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

Core: betadex (beta-cyclodextrin) - 10.0 mg / 20.0 mg / 30.0 mg; Copovidone 9.0 mg / 18,0 mg / 27.0 mg; pregelatinized starch - 18.0 mg / 36.0 mg / 54.0 mg; silicon dioxide colloid (aerosil brand A-300) 3.0 mg / 6.0 mg / 9.0 mg; sodium stearyl fumarate 5.0 mg / 10.0 mg / 15.0 mg; magnesium hydroxycarbonate 28.0 mg / 56.0 mg / 84.0 mg.

Sheath: ready water-soluble film shell - 7.0 mg / 14.0 mg / 21.0 mg.

(Composition of the coating: hydroxypropyl methylcellulose (hypromellose) - 74.2%, talc - 2.3%, polyethylene glycol 6000 (Macrogol 6000) - 14.3%, titanium dioxide 3.5%, iron dye red oxide 1.4% , iron oxide dye yellow oxide - 4.3%).

Description:

For the dosage of 200 mg: tablets, film-coated, round, biconvex, from light brown to dark brown.

For a dosage of 400 mg: tablets, film-coated, capsular, biconvex, from light brown to dark brown.

For a dosage of 600 mg: the tablets covered with a film cover, oval, biconcave, from light brown to dark brown color.

On a cross-section a tablet of white or white with a yellowish shade of color.

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 is 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 pyrogenes

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.

There is no cross-resistance of microorganisms between linezolid and Pseudomonas spp. antimicrobials of other classes (aminoglycosides, beta-lactam antibiotics, folic acid antagonists, glycopeptides, lincosamides, quinolones, rifamycins, tetracyclines and chloramphenicol).

Linezolid is active against both sensitive and resistant to these drugs microorganisms.

Resistance to linezolid develops very slowly through a multistage mutation 23Sribosomal 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:

After oral administration linezolid quickly and intensively absorbed from the gastrointestinal tract. Eating does not affect the absorption of the drug. Absolute bioavailability is about 100%.

When ingesting tablets coated with a film membrane, 400 mg (once and twice a day) the maximum concentration in the blood (C_mOh) is - 8.1 and 11 μg / ml; time to reach the maximum concentration (TC_mOh) - 1.52 and 1.12 hours; area under the pharmacokinetic curve "concentration-time" (AUC) - 55.1 and 73.4 μg * h / ml; half-life (T_1/2) - 5.2 and 4.69 h; clearance of 146 and 110 ml / min, respectively.

When taking tablets coated with a film membrane, 600 mg (once and twice a day) C_mOh is 12.7 and 21.2 μg / ml; TS_mOh - 1.28 and 1.03 h; AUC - 91.4 and 138 μg * h / ml; T_1/2- 4.26 and 5.4 h; clearance - 127 and 80 ml / min respectively.

The equilibrium concentration (Css) of the drug in the blood is achieved on the 2-3 day of application. Rapidly distributed in tissues with good perfusion. The volume of distribution upon reaching Css in a healthy adult averages 40-50 liters. The connection with plasma proteins is 31% (independent of concentration).

It is established that cytochrome P450 isoenzymes do not participate in the metabolism of linezolid in vitro. Linezolid also does not inhibit the activity of clinically important cytochrome isoenzymes (P450 CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4). Metabolic oxidation leads to the formation of 2 inactive metabolites: hydroxyethylglycine (is the main metabolite in humans and is formed as a result of a non-enzymatic process) and aminoethoxyacetic acid (formed e. smaller quantities). Other "small" inactive metabolites are also described.

Linezolid is excreted by the kidneys in the form of hydroxyethyl glycine (40%), unchanged drug (30-35%) and aminoethoxyacetic acid (10%). Through the intestine it is released as hydroxyethyl glycine (6%) and aminoethoxyacetic acid (3%).

The clearance of linezolid is higher in children and decreases with increasing age.

