INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINOZID (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 concentrated; water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical characteristics: clear, colorless solution.

Pharmacotherapeutic group.

Antibacterials for systemic use. ATC code J01X X08.

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 50S subunits) and interferes with the formation of the functional 70S initiation complex (an essential component in the translation process).

The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, it is advisable to refer to local information on microbial resistance, especially when treating severe infections. If necessary, when the local prevalence of microbial 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. Studies of clinical isolates (methicillin-resistant staphylococci, vancomycin-resistant enterococci, as well as penicillin- and erythromycin-resistant streptococci) in vitro 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.

The medicinal product LINOSID contains linezolid, which is the biologically active substance and is metabolized to inactive derivatives.

Absorption.

Maximum (Cmax) and minimum (Cmin) plasma concentrations of linezolid (mean value and [standard deviation]) at steady state after intravenous administration twice daily at a dose of 600 mg 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 doses of linezolid. 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 through oxidation of the morpholine ring, forming two inactive ring-opened carboxylic acid derivatives: 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 under in vitro conditions. In vitro studies have demonstrated that linezolid undergoes minimal metabolism, possibly involving the human cytochrome P450 system. However, the metabolic pathways for linezolid are not fully understood.

Elimination.

Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. At steady state, approximately 30% of the administered dose is excreted in urine as 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 excreted in feces as metabolite B and 3% as metabolite A.

Minor nonlinearity in clearance was observed with increasing linezolid doses, 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 main 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, dose adjustment is not recommended for patients with renal impairment. However, given the lack of information on the clinical significance of accumulation of the main metabolites, the appropriateness of using linezolid in patients with renal impairment and the potential risks of metabolite accumulation 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 dysfunction (Child-Pugh class A or B). Based on available data, dose adjustment is not recommended for patients with mild to moderate hepatic impairment. 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 ulcers;
• Uncomplicated skin and soft tissue infections caused by Staphylococcus aureus (only methicillin-susceptible isolates) 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 suspected or confirmed Gram-negative pathogens, 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 monoamine oxidase inhibitors (MAOIs) of types A and B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide), or within two weeks of 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 syndrome, 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 the 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 reversible, non-selective inhibitor of monoamine oxidase (MAO). Data from drug interaction and safety studies of linezolid provide very limited information on its use in patients receiving concomitant medications that pose certain risks due to MAO inhibition. Therefore, the use of linezolid in such circumstances is not recommended unless careful patient monitoring and surveillance are possible (see sections "Contraindications" and "Special precautions for use").

Potential interactions leading to increased blood pressure.

Linezolid enhances the blood pressure-elevating effect of 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. Careful dose adjustment of vasoactive agents, including dopaminergic drugs, is recommended when used concomitantly with linezolid.

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, hallucinations, agitation, tremor, flushing, diaphoresis, hyperpyrexia) were observed.

Post-marketing experience: one report described symptoms resembling serotonin syndrome in a patient taking linezolid and dextromethorphan; 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. Therefore, although concomitant use of these agents is contraindicated (see section "Contraindications"), management of patients requiring treatment with both linezolid and serotonergic agents 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 suggests 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.

Medicinal products 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 drugs metabolized by CYP450 is not expected.

The effect of rifampicin on the pharmacokinetics of linezolid was studied in 16 healthy male volunteers who received linezolid (600 mg twice daily for 2.5 days) alone and in combination with rifampicin (600 mg once daily for 8 days). Rifampicin reduced C_max 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, while AUC of INR 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

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 developing blood abnormalities 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 impairment.

Therefore, careful monitoring of blood parameters is necessary in the following patients: those with pre-existing anemia, granulocytopenia, or thrombocytopenia; patients receiving concomitant medications that may reduce hemoglobin levels, decrease blood cell counts, or negatively affect platelet number or function; patients with severe renal impairment; patients with moderate to severe hepatic impairment; and patients undergoing treatment for 10–14 days. The drug should be used in such patients only with careful monitoring of hemoglobin levels, complete blood count, and, if possible, platelet count.

If significant myelosuppression develops during treatment with the drug, therapy should be discontinued, except in cases where continuation is deemed absolutely necessary. In such situations, careful monitoring of complete blood count parameters and appropriate therapeutic interventions should be implemented.

Additionally, it is recommended to monitor complete blood count parameters (including hemoglobin levels, platelet count, total white blood cell count, and differential leukocyte count) weekly in patients receiving linezolid, regardless of initial blood test results.

In studies using unapproved linezolid under compassionate use programs, an increased incidence of severe anemia was observed in patients treated for more than 28 days (the maximum recommended treatment duration). These patients more frequently required blood transfusions. Cases of anemia requiring blood transfusion have also been reported in the post-marketing period. Such 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 timing, most patients had received linezolid for more than 28 days. After discontinuation of linezolid, most patients fully or partially recovered with or without treatment for anemia.

