Зивокс

Зивокс – the antimicrobic drug of a class of oksazolidinon showing activity concerning anaerobic microorganisms, a wide range of aerobic gram-positive bacteria, some gram-negative bacteria.

Form of release and structure

Зивокс release in the following dosage forms:

• Solution for infusions: transparent, colourless or slightly yellowish liquid (on 100, 200 or 300 ml in one-time infusional packages from a film of Excel sealed in the laminated foil on 1, 2, 5, 10 or 25 packages in a cardboard pack);
• Tablets, coated: oval, white or almost white, on one of the parties the text of "ZYVOX 600 mg" is made red paint (on 10 pieces in blisters or blister strip packagings, on 1 blister or packaging in a cardboard pack);
• Granules for preparation of suspension for intake: white or light yellow; the suspension prepared from granules – homogeneous, from white till light yellow color (on 66 g in bottles of dark glass of 150 ml complete with a measured spoon, on 1 bottle in a cardboard pack).

Is a part of 1 ml of infusion solution:

• Active agent: линезолид – 2 mg;
• Auxiliary components: anhydrous citric acid, a sodium citrate dihydrate, monohydrate of glucose, water for injections.

Is a part of 1 tablet:

• Active agent: линезолид – 600 mg;
• Auxiliary components: corn starch, hydroxypropyl cellulose, microcrystallic cellulose (MKTs), magnesium stearate, sodium glikolit starch, Opadry dye white, red pharmaceutical ink, karnaubsky wax.

Is a part of 1 dose of the suspension (5 ml) prepared from granules:

• Active agent: линезолид – 100 mg;
• Auxiliary components: citric acid, sucrose, sodium citrate, xanthane pitch, sodium salt of carboxymethylcellulose and MKTs, aspartame, sodium benzoate, mannitol, colloid silicon dioxide, fragrances (orange, mint, vanilla, orange cream), sodium chloride, sweeteners.

Indications to use

Зивокс apply to therapy of infectious and inflammatory diseases when it is suspected or it is for certain known that they were caused by aerobic and anaerobic gram-positive microorganisms, sensitive to a linezolid (including the infections which are followed by bacteremia):

• Community-acquired pneumonia: the activator – Streptococcus pneumoniae (including its polyresistant strains, including followed by bacteremia); the activator – Staphylococcus aureus (only the strains sensitive to Methicillinum);
• Intrahospital (hospital) pneumonia: the activator – Staphylococcus aureus (including metitsillinrezistentny and metitsillinchuvstvitelny strains); the activator – Streptococcus pneumoniae (including polyresistant strains);
• The complicated infections of soft tissues and skin, including infections at the syndrome of diabetic foot (SDF), without symptoms of osteomyelitis: activators – Staphylococcus aureus (including metitsillinrezistentny and metitsillinchuvstvitelny strains), Streptococcus agalactiae and Streptococcus pyogenes;
• Uncomplicated infections of soft tissues and skin: activators – Staphylococcus aureus (only the strains sensitive to Methicillinum) or Streptococcus pyogenes;
• Infections, resistant to Vancomycinum: the activator – Enterococcus faecium, including infections which are followed by bacteremia.

Contraindications

It is contraindicated to apply all forms of release of Zivoks in case of hypersensitivity to drug components.

Absolute contraindications for oral administration of Zivoks (a tablet, a granule):

• Concomitant use of monoamine oxidase inhibitors A or B (an isocarboxazid, фенелзин), and also the two-week period after the termination of their use;
• Lack of an opportunity to control arterial pressure during therapy of patients with a pheochromocytoma, uncontrollable arterial hypertension, a thyrotoxicosis, and also the patients receiving adrenomimetik (фенилпропаноламин, pseudoephedrine, Epinephrinum, Dobutaminum) and/or dofaminomimetik (a levodopa, амантадин, dopamine);
• Lack of a possibility of monitoring of patients with risk of a serotoninovy syndrome;
• Carcinoid syndrome and/or reception of inhibitors of the return serotonin reuptake, tricyclic antidepressants, agonists _{of 5-HT1} receptors (triptanes), Meperidinum or buspiron;
• Children's age up to 12 years (for tablets, because of impossibility of adequate selection of a dose).

