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

Pharmaceutical inks (shellac 39.663%, butanol 7%, macrogol 3.5%, iron dye oxide red 22.5%, ammonia solution concentrated 2.479%, purified water 24.858%).

Description:

White or almost white, oval, biconvex tablets, covered with a film shell, with an inscription in red ink "ZYVOX 600 mg"On one side.

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. By binding to bacterial ribosomes, it prevents the formation of

functional initiating complex 70SWhich is an essential component of the translation process of 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

Group streptococci 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 of less than 1 x 10^-9 - 1 x 10^-11.

Pharmacokinetics:

Suction

After oral administration linezolid quickly and intensively absorbed from the gastrointestinal tract. The maximum concentration of linezolid in blood plasma (C_mOh) - 21.2 mg / l, the average period of time until the maximum concentration of linezolid in the blood (TS_mOh) -2 h, 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

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

It has been established that cytochrome P isoenzymes₄₅₀ Do not participate in the metabolism of linezolid in vitro. Linezolid does not inhibit or potentiate the activity of clinically important cytochrome P450 isoenzymes (1A2,2C9,2S19,2D6,2E1, 3A4).

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 excreted as hydroxyethyl glycine (6%) and aminoethoxyacetic acid (3%).

Linezolid in an unmodified form is practically not excreted by the intestine.

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

Pharmacokinetics in selected groups of patients

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 main metabolites increased by a factor of 7-8. However, increases AUC (the area under the "concentration-time" curve) of the initial preparation 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 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

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

Women

In women, the distribution of linezolid is somewhat lower than that of men; they also have 20% reduced the average clearance when calculated for 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 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 linezolid-sensitive aerobic and anaerobic Gram-positivemicroorganisms (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, 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;

uncomplicated infection leather and soft fabrics, caused by Staphylococcus aureus (only methicillin-sensitive strains) or Streptococcus pyogenes;

- vancomycin-resistant infections caused by Enterococcus faecium, including those accompanied by bacteremia.

Contraindications:

Hypersensitivity to linezolid and / or other components of the drug.

Simultaneous administration of linezolid with preparations inhibiting monoamine oxidase A or B (for example, phenelzine, isocarboxazide),and also within two weeks after the termination of reception of the named preparations.

In the absence of monitoring of blood pressure should not be appointed linezolid patients with uncontrolled arterial hypertension, pheochromocytoma, thyrotoxicosis and / or patients receiving the following types of 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, one should not prescribe linezolid Persons with carcinoid syndrome and / or patients receiving the following drugs: serotonin reuptake inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists (tryptanes), meperidine or buspirone.

The use of linezolid in children under the age of 12 in the form of tablets is contraindicated in view of the impossibility of adequate dose selection.

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 is no safety study of linezolid in pregnancy, therefore, the use of ZIVOX® during 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 with the breast milk of lactating women, therefore, breastfeeding should be stopped with the appointment of the mother's drug during lactation.

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)

Indications (including infections accompanied by bacteremia)

Single dose

Recommended duration of 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 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;

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

600 mg orally every 12 hours

10-14 days

- vancomycin-resistant infections caused by Enterococcus faecium, including those accompanied by bacteremia.

600 mg orally every 12 hours

14-28 days

Elderly patients: correction of the dose 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 should be taken 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 taking 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:

Frequent: diarrhea, nausea, vomiting, constipation, abdominal pain (including spastic), flatulence, candidiasis of the oral mucosa

Infrequent: changing the color 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 (APF), lactate dehydrogenase (LDH), lipase, amylase, total bilirubin and creatinine concentration), increasing prolactin concentration

Co the sides of the nervous system:

Frequent: headache, dizziness, convulsions

Infrequent: perversion of taste

Co the central nervous system:

Frequent: insomnia

Co the side of the genitourinary system:

Frequent: vaginal candidiasis

Co skin:

Frequent: rash

Other:

Frequent: fever

Infrequent: opportunistic fungal infection

Also were noted: increased blood pressure, indigestion, itching

Adolescents (12 to 17 years of age)

From the digestive system:

Frequent: diarrhea, nausea, vomiting, abdominal pain (local and generalized), loose stools

Laboratory indicators:

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

From the nervous system:

Frequent: headache, vertigo

From the skin:

Frequent: rash

Infrequent: pruritus

From the respiratory system:

Frequent: upper respiratory tract infection, pharyngitis, cough

Other:

Frequent: fever, pain of unspecified site

Spontaneous (post-marketing) data

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

Co sensory side: cases of optic nerve neuropathy, sometimes leading to loss of vision (see "Special instructions")

Allergic reactions: anaphylaxis

Co skin: rash, angioedema; Bullous skin lesions, similar to Stevens-Johnson syndrome

Co sides of metabolism: lactic acidosis

Co the sides of the nervous system: peripheral neuropathy, convulsions (see "Special instructions")

Co the sides of the digestive system: change in color of tooth enamel (see "Special instructions")

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

Overdose:

No cases of overdose of linezolid have been reported.Recommended symptomatic treatment (including the need to maintain the speed of glomerular filtration). 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 P isoenzymes₄₅₀ (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 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 and III phases there was no development of serotonin syndrome in patients who received linezolid together with serotonergic drugs.However, there were several reports about the development of serotonin syndrome during treatment with 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 in C_mOhand AUC linezolid on average by 21% and 32%, respectively.

Special instructions:

When an infection (or suspected infection), caused by concomitant gram-negative microorganisms, is established, additional application of the agents acting on the 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 monitor blood values in patients with an increased risk of bleeding, myelosuppression in the history, and also with the simultaneous use of drugs that reduce hemoglobin or platelet count 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, 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.

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 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 anhydrous hydrogen carbonate, 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 ZIVOX® is required in combination with selective serotonin reuptake inhibitors, patients should be monitored continuously 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 treatment linezolid drive vehicles, special technology or engage in activities associated with increased risk is not recommended.

Form release / dosage:

Film-coated tablets, 600 mg.

Packaging:

10 tablets in a blister of PVC / alum. foil or 10, 14, 20, 24, 30, 50 or 100 tablets into a vial of HDPE.

1, 2, 3, 5, 6 or 10 blisters or 1 bottle together with instructions for use are placed in a cardboard box.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 30 ° 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:П N012549 / 01

Date of registration:24.12.2010 / 21.08.2013

Expiration Date:Unlimited

The owner of the registration certificate:Pharmacy and Upjohn CampaniPharmacy and Upjohn Campani USA

Manufacturer: & nbsp

PFIZER PHARMACEUTICALS, LLC Puerto Rico

Representation: & nbspPfizer H. Si. Pi. CorporationPfizer H. Si. Pi. Corporation

Information update date: & nbsp12.10.2017

Illustrated instructions

Instructions

Zivox® (Zivox®)