Linocid

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LYNOZID (LYNOZID)

Composition:

Active substance: linezolid;

1 ml of solution contains 2 mg of linezolid;

Excipients: glucose monohydrate; sodium citrate; citric acid anhydrous; sodium hydroxide*; hydrochloric acid diluted*; water for injections.

* – 10 % solution of sodium hydroxide or 10 % solution of hydrochloric acid is used for pH adjustment.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group.

Antibacterials for systemic use. ATC code J01XX08.

Pharmacological properties.

Pharmacodynamics.

Linezolid is a synthetic antibacterial agent belonging to a new class of antimicrobial agents – oxazolidinones. It exhibits in vitro activity against aerobic Gram-positive and anaerobic microorganisms. Linezolid selectively inhibits bacterial protein synthesis via a unique mechanism of action. It directly binds to bacterial ribosomes (23S of the 50S subunit) and interferes with the formation of the functional 70S initiation complex (a key component of the translation process).

The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, local information on microbial resistance should be consulted, especially when treating severe infections. If necessary, when the local prevalence of resistance is such that the benefit of using linezolid, at least for certain types of infections, is questionable, expert consultation should be sought.

Susceptible microorganisms:
Gram-positive aerobic microorganisms: Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Group C streptococci, Group G streptococci;
Gram-positive anaerobic microorganisms: Clostridium perfringens, Peptostreptococcus anaerobius, Peptostreptococcus species.

Resistant microorganisms: Haemophilus influenzae, Moraxella catarrhalis, Neisseria species, Enterobacteriaceae, Pseudomonas species.

* Clinical efficacy has been demonstrated for susceptible strains according to approved indications.

Although linezolid demonstrates some in vitro activity against Legionella, Chlamydia pneumoniae, and Mycoplasma pneumoniae, there is insufficient data to confirm clinical efficacy in these cases.

Cross-resistance

The mechanism of action of linezolid differs from that of other classes of antibiotics. In vitro studies of clinical isolates (methicillin-resistant staphylococci, vancomycin-resistant enterococci, as well as penicillin- and erythromycin-resistant streptococci) show that linezolid is generally active against microorganisms resistant to one or more other classes of antimicrobial agents.

Resistance to linezolid is associated with point mutations in the 23S rRNA.

Pharmacokinetics.

Absorption.

Maximum (C_max) and minimum (C_min) plasma concentrations of linezolid (mean value and [standard deviation]) at steady state after intravenous administration of 600 mg twice daily are 15.1 [2.5] mg/L and 3.68 [2.68] mg/L, respectively.

Distribution.

Pharmacokinetic studies have shown that linezolid rapidly distributes into well-perfused tissues. Approximately 31% of linezolid is protein-bound in plasma, and this binding is independent of its concentration. The volume of distribution at steady state in healthy adult volunteers averages 40–50 L.

Linezolid concentrations were measured in various fluids involving a limited number of participants in Phase 1 studies after multiple dosing. The ratio of linezolid concentration in saliva to plasma concentration was 1.2:1, and the ratio of linezolid concentration in sweat to plasma concentration was 0.55:1.

Metabolism.

Linezolid is primarily metabolized via oxidation of the morpholine ring, forming two inactive ring-opened carboxylic acid metabolites: the metabolite of aminoethoxyacetic acid (A) and the metabolite of hydroxyethylglycine (B). Formation of metabolite A is thought to occur via an enzymatic pathway, whereas formation of metabolite B is mediated by a non-enzymatic mechanism involving chemical oxidation in vitro. In vitro studies have demonstrated that linezolid is minimally metabolized, with possible involvement of the human cytochrome P450 system in this process. However, the metabolic pathways for linezolid have not been fully elucidated.

Excretion.

Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. At steady state, approximately 30% of the administered dose is recovered in urine as unchanged linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min, indicating net tubular reabsorption. Linezolid is virtually undetectable in feces, while approximately 6% of the administered dose is recovered in feces as metabolite B and 3% as metabolite A.

