Selezolid infusion solution 2mg/ml 300ml bottles, 1pc

Composition

Active ingredient: linezolid 2 mg. Auxiliary substances: sodium citrate dihydrate 1.64 mg, citric acid anhydrous 0.85 mg, dextrose monohydrate 50.24 mg, water for injection up to 1 ml. Theoretical osmolarity is 291 mOsm/l.

Pharmacological action

Pharmacotherapeutic group: antibiotic-oxazolidinone. ATX code: J01XX08Pharmacological properties

Pharmacodynamics .

Synthetic antibacterial agent from the group of oxazolidinones. The mechanism of action is due to selective inhibition of protein synthesis in bacteria. By binding to the 23S and 50S subunits of the bacterial ribosome, it prevents the formation of a functional 70S-ribosome initiating complex, which is a component of the translation process during protein synthesis.

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 polyresistant 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., viridans group;

gram-negative aerobes:  Pasteurella multocida;

gram-positive anaerobes:  Clostridium perfringens, Peptostreptococcus anaerohius, Peptostreptococcus spp.

Linezolid-resistant microorganisms:  Haemophilus influenzae, Moraxella catarrhalis, Neisseria spp., Enterobacteriaceae spp., Pseudomonas spp.

There was no cross-resistance between linezolid and aminoglycosides, beta-lactam antibiotics, folic acid antagonists, glycopeptides, lincosamides, quinolones, rifamycins, streptomycin, tetracyclines, and chloramfinecol due to the difference in the mechanism of action of linezolid from the mechanisms of action of these antibacterial agents. Linezolid is active against pathogenic microorganisms, both sensitive and resistant to these drugs. Resistance to linezolid develops slowly due to a multi-stage mutation of 23S ribosomal ribonucleic acid (RNA) and occurs with a frequency of less than 1 × 10-9-1×10-11.

Suction. The mean maximum concentration (Cmax) and mean minimum concentration (Cmin) of linezolid in blood plasma at steady state after intravenous use twice daily 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 drug use. Distribution. The volume of distribution of linezolid when reaching an equilibrium concentration in a healthy adult is on average 40-50 liters, which is approximately equal to the total water content in the body. Binding to plasma proteins is 31% and does not depend on the concentration of linezolid in the blood.

Metabolism. Cytochrome P450 isoenzymes are not involved in the metabolism of linezolid in vitro. Linezolid also does not inhibit or potentiate the activity of clinically important cytochrome P450 isoenzymes (1A2,2C9,2C19,2D6,2E1A4). 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.

Output. Extrarenal clearance is about 65% of linezolid clearance. With an increase in the dose of linezolid, a small degree of nonlinearity in clearance is noted. This may be due to a decrease in renal and extrarenal clearance at a high dose of linezolid. However, the differences in clearance are small and do not affect the apparent half-life. In patients with normal renal function and mild to moderate renal insufficiency, linezolid is excreted by the kidneys in the form of hydroxyethylglycine (40%), aminoethoxyacetic acid (10%) and unchanged (30-35%). It is excreted by the intestines in the form of hydroxyethylglycine (6%) and aminoethoxyacetic acid (3%). In unchanged form, linezolid is practically not excreted by the intestines. The average half-life of linezolid is 5-7 hours

. Pharmacokinetics in patients of certain groups

Patients with renal insufficiency. After a single use of 600 mg of linezolid in patients with severe renal insufficiency (creatinine clearance However, an increase in the area under the pharmacokinetic curve “concentration-time” (AUC) of the initial drug was not observed. Despite the fact that a certain amount of major metabolites were eliminated during hemodialysis, their plasma concentrations remained significantly higher after use of 600 mg of linezolid and dialysis 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 main metabolites do not change in patients with mild to moderate hepatic insufficiency (Child-Pugh class A and B), while the pharmacokinetics have not been studied in patients with severe hepatic insufficiency (Child-Pugh class C). However, since linezolid is metabolized nonenzymatically, it is not expected that its metabolism is significantly impaired in hepatic insufficiency.

Children and teenagers. In adolescents (12-17 years), the pharmacokinetics of linezolid taken at a dose of 600 mg did not differ from those in adults. Thus, when prescribing 600 mg of linezolid to adolescents every 12 hours, its concentration will be the same as in adults when prescribed at the same dose. In children aged 1 week to 12 years, the use of linezolid at a dose of 10 mg / kg every 8 hours daily allows you to achieve the same exposure as in adults with 600 mg of linezolid 2 times a day.

