Linezolid Canon, 600 mg 10 pcs

Pharmacotherapeutic group

An antibiotic – oxazolidinone

ATX code: J01XX08

The antimicrobial agent belongs to the class of oxazolidinones. The mechanism of action of the drug is due to the inhibition of protein synthesis in bacteria. Linezolid binds to site 23S of bacterial ribosomal RNA 50S subunit and prevents formation of functional initiating complex 70S which is an important component of translation process at protein synthesis. Linezolid is active in-vitro against aerobic gram-positive bacteria of some gram-negative bacteria and anaerobic microorganisms.

Sensitivity

The drug is active invitro and invivo:

Gram-positive aerobes

Enterococcusfaecium (including vancomycin-resistant strains)

Staphylococcusaureus (including methicillin-resistant strains)

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Streptococcusagalactiae

Streptococcuspneumoniae (including multidrug-resistant strains)

Streptococcuspyogenes

The drug is active invitro:

Gram-positive aerobes

Enterococcusfaecalis (including vancomycin-resistant strains)

Enterococcusfaecium (vancomycin-sensitive strains)

Staphylococcusepidermidis (including methicillin-resistant strains)

Staphylococcushaemolyticus

Streptococcus viridans

Gram-negative aerobes: Pasteurellamultocida

Linezolid-resistant microorganisms:

Haemophilusinfluenzae

Mogachella catarrhalis

Neisseria spp.

Enterobacteriaceae spp

Pseudomonas spp.

There is no cross-resistance of microorganisms between linezolid and antimicrobials of other classes (aminoglycosides beta-lactam antibiotics folic acid antagonists glycopeptides lincosamides quinolones rifampicin tetracyclines and chloramphenicol). Linezolid is active against both sensitive and resistant microorganisms to these drugs. Resistance to linezolid develops very slowly through a multistep mutation of 23S -ribosomal RNA. In addition to its main antimicrobial action, it has the properties of a weak non-selective inhibitor of monoamine oxidase (MAO) types A and B.

Pharmacokinetics:

Intake

Linezolid is rapidly and intensively absorbed from the gastrointestinal tract after oral administration. Maximal concentration of linezolid in blood plasma (Cmax) is 212 mg/l Mean time period before reaching maximal concentration of linezolid in blood (TSmax) – 2 hours Absolute bioavailability is about 100%.

Eating does not affect absorption of linezolid. Equilibrium concentration of linezolid in blood is reached on the 2nd day of use.

Distribution

The volume of distribution of linezolid at equilibrium concentration in a healthy adult averages 40-50 liters, which is approximately equal to the total body water content. Binding to plasma proteins is 31% and does not depend on the concentration of linezolid in the blood.

Metabolism

It was found that cytochrome P450 isoenzymes are not involved in the metabolism of linezolid. 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 is formed by a non-enzymatic process) and aminoethoxyacetic acid (formed in smaller amounts). Other inactive metabolites have also been described.

Extrarenal clearance is about 65% of linezolid clearance. As the dose of linezolid increases, a slight degree of nonlinearity in clearance is noted. This may be due to decreased renal and extrarenal clearance at high dose of linezolid. However, the differences in clearance are small and do not affect the apparent elimination half-life.

Linesolid in patients with normal renal function and in mild to moderate renal failure is excreted by the kidneys as hydroxyethylglycine (40%) aminoethoxyacetic acid (10%) and unchanged (30-35%). The intestine excreted as hydroxyethylglycine (6%) and aminoethoxyacetic acid (3%). Linezolid in unchanged form is practically not excreted by the intestine.

The half-life of linezolid is on average 5-7 hours.

Pharmacokinetics in selected patient groups

Patients with renal impairment

After a single administration of linezolid at a dose of 600 mg in patients with severe renal impairment (creatine clearance <30 ml/min), concentrations of its two major metabolites increased 7-8-fold.

