Зивокс®

General characteristics. Structure:

International unlicensed name: линезолид
Dosage form: tablets are film coated

Active component: линезолид – 600 mg;
Excipients: starch of corn 60 mg, cellulose of microcrystallic 117,6 mg, hypro rod of 12 mg, carboxymethylstarch of sodium of 42 mg, magnesium stearate 8,4mg;
Film cover: wax of karnaubsky 0,0336 mg, Opadray white YS-1-18202-A (titanium dioxide of 31%, gipromelloza of 63%, macrogoal of 6%) 21 mg.
Ink pharmaceutical (shellac of 39,663%, butanol of 7%, a macrogoal of 3,5%, dye ferrous oxide of red 22,5%, ammonia the solution concentrated 2,479%, the water purified 24,858%).

Description. White or almost white oval biconvex tablets, film coated, with a text red ink "ZYVOX 600 mg" on one party.

Pharmacological properties:

Pharmacodynamics. Linezolid, synthetic antibacterial drug, belongs to the new class of antimicrobic means, oksazolidinona, active in vitro concerning aerobic gram-positive bacteria, some gram-negative bacteria and anaerobic microorganisms. Linezolid selectively inhibits synthesis of protein in bacteria. Due to linkng with bacterial ribosomes it prevents formation of the functional initiating complex 70S which is an important component of process of broadcasting at protein synthesis.


Sensitivity

Drug is active in vitro and in vivo

Gram-positive aerobes
Enterococcus faecium (including strains, resistant to Vancomycinum)
Staphylococcus aureus (including metitsillinrezistentny strains)
Streptococcus agalactiae
Streptococcus pneumoniae (including polyresistant strains)
Streptococcus pyogenes
Drug is active in vitro
Gram-positive aerobes
Enterococcus faecalis (including strains, resistant to Vancomycinum)
Enterococcus faecium (strains sensitive to Vancomycinum)
Staphylococcus epidermidis (including metitsillinrezistentny strains) Staphylococcus haemolyticus
Viridans group streptococci
Gram-negative aerobes
Pasteurella multocida

Microorganisms, resistant to linezolid
Haemophilus influenzae
Moraxella catarrhalis
Neisseria spp.
Enterobacteriaceae spp.
Pseudomonas spp.

Rezistetnost
The mechanism of action of a linezolid differs from mechanisms of effect of antimicrobic drugs of other classes (for example, aminoglycosides, beta lactams, antagonists of folic acid, glycopeptides, linkozamid, hinolon, Rifamycinums, streptogramin, tetracyclines and chloramphenicol) therefore cross resistance between linezolidy and these drugs does not exist. Linezolid is active concerning pathogenic microorganisms, both sensitive, and resistant to these drugs. Resistance in relation to a linezolid develops slowly by a multistage mutation 23S of ribosomalny RNA and happens to frequency less than 1 x 10-9 - 1 x 10-11.

Pharmacokinetics
Absorption
After intake линезолид it is quickly and intensively soaked up from digestive tract. The maximum concentration of a linezolid in a blood plasma (Cmax) – 21,2 mg/l, an average span before achievement of the maximum concentration of a linezolid in blood (TCmax) - 2 h, absolute bioavailability makes about 100%. Meal does not influence absorption of a linezolid. Equilibrium concentration of a linezolid in blood is reached for the 2nd day of reception.