A slight non-linearity in clearance was observed with increasing doses of linezolid, apparently due to lower renal and non-renal clearance at higher concentrations. However, this difference in clearance was minor and did not affect the apparent half-life.

Patients with renal impairment.

The pharmacokinetics of linezolid are not altered in patients with any degree of renal impairment; however, its two major metabolites accumulate in patients with renal impairment, and their accumulation increases with greater severity of renal dysfunction. The pharmacokinetics of linezolid and its two metabolites were also studied in patients with end-stage renal disease (ESRD) undergoing hemodialysis. In the ESRD study, 14 patients received 600 mg of linezolid every 12 hours for 14.5 days. Since plasma concentrations of linezolid were similar regardless of renal function, no dose adjustment is recommended for patients with renal impairment. However, due to the lack of information on the clinical significance of accumulation of the major metabolites, the appropriateness of using linezolid in patients with renal impairment and the potential risks associated with accumulation of these metabolites should be carefully considered. Both linezolid and its two metabolites are removed by hemodialysis. Information on the effect of peritoneal dialysis on the pharmacokinetics of linezolid is lacking.

Patients with hepatic impairment.

The pharmacokinetics of linezolid were not altered in 7 patients with mild to moderate hepatic impairment (Child–Pugh class A or B). Based on available data, dose adjustment is not recommended for patients with mild to moderate hepatic impairment. The pharmacokinetics in patients with severe hepatic impairment have not been evaluated.

Clinical characteristics.

Indications.

Treatment of infections caused by susceptible strains of specified microorganisms in the following conditions:

• nosocomial pneumonia;
• community-acquired pneumonia;
• complicated skin and soft tissue infections, including infections associated with diabetic foot without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae; linezolid has not been studied in the treatment of pressure ulcer infections;
• uncomplicated skin and soft tissue infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes;
• vancomycin-resistant infections caused by Enterococcus faecium strains, including infections associated with bacteremia.

Linezolid is not indicated for the treatment of infections caused by Gram-negative microorganisms. In case of suspicion or identification of a Gram-negative pathogen, specific Gram-negative therapy should be initiated immediately.

Contraindications.

• Known hypersensitivity to the active substance and/or to any of the excipients of the medicinal product.
• Concomitant use with medicinal products that inhibit monoamine oxidase A and B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide), or within two weeks after discontinuation of such agents.
• Use in patients with the following concomitant clinical conditions (except when close monitoring and blood pressure surveillance are possible): uncontrolled hypertension, pheochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute episodes of dizziness.
• Concomitant use with the following agents (except when close monitoring and blood pressure surveillance are possible): serotonin reuptake inhibitors, tricyclic antidepressants, 5-HT1 serotonin receptor agonists (triptans), direct and indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine, phenylpropanolamine), vasopressors (epinephrine, norepinephrine), dopaminergic compounds (dopamine, dobutamine), meperidine, or buspirone.

Breastfeeding should be discontinued during treatment with this medicinal product (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other types of interactions.

Monoamine oxidase inhibitors.

Linezolid is a non-selective, reversible inhibitor of monoamine oxidase (MAO). Data from drug interaction and safety studies on the use of linezolid in patients receiving concomitant medications that pose certain risks due to MAO inhibition are very limited. Therefore, the use of linezolid in such circumstances is not recommended unless close patient monitoring and surveillance are possible (see sections "Contraindications" and "Special precautions for use").

Potential interactions leading to increased blood pressure.

In healthy volunteers with normal blood pressure, linezolid enhances the blood pressure increase caused by pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant administration of linezolid with pseudoephedrine or phenylpropanolamine hydrochloride results in an average increase in systolic blood pressure of 30–40 mm Hg, compared to an increase of 11–15 mm Hg with linezolid alone, 14–18 mm Hg with pseudoephedrine or phenylpropanolamine alone, and 8–11 mm Hg with placebo. Similar studies in patients with hypertension have not been conducted. When used concomitantly with linezolid, doses of vasoactive agents, including dopaminergic drugs, should be carefully titrated.