Patients with hepatic impairment

There is limited evidence that in patients with mild to moderate hepatic impairment (Child-Pugh class A and B) the pharmacokinetics of linezolid and its two major metabolites are not altered. Pharmacokinetics in patients with severe hepatic impairment (Child-Pugh class C) have not been studied. However, since linezolid is metabolized by a non-enzymatic pathway, no significant impairment of its metabolism in hepatic insufficiency is expected.

Children and adolescents

In adolescents (12-17 years), the pharmacokinetics of linezolid taken at a dose of 600 mg was not different from that of adults. Thus, when adolescents are prescribed linezolid 600 mg every 12 hours, its concentration will be the same as in adults at the same dose.

Patients in the elderly

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

Patients who are female

Women have slightly lower volume of distribution of linezolid than men; they also have a 20% lower average clearance per body weight. Plasma concentration of linezolid in women is higher than in men which may be partially 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 elevated plasma concentrations of linezolid in women above the tolerated level, so no dose adjustment is required.

Indications

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

– community-acquired pneumonia caused by Streptococcuspneumoniae (including polyresistant strains) including cases accompanied by bacteremia or Staphylococcusaureus (methicillin-sensitive strains only);

Hospital pneumonia caused by Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains) or Streptococcuspneumoniae (including multiresistant strains);

– Complicated skin and soft tissue infections including diabetic foot syndrome infections not accompanied by osteomyelitis caused by Staphylococcusaureus (including methicillin-sensitive and methicillin-resistant strains) Streptococcuspyogenes and Streptococcusagalactiae;

– uncomplicated skin and soft tissue infections caused by Staphylococcusaureus (only methicillin-sensitive strains) or Streptococcuspyogenes;

– infections caused by Enterococcusfaecalis (vancomycin-resistant strains) including those accompanied by bacteremia.

Active ingredient

Composition

1 film-coated tablet, 600 mg contains:

The active ingredient: linezolid 600 mg;

Excipients: corn starch 40 mg, croscarmellose sodium 38 mg, mannitol 54 mg, magnesium stearate 8 mg, povidone K-30 20 mg, microcrystalline cellulose 100 mg;

The film jacket: Opadray white 26 mg, including: hypromellose (hydroxypropyl methylcellulose) 8.775 mg, hyprolose (hydroxypropylcellulose) 8.775 mg, talc 5.2 mg, titanium dioxide 3.25 mg.

How to take, the dosage

The drug can be taken both with meals and between meals.

Patients who were prescribed linezolid intravenously at the beginning of therapy can be subsequently switched to linezolid dosage forms for oral administration, and no dosage adjustment is required because the bioavailability of linezolid when taken orally is almost 100%.

The duration of treatment depends on the causative agent, the localization and severity of the infection and the clinical effect.

Interaction

Cytochrome P450 isoenzymes have not been found to be involved in the in-vitro metabolism of linezolid. Linezolid does not inhibit or potentiate the activity of clinically important cytochrome P450 isoenzymes (1A2 2C9 2C19 2D6 2E1 3A4). Thus, no SUR450-induced interaction is expected when using linezolid. When linezolid and (S)-warfarin, which is largely metabolized by the CYP2C9 isoenzyme, are used concomitantly, the pharmacokinetic characteristics of warfarin are not altered. Drugs such as warfarin and phenytoin, which are substrates of CYP2C9 isoenzyme, can be used simultaneously with linezolid without dose adjustment.

Moamine oxidase inhibitors

Linezolid is a non-selective reversible monoamine oxidase inhibitor; therefore, in some patients receiving linezolid a moderate reversible increase of the pressor effect of pseudoephedrine and phenylpropanolamine may be noted. Because of this it is recommended to decrease initial doses of the following groups of drugs: adrenomimetics (e.g. pseudoephedrine phenylpropanolamine epinephrine norepinephrine dobutamine) dopamimetics (e.g. dopamine) and further adjust the dose by titration.

