Composition
Active ingredient: Â
linezolid 2 mg;
Auxiliary substances:
sodium citrate dihydrate;
citric acid anhydrous;
glucose monohydrate;
water for injection
Pharmacological action
Linezolid, a synthetic antibacterial drug, belongs to a new class of antimicrobial agents, oxazolidinones, active in vitro against aerobic gram-positive bacteria, some gram-negative bacteria and anaerobic microorganisms.
Linezolid selectively inhibits protein synthesis in bacteria. By binding to bacterial ribosomes, it prevents the formation of the functional initiating complex 70S, which is an important component of the translation process during protein synthesis.
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 drugs.
Linezolid is active against pathogenic microorganisms, both sensitive and resistant to these drugs. Resistance to linezolid develops slowly due to a multi-stage mutation of 23S ribosomal RNA and occurs with a frequency of less than 1 x 10-9-1 x 10-11.
Pharmacokinetics
Absorption The mean maximum concentration (Cmax) and mean minimum concentration (Cmin) of linezolid in blood plasma at steady state after intravenous use twice daily at a dose of 600 mg were 15.1 mg/l and 3.68 mg/L, respectively.
The equilibrium concentration of linezolid in the blood is reached on the 2nd day of drug use.
Distribution The volume of distribution of linezolid when reaching an equilibrium concentration in a healthy adult is on 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 Cytochrome P 450 isoenzymes are not involved in the in vitro metabolism of linezolid. Linezolid does not inhibit or potentiate the activity of clinically important cytochrome P 450 isoenzymes (1 A 2,2 C 9,2 C 19,2D6,2 E 1,3 A 4).
Metabolic oxidation leads to the formation of two inactive metabolites-hydroxyethylglycine (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.
Deduction
Extrarenal clearance is about 65% of linezolid clearance. With an increase in the dose of linezolid, a small degree of nonlinearity in clearance is noted. This may be due to a decrease in renal and extrarenal clearance at 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 mild to moderate renal insufficiency is excreted by the kidneys in the form of hydroxyethylglycine (40%), aminoethoxyacetic acid (10%) and unchanged (30-35%). It is excreted by the intestines in the form of hydroxyethylglycine (6%) and aminoethoxyacetic acid (3%).
In unchanged form, linezolid is practically not excreted by the intestines.
The average half-life of linezolid is 5-7 hours
. Pharmacokinetics in certain groups of patients
Patients with renal insufficiency
After a single dose of 600 mg of the drug in patients with severe renal insufficiency (creatinine clearance However, there was no increase in the area under the concentration-time curve (AUC) of the initial drug.
Although some major metabolites were eliminated during hemodialysis, their plasma concentrations remained significantly higher after taking 600 mg of linezolid and undergoing dialysis in patients with severe renal insufficiency than 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 to moderate hepatic insufficiency (Child-Pugh class A and B). The pharmacokinetics of linezolid in patients with severe hepatic insufficiency (Child-Pugh class C) have not been studied.
However, since linezolid is metabolized nonenzymatically, it is not expected that its metabolism is significantly impaired in hepatic insufficiency.
Children and teenagers
In adolescents (12-17 years), the pharmacokinetics of linezolid taken at a dose of 600 mg did not differ from those in adults. Thus, when prescribing 600 mg of linezolid to adolescents every 12 hours, the drug concentration will be the same as in adults with the same dose.
In children aged 1 week to 12 years, the use of linezolid at a dose of 10 mg / kg daily every 8 hours allows you to achieve the same exposure as in adults when using 600 mg of linezolid twice a day.
In newborns, the systemic clearance of linezolid increases rapidly during the first week of life (calculated per kg of body weight). Thus, when administered at a dose of 10 mg / kg every 8 hours, the maximum exposure of linezolid will be reached in a 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 use with this prescription scheme will still not occur due to a rapid increase in clearance.
Elderly people
In elderly patients aged 65 years and older, the pharmacokinetics of linezolid do not change significantly.