Potential serotonergic interactions.

Potential interactions between linezolid and dextromethorphan were studied in a trial involving healthy volunteers. Participants received dextromethorphan (two 20 mg doses administered 4 hours apart) with or without linezolid. In healthy volunteers receiving both linezolid and dextromethorphan, no symptoms of serotonin syndrome (confusion, delirium, agitation, tremor, flushing, diaphoresis, hyperpyrexia) were observed.

Post-marketing experience: one report has been received regarding the occurrence of symptoms resembling serotonin syndrome in a patient taking linezolid and dextromethorphan; these symptoms resolved after discontinuation of both agents.

During clinical use of linezolid with serotonergic agents, including antidepressants (such as selective serotonin reuptake inhibitors [SSRIs]) and opioids, cases of serotonin syndrome have been reported. Thus, although concomitant use of these agents is contraindicated (see section "Contraindications"), management of patients for whom treatment with both linezolid and serotonergic agents is essential is described in section "Special precautions for use".

Concomitant use with tyramine-rich foods.

In patients receiving linezolid and tyramine in amounts less than 100 mg, no significant pressor effect was observed. This indicates that only excessive consumption of foods and beverages high in tyramine (such as aged cheeses, yeast extracts, non-distilled alcoholic beverages, and fermented soy products such as soy sauce) should be avoided.

Agents metabolized by cytochrome P450.

Linezolid is not metabolized by the cytochrome P450 enzyme system and does not inhibit the function of any clinically significant human cytochrome P450 isoenzymes (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Similarly, linezolid does not induce cytochrome P450 isoenzymes in rats. Therefore, an effect of linezolid on the pharmacokinetics of other medicinal products metabolized by CYP450 is not expected.

The effect of rifampicin on the pharmacokinetics of linezolid was studied in 16 healthy male adult volunteers who received linezolid (600 mg twice daily for 2.5 days) with and without rifampicin (600 mg once daily for 8 days). Rifampicin reduced Cmax and AUC (area under the concentration-time curve) of linezolid by an average of 21% and 32%, respectively. The mechanism of this interaction and its clinical significance are unknown.

When warfarin was co-administered with linezolid at steady state, a 10% reduction in mean maximum INR (International Normalized Ratio) was observed during co-administration, and INR AUC decreased by 5%. Data on patients receiving warfarin and linezolid concomitantly are insufficient to assess the clinical significance, if any, of these findings.

Antibiotics.

The pharmacokinetics of linezolid or aztreonam are not altered when these agents are administered concomitantly.

The pharmacokinetics of linezolid or gentamicin are not altered when these agents are administered concomitantly.

In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampicin, imipenem-cilastatin, aztreonam, ampicillin, and streptomycin.

Antioxidants.

No dose adjustment of linezolid is recommended when administered concomitantly with vitamin C or vitamin E.

Special precautions for use.

Myelosuppression risk.

Cases of myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) have been reported in patients receiving linezolid. In such cases, hematological parameters returned to pre-treatment levels after discontinuation of the drug. The risk of these effects is likely related to the duration of treatment. Elderly patients may have a higher risk of hematological abnormalities during treatment with linezolid compared to younger patients. An increased incidence of thrombocytopenia may occur in patients with severe renal impairment (regardless of whether they are undergoing dialysis) and in patients with moderate to severe hepatic dysfunction.

Therefore, careful monitoring of blood counts is required in the following patient groups: patients with pre-existing anemia, granulocytopenia, or thrombocytopenia; patients receiving concomitant medications capable of reducing hemoglobin levels, decreasing blood cell counts, or negatively affecting platelet number or function; patients with severe renal impairment and those with moderate to severe hepatic dysfunction; and patients receiving treatment for more than 10–14 days. The medicinal product should be used in such patients only with close monitoring of hemoglobin levels, complete blood count, and, if possible, platelet count.

If significant myelosuppression develops during treatment, therapy should be discontinued, except in cases where continuation is deemed absolutely necessary. In such situations, careful monitoring of complete blood count parameters and implementation of appropriate treatment strategies are required.

