Active substanceLinezolidLinezolid
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  • Dosage form: & nbspsolution for infusions
    Composition:

    Composition per ml:

    Active substance: linezolid - 2.00 mg;

    Excipients: Dextrose monohydrate - 50,24 mg, sodium citrate - 1,64 mg, citric acid - 0,85 mg, 1 M sodium hydroxide solution to pH 4.6 - 5.0, 1 M solution of hydrochloric acid to pH 4.6 - 5.0, water for injection up to 1 ml.

    Description:Transparent solution from colorless to yellow with a brownish hue.
    Pharmacotherapeutic group:Antibiotic-oxazolidinone
    ATX: & nbsp

    J.01.X.X.08   Linezolid

    J.01.X.X   Other antibacterial drugs

    Pharmacodynamics:

    Synthetic antibacterial drug, refers to a new class of antimicrobial agents, oxazolidinones, active in vitro in relation to aerobic Gram-positive bacteria, certain gram-negative bacteria and anaerobic microorganisms. Linezolid selectively inhibits protein synthesis in bacteria. By binding to bacterial ribosomes, it prevents the formation of a functional initiating complex 70S, which the is an important component of the translation process in protein synthesis. Sensitivity

    Linezolid active in vitro and in vivo

    Gram-positive aerobes

    Enterococcus faecium (Including strains resistant to vancomycin)

    Staphylococcus aureus (including methicillin-resistant strains)

    Streptococcus agalactiae

    Streptococcus pneumoniae (including multidrug-resistant strains)

    Streptococcus pyogenes

    Linezolid is active in vitro

    Gram-positive aerobes

    Enterococcus faecalis (including strains resistant to vancomycin),

    Enterococcus faecium (strains sensitive to vancomycin),

    Staphylococcus epidermidis (including methicillin-resistant strains)

    Staphylococcus haemolyticus

    Streptococcus spp. groups viridans

    Gram-negative aerobes

    Pasteurella multocida

    Resistant to linezolid microorganisms

    Haemophilus influenzae

    Moraxella catarrhalis

    Neisseria spp.

    Enterobacteriaceae spp.

    Pseudomonas spp.

    Resistance

    The mechanism of action of linezolid differs from the mechanisms of action of antimicrobials of other classes (for example, aminoglycosides, beta-lactams, folic acid antagonists, glycopeptides, lincosamides, quinolones, rifampicins, streptogramins, tetracyclines and chloramphenicol), so there is no cross-resistance between linezolid and these drugs. Linezolid is active against pathogenic microorganisms, both sensitive and resistant to these drugs. Resistance to linezolid develops slowly through a multistage mutation 23S ribosomal RNA and occurs at a frequency of less than 1 × 10-9 - 1x10-11 .

    Pharmacokinetics:

    Suction

    The maximum concentration (Cmax) and the minimum concentration (Cmin) linezolid in blood plasma in an equilibrium state after intravenous administration twice a day at a dose of 600 mg were 15.1 mg / L and 3.68 mg / L, respectively. The equilibrium concentration of linezolid in the blood is reached on the 2nd day of the drug administration.

    Distribution

    The volume of distribution of linezolid at equilibrium concentration in a healthy adult is on the average 40-50 liters, which is approximately equal to the total water content in the body. The 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 does not inhibit or potentiate the activity of clinically important cytochrome P450 isoenzymes (1A2, 2C9, 2C19, 2D6, 2E1.3A4).

    Metabolic oxidation leads to the formation of two inactive metabolites - hydroxyethylglycine (the main metabolite in humans, formed as a result of a non-enzymatic process), and aminoethoxyacetic acid (formed in smaller amounts). Other inactive metabolites are also described.

    Excretion

    The extrarenal clearance is about 65% of the linezolid clearance.With increasing dose of linezolid, a small degree of nonlinearity of clearance is noted. This can be explained by a decrease in renal and extrarenal clearance with a high dose of linezolid. However, the differences in clearance are small and do not affect the apparent half-life.

    Linezolid in patients with normal renal function and with renal insufficiency of mild and moderate degree is excreted by the kidneys in the form of hydroxyethyl glycine (40%), aminoethoxyacetic acid (10%) and unchanged (30-35%). The intestine is excreted as hydroxyethyl glycine (6%) and aminoethoxyacetic acid (3%).

    Unchanged linezolid practically not excreted by the intestine. The half-life of linezolid on average is 5-7 hours.

    Pharmacokinetics in selected patient groups

    Patients with renal insufficiency

    After a single administration of 600 mg of the drug to patients with severe renal insufficiency (creatinine clearance <30 ml / min), the concentration of its two main metabolites increased 7-8 times. However, the increase in the area under the "concentration-time" curve (AUC) of the starting drug was not observed. Despite the fact that during hemodialysis a number of major metabolites were excreted,their plasma concentration after the administration of 600 mg of linezolid and the dialysis procedure in patients with severe renal insufficiency remained significantly higher than the blood concentration in patients with normal renal function, mild or moderate renal insufficiency.

    Patients with hepatic insufficiency

    There is limited evidence that the pharmacokinetics of linezolid and its two major metabolites do not change in patients with mild or moderate hepatic impairment (Child-Pugh classes A and B). The pharmacokinetics of linezolid in patients with severe hepatic impairment (Child-Pugh class C) has not been studied. However, since linezolid it is not metabolized by a non-enzyme route, it is not expected to significantly impair its metabolism in liver failure.

    Children and teens

    In adolescents (12-17 years old), the pharmacokinetics of linezolid, taken in a dose of 600 mg, did not differ from the kinetics in adults. Thus, with the appointment of adolescents 600 mg of linezolid every 12 hours, the concentration of the drug will be the same as in adults when the same dose is given.

    In children from 1 week to 12 years, the use of linezolid at a dose of 10 mg / kg every 8 hours allows achieving the same exposure as in adults with 600 mg of linezolid twice daily.

    In newborns, the systemic clearance of linezolid rapidly increases during the first week of life (based on kg of body weight). Thus, when applied at a dose of 10 mg / kg every 8 hours, the maximum exposure of linezolid will be achieved in the child of the first day of life faster on the first day after birth. However, the excessive accumulation of the drug in the first week of use with this designation scheme still will not happen due to the rapid increase in clearance.

    Elderly

    In elderly patients aged 65 years and older, the pharmacokinetics of linezolid do not change significantly.

    Women

    In women, the distribution of the drug is somewhat lower than that of men; they also reduced by 20% the average clearance in terms of body weight. The concentration of linezolid in the blood plasma of women is higher than that of men, which can partly be explained by differences in body weight. However, since the half-life of linezolid in men and women is not significantly different,there is no reason to expect an increase in the concentration of linezolid in the blood of women above the tolerated value, so that dose adjustments are not it takes.

    Indications:

    Treatment of infectious inflammatory diseases, if known or suspected, that they are caused by aerosol and anaerobic Gram-positive microorganisms sensitive to linezolid (including infections accompanied by bacteremia):

    - Community-acquired pneumonia Streptococcus pneumoniae (including multidrug resistant strains), including cases accompanied by bacteraemia, or Staphylococcus aureus (only methicillin-sensitive strains);

    - hospital pneumonia caused by Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains) or Streptococcus pneumoniae {including multidrug resistant strains);

    - complicated skin and soft tissue infections, including infections with diabetic foot syndrome not accompanied by osteomyelitis, caused by Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains), Streptococcus pyogenes or Streptococcus agalactiae;

    - infections caused by Enterococcus faecium (strains resistant to vancomycin), including those accompanied by bacteremia.

    Contraindications:

    Hypersensitivity to linezolid and / or other components of the drug.

    Simultaneous use with drugs that inhibit monoamine oxidase A or B (for example, phenelzine, isocarboxazide), and also within two weeks after discontinuation of the use of these drugs. In the absence of blood pressure monitoring, the drug should not be administered to patients with uncontrolled arterial hypertension, pheochromocytoma, thyrotoxicosis and / or patients receiving the following types of drugs: adrenomimetics (for example, pseudoephedrine phenylpropanolamine, epinephrine, norepinephrine, dobutamine), dopaminomimetics (for example, dopamine).

    In the absence of careful monitoring of patients with possible development of serotonin syndrome, the drug should not be administered to persons with carcinoid syndrome and / or patients receiving the following drugs: serotonin reuptake inhibitors, tricyclic antidepressants, 5-HT1 receptor (tryptane) agonists, meperidine or buspirone.

    Carefully:

    Patients with renal insufficiency

    Due to the unexplained clinical significance of the two primary metabolites of linezolid in patients with severe renal failure,the drug should be used with caution in such patients, and only if the intended benefit exceeds the potential risk. There is also no data on the use of linezolid in patients on ambulatory peritoneal dialysis or other alternative methods of treating renal failure.

