Linessa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINESSA

Composition:

Active substance: linezolid;

1 ml of solution contains 2 mg of linezolid;

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

Pharmaceutical form. Infusion solution.

Main physicochemical properties:

clear, colorless to slightly yellowish solution.

Pharmacotherapeutic group. Antibacterials for systemic use. Other antibacterials. ATC code J01XX08.

Pharmacological Properties

Pharmacodynamics

Linezolid is a synthetic antibacterial agent belonging to a new class of antimicrobials – 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 directly binds to bacterial ribosomes (23S portion of the 50S subunit) and prevents the formation of the functional 70S initiation complex (a key component in the translation process).

The prevalence of acquired resistance may vary geographically and over time for specific species; therefore, it is advisable to refer to local information on microbial resistance patterns, especially when treating severe infections. If necessary, when the local prevalence of resistance is such that the benefit of using the medicinal product, 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

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

Absorption

Linezolid is extensively absorbed after oral administration. Maximum plasma concentrations are reached approximately 1–2 hours after dosing, and the absolute bioavailability of the drug is about 100%. Therefore, linezolid can be administered orally or intravenously without dose adjustment.

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

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 drug concentration. The volume of distribution at steady state in healthy adult volunteers averages 40–50 L.

Concentrations of linezolid 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 via oxidation of the morpholine ring, forming two inactive open-ring 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 under in vitro conditions. In vitro studies have demonstrated that linezolid undergoes minimal metabolism, with possible involvement of the human cytochrome P450 system. However, the metabolic pathways of linezolid have not been fully elucidated.

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 tubular reabsorption. Linezolid is virtually undetectable in feces, whereas approximately 6% of the dose is recovered in feces as metabolite B and 3% as metabolite A.

A minor non-linearity in clearance was observed with increasing doses of linezolid, 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 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 increased 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. Plasma concentrations of linezolid were comparable regardless of renal function; therefore, 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 use of linezolid in patients with renal impairment should be carefully considered in relation to the potential risks of metabolite accumulation. 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 of linezolid 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 (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 cases of suspected or confirmed gram-negative pathogens, specific gram-negative therapy should be initiated immediately.

Contraindications.

Known hypersensitivity to linezolid or to any other component of the medicinal product.

Linessa must not be administered to patients receiving any medicinal products that inhibit monoamine oxidase A and B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide), or within two weeks of receiving such agents.

Except in cases where close monitoring and blood pressure surveillance are possible, Linessa must not be administered to patients with the following concomitant clinical conditions or concomitant use of the following medications:

• Uncontrolled hypertension, pheochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute episodes of dizziness;
• Serotonin reuptake inhibitors, tricyclic antidepressants, serotonin 5-HT₁ receptor agonists (triptans), direct and indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine, phenylpropanolamine), vasopressors (epinephrine, norepinephrine), dopaminergic compounds (dopamine, dobutamine), meperidine, or buspirone.

Breastfeeding must be discontinued during treatment (see section "Use in pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Monoamine oxidase inhibitors

Linezolid is a reversible, nonselective 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 observation and patient monitoring 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 with 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 titration of vasoactive agents, including dopaminergic agents, is recommended when used concomitantly with linezolid to achieve the desired effect.

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 case of reactions resembling serotonin syndrome was reported in a patient receiving both linezolid and dextromethorphan; symptoms resolved after discontinuation of both drugs.

During clinical use of linezolid with serotonergic agents, including antidepressants (such as selective serotonin reuptake inhibitors [SSRIs]), cases of serotonin syndrome have been described. Thus, although the 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 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 (i.e., aged cheeses, yeast extracts, undistilled alcoholic beverages, and fermented soy products such as soy sauce) should be avoided.

Drugs 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, a pharmacokinetic interaction between linezolid and other drugs metabolized by CYP450 is not expected.

Rifampicin.

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) in combination with rifampicin (600 mg once daily for 8 days) and without. Rifampicin reduced C_max and AUC of linezolid by an average of 21% (90% CI 15, 27) and 32% (90% CI 27, 37), respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin.

When warfarin was added to linezolid treatment at steady state, a 10% decrease in mean maximum INR was observed with concomitant use, 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

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, streptomycin.

Antioxidants

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

Special precautions for use.

Myelosuppression

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. After discontinuation of linezolid, hematological parameters returned to pre-treatment levels. The risk of these effects is likely related to the duration of treatment. Elderly patients may have a higher risk of hematological abnormalities during linezolid therapy compared to younger patients. An increased incidence of thrombocytopenia may occur in patients with severe renal impairment (regardless of whether they are undergoing dialysis). 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 considered absolutely necessary. In such situations, careful monitoring of complete blood count parameters and appropriate therapeutic interventions are required.

Furthermore, it is recommended to perform weekly monitoring of complete blood count parameters (including hemoglobin levels, platelet count, total leukocyte count, and differential leukocyte count) in all patients receiving linezolid, regardless of baseline blood test results.

In compassionate use studies involving patients treated with linezolid for more than 28 days (the maximum recommended treatment duration), an increased incidence of severe anemia was observed. 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 also 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 recovered fully or partially 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

An increased mortality rate was observed in a trial involving patients with serious intravascular infections due to catheter use, in the group treated with linezolid compared to the vancomycin/dicloxacillin/oxacillin treatment groups (78 out of 363 (21.5%) vs. 58 out 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 the mortality rate was significantly higher (p=0.0162) in the linezolid treatment group among patients with any additional pathogen or no pathogen identified 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 the investigational drug. 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 established or suspected concomitant Gram-negative infection, linezolid should be used only if no other treatment options are available (see section "Indications"). In such circumstances, concomitant therapy for Gram-negative infection should be initiated.

Diarrhea and antibiotic-associated colitis

Diarrhea and colitis, 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. It is therefore important to consider this diagnosis in patients who develop diarrhea during or after linezolid therapy. 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 antiperistaltic agents is contraindicated.

Lactic acidosis

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

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 with treatment durations exceeding 28 days.

Potential interactions causing increased blood pressure

Linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, and/or concomitant use of drugs such as direct and indirect sympathomimetics (e.g., pseudoephedrine), vasoconstrictors (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine), unless careful monitoring for possible increases in blood pressure is possible.

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), have been received. Therefore, concomitant use of linezolid and serotonergic drugs is contraindicated (see "Contraindications"), except when the use of both linezolid and serotonergic agents is deemed 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 agents. Symptoms of withdrawal may occur after discontinuation of the serotonergic agent.

Peripheral neuropathy and optic neuropathy

Peripheral neuropathy, optic neuropathy, and optic neuritis, sometimes progressing to vision loss, have been reported in patients receiving linezolid therapy. 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 ophthalmological evaluation is recommended, if necessary. Patients receiving Linessa for longer than the recommended 28 days should have regular vision monitoring.

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

The risk of neuropathies may increase when linezolid is used in patients who are receiving or have recently received antibacterial therapy for tuberculosis.

Seizures

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 reversible, non-selective 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 regarding the use of linezolid in patients with underlying conditions and/or concomitant medications associated with risks due to MAO inhibition. Therefore, linezolid use under such circumstances is not recommended unless close monitoring and patient surveillance are possible (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 (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 while being treated with linezolid, a reversible non-selective 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 of the potential for hypoglycemic reactions during linezolid therapy.

If hypoglycemia occurs, 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 receiving linezolid in the post-marketing period. Signs and symptoms in these cases included confusion, somnolence, general weakness, and in severe cases, respiratory failure and even fatal outcomes. Regular monitoring of serum sodium levels is recommended in elderly patients, patients taking diuretics, and other patients at risk of hyponatremia and/or SIADH during drug use. If signs and symptoms of hyponatremia and/or SIADH appear, 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 non-susceptible 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 impairment and only when the expected benefit outweighs the theoretical risk (see section "Method of administration and dosage").

Linezolid should be used in patients with severe hepatic impairment only when the expected benefit outweighs the theoretical risk (see section "Method of administration and dosage").

No dose adjustment 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 for use beyond 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 linezolid for treating these conditions is limited.

Excipients

1 ml of solution contains 50 mg (i.e., 15 g/300 ml) of glucose. This should be considered when treating patients with diabetes mellitus or other conditions associated with glucose intolerance.

1 ml of solution also contains 0.48 mg (144 mg/300 ml) of sodium. Sodium content should be considered for patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Use during 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. Linessa should not be used during pregnancy except when the expected benefit outweighs the potential risk.

Use during breastfeeding.

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

Ability to influence reaction speed when driving or operating machinery.

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

Method of Administration and Dosage.

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

The therapy duration recommendations provided below were applied in clinical studies. A shorter treatment duration may be appropriate for certain types of infections, although this has not been evaluated in clinical trials.

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 initiated treatment with Linessa administered as intravenous 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%.

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 a dose 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.

Instructions for use.

Do not use if the seal is broken or if the contents of the vial are not clear. Any unused medicinal product remaining should be discarded.

Intravenous infusion should be administered over 30–120 minutes. Infusion bags must not be connected in series! Other medicinal products must not be added to this solution.

When administering Linessa for intravenous injection simultaneously with another agent, each product should be administered separately, according to the recommended dose and route of administration for each medicinal product.

When using the same intravenous line for sequential administration of multiple drugs, the line must be flushed before and after administration of the intravenous injection product with an infusion solution compatible with both Linessa and the other agent 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 sodium ceftriaxone.

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 undergoing 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 daily provides exposure approaching that achieved in adults receiving the drug at a dose of 600 mg twice daily.

In neonates under 1 week of age, 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 daily, higher systemic exposure to the drug is observed on the first day after birth. However, excessive accumulation of the drug is not expected with this dosing regimen during the first week of life (due to rapidly increasing clearance of the drug during the first 7 days of life) (see section “Dosage and administration”).

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 daily, 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 with measures to support glomerular filtration rate is indicated. Approximately 30% of the administered dose 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 primary metabolites of linezolid are also removed by hemodialysis.

Adverse Reactions

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

The most frequently reported adverse reactions were diarrhea (8.4%), headache (6.5%), nausea (6.3%), and vomiting (4.0%).

The most common 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 below, listed with frequency as "frequency not known," since the frequency cannot be estimated from the available data.

The adverse reactions reported during treatment are listed below, classified by frequency as follows: 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*, hypoaesthesia, 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, tongue disorders or color changes; 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, hyperhidrosis; 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. 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 without 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".

† Data from controlled clinical trials using linezolid for up to 28 days indicate that 2.0% of patients developed anemia. In a compassionate use program involving patients with life-threatening infections and comorbid conditions, the incidence of anemia was 2.5% (33 of 1326) among patients treated for ≤ 28 days compared to 12.3% (53 of 430) among those treated for > 28 days. The proportion of documented cases of severe anemia requiring blood transfusion was 9% (3 of 33) in patients treated for ≤ 28 days and 15% (8 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 in diabetic patients receiving insulin or oral hypoglycemic agents when treated with linezolid, a non-selective, reversible monoamine oxidase inhibitor (MAOI). Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or 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 failure and even fatal outcomes.

Reporting of Adverse Reactions

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing 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 drug efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf Life. 2 years.

Storage Conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Any unused medicinal product should be destroyed.

Packaging.

300 ml of the preparation in a polyethylene or polypropylene container. One container in a silver pouch, placed in a cardboard box.

Prescription Category. Prescription only.

Manufacturer.

EuroLife Healthcare Pvt. Ltd.

Manufacturer's Address and Place of Business.

Plot No. 520, Bhagwanpur, Roorkee, Haridwar, Uttarakhand, India.

Marketing Authorization Holder.

Ananta Medikare Ltd.

Address of the Marketing Authorization Holder.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.