Among women lower volume of distribution, clearance (20% less), and a higher plasma concentration than men. T_1/2linezolid in women and men does not differ significantly, there is no need to correct the dosage regimen.

In patients with chronic renal insufficiency (CRF) correction of the dosing regimen is not required, because There is no relationship between the clearance of creatinine and the excretion of the drug through the kidneys. Since 30% of the dose is excreted within 3 hours of hemodialysis, in patients receiving similar treatment, linezolid should be used after dialysis.

The pharmacokinetics of linezolid does not change in patients with moderate or moderate hepatic impairment, in connection with which there is no need to adjust the dose of the drug.

Indications:

Infectious-inflammatory diseases caused by line-sensitive microorganisms; pneumonia (community-acquired and hospital); infections of the skin and soft tissues; Enterococcal infections (including those caused by vancomycin-resistant strains Enterococcus faecalis and Enterococcus faecium).

Contraindications:

Hypersensitivity to linezolid and / or other components of the drug; Children under 12 years of age and weighing less than 40 kg; the period of breastfeeding; 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 blood pressure monitoring, the drug should not be used in patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and / or patients receiving the following drugs: adrenomimetics (for example, pseudoephedrine, phenylpropanolamine, epinephrine, norepinephrine, dobutamine), dopaminomimetics (for example, dopamine); in the absence of careful monitoring of patients with possible development of serotonin syndrome should not be used for persons with carcinoid syndrome and / orpatients receiving the following drugs: serotonin reuptake inhibitors, tricyclic antidepressants, 5-H agonistsT₁receptors (triptans), meperidine, or buspirone.

Carefully:

Pregnancy, severe renal failure, liver failure.

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.

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 received the drug IV, can later be transferred to any dosage form of the drug 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, 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
- community-acquired pneumonia caused by Streptococcus pneumoniae (including multidrug-resistant strains), including cases accompanied by bacteraemia, or Staphylococcus aureus (only methicillin-sensitive strains);	600 mg every 12 hours	10-14 days
- hospitalized pneumonia caused by Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains) or Streptococcus pneumoniae (including multidrug-resistant strains);	600 mg every 12 hours	10-14 days
- complicated skin and soft tissue infections, including infections with diabetic foot syndrome not accompanied by osteomyelitis, caused by Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains), Streptococcus pyogenes or Streptococcus agalactiae;	600 mg every 12 hours	10-14 days
- vancomycin-resistant Enterococcus faecium, including, accompanied by bacteremia.	600 mg every 12 hours	14-28 days

Elderly patients: dose adjustment is not required.

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

Patients with hepatic insufficiency: correction of the dose is not required.

Side effects:

The frequency of unwanted reactions is represented by the following classification:

Very frequent: ≥ 10%

Frequent: ≥1% and <10%

Infrequent: ≥ 0.1% and <1%

Rare: ≥ 0.01% and <0.1%

Very rare: <0.01%

The undesirable phenomena associated with the use of linezolid are usually of mild or moderate severity. Most often, diarrhea, headache and nausea are noted.

Adult patients

Co the sides of the digestive system: nausea, vomiting, diarrhea, constipation, abdominal pain (including spastic), flatulence, candidiasis of the oral mucosa, convulsions.

Infrequent: change the coloration of the tongue.

Laboratory indicators:

Frequent: thrombocytopenia.

Infrequent: an increase in the concentration of triglycerides in the blood, an increase in the activity of "hepatic enzymes" (including alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase (FA), lactate dehydrogenase (LDH), lipase, amylase, total bilirubin and creatinine concentration), increasing prolactin concentration.

From the nervous system:

Frequent: headache, dizziness, convulsions.

Infrequent: perversion of taste.

From the central nervous system:

Frequent: Insomnia.

From the genitourinary system:

Frequent: vaginal candidiasis.

From the skin:

Frequent: a rash.

Other:

Frequent: fever.

Infrequent: opportunistic fungal infection.

