Linezolid-Teva - instructions for use, dose, side effects, contraindications

Composition:1 ml of the solution contains: active substance linezolid 2.00 mg; Excipients: citric acid anhydrous 0.85 mg, sodium citrate dihydrate 1.64 mg, dextrose monohydrate 50.24 mg, water for injection up to 1 ml.

Description:Transparent colorless or with a brownish hue solution.

Pharmacotherapeutic group:Antibiotic-oxazolidinone.

ATX: & nbsp

J.01.X.X.08 Linezolid

J.01.X.X Other antibacterial drugs

Pharmacodynamics:Synthetic antibacterial agent from the group of oxazolidones. The mechanism of action of the drug is due to selective inhibition of protein synthesis in bacteria. By binding to the 23 S and 50 S subunits of the bacterial ribosome, it prevents the formation of a functional initiating complex of the 708-ribosome, which is a component of the translation process in protein synthesis.
The minimum inhibitory concentration (MIC) of linezolid for sensitive microorganisms is not more than 4 mg / L and more than 4 mg / L for resistant microorganisms.
The drug is active in vitro and in vivo against the following microorganisms: gram-positive aerobes: Enterococcus faecium (including strains resistant to vancomycin), Staphylococcus aureus (including methicillin-resistant strains), Streptococcus agalactiae, Streptococcus pneumoniae (including multiresistant strains), Streptococcus pyogenes.The drug is active in vitro against the following microorganisms: 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 of viridans; gram-negative aerobes: Pasteurella multocida.
Resistant to linezolid microorganisms: Haemophilus influenzae, Moraxella catarrhalis, Neisseria spp., Enterobacteriaceae spp., Pseudomonas spp.
There was no cross-resistance between linezolid and aminoglycosides, β-lactam antibiotics, folic acid antagonists, glycopeptides, lincosamides, quinolones, rifamycins, streptograms, tetracyclines, chloramphenicol due to the difference in the mechanism of action of linezolid from the mechanisms of action of these antibacterial agents.
Resistance to linezolid develops slowly by a multistage mutation of 23S ribosomal RNA.

Pharmacokinetics:The active substance is (s) -lenezolid, which is biologically active and metabolized in the body with the formation of inactive derivatives.
The maximum concentration (C_max) after infusion of 600 mg 2 times a day is achieved within 30 minutes and is 15.1 μg / ml. Linezolid quickly distributed in tissues with good perfusion. Apparent volume of distribution (V_d) when a stable average concentration is achieved in healthy volunteers averages 40-50 liters. Binding to plasma proteins is 31% and does not depend on the concentration of linezolid in the blood. Isozymes of cytochrome P450 do not participate in the metabolism of linezolid. 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. Linezolid is excreted mainly by kidneys in the form of hydroxyethyl glycine (40%), aminoethoxyacetic acid (10%) and unchanged drug (30-35%). Intestine linezolid is derived as hydroxyethyl glycine (6%) and aminoethoxyacetic acid (3%).
The unchanged drug is almost not excreted by the intestine. The total clearance of linezolid with a double infusion introduction is 123 ml / min, 65% of the total clearance is a non-parasite clearance. The half-life (T_1/2) is on average 5-7 hours.
Linezolid penetrates into breast milk and through the placental barrier.
Pharmacokinetics in special groups of patients.
After a single application 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, no increase in the area under the pharmacokinetic "concentration-time" curve (AUC) of the parent drug was observed. Despite the fact that some basic metabolites were removed during hemodialysis, their concentration in the blood plasma after applying 600 mg of linezolid and carrying out the dialysis procedure remained significantly higher than the concentration in the blood in patients with normal kidney function, mild or moderate renal insufficiency. Since 30% of the dose is excreted within 3 hours of hemodialysis, in patients receiving similar treatment, linezolid should be used after dialysis.
There is limited evidence that in patients with mild to moderate hepatic insufficiency (class A and B according to the Child-Pugh classification) the pharmacokinetics of linezolid and its two major metabolites do not change,In patients with severe hepatic impairment (Child-Pugh C index), pharmacokinetics have not been studied. However, given that linezolid is metabolized as a result of a non-enzymatic process, it can be argued that the function of the liver does not significantly affect the metabolism of the drug.
When used in children (12-17 years), doses of 600 mg of pharmacokinetic indices of linezolid did not differ from those of adults. Thus, when administered in children over 12 years of doses of 600 mg every 12 hours, the concentration of linezolid in plasma will be the same as in adults.
In children from 1 week to 12 years, the use of linezolid at a dose of 10 mg / kg every 8 hours daily allows achieving the same exposure as in adults with 600 mg of linezolid 2 times a day. In newborns under the age of 1 week, the systemic clearance of linezolid (per kg of body weight) increases rapidly during the first week of life. Thus, when applied at a dose of 10 mg / kg every 8 hours, the maximum exposure of linezolid is achieved in newborns on the first day after birth. However, excessive accumulation of linezolid in the first week of use under this scheme will not occur due to a rapid increase in clearance.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 lower V_d, a decrease in the average clearance by approximately 20% with respect to body weight, sometimes at higher concentrations in the blood plasma. However, since T_1/2 linezolid in women and men does not differ significantly, there is no reason to expect an increase in the concentration of linezolid in blood plasma in women above the concentration that is well tolerated, therefore, dose adjustment is not required.

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 caused by Streptococcus pneumoniae (including multiresistant strains), including cases accompanied by bacteremia, or Staphylococcus aureus (methicillin-sensitive strains only);
- 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 monoamine oxidase (MAO) A or B inhibitors for 14 days before or after termination of linezolid therapy.
In the absence of blood pressure monitoring, the drug should not be used in patients with uncontrolled arterial hypertension, pheochromocytoma, thyrotoxicosis, and / or patients receiving the following 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 used in patients with carcinoid syndrome and / or in patients receiving the following drugs: serotonin reuptake inhibitors, tricyclic antidepressants,agonists of 5-HT1 receptors (triptans), meperidine or buspirone.

Carefully:Severe renal insufficiency, bipolar disorders, myelosuppressive conditions, visual impairment, ischemic damage to organs and tissues, pressure sores, diabetic foot, gangrene, extensive burns, liver failure, history of seizures. Linezolid use with caution in patients with systemic infections posing a risk to life, such as those associated with venous catheters in intensive care units.

Pregnancy and lactation:There has been no safety study of linezolid in pregnancy, therefore the use of linezolid-Teva during pregnancy is possible only if the intended benefit from therapy for the mother exceeds the potential risk to the fetus.
It is not known whether linezolid with the breast milk of nursing women, so if you need to use the drug during lactation should stop breastfeeding.

Dosing and Administration:The drug is intended for intravenous administration.
The duration of the infusion is 30-120 minutes.
The dosage regimen and duration of treatment depend on the causative agent, localization and severity of the infection, as well as on clinical efficacy.
Recommended dosing regimen for adults and children (12 years and over)

Indications (including infections, withProvingswhich are bacteremia)	Single dose and multiplicity introduction of	Recommended Duration treatment
- extra-billMr.ichMr.pneumonia caused by Streptococcus pneumoniae (including multirester strains), including cases accompanied by bacteraemia, or Staphylococcus aureus (only methicilliMr.sensoryMr.th strains);	600 mg iv every 12 h	10-14 days
- hospitalized pneumonia caused by Staphylococcus aureus (including metitsIllinesensitive and methylcylinderresistentonese strains) or Streptococcus pneumoniae (including polyresisfromstrains);	600 mg iv every 12 h	10-14 days
- complicated skin and soft tissue infections, including infections with diabetic foot syndrome not accompanied by osteomyelitis, caused by Staphylococcus aureus (including methicilliMr.sensoryMr.th and methylcentnersillinesistentMr.th strains), Streptococcus pyogenes or Streptococcus agalactiae;	600 mg iv every 12 h	10-14 days
infections caused by Enterococcus faecium, resistant to vancomycin, including those accompanied by bacteremia.	600 mg iv every 12 h	14-28 days

Recommended dosage regimen for children younger than 12 years (including newborns *)

