Infuzolid®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INFUZOLID® (INFUZOLID®)

Composition:

Active substance: linezolid;

1 ml of solution contains 2 mg of linezolid (calculated as dry 100% substance);

Excipients: sodium citrate dihydrate; citric acid monohydrate; sodium chloride; sodium hydroxide; hydrochloric acid diluted; water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical characteristics: clear, colorless or slightly yellow liquid. Theoretical osmolarity 290 mOsmol/L.

Pharmacotherapeutic group. Antibacterials for systemic use.

ATC code J01XX08.

Pharmacological Properties.

Pharmacodynamics. Linezolid is a synthetic antibacterial agent belonging to a new class of antimicrobials — the oxazolidinones. It exhibits in vitro activity against aerobic gram-positive bacteria and anaerobic microorganisms. Linezolid selectively inhibits bacterial protein synthesis through a unique mechanism of action. It binds directly to the bacterial ribosome (23S portion of the 50S subunit), thereby preventing the formation of the functional 70S initiation complex (an essential component of the translation process).

The prevalence of acquired resistance in specific species may vary geographically and over time; therefore, it is advisable to refer to local information on microbial resistance, especially when treating severe infections. If necessary, when local resistance prevalence raises doubts about the benefit of using the medicinal product, at least for certain types of infections, consultation with an expert should be sought.

Susceptible microorganisms. Gram-positive aerobes: Enterococcus faecalis, Enterococcus faecium*, Staphylococcus aureus*, coagulase-negative staphylococci, Streptococcus agalactiae*, Streptococcus pneumoniae*, Streptococcus pyogenes*, group C streptococci, group G streptococci.

Gram-positive anaerobes: 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. Infusolid**®** contains linezolid, which is the biologically active substance and is metabolized to inactive derivatives.

Absorption. Linezolid is rapidly absorbed after oral administration. Maximum plasma concentration (Cmax) is reached approximately 1–2 hours after dosing, and absolute bioavailability is about 100%. Therefore, linezolid can be administered orally or intravenously without dose adjustment.

Linezolid can be administered regardless of food intake. Time to reach Cmax increases from 1.5 to 2.2 hours, and Cmax is reduced by approximately 17% when linezolid is taken with a high-fat meal. However, total exposure, assessed by AUC0–∞, is similar in both cases.

Distribution. Linezolid rapidly distributes into well-perfused tissues. Approximately 31% of linezolid is protein-bound in plasma, independent of drug concentration. The volume of distribution at steady state in healthy adult volunteers averages 40–50 L. The ratio of linezolid concentration in saliva to plasma concentration is 1.2:1, and the ratio of linezolid concentration in sweat to plasma concentration is 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 metabolite B formation is mediated by a non-enzymatic mechanism involving chemical oxidation under in vitro conditions. In vitro studies have shown that linezolid undergoes minimal metabolism, with possible involvement of the human cytochrome P450 system in this process. However, the metabolic pathways of 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 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 dose is recovered in feces as metabolite B and 3% as metabolite A. Slight non-linearity in clearance was observed with increasing linezolid doses, likely due to lower renal and non-renal clearance at higher concentrations of the drug. However, this difference in clearance was minor and did not affect the apparent elimination half-life.

Patients with renal impairment. The pharmacokinetics of linezolid are not altered in patients with any degree of renal impairment; however, the two main metabolites of linezolid accumulate in patients with renal impairment, with greater accumulation observed in patients with more severe renal dysfunction. The pharmacokinetics of linezolid and its two metabolites were also studied in patients with end-stage renal disease (ESRD) undergoing hemodialysis. In an 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, due to the lack of information on the clinical significance of accumulation of the main metabolites, the benefits and potential risks of linezolid use in patients with renal impairment, including the risk 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 linezolid pharmacokinetics 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. The pharmacokinetics in patients with severe hepatic impairment have not been evaluated.

Clinical characteristics.

Indications.

For the treatment of infections caused by susceptible strains of specified microorganisms: hospital-acquired and 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) or Streptococcus pyogenes (the use of linezolid in the treatment of pressure ulcers has not been studied); 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 cases of suspected or confirmed Gram-negative pathogens, specific therapy should be initiated immediately.

Contraindications.

