Linebiotic

INSTRUCTION for medical use of the medicinal product Linebiotic (Linebiotic)

Composition:

Active substance: linezolid;

1 ml of solution contains 2 mg of linezolid;

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

Pharmaceutical form. Infusion solution.

Main physico-chemical properties: clear, light yellow to colorless, homogeneous solution.

Pharmacotherapeutic group. Antibacterial agents for systemic use. ATC code J01X X08.

Pharmacological properties.

Pharmacodynamics.

General characteristics.

Linezolid is a synthetic antibacterial medicinal product belonging to a new class of antimicrobial agents – 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 (an essential component of the translation process). The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, local data on microbial resistance should be taken into account, especially when treating severe infections. If necessary, when the local prevalence of microbial resistance 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.

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

Anaerobic Gram-positive 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 strains (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 to inactive derivatives.

Absorption.

Linezolid is extensively absorbed after oral administration. Maximum plasma concentration (Cmax) is reached approximately 1–2 hours after administration, and absolute bioavailability is approximately 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 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 of linezolid at steady state in healthy adult volunteers averages 40–50 L. Linezolid concentrations were 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 via oxidation of the morpholine ring, forming two inactive open-ring carboxylic acid derivatives: the aminoethoxyacetic acid metabolite (A) and the hydroxyethylglycine metabolite (B). Metabolite A is thought to be formed via an enzymatic pathway, whereas formation of metabolite B is mediated by a non-enzymatic mechanism involving chemical oxidation in vitro. In vitro studies have demonstrated that linezolid undergoes minimal metabolism, possibly involving the human cytochrome P450 system. However, the metabolic pathways of linezolid are not fully understood.

Elimination.

Non-renal clearance accounts for approximately 65% of total linezolid clearance. At steady state, approximately 30% of the dose is excreted in urine as linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min, indicating net tubular reabsorption. Linezolid is almost undetectable in feces, while approximately 6% of the dose is excreted 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. 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 increasing 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 similar plasma concentrations of linezolid were achieved 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 appropriateness of using linezolid in patients with renal impairment and the potential risks of metabolite accumulation should be carefully considered. Both linezolid and its two metabolites are removed by hemodialysis. Information on the effect of peritoneal dialysis on 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. Pharmacokinetics in patients with severe hepatic impairment have not been evaluated.

Clinical characteristics.

Indications.

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

• 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 (both 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 skin structure infections caused by Staphylococcus aureus (only methicillin-susceptible isolates) or Streptococcus pyogenes;
• Vancomycin-resistant infections caused by Enterococcus faecium strains, including infections associated with bacteremia.

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

Contraindications.

Known hypersensitivity to linezolid or to any other component of the medicinal product. Linobiotic should 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 after discontinuation of such medicinal products. Except in cases where close monitoring and blood pressure surveillance are possible, Linobiotic should not be prescribed to patients with the following concomitant clinical conditions or concurrently with the following medicinal products:

• 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 with the medicinal product (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other types of interactions.

Monoamine oxidase (MAO) inhibitors.

Linezolid is a reversible non-selective inhibitor of 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 that pose certain risks due to MAO inhibition. Therefore, the use of linezolid under such circumstances is not recommended unless close monitoring and surveillance of the patient's condition 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 medicinal products.

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, pathological flushing, excessive sweating, hyperpyrexia) were observed.

Post-marketing experience: one report of symptoms resembling serotonin syndrome was received in a patient receiving linezolid and dextromethorphan; these symptoms resolved after discontinuation of both drugs. During clinical use of linezolid and serotonergic agents, including antidepressants (such as selective serotonin reuptake inhibitors (SSRIs)), cases of serotonin syndrome have been reported. 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."

Concomitant use with tyramine-rich foods.

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

Medicinal products metabolized by cytochrome P450.

Linezolid is not subject to metabolic transformation 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, no effect 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 the Cmax and area under the concentration-time curve (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 a course of linezolid treatment at steady state, a 10% decrease in the mean maximum international normalized ratio (INR) was observed during concomitant use, with a 5% decrease in INR AUC. 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 administered concomitantly.