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

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

Women. In women, the volume of distribution of linezolid is slightly lower than in men; they also have a 20% reduction in the average clearance per body weight. The concentration of the drug in the blood plasma of women is higher than in men, which may partly be explained by differences in body weight. However, since the half-life of linezolid in men and women does not differ significantly, there is no reason to expect an increase in the concentration of the drug in the blood of women above the tolerated value, so no dose adjustment is required.

Indications

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

• community-acquired pneumonia caused by Staphylococcus aureus (only methicillin-sensitive strains) or Streptococcus pneumoniae (including multi-resistant strains), including cases involving bacteremia;
• hospital-acquired pneumonia caused by Staphylococcus aureus (methicillin-sensitive and methicillin-resistant strains) or Streptococcus pneumoniae (including multi-resistant strains);
• complicated skin and soft tissue infections, including infections in diabetic foot syndrome, not accompanied by osteomyelitis, caused by Staphylococcus aureus (methicillin-sensitive and methicillin-resistant strains), Streptococcus pneumoniae or Streptococcus agalactiae;
• infections caused by Enterococcus faecium strains resistant to vancomycin, including those accompanied by bacteremia.

Use during pregnancy and lactation

No safety studies have been conducted on the use of linezolid during pregnancy, so the use of Selezolid during pregnancy is possible only if the intended benefit of therapy for the mother outweighs the potential risk to the fetus. It is not known whether linezolid is excreted in breast milk of nursing women, so if it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Contraindications

• Hypersensitivity to linezolid and / or other components of the drug.
• Simultaneous use of linezolid with monoamine oxidase (MAO) inhibitors A or B (for example, phenelzine, isocarboxazide), as well as for 14 days after the end of taking these drugs.

In the absence of blood pressure monitoring and careful monitoring of patients, linezolid should not be prescribed:

• patients with uncontrolled arterial hypertension, pheochromocytoma, thyrotoxicosis, carcinoid syndrome, bipolar disorder, schizoaffective disorder, acute state of confusion;
• patients receiving the following medications: adrenomimetics (e. g. pseudoephedrine, phenylpropanolamine, epinephrine, norepinephrine, dobutamine), dopaminomimetics (e. g. dopamine); serotonin reuptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), meperidine or buspirone.

With caution

Patients with renal insufficiency. Due to the unexplored clinical significance of the two primary metabolites of linezolid in patients with severe renal insufficiency, linezolid should be used with caution in such patients if the intended benefit outweighs the potential risk. There are also no data on the use of linezolid in patients undergoing outpatient peritoneal dialysis or receiving other alternative treatments for renal failure. Patients with hepatic insufficiency. There are limited data that recommend the use of linezolid in patients with severe hepatic insufficiency only if the intended benefit outweighs the potential risk. Linezolid is used with caution in patients with life-threatening systemic infections, such as those associated with venous catheters in intensive care units.