Indications (including infections, withProvingswhich are bacteremia)	Single dose and multiplicity introduction of	Recommended Duration treatment
- extra-billMr.ichMr.pneumonia caused by Streptococcus pneumoniae (including multirester strains), including cases accompanied by bacteraemia, or Staphylococcus aureus (only methicilliMr.sensoryMr.th strains);	10 mg /kg in / in every 8 h	10-14 days
- hospitalized pneumonia caused by Staphylococcus aureus (including metitsIllinesensitive and methylcylinderresistentonese strains) or Streptococcus pneumoniae (including polyresisfromstrains);	10 mg /kg in / in every 8 h	10-14 days
- complicated skin and soft tissue infections, including infections with diabetic foot syndrome not accompanied by osteomyelitis, caused by Staphylococcus aureus (including methicilliMr.sensoryMr.th and methylcentnersillinesistentMr.th strains), Streptococcus pyogenes or Streptococcus agalactiae;	10 mg /kg in / in every 8 h	10-14 days
infections caused by Enterococcus faecium, resistant to vancomycin, including those accompanied by bacteremia.	10 mg /kg in / in every 8 h	14-28 days

* In preterm infants less than 7 days of age (pregnancy less than 34 weeks) systemic clearance of linezolid is lower, and AUC is higher than in most newborns and children. By the 7th day after birth, the linezolid clearance and AUC in preterm infants approach that of full-term newborns and children.
The maximum dose for adults and children is 1.2 g / day.
In elderly patients, dose adjustment is not required.
In patients with renal insufficiency, dose adjustment is not required. Due to the fact that 30% of linezolid is removed during hemodialysis within 3 hours, the Linezolid-Teva preparation should be administered after the end of the hemodialysis procedure.
In patients with hepatic insufficiency, dose adjustment is not required.

Side effects:The incidence of side effects is classified according to the recommendations of the World Health Organization: very often - at least 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely (including isolated cases) - 0.01%.
Infections and infestations: often candidiasis, especially oral and vaginal, or fungal infections; rarely - vaginitis.
From the hematopoietic and lymphatic systems: often - neutrophilia, eosinophilia, anemia, decreased hematocrit, leukocytosis, leukopenia, thrombocytopenia, thrombocytosis; infrequently - neutropenia, reticulocytosis.
From the nervous system: often - a headache, a violation of perception of taste sensations; infrequently - insomnia, dizziness, hypostension, paresthesia; rarely peripheral neuropathy; very rarely - cramps.
From the side of the organ of vision: infrequent - visual acuity reduction, tinnitus; very rarely - cases of neuropathy of the optic nerve, sometimes leading to loss of vision.
From the cardiovascular system: infrequently - increased blood pressure, phlebitis, thrombophlebitis.
From the side of the organ of hearing and labyrinth: infrequently, noise in the ears.
From the gastrointestinal tract: often - diarrhea, nausea, vomiting; infrequently - abdominal pain, flatulence; constipation, dryness of the oral mucosa, dyspepsia, gastritis, glossitis, pancreatitis, stomatitis, discoloration of the tongue.
From the skin and subcutaneous tissues: infrequently - dermatitis, profuse sweating, itching, rash, hives.
From the side of the kidneys and urinary tract: infrequently polyuria.
On the part of the reproductive system: infrequently - vulvovaginitis.
Common disorders and reactions at the site of administration: rarely - chills, weakness, fever, pain at the injection site, thirst.
Allergic reactions: very rarely - anaphylaxis, angioedema, Stevens-Johnson syndrome.
From the laboratory indicators: Increase in activity of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, creatine phosphokinase, lipase and amylase in blood plasma, hyperbilirubinemia, hyperglycemia, decrease in the concentration of total protein, albumin, sodium or calcium ions in blood plasma, increase or decrease in the concentration of bicarbonates or potassium ions in blood plasma; infrequently hypercreatininemia, increased concentration of sodium or calcium ions in the blood plasma, hypoglycemia, an increase or decrease in the concentration of chlorides in the blood plasma.
Other: very rarely - lactic acidosis, discoloration of teeth, serotonin syndrome.

Overdose:At present, no cases of overdose of linezolid have been reported.
Treatment: if necessary, conduct symptomatic therapy (it is necessary to maintain the glomerular filtration rate).Approximately 30% of the administered dose is excreted within 3 hours of hemodialysis. The specific antidote is unknown.