The development of serotonin syndrome in patients receiving linezolid together with serotoninergic drugs has not been reported in phase I II III studies. However, there were several reports about the development of serotonin syndrome with linezolid and antidepressant selective serotonin reuptake inhibitors. No changes in linezolid pharmacokinetics were observed when concomitant use with aztreonam and gentamicin.

Rifampicin caused decreases in Cmax and AUC of linezolid by an average of 21% and 32%, respectively.

Special Instructions

In an open study among critically ill patients with intravascular catheter-associated infections, there was an excess mortality in patients receiving linezolid compared with patients receiving vancomycin/diloxacillin/oxacillin [78/363 (21.5%) versus 58/363 (16.0%)]. The main factor influencing mortality was a Gram-positive infectious agent at baseline.

The mortality rate was similar among patients whose infections were caused only by Gram-positive microorganisms, but was significantly higher in the linezolid group when other microorganisms were also detected or could not be detected at baseline. The greatest imbalance was noted during treatment and within 7 days after the end of antibiotic therapy. Many patients in the linezolid group had Gram-negative microorganisms detected during the study and died from infection with Gram-negative microorganisms or polymicrobial infections.

Thus, in cases of complicated skin and soft tissue infections, linezolid should be used in patients with known or possible co-infection with Gram-negative microorganisms only if no alternative treatment options are available. In these cases, the concomitant use of drugs acting on Gram-negative microflora is indicated. Some patients taking linezolid may develop reversible myelosuppression (with anemia, thrombocytopenia, leukopenia and pancytopenia), depending on the duration of therapy. Elderly patients also have an increased risk of developing this condition.

Thrombocytopenia occurred more frequently in patients with severe renal impairment, regardless of the patient’s use of hemodialysis. In this regard during the treatment it is necessary to monitor blood parameters in patients with increased risk of bleeding, myelosuppression in anamnesis, as well as in concurrent usage of agents decreasing hemoglobin or platelets’ number and/or their functional properties, with severe renal insufficiency and in patients who took linezolid more than 2 weeks.

Linezolid in such patients is used only if close monitoring of hemoglobin, leukocyte and platelet counts is possible. If severe myelosuppression develops during linezolid therapy, therapy should be discontinued, unless continuation is considered absolutely necessary. In this case intensive monitoring of blood values and appropriate treatment is necessary.

In addition, it is recommended that blood tests (including hemoglobin, platelet count and leukocyte count (with calculation of the leukocyte formula)) be performed weekly in patients receiving linezolid regardless of baseline blood counts. A higher incidence of severe anemia was noted in patients who received linezolid longer than the maximum recommended duration of 28 days. These patients were more likely to require blood transfusions. Cases of sideroblast anemia were reported in the post-registration period. In most cases, the duration of linezolid therapy exceeded 28 days. In most patients, the manifestations were completely or partially reversible after discontinuation of linezolid treatment with/without specific treatment for anemia.

In patients taking antibacterial drugs, including linezolid, the risk of pseudomembranous colitis of varying severity should be considered. Cases of diarrhea associated with Clostridium difficile have been reported in association with the use of almost all antibacterial drugs, including linezolid. The severity of diarrhea can range from mild to severe. Treatment with antibiotics disrupts normal gut microflora, leading to an overgrowth 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 strains of Clostridium difficile can cause increased mortality in patients, as such infections may be resistant to antimicrobial therapy, and colonectomy may be required. Drugs that inhibit intestinal peristalsis should not be used. The possibility of Clostridium difficile-associated diarrhea should be considered in all patients with diarrhea following antibiotic use. Close medical follow-up for 2 months is necessary in patients who have had diarrhea associated with Clostridium difficile after antibiotic administration.

If symptoms of visual impairment, such as changes in visual acuity, changes in color perception, blurred vision, visual field defects appear, it is recommended that an ophthalmologist be consulted urgently. Monitoring of visual function should be performed in all patients receiving linezolid for a long time (more than 28 days) and also in all patients with newly developed symptoms of visual impairment regardless of the duration of therapy.