Distribution
The volume of distribution of a linezolid at achievement of equilibrium concentration at the healthy adult averages 40-50 l that to approximately equally general content of water in an organism. Linkng with proteins of a blood plasma makes 31% and does not depend on concentration of a linezolid in blood.
Metabolism
It is established that isoenzymes of P450 cytochrome do not participate in metabolism of a linezolid of in vitro. Linezolid does not inhibit and does not exponentiate activity of clinically important isoenzymes of P450 cytochrome (1A2, 2S9, 2S19, 2D6, 2E1, ZA4).
Metabolic oxidation leads to formation of two inactive metabolites - hydroxyethylglycine (the main metabolite at the person, is formed as a result of non-enzymatic process) and aminoethoxy-acetic acid (it is formed in smaller quantities). Other inactive metabolites are also described.
Removal
The extrarenal clearance makes about 65% of clearance of a linezolid. With increase in a dose of a linezolid small degree of nonlinearity of clearance is noted. It can speak decrease in renal and extrarenal clearance at a high dose of a linezolid. However distinctions of clearance are small and do not influence the seeming elimination half-life.
Linezolid at patients with normal function of kidneys and at a renal failure of easy and average degree is brought by kidneys in the form of hydroxyethylglycine (40%), aminoethoxy-acetic acid (10%) and in not changed look (30-35%). By intestines it is removed in the form of hydroxyethylglycine (6%) and aminoethoxy-acetic acid (3%).
Linezolid in not changed look is practically not brought by intestines.
The elimination half-life of a linezolid averages 5-7 h.
Pharmacokinetics in separate groups of patients

Patients with a renal failure
After a single dose of 600 mg of a linezolid patients with a heavy renal failure (clearance of creatinine <30 ml/min.) concentration of two of its main metabolites increased by 7 – 8 times. However increases in AUC (the area under a curve "concentration time") initial drug was not observed. In spite of the fact that at a hemodialysis a quantity of the main metabolites was removed, their concentration in a blood plasma after reception of 600 mg of a linezolid and holding a procedure of dialysis remained significantly higher than concentration in blood with patients with normal function of kidneys, a slight or medium-weight renal failure.
Patients with a liver failure
There are limited data that at patients with a slight and medium-weight liver failure (a class A and B on classification of Chayld-Pyyu) the pharmacokinetics of a linezolid and two of its main metabolites does not change. The pharmacokinetics of a linezolid at patients with a heavy liver failure (a class C on classification of Chayld-Pyyu) was not studied. However, as линезолид it is metabolized in not fermental way, significant disturbance of his metabolism at a liver failure is not expected.
Children and teenagers
At teenagers (12 – 17 years) the pharmacokinetics of the linezolid accepted in a dose of 600 mg did not differ from kinetics at adults. Thus, at appointment to teenagers of 600 mg of a linezolid each 12 h its concentration will be same, as at adults at purpose of the same dose.
Elderly
At elderly patients at the age of 65 years the pharmacokinetics of a linezolid significantly is also more senior does not change.
Women
At women the volume of distribution of a linezolid is slightly lower, than at men; at them also the average clearance when calculating on body weight is reduced by 20%. Concentration of a linezolid in a blood plasma of women is higher, than at men that can speak partly distinctions of body weight. However, as the elimination half-life of a linezolid at men and women significantly does not differ, there is no occasion to expect increase in concentration of a linezolid in blood of women above the transferable level so dose adjustment is not required.

Indications to use:

Treatment of infectious and inflammatory diseases if it is known or is suspected that they are caused by aerobic and anaerobic gram-positive microorganisms, sensitive to a linezolid (including the infections which are followed by bacteremia):
- the community-acquired pneumonia caused by Streptococcus pneumoniae (including polyresistant strains), including the cases which are followed by bacteremia, or Staphylococcus aureus (only metitsillinchuvstvitelny strains);
- the hospital pneumonia caused by Staphylococcus aureus (including metitsillinchuvstvitelny and metitsillinrezistentny strains) or Streptococcus pneumoniae (including polyresistant strains);
- the complicated infections of skin and soft tissues, including the infections at a syndrome of diabetic foot which are not followed by osteomyelitis, caused by Staphylococcus aureus (including metitsillinchuvstvitelny and metitsillinrezistentny strains), Streptococcus pyogenes or Streptococcus agalactiae;
- the uncomplicated infections of skin and soft tissues caused by Staphylococcus aureus (only metitsillinchuvstvitelny strains) or Streptococcus pyogenes;
- infections, resistant to Vancomycinum, the caused Enterococcus faecium, including, followed by bacteremia.