Hypersensitivity to linezolid or any other component of the medicinal product. Linezolid should not be used during treatment with any medicinal products that inhibit monoamine oxidase A and B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide), or within two weeks after discontinuation of such agents. Except in cases where close monitoring and blood pressure surveillance are possible, linezolid should not be administered to patients with the following concomitant clinical conditions or concomitant use of the following medications: uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute episodes of dizziness; serotonin reuptake inhibitors, tricyclic antidepressants, 5-HT1-serotonin receptor agonists (triptans), direct and indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine, phenylpropanolamine), vasopressors (epinephrine, norepinephrine), dopaminergic agents (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). In drug interaction and safety studies of linezolid, very limited data are available on the use of linezolid in patients receiving concomitant therapy with agents posing certain risks due to MAO inhibition. Therefore, the use of linezolid under such circumstances is not recommended unless close monitoring and patient 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. Careful dose selection of vasoactive agents, including dopaminergic drugs, is recommended to achieve the desired effect when linezolid is used concomitantly with these agents.

Potential serotonergic interactions. Potential interactions between linezolid and dextromethorphan were studied in a trial involving healthy volunteers. Participants received dextromethorphan (two 20 mg doses given 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 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 drugs.

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

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

Drugs metabolized by cytochrome P450. Linezolid is not metabolized by the cytochrome P450 enzyme system and does not inhibit the activity 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, no influence of linezolid on the pharmacokinetics of other drugs metabolized by CYP450 is expected.

Rifampicin. The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen 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 Cmax and AUC of linezolid by an average of 21% and 32%, respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin. At steady state, when warfarin was added to linezolid therapy, a 10% decrease in mean maximum INR (International Normalized Ratio) was observed, with a 5% reduction in INR AUC. Data on patients receiving warfarin and linezolid concomitantly are insufficient to assess the clinical significance of these findings.

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

Gentamicin. 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. Dose adjustment of linezolid is not 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. Hematologic parameters returned to pre-treatment levels after discontinuation of linezolid. The risk of these effects is likely related to the duration of treatment. Elderly patients receiving linezolid are at higher risk of developing blood abnormalities compared to younger patients. In patients with severe renal insufficiency (regardless of whether they are undergoing dialysis), there may be an increased frequency of thrombocytopenia. Therefore, careful monitoring of blood counts is necessary in the following patients: those 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 patients receiving treatment for more than 10–14 days. Linezolid 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 linezolid, therapy should be discontinued, except in cases where continuation is deemed absolutely necessary. In such cases, careful monitoring of complete blood count parameters and appropriate therapeutic strategies should be implemented. Additionally, it is recommended to perform weekly monitoring of complete blood count (including hemoglobin levels, platelet count, total leukocyte count, and differential leukocyte count) in all patients receiving linezolid, regardless of baseline blood test results. In clinical trials, an increased incidence of severe anemia was observed in patients treated with linezolid 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 also been reported in the post-marketing period. Among cases where the onset of anemia was known, 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.

Mortality imbalance in a clinical study involving patients with catheter-related bloodstream infections caused by gram-positive pathogens. In an open-label study involving patients with serious intravascular infections due to catheter use, an increased mortality rate was observed in the group receiving linezolid compared to the groups treated with vancomycin/dicloxacillin/oxacillin (78 of 363 [21.5%] vs. 58 of 363 [16.0%]). The main 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; however, in the linezolid treatment group, the frequency of fatal outcomes was significantly higher in patients with any additional pathogen or no pathogen identified at baseline. The greatest imbalance occurred during treatment and within 7 days after discontinuation of the study drug. 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 confirmed or suspected concomitant infection caused by gram-negative pathogens, linezolid should be used only when no other treatment options are available (see section "Indications"). In such circumstances, concomitant treatment for gram-negative infection should be initiated.

Diarrhea and antibiotic-associated colitis. 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, with severity ranging from mild diarrhea to colitis with fatal outcomes. 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 drugs that inhibit peristalsis is contraindicated.

Lactic acidosis. Cases of lactic acidosis have been reported during treatment with linezolid. Patients who develop symptoms and signs of metabolic acidosis during treatment with linezolid, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels, or hyperventilation, should seek immediate medical attention. If lactic acidosis develops, the benefits 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 effects are more common when the drug is used for more than 28 days.

Potential interactions causing elevated blood pressure. Except in cases where patients can be closely monitored for possible increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, and/or those receiving concomitant medications such as: direct and indirect-acting sympathomimetics (e.g., pseudoephedrine); vasopressors (e.g., epinephrine, norepinephrine); dopaminergic agents (e.g., dopamine, dobutamine).

