephedrine and phenylpropanolamine. Considering this, with simultaneous application it is recommended to reduce initial doses of adrenergic drugs (including dopamine and its agonists) and further dose selection by titration.
Pharmacokinetic interaction
With the simultaneous administration of Zyvox with aztreonam and gentamicin, there was no change in the pharmacokinetics of linezolid.
Pharmaceutical interaction
Zyvox В® in the form of a solution for infusions is compatible with the following solutions: 5% glucose solution (dextrose), 0.9% sodium chloride solution, Ringer's injection solution with lactose.
Solution for infusion is pharmaceutically incompatible with amphotericin B, chlorpromazine, diazepam, pentamidine isethionate, phenytoin, erythromycin, co-trimoxazole.
Solution for infusion is chemically incompatible with ceftriaxone sodium.
Do not add additional ingredients to the infusion solution. When prescribing Zyvox simultaneously with other drugs, each drug should be administered separately.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored at a temperature of no higher than 25 В° C. Shelf life - 3 years.
Before use, infusion bags should be stored in a foil wrap and in a cardboard box. After opening, the contents of the package should be used immediately.