Gentamicin. The pharmacokinetics of linezolid or gentamicin are not altered when 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.

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has 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 developing blood abnormalities compared to younger patients. An increased incidence of thrombocytopenia has been observed in patients with severe renal impairment (regardless of whether they are undergoing dialysis) and in patients with moderate to severe hepatic impairment. Therefore, careful monitoring of blood counts is necessary in the following patient groups: patients with pre-existing anemia, granulocytopenia, or thrombocytopenia; patients receiving concomitant medications that may reduce hemoglobin levels, decrease blood cell counts, or negatively affect platelet number or function; patients with severe renal impairment or moderate to severe hepatic impairment; and patients receiving treatment for more than 10–14 days. Linezolid should be used for treatment of 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. Additionally, weekly monitoring of complete blood count (including hemoglobin, platelet count, total white blood cell count, and differential white blood cell count) is recommended in all patients receiving linezolid, regardless of baseline blood test results.

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 time, most patients had received linezolid for more than 28 days. After discontinuation of linezolid, most patients recovered fully or partially with treatment for anemia or even without treatment.

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

In an open-label study of patients with serious intravascular infections caused by catheter use, an increased number of deaths was observed in the group receiving linezolid compared to the vancomycin/dicloxacillin/oxacillin treatment groups (78 of 363 (21.5%) vs. 58 of 363 (16.0%)). The 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 (relative risk 0.96; 95% CI 0.58–1.59), but in the linezolid treatment group, the mortality rate was significantly higher (p=0.0162) in patients with any additional pathogen or no pathogen identified at baseline (relative risk 2.48; 95% CI: 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 established 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 fatal colitis. It is therefore important to consider this diagnosis in patients who develop diarrhea during or after treatment with linezolid. If antibiotic-associated diarrhea or colitis is suspected or confirmed, current antibacterial therapy (including linezolid) should be discontinued and appropriate therapeutic measures should be initiated immediately. In such cases, the use of drugs that inhibit peristalsis is contraindicated.

Lactic acidosis.

Lactic acidosis has been reported with the use of 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 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.

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 drugs such as direct and indirect-acting sympathomimetics (e.g., pseudoephedrine), vasoconstrictors (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine).

Serotonin syndrome.

Spontaneous reports of serotonin syndrome associated with concomitant use of linezolid and serotonergic agents, including antidepressants such as SSRIs and opioids, have been received. Therefore, concomitant use of linezolid and serotonergic drugs is contraindicated (see section "Contraindications"), except when the use of both linezolid and serotonergic agents is deemed essential. In such cases, the patient should be under close observation for symptoms of serotonin syndrome, such as cognitive disturbances, hyperpyrexia, hyperreflexia, and motor incoordination. If such symptoms occur, the physician should consider discontinuing one or both drugs. 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 treatment with Linebiotic. 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, changes in color perception, blurred vision, or visual field defects. In such cases, prompt ophthalmological evaluation is recommended, if necessary. Patients receiving the drug for more than the recommended 28 days should have regular vision testing. If peripheral neuropathy or optic neuropathy develops, the benefit of continuing linezolid therapy versus potential risks should be carefully evaluated. The risk of neuropathy may be increased when linezolid is used in patients receiving or who 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.

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

Concomitant use with tyramine-rich foods.

Patients should be advised to avoid consuming large amounts of tyramine-rich foods (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. Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. Although a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be warned about the potential for hypoglycemic reactions during treatment with linezolid.

If hypoglycemia occurs, a reduction in the dose 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, drowsiness, general weakness, and, in severe cases, respiratory failure 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 Linebiotic. If signs and symptoms of hyponatremia and/or SIADH appear, the drug should be discontinued and appropriate supportive measures should be 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, candidiasis associated with linezolid use was observed in approximately 3% of patients receiving linezolid at recommended doses during clinical trials. Appropriate measures should be taken if superinfection occurs 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 "Dosage and administration").