Serotonin syndrome. Spontaneous reports of serotonin syndrome associated with concomitant use of linezolid and serotonergic drugs, including antidepressants (such as selective serotonin reuptake inhibitors [SSRIs]), have been received. Therefore, concomitant use of linezolid and serotonergic drugs is contraindicated (see "Contraindications"), except in cases where the use of both linezolid and concomitant 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 impaired coordination. If such symptoms occur, the physician should consider discontinuing one or both drugs. Withdrawal symptoms may occur after discontinuation of the serotonergic drug.

Peripheral neuropathy and optic neuropathy. Cases of peripheral neuropathy, as well as optic neuropathy and optic neuritis, sometimes progressing to vision loss, have been reported in patients receiving linezolid treatment. These reports primarily involved patients treated for more than 28 days (the maximum recommended treatment duration). All patients 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 benefits of continuing linezolid therapy versus potential risks should be carefully considered. The risk of developing neuropathies may be increased when linezolid is used to treat patients who are receiving or have recently received anti-tuberculosis therapy with other antibacterial agents.

Seizures. Cases of seizures have been reported in patients receiving linezolid therapy. 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.

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 are available from drug interaction studies and safety trials regarding the use of linezolid for the treatment of the primary condition and/or concomitant therapy with drugs that may carry certain risks due to MAO inhibition. Therefore, the use of linezolid under such circumstances is not recommended unless close patient monitoring can be ensured (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 (see section "Interaction with other medicinal products and other forms of interaction").

Hypoglycemia. Cases of symptomatic hypoglycemia have been reported in the post-marketing period in diabetic patients receiving insulin or oral hypoglycemic agents while being treated 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 linezolid therapy. In case of hypoglycemia, dose reduction of insulin or oral hypoglycemic agent, discontinuation of the oral hypoglycemic agent, insulin, or linezolid may be required.

Hypnatremia 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 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 serum sodium levels is recommended during linezolid therapy in elderly patients, patients taking diuretics, and other patients at risk of hyponatremia and/or SIADH. If symptoms of hyponatremia and/or SIADH occur, 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 sometimes lead to overgrowth of resistant organisms. For example, approximately 3% of patients receiving linezolid at recommended doses in clinical trials developed drug-related candidiasis. Appropriate measures should be taken if superinfections occur during treatment.

Special patient groups. Linezolid should be used with caution in patients with severe renal insufficiency and only when the expected benefit outweighs the theoretical risk (see section "Dosage and administration"). Linezolid should be used in patients with severe hepatic insufficiency only when the expected benefit outweighs the theoretical risk (see section "Dosage and administration"). Dose adjustment is not necessary based on patient gender.

Impairment of fertility. Linezolid decreased 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 more than 28 days have not been established. Patients with 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. 1 mL of solution contains 3.6 mg (1080 mg / 300 mL) of sodium. The sodium content should be taken into account for 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. Linezolid should not be used during pregnancy except when the expected benefit outweighs the potential risk.

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

Ability to affect reaction speed when driving or operating machinery.

Patients should be warned about the possible development of dizziness or visual disturbances (see section "Special precautions for use" and "Adverse reactions") during linezolid therapy and advised not to drive or operate machinery if these symptoms occur.

Dosage and Administration

The duration of treatment depends on the causative organism, site and severity of infection, as well as the clinical response. The treatment duration recommendations provided below are based on results from clinical studies. For certain types of infections, a shorter duration of therapy may be appropriate, although this has not been evaluated in clinical trials. The maximum duration of treatment is 28 days. The safety and efficacy of linezolid administered for longer than 28 days have not been established. There is no need to increase the recommended doses or duration of treatment in cases of infections associated with bacteremia.

Patients who were initially treated with intravenous infusions of linezolid may be switched to oral linezolid therapy. Dose adjustment is not required when switching, as the oral bioavailability of linezolid is nearly 100%.

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

* Neonates < 7 days. Most preterm neonates aged < 7 days (< 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 with 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 term neonates aged up to 7 days should receive a dose of 10 mg/kg every 8 hours.

** Linezolid in another pharmaceutical form allowing appropriate dosing should be used.

Instructions for use. Linezolid for intravenous injection is supplied in single-use, ready-to-use infusion bags. Immediately before administration, remove the light-protective overwrap and visually inspect the medicinal product for the presence of particulate matter; squeeze the bag for approximately 1 minute to ensure its integrity. If the bag leaks, do not use the solution, as its sterility may be compromised. Any unused solution should be disposed of according to current requirements.

