Indications for use
— hospital pneumonia
— community-acquired pneumonia
The Linezol medicine is indicated in adults for the treatment of community-acquired and hospital-acquired pneumonia caused by gram-positive bacteria. When prescribing Linezol, the results of microbiological studies and information on the resistance of gram-positive bacteria should be taken into account.
Linezolid is not active against infections caused by gram-negative microorganisms. Specific therapy against gram-negative microorganisms should be initiated simultaneously if a gram-negative pathogen is known or suspected.
- complicated skin and soft tissue infections
Linezol is indicated for the treatment of complicated skin and soft tissue infections only if microbiological testing has established that the infection is caused by susceptible gram-positive bacteria.

It is not active against infections caused by gram-negative microorganisms. Linezol medicine shall be prescribed to patients with complicated skin and soft tissue infections with known pathogens or in case of combined infection with gram-negative microorganisms in the absence of alternative treatment options. In these conditions, treatment against gram-negative microorganisms should be initiated simultaneously.
Therapy with linezolid should be carried out in a hospital setting and after consultation with a microbiologist or infectious disease specialist.

List of information required before use
Contraindications
— hypersensitivity to linezolid or to any of the excipients
— concomitant use with monoamine oxidase A or monoamine oxidase B inhibitors (e.g. phenelzine, isocarboxazid, selegiline, moclobemide) or within 2 weeks of stopping specified drugs
— uncontrolled hypertension
— pheochromocytoma
— carcinoid syndrome
— thyrotoxicosis
— bipolar depression, schizoaffective disorder, acute episodes of confusion
— concomitant use with serotonin reuptake inhibitors (e.g. antidepressants (SSRIs)), opioids, tricyclic antidepressants, 5-HT1 receptor agonists (triptans), direct and indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine and phenylpropanolamine), vasopressors (e.g. epinephrine, norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine), meperidine or buspirone
- hereditary galactose intolerance, Lapp lactase deficiency (LAPD), glucose-galactose malabsorption
- pregnancy and lactation
- children and adolescents up to 18 years of age

