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

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;

Film Sheath: opadray white 26 mg, including: hypromellose (hydroxypropylmethylcellulose) 8.775 mg, giprolose (hydroxypropyl cellulose) 8.775 mg, talc 5.2 mg, titanium dioxide 3.25 mg.

Description:Oval biconvex tablets covered with a film coat of white or almost white color. On the cross-section - almost white.

Pharmacotherapeutic group:Antibiotic - oxazolidinone

ATX: & nbsp

J.01.X.X.08 Linezolid

J.01.X.X Other antibacterial drugs

Pharmacodynamics:

Antimicrobial, refers to the class of oxazolidinones. The mechanism of action of the drug is due to the inhibition of protein synthesis in bacteria. Linezolid communicates with site 23S on bacterial ribosomal RNA 50S subunit and prevents the formation of a functional initiating complex 70S, which is an important component of the translation process in protein synthesis. Linezolid active in vitro in relation to aerobic Gram-positive bacteria, certain gram-negative bacteria and anaerobic microorganisms. Sensitivity

The drug is 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

The drug 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

Group streptococci viridans

Gram-negative aerobes

Pasteurella multocida

Resistant to linezolid microorganisms

Haemophilus influenzae

Moraxella catarrhalis

Neisseria spp.

Enterobacteriaceae spp,

Pseudomonas spp.

He cross-resistance of microorganisms between linezolid and antimicrobial preparations of other classes (aminoglycosides, beta-lactam antibiotics, folic acid antagonists, glycopeptides, lincosamides, quinolones, rifampicins, tetracyclines and chloramphenicol) is noted. Linezolid is active against both sensitive and resistant to these drugs microorganisms.Resistance to linezolid develops very slowly through a multistage mutation 23S ribosomal RNA. In addition to the main antimicrobial effect, it exhibits the properties of a weak non-selective monoamine oxidase (MAO) inhibitor of types A and B.

Pharmacokinetics:

Suction

After oral administration linezolid quickly and intensively absorbed from the gastrointestinal tract. The maximum concentration of linezolid in blood plasma (FROM_m_Oh) - 21,2 mg / l, the average period of time until the maximum concentration of linezolid in the blood (TC_m_Oh) - 2 hours, absolute bioavailability is about 100%.

The intake of food does not affect the absorption of linezolid. The equilibrium concentration of linezolid in the blood is reached on the 2nd day of admission.

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. Binding to plasma proteins is 31% and does not depend on the concentration of linezolid in the blood.

Metabolism

Metabolic oxidation leads to the formation of two inactive metabolites - hydroxyethyl glycine (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 also derived as hydroxyethyl glycine (6%) and aminoethoxyacetic acid (3%). Linezolid in an unchanged form is practically not excreted by the intestine.

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

Pharmacokinetics in selected patient groups

Patients with renal insufficiency

After a single dose of 600 mg of linezolid at patients with severe renal insufficiency (creatinine clearance <30 ml / min), the concentration of its two main metabolites increased 7-8 times.

However, increases AUC (the area under the concentration-time curve) of the initial preparation was not observed.In spite of the fact that some basic metabolites were removed during hemodialysis, their concentration in the blood plasma after taking 600 mg of linezolid and carrying out the dialysis procedure remained substantially higher than the blood concentration in patients with normal kidney function, mild or moderate renal failure.

Patients with hepatic insufficiency

There is limited evidence that in patients with mild and 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. Pharmacokinetics in patients with severe hepatic insufficiency (class C according to the Child-Pugh classification) 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, its concentration will be the same as in adults with the same dose.

Elderly patients

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

Female Patients

In women, the distribution of linezolid 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 plasma of women above the tolerable level, so no dose adjustment is required.