If peripheral neuropathy and optic neuropathy develop, the risk/benefit ratio of continuing therapy with linezolid in these patients should be evaluated. The risk of neuropathy is higher if linezolid is used in patients who are currently using or who have recently taken antibacterial agents to treat tuberculosis.
Lactoacidosis has been reported in connection with linezolid use. Patients who have recurrent nausea or vomiting, abdominal pain, unexplained acidosis or decreased bicarbonate anion concentrations while taking linezolid require close medical monitoring.

Linesolid inhibits mitochondrial protein synthesis. Side effects such as, lactoacidosis, anemia, and neuropathy (peripheral and optic nerve) may result from this inhibition; these effects are more common when the drug is used for more than 28 days.

Convulsions have been reported in patients taking linezolid, with most having a history of or risk factors for seizures. Patients should have a detailed history of prior seizure episodes.

If it is necessary to use the drug in combination with selective serotonin reuptake inhibitors, patients should be continuously monitored for signs and symptoms of serotonin syndrome, such as impaired cognitive function, hyperpyrexia, hyperreflexia, and impaired motor coordination. If these symptoms occur, one or both of the drugs taken should be discontinued. Withdrawal symptoms may occur if serotoninergic medication is discontinued.

There have been reported cases of reversible superficial discoloration of tooth enamel when using linezolid. These discoloration changes were removed by professional tooth cleaning.

Symptomatic hypoglycemia has been reported in diabetic patients receiving linezolid concomitantly with insulin or hypoglycemic medications. Although the causal relationship between taking linezolid and the development of hypoglycemia has not been established, patients with diabetes mellitus should be warned about the possibility of hypoglycemia. If hypoglycemia occurs, correction of the dose of insulin/hypoglycemic drugs or cancellation of linezolid is necessary.
Patients should be advised to avoid taking large amounts of food containing tyramine (such as red wine, old cheese, some alcoholic drinks, smoked meat).

There have been no clinical studies examining the effect of linezolid on normal human microflora.

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

Clinical studies.

The safety and efficacy of linezolid for longer than 28 days has not been established.
Controlled clinical trials have not included patients with diabetic foot syndrome, bedsores or ischemic disorders, severe burns or gangrenous lesions. Thus, there is limited experience with linezolid in the therapy of these conditions.

Impact on driving, operating machinery

During treatment, driving and engaging in potentially hazardous activities requiring increased concentration and rapid psychomotor reactions are not recommended.

Contraindications

– Hypersensitivity to linezolid and/or other components of the drug;

– Children under 12 years of age (due to the inability to adequately adjust the dose;

– concomitant use with drugs that inhibit monoamine oxidase A or B (e.g., phenelzine isocarboxazide) and within two weeks after discontinuation of these drugs;

Linezolid should not be prescribed in the absence of close patient monitoring and blood pressure monitoring:

– patients with uncontrolled arterial hypertension pheochromocytoma thyrotoxicosis carcinoid syndrome bipolar disorder schizoaffective disorder and acute state of confusion;

– patients receiving the following types of drugs: Adrenomimetics (e.g., pseudoephedrine phenylpropanolamine epinephrine norepinephrine dobutamine) dopaminomimetics (e.g., dopamine) serotonin reuptake inhibitors tricyclic antidepressants 5HTH1 receptor agonists (triptans) meperidine or buspirone.

Patients with renal impairment

Because of the unstudied clinical significance of the two primary metabolites of linezolid in patients with severe renal impairment, linezolid should be used with caution in such patients and only if the anticipated benefit exceeds the potential risk.

Patients with hepatic impairment

There is limited clinical data recommending the use of linezolid in these patients only if the expected benefit exceeds the potential risk.