Necessary precautions for use
Myelosuppression
Myelosuppression (including anemia, leukopenia, pancytopenia and thrombocytopenia) has been observed in patients receiving linezolid. After discontinuation of linezolid, hematological parameters returned to pre-treatment levels. The risk of developing these effects may be related to the duration of treatment. Elderly patients treated with linezolid may be at greater risk of developing blood abnormalities than younger patients.
Thrombocytopenia may be more common in patients with severe renal impairment, whether or not the patient is on hemodialysis. Close monitoring of complete blood count is recommended in patients with pre-existing anemia, granulocytopenia, or thrombocytopenia; as well as in those receiving concomitant medications that may decrease hemoglobin levels or platelet counts in peripheral blood or inhibit their function; severe renal impairment; receiving linezolid for more than 10-14 days.
Linezolid should only be administered to such patients after careful monitoring of blood counts, hemoglobin levels, and platelet counts.
If significant myelosuppression occurs during therapy with Linezolid, treatment should be discontinued unless continued treatment is considered absolutely necessary. In such cases, intensive monitoring of complete blood count parameters and appropriate patient management strategies should be implemented.
Additionally, it is recommended to monitor complete blood count parameters (including hemoglobin, platelets, total and differential white blood cell count) in patients receiving linezolid once a week, regardless of baseline blood count parameters.
There is evidence of a higher incidence of serious anemia in patients receiving linezolid beyond the maximum recommended period of 28 days. These patients are more likely to require blood transfusion. Cases of sideroblastic anemia have been reported in the postmarketing period. Sideroblastic anemia occurred in the majority of patients receiving linezolid for more than 28 days.
Most patients fully or partially recovered after discontinuing linezolid.
Mortality Imbalance in a Clinical Trial in Patients with Catheter-Associated Gram-Positive Blood Infections
There is evidence of an increased mortality rate in seriously ill patients with catheter-associated septic infections caused by gram-positive pathogens treated with linezolid compared with vancomycin/dicloxacillin/oxacillin. The fatality rates were 78/363 (21.5%) and 58/363 (16.0%) with linezolid and comparators, respectively. The main predictor of mortality was the presence of a Gram-positive infection before treatment. Mortality rates were similar to those in patients with Gram-positive infections only (odds ratio 0.96; 95% CI 0.58 to 1.59) but were significantly higher (p = 0.0162) with linezolid in patients with any other pathogen or nonpathogen infection before treatment (odds ratio 2.48; 95% CI 1.38 to 4.46). The greatest imbalance occurred during treatment and within 7 days after discontinuing linezolid.
Most patients receiving linezolid developed Gram-negative infections during the study and had mortality due to Gram-negative and polymicrobial infections. Therefore, in complicated skin and soft tissue infection, linezolid should be used only in patients with known or possible co-infection with gram-negative organisms, unless alternative treatment options are available. In these circumstances, treatment against gram-negative organisms should be initiated simultaneously.
Antibiotic-Associated Diarrhea and Colitis
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Linezolid, and its severity can range from mild to life-threatening. It is therefore important to consider this diagnosis in patients who present with diarrhea after taking any antibacterial agent. If antibiotic-associated colitis is suspected or confirmed, discontinuation of Linezolid is warranted. Appropriate measures should be taken.
Antibiotic-associated diarrhea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been reported with the use of nearly all antibacterial agents, including linezolid, and may range in severity from mild diarrhea to fatal colitis. It is therefore important to consider this diagnosis in patients who experience severe diarrhea during or after use of Linezolid.
Linezolid treatment should be discontinued if antibiotic-associated diarrhea or antibiotic-associated colitis is suspected or confirmed, and appropriate therapeutic measures should be instituted promptly. Drugs that inhibit intestinal motility are contraindicated in this situation.
Potential Interactions Causing Increases in Blood Pressure
Unless patients can be monitored for possible increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, and/or concomitant use of drugs such as: direct and indirect sympathomimetics (e.g. pseudoephedrine), vasopressors (e.g. epinephrine, norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine).
Lactic acidosis
Cases of lactic acidosis have been reported with linezolid. Patients with signs and symptoms of metabolic acidosis, including recurrent nausea or vomiting, abdominal pain, low blood bicarbonate, should receive immediate medical attention while receiving Linezolid. If lactic acidosis occurs, a decision should be made regarding the continued use of the drug, weighing the potential risks.
Mitochondrial dysfunction
Linezolid inhibits mitochondrial protein synthesis. Adverse effects such as lactic acidosis, anemia, and neuropathy (optic and peripheral) may result from inhibition of protein synthesis; these effects are more common when the drug is used for more than 28 days.
Serotonin syndrome
There have been reports of serotonin syndrome associated with the concomitant use of linezolid and serotonergic drugs, including antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs). Coadministration of linezolid and serotonergic drugs are contraindicated unless linezolid and serotonergic drugs are clinically necessary. In this case, the patient should be closely monitored for signs and symptoms of serotonin syndrome, such as cognitive dysfunction, hyperpyrexia, hyperreflexia, and impaired coordination. If these signs and symptoms occur, the physician should consider discontinuing one or both of these drugs. These symptoms may resolve when the serotonergic drug is discontinued.
Peripheral and optic neuropathy
Peripheral neuropathy, optic neuropathy, optic neuritis, and vision loss may occur in patients taking linezolid, most often when the drug is used longer than the maximum recommended period of 28 days.
Urgent ophthalmologic examination is recommended if symptoms such as decreased visual acuity, changes in color perception, blurred vision, or visual field defects occur. When linezolid is administered for more than 28 days, visual function should be monitored regularly.
If peripheral or optic neuropathy develops, the benefit of linezolid should be weighed against the potential risks involved.
An increased risk of neuropathies is observed in patients taking or who have recently taken antimycobacterial agents for the treatment of tuberculosis.
Seizures
There have been reports of seizures in patients taking linezolid. Most of these cases involved a history of seizures or risk factors for seizures. Patients should inform their physician of any history of seizures or seizures.
Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective monoamine oxidase inhibitor. Due to limited clinical data, linezolid should not be co-administered with monoamine oxidase inhibitors.
Use of tyramine-rich foods
Patients should avoid tyramine-rich foods.
Superinfection
Clinical studies of the effect of linezolid on normal intestinal flora have not been conducted.
Antibiotic use may result in the growth of non-susceptible organisms, for example, candidiasis has been reported in approximately 3% of patients receiving recommended doses of linezolid. If superinfection occurs during treatment with linezolid, appropriate measures should be taken.
Use in hepatic and renal impairment
It is recommended to exercise particular caution in patients with severe renal impairment and to use linezolid only if the expected benefit outweighs the potential risk.
In patients with severe hepatic impairment, linezolid should be used only if the expected benefit outweighs the potential risk.
Effects on fertility
Linezolid reversibly reduces fertility and induces abnormal sperm morphology in adult male rats at exposure levels approximately equivalent to those in humans. The potential effects of linezolid on the human male reproductive system are unknown.

