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

Excipients: sucrose - 1052.9 mg (0.088 XE), citric acid - 9.1 mg, sodium citrate - 15.0 mg, microcrystalline cellulose + carmellose sodium - 50.0 mg, aspartame - 35.0 mg, xanthan gum - 15, 0 mg, mannitol - 500 mg, sodium benzoate - 10.0 mg, orange flavor Nor-Sap Natural & Artificial Orange Flavor - 50.0 mg, silicon dioxide colloid - 15.0 mg, flavoring peppermint Natural & Artificial S.D. F93125 - 2.0 mg, flavoring vanilla S.D. Natural & Artiaicial Vanilla Flavor - 5.0 mg, sodium chloride - 13.5 mg, sweetener Sweet-am Powder # 918.005¹ - 30.0 mg, sweetener Mafco Magnasweet # 1352 * - 60,0 mg, flavoring orange cream Nor-Sap Natural & Artificial Orange Cream Flavor 37.5 mg.

¹ - Contains fructose, maltodextrin, ammonium glycyrrhizinate and sorbitol.

The content of sorbitol and fructose in both sugar substitutes is 36 mg / 5 ml (0.003 XE) and 12 mg / 5 ml (0.001 XE), respectively.

Description:

White or light yellow powder.

Finished suspension: homogeneous from white to yellow-orange color.

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 the bacterial ribosome, it prevents formation of a functional initiation complex 70SWhich is an essential component of the translation process of protein synthesis.

Sensitivity

Linezolid 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

Linezolid 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, antagonists of folic acid,glycopeptides, lincosamides, quinolones, rifamycins, streptogramins, tetracyclines and chloramphenicol), so there is no cross-resistance between linezolid and these drugs. 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 hours, 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 P isoenzymes₄₅₀ (1A2, 2C9, 2C19, 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 mild to moderate renal failure 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%).

Unchanged linezolid 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 7-8 times. However, the increase in the area under the concentration-time curve (AUC) of the starting drug was not observed. Despite the fact that some basic metabolites were removed during hemodialysis, their plasma concentration after taking 600 mg of linezolid and carrying out the dialysis procedure in patients with severe renal insufficiency 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 the pharmacokinetics of linezolid and its two major metabolites do not change in patients with mild and moderate hepatic insufficiency (A and B classes according to the Child-Pugh classification).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, in the appointment of adolescents with 600 mg of linezolid every 12 hours, the concentration of the drug will be the same as in adults when the same dose is given.

In children from 1 week to 12 years of age, the use of linezolid at a dose of 10 mg / kg daily every 8 hours achieves the same concentration as in adults with 600 mg of linezolid twice daily.

In newborns, the systemic clearance of linezolid rapidly increases during the first week of life (based on kg of body weight). Thus, with a dose of 10 mg / kg every 8 hours, the maximum concentration of the drug will be achieved in the child of the first day of life faster on the first day after birth. However, excessive accumulation of the drug in the first week of admission with such an appointment scheme will still not occur due to rapid clearance.

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 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 half-life of linezolid in men and women does not differ significantly, there is no reason to expect an increase in the concentration of linezolid in the blood of women above the tolerated value, 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 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, 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;

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

Contraindications:

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

Phenylketonuria.

Simultaneous administration of linezolid with preparations 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 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.

Deficiency of sugar / isomaltase, intolerance to fructose, 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. There is also no data on the use of linezolid in patients on ambulatory peritoneal dialysis or other alternative methods of treating renal failure.

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:

Patients who at the beginning of therapy received the drug intravenously, then can be transferred to any dosage form of the drug for oral administration, while the dose is not required, because 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 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 orally every 12 hours	10-14 days
· Uncomplicated skin and soft tissue infections caused by Staphylococcus aureus (only methicillin-sensitive strains) or Streptococcus pyogenes;	Adults: 400 mg orally every 12 hours	10-14 days
	Children (12 years and over): 600 mg orally every 12 hours	10-14 days
· infections caused by Enterococcus faecium, resistant to vancomycin, including, accompanied by bacteremia.	600 mg orally every 12 hours	14 -28 days

Children (newborns) * and children under 11 years old)

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 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;	10 mg / kg orally every 8 hours	10-14 days
· Uncomplicated skin and soft tissue infections caused by Staphylococcus aureus (only methicillin-sensitive strains) or Streptococcus pyogenes;	Children (<5 years): 10 mg / kg orally every 8 hours Children (5-11 years old): 10 mg / kg orally every 12 hours	10-14 days
· infections caused by Enterococcus faecium, resistant to vancomycin, including, accompanied by bacteremia.	10 mg / kg orally every 8 hours	14-28 days

* In preterm infants less than 7 days of age (pregnancy less than 34 weeks) systemic clearance of linezolid is lower, and the values AUC higher than most newborns and children.By day 7 after birth linezolid clearance and values AUC in premature newborns is close to those of full-term newborns and children.

