Bactolin - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 58.0 mg, corn starch 100.0 mg, microcrystalline cellulose 90.0 mg, magnesium stearate 5.0 mg, sodium carboxymethyl starch 35.0 mg, hypromellose 15 cps) - 15.728 mg, propylene glycol - 2,000 mg, talc - 3,636 mg, titanium dioxide - 3,636 mg.

Description:

Oval biconvex tablets covered with a film coating of white or almost white color with a risk on one side. The color at the break is white.

Pharmacotherapeutic group:Antibiotic-oxazolidinone

ATX: & nbsp

J.01.X.X.08 Linezolid

J.01.X.X Other antibacterial drugs

Pharmacodynamics:

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

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. Streptococcus spp. groups Viridans.

Gram-negative aerobes: Pasteurella multocida.

Resistant to linezolid microorganisms: Haemophilus influenzae, Moraxella catarrhalis, Neisseria spp., Enterobacteriaceae spp., Pseudomonas spp.

Resistance

The mechanism of action of linezolid differs from the mechanisms of action of antimicrobials of other classes (for example, aminoglycosides, beta-lactams, folic acid antagonists, glycopeptides, lincosamides, quinolones, rifamycins, streptogramins, tetracyclines and chloramphenicol), so there is no cross-resistance between linezolid and these preparations. Linezolid is active against pathogenic microorganisms, both sensitive and resistant to these drugs. Resistance to linezolid develops slowly through a multistage mutation 23S ribosomal RNA and occurs at a frequency less than l x l0^-9 - 1x10^-11.

Pharmacokinetics:

Suction

After oral administration linezolid quickly and intensively absorbed from the gastrointestinal tract. The maximum concentration in the blood plasma (C_m_Oh) linezolid in blood plasma - 21.2 mg / l, the average period of time to reach (TC_m_Oh) linezolid in the blood for 2 hours, the 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

Volume of distribution (Vd) linezolid at an equilibrium concentration in a healthy adult is an average of 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

It has been established that isoenzymes of the cytochrome P450 system do not participate in the metabolism of linezolid in vitro. Linezolid does not inhibit or potentiate the activity of clinically important cytochrome P450 isoenzymes (1A2, 2C9, 2C19, 2D6, 2E1, 3A4).

Metabolic oxidation leads to the formation of two inactive metabolites - hydroxyethyl glycine (the main metabolite in humans,is 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 (T_1/2).

Linezolid in patients with normal renal function and with renal insufficiency of mild and moderate degree is excreted by the kidneys in the form of hydroxyethyl glycine (40%), aminoethoxyacetic acid (10%) and unchanged (30-35%). The intestine is excreted as hydroxyethyl glycine (6%) and aminoethoxyacetic acid (3%). Linezolid in an unmodified form is practically not excreted by the intestine. T_1/2linezolid on the average is 5-7 hours.

Pharmacokinetics in selected patient groups

Patients with renal insufficiency

After a single dose of 600 mg of linezolid in patients with severe renal insufficiency (creatinine clearance <30 mL / min), the concentration of its two major metabolitesincreased by 7-8 times. However, an increase in the area under the concentration-time curve (AUC) linezolid was not observed. Despite the fact that some basic metabolites were excreted during hemodialysis, their concentration in the blood plasma after taking 600 mg of linezolid and carrying out the dialysis procedure remained significantly higher than the concentration in the blood in patients with normal renal function, mild or moderate renal insufficiency.

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. The pharmacokinetics of linezolid 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) 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 when administered at the same dose. In children up to the age of 12, the use of linezolid at a dose of 10 mg / kg daily every 8 hours allows achieving the same concentration as in adults when 600 mg of linezolid is administered twice a day.

Elderly patients

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

Female Patients

Among women Vd The 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 elimination half-life (T_1/2) linezolid in men and women is not significantly different, there is no reason to expect a higher concentration of linezolid in the blood of women above the tolerable level, so no dose adjustment is 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 multidrug-resistant strains), including cases accompanied by bacteraemia, or Staphylococcus aureus (only methicillin-sensitive strains);

- hospitalized 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 caused by Staphylococcus aureus (including strains sensitive and not sensitive to methicillin), Streptococcus pyogenes or Streptococcus agalactiae;

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

- 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 reception of linezolid with drugs that inhibit monoamine oxidase A or B (for example, phenelzine, isocarboxazide), and also within two weeks after discontinuation of these 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, 5-HT1 receptor agonists (tryptanes), meperidine or buspirone.

Children under 12 years (for this dosage form).

Deficiency of lactase, intolerance to galactose, glucose-galactose malabsorption.

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:

There has been no safety study of linezolid in pregnancy, therefore the use of Bactolin in 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 in the breast milk of nursing women, and therefore, breastfeeding should be stopped for the period of treatment with the mother's drug during lactation.

Dosing and Administration:

The drug can be taken as during a meal. and between meals.

Patients who at the beginning of therapy linezolid was administered intravenously, in the future it can be transferred to any dosage form of linezolid for oral administration. the bioavailability of linezolid upon ingestion is almost 100%.The duration of treatment depends on the pathogen, the localization and severity of the infection, and also on the clinical effect.

Adults and children (12 years and older)

Indications (including infections accompanied by bacteremia)		One-time dose		Recommended Duration treatment
- Community-acquired pneumonia Streptococcus pneumoniae (including multidrug-resistant strains), including cases accompanied by bacteraemia, or Staphylococcus aureus (only methicillin-sensitive strains); - hospital pneumonia caused by Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains) or Streptococcus pneumoniae (including multidrug-resistant strains); - complicated skin and soft tissue infections caused by Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains), Streptococcus pyogenes or Streptococcus agalactiae\ - Uncomplicated skin and soft tissue infections caused by Streptococcus pyogenes or Staphylococcus aureus.		600 mg orally every 12 hours		10-14 days
- infections caused by Enterococcus faecium,	600 mg
(resistant to vancomycin) including,	inwards		14-28 days
accompanied by bacteremia.	every 12 hours

Older patients are not required to adjust the dose.