Clinical studies
The safety and efficacy of linezolid when administered for more than 28 days have not been established.
Experience with linezolid in patients with diabetic foot disease, pressure ulcers, ischemic lesions, severe burns, or gangrene is limited.
Lactose
Linezolid contains lactose. It is not recommended for use in patients with hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Interactions with other medicinal products
Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective monoamine oxidase inhibitor. There are limited clinical interaction data with linezolid. Therefore, linezolid should not be co-administered with monoamine oxidase inhibitors unless close observation and monitoring of the patient is not possible.
Interactions with drugs that increase blood pressure
Coadministration of linezolid with pseudoephedrine or phenylpropanolamine results in an increase in systolic blood pressure of 30-40 mmHg, compared with an increase of 11-15 mmHg with linezolid alone, 14-18 mmHg with pseudoephedrine or phenylpropanolamine alone, and 8-11 mmHg with placebo. Dose titration of drugs with vasopressor action, including dopaminergic drugs, is recommended.
Serotonergic drugs
Cases of serotonin syndrome have been reported during the use of linezolid with serotonergic drugs, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs).
Therefore, concomitant administration of these drugs is contraindicated.
Tyramine-rich foods
No significant pressor response was observed in patients receiving linezolid and tyramine at least 100 mg. Foods and beverages with high tyramine content (e.g. cheese, yeast extracts, non-distilled alcoholic beverages, soy sauce) should be avoided.
Cytochrome P450 metabolized drugs
Cytochrome P450 isoenzymes have not been shown to be involved in the metabolism of linezolid in vitro. Linezolid does not inhibit or potentiate the activity of clinically important cytochrome P450 isoenzymes (1A2, 2C9, 2C19, 2D6, 2E1, 3A4).
Rifampin
Rifampin decreases linezolid Cmax and AUC by an average of 21%. The mechanism of this interaction and its clinical significance are unknown.
Warfarin
When warfarin and linezolid were co-administered at steady state, a 10% decrease in mean peak INR and a 5% decrease in linezolid AUC were observed. There is insufficient data to assess the clinical significance of these findings.

Special warnings
Pediatric use
Contraindicated for use in children and adolescents under 18 years of age.
During pregnancy or lactation
Linezolid should not be used during pregnancy or lactation.
Peculiarities of the drug’s effect on the ability to drive a vehicle or potentially dangerous machinery
Due to the presence of adverse reactions (dizziness, visual impairment) during linezolid administration, and if any of these symptoms occur, you should refrain from driving vehicles or operating machinery.

Recommendations for use
Dosage regimen
Recommended dosages and duration of treatment for adults. The duration of treatment depends on the pathogen, localization and severity of the infection, as well as the clinical effect.
Patients who were initially administered the drug intravenously can be subsequently transferred to the oral dosage form of the drug, and no dose adjustment is required, since the bioavailability of Linezolid when administered orally is almost 100%.

Special patient groups
Children
The safety and efficacy of linezolid in children under 18 years of age have not been established. Based on currently available data, the use of linezolid in children under 18 years of age is not recommended.
Elderly patients
No dose adjustment is required.
Patients with renal impairment
No dose adjustment is required.
Patients with severe renal impairment (CLCR <30 mL/min)
No dose adjustment is required.
Due to the unknown clinical significance of high exposure (up to 10-fold) to the two main metabolites of linezolid in patients with severe renal impairment, Linezolid should be used with caution in such patients and only if the expected benefit of therapy outweighs the potential risk.
Due to the fact that 30% of the administered linezolid dose is removed by hemodialysis within 3 hours, Linezolid should be used after the hemodialysis procedure. A certain portion of the primary metabolites of linezolid is removed during hemodialysis, but the concentration of these metabolites remains significantly higher after dialysis than in patients with normal renal function or mild to moderate renal impairment.
Therefore, Linezolid should be used with particular caution in patients with severe renal impairment receiving hemodialysis and only if the expected benefit outweighs the potential risk.
There is no experience with linezolid in patients receiving continuous ambulatory peritoneal dialysis.
Patients with liver failure
No dose adjustment is required. However, due to limited clinical data, the use of Linezolid in such patients is recommended only if the expected benefit outweighs the potential risk.
Method and route of administration
Oral.
Linezolid can be taken both during and between meals.
Measures to be taken in case of overdose
Symptoms: In case of accidental overdose, side effects may increase.
Treatment: symptomatic therapy; measures aimed at maintaining glomerular filtration, hemodialysis. Approximately 30% of the linezolid dose is eliminated after 3 hours of hemodialysis.
For clarification on the method of administration of the drug, consult a healthcare professional.