Relative contraindications (the risk of side effects is increased):

• Heavy renal failure;
• Liver failure;
• The system infections representing risk for life (using venous catheters in intensive care units);
• Pregnancy;
• The lactation period (there are no data on allocation of a linezolid with breast milk therefore for the period of therapy by drug breastfeeding should be stopped).

Route of administration and dosage

Depending on a contagium, localization and weight of a course of a disease, and also from clinical performance duration of a course of therapy and the mode of dosing is defined.

Solution for infusions
It is necessary to enter solution intravenously, introduction duration – from 30 to 120 minutes, the daily dose is recommended to be divided into 2 times.

To adults and children 12 years are more senior the following mode of dosing is recommended:

• Community-acquired pneumonia, hospital pneumonia, infections of soft tissues and skin (including followed by bacteremia) – on 600 mg each 12 h for ^11/2-2 weeks;
• Enterokokkovy infections (including followed by bacteremia) – on 600 mg each 12 h for 2-4 weeks.

The following mode of dosing is recommended to children up to 12 years:

• Community-acquired pneumonia, hospital pneumonia, infections of soft tissues and skin (including followed by bacteremia) – on 10 mg/kg each 8 h for ^11/2-2 weeks;
• Enterokokkovy infections (including followed by bacteremia) – on 10 mg/kg each 8 h for 2-4 weeks.

Just before use of solution it is necessary to remove a protective cover from a foil, then to squeeze an infusional package about a minute to be convinced of lack of leakages. Course of a package demonstrates disturbance of its tightness, therefore, solution is unsterile, is not suitable for use.

It is impossible to connect consistently infusional packages and to use the packagings filled partially.

Upon termination of the procedure the remains of unused solution need to be poured out in waste.

The patients who began therapy with a parenteral form of Zivoks it is possible to switch to a dosage form for oral administration according to clinical indications. In this case selection of a dose is not required as bioavailability of a linezolid at intake of nearly 100%.

Granules for preparation of suspension for intake, a tablet, coated
The suspension prepared from granules, and a pill is taken inside, irrespective of meal.

The recommended dosing mode for therapy of infections (including followed by bacteremia):

• Community-acquired pneumonia, hospital pneumonia – on 600 mg each 12 hours for ^11/2-2 weeks;
• Infections of soft tissues and skin – from 400 to 600 mg (depending on disease severity) each 12 hours for ^11/2-2 weeks;
• Enterokokkovy infections – on 600 mg each 12 hours for 2-4 weeks.

To children of 5 years is also more senior (of 12 years – for tablets) Zivoks is recommended in a dose of 10 mg/kg of the body weight a day divided into 2 receptions.

For children and adults the maximum dose should not exceed 600 mg 2 times a day.

Preparation of suspension for intake from granules:

1. To knock slightly on a bottle that packed powder was scattered;
2. To precisely measure 123 ml of water by means of the measured cylinder;
3. To add to a bottle the first portion of water (about a half from 123 ml) then strongly to stir up a bottle evenly to humidify its contents;
4. To add the remained water and to stir up a bottle again before receiving homogeneous suspension of 150 ml.

Before the use suspension needs to be resuspended, overturning a bottle of 3-5 times. Not to stir up.

Side effects

The undesirable effects connected with reception of peroral forms of Zivoks, easy or moderate severity are usually observed. The headache, nausea and diarrhea were most often noted.

Classification of frequency of undesirable reactions: very seldom (<0,01%), it is rare (≥0,01%-<0,1%), infrequently (≥0,1%-<1%), is frequent (≥1%-<10%), is very frequent (≥10%).