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

Patients with hepatic impairment: dose adjustment is not required.

Side effects:

The frequency of side effects listed 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 (it is impossible to estimate the frequency of development according to available data).

The undesirable phenomena associated with taking linezolid are usually of mild or moderate severity. More often than others the diarrhea, a headache, 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 use of antibiotics (including pseudomembranous colitis).

Violations from the blood and lymphatic system: often - anemia; infrequently - leukopenia, neutropenia, thrombocytopenia, eosinophilia; rarely - pancytopenia; frequency unknown - myelosuppression, sideroblastic anemia.

Immune system disorders: frequency is unknown - anaphylaxis.

Disorders from the metabolism and nutrition: infrequently - hyponatremia; frequency is unknown - lactic acidosis.

Disorders of the psyche: often - insomnia.

Impaired nervous system: often - headache, perversion of taste ("metallic" taste in the mouth), dizziness; infrequently - convulsions, hyposthenia. paresthesia; frequency is unknown - serotonin syndrome, peripheral neuropathy.

Disorders from the side of the organ of vision: infrequently - blurred vision; rarely - the 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 disturbances: infrequent - ringing in the ears.

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,dyspepsia; infrequently pancreatitis, gastritis, bloating, dry mouth, glossitis, loose stools, stomatitis, discoloration of the tongue mucosa and other abnormalities of the tongue; rarely - a superficial change in the color of the enamel of the teeth.

Disorders from the liver and bile ducts: often - changes in the results of functional liver tests; an increase in the activity of "hepatic" enzymes (including alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase (AFP)); infrequently, an increase in the concentration of total bilirubin.

Disturbances from the skin and subcutaneous tissues: often - itching, rash; infrequently - hives, 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 breast: 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 - increasing the number of neutrophils, eosinophils, reducing hemoglobin hematocrit or the number of erythrocytes, increasing or decreasing the number of platelets or white blood cells, increasing the activity of lactate dehydrogenase. creatine kinase, lipase, amylase, increased fasting glucose, reduced total protein, albumin, sodium or calcium, increased or decreased potassium or bicarbonate; infrequent - an increase in the content of sodium or calcium in the blood plasma, a decrease in glucose concentration not fasting, an increase or decrease in blood chlorides, an increase in the number of reticulocytes, a decrease in 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 was used for a maximum of 28 days, 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 cases of overdose have been reported. Symptomatic treatment is recommended (including the need to maintain the glomerular filtration rate). 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 isoenzymes of cytochrome P450 (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Thus, no CD450-induced interaction is expected with linezolid.With simultaneous use of linezolid and (8) -varpharin, which is largely metabolized by isoenzyme CYP2C9, pharmacokinetic characteristics of warfarin do not change. Such drugs as warfarin and phenytoin, which are the substrates of the isoenzyme CYP2C9, can be used simultaneously with 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 subsequently to carry out the dose selection by titration.

In studies, 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 antidepressants -selective serotonin reuptake inhibitors.

When used simultaneously with aztreonam and gentamicin there was no change in the pharmacokinetics of linezolid.

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

Special instructions:

In an open study among critically ill patients with intravascular catheter-related infections were observed excess mortality in patients treated with 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 use in patients with known or possible co-infection by gram-negative microorganisms, only if 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 occurred more often in patients with severe renal failure, regardless of the patient's hemodialysis. In this connection, in the course of treatment is necessary to monitor blood parameters in patients with an increased risk of myelosuppression bleeding history, and while the use of drugs that reduce hemoglobin or platelet count and / or functional properties, with severe renal insufficiency, and also in patients receiving linezolid more than 2 weeks. Linezolid these patients are only used when it is possible to carefully monitor hemoglobin, the number of leukocytes and platelets. If during treatment with linezolid develops marked 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 (with the calculation of 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 specifictreatment of 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 may require a colonectomy. 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 that followed 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 for all patients with newly appeared 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 It is used in patients who are currently using or who have recently taken antimycobacterial 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 or optic nerve), may occur as a result of 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 the drug is to be used in combination with selective serotonin reuptake inhibitors, patients should be constantly monitored to identify signs and symptoms of serotonin syndrome, such as cognitive impairment, hyperpyrexia, hyperreflexia and impaired coordination of movements. If these symptoms appear, you should cancel one or both of the drugs taken. When discontinuing the use of a serotonergic 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 large amounts of 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 use of linezolid, it is not recommended to operate vehicles, special equipment or engage in activities requiring increased attention and speed of psychomotor reactions.

Form release / dosage:Film-coated tablets, 600 mg.

Packaging:4 tablets per strips of Aluminum foil, 1 strip per cardboard pack, along with instructions for medical use, 5 cardboard packs in a cardboard box. For 10 tablets in a strip of aluminum foil. For 1 or 2 strips with instructions for use in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004097

Date of registration:24.01.2017

Expiration Date:24.01.2022

The owner of the registration certificate:Micro Labs LimitedMicro Labs Limited India

Manufacturer: & nbsp

MICRO LABS, Limited India

Representation: & nbspMICRO LABS LIMITED MICRO LABS LIMITED India

Information update date: & nbsp06.02.2017

Illustrated instructions

Instructions

Bactolin (Baktolin)