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

In an open-label study of patients with serious intravascular infections caused by catheter use, increased mortality was observed in the group receiving linezolid compared to the vancomycin/dicloxacillin/oxacillin treatment groups (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, 95% confidence interval: 0.58–1.59), but in the linezolid treatment group, mortality was significantly higher (p=0.0162) in patients with any additional pathogen or no pathogen at baseline (odds ratio 2.48, 95% confidence interval: 1.38–4.46). 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 pathogens or polymicrobial infections. Therefore, in complicated skin and soft tissue infections in patients with established or suspected concomitant gram-negative infection, the drug should be used only when no other treatment options are available (see section "Indications"). In such cases, concomitant treatment for gram-negative infection should be initiated.

Diarrhea and colitis associated with antibiotic use

Diarrhea and colitis associated with antibiotic use, including pseudomembranous colitis and Clostridium difficile-associated diarrhea (CDAD), have been reported with 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 initiated immediately. In such cases, the use of agents that inhibit peristalsis is contraindicated.

Lactic acidosis

Cases of lactic acidosis have been reported during treatment with linezolid. Patients who develop symptoms or 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 considered.

Mitochondrial dysfunction

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 longer than 28 days.

Potential interactions leading to increased blood pressure

Except in cases where patients can be monitored for possible increases in blood pressure, the drug should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, and/or concomitant use of medications such as direct and indirect sympathomimetics (e.g., pseudoephedrine), vasoconstrictors (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine).

Serotonin syndrome

Spontaneous reports of serotonin syndrome associated with concomitant use of linezolid and serotonergic agents, including antidepressants (such as selective serotonin reuptake inhibitors [SSRIs]) and opioids, have been received (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, concomitant use of linezolid and serotonergic agents is contraindicated (see section "Contraindications"), except when use of both linezolid and serotonergic agents is considered life-saving. In such cases, the patient 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 agents. Symptoms of withdrawal may occur after discontinuation of the serotonergic agent.

Rhabdomyolysis

Cases of rhabdomyolysis have been reported during treatment with linezolid. The drug should be used with caution in patients with risk factors for rhabdomyolysis. If signs or symptoms of rhabdomyolysis occur, the drug should be discontinued and appropriate therapy initiated.

Peripheral neuropathy and optic neuropathy

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

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

The risk of neuropathies may be increased in patients receiving or who have recently received treatment with antibacterial agents for tuberculosis.

Seizures

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

Monoamine oxidase inhibitors

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 on the use of linezolid for primary disease treatment and/or concomitant use with agents that may carry certain risks due to MAO inhibition have been obtained from drug interaction and safety studies. Therefore, use of the drug under such conditions is not recommended unless close monitoring and patient observation are possible (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use with tyramine-rich foods

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

Hypoglycemia

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. Hypoglycemic episodes have been associated with some MAO inhibitors 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 with the drug.

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

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

Cases of hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been observed in patients treated with linezolid in the post-marketing period. Signs and symptoms 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 or symptoms of hyponatremia and/or SIADH develop, the drug should be discontinued and appropriate supportive measures taken.

Superinfection

The effect of linezolid on normal flora was not studied during 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 trials developed candidiasis associated with its use. Appropriate measures should be taken if superinfections occur during treatment.

Special patient groups

The drug should be used with caution in patients with severe renal impairment and only when the expected benefit outweighs the theoretical risk (see sections "Dosage and administration" and "Pharmacological properties").

The drug should be used in patients with severe hepatic impairment only when the expected benefit outweighs the theoretical risk (see sections "Dosage and administration" and "Pharmacological properties").

No dose adjustment of the drug is necessary based on patient gender.

Impairment of fertility

Linezolid reduced fertility and caused morphological abnormalities in sperm quality in healthy adult male rats at exposure levels approximately similar 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 when used for longer than 28 days have not been established.

Patients with diabetic foot infections, pressure ulcers, ischemic lesions, severe burns, or gangrene were not included in controlled clinical trials. Therefore, experience with the use of linezolid for the treatment of these conditions is limited.

Excipients

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

The drug contains 114 mg of sodium per dose. Caution should be exercised when administering the drug 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 drug should not be used during pregnancy except when the expected benefit outweighs the potential risk.

Breastfeeding period.

Animal studies indicate that linezolid and its metabolites may pass into breast milk. Therefore, breastfeeding should be discontinued during treatment with the drug.

Ability to affect reaction speed when driving or operating machinery.

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

Method of administration and dosage.

Dosing.

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

†Neonates <7 days of age. Most preterm neonates <7 days of age (<34 weeks gestation) have lower systemic clearance and higher AUC values of linezolid than 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 under 7 days of age should receive a dose of 10 mg/kg every 8 hours.

‡ Use another pharmaceutical 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. For certain types of infections, a shorter treatment duration may be appropriate, although this has not been evaluated in clinical trials.

The 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 whose treatment was initiated with intravenous linezolid infusions may be switched to oral linezolid therapy. In such cases, dose adjustment is not required, as the bioavailability of linezolid administered orally is nearly 100%.

Use in elderly patients.

No dose adjustment is necessary for these patients.

Use in patients with renal impairment.