Side effects

The frequency of side effects is classified according to the recommendations of the World Health Organization: very common ≥10%; often ≥1% and <10%; infrequently ≥0.1% and <1%; rarely ≥0.01% and <0.1%; very rare (including isolated cases) Adult patientsinfections and Infestations: often-candidiasis (including oral and vaginal); infrequently-opportunistic fungal infections, vaginitis; rarely-colitis caused by the use of antibiotics (including pseudomembranous colitis). Hematopoietic and lymphatic system disorders: often-anemia; infrequently-eosinophilia, leukopenia, thrombocytopenia, neutropenia; rarely-pancytopenia; frequency unknown-myelosuppression, sideroblastic anemia. From the immune system: frequency unknown – anaphylaxis. Metabolic and nutritional disorders: infrequently-hyponatremia; frequency unknown-lactic acidosis. From the side of the psyche: often – insomnia. Nervous system disorders: often-headache, “metallic taste” in the mouth; infrequently-paresthesia, hypesthesia, convulsions; frequency unknown-peripheral neuropathy, serotonin syndrome. From the side of the visual organ: infrequently – “blurred” vision; rarely-the appearance of visual field defects; frequency unknown-neuropathy and neuritis of the optic nerve, vision loss, changes in visual acuity, changes in color perception. From the side of the organ of hearing and labyrinth: infrequently-tinnitus. Disorders of the cardiovascular system: often-increased blood pressure; infrequently-arrhythmia (tachycardia), transient ischemic attack, phlebitis, thrombophlebitis. From the gastrointestinal tract: often – diarrhea, nausea, vomiting, localized or diffuse abdominal pain, constipation, dyspepsia; infrequently-dryness of the oral mucosa, flatulence, unstable stools, gastritis, glossitis, pancreatitis, stomatitis, discoloration of the tongue mucosa; rarely-superficial discoloration of tooth enamel. Liver and biliary tract disorders: often – changes in functional liver tests, increased activity of “liver” enzymes (including alanine aminotransferase (ALT), aspartate aminotransferase (ACT), lactate dehydrogenase (LDH), alkaline phosphotase (ALP)); infrequently – increased concentration of total bilirubin in blood plasma. Skin and subcutaneous tissue disorders: often – pruritus, rash; infrequently-dermatitis, increased sweating, urticaria; frequency unknown-bullous skin lesions (such as Stevens-Johnson syndrome, toxic epidermal necrolysis), angioedema, alopecia. From the side of the kidneys and urinary tract: often-increased plasma urea nitrogen; infrequently-polyuria, increased plasma creatinine concentration; frequency unknown-renal failure. Genital and breast disorders: infrequently-disorders of the vagina and vulva. General disorders and disorders at the injection site: often – fever, localized pain, infrequently-chills, weakness, pain at the injection site, thirst. Laboratory parameters: often – an increase in the number of neutrophils, eosinophils, a decrease in hemoglobin, hematocrit or the number of red blood cells, an increase or decrease in the number of platelets or white blood cells, an increase in the activity of lactate dehydrogenase, creatine kinase, lipase, amylase, an increase in the concentration of non – fasting glucose, a decrease in total protein, albumin, sodium or calcium, an increase or decrease in potassium or bicarbonates; infrequently-an increase in the content of sodium or calcium in blood plasma, a decrease in non-fasting glucose concentrations, an increase or decrease in blood chlorides, an increase in the number of reticulocytes, a decrease in the number of neutrophils. In rare cases, the following side effects associated with linezolid were classified as serious: localized abdominal pain, transient ischemic attack, and arterial hypertension. In controlled clinical trials in which linezolid was used for a maximum of 28 days, only 2% of patients developed anemia. In another study, among patients with life-threatening infections,2.5% (33/1326) of patients who received linezolid for less than 28 days developed anemia, while 12.3% (53/430) of patients who received linezolid for more than 28 days developed anemia. The ratio of cases of anemia requiring blood transfusion was 9% among patients receiving linezolid for less than 28 days (3/33), and 15% (8/53) in cases where linezolid was used for more than 28 days. Side effects in children do not differ from those in adult patients.

Interaction

Drugs that are metabolized by the cytochrome P450 system. Linezolid does not affect the pharmacokinetics of drugs metabolized by cytochrome P450 isoenzymes. Linezolid does not inhibit or potentiate the activity of clinically significant cytochrome P 450 isoenzymes (1A2,2C2,2C19,2D6,2E1A4). Thus, no SUR 450-induced interaction is expected with linezolid use. The pharmacokinetics of warfarin did not change when linezolid was co-administered with (S) – warfarin, which is largely metabolized by the CYP2C9 isoenzyme. Drugs such as warfarin and phenytoin, which are substrates of the CYP2C9 isoenzyme, can be used simultaneously with linezolid without dose adjustment. Monoamine oxidase (MAO) inhibitors. Linezolid is a reversible, non-selective MAO inhibitor, so it may cause a moderate reversible increase in the pressor action of pseudoephedrine and phenylpropanolamine in some patients. Taking this into account, it is recommended to reduce the initial doses of adrenergic drugs with simultaneous use and then titrate the dose. Serotonin syndrome has not been reported in patients treated with linezolid in combination with serotonergic drugs. However, there have been several reports of the development of serotonin syndrome with the use of linezolid and antidepressants-selective serotonin reuptake inhibitors. The use of linezolid against the background of excessive consumption of products with a high tyramine content (mature cheese, yeast extracts, fermented soy bean products, for example, soy sauce, unfiltered beer, red wine, smoked meat) can lead to increased blood pressure. When linezolid and rifampicin are co-administered, the Cmax and AUC of linezolid decrease by 21% and 32%, respectively. The mechanism and clinical significance of this action are unknown. When linezolid and warfarin are co-administered, the international normalized ratio (INR) decreases by 10% and the AUC decreases by 5%, but there is insufficient data to assess the clinical significance of this phenomenon. When used concomitantly with aztreonam and gentamicin, no changes in the pharmacokinetics of linezolid were observed. Linezolid in the form of an infusion solution is compatible with the following solutions: 5% dextrose solution,0.9% sodium chloride solution, Ringer’s solution for injection with lactose. Linezolid infusion solution is pharmacologically incompatible with amphotericin B, chlorpromazine, diazepam, pentamidine isethionate, phenytoin, erythromycin, co-trimoxazole and ceftriaxone sodium. Do not add additional components to the linezolid infusion solution. When using Selezolid concomitantly with other medications not listed above, each drug should be administered separately.