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

Side effects

The frequency of side effects presented below was determined according to the following (World Health Organization classification):

Adverse events associated with taking linezolid are usually mild to moderate in severity. Diarrhea, headache and nausea, and vomiting are the most common.

Adult patients

Infectious and parasitic diseases

Often – candidiasis (including oral candidiasis vaginal candidiasis) fungal infections; infrequently – vaginitis; rarely – colitis caused by taking antibiotics (including pseudomembranous colitis).

Blood and lymphatic system disorders

Often – anemia; infrequent – leukopenia neutropenia thrombocytopenia eosinophilia; rare – pancytopenia; frequency unknown – myelosuppression sideroblastic anemia.

Immune system disorders

Area of unknown frequency – anaphylaxis.

Metabolic and nutrition disorders

Infrequent – hyponatremia; frequency unknown – lactoacidosis.

Mental disorders

Often – insomnia.

Nervous system disorders

Often – headache perversion of taste (“metallic” taste in the mouth) dizziness; infrequent – convulsions hyposthesia parasthesia; frequency unknown – serotonin syndrome peripheral neuropathy.

Visual disorders

Infrequent – blurred vision; rare – appearance of visual field defects; frequency unknown – optic neuropathy neuritis optic nerve loss vision change visual acuity change color vision.

Hearing and labyrinth disorders

Infrequent – tinnitus.

Cardiovascular system disorders

Often – increase of blood pressure; infrequent: arrhythmia (tachycardia) transient ischemic attack phlebitis thrombophlebitis.

Gastrointestinal disorders

Often – diarrhea nausea vomiting localized or diffuse abdominal pain constipation dyspepsia; infrequent – pancreatitis gastritis abdominal bloating dry mouth glossitis liquid stool stomatitis discoloration of the mucous membrane of the tongue and other language disorders; rarely – superficial discoloration of dental enamel.

Hepatic and biliary tract disorders

Often – changes in the results of liver function tests – increased activity of “liver enzymes” (including alanine aminotransferase (ALT) aspartate aminotransferase (ACT) alkaline phosphatase (ALP)) infrequent – increased concentration of total bilirubin.

Skin disorders

Often – rash itching; infrequent – urticaria dermatitis increased sweating; frequency unknown – bullous skin lesions (such as Stevens-Johnson syndrome toxic epidermal necrolysis) angioedema alopecia.

Recreational and urinary tract disorders

Often – increased concentration of urea in blood; infrequent – renal failure increased concentration of creatinine in plasma polyuria.

Genital and mammary disorders

Infrequent – disorders of the vagina and vulva.

General disorders and disorders at the site of injection

Often – fever localized pain; infrequent – chills weakness thirst; pain at the site of injection (for solution for infusion).

Laboratory indices

Often – increased or decreased potassium or hydrocarbonate increased neutrophil count eosinophils decreased hemoglobin hematocrit or red blood cell count increased or decreased platelet or white blood cell count increased lactate dehydrogenase creatine kinase lipase amylase increased glucose concentration not on an empty stomach decreased total albumin protein decreased sodium or calcium in the blood plasma infrequent – increased plasma sodium or calcium decreased plasma glucose concentration not on an empty stomach increased or decreased blood chloride increased reticulocyte count decreased neutrophil count.

The following side effects when using linezolid have rarely been classified as serious: localized abdominal pain transient ischemic attack 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, 25% (33/1326) of patients who received linezolid less than 28 days developed anemia while when linezolid was used for more than 28 days, 123% (53/430) of patients developed anemia.

The ratio of anemia requiring transfusion was 9% among patients receiving linezolid 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 did not differ from those in adult patients.

Overdose

There have been no reports of overdose.

If necessary, symptomatic therapy (including maintenance of glomerular filtration rate) is administered. About 30% of the dose is eliminated within 3 hours by hemodialysis.

There are no data about acceleration of linezolid excretion by peritoneal dialysis or hemoperfusion.

Pregnancy use