Intravenous infusion should be administered over 30–120 minutes. Infusion bags must not be connected in series! Other drugs must not be added to this solution. When administering linezolid intravenously together 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 linezolid for intravenous injection with an infusion solution compatible with both linezolid and the other agent administered through the line.

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

Major cases of incompatibility. Physical incompatibility occurred when linezolid solution was administered intravenously via a Y-connector together with the following drugs: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, sodium phenytoin, and trimethoprim-sulfamethoxazole. In addition, linezolid for intravenous injection was chemically incompatible with ceftriaxone sodium.

Use in elderly patients. Dose adjustment is not required.

Use in patients with renal impairment. Dose adjustment is not required. Since approximately 30% of the dose is removed during a 3-hour hemodialysis session initiated 3 hours after drug administration, linezolid should be administered after hemodialysis in patients receiving such treatment (see section "Pharmacological properties. Pharmacokinetics").

Use in patients with hepatic impairment. Dose adjustment is not required (see section "Pharmacological properties. Pharmacokinetics").

Children.

Can be used from the first days of life.

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

In neonates aged up to 1 week, systemic clearance of linezolid (per kg body weight) increases rapidly during the first week of life. Thus, in neonates receiving the drug at a dose of 10 mg/kg every 8 hours, higher systemic exposure to the drug is observed on the first day after birth. However, excessive drug accumulation is not expected with this dosing regimen during the first week of life due to the rapid increase in drug clearance during the first 7 days of life (see section "Method of administration and dosage").

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

Overdose. There is no specific antidote. No cases of overdose have been reported. In case of overdose, symptomatic treatment together with measures to support glomerular filtration is indicated. Approximately 30% of the administered dose of the drug is removed during 3 hours of hemodialysis, but there are no data on the removal of linezolid during peritoneal dialysis or hemoperfusion procedures. The two main metabolites of linezolid are also removed by hemodialysis.

Adverse reactions.

Data on adverse reactions were obtained from clinical trials in which more than 2000 adult patients received 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 the drug were headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to drug-related adverse reactions.

Adverse reactions reported after marketing of the drug are included in the list below with frequency categorized as "frequency not known," since the frequency cannot be estimated from available data.

The 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: 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 perversion (metallic taste), dizziness. Uncommon: seizures*, hypesthesia, paresthesia. 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*, altered visual sensation*, color vision changes*.

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 tests, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (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 reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, alopecia.

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. Chemistry. Common: increased lactate dehydrogenase, creatine kinase, lipase, amylase, or postprandial (non-fasting) glucose levels; decreased total protein, albumin, sodium, or calcium; increased or decreased potassium or bicarbonate levels. Uncommon: increased sodium or calcium, decreased glucose (non-fasting), increased or decreased chloride levels.

Hematology. Common: increased neutrophils or eosinophils, decreased hemoglobin, hematocrit, or erythrocyte count, increased or decreased platelet or leukocyte count. Uncommon: increased reticulocytes, 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".

^ In controlled clinical trials where linezolid was administered for up to 28 days, anemia was observed in 2.0% of patients. In an unregistered compassionate use program for patients with life-threatening infections and comorbid conditions, the incidence of anemia was 2.5% among patients treated for ≤ 28 days compared to 12.3% among those treated for > 28 days. The incidence of severe anemia requiring blood transfusion due to drug exposure was 9% in patients treated for ≤ 28 days and 15% in those treated for > 28 days.

Adverse reactions associated with linezolid use that were assessed as severe in rare cases: 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 while being treated with linezolid, a non-selective, reversible monoamine oxidase inhibitor (MAO-I). Hypoglycemic episodes have been associated with the use of some MAO inhibitors in diabetic patients receiving insulin or oral hypoglycemic agents.

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

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. 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 in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children. The contents of the bag should be used immediately after opening.

Incompatibilities. See section "Dosage and administration".

Packaging. 300 ml in a polymer bag, placed in a metallized pouch.

Prescription status. Prescription only.

Manufacturer. Private Joint Stock Company "Infuziya", Ukraine.

Manufacturer's address and location of business activity.
Ukraine, 23219, Vinnytsia region, Vinnytsia district, village Vinnytski Khutory, Nemirivske Highway, b. 84A.