Additionally, during treatment with linezolid, weekly monitoring of complete blood count parameters (including hemoglobin levels, platelet count, total white blood cell count, and differential white blood cell count) is recommended in all patients, regardless of baseline blood test results.

In compassionate use studies involving unapproved use of linezolid, an increased incidence of severe anemia was observed in patients treated for more than 28 days (the maximum recommended treatment duration). Such patients more frequently required blood transfusions. Cases of anemia requiring blood transfusion have also been reported in the post-marketing period. This type of anemia occurred more frequently in patients treated with linezolid for more than 28 days.

Cases of sideroblastic anemia have been reported in the post-marketing period. Among cases with known onset time of anemia, most patients had received linezolid for more than 28 days. After discontinuation of linezolid, most patients recovered fully or partially with or without treatment for anemia.

Imbalance in mortality rates observed in a clinical trial involving patients with catheter-related bloodstream infections caused by gram-positive organisms.

In an open-label study involving patients with serious intravascular infections due to catheter use, an increased mortality rate was observed in the group treated with linezolid compared to the vancomycin/dicloxacillin/oxacillin treatment group (78 of 363 (21.5%) vs 58 of 363 (16.0%)). The primary factor influencing mortality was the presence of gram-positive infection at baseline.

Mortality rates in patients with infections caused exclusively by gram-positive organisms were similar (odds ratio 0.96), but in the linezolid treatment group, mortality was significantly higher (p=0.0162) in patients with any additional pathogen or no pathogen identified at baseline (odds ratio 2.48). The greatest imbalance occurred during treatment and within 7 days after discontinuation of linezolid. Most patients in the linezolid group developed gram-negative infections during the study and died from infections caused by gram-negative or polymicrobial pathogens. Therefore, in complicated skin and soft tissue infections in patients with confirmed or suspected concomitant gram-negative infection, the medicinal product should be used only when no other treatment options are available (see section "Indications"). In such cases, concomitant therapy for gram-negative infection should be initiated.

Risk of antibiotic-associated diarrhea and colitis.

Cases of diarrhea and colitis associated with antibiotic use, including pseudomembranous colitis and Clostridium difficile-associated diarrhea (CDAD), have been reported with the use of nearly all antibiotics, including linezolid. The severity of these conditions may range from mild diarrhea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after treatment with linezolid. If antibiotic-associated diarrhea or colitis is suspected or confirmed, current antibacterial therapy (including linezolid) should be discontinued and appropriate therapeutic measures should be initiated immediately. In such cases, the use of drugs that inhibit peristalsis is contraindicated.

Lactic acidosis risk.

Cases of lactic acidosis have been reported during treatment with linezolid. Patients who develop symptoms and signs of metabolic acidosis during treatment, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels, or hyperventilation, should seek immediate medical attention. If lactic acidosis develops, the benefit of continuing linezolid therapy versus potential risks should be carefully evaluated.

Mitochondrial dysfunction risk.

Linezolid inhibits mitochondrial protein synthesis. As a result of this inhibition, adverse reactions such as lactic acidosis, anemia, and neuropathy (peripheral and optic nerve) may occur. These events are more common when linezolid is used for more than 28 days.

Potential interactions causing increased blood pressure.

Except in cases where patients can be closely monitored for possible increases in blood pressure, the medicinal product 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), vasoconstrictors (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine).

Serotonin syndrome risk.

Spontaneous reports have been received regarding serotonin syndrome associated with concomitant use of linezolid and serotonergic drugs, including antidepressants (such as selective serotonin reuptake inhibitors (SSRIs)) and opioids (see "Interaction with other medicinal products and other forms of interaction"). Therefore, concomitant use of linezolid and serotonergic drugs is contraindicated (see "Contraindications"), except when the use of both linezolid and serotonergic drugs is considered essential. In such cases, patients should be closely monitored for symptoms of serotonin syndrome, such as cognitive disturbances, hyperpyrexia, hyperreflexia, and motor incoordination. If such symptoms occur, the physician should consider discontinuing one or both drugs. Symptoms of withdrawal may occur after discontinuation of the serotonergic drug.