Route of administration and doses:

Drug can be accepted both during food, and between meals.
Patients to whom at the beginning of therapy drug was appointed in/in can be transferred further to any dosage form of drug for intake, at the same time selection of a dose is not required since bioavailability of a linezolid at intake makes nearly 100%. Duration of treatment depends on the activator, localization and weight of an infection, and also on clinical effect.

Adults and children (12 years are also more senior)


Indications (including the infections which are followed by bacteremia) the Single dose the Recommended treatment duration
- the community-acquired pneumonia caused by Streptococcus pneumoniae (including polyresistant strains), including the cases which are followed by bacteremia, or Staphylococcus aureus (only metitsillinchuvstvitelny strains);
- the hospital pneumonia caused by Staphylococcus aureus (including metitsillinchuvstvitelny and metitsillinrezistentny strains) or Streptococcus pneumoniae (including polyresistant strains);

600 mg inside each 12 h
10 - 14 days
- the complicated infections of skin and soft tissues, including the infections at a syndrome of diabetic foot which are not followed by osteomyelitis, caused by Staphylococcus aureus (including metitsillinchuvstvitelny and metitsillinrezistentny strains), Streptococcus pyogenes or Streptococcus agalactiae;
- the uncomplicated infections of skin and soft tissues caused by Staphylococcus aureus (only metitsillinchuvstvitelny strains) or Streptococcus pyogenes
- infections, resistant to Vancomycinum, the caused Enterococcus faecium, including, followed by bacteremia.

600 mg inside each 12 h
10 - 14 days
infections, resistant to Vancomycinum, the caused Enterococcus faecium, including, followed by bacteremia. 600 mg inside each 12 h
14 - 28 days

Elderly patients: dose adjustment is not required.
Patients with a renal failure: dose adjustment is not required. Because 30% of a linezolid are removed at a hemodialysis within 3 hours, линезолид has to be accepted after carrying out dialysis to the patients needing it.
Patients with a liver failure: dose adjustment is not required.

Features of use:

At the established infection (or suspicion of an infection) caused by the accompanying gram-negative microorganisms additional use of the means operating on gram-negative flora is shown.
At some patients receiving линезолид the reversible miyelosupressiya (with anemia, thrombocytopenia, a leukopenia and a pancytopenia) depending on therapy duration can develop. In this regard in the course of treatment it is necessary to carry out monitoring of indicators of blood at patients with the increased risk of development of bleeding, a miyelosupressiya in the anamnesis, and also at simultaneous use of the drugs reducing a hemoglobin content or quantity of thrombocytes and/or their functional properties and also for the patients receiving линезолид more than 2 weeks.
At the patients accepting antibacterial drugs including линезолид, it is necessary to consider risk of development of pseudomembranous colitis of varying severity.
About cases of the diarrhea connected with Clostridium difficile it was reported in connection with use practically of all antibacterial drugs, including линезолид. Weight of diarrhea can vary from easy forms to heavy. Treatment by antibacterial drugs breaks normal intestinal microflora that leads to the excess growth of Clostridium difficile. Clostridium difficile produces toxins A and B which lead to development of the diarrhea connected with Clostridium difficile. The excess amount of toxins produced by Clostridium difficile strains can cause increase in a lethality among patients as such infections can be steady against antimicrobic therapy, and also the kolonektomiya can be required.
The possibility of development of the diarrhea connected with Clostridium difficile has to be considered at all patients with the diarrhea which followed use of antibiotics. Careful medical observation within 2 months is necessary for the patients who transferred diarrhea, connected with Clostridium difficile after administration of antibacterial drugs.
At emergence of symptoms of deterioration in visual function, such as visual acuity change, change of color perception, zatumanennost, defects of fields of vision, it is recommended to address urgently the ophthalmologist for consultation. It is necessary to carry out monitoring of visual function at all patients accepting линезолид for a long time (more than 3 months), and also at all patients with again appeared symptoms of visual disturbances irrespective of therapy duration. In case of development of peripheral neuropathy and neuropathy of an optic nerve, it is necessary to estimate a ratio risk/advantage of continuation of therapy linezolidy at these patients.
Due to the use of a linezolid it was reported about lactoacidosis. Patients who against the background of reception of a linezolid have a repeated nausea or vomiting, inexplicable acidosis or decrease in concentration a hydrocarbonate of anions is noted, demand careful observation from the doctor.
It was reported about spasms at the patients accepting линезолид, at the same time in most cases in the anamnesis there was an instruction on spasms or existence of risk factors of their development.
In need of use of the drug ZIVOKS® in combination with selective serotonin reuptake inhibitors it is necessary to watch constantly patients for the purpose of identification of signs and symptoms of a serotoninovy syndrome, such as disturbance of cognitive function, hyper pyrexia, hyperreflexia and lack of coordination of movements.
In case of these symptoms it is necessary to cancel one or both accepted drug. At the termination of reception of serotonergic means symptoms of a syndrome of "cancellation" can be observed.
It was reported about cases of reversible superficial change of coloring of an adamantine substance of tooth when using a linezolid. These changes of coloring were removed by means of professional clarification of teeth.