No dosage 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 treatment durations exceeding 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 45.7 mg (i.e., 13.7 g/300 ml) of glucose, which should be considered when treating patients with diabetes or other conditions associated with glucose intolerance;
• 1 ml of solution also contains 0.38 mg (114 mg/300 ml) of sodium; sodium content should be considered for patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of the medicinal product in pregnant women are limited. Animal studies have demonstrated reproductive toxicity. There is a potential risk for humans. Linebiotic 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 medicinal product.

Ability to affect reaction speed when driving or operating machinery.

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

Administration and Dosage

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

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

Maximum duration of treatment – 28 days.

The safety and efficacy of linezolid treatment 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 have initiated treatment 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

†Newborns < 7 days.

Most preterm neonates < 7 days of age (< 34 weeks gestation) have lower systemic clearance and higher AUC values of linezolid compared to most term neonates and children up to 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 linezolid, 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.

‡ Linezolid is administered in another pharmaceutical form allowing appropriate dosing.

Instructions for use.

Any unused solution remaining should be disposed of according to applicable requirements. Intravenous infusion should be administered over 30–120 minutes.

Other medicinal products should not be added to this solution. When administering linezolid for intravenous infusion concomitantly with other medicinal products, each product should be administered separately, in accordance with the recommended dose and route of administration for each medicinal product.

When using the same intravenous line for sequential administration of multiple agents, the line should be flushed before and after administration of linezolid 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 solution, 5% dextrose injection solution, lactated Ringer’s injection solution.

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 eliminated during a 3-hour hemodialysis session initiated 3 hours after drug administration, linezolid should be administered after hemodialysis in patients undergoing such treatment (see section “Pharmacological properties. Pharmacokinetics”).

Use in patients with hepatic impairment. Dose adjustment is not 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 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. Therefore, neonates receiving the drug at 10 mg/kg every 8 hours daily show higher systemic exposure to linezolid on the first day after birth. However, excessive accumulation of the drug in the body 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 linezolid at 600 mg every 12 hours daily will have the same exposure as adult patients receiving the drug at the same dose.

Overdose.

Symptoms. No cases of overdose have been reported.

Treatment. There is no specific antidote. In case of overdose, symptomatic treatment should be administered together with measures to support glomerular filtration rate. Approximately 30% of the administered dose of the drug is eliminated during 3 hours of hemodialysis; however, there are no data on the elimination of linezolid during peritoneal dialysis or hemoperfusion. The two main metabolites of linezolid are also eliminated by hemodialysis.

Adverse Reactions

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

The most frequently reported adverse reactions were diarrhea (8.4%), 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 linezolid-related adverse reactions. Adverse reactions reported after linezolid was marketed are included below, listed with frequency categorized as "frequency not known," since the frequency cannot be estimated from available data.

Adverse reactions reported during treatment are listed below, 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 (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 disturbances (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 perception*, color vision changes*.

Ear and labyrinth disorders:
Uncommon – tinnitus.

Cardiac disorders:
Common – arterial hypertension;
Uncommon – arrhythmia (tachycardia), 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 – tooth discoloration.

Hepatobiliary disorders:
Common – abnormal liver function tests, increased ALT, AST, or alkaline phosphatase levels;
Uncommon – increased total bilirubin.

Skin and subcutaneous tissue disorders:
Common – pruritus, rash;
Uncommon – urticaria, dermatitis, excessive sweating;
Rare – allergic vasculitis;
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, 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 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 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) in 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 reported rarely but considered severe, included localized abdominal pain, transient ischemic attack, and arterial hypertension.

During the postmarketing period, cases of symptomatic hypoglycemia have been reported in diabetic patients receiving insulin or oral hypoglycemic agents while being treated with linezolid, a reversible non-selective 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 postmarketing 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 important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibilities.

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

Packaging.

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

Prescription category. Prescription only.

Manufacturer.

VEM ILAC San. ve Tic. A.S.

Manufacturer's address and place of business.

Cerkezkoy Organize Sanayi Bolgesi, Karaagac Mahallesi, Fatih Bulvari No: 38, Kapakli/Tekirdag/Turkey.