Indications:

Treatment of infectious and inflammatory diseases, if known or suspected,that they are caused by lineage-sensitive aerobic and anaerobic Gram-positive microorganisms (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 and Streptococcus agalactiae;

- Uncomplicated skin and soft tissue infections caused by Staphylococcus aureus (only methicillin-sensitive strains) or Streptococcus pyogenes;

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

Contraindications:

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

- children's age to 12 years (due to the impossibility of adequate dose selection;

- simultaneous administration with drugs inhibiting monoamine oxidase A or B (for example, phenelzine, isocarboxazide), and also within two weeks after discontinuation of the said drugs;

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

- patients with uncontrolled arterial hypertension, pheochromocytoma, thyrotoxicosis, carcinoid syndrome, bipolar disorder, schizoaffective disorder and acute confusion;

- patients receiving the following types of drugs: adrenomimetics (for example, pseudoephedrine, phenylpropanolamine, epinephrine, norepinephrine, dobutamine), dopaminomimetics (eg, dopamine), serotonin reuptake inhibitors, tricyclic antidepressants, 5HT1 receptor agonists (tryptanes), 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, linezolid should be used with caution in such patients, and only if the intended benefit exceeds the potential risk.

Patients with hepatic insufficiency

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

Linezolid 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:

The use of linezolid during pregnancy is only possible if the intended benefit of therapy for the mother exceeds the potential risk to the fetus. It is not known whether linezolid with breast milk, therefore, during the period of linezolid therapy, it is recommended to abandon breastfeeding.

Dosing and Administration:

The drug can be taken both during meals and between meals. Patients who at the beginning of therapy linezolid it was prescribed intravenously, in the future it can be transferred to dosage forms of linezolid for oral administration, while dose selection is not required, since the bioavailability of linezolid when administered 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, with a body weight of at least 40 kg)

Indications (including infections accompanied by bacteremia)	Single dose and multiplicity of administration	Recommended duration of treatment
-hospital pneumonia caused by Streptococcus pneumoniae (including multidrug resistant strains), including cases accompanied by bacteraemia, or Staphylococcus aureus (methicillin-sensitive strains only);	600 mg every 12 hours	10-14 days
-Hospital pneumonia caused by Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains) or Streptococcus pneumoniae (including multiresistant strains);	600 mg every 12 hours	10-14 days
-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;	600 mg every 12 hours	10-14 days
uncomplicated skin and soft tissue infections caused by Staphylococcus aureus (methicillin-sensitive strains only) or Streptococcus roogenes	600 mg every 12 hours	10-14 days
infections caused by Enterococcus faecal is (strains resistant to vancomycin), including those accompanied by bacteremia.	600 mg every 12 hours	14-28 days

Elderly patients do not need dose adjustment.

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

Patients with hepatic impairment: dose adjustment is not required.

Side effects:

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

"very often" (≥1 / 10),
"often" (≥1 / 100, <1/10),
"infrequently" (≥1 / 1000, <1/100),
"rarely" (≥1 / 10000, <1/1000)
"very rarely" (<1/10000)
the frequency is unknown (according to available data, it is impossible to estimate the frequency of development).

The undesirable phenomena associated with the use of linezolid are usually of mild or moderate severity. More often than others the diarrhea, a headache and a nausea, vomiting are marked.

Adult patients

Infectious and parasitic diseases

Often - Candidiasis (including candidiasis of the oral cavity, vaginal candidiasis), fungal infections; infrequently - Vaginitis; rarely - Colitis caused by the intake of antibiotics (including pseudomembranous colitis).

Violations of the blood and lymphatic system

Often - anemia; infrequently - Lakopenia, neutropenia, thrombocytopenia, eosinophilia; rarely - Pancytopenia; frequency unknown - Myelosuppression, sideroblastic anemia.

Immune system disorders

Frequency unknown anaphylaxis.

Disorders from the metabolism and nutrition

Infrequently - hyponatremia; frequency unknown lactoacidosis.

Disorders of the psyche

Often - Insomnia.

Disturbances from the nervous system

Often - headache, perversion of taste ("metallic" taste in the mouth), dizziness; infrequently - convulsions, hyposthenia, parasthesia; frequency unknown - serotonin syndrome, peripheral neuropathy.

Disturbances on the part of the organ of sight

Infrequently - blurred vision; rarely - appearance of visual field defects; frequency unknown - Neuropathy of the optic nerve, optic neuritis, loss of vision, changes in visual acuity, change in color vision.

Hearing disorders and labyrinthine disorders

Infrequently - tinnitus.

Disorders from the cardiovascular system

Often - increased blood pressure; infrequently: arrhythmia (tachycardia), transient ischemic attack, phlebitis, thrombophlebitis.

Disorders from the gastrointestinal tract

Often - diarrhea, nausea, vomiting, localized or diffuse pain in the abdomen, constipation, indigestion; infrequently - pancreatitis, gastritis, bloating, dry mouth, glossitis, loose stools, stomatitis, discoloration of the tongue mucosa and other disorders of the language; rarely - surface discoloration of tooth enamel.

Disturbances from the liver and bile ducts

Often - change in the results of functional liver tests, increase activity of "hepatic enzymes" (including, alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase (APF)), infrequently - increase in the concentration of total bilirubin.

Disturbances from the skin

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

Disorders from the kidneys and urinary tract

Often - Increased blood urea concentration; infrequently - Renal insufficiency, increase in the concentration of creatinine in the blood plasma, polyuria.

Violations of the genitals and mammary gland

Infrequently - violations of the vagina and vulva.

General disorders and disorders at the site of administration

Often - fever, localized pain; infrequently - chills, weakness, thirst; pain at the injection site (for solution for infusion).

Laboratory indicators

Often - increase or decrease potassium or hydrogen, increasing the number of neutrophils, eosinophils, decreased hemoglobin, hematocrit or red blood cell count, increased or decreased number of platelets or leukocytes, increased lactate dehydrogenase activity, creatine kinase, lipase, amylase, increased glucose concentration not fasting, a decrease of total protein, albumin, a decrease in the content of sodium or calcium in the blood plasma; infrequently - increasing the sodium or calcium content in blood plasma, reduction of fasting blood glucose levels, increase or decrease in blood chlorides, increasing the number of reticulocytes, reducing the number of neutrophils.

The following side effects with linezolid in rare cases were classified as serious: localized abdominal pain, transient ischemic attack, arterial hypertension.

In controlled clinical trials in which linezolid a maximum of 28 days was used, only 2% of the patients developed anemia. In another study among patients with life-threatening infections, 2.5% (33/1326) of patients who received linezolid less than 28 days, anemia developed, while with linezolid more than 28 days, anemia developed in 12.3% (53/430) patients.

The proportion of cases of development of anemia requiring a blood transfusion was 9% among patients receiving linezolid less than 28 days (3/33), and 15% (8/53) in those cases where linezolid used more than 28 days. Side effects in children do not differ from those in adult patients.

Overdose:

No reports of overdose cases.

If necessary, conduct symptomatic therapy (including the need to maintain the level of glomerular filtration). Approximately 30% of the dose is excreted within 3 hours of hemodialysis. 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, 3A4). Thus, it is not expected that the CD450-induced interaction when using linezolid. With simultaneous application of linezolid and (S) -warfarin, which is largely metabolized by the isoenzyme CYP2C9, pharmacokinetic the 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 linezolid without dose adjustment.

Inhibitors of monoamine oxidase

Linezolid is a non-selective reversible inhibitor of monoamine oxidase, therefore, in some patients receiving linezolid, there may be a moderate reversible strengthening of the pressor action pseudoephedrine and phenylpropanolamine. 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 I, II, III phase there was no development of serotonin syndrome in patients who received linezolid together with serotonergic drugs.However, there have been several reports of the development of serotonin syndrome in the context of the use of linezolid and antidepressant-selective serotonin reuptake inhibitors. With simultaneous use with aztreonam and gentamicin, the change in the pharmacokinetics of linezolid was not noted.

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

Special instructions:In the open study among critically ill patients with Intravascular catheter-associated infections showed an excess of mortality in patients who received linezolid, Compared with patients who received vancomycin / dicloxacillin / oxacillin [78/363 (21.5%) vs. 58/363 (16.0%)]. The main factor influencing mortality was the gram-positive pathogen of infection at the initial stage. The mortality rate was similar among patients who had infections caused by Gram-positive microorganisms only, but was significantly higher in the linezolid group when detected, and other microorganisms, or could not be detected at an early stage. The greatest imbalance was noted during treatment and within 7 days after the end of antibiotic therapy.In many patients linezolid groups were detected during the study of gram-negative microorganisms, and they died from infection caused by gram-negative microorganisms or polymicrobial infections. Thus, in the case of complicated infections of the skin and soft tissues linezolid should be use in patients with known or potential co-infection Gram-negative microorganisms, only if there are no alternative treatment options. In these cases, additional use of drugs acting on gram-negative microflora is shown simultaneously. In some patients taking linezolid, reversible myelosuppression may develop (with anemia, thrombocytopenia, leukopenia and pancytopenia), depending on the duration of therapy. In elderly patients, the risk of developing this condition is also increased. Thrombocytopenia is more common occurred in patients with severe renal disease insufficiency, regardless of the patient's hemodialysis. In connection with this, during the treatment it is necessary to monitor the blood values in patients with an increased risk of development hemorrhage, myelosuppression in anamnesis, as well as with the simultaneous use of drugs that reduce hemoglobin or platelet count and / or their functional properties, with severe renal failure, as well as in patients taking linezolid more than 2 weeks. Linezolid These patients are only used when it is possible to carefully monitor hemoglobin, the amount leukocytes and platelets. If during linezolid therapy develops expressed myelosuppression, treatment should be discontinued unless continuation of therapy is considered absolutely necessary. In this case, intensive monitoring of blood counts and appropriate treatment is necessary. In addition, it is recommended that a blood test (including determination of hemoglobin, platelet count and leukocyte counts (calculating the leukocyte count)) be performed weekly in patients receiving linezolid regardless of the initial blood test. A higher incidence of severe anemia was observed in patients who received linezolid more than the maximum recommended duration of 28 days.These patients were more likely to require a blood transfusion. Cases of sideroblastic anemia were registered in the post-marketing 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 treatment with linezolid with / without specific treatment for anemia.

In patients taking 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 difficile, may cause an increase in mortality among patients, since such infections can be resistant to antimicrobial therapy, and colonoscopy may also be required.Do not use drugs that inhibit the intestinal motility. 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 28 days), as well as in all patients with newly developed 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. The risk of developing neuropathy is higher if linezolid is used in patients who are currently using or who have recently taken antibacterial drugs for the treatment of tuberculosis.

In connection with the use of linezolid, lactoacidosis was reported. Patients who experience repeated nausea or vomiting with linezolid, abdominal pain, unexplained acidosis, or a decrease in the concentration of bicarbonate anions, require close monitoring by the physician.

Linezolid inhibits the synthesis of the mitochondrial protein. Side effects such as, lactic acidosis, anemia and neuropathy (peripheral and visual nerve), can occur as a result of this inhibition, these effects are more common when the drug is used more than 28 days.

Cramping was reported in patients taking linezolid, and in most cases in the history there was an indication of convulsions or the presence of risk factors for their development. Patients need to collect a detailed 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 tothe detection of 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 drug, 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. There were reported cases of symptomatic hypoglycemia in patients with diabetes mellitus who received linezolid simultaneously with insulin or hypoglycemic drugs. Although a causal relationship between the use of linezolid and the development of hypoglycemia has not been established, patients with diabetes should be warned about the possibility of developing hypoglycemia. In case of hypoglycaemia, correction of insulin dose / hypoglycemic drugs or cancellation of linezolid is necessary.

Patients should be advised not to take food containing tyramine (such as red wine, old cheese, some alcoholic drinks, smoked meat).

Clinical studies that studied the effect of linezolid on the normal microflora of the human body were not carried out.

The use of antibacterial drugs can sometimes lead to an increased growth of microorganisms that are not susceptible to it. In clinical studies, it was shown that approximately 3% of patients receiving recommended doses of linezolid developed candidiasis associated with taking antibiotics. If superinfections occur against the background of linezolid, appropriate medical measures should be taken.

Clinical researches.

The safety and efficacy of linezolid for more than 28 days have not been established.

In controlled clinical trials, patients with "diabetic foot" syndrome, bedsores or ischemic impairment, severe burns or gangrenous lesions did not participate. Thus, the experience of using linezolid in the therapy of these conditions is limited.

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

During the period of treatment, the management of vehicles and the employment of potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions are not are recommended.

Form release / dosage:

Film-coated tablets, 600 mg.

Packaging:

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 1, 2, 3 contour packs of 10 tablets together with the instructions for use are placed in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C in the manufacturer's packaging.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004087

Date of registration:19.01.2017

Expiration Date:19.01.2022

The owner of the registration certificate:CANONFARMA PRODUCTION, CJSC CANONFARMA PRODUCTION, CJSC Russia

Manufacturer: & nbsp

CANONFARMA PRODUCTION, CJSC Russia

Information update date: & nbsp06.02.2017

Illustrated instructions

Instructions

Linezolid Canon (Linezolid Canon)