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.

Preparation of the suspension:

Slightly tap on the vial to make the caked powder scatter. To obtain 150 ml of the suspension add 123 ml of water to the bottle in two divided doses (two approximately equal portions). In the resulting suspension, the concentration of the drug is 100 mg / 5 ml. After adding the first portion, shake the bottle to thoroughly moisten all contents. Then add the rest of the water and shake again until a uniform suspension is obtained. Before use, mix the suspension carefully by turning the bottle 3-5 times. (Do not shake!). Use the suspension for 3 weeks from the time of preparation (the remainder should be discarded).

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%

Adult patients

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

From the digestive system:

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

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, peripheral neuropathy, convulsions (see section "Special instructions").

Infrequent: perversion of taste.

From the central nervous system:

Frequent: insomnia.

From the genitourinary system:

Frequent: vaginal candidiasis.

From the skin:

Frequent: rash.

Other:

Frequent: fever.

Infrequent: opportunistic fungal infection.

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

Children and teens

From the digestive system:

Frequent: diarrhea, nausea, vomiting, abdominal pain (local and generalized), gastrointestinal bleeding, candidiasis of the oral mucosa, loose stools.

Laboratory indicators:

Frequent: thrombocytopenia, anemia, hypokalemia, thrombocythemia.

Infrequent: eosinophilia, an increase in the concentration of triglycerides in the blood, increased activity of ALT, lipase, amylase, the concentration of total bilirubin and creatinine.

From the nervous system:

Frequent: headache, convulsions (see section "Special instructions"), vertigo.

From the skin:

Frequent: rash.

Infrequent: itching.

From the respiratory system:

Frequent: respiratory depression, apnea, upper respiratory tract infection, pharyngitis, pneumonia, cough.

Other:

Frequent: fever, sepsis, generalized edema.

Spontaneous (post-marketing) data

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

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

From the digestive system: change in the color of enamel of the teeth (see section "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 induce the activity of clinically important cytochrome P450 isoenzymes (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Thus, it is not expected CYP450-induced interaction when taking linezolid. With simultaneous application of linezolid and (S) -warfarin, which is largely metabolized by the isoenzyme CYP2C9, the 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 phenyl-phenanolamine. In this regard, it is recommended to reduce the initial doses of the following drug groups: adrenomimetics (eg, pseudoephedrine, phenylpropanolamine, epinephrine, norepinephrine, dobutamine), dopaminomimetics (eg, dopamine) and subsequently to carry out the 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 C caused a decrease in C_mOh and 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 a history, and also with simultaneous use of drugs,reducing 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 bicarbonate anions, require close monitoring by the physician

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.

The composition of the granules is sucrose (content in 5 ml of the finished suspension - 0.088 XE), which should be taken into account when prescribing the patient with diabetes, as well as with a diet low in carbohydrates.

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

During the treatment with linezolid, it is not recommended to operate vehicles, special equipment or engage in activities involving an increased risk.

Form release / dosage:

Granules for oral suspension, 100 mg / 5 ml.

Packaging:

To 66 g of granules in a bottle of dark glass (type III Hebrew F.) with a capacity of 150 ml with a plastic screw cap providing protection from opening by children.

1 bottle together with a plastic measuring spoon and instructions for use are placed in a cardboard box.

Packaging for hospitals: 5 or 10 bottles with an equal number of instructions for use in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C, do not freeze.

The ready-made suspension should be stored in a tightly closed vial, placed in a cardboard box, at a temperature of no higher than 25 ° C for not more than 21 days, do not freeze.

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 / 02

Date of registration:08.08.2011 / 10.04.2014

Expiration Date:Unlimited

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

Manufacturer: & nbsp

PHARMACIA & UPJOHN COMPANY USA

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

Information update date: & nbsp12.10.2017

Illustrated instructions

Instructions

Zivox® (Zivox®)