At adult patients:

• Alimentary system: infrequently – change of coloring of language; often – nausea, vomiting, diarrhea, abdominal pains (including spastic), a lock, a meteorism, candidiasis of a mucous oral cavity;
• Central and peripheral nervous system: infrequently – a perversion of flavoring perception; often – sleeplessness, spasms, dizziness, a headache;
• Urinogenital system: often – vaginal candidiasis;
• Integuments: often – rash;
• Laboratory indicators: infrequently – increase in concentration in blood of triglycerides, increase in activity of liver enzymes (including ALT (alaninaminotranspherase), nuclear heating plant (aspartate aminotransferase), ShchF (alkaline phosphatase), LDG (lactate dehydrogenase), amylase, a lipase, concentration of the general creatinine and bilirubin), increase in concentration of prolactin; often – thrombocytopenia;
• Others: infrequently – an opportunistic fungal infection; often – fever.

Besides, were noted: itch, dyspepsia, increase AP (arterial pressure).

At teenagers aged from 12 up to 17 years:

• Alimentary system: often – nausea, vomiting, diarrhea, abdominal pains (generalized and local), a liquid chair;
• Nervous system: often – вертиго, a headache;
• Integuments: infrequently – an itch; often – rash;
• From respiratory system: often – upper respiratory tract infections, cough, pharyngitis;
• Laboratory indicators: infrequently – increase in concentration in blood of triglycerides, an eosinophilia, increase in activity of ALT, concentration of creatinine, a lipase;
• Others: often – pain of not specified localization, fever.

Data of post-market researches (spontaneous):

• Nervous system: spasms, peripheral neuropathy;
• Alimentary system: change of coloring of enamel of teeth;
• Sense bodys: the episodes of neuropathy of an optic nerve which are perhaps leading to sight loss;
• Metabolism: lactoacidosis;
• Allergic answers: anaphylaxis;
• Integuments: a Quincke's disease, rash, violent damages of skin (as Stephens-Johnson's syndrome);
• Laboratory indicators: reversible miyelosupressiya (anemia, leukopenia, thrombocytopenia, pancytopenia);
• Others: fatigue, fever, serotoninovy syndrome.

Side reactions at Zivoks's use in the form of solution for infusions:

• Alimentary system: often – nausea, vomiting, a food faddism, diarrhea, a meteorism, pains in epigastric to acquire (including spastic), change of indicators: general bilirubin, nuclear heating plant, ALT, ShchF;
• System of a hemopoiesis: often – reversible anemia, a leukopenia, thrombocytopenia, a pancytopenia;
• Others: seldom – cases of a peripheral neuropathy and a neuropathy of an optic nerve at use more than 28 days *; often – a headache, candidiasis.

Note

* communication between use of solution for infusions of Zivoks and development of a neuropathy is not proved as in the majority of the observed cases patients or at the same time received the drugs capable to cause a neuropathy (пароксетин, amitriptyline, an isoniazid) and/or had the diseases capable to lead to development of a neuropathy (arterial hypertension, a diabetes mellitus, a chronic renal failure, brain abscess, an osteosarcoma).

Side reactions at parenteral use do not depend on a dose and, as a rule, the terminations of treatment do not demand.

Special instructions

In case of the established infection or at suspicion of the infections caused by the accompanying gram-negative microorganisms it is recommended to apply in addition the means operating on gram-negative flora.

In certain cases at the patients receiving линезолид depending on treatment duration, the reversible miyelosupressiya can develop (with thrombocytopenia, a leukopenia, anemia and a pancytopenia). Therefore during therapy it is necessary to carry out monitoring of indicators of blood at patients with a miyelosupressiya in the anamnesis, with the increased risk of development of bleedings, at simultaneous use of a linezolid with the drugs reducing quantity of thrombocytes, a hemoglobin content and/or their functional properties and also lasting therapy more than 2 weeks.

At reception of antibacterial drugs, including a linezolida, it is necessary to consider risk of development of pseudomembranous colitis of varying severity, especially in case of existence of diarrhea.

As a result of use practically of all antibacterial drugs, including a linezolid, it was reported about cases of Clostridium difficile-associated of diarrhea (from easy forms to heavy). Therapy by antibiotics breaks natural intestinal microflora, activating growth of a microorganism of Clostridium difficile producing toxins A and B that becomes the reason of development of diarrhea. As a result of excess amount of toxins increase in probability of a lethal outcome among patients as these infections can be steady against antimicrobic therapy is possible, in certain cases there can be a need for a colectomy. Careful monitoring of a condition of the patients after antibacterial therapy who had the diarrhea connected with Clostridium difficile is necessary within 2 months.