How to take it, course of use and dosage

The drug is intended for intravenous use. The duration of the infusion is 30-120 minutes.

It is forbidden to consistently connect infusion bottles (containers) and add other drugs to the infusion solution. If linezolid is to be administered with other medications, all medications should be administered separately according to the recommended doses and routes of use.

Linezolid for injection is pharmacologically incompatible with the following drugs: amphoteric B, chlorpromazine, diazepam, phenytoin, erythromycin, lactobionate, cotrimoxazole (trimethoprim+sulfometaxozole), ceftriaxone.

Compatible infusion solutions: 5% dextrose solution for injection,0.9% sodium chloride solution for injection, Ringer-Locke solution for injection.

Patients who were prescribed intravenously at the beginning of therapy can then be transferred to any dosage form of the drug for oral use, while dose selection is not required, the bioavailability of linezolid when taken orally is almost 100%.

The dosage regimen and duration of treatment depend on the pathogen, the location and severity of the infection, as well as on clinical efficacy.

Recommended dosage regimen for adults and children aged 12 years and older

Recommended dosage regimen for children under 12 years of age (including newborns *)

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

No dose adjustment is required in elderly patients.

No dose adjustment is required in patients with renal insufficiency. Due to the fact that 30% of linezolid is removed during hemodialysis within 3 hours, the drug Selezolid should be administered after the end of the hemodialysis procedure.

No dose adjustment is required in patients with hepatic insufficiency.

Overdose

No cases of linezolid overdose have been reported. If necessary, carry out symptomatic therapy (it is necessary to maintain the glomerular filtration rate). There are no data on accelerating the elimination of linezolid during peritoneal dialysis or hemoperfusion. The specific antidote is unknown.

Special instructions

In an open-label study, among critically ill patients with intravascular catheter-associated infections, there was an increase in mortality in the linezolid-only group compared to patients treated with vancomycin/dicloxacillin/oxacillin [78/363 (21.5%) vs. 58/363 (16.0%)]. In many patients treated with linezolid monotherapy, gram-negative microorganisms were detected during the study, so infections caused by gram-negative microorganisms or polymicrobial associations were the cause of death. Thus, if a mixed etiology of the infectious process is suspected, linezolid should be used in combination with antibacterial drugs that are active against gram-negative pathogens.

Some patients taking linezolid may develop reversible myelosuppression (with anemia, thrombocytopenia, leukopenia, and pancytopenia), depending on the duration of therapy. Older patients also have an increased risk of developing this condition. Thrombocytopenia was more likely to occur in patients with severe renal insufficiency, regardless of the use of hemodialysis in the patient. In this regard, during treatment, it is necessary to monitor blood parameters in patients with an increased risk of bleeding, a history of myelosuppression, as well as with the simultaneous use of drugs that reduce hemoglobin or platelet count and/or their functional properties, with severe renal insufficiency, as well as in patients taking linezolid for more than 2 weeks.

Linezolid in such patients is used only when careful monitoring of hemoglobin, white blood cell count and platelets is possible. If severe myelosuppression develops during linezolid therapy, treatment should be discontinued unless continuation of therapy is considered absolutely necessary. In this case, intensive monitoring of blood parameters and appropriate treatment is necessary. In addition, it is recommended that a blood test (including the determination of hemoglobin, platelet count and white blood cells (with the calculation of the white blood cell formula)) It was performed weekly in patients receiving linezolid, regardless of the parameters of the initial blood test. A higher incidence of severe anemia was observed in patients treated with linezolid for more than the maximum recommended duration of 28 days. These patients were more likely to require blood transfusions. Cases of sideroblastic anemia were reported in the post-marketing period. In most cases, the duration of linezolid therapy exceeded 28 days. In most patients, the symptoms were fully or partially reversible after discontinuation of linezolid treatment with / without specific treatment for anemia.