Description of adverse reactions that occur during standard use of the medicinal product and measures to be taken in this case
The frequency of adverse reactions is determined according to the following criteria: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), unknown (cannot be estimated from the available data).

Common
— nausea, vomiting, diarrhea
— abdominal pain (localized or generalized); constipation, dyspepsia
— headache, dizziness
— insomnia
— oral candidiasis, vaginal candidiasis, fungal infections
— anemia
— arterial hypertension
— increased liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP)
— increased residual nitrogen, LDH, creatine kinase, lipase, amylase, fasting glucose
— decreased total protein, albumin, sodium, calcium; increased or decreased potassium, bicarbonate
— fever
— neutrophilia, eosinophilia, decreased hemoglobin, hematocrit and red blood cells
— thrombocytopenia, leukopenia or thrombocytosis and leukocytosis
— taste change (metallic taste)
— skin rash, itching
Uncommon
— neutropenia
— vaginitis
— hyponatremia
— seizures, hypoesthesia, paresthesia
— blurred vision
— tinnitus
— chills
— arrhythmia, tachycardia
— phlebitis, thrombophlebitis, transient ischemic attack
— pancreatitis, gastritis, dry mouth, glossitis, stomatitis, tongue discoloration, bloating, loose stools
— total bilirubin increased
— thrombocytopenia, eosinophilia
— sodium and calcium levels increased
— urticaria, dermatitis, sweating
— creatinine increased, polyuria, renal failure
— vulvovaginal disorders
— fatigue, thirst
— fasting glucose decreased, chlorides increased or increased
— reticulocytes increased
Rare
— antibiotic-associated colitis (including pseudomembranous colitis)
— pancytopenia
— visual field changes
— changes tooth color
Unknown
— myelosuppression, sideroblastic anemia
— anaphylaxis
— lactic acidosis
— serotonin syndrome, peripheral neuropathy, optic neuropathy, changes in color vision, optic neuritis, vision loss, changes in visual acuity
— bullous skin lesions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, alopecia.

If adverse drug reactions occur, contact your health care provider, pharmacist, or directly to the Adverse Drug Reactions (Actions) Information Database, including reports of drug ineffectiveness
Republican State enterprise on the Right of Economic Management National Center for Expertise of Medicines and Medical Devices of the Committee for Medical and Pharmaceutical Control of the Ministry of Healthcare of the Republic of Kazakhstan
http://www.ndda.kz

Additional information
Composition of the medicinal product
One tablet contains
active substance - linezolid (Form II) 600 mg,
excipients: lactose monohydrate (Pharmatose 200 M), corn starch (extra white), hydroxypropyl cellulose (Klucel LXF), lactose monohydrate (Supertab 11 SD), purified water*, sodium starch glycolate (Primogel), magnesium stearate,
shell composition: Opadry White 03B58 895**

* absent in the final product
** HPMC 2910/Hypromellose 6cP, titanium dioxide (E171,) macrogol/PEG 400, carnauba wax

Description of appearance, smell, taste
Oval-shaped tablets, biconvex, film-coated from white to almost white, engraved with 'H' on one side and 'L8' on the other side.

Dosage forms and packaging
10 tablets are placed in a blister pack made of aluminum foil on one side and printed aluminum foil on the other side.
1 blister pack together with instructions for medical use in Kazakh and Russian are placed in a cardboard pack.
10 such cardboard packs together with instructions for medical use in Kazakh and Russian are placed in a cardboard pack.

Shelf life
2 years
Do not use after expiration date.

Storage conditions
Store in a dry, dark place at a temperature not exceeding 25 ºС.
Keep out of reach of children!