Women
In women, the volume of distribution of the drug is slightly lower than in men; they also have a 20% reduced average clearance based on body weight. The concentration of the drug in the blood plasma of women is higher than in men, which may 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 the drug in the blood of women above the tolerated value, so no dose adjustment is required.
Indications
Treatment of infectious and inflammatory diseases caused by anaerobic and aerobic gram-positive microorganisms sensitive to the drug (including infections accompanied by bacteremia):
- community-acquired pneumonia;
- hospital-acquired pneumonia;
- skin and soft tissue infections;
- infections caused by Enterococcus spp. (including strains of Enterococcus faecalis and Enterococcus faecium resistant to vancomycin).
Infections caused by gram-negative microorganisms, confirmed or suspected (as part of combination therapy).
Use during pregnancy and lactation
No safety studies have been conducted on the use of linezolid during pregnancy, so the use of Zyvox® during pregnancy is possible only if the intended benefit of therapy for the mother outweighs the potential risk to the fetus.
It is not known whether linezolid is excreted in breast milk of nursing women, so you should stop breastfeeding when prescribing the drug to the mother during lactation.
Contraindications
Hypersensitivity to linezolid and / or other components of the drug.
Concomitant use of linezolid with drugs that inhibit monoamine oxidase A or B (for example, phenelzine, isocarboxazide), as well as for two weeks after discontinuation of these drugs.
In the absence of blood pressure monitoring, linezolid should not be prescribed to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or patients receiving the following types of medications: adrenomimetics (for example, pseudoephedrine, phenylpropanolamine, epinephrine, norepinephrine, dobutamine), dopaminomimetics (for example, dopamine).
In the absence of careful monitoring of patients with possible serotonin syndrome, linezolid should not be prescribed to persons with carcinoid syndrome and/or patients receiving the following medications: serotonin reuptake inhibitors, tricyclic antidepressants,5-HT1 receptor agonists (triptans), meperidine or buspirone.
With caution
Patients with renal insufficiency
Due to the unexplored clinical significance of the two primary metabolites of linezolid in patients with severe renal insufficiency, linezolid should be used with caution in such patients, and only if the intended benefit outweighs the potential risk.
There are also no data on the use of linezolid in patients undergoing outpatient peritoneal dialysis or other alternative treatments for 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 outweighs the potential risk.
Linezolid should be used with caution in patients with life-threatening systemic infections, such as those associated with venous catheters in intensive care units.
Side effects
Adverse events associated with taking linezolid are usually mild to moderate in severity. Diarrhoea, headache and nausea are the most common symptoms.
From the digestive system:Frequent ones:Â diarrhea, nausea, vomiting, constipation, abdominal pain (including spastic), flatulence, candidiasis of the oral mucosa. Infrequent ones:Â changing the color of the tongue.
Laboratory parameters:
Frequent ones:Â thrombocytopenia.
Infrequent ones:Â an increase in the concentration of triglycerides in the blood, an increase in the activity of “liver” enzymes (including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), lipase, amylase, total bilirubin and creatinine concentrations), an increase in the concentration of prolactin.
Nervous system disorders:Frequent ones:Â headache, dizziness, peripheral neuropathy, convulsions (see section “Special instructions”). Infrequent ones:Â perversion of taste.
From the central nervous system:Frequent ones:Â insomnia.
From the genitourinary system:Frequent ones:Â vaginal candidiasis.
From the side of the skin:Frequent ones:Â a rash.
Other services:Frequent ones:Â fever. Infrequent ones:Â opportunistic fungal infection. Increased blood pressure, dyspepsia, and pruritus were also noted.
Children and adolescents from the digestive system:Frequent ones:Â diarrhea, nausea, vomiting, abdominal pain (local and generalized), gastrointestinal bleeding, candidiasis of the oral mucosa, loose stools.
Laboratory parameters:Frequent ones:Â thrombocytopenia, anemia, hypokalemia, thrombocytemia. Not frequent:Â eosinophilia, increased blood triglyceride concentrations, increased ALT, lipase, amylase activity, total bilirubin and creatinine concentrations.