Also were noted: increased blood pressure, dyspepsia, itching.

Adolescents (12 to 17 years of age)

Co the sides of the digestive system: nausea, vomiting, diarrhea, abdominal pain (local and generalized), loose stools.

Laboratory indicators:

Infrequent: eosinophelia, an increase in the concentration of triglycerides in the blood, increased activity of alanine aminotransferase (ALT), lipase, and creatinine concentrations.

From the nervous system:

Frequent: headache, vertigo.

From the skin:

Frequent: rash.

Infrequent: itching.

From the respiratory system:

Frequent: upper respiratory tract infection, pharyngitis, cough.

Other:

Frequent: fever, pain of unspecified localization.

Spontaneous (postmarketing) data:

Laboratory indicators: reversible myelosuppression (thrombocytopenia, anemia, leukopenia, pancytopenia).

From the sense organs: cases of optic nerve neuropathy, sometimes leading to loss of vision (see "Special instructions").

Allergic reactions: anaphylaxis.

From the skin: rash, angioedema; Bullous skin lesions, similar to Stevens-Johnson syndrome.

From the side of metabolism: lactic acidosis.

From the nervous system: peripheral neuropathy, convulsions (see "Special instructions").

From the digestive system: change in the color of the enamel of the teeth (see "Special instructions").

Other: chills, fatigue, serotonin syndrome (see the sections "Interaction with other medicines" and "Special instructions").

Overdose:

Treatment: 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.

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).

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 psevdephedrine 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 gentamycin, there was no change in the pharmacokinetics of linezolid.

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

Special instructions:

If infection (or suspected infection, caused by concomitant gram-negative microorganisms, is shown, additional application of the agents acting on gram-negative flora is shown.

In some patients receiving linezolid, reversible myelosuppression may develop (with anemia, thrombocytopenia, leukopenia and pancytopenia), depending on the duration of therapy. In connection with this, during the treatment it is necessary to control the amount of platelets and hemoglobin in the blood in patients with an increased risk of bleeding, myelosuppression in the anamnesis, and also with the simultaneous use of drugs that reduce the hemoglobin or the number of platelets and / or their functional properties, as well as in patients receiving linezolid more than 2 weeks.

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, can cause an increase in mortality among patients, since such infections can be resistant to antimicrobial therapy, and may require a columnectomy.

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 visual impairment, such as changes in visual acuity, changes in color perception, blurred vision, visual field defects, are recommended, it is recommended that an ophthalmologist be urgently consulted. Monitor visual function in all patients taking linezolid for a long time (more than 3 months), as well as in all patients with newly emerging 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.

In connection with the use of linezolid, lactoacidosis was reported. Patients who experience repeated nausea or vomiting, inexplicable acidosis, or a decrease in the concentration of anion hydrocarbonate, require close monitoring by the doctor.

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. If necessary, the use of the drug Amizolide in combination with selective serotonin reuptake inhibitors should be constantly monitored by patients 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.

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

During the treatment period, vehicle management and the employment of potentially hazardous activities requiring increased concentration and speed of psychomotor reactions are not recommended.

Form release / dosage:

Film coated tablets, 200 mg, 400 mg and 600 mg.

Packaging:

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

For 10, 14, 20, 24, 30, 50 or 100 tablets in a can of polymer with a lid pulled with the control of the first opening. Free space is filled with cotton wool. On cans are labeled with paper label or from polymer materials, self-adhesive.

For 1, 2, 3, 5, 6 or 10 contour mesh packages together with the instruction for use are placed in a pack of cardboard.

On 1 bank together with the instruction on application place in a pack from a cardboard.

Storage conditions:

In the original packaging of the manufacturer, 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 expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002276

Date of registration:11.10.2013 / 01.04.2016

Expiration Date:11.10.2018

The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Information update date: & nbsp03.08.2017

Illustrated instructions

Instructions

Amisolide (Amizolid)