Interaction:Linezolid is a reversible non-selective MAO inhibitor, therefore, in some patients it can cause a moderate reversible enhancement of the pressor action of pseudoephedrine and phenylpropanolamine. Considering this, with simultaneous application it is recommended to reduce initial doses of adrenergic drugs and subsequently to perform dose selection by titration.
Simultaneous use of linezolid with selective serotonin reuptake inhibitors can lead to the development of serotonin syndrome.
The use of linezolid against the background of the consumption of products containing tyramine may lead to an increase in blood pressure.
With the simultaneous use of linezolid and rifampicin, there is a decrease in C_max linezolid by 21%. The mechanism of this action is unknown.
Linezolid does not affect the pharmacokinetics of drugs metabolized by cytochrome P450 isoenzymes.
Linezolid-Teva in the form of a solution for infusion 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 using Linezolid-Teva drug simultaneously with other drugs, each drug should be administered separately.

Special instructions:Although linezolid is a reversible nonselective MAO inhibitor, in doses intended for antibiotic therapy, the drug does not have an antidepressant effect.
Patients during the treatment with linezolid should refuse food containing a large amount of tyramine (soft cheeses, yeast fermentation products, unfiltered beer, soy sauce).
Each vial contains 13.7 g of glucose, which may require a change in antidiabetic therapy. Each bottle contains 114 mg of sodium. In the treatment with linezolid, the development of myelosuppression (including anemia, leukopenia, thrombocytopenia and pancytopenia) is possible.With the withdrawal of the drug, hematological parameters were quickly restored. Thrombocytopenia occurs more frequently in patients receiving, linezolid against a background of severe renal failure, regardless of hemodialysis. Patients receiving linezolid on the background of anemia, granulocytopenia, thrombocytopenia, or simultaneously with other drugs that reduce the concentration of hemoglobin or the number of blood elements, or the duration of linezolid therapy exceeds 14 days, a regular weekly monitoring of the number of blood elements is shown. With the development of clinically significant myelosuppression, linezolid should be discontinued, except in cases of vital necessity, and appropriate treatment should be prescribed.
During treatment with linezolid, the development of lactic acidosis is possible. When symptoms of lactic acidosis (nausea, vomiting, abdominal pain, low concentration of bicarbonate in the blood plasma or hyperventilation of the lungs) occur, appropriate treatment should be immediately given during the administration of linezolid.
Linezolid is ineffective against gram-negative microorganisms.If there is a suspicion of a mixed etiology of the infectious process, antibacterial drugs should be used to treat gram-negative infection.
It should be used with caution linezolid patients with diabetic foot, bedsores or ischemic lesions of organs and tissues, severe burns or gangrene.
Patients with severe hepatic insufficiency (Child-Pugh C index) linezolid It should be used only if the expected benefit exceeds the possible risk.
During treatment with linezolid, pseudomembranous colitis may develop. With the development of long-term diarrhea on the background of such treatment, it is necessary to cancel the drug and prescribe the appropriate therapy.
The effectiveness and safety of taking linezolid for more than 28 days is unknown. With prolonged treatment, it is possible to develop peripheral neuropathy or optic nerve neuropathy. With a decrease in visual acuity or the appearance of visual field defects, urgent consultation of the ophthalmologist is necessary.
In the presence of cramps in the anamnesis linezolid should be used under close medical supervision.
During treatment with linezolid, a reversible decrease in fertility and changes in the structure of spermatozoa are possible.

Effect on the ability to drive transp. cf. and fur:Care should be taken during the use of Linezolid-Teva because of the possible development of adverse reactions that may adversely affect the ability to drive vehicles and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:Solution for infusions 2 mg / ml.

Packaging:For 300 ml of the drug in infusion bags of a multilayer polymer film with two tubes, one of which is sealed, and the second is equipped with a device for connecting with the infusion system. 10 or 30 bags placed one by one in a polymer package, together with instructions for use in a cardboard box.

Storage conditions:Store in a dark place at a temperature of at least 8 ° C.
After opening, use immediately.
Keep out of the reach of children.

Shelf life:2 years.
Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001100

Date of registration:03.11.2011

Expiration Date:Unlimited

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

TEVA Pharmaceutical Industries, Ltd. Israel

Representation: & nbspTeva Teva Israel

Information update date: & nbsp2016-10-20

Illustrated instructions

Instructions

Linezolid-Teva (Linezolid-Teva)