Nervous system disorders:Frequent ones:Â headache, convulsions (see section “Special instructions”), vertigo.
From the side of the skin:Frequent ones:Â a rash. Not frequent:Â itching (not at the injection site).
Respiratory system disorders:Frequent ones:Â respiratory disorders, apnea, upper respiratory tract infections, pharyngitis, pneumonia, cough.
Other services:Frequent ones:Â fever, sepsis, generalized edema, injection site reactions.
Spontaneous (post-marketing) data
Laboratory parameters:Â reversible myelosuppression (thrombocytopenia, anemia, leukopenia, pancytopenia). From the side of the senses:Â cases of optic neuropathy, sometimes leading to vision loss (see section “Special instructions”).
Allergic reactions:Â anaphylaxis. From the side of the skin:Â rash, angioedema; bullous skin lesions similar to Stevens-Johnson syndrome.
From the side of metabolism:Â lactic acidosis.
Nervous system disorders:Â peripheral neuropathy, seizures (see section “Special instructions”). From the digestive system:Â discoloration of tooth enamel (see the section “Special instructions”). Other services:Â chills, fatigue, serotonin syndrome (see sections “Interaction with other drugs” and “Special instructions”).
Interaction
It was found 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 (1 A 2,2 C 9,2 C 19,2D6,2 E 1,3 A 4).
Thus, no CYP450-induced interaction is expected when taking linezolid. When linezolid is co-administered with (S) – warfarin, which is largely metabolized by the CYP2C9 isoenzyme, the pharmacokinetic characteristics of warfarin do not change.
Drugs such as warfarin and phenytoin, which are substrates of the CYP2C9 isoenzyme, can be used simultaneously with linezolid without dose adjustment.
Monoamine oxidase inhibitors
Linezolid is a non-selective reversible monoamine oxidase inhibitor, so some patients receiving linezolid may experience a moderate reversible increase in the pressor action of pseudoephedrine and phenylropanolamine.
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 then titrate the dose.
In phase I, II, and III studies, no serotonin syndrome was observed in patients treated with linezolid in combination with serotonergic drugs. However, there have been several reports of the development of serotonin syndrome with the use of linezolid and antidepressants-selective serotonin reuptake inhibitors.
When used concomitantly with aztreonam and gentamicin, no changes in the pharmacokinetics of linezolid were observed.
Rifampicin reduced linezolid Cmax and AUC by an average of 21% and 32%, respectively.
How to take, course of use and dosage
The drug is prescribed as an intravenous infusion lasting 30 -120 minutes. It is forbidden to consistently connect the infusion bags and add other drugs to the infusion solution.
If linezolid is to be administered with other medications, all medications should be administered separately according to the recommended doses and routes of use.
Linezolid for injection is pharmacologically incompatible with the following drugs:
Amphotericin B, chlorpromazine, diazepam, phenytoin, erythromycin lactobionate, co-trimoxazole (trimethoprim + sulfamethoxazole), ceftriaxone.
Compatible solutions for infusions:
5% dextrose solution for injection 0.9% sodium chloride solution for injectio Nringer-Locke solution for injection
Patients who were prescribed intravenous therapy at the beginning of therapy can then be transferred to any dosage form of the drug for oral use, while dose selection is not required, since the bioavailability of linezolid when taken orally is almost 100%.
The duration of treatment depends on the pathogen, the location and severity of the infection, as well as on the clinical effect.
Adults and children (12 years and older)Children (newborns* and children under 11 years of age)* In preterm children less than 7 days of age (pregnancy less than 34 weeks), the systemic clearance of linezolid is lower and AUC values are higher than in most newborns and children. By day 7 after birth, linezolid clearance and AUC values in preterm newborns are close to those in full-term newborns and children.
Elderly patients:Â no dose adjustment is required.