In case of symptoms of deterioration in sight (sharpness change, change of color perception, defects of fields of vision, a zatumanennost) it is necessary to address urgently for consultations the ophthalmologist. Need to carry out monitoring of visual function by everything the patients applying Zivoks throughout a long span (3 months and more), and also the patient with again appeared symptoms of visual disturbances, regardless of therapy duration. At development of neuropathy of an optic nerve and peripheral neuropathy the risk/advantage for making decision on expediency of continuation of therapy linezolidy is recommended to carry out ratio assessment.

It was reported about lactoacidosis cases in connection with use of a linezolid therefore careful observation of the doctor of a condition of patients who against the background of an antibioticotherapia have repeated vomiting or nausea, inexplicable acidosis is required, or decrease in mass concentration a hydrocarbonate anions is noted.

Developing of spasms at the patients accepting линезолид was noted in most cases in the presence in the anamnesis of data on the spasms taking place or about risk of their development.

If Zivoks needs to apply in combination with selective serotonin reuptake inhibitors, then continuous monitoring of patients, for the purpose of identification of symptoms and signs of a serotoninovy syndrome (a hyper pyrexia, disturbance of cognitive function, a hyperreflexia, a lack of coordination of movements) is necessary. At their emergence immediate cancellation of one or both accepted drugs is required. The termination of reception of serotonergic means can cause a withdrawal.

In case of the return superficial change of coloring of an adamantine substance of tooth it is recommended to carry out professional clarification of teeth at the stomatologist.

During therapy peroral forms of Zivoks are not recommended to be managed the special equipment and vehicles, to be engaged in the activity connected with the increased risk.

Parenteral use of drug does not exert impact on the speed of psychomotor reactions.

Medicinal interaction

Cytochrome isoenzymes, by results of the researches in vitro, do not take part in metabolism of a linezolid which, in turn, does not potentiate and does not inhibit activity of clinically significant isoenzymes of cytochrome.

Linezolid – reversible non-selective monoamine oxidase inhibitor therefore at some patients receiving it moderate reversible strengthening of pressor action of a fenilpropanolamin and pseudoephedrine in this connection decrease in initial doses of such groups of drugs as dofaminomimetik (a levodopa, амантадин, dopamine), adrenomimetik (фенилпропаноламин, pseudoephedrine, Epinephrinum, Dobutaminum, Norepinephrinum is recommended can be noted), and further selection of doses titration.

Development of a serotoninovy syndrome was not noted (in results of a research I, II and III of a phase) when using a linezolid together with serotonergic drugs, but in several messages there were data on development of a serotoninovy syndrome against the background of simultaneous use of Zivoks and antidepressants – selective serotonin reuptake inhibitors.

As a result of simultaneous use with gentamycin and aztreonamy change of pharmacokinetics of a linezolid was not noted.

Rifampicin caused decrease in Cmax (the maximum concentration of substance in blood) and AUC (Area Under Curve) of a linezolid on average respectively for 21% and 32%.

Зивокс in the form of solution for infusions it is compatible from 0,9% solution of sodium of chloride, 5% solution of glucose (dextrose), Ringer's solution for injections to lactose.

Pharmaceutical solution for infusions is incompatible with Chlorpromazinum, diazepam, Amphotericinum In, pentamidine izetionaty, erythromycin, Phenytoinum, co-trimoxazole.

Chemically solution for infusions is incompatible with tseftriaksony sodium.

For infusions it is contraindicated to enter additional components into solution therefore at Zivoks's appointment along with other drugs, each of them should be entered separately.

Terms and storage conditions

To store in the dry, dark place unavailable to children. Temperature of storage of tablets and granules – is not above 30 °C, – it is not above 25 °C of solution.

Period of validity of tablets and solution for infusions – 3 years, granules for suspension preparation – 2 years.

The bottle with the suspension prepared from granules is recommended to store in a cardboard pack at the room temperature to 25 °C, no more than 3 weeks. The bottle with granules for preparation of suspension for intake needs to be closed densely.