Influence on ability to driving of motor transport and control of mechanisms
During treatment linezolidy to manage vehicles, the special equipment or to be engaged in the activity connected with the increased risk it is not recommended.

Side effects:

Frequency of undesirable reactions is presented on the following classification:
Very frequent: % 10
Frequent: 1 of % and <10%
Infrequent: 0,1 of % and 1 of %
Rare: 0,01 of % and 0,1 of %
Very rare: % 0,01

The undesirable phenomena connected with reception of a linezolid happen usually easy or average degree of manifestation. More often the others diarrhea, a headache and nausea are noted.

Adult patients
From the alimentary system:
Frequent: diarrhea, nausea, vomiting, lock, abdominal pains (including spastic), meteorism, candidiasis of a mucous membrane of an oral cavity
Infrequent: change of coloring of language
Laboratory indicators:
Frequent: thrombocytopenia
Infrequent: increase in concentration of triglycerides in blood, increase in activity of "hepatic" enzymes (including, alaninaminotranspherases (ALT), aspartate aminotransferases (nuclear heating plant), the alkaline phosphatase (AP), a lactate dehydrogenase (LDG), a lipase, amylase, concentration of the general bilirubin and creatinine), increase in concentration of prolactin

From a nervous system:
Frequent: headache, dizziness, spasms
Infrequent: food faddism
From the central nervous system:
Frequent: sleeplessness
From urinogenital system:
Frequent: vaginal candidiasis
From integuments:
Frequent: rash
Others:
Frequent: fever
Infrequent: opportunistic fungal infection
Also were noted: increase in arterial pressure, dyspepsia, itch

Teenagers (from 12 to 17 years)
From the alimentary system:
Frequent: diarrhea, nausea, vomiting, abdominal pains (local and generalized), liquid chair
Laboratory indicators:
Not frequent: an eosinophilia, increase in concentration of triglycerides in blood, increase in activity of alaninaminotranspherase (ALT), a lipase, concentration of creatinine
From a nervous system:
Frequent: headache, вертиго
From integuments:
Frequent: rash
Not frequent: itch
From respiratory system:
Frequent: upper respiratory tract infections, pharyngitis, cough
Others:
Frequent: fever, pain of not specified localization

Spontaneous (post-marketing) data
Laboratory indicators: reversible miyelosupressiya (thrombocytopenia, anemia, leukopenia, pancytopenia)
From sense bodys: cases of the neuropathy of an optic nerve sometimes leading to sight loss (see. "Special instructions")
Allergic reactions: anaphylaxis
From integuments: rash, Quincke's disease; violent damages of skin, similar to Stephens-Johnson's syndrome
From a metabolism: lactoacidosis
From a nervous system: peripheral neuropathy, spasms (see. "Special instructions")
From the alimentary system: change of coloring of enamel of teeth (see. "Special instructions")
Others: a fever, fatigue, a serotoninovy syndrome (see the sections "Interaction with Other Medicines" and "Special Instructions")

Interaction with other medicines:

It is established that isoenzymes of P450 cytochrome do not participate in metabolism of a linezolid of in vitro. Linezolid does not inhibit and does not exponentiate activity of clinically important isoenzymes of P450 cytochrome (1A2, 2S9, 2S19, 2D6, 2E1, ZA4).
Monoamine oxidase inhibitors
Linezolid is non-selective reversible monoamine oxidase inhibitor therefore at some patients receiving линезолид moderate reversible strengthening of pressor effect of pseudoephedrine and a fenilropanolamin can be noted. In this regard it is recommended to reduce initial doses of the following groups of drugs: adrenomimetik (for example, pseudoephedrine, фенилпропаноламин, Epinephrinum, Norepinephrinum, Dobutaminum), dofaminomimetik (for example, dopamine) and further to carry out selection of a dose titration.
In researches I, II and III of a phase development of a serotoninovy syndrome in the patients receiving линезолид together with serotonergic drugs was not noted. However there were several messages on development of a serotoninovy syndrome against the background of use of a linezolid and antidepressants – selective serotonin reuptake inhibitors.
At simultaneous use with aztreonamy and gentamycin of change of pharmacokinetics of a linezolid it was not noted.
Rifampicin caused decrease in Cmax and AUC of a linezolid on average by 21% and 32%, respectively.

Contraindications:

Hypersensitivity to a linezolid and/or other components of drug.
Concomitant use of a linezolid with the drugs inhibiting monoamine oxidase A or B (for example, фенелзин, an isocarboxazid), and also within two weeks after the termination of reception of the called drugs.
In the absence of monitoring of arterial pressure it is not necessary to appoint линезолид to patients with uncontrollable arterial hypertension, a pheochromocytoma, a thyrotoxicosis and/or to the patients receiving the following types of drugs: adrenomimetik (for example, pseudoephedrine, фенилпропаноламин, Epinephrinum, Norepinephrinum, Dobutaminum), dofaminomimetik (for example, dopamine).
In the absence of careful observation of patients with possible development of a serotoninovy syndrome it is not necessary to appoint линезолид to persons with a carcinoid syndrome and/or to the patients receiving the following drugs: inhibitors of the return serotonin reuptake, tricyclic antidepressants, agonists of 5-HT1 receptors (triptanes), Meperidinum or буспирон.
Use of a linezolid for children is younger than 12 years in the form of tablets contraindicated in a type of impossibility of adequate selection of a dose.

With CARE. Patients with a renal failure
Owing to not studied clinical importance of two primary metabolites of a linezolid at patients with a heavy renal failure, линезолид it has to be used with care at such patients, and only if the estimated advantage exceeds potential risk.


Patients with a liver failure
There are limited clinical data recommending to use линезолид at such patients only if the estimated advantage exceeds potential risk.
Linezolid has to be used with care at patients with the system infections representing risk for life such as the infections connected with venous catheters in intensive care units.

USE AT PREGNANCY AND DURING BREASTFEEDING
Researches of safety of use of a linezolid at pregnancy were not conducted therefore use of the drug ZIVOKS® at pregnancy is possible only if the estimated advantage of therapy for mother surpasses potential risk for a fruit.
It is unknown whether it is allocated линезолид with breast milk of the feeding women therefore it is necessary to stop breastfeeding at purpose of drug of mother in the period of a lactation.

Overdose:

About cases of overdose of a linezolid it was not reported. The symptomatic treatment is recommended (including it is necessary to support a glomerular filtration rate). There are no data on acceleration of removal of a linezolid at peritoneal dialysis or hemoperfusion.

Storage conditions:

In the dry, protected from light place, at a temperature not above 30 °C. To store in the place, unavailable to children!

Issue conditions:

According to the recipe

Packaging:

Tablets film coated 600 mg.
10 tablets in the blister from PVC / алюм. a foil or 10, 14, 20, 24, 30, 50 or 100 tablets in a bottle from PEVP. 1, 2, 3, 5, 6 or 10 blisters or 1 bottle together with the application instruction place in a cardboard pack.