Patients with renal insufficiency:Â no dose adjustment is required. Due to the fact that 30% of linezolid is removed during hemodialysis within 3 hours, linezolid should be taken after dialysis in patients who need it.
Patients with hepatic insufficiency:Â no dose adjustment is required.
Overdose
No cases of linezolid overdose have been reported. Symptomatic treatment is recommended (including maintaining glomerular filtration rate). There are no data on accelerating the elimination of linezolid during peritoneal dialysis or hemoperfusion.
Special instructions
If an established infection (or suspected infection) is caused by concomitant gram-negative microorganisms, additional use of agents acting on gram-negative flora is indicated.
Some patients receiving linezolid may develop reversible myelosuppression (with anemia, thrombocytopenia, leukopenia, and pancytopenia), depending on the duration of therapy.
In this regard, during treatment, it is necessary to monitor blood parameters in patients with an increased risk of bleeding, a history of myelosuppression, as well as with the simultaneous use of drugs that reduce the hemoglobin content or platelet count and/or their functional properties, as well as in patients receiving linezolid for more than 2 weeks.
Patients taking antibacterial drugs, including linezolid, should be considered for the risk of developing pseudomembranous colitis of varying severity.
Cases of Clostridium difficile-related diarrhea have been reported in connection with the use of virtually all antibacterial drugs, including linezolid. The severity of diarrhea can range from mild to severe. Treatment with antibacterial drugs disrupts the normal intestinal microflora, which leads to excessive growth of Clostridium difficile.
Clostridium Difficile produces toxins A and B, which lead to the development of diarrhea associated with Clostridium difficile. Excessive amounts of toxins produced by Clostridium difficile strains can lead to increased mortality among patients, as such infections may be resistant to antimicrobial therapy, and colonectomy may also be required.
The possibility of developing diarrhea associated with Clostridium difficile should be considered in all patients with diarrhea following the use of antibiotics. Close medical monitoring for 2 months is necessary for patients who have experienced diarrhea associated with Clostridium difficile after the introduction of antibacterial drugs.
If you experience symptoms of visual impairment, such as changes in visual acuity, changes in color perception, blurred vision, or visual field defects, it is recommended to consult an ophthalmologist immediately.
Visual function should be monitored in all patients taking linezolid for a long time (more than 3 months), as well as in all patients with newly developed symptoms of visual impairment, regardless of the duration of therapy.
In the case of peripheral neuropathy and optic neuropathy, the risk/benefit ratio of continuing linezolid therapy in these patients should be evaluated.
Lactic acidosis has been reported in association with the use of linezolid.Patients who experience recurrent nausea or vomiting, unexplained acidosis, or a decrease in the concentration of bicarbonate anions while taking linezolid should be carefully monitored by a doctor.
Seizures have been reported in patients taking linezolid, and in most cases there was a history of seizures or the presence of risk factors for their development.
If the use of Zyvox® in combination with selective serotonin reuptake inhibitors is necessary, patients should be constantly monitored for signs and symptoms of serotonin syndrome, such as impaired cognitive function, hyperpyrexia, hyperreflexia and impaired coordination of movements.
If these symptoms occur, one or both medications should be discontinued. When stopping taking a serotonergic agent, symptoms of “withdrawal” syndrome may occur.
Cases of reversible surface discoloration of tooth enamel have been reported with linezolid. These discoloration changes were removed by professional tooth cleaning.
Influence on the ability to drive motor vehicles and manage mechanisms
During treatment with linezolid, it is not recommended to drive vehicles, special equipment or engage in activities associated with an increased risk.
Product form
solution for infusions
Storage conditions
Store at a temperature not exceeding 25 ° C. Keep out of reach of children!
Shelf
life is 3 years.
Active ingredient
Linezolid
Conditions of release from pharmacies
By prescription
Dosage form
solution for infusions
Purpose
Children as prescribed by a doctor, Adults as prescribed by a doctor
Indications
Pneumonia, From skin infections, From pneumonia
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Side effects of Zyvox solution for infusion 2mg/ml 100ml bags, 10pcs.
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