Peripheral neuropathy and optic neuropathy risk.

Cases of peripheral neuropathy, optic neuropathy, and optic neuritis, sometimes progressing to vision loss, have been reported during treatment with linezolid. These reports primarily involved patients treated for more than 28 days (the maximum recommended treatment duration).

Patients should be advised to report any visual disturbances, such as changes in visual acuity, color vision changes, blurred vision, or visual field defects. In such cases, prompt ophthalmological evaluation is recommended, if necessary. Patients receiving linezolid for longer than the recommended 28 days should have regular vision testing.

If peripheral or optic neuropathy develops, the benefit of continuing linezolid therapy versus potential risks should be carefully evaluated.

The risk of neuropathy may be increased in patients receiving or who have recently received antituberculosis therapy with antibacterial agents.

Seizure risk.

Seizures have been reported in patients receiving linezolid. In most cases, a risk factor such as a history of seizures was reported. Patients should inform their physicians if they have previously experienced seizures.

Concomitant use with monoamine oxidase inhibitors (MAOIs).

Linezolid is a non-selective, reversible inhibitor of monoamine oxidase (MAO). However, at doses used for antibacterial therapy, it does not exhibit antidepressant effects. Very limited data are available from drug interaction and safety studies on the use of linezolid for treating the primary condition and/or concomitant use with drugs that may carry certain risks due to MAO inhibition. Therefore, linezolid use under such circumstances is not recommended unless close monitoring and patient surveillance can be ensured (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Use with tyramine-rich foods.

Patients should be advised to avoid consuming large amounts of tyramine-rich foods during treatment with the medicinal product (see section "Interaction with other medicinal products and other forms of interaction").

Hypoglycemia risk.

Post-marketing reports indicate cases of symptomatic hypoglycemia in diabetic patients receiving insulin or oral hypoglycemic agents during treatment with linezolid, a non-selective, reversible MAO inhibitor. Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. Although a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be warned about the potential for hypoglycemic reactions during treatment.

If hypoglycemia occurs, dose reduction of insulin or oral hypoglycemic agent, or discontinuation of the oral hypoglycemic agent, insulin, or linezolid may be necessary.

Superinfection risk.

The effect of linezolid on normal flora has not been studied in clinical trials.

Antibiotic use may occasionally lead to overgrowth of resistant organisms. For example, approximately 3% of patients receiving linezolid at recommended doses in clinical studies developed candidiasis associated with its use. Appropriate measures should be taken if superinfections occur during treatment.

Hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) risk.

Cases of hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been observed in patients receiving linezolid in the post-marketing period. Signs and symptoms in these cases included confusion, drowsiness, general weakness, and in severe cases, respiratory failure and even death. Regular monitoring of plasma sodium levels is recommended during treatment in elderly patients, patients taking diuretics, and other patients at risk of hyponatremia and/or SIADH. If signs and symptoms of hyponatremia and/or SIADH develop, the medicinal product should be discontinued and appropriate supportive measures should be taken.

Use in special patient groups.

The medicinal product should be used with caution in patients with severe renal impairment and only when the expected benefit outweighs the theoretical risk (see section "Dosage and administration").

The medicinal product is recommended for use in patients with severe hepatic impairment only when the expected benefit outweighs the theoretical risk (see section "Dosage and administration").

No dose adjustment of the medicinal product is necessary based on patient sex.

Fertility impairment risk.

Linezolid decreased fertility and caused morphological changes in sperm quality in healthy adult male rats at exposure levels approximately equivalent to those expected in humans. These changes were reversible. The potential effect of linezolid on male reproductive function is unknown.

Clinical trials.

The safety and efficacy of linezolid for treatment durations exceeding 28 days have not been established.

Controlled clinical trials did not include patients with pressure ulcers, ischemic lesions, severe burns, or gangrene. Therefore, experience with the use of linezolid for treating these conditions is limited.

Warnings related to excipients.

The medicinal product contains 15.072 g of glucose monohydrate per dose (300 mL) and should therefore be used with caution in patients with diabetes mellitus.

The medicinal product contains 114 mg of sodium per dose. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy.

Data on the use of linezolid in pregnant women are limited. Animal studies have demonstrated reproductive toxicity. There is a potential risk for humans. The medicinal product should not be used during pregnancy except when the expected benefit outweighs the potential risk.

Breastfeeding period.

Animal studies have shown that linezolid and its metabolites may pass into breast milk. Therefore, breastfeeding should be discontinued during treatment with the medicinal product.

Ability to affect reaction speed when driving or operating machinery.

Dizziness or visual disturbances may occur during treatment with linezolid (see sections "Special precautions for use" and "Adverse reactions"). If such reactions occur, patients should refrain from driving or operating machinery.

Method of administration and dosage.

Dosing.

Dosage recommendations according to indications are presented in the table below.

†Neonates <7 days of age. Most preterm neonates aged <7 days (<34 weeks gestation) have lower systemic clearance and higher AUC values of linezolid compared to most term neonates and children under 1 year of age. Treatment of such neonates should be initiated at a dose of 10 mg/kg every 12 hours. For neonates with inadequate clinical response to the drug, administration of 10 mg/kg every 8 hours may be considered. All patients aged up to 7 days should receive a dose of 10 mg/kg every 8 hours.

‡ Use an alternative dosage form allowing appropriate dosing.

The duration of treatment depends on the causative pathogen, site and severity of infection, as well as the clinical response.

The treatment duration recommendations provided above were applied in clinical studies. Shorter treatment durations may be appropriate for certain types of infections, although this has not been evaluated in clinical trials.

Maximum treatment duration is 28 days. The safety and efficacy of linezolid use beyond 28 days have not been studied.

There is no need to increase the recommended doses or duration of treatment in cases of infections associated with bacteremia.

Patients who initiated treatment with intravenous linezolid may be switched to oral linezolid therapy. In such cases, dose adjustment is not required, as the oral bioavailability of linezolid is nearly 100%.

Use in elderly patients.

Dose adjustment is not necessary for these patients.

Use in patients with renal impairment.

Dose adjustment is not necessary for these patients. Since approximately 30% of the dose is eliminated during a 3-hour hemodialysis session initiated 3 hours after drug administration, linezolid should be administered after hemodialysis in patients undergoing such treatment. (See section "Pharmacological properties. Pharmacokinetics").

Use in patients with hepatic impairment.

Dose adjustment is not necessary for these patients (see section "Pharmacological properties. Pharmacokin游戏副本

Adverse Reactions

The information provided is based on data obtained from clinical trials in which more than 2000 adult patients received the recommended doses of linezolid for up to 28 days.

The most commonly reported adverse reactions were diarrhea (8.4%), headache (6.5%), nausea (6.3%), and vomiting (4.0%). The most frequent adverse reactions leading to discontinuation of linezolid were headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to linezolid-induced adverse reactions.

Adverse reactions reported during the post-marketing period are listed with frequency categorized as "frequency not known," since the frequency cannot be estimated from the available data.

Adverse reactions reported during treatment are listed below according to the following frequency classification: 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); frequency not known – frequency cannot be estimated from the available data.

Infections and infestations:

Common – candidiasis, oral candidiasis, vaginal candidiasis, fungal infections; uncommon – vaginitis; rare – antibiotic-associated colitis, including pseudomembranous colitis*.

Blood and lymphatic system disorders:

Common – anemia*†; uncommon – leukopenia*, neutropenia, thrombocytopenia*, eosinophilia; rare – pancytopenia*; frequency not known – myelosuppression*, sideroblastic anemia*.

Immune system disorders:

Frequency not known – anaphylaxis.

Metabolism and nutrition disorders:

Uncommon – hyponatremia; frequency not known – lactic acidosis*.

Psychiatric disorders:

Common – insomnia.

Nervous system disorders:

Common – headache, taste disturbances (metallic taste), dizziness; uncommon – seizures*, hypoesthesia, paraesthesia; frequency not known – serotonin syndrome**, peripheral neuropathy*.

Eye disorders:

Uncommon – blurred vision*; rare – visual field defect*; frequency not known – optic neuropathy*, optic neuritis*, vision loss*, change in visual sensation*, change in color perception*.

Ear and labyrinth disorders:

Uncommon – tinnitus.

Cardiac disorders:

Uncommon – arrhythmia (tachycardia).

Vascular disorders:

Common – arterial hypertension; uncommon – transient ischemic attack, phlebitis, thrombophlebitis.

Gastrointestinal disorders:

Common – diarrhea, nausea, vomiting, localized or generalized abdominal pain, constipation, dyspepsia; uncommon – pancreatitis, gastritis, abdominal distension, dry mouth, glossitis, frequent loose stools, stomatitis, disorders or changes in tongue color; rare – discoloration of tooth surfaces.

Hepatobiliary disorders:

Common – abnormal liver function test results, increased levels of ALT, AST, or alkaline phosphatase; uncommon – increased total bilirubin.

Skin and subcutaneous tissue disorders:

Common – pruritus, rash; uncommon – urticaria, dermatitis, excessive sweating; frequency not known – bullous skin lesions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioneurotic edema, alopecia, allergic vasculitis.

Renal and urinary disorders:

Common – increased plasma urea nitrogen; uncommon – renal failure, increased creatinine, polyuria.

Reproductive system and breast disorders:

Uncommon – vulvovaginal disorders.

General disorders and administration site conditions:

Common – fever, localized pain; uncommon – chills, fatigue, injection site pain, thirst.

Investigations:

Common – biochemistry: increased lactate dehydrogenase, creatine kinase, lipase, amylase, or postprandial (non-fasting) glucose levels; decreased total protein, albumin, sodium, and calcium; increased or decreased potassium or bicarbonate; hematology: increased neutrophil or eosinophil count, decreased hemoglobin, hematocrit, or erythrocyte count, increased or decreased platelet or leukocyte count; uncommon – biochemistry: increased sodium or calcium, decreased glucose (non-fasting), increased or decreased chloride; hematology: increased reticulocyte count, decreased neutrophil count.

* See section "Special Warnings and Precautions for Use".

** See sections "Contraindications" and "Interaction with Other Medicinal Products and Other Forms of Interaction".

† During controlled clinical trials in which linezolid was administered for up to 28 days, anemia was observed in 2.0% of patients. In a compassionate use program involving patients with life-threatening infections and comorbid conditions, the percentage of patients who developed anemia after receiving linezolid for ≤ 28 days was 2.5% (33 out of 1326), compared to 12.3% (53 out of 430) in those treated for > 28 days. The proportion of documented cases of severe anemia requiring blood transfusion was 9% (3 out of 33) in patients treated for ≤ 28 days and 15% (8 out of 53) in those treated for > 28 days.

Adverse reactions associated with linezolid use that were assessed as severe in rare cases include localized abdominal pain, transient ischemic attack, and arterial hypertension.

During the post-marketing period, cases of symptomatic hypoglycemia have been reported in diabetic patients receiving insulin or oral hypoglycemic agents when treated with linezolid, a non-selective, reversible monoamine oxidase (MAO) inhibitor. Use of certain MAO inhibitors has been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents.

In patients receiving linezolid during the post-marketing period, cases of hyponatremia and/or syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have been observed. Signs and symptoms in these cases included confusion, drowsiness, general weakness, and in severe cases, led to respiratory failure and even death.

Suspected adverse reaction reporting.

Reporting of suspected adverse reactions after drug registration is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

5 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Do not freeze.

The infusion solution should be used immediately after opening.

Incompatibility.

See section "Dosage and Administration".

Packaging.

300 ml of solution in a colorless glass vial with a rubber stopper coated with Teflon and an aluminum Flip-off cap; 1 vial in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Mefar Ilac San. A.S., Turkey.

Manufacturer's address and location of operations.

Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.