No dose adjustment is necessary for these patients. Since approximately 30% of the dose is removed during a 3-hour hemodialysis session initiated 3 hours after drug administration, linezolid should be administered to patients undergoing hemodialysis after the procedure (see section "Pharmacological properties").

Use in patients with hepatic impairment.

No dose adjustment is necessary for these patients (see section "Pharmacological properties").

Children.

In neonates up to 1 week of age, systemic clearance of linezolid (per kg body weight) increases rapidly during the first week of life. Therefore, in neonates receiving the drug at a dose of 10 mg/kg every 8 hours daily, higher systemic exposure to the drug is observed on the first day of life. However, excessive drug accumulation during this dosing regimen over the first week of life is not expected due to the rapidly increasing clearance of the drug during the first 7 days of life (see section "Dosage and administration").

In children aged 1 week to 12 years, administration of the drug at a dose of 10 mg/kg every 8 hours daily provides exposure comparable to that achieved in adults receiving 600 mg twice daily.

In children aged 12 to 17 years, the pharmacokinetics of linezolid are similar to those in adults when the drug is administered at a dose of 600 mg. Thus, adolescents receiving the drug at 600 mg every 12 hours daily will have the same exposure as adult patients receiving the same dose.

Method of administration.

The medicinal product is intended for intravenous administration.

Intravenous infusion should be administered over 30–120 minutes.

Immediately before use, visually inspect the medicinal product for the presence of mechanical particulates.

Any unused solution should be disposed of according to current regulations.

Do not connect infusion bags in series! Do not add other drugs to this solution.

When administering this medicinal product concomitantly with other agents, each drug should be administered separately according to the recommended dose and route of administration for each medicinal product.

When using a single intravenous line for sequential administration of multiple drugs, the line should be flushed before and after administration of this medicinal product with an infusion solution compatible with both this medicinal product and the other drug being administered through the same line.

Compatible infusion solutions: 0.9% sodium chloride injection solution, 5% dextrose injection solution, lactated Ringer's injection solution.

Major incompatibilities.

Physical incompatibility occurred when intravenous linezolid was administered via a Y-site connector together with the following drugs: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, sodium phenytoin, and trimethoprim/sulfamethoxazole. Additionally, intravenous linezolid was chemically incompatible with ceftriaxone sodium.

Children.

The medicinal product may be used from the first days of life.

Overdose.

No cases of overdose have been reported.

In the event of overdose, symptomatic treatment should be administered along with measures to support glomerular filtration rate. Approximately 30% of the administered dose of linezolid is removed during 3 hours of hemodialysis; however, there are no data on the removal of linezolid during peritoneal dialysis or hemoperfusion procedures. The two major metabolites of linezolid are also removed by hemodialysis. There is no specific antidote.

Adverse Reactions

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

The most frequently reported adverse reactions were diarrhea (8.9%), headache (4.2%), nausea (6.9%), and vomiting (4.3%). The most common adverse reactions leading to discontinuation of linezolid were headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to linezolid-related 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 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 – cannot be estimated from available data.

Infections and infestations:

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

Blood and lymphatic system disorders:

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

Immune system disorders:

Rare – anaphylaxis.

Metabolism and nutrition disorders:

Uncommon – hyponatremia; rare – lactic acidosis*.

Psychiatric disorders:

Common – insomnia.

Nervous system disorders:

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

Eye disorders:

Uncommon – optic neuropathy*, blurred vision*; rare – visual field defect*; frequency not known – 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 – 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, tongue disorders or color changes; rare – discoloration of tooth surface.

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 – angioedema, urticaria, bullous dermatitis, dermatitis, excessive sweating; rare – Stevens-Johnson syndrome# and toxic epidermal necrolysis#, allergic vasculitis; frequency not known – alopecia.

Musculoskeletal and connective tissue disorders:

Rare – rhabdomyolysis*.

Renal and urinary disorders:

Common – increased blood 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:

Biochemistry: common – 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; uncommon – increased sodium or calcium, decreased glucose (non-fasting), increased or decreased chloride. Hematology: common – increased neutrophil or eosinophil count, decreased hemoglobin, hematocrit, or erythrocyte count, increased or decreased platelet or leukocyte count; uncommon – 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".

Frequency of adverse reactions assessed according to the rule of 3.

† In controlled clinical trials where 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 due to drug use 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, which were assessed in rare cases as severe reactions: localized abdominal pain, transient ischemic attack, and arterial hypertension.

During the post-marketing period, cases of symptomatic hypoglycemia have been reported when linezolid, a non-selective, reversible MAO inhibitor, was administered to diabetic patients receiving insulin or oral hypoglycemic agents. Hypoglycemic episodes have been associated with the use of some MAO inhibitors 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 antidiuretic hormone secretion (SIADH) have been observed. Signs and symptoms in these cases included confusion, drowsiness, general weakness, and in severe cases, respiratory failure and even death.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 ºC in the original packaging and in a place inaccessible to children.

Do not freeze.

The infusion solution should be used immediately after opening.

Incompatibilities.

See section "Instructions for use and dosage".

Packaging.

300 ml of solution in a vial; 1 vial in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of operations.

COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey.