Linelyd

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

Composition:

Active substance: linezolid;

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

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

* pH adjusters.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless or slightly yellowish liquid.

Pharmacotherapeutic group. Antibacterials for systemic use.

ATC code J01X X08.

Pharmacological properties.

Pharmacodynamics.

General properties

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 of 50S subunits) and interferes with 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 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 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, Chlamydophila 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 Linelid contains linezolid, which is the biologically active substance and is metabolized to inactive derivatives.

Absorption

Linezolid is extensively absorbed after oral administration. Maximum plasma concentration is 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 administered 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.

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

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 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, whereas 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, apparently due to lower renal and non-renal clearance of the drug 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 is 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. 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 benefits and potential risks of metabolite accumulation should be carefully considered when using linezolid in patients with renal impairment. 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 was 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 has not been evaluated.

Clinical characteristics.

Indications.

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

• Hospital-acquired pneumonia;
• Community-acquired pneumonia;
• Complicated skin and skin structure 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. Lineled has not been studied in the treatment of pressure ulcers;
• Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes;
• Vancomycin-resistant infections caused by strains of Enterococcus faecium, including infections associated with bacteremia.

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

Contraindications.

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

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

Except in cases where careful observation and blood pressure monitoring are possible, Lineled should not be prescribed to patients with the following concomitant clinical conditions or concurrently with the following medications:

• Uncontrolled hypertension, pheochromocytoma, carcinoid, 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). Very limited data on the use of linezolid in patients receiving concomitant therapy with agents posing certain risks due to MAO inhibition have been obtained from drug interaction and safety studies of linezolid. Therefore, the use of linezolid under such circumstances is not recommended unless careful observation and patient monitoring are possible (see sections "Contraindications" and "Special warnings and precautions for use").

Potential interactions leading to increased blood pressure

In healthy volunteers with normal blood pressure, linezolid enhanced the blood pressure increase caused by pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant administration of linezolid with pseudoephedrine or phenylpropanolamine hydrochloride resulted 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 agents with vasopressor effects, including dopaminergic agents, is recommended to achieve the desired outcome 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 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 of symptoms resembling serotonin syndrome was received in a patient taking both 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. Thus, although combination therapy with these agents 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 warnings and precautions for use".

Concomitant use with tyramine-rich foods

No significant pressor effect was observed in patients who received linezolid and tyramine in amounts less than 100 mg. This suggests that only excessive consumption of foods and beverages high in tyramine (i.e., aged cheeses, yeast extracts, non-distilled 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 significant effect of linezolid on the pharmacokinetics of other drugs metabolized by CYP450 is not expected.

Rifampicin

The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen healthy adult 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 of linezolid by an average of 2% (90% CI 15, 27) and 32% (90% CI 27, 37), respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin

A 10% decrease in mean peak INR and a 5% decrease in INR AUC were observed when warfarin was coadministered with linezolid at steady state. Data on patients receiving both warfarin and linezolid concurrently 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

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. In such cases, hematological 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 may have a higher risk of hematological abnormalities during linezolid treatment compared to younger patients. An increased incidence of thrombocytopenia may occur in patients with severe renal impairment (regardless of whether they are undergoing dialysis) and in patients with moderate to severe hepatic dysfunction. Therefore, careful monitoring of blood counts is 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 or moderate to severe hepatic dysfunction; 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 implementation of appropriate treatment strategies are required.

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

In compassionate use studies involving unapproved medicinal products, an increased incidence of severe anemia was observed in patients who received linezolid 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 recovered fully or partially with or without treatment for anemia.

Imbalance in mortality rates 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, increased mortality was observed in the group treated with 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 (relative risk 0.96; 95% confidence interval 0.58–1.59), but the rate of fatal outcomes was significantly higher (p=0.0162) in the linezolid treatment group among patients with any additional pathogen or no pathogen identified at baseline (relative risk 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 pathogens or polymicrobial infections. Therefore, in complicated skin and soft tissue infections in patients with confirmed 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 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 nearly all antibiotics, including linezolid, with severity ranging from mild diarrhea to fatal colitis. It is therefore important to consider this diagnosis in patients who develop diarrhea during or after linezolid treatment. 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 linezolid use. Patients who develop symptoms and signs of metabolic acidosis during linezolid treatment, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels, or hyperventilation, should seek immediate medical attention. If lactic acidosis develops, the benefit of continuing linezolid therapy versus potential risks should be carefully evaluated.

Mitochondrial dysfunction

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 with treatment durations exceeding 28 days.

Potential interactions causing increased blood pressure

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

Serotonin syndrome

Spontaneous reports of serotonin syndrome associated with concomitant use of linezolid and serotonergic agents, including antidepressants (SSRIs) and opioids, have been received. Therefore, concomitant use of linezolid and serotonergic agents is contraindicated (see "Contraindications"), except when the use of both linezolid and serotonergic agents is considered essential. In such cases, patients should be closely monitored for symptoms of serotonin syndrome, such as cognitive disturbances, hyperpyrexia, hyperreflexia, and motor incoordination. If such symptoms occur, the physician should consider discontinuing one or both agents. Withdrawal symptoms may occur after discontinuation of the serotonergic agent.

Peripheral neuropathy and optic neuropathy

Cases of peripheral neuropathy, optic neuropathy, and optic neuritis, sometimes progressing to vision loss, have been reported in patients receiving Linelid. 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 Linelid for more than the recommended 28 days should have regular vision assessments.

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

The risk of neuropathies may be increased when linezolid is used to treat patients who are receiving or have recently received antibacterial therapy for tuberculosis.

Seizures

Cases of seizures have been reported in patients receiving Linelid 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 on the use of linezolid for primary disease treatment and/or concomitant use of agents that may pose risks due to MAO inhibition were obtained in drug interaction and safety studies. Therefore, linezolid use under such circumstances is not recommended unless careful patient observation and 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

Post-marketing reports indicate cases of symptomatic hypoglycemia in diabetic patients receiving insulin or oral hypoglycemic agents while being treated with linezolid, a non-selective, reversible MAO inhibitor. Hypoglycemic episodes have been associated with the use of 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 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 insufficiency and even death. 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 treatment with Linelid. If signs and symptoms of hyponatremia and/or SIADH appear, the medicinal product 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 studies developed drug-related candidiasis. Appropriate measures should be taken if superinfections occur during treatment.

Special patient groups

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

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

No dose adjustment is necessary based on patient gender.

Fertility impairment

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

Clinical trials

The safety and efficacy of linezolid for use beyond 28 days have not been established.

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

Excipients

1 mL of solution contains 45.7 mg (i.e., 13.7 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 0.45 mg (135 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 Linelid in pregnant women are limited. Animal studies have demonstrated reproductive toxicity. There is a potential risk for humans. Linelid should not be used during pregnancy except when the expected benefit outweighs the potential risk.

Use during breastfeeding

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

Ability to affect reaction speed when driving or operating machinery.

Patients should be warned of the possible development 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.

Dosage and Administration

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

Therapy duration recommendations provided below were applied in clinical trials. For certain types of infections, a shorter treatment duration 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 linezolid infusions may be switched to oral linezolid therapy. In such cases, dose adjustment is not required, as the oral bioavailability of linezolid is nearly 100%.

Dosing recommendations according to indications are presented 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 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, 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.

‡ Administered using another pharmaceutical form allowing appropriate dosing.

Instructions for Use

Linezolid for intravenous infusion is supplied in single-use, ready-to-use infusion bags. Immediately before use, remove the foil protective overwrap and visually inspect the medicinal product for particulate matter; squeeze the bag for approximately 1 minute to ensure its integrity. If the bag leaks, do not use the solution, as sterility may be compromised. Any unused solution should be discarded according to applicable regulations.

Intravenous infusion should be administered over 30–120 minutes. Do not use infusion bags in series connection! Do not add other drugs to this solution.

When administering linezolid for intravenous infusion concurrently with other agents, each agent 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 agents, the line should be flushed before and after administration of linezolid for intravenous infusion with an infusion solution compatible with both linezolid and the other agent being administered through the line.

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

Major incompatibilities

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

Use in elderly patients

No dose adjustment is required.

Use in patients with renal impairment

No dose adjustment is required. Since approximately 30% of the dose is eliminated during a 3-hour hemodialysis session initiated 3 hours after drug administration, linezolid should be administered after hemodialysis in patients undergoing such treatment (see section “Pharmacological properties. Pharmacokinetics”).

Use in patients with hepatic impairment

No dose adjustment is required (see section “Pharmacological properties. Pharmacokinetics”).

Children

May 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 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, neonates receiving the drug at 10 mg/kg every 8 hours exhibit higher systemic exposure on the first day of life. 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 600 mg. Thus, adolescents receiving the drug at 600 mg every 12 hours will have exposure comparable to that in adult patients receiving the same dose.

Overdose.

There is no specific antidote.

No cases of overdose have been reported.

In case of overdose, symptomatic treatment should be administered along with measures to support glomerular filtration. Approximately 30% of the administered dose is removed during 3 hours of hemodialysis, but there are no data on the elimination of linezolid during peritoneal dialysis or hemoperfusion. The two major metabolites of linezolid are also removed by hemodialysis.

Adverse reactions.

The information provided is based on data obtained from clinical trials in which more than 2000 adult patients received the recommended doses of Linelid 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 drug discontinuation were headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to drug-related adverse reactions.

Adverse reactions reported after marketing authorization are listed below 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 (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known – frequency 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 perversion (metallic taste), dizziness.

Uncommon: seizures*, peripheral neuropathy*, hypoesthesia, paraesthesia.

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: 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 tests, increased levels of ALT, AST, or alkaline phosphatase.

Uncommon: increased total bilirubin.

Skin and subcutaneous tissue disorders

Common: pruritus, rash.

Uncommon: angioedema, urticaria, bullous skin lesions, dermatitis, excessive sweating.

Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, hypersensitivity vasculitis.

Frequency not known: 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 (non-fasting), increased or decreased chloride.

Hematology

Common: increased neutrophils or eosinophils, decreased hemoglobin, hematocrit, or erythrocyte count, increased or decreased platelet or leukocyte count.

Uncommon: increased reticulocyte count, decreased neutrophil count.

* See section "Special precautions".

** 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 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 of 1326), 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 rarely assessed as severe: 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). 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, led to respiratory failure and even death.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is an important procedure. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are required to report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Do not freeze.

Keep out of reach of children. Open the secondary vacuum packaging immediately before use.

Incompatibilities.

See section "Dosage and administration".

Packaging.

300 ml in a polymer container in a vacuum polymer pack; 1 polymer container in a vacuum polymer pack per cardboard box.

Prescription category. Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's location and address of business activity.

108 Kobzarska Street, Cherkasy, Cherkasy region, 18030, Ukraine. Tel. (044) 281-01-01.