    Patients with hepatic insufficiency

    There are limited clinical data that recommend the use of the drug in such patients only if the intended benefit exceeds the potential risk.

    The drug should be used with caution in patients with systemic infections that pose a risk to life, such as those associated with venous catheters in intensive care units.

    Pregnancy and lactation:

    No safety studies have been conducted on linezolid in pregnancy, therefore Zenix during pregnancy is possible only if the expected benefit from therapy for the mother exceeds the potential risk to the fetus.

    It is not known whether linezolid with the breast milk of lactating women, therefore, breastfeeding should be stopped with the appointment of the mother's drug during lactation.

    Dosing and Administration:

    The drug is used as an intravenous infusion lasting 30-120 minutes. It is forbidden to consistently connect the infusion packets and add other preparations to the infusion solution. If it is necessary to administer the drug with other drugs, then all medications should be administered separately in accordance with the recommended doses and routes of administration.

    Incompatible with the following drugs: amphotericin B, chlorpromazine, diazepam, phenytoin, erythromycin lactibionate, co-trimoxazole (trimethoprim + sulfamethoxazole), ceftriaxone.

    Compatible solutions for infusion:

    5% dextrose solution for injection;

    0.9% solution of sodium chloride for injection;

    Ringer-Locka solution for injections.

    Patients who were prescribed IV at the beginning of therapy can then be transferred to any dosage form of linezolid for oral administration, while dose selection is not required, since the bioavailability of linezolid upon ingestion is almost 100%. The duration of treatment depends on the pathogen, the localization and severity of the infection, and also on the clinical effect.

    Adults and children (12 years and older)

    Indications (including infections accompanied by bacteremia)

    Single dose

    Recommended duration of treatment

    - Community-acquired pneumonia Streptococcus pneumoniae (including multidrug-resistant strains), including cases, accompanied by bacteremia, or Staphylococcus aureus (only methicillin-sensitive strains);

    - hospital pneumonia caused by Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains) or Streptococcus pneumoniae (including multidrug-resistant strains);

    - complicated skin and soft tissue infections, including infections with diabetic foot syndrome not accompanied by osteomyelitis, caused by Staphylococcus aureus (iincluding methicillin-sensitive and methicillin-resistant strains), Streptococcus pyogenes or Streptococcus agalactiae.

    600 mg IV every 12 hours


    10-14 days

    - infections caused by Enterococcus faecium (strains resistant to vancomycin), including those accompanied by bacteremia

    600 mg IV every 12 hours


    14-28 days


    Children (newborns * and children under 11 years old)

    Indications (including infections accompanied by bacteremia)

    Single dose

    Recommended

    Duration

    treatment

    - Community-acquired pneumonia Streptococcus pneumoniae (including multidrug-resistant strains), including cases accompanied by bacteraemia, or Staphylococcus aureus (only methicillin-sensitive strains);

    - hospital pneumonia caused by Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains) or Streptococcus pneumoniae (including multidrug-resistant strains);

    - complicated infections of the skin and soft tissues, including infections with diabetic foot syndrome, not accompanied by osteomyelitis, caused by Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains), Streptococcus pyogenes or Streptococcus agalactiae;

    10 mg / kg IV every 8 hours

    10-14 days

    - infections caused by Enterococcus faecium (strains resistant to vancomycin), including those accompanied by bacteremia

    10 mg / kg IV every 8 hours

    14-28 days

    * In preterm infants less than 7 days of age (pregnancy less than 34 weeks) systemic clearance of linezolid is lower, and the values AUC higher than most newborns and children. By the 7th day after birth, the linezolid clearance and the value AUC in premature newborns is close to those of full-term newborns and children.

    Elderly patients: dose adjustment is not required.

    Patients with renal insufficiency: correction of the dose is not required. Due to the fact that 30% of linezolid is removed during hemodialysis within 3 hours, linezolid should be administered after dialysis to patients who need it.

    Patients with hepatic impairment: correction of the dose is not required.

    Side effects:

    The frequency of unwanted reactions is represented by the following classification:

    Very often: ≥10%

    Frequently: ≥1% and <10%

    Infrequently: ≥0.1% and <1%

    Rarely: ≥0.01% and <0.1%

    Very rarely: <0.01%

    Adult patients

    The undesirable phenomena associated with the use of linezolid are usually of mild or moderate severity. Most often, diarrhea, headache and nausea are noted.

    From the digestive system:

    Often: diarrhea, nausea, vomiting, constipation, abdominal pain (including spastic), flatulence, candidiasis of the oral mucosa.

    Infrequently: change the coloration of the tongue.

    Laboratory indicators:

    Often: thrombocytopenia.

    Infrequently: an increase in the concentration of triglycerides in the blood, an increase in the activity of "hepatic" enzymes (including alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase (LF), lactate dehydrogenase (LDH), lipase, amylase), increasing the concentration of total bilirubin and creatinine, increasing the concentration of prolactin.

    From the nervous system:

    Often: headache, dizziness, peripheral neuropathy, convulsions (see section "Special instructions").

    Infrequently: perversion of taste.

    From the central nervous system:

    Often: insomnia.

    From the genitourinary system:

    Often: vaginal candidiasis.

    From the skin:

    Often: rash.

    Other:

    Often: fever.

    Infrequently: opportunistic fungal infection.

    Also were noted: increased blood pressure, dyspepsia, itching.

    Children and teens

    From the digestive system:

    Often: diarrhea, nausea, vomiting, abdominal pain (local and generalized), gastrointestinal bleeding, candidiasis of the oral mucosa, liquid stools.

    Laboratory indicators:

    Often: thrombocytopenia, anemia, hypokalemia, thrombocythemia.

    Infrequently: eosinophilia, an increase in the concentration of triglycerides in the blood, increased activity of ALT, lipase, amylase, the concentration of total bilirubin and creatinine.

    From the nervous system:

    Often: headache, convulsions (see section "Special instructions"), vertigo.

    From the skin:

    Often: rash.

    Infrequently: itching (not at the injection site).

    From the respiratory system:

    Often: respiratory depression, apnea, upper respiratory tract infection, pharyngitis, pneumonia, cough.

    Other:

    Often: fever, sepsis, generalized edema, reactions at the site of administration.

    Spontaneous (postmarketing) data.

    Laboratory indicators: reversible myelosuppression (thrombocytopenia, anemia, leukopenia, pancytopenia).

    From the sense organs: cases of neuropathy of the optic nerve, sometimes leading to loss of vision (see section "Special instructions").

    Allergic reactions: anaphylaxis.

    From the skin: rash, angioedema; Bullous skin lesions, similar to Stevens-Johnson syndrome.

    From the side of metabolism: lactic acidosis.

    From the nervous system: peripheral neuropathy, convulsions (see section "Special instructions").

    From the digestive system: change in the color of enamel of the teeth (see section "Special instructions").

    Other: chills, fatigue, serotonin syndrome (see section "Interaction with other medicinal products" and "Special instructions").

    Overdose:

    No cases of overdose of linezolid have been reported. Recommended symptomatic treatment (including the need to maintain the speed of the glomerularfiltering). There is no data on the acceleration of deducing linezolid in peritoneal dialysis or hemoperfusion.

    Interaction:

    It is established that cytochrome P450 isoenzymes do not participate in the metabolism of linezolid in vitro. Linezolid does not inhibit or potentiate the activity of clinically important cytochrome P450 isoenzymes (1A2, 2C9, 2C19, 2D6, 2E1, ZA4). Thus, it is not expected that the CD450-induced interaction when using linezolid. With the simultaneous use of the drug and (8) -varfarin, which is largely metabolized by the isoenzyme CYP2C9, pharmacokinetic characteristics of warfarin do not change. Such drugs as warfarin and phenytoin, which are the substrates of the isoenzyme CYP2C9, can be used simultaneously with the drug without dose adjustment.

    Inhibitors of monoamine oxidase

    Linezolid is a non-selective reversible inhibitor of monoamine oxidase, therefore, in some patients using linezolid, a moderate reversible enhancement of the pressor action of pseudoephedrine and phenylpropanolamine can be observed. In this regard, it is recommended to reduce the initial doses of the following groups of drugs: adrenomimetics (for example, pseudoephedrine, phenylpropanolamine, epinephrine, norepinephrine, dobutamine), dopaminomimetics (for example, dopamine) and further dose selection by titration.

    In studies, there was no development of serotonin syndrome in patients who received linezolid together with serotonergic drugs. However, there were several reports about the development of serotonin syndrome during treatment with linezolid and antidepressants - selective serotonin reuptake inhibitors.

    With simultaneous use with aztreonam and gentamycin, there was no change in the pharmacokinetics of linezolid.

    Rifampicin caused a decrease in Cmah and AUC linezolid on average by 21% and 32%, respectively.

    Special instructions:

    With the established infection (or suspected infection) caused by concomitant gram-negative microorganisms, additional use of antimicrobial agents acting on gram-negative flora is indicated.

    In some patients using linezolid, reversible myelosuppression may develop (with anemia, thrombocytopenia, leukopenia and pancytopenia), depending on the duration of therapy. In connection with this, during the treatment it is necessary to monitor blood levels in patients with an increased risk of developinghemorrhage, myelosuppression in a history, and also with simultaneous use of drugs that reduce hemoglobin or platelet count and / or their functional properties, as well as in patients receiving linezolid more than 2 weeks.

    Patients who use antibacterial drugs, including linezolid, should take into account the risk of developing pseudomembranous colitis of varying severity.

    About cases of diarrhea associated with Clostridium difficile, was reported in connection with the use of almost all antibacterial drugs, including linezolid. The severity of diarrhea can range from mild to severe forms. Treatment with antibacterial drugs disrupts the normal intestinal microflora, which leads to excessive growth Clostridium difficile. Clostridium difficile produces toxins A and B, which lead to the development of diarrhea associated with Clostridium difficile. Excessive amount of toxins produced by strains Clostridium difficilemay cause an increase in mortality among patients, since such infections can be resistant to antimicrobial therapy, and may require a columnectomy.

    The possibility of developing diarrhea associated with Clostridium difficile, should be considered in all patients with diarrhea, followed by the use of antibiotics. Careful medical supervision for 2 months is necessary for patients who have had diarrhea associated with Clostridium difficile after the introduction of antibacterial drugs.

    When symptoms of impaired visual function appear, such as changes in visual acuity, changes in color perception, blurred vision, visual field defects, it is recommended that you urgently consult an ophthalmologist for advice. Monitor visual function in all patients taking linezolid for a long time (more than 3 months), as well as in all patients with newly emerging symptoms of visual disturbances, regardless of the duration of therapy. In the case of peripheral neuropathy and optic nerve neuropathy, the risk / benefit ratio of linezolid therapy in these patients should be assessed.

    In connection with the use of linezolid, lactoacidosis was reported. Patients who, with the use of linezolid, experience repeated nausea or vomiting, unexplained acidosis, or a decrease in the concentration of bicarbonate,require careful monitoring by the doctor. Reported seizures in patients using linezolid, and in most cases in the history there was an indication of convulsions or the presence of risk factors for their development.

    If linezolid is to be used in combination with selective serotonin reuptake inhibitors, patients should be monitored continuously to identify signs and symptoms of serotonin syndrome, such as cognitive impairment, hyperpyrexia, hyperreflexia and impaired coordination of movements. If these symptoms appear, you should cancel one or both of the drugs taken.

    When discontinuing the use of a serotonergic agent, symptoms of the withdrawal syndrome may be observed.

    There have been reports of reversible surface changes in tooth enamel staining with linezolid. These changes in staining were removed by professional dental cleaning.

    The solution should be used immediately after opening the vial. Do not store open vials.

    Effect on the ability to drive transp. cf. and fur:

    During drug treatment, it is not recommended to drive vehicles, special equipment or engage in activities involving increased risk.

    Form release / dosage:

    Solution for infusions 2 mg / ml.

    Packaging:

    Original packaging:

    100 ml into a bottle of colorless neutral glass or 300 ml into a bottle of colorless neutral glass. The bottle is sealed with a bromobutyl stopper, crimped with an aluminum cap with a seal. A label and a plastic tape for hanging the vial are pasted onto the vial.

    1 bottle in a package of aluminum foil. A label is attached to the package.

    1 package together with instructions for use in a pack of cardboard.

    For hospitals: 1 bag together with instructions for use in a pack of cardboard or 10 packs together with an equal number of instructions for use in a three-ply cardboard box with separating cardboard inserts.

    Storage conditions:

    In the original packaging in a dark place at a temperature of no higher than 25 ° C. Do not freeze.

    Keep out of the reach of children.

    Shelf life:

    3 years. Do not use the drug after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002657
    Date of registration:14.10.2014 / 17.06.2016
    Expiration Date:14.10.2019
    The owner of the registration certificate:Hemofarm ADHemofarm AD Serbia
    Manufacturer: & nbsp
    Representation: & nbspNizhpharm, JSCNizhpharm, JSCRussia
    Information update date: & nbsp11.10.2017
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