Patients taking antibacterial drugs, including linezolid, should be considered for the risk of developing pseudomembranous colitis of varying severity. Cases of Clostridium difficile-related diarrhea have been reported in connection with the use of virtually all antibacterial drugs, including linezolid. The severity of diarrhea can range from mild to severe. Treatment with antibacterial drugs disrupts the normal intestinal microflora, which leads to excessive growth of Clostridium difficile. Clostridium difficile produces toxins A and B, which lead to the development of diarrhea associated with Clostridium difficile. Excessive amounts of toxins produced by Clostridium difficile strains can lead to increased mortality among patients, as such infections may be resistant to antimicrobial therapy, and colectomy may also be required. Do not use medications that inhibit intestinal motility. The possibility of developing diarrhea associated with Clostridium difficile should be considered in all patients with diarrhea following antibiotic use. Close medical monitoring for 2 months is necessary for patients who have experienced diarrhea associated with Clostridium difficile after the introduction of antibacterial drugs.

If you experience symptoms of visual impairment, such as changes in visual acuity, changes in color perception, or visual field defects, it is recommended to consult an ophthalmologist immediately. Visual function should be monitored in all patients taking linezolid for a long time (more than 28 days), as well as in all patients with newly developed symptoms of visual impairment, regardless of the duration of therapy.

In the case of peripheral neuropathy and optic neuropathy, the risk/benefit ratio of continuing linezolid therapy in these patients should be evaluated.

The risk of developing neuropathy is higher if linezolid is used in patients who are currently using or who have recently taken antimycobacterial drugs for the treatment of tuberculosis.

Lactic acidosis has been reported in association with the use of linezolid.Patients who experience repeated nausea or vomiting, abdominal pain, unexplained acidosis, or a decrease in the concentration of bicarbonate anions while taking linezolid should be carefully monitored by a doctor.

Side effects such as lactic acidosis, anemia, and neuropathy (peripheral or optic nerve) may be related to linezolid’s ability to inhibit mitochondrial protein synthesis. These effects are more common when the drug is used for more than 28 days.

Seizures have been reported in patients taking linezolid, and in most cases there was a history of seizures or the presence of risk factors for their development.

Patients should have a detailed medical history of previous episodes of seizures.

If it is necessary to use the drug in combination with selective serotonin reuptake inhibitors, patients should be constantly monitored for signs and symptoms of serotonin syndrome, such as impaired cognitive function, hyperpyrexia, hyperreflexia and impaired coordination of movements. If these symptoms occur, one or both medications should be discontinued. When stopping taking a serotonergic agent, a “withdrawal syndrome” may occur.

Cases of reversible surface discoloration of tooth enamel have been reported with linezolid. These discoloration changes were removed by professional tooth cleaning.

Cases of symptomatic hypoglycemia have been reported in diabetic patients treated with linezolid concomitantly with insulin or hypoglycemic drugs.

Although a causal relationship between linezolid and hypoglycaemia has not been established, patients with diabetes should be warned about the possibility of hypoglycaemia.

Patients should be advised not to eat large amounts of foods that have an excessive tyramine content (such as mature cheese, yeast extracts, fermented soy bean products, such as soy sauce, unfiltered beer, red wine, smoked meat).

No clinical studies have been conducted to study the effect of linezolid on the normal microflora of the human body.

The use of antibacterial drugs can sometimes lead to increased growth of non-susceptible microorganisms. In clinical studies, it has been shown that approximately 3% of patients who received the recommended doses of linezolid. candidiasis associated with taking antibiotics developed. If superinfection occurs while taking linezolid, appropriate medical measures should be taken.

Clinical trials: The safety and efficacy of linezolid with a duration of more than 28 days have not been established. Patients with diabetic foot syndrome, pressure sores or ischemic disorders, severe burns or gangrenous lesions were not included in controlled clinical trials. Thus, the experience of using linezolid in the treatment of these conditions is limited.

Each 300 ml of the drug contains 13.7 g of dextrose (which should be taken into account when conducting antidiabetic therapy) and 114 mg of sodium.

Influence on the ability to drive vehicles and mechanisms

Caution should be exercised when using Selezolid due to the possible development of adverse reactions that may adversely affect the ability to drive vehicles and perform potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.

Storage conditions

In a dark place at a temperature not exceeding 25 °C. Do not freeze it.

Shelf

life is 2 years. Do not use after the expiration date.

Active ingredient

Linezolid

Conditions of release from pharmacies

By prescription

Dosage form

infusion solution