INSTRUCTION

for medical use of the medicinal product

 

LINESSA

(LINESSA)

 

Composition:

active substance: linezolid;

1 ml of solution contains linezolid 2 mg;

excipients: anhydrous glucose; sodium citrate; citric acid, monohydrate; sodium hydroxide; hydrochloric acid; water for injection.

 

Pharmaceutical form. Solution for infusion.

Basic physical and chemical properties: clear, colourless to slightly yellowish solution.

 

Pharmacotherapeutic group. Antibacterials for systemic use.

ATC code J01X X08.

 

Pharmacological properties.

Pharmacodynamics.

Linezolid is a synthetic antibacterial drug belonging to a new class of antimicrobial agents – oxazolidinones. It exhibits activity in vitro against aerobic gram-positive bacteria and anaerobic microorganisms. Linezolid selectively inhibits bacterial protein synthesis through a unique mechanism of action. It binds directly to bacterial ribosomes (23S of the 50S subunit) and prevents the formation of a functional 70S initiation complex (an important component of the translation process).

The prevalence of acquired resistance may vary geographically and over time for specific species, so it is advisable to rely on local information regarding microbial resistance, especially in the treatment of severe infections. If necessary, when the level of prevalence of microbial resistance at the local level is such that the benefit of using the drug, at least for some types of infections, is doubtful, an 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 activity in vitro against Legionella, Chlamydia pneumoniae, and Mycoplasma pneumoniae, there are insufficient data to confirm clinical efficacy in these cases.

Cross-resistance

The mechanism of action of linezolid differs from that of other classes of antibiotics. Studies of clinical strains (methicillin-resistant staphylococci, vancomycin-resistant enterococci, as well as penicillin- and erythromycin-resistant streptococci) in vitro show that linezolid is usually 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 drug contains linezolid, which is the biologically active substance and is metabolized to inactive derivatives.

Absorption

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

Linezolid can be taken regardless of meals. Time to reach maximum concentration increases from 1.5 to 2.2 hours, and C_max decreases by approximately 17% when linezolid is taken with a high-fat meal. However, the total exposure, as assessed by AUC_0‑∞, is similar in both cases.

Distribution

Pharmacokinetic studies have shown that linezolid is rapidly distributed into well-perfused tissues. Approximately 31% of linezolid is bound to plasma proteins, and this is independent of the drug concentration. The volume of distribution of linezolid at steady state in healthy adult volunteers averages 40–50 L.

Linezolid concentrations have been determined in various fluids with the participation of a limited number of participants in Phase 1 studies after multiple linezolid administration. 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 predominantly metabolized by oxidation of the morpholine ring to form two inactive open-ring carboxylic acid derivatives: aminoethoxyacetic acid metabolite (A) and hydroxyethylglycine metabolite (B). Metabolite A is thought to be formed enzymatically, 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. However, the metabolic pathways for linezolid are not fully understood.

Excretion

Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. At steady state, approximately 30% of the drug 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 tubular reabsorption. Linezolid is virtually undetectable in faeces, while approximately 6% of the drug dose is found in faeces as metabolite B and 3% as metabolite A.

Minor nonlinearity in clearance was observed with increasing linezolid dose, which is apparently a consequence of lower renal and non-renal clearance of this drug at its higher concentrations. However, this difference in clearance was minor and did not affect the apparent elimination half-life.

Patients with renal insufficiency. The pharmacokinetics of linezolid do not change in patients with any degree of renal impairment; however, the two major metabolites of linezolid accumulate in patients with renal impairment, with greater accumulation 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) on haemodialysis. In the ESRD study, 14 patients received 600 mg linezolid every 12 hours for 14.5 days. Regardless of renal function, similar linezolid plasma concentrations were achieved, therefore dose adjustment is not recommended for patients with renal impairment. However, considering the lack of information on the clinical significance of the accumulation of the major metabolites, the use of linezolid in patients with renal impairment and the potential risks of accumulation of such metabolites should be weighed. Both linezolid and the two metabolites are removed by haemodialysis. Information on the effect of peritoneal dialysis on the pharmacokinetics of linezolid is not available.

Patients with hepatic insufficiency. The pharmacokinetics of linezolid did not change 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. Pharmacokinetics in patients with severe hepatic impairment has not been evaluated.

 

Clinical characteristics.

Indications.

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

• - nosocomial pneumonia;
• - community-acquired pneumonia;
• - complicated infections of the skin and its structures, including diabetic foot infections 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 decubitus ulcers.
• - uncomplicated infections of the skin and its structures, caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes;
• - vancomycin-resistant infections caused by Enterococcus faecium strains, including infections accompanied by bacteraemia.

Linezolid is not indicated for the treatment of infections caused by gram-negative microorganisms. If a gram-negative pathogen is suspected or identified, specific gram-negative therapy should be initiated immediately.

 

Contraindications.

Known hypersensitivity to linezolid or to any other component of the drug.

Linessa should not be used in patients taking any medicinal products that inhibit monoamine oxidase A and B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide), or within two weeks after taking such drugs.

Except in cases where careful supervision and blood pressure monitoring is possible, Linessa should not be prescribed to patients with the following concomitant clinical conditions or concomitant use of the medications listed below:

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

Breastfeeding should be discontinued during drug use (see section "Pregnancy and lactation").

 

Interaction with other medicinal products and other forms of interaction.

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective monoamine oxidase (MAO) inhibitor. In drug interaction studies and linezolid safety studies, very limited data were obtained on the use of linezolid for the treatment of patients receiving concomitant therapy with drugs that pose certain risks due to MAO inhibition. Therefore, the use of linezolid under such circumstances is not recommended unless careful patient observation and monitoring is possible (see sections "Contraindications" and "Precautions for use").

Potential interactions leading to increased blood pressure

In healthy volunteers with normal blood pressure, linezolid increased the blood pressure elevation caused by pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant use of linezolid and 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 under the influence of linezolid alone, 14–18 mm Hg under the influence of pseudoephedrine or phenylpropanolamine alone, and 8–11 mm Hg with placebo. Similar studies involving patients with arterial hypertension have not been conducted. It is recommended to carefully titrate the doses of drugs that exhibit vasopressor effects, including dopaminergic drugs, to achieve the desired effect when linezolid is used in combination with these drugs.

Potential serotonergic interactions

Potential interactions between linezolid and dextromethorphan were studied in a study involving healthy volunteers. Participants received dextromethorphan (two doses of 20 mg at 4-hour intervals) in combination with or without linezolid. In healthy volunteers receiving linezolid and dextromethorphan, manifestations of serotonin syndrome (confusion, delirium, anxiety, tremor, pathological flushing, increased sweating, hyperpyrexia) were not observed.

Post-marketing experience: one report was received of reactions similar to serotonin syndrome in a patient taking linezolid and dextromethorphan; these manifestations resolved after discontinuation of both drugs.

During the clinical use of linezolid and serotonergic drugs, including antidepressants (such as selective serotonin reuptake inhibitors (SSRIs)), cases of serotonin syndrome have been described. Thus, although concomitant use of these drugs is contraindicated (see section "Contraindications"), the treatment of patients for whom treatment with both linezolid and serotonergic drugs is critical is described in the "Precautions for use" section.

Use in combination with tyramine-rich foods

In patients receiving linezolid and tyramine in amounts less than 100 mg, no significant vasopressor effect was observed. This indicates the need to avoid only excessive consumption of foods and drinks with high tyramine content (namely, aged cheeses, yeast extracts, undistilled alcoholic beverages, and fermented soybean products such as soy sauce).

Drugs metabolized by cytochrome P450

Linezolid does not undergo metabolic transformations under the influence of the cytochrome P450 enzyme system and does not inhibit the function of any clinically significant human cytochrome P450 isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Similarly, linezolid does not cause induction of cytochrome P450 isoenzymes in rats. Therefore, an 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 16 healthy adult male 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 linezolid C_max and AUC values by an average of 21% (90% CI 15, 27) and by an average of 32% (90% CI 27, 37), respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin.

When warfarin was added to a steady-state linezolid treatment regimen, a 10% decrease in mean maximum INR was observed upon concomitant use, while INR AUC decreased by 5%. Data on patients who received warfarin and linezolid concomitantly are insufficient to assess the clinical significance, if any, of these results.

Antibiotics

Aztreonam.

The pharmacokinetics of linezolid or aztreonam are not altered when these drugs are used concomitantly.

Gentamicin.

The pharmacokinetics of linezolid or gentamicin are not altered when these drugs are used concomitantly.

In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampin, imipenem-cilastatin, aztreonam, ampicillin, streptomycin.

Antioxidants

When the drug is used concomitantly with vitamin C or vitamin E, dose adjustment of linezolid is not recommended.

 

Precautions for use.

Rhabdomyolysis

Cases of rhabdomyolysis have been reported with the use of linezolid (see section "Adverse Reactions"). If signs or symptoms of rhabdomyolysis occur, such as muscle pain, tenderness, or weakness, dark urine, or elevated creatine phosphokinase levels, linezolid should be discontinued and appropriate therapy should be initiated.

Myelosuppression

Myelosuppression (including anaemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients during linezolid use. After discontinuation of linezolid, the altered blood parameters returned to values observed prior to treatment. It is likely that the risk of developing these effects is related to the duration of treatment. In elderly patients, the use of linezolid may be associated with a higher risk of haematological abnormalities compared to younger patients. In patients with severe renal insufficiency (regardless of whether they undergo dialysis), an increased frequency of thrombocytopenia development may be possible. Thus, careful monitoring of the blood count is necessary in such patients: patients with pre-existing anaemia, granulocytopenia, or thrombocytopenia; patients receiving concomitant drugs that can lower haemoglobin levels, reduce blood cell counts, or adversely affect platelet count or functional activity; patients with severe renal impairment; patients whose course of treatment lasts more than 10–14 days. It is advisable to use linezolid for the treatment of such patients only in conjunction with careful monitoring of haemoglobin levels, complete blood count, and, if possible, platelet count.

If significant myelosuppression develops during linezolid treatment, treatment should be discontinued. An exception is cases where continuation of treatment is deemed absolutely necessary. In such situations, careful monitoring of complete blood count parameters should be carried out and appropriate treatment strategies should be implemented.

Furthermore, it is recommended to monitor complete blood count parameters (including determination of haemoglobin levels, platelet count, total leukocyte count, and detailed leukocyte formula) weekly in patients undergoing linezolid treatment, regardless of the initial blood test results.

In studies using an unregistered drug under a compassionate use program, in a group of patients who received linezolid for more than 28 days (the maximum recommended treatment duration), an increased incidence of serious anaemia was observed. Such patients more often required blood transfusions. Cases of anaemia requiring blood transfusion have also been reported in the post-marketing period. Such anaemia occurred more frequently in patients who received linezolid for more than 28 days.

Cases of sideroblastic anaemia have also been reported in the post-marketing period. Among cases where the time of anaemia onset was known, the majority of patients received linezolid for more than 28 days. After discontinuation of linezolid, most patients recovered completely or partially as a result of anaemia treatment or even without treatment.

Mortality imbalance in a clinical trial involving patients with catheter-related bloodstream infections caused by gram-positive pathogens

It is known that during an open-label study involving patients with serious intravascular infections caused by catheter use, an increase in mortality was observed in the group of patients who received linezolid compared to the treatment groups with vancomycin / dicloxacillin / oxacillin (78 of 363 (21.5%) vs. 58 of 363 (16.0%)). The main factor influencing the mortality rate was the presence of a gram-positive infection at baseline.

Mortality rates in patients with infections caused exclusively by gram-positive organisms were similar (odds ratio 0.96; 95% confidence interval 0.58–1.59), but in the linezolid treatment group, the mortality rate was significantly higher (p=0.0162) in patients with any additional pathogen or no pathogens at baseline (odds ratio 2.48; 95% confidence interval: 1.38–4.46). The greatest imbalance was observed during treatment and within 7 days of discontinuation of the study drug. Most patients in the linezolid treatment group acquired gram-negative infections during the study and died from infections caused by gram-negative pathogens and from 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 there are no other treatment options (see section "Indications"). Under such circumstances, parallel treatment of the gram-negative infection must be initiated.

Antibiotic-associated diarrhea and colitis

With the use of almost all antibiotics, including linezolid, antibiotic-associated diarrhea and colitis, including pseudomembranous colitis, and Clostridium difficile-associated diarrhea (CDAD) have been reported, the severity of which can range from mild diarrhea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after linezolid use. 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 situations, 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 manifestations of metabolic acidosis during linezolid use, 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 treatment and the potential risks should be weighed.

Mitochondrial dysfunction

Linezolid inhibits mitochondrial protein synthesis. As a result of this inhibition, adverse reactions such as lactic acidosis, anaemia, and neuropathy (peripheral and optic) may develop. These phenomena are more common when the drug is used for more than 28 days.

Potential interactions causing increased blood pressure

Except in cases where patient observation for possible blood pressure elevation is possible, linezolid should not be prescribed to patients with uncontrolled arterial hypertension, pheochromocytoma, thyrotoxicosis and/or concomitant use of such types of drugs as: direct and indirect sympathomimetics (e.g., pseudoephedrine), vasopressors (e.g., epinephrine, norepinephrine), dopaminergic agents (e.g., dopamine, dobutamine).

Serotonin syndrome

Spontaneous reports of serotonin syndrome associated with concomitant use of linezolid and serotonergic drugs, including antidepressants (such as selective serotonin reuptake inhibitors (SSRIs)), have been received. Thus, concomitant use of linezolid and serotonergic drugs is contraindicated (see "Contraindications"), except in cases where the use of both linezolid and concomitant use of serotonergic drugs is critical. In such cases, the patient should be under close supervision to detect symptoms of serotonin syndrome, such as cognitive impairment, hyperpyrexia, hyperreflexia, and impaired coordination of movements. If such symptoms occur, the physician should consider the possibility of discontinuing one or the other drug. Withdrawal symptoms may occur after discontinuation of the serotonergic drug.

Peripheral neuropathy and optic neuropathy

Development of peripheral neuropathy, as well as optic neuropathy and optic neuritis, which sometimes progressed to vision loss, has been reported in patients receiving linezolid treatment. Such reports primarily concerned patients who received treatment for more than 28 days (the maximum recommended treatment duration).

All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity, changes in colour perception, blurred vision, or loss of part of the visual field. In such cases, an urgent examination with referral to an ophthalmologist is recommended, if necessary. If a patient takes Linessa longer than the recommended 28 days, vision should be checked regularly.

If peripheral neuropathy or optic neuropathy develops, the benefit of continuing linezolid treatment and the potential risks should be weighed.

Possible increased risk of neuropathies when using linezolid to treat patients who are receiving or have recently received antibacterial therapy for tuberculosis.

Seizures

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

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective monoamine oxidase (MAO) inhibitor. However, at doses used for antibacterial therapy, it does not exhibit an antidepressant effect. In the course of drug interaction studies and linezolid safety studies, very limited data were obtained on the use of linezolid for the treatment of patients with underlying diseases and/or concomitant treatment with drugs that pose certain risks due to MAO inhibition. Therefore, the use of linezolid under such circumstances is not recommended unless careful supervision and patient monitoring is possible (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Use in combination with tyramine-rich foods

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

Hypoglycaemia

Reports received in the post-marketing period indicate cases of symptomatic hypoglycaemia when linezolid, a reversible non-selective MAO inhibitor, was used in diabetic patients taking insulin or oral hypoglycaemic drugs. The use of some MAO inhibitors is associated with hypoglycaemic episodes in diabetic patients receiving insulin or hypoglycaemic agents. Although a causal relationship between linezolid and hypoglycaemia has not been established, diabetic patients should be warned about a potential hypoglycaemic reaction during linezolid use.

If hypoglycaemia occurs, a reduction in the dose of insulin or oral hypoglycaemic agent, or discontinuation of the oral hypoglycaemic agent, insulin, or linezolid may be required.

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

Cases of hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion have been observed in patients receiving linezolid in the post-marketing period. In the reported cases, signs and symptoms included confusion, drowsiness, general weakness, and in severe cases led to respiratory failure and even death. Regular monitoring of serum sodium levels is recommended in the elderly, in patients taking diuretics, and in other patients at risk of hyponatremia and/or SIADH during drug use. If signs and symptoms of hyponatremia and/or SIADH appear, drug intake 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 non-susceptible organisms. For example, in approximately 3% of patients receiving linezolid at recommended doses, drug-associated candidiasis was observed during clinical studies. If superinfections occur during treatment, appropriate measures should be taken.

Special patient groups

Linezolid should be used with caution for the treatment of patients with severe renal impairment and only in situations where the expected benefit outweighs the theoretical risk (see section "Method of administration and dosage").

It is recommended to use linezolid for the treatment of patients with severe hepatic impairment only in situations where the expected benefit outweighs the theoretical risk (see section "Method of administration and dosage").

There is no need to adjust the drug dose depending on the patient's gender.

Fertility impairment

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

Clinical trials

The safety and efficacy of linezolid when used for more than 28 days have not been established.

Controlled clinical trials did not include patients with decubitus ulcers or ischemic lesions, severe burns, or gangrene. Accordingly, experience with linezolid for the treatment of such conditions is limited.

Excipients

1 ml of solution contains 50 mg (i.e., 15 g/300 ml) of glucose. This should be taken into account 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 taken into account in patients on a low-sodium diet.

 

Pregnancy and lactation.

Pregnancy.

Data on the use of linezolid in pregnant women are limited. Results of animal studies have demonstrated the presence of reproductive toxicity. There is a potential risk to humans. Linessa should not be used during pregnancy, except in cases where the expected benefit outweighs the potential risk.

Breastfeeding.

Results of animal studies have shown that linezolid and its metabolites may pass into breast milk. Therefore, breastfeeding should be discontinued during drug use.

 

Effects on ability to drive vehicles or other mechanisms.

Patients should be warned about the possibility of developing dizziness or symptoms of visual impairment (see sections "Precautions for use" and "Adverse reactions") while taking linezolid and advised not to drive a car or operate machinery if these symptoms occur.

 

Method of administration and dosage.

The duration of treatment depends on the pathogen, location and severity of the infection, as well as on the clinical effect.

The recommendations regarding the duration of therapy given below were applied in clinical studies. For some types of infections, a shorter duration of treatment may be appropriate, but this has not been evaluated in clinical studies.

The maximum duration of treatment is 28 days. The safety and efficacy of linezolid use beyond 28 days have not been studied.

Increase in recommended doses or duration of treatment is not required in cases of infections accompanied by bacteraemia.

Patients whose treatment was started with Linessa as intravenous infusions can be switched to linezolid in oral form. In this case, dose selection is not required, since the bioavailability of linezolid when taken orally is almost 100%.

 

Dosing recommendations according to indications are given in the table below.

 

Indications*	Dose and method of administration		Recommended treatment duration (consecutive days)
	Paediatric patients† (from birth to 11 years)	Adults and children‡ (aged 12 years and over)
Nosocomial pneumonia Community-acquired pneumonia (including forms accompanied by bacteraemia) Complicated infections of the skin and its structures	10 mg/kg intravenously or orally‡ every 8 hours	600 mg intravenously or orally‡ every 12 hours	10–14
Infections caused by Enterococcus faecium, resistant to vancomycin, including infections accompanied by bacteraemia	10 mg/kg intravenously or orally‡ every 8 hours	600 mg intravenously or orally‡ every 12 hours	14–28
Uncomplicated infections of the skin and its structures	Children aged less than 5 years: 10 mg/kg orally‡ every 8 hours. Children aged 5–11 years: 10 mg/kg orally‡ every 12 hours.	Adults: 400 mg orally‡ every 12 hours. Children aged 12 years and over: 600 mg orally‡ every 12 hours.	10–14

* Depending on the pathogens (see section "Indications").

 

^† Neonates <7 days. Most preterm neonates aged <7 days (<34 weeks gestation) have lower systemic clearance of linezolid and higher AUC values than most term neonates and infants up to 1 year. Treatment of such neonates should be started with a dose of 10 mg/kg every 12 hours. For neonates with insufficient clinical response to the drug, the possibility of using a dose of 10 mg/kg every 8 hours may be considered. All patients aged under 7 days should receive a dose of 10 mg/kg every 8 hours.

^‡ Use the drug in another pharmaceutical form with the possibility of appropriate dosing.

Instructions for use.

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

Intravenous infusion is performed over 30–120 minutes. Do not connect infusion bags in series! Other drugs should not be added to this solution.

When administering Linessa for intravenous injections concomitantly with another agent, each drug should be administered separately, according to the recommended dose and method of administration of each medicinal product.

When using one intravenous system for sequential administration of several drugs, this system should be flushed before and after administration of the drug for intravenous injections with an infusion solution compatible with Linessa and with the other drug administered through this system.

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

Main incompatibilities

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

Use in elderly patients. No dose adjustment is required.

Use in patients with renal insufficiency. No dose adjustment is required. Since approximately 30% of the dose is excreted during a three-hour haemodialysis session started 3 hours after drug administration, linezolid should be prescribed to patients who received such treatment after haemodialysis (see section "Pharmacological properties. Pharmacokinetics").

Use in patients with hepatic insufficiency. No dose adjustment is required (see section "Pharmacological properties. Pharmacokinetics").

 

Children.

Use from the first days of life.

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

In neonates under 1 week of age, the systemic clearance of linezolid (per 1 kg of 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 in the body is not expected with such dosing during the first week of the infant's life (due to the rapidly increasing clearance of the drug during the first 7 days of life) (see section "Method of administration and dosage").

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

 

Overdose.

There is no specific antidote.

No cases of overdose have been registered.

In case of overdose, symptomatic treatment with measures to support glomerular filtration rate is indicated. Approximately 30% of the administered drug dose is excreted during 3 hours of haemodialysis, but there are no data on the excretion of linezolid during peritoneal dialysis or haemoperfusion procedures. The two primary metabolites of linezolid are also excreted by haemodialysis.

 

Adverse reactions.

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

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

The most common adverse reactions leading to drug discontinuation were headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to drug-induced adverse reactions.

Adverse reactions reported after the drug was marketed are included in the list below with the frequency of occurrence indicated as "frequency unknown" because the frequency cannot be established from the available data.

Adverse reactions reported during treatment are listed below according to the following frequency classification: very common (≥ 1/10); common (from ≥ 1/100 to < 1/10); uncommon (from ≥ 1/1000 to < 1/100); rare (from ≥ 1/10000 to < 1/1000); very rare (<1/10000); frequency unknown – cannot be established 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 – anaemia*^†; uncommon – leukopenia*, neutropenia, thrombocytopenia*, eosinophilia; rare – pancytopenia*; frequency unknown – myelosuppression*, sideroblastic anaemia*.

Immune system disorders: frequency unknown – anaphylaxis.

Metabolism and nutrition disorders: uncommon – hyponatremia; frequency unknown – lactic acidosis*.

Psychiatric disorders: common – insomnia.

Neurological disorders: common – headache, taste perversion (metallic taste), dizziness; uncommon – seizures*, hypoesthesia, paraesthesia; frequency unknown – serotonin syndrome**, peripheral neuropathy*.

Eye disorders: uncommon – blurred vision*; rare – visual field defect*; frequency unknown – optic neuropathy*, optic neuritis*, loss of vision*, altered visual sensation*, altered colour perception*.

Ear and labyrinth disorders: uncommon – tinnitus.

Cardiac disorders: uncommon – arrhythmia (tachycardia).

Vascular disorders: common – arterial hypertension; uncommon – transient ischemic attack, phlebitis, thrombophlebitis.

Skin and subcutaneous tissue disorders: common – pruritus, rash; uncommon – angioedema, urticaria, bullous dermatitis, dermatitis, hyperhidrosis; rare – toxic epidermal necrolysis#, Stevens–Johnson syndrome#, hypersensitivity vasculitis; frequency unknown – alopecia.

Musculoskeletal and connective tissue disorders: rare – rhabdomyolysis*.

Renal and urinary disorders: common – increased blood urea nitrogen; uncommon – renal failure, increased creatinine, polyuria.

Reproductive system and breast disorders: uncommon – vulvovaginal disorders.

General disorders and administration site conditions: common – pyrexia, localized pain; uncommon – chills, fatigue, injection site pain, thirst.

Investigations. Biochemistry: common – increased lactate dehydrogenase, creatine kinase, lipase, amylase or postprandial (non-fasting) glucose, decreased total protein, albumin, sodium and calcium, increased or decreased potassium or bicarbonate; uncommon – increased sodium or calcium, decreased non-fasting glucose, increased or decreased chlorides.

Haematology: common – increased neutrophil or eosinophil count, decreased haemoglobin, haematocrit or erythrocyte count, increased or decreased platelet or leukocyte count; uncommon – increased reticulocyte count, decreased neutrophil count.

*See section "Precautions for use".

**See sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction".

# The frequency of adverse reactions is estimated based on the rule of 3.

^† There are data that during controlled clinical studies in which linezolid was used for up to 28 days, anaemia was noted in 2.0% of patients. In the compassionate use program involving patients with life-threatening infections and comorbidities, the percentage of patients who developed anaemia after taking linezolid for ≤ 28 days was 2.5% (33 out of 1326) compared to 12.3% (53 out of 430) who were treated for > 28 days. The ratio of recorded cases of severe drug-induced anaemia requiring blood transfusion was 9% (3 out of 33) in patients treated for ≤ 28 days and 15% (8 out of 53) in those treated for > 28 days.

Adverse reactions, associated with linezolid use that were assessed as severe in rare cases: localized abdominal pain, transient ischemic attack, and arterial hypertension.

In the post-marketing period, cases of symptomatic hypoglycaemia have been reported when linezolid, a reversible non-selective MAO inhibitor, was used in diabetic patients taking insulin or oral hypoglycaemic drugs. The use of some MAO inhibitors is associated with hypoglycaemic episodes in diabetic patients receiving insulin or hypoglycaemic agents.

Cases of hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion have been observed in patients receiving linezolid in the post-marketing period. In the reported cases, signs and symptoms included confusion, drowsiness, general weakness, and in severe cases led to respiratory failure and even death.

During post-registration use of linezolid, the following adverse reactions have been identified:

• - rhabdomyolysis;
• - myelosuppression (including anaemia, leukopenia, pancytopenia, and thrombocytopenia). Thrombocytopenia was more commonly observed in patients with severe renal impairment and in patients with moderate to severe hepatic impairment (see section "Special precautions for use");
• - sideroblastic anaemia.

Since these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following clinically significant adverse reactions are described in section "Precautions for use": myelosuppression, peripheral neuropathy and optic neuropathy, serotonin syndrome, Clostridium difficile-associated diarrhoea, lactic acidosis, seizures, rhabdomyolysis, hypoglycaemia, hyponatraemia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH).

 

Adverse Reaction Reporting

Reporting adverse reactions after the registration of a medicinal product is of great importance. It enables the monitoring of the benefit/risk ratio associated with the use of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and cases of lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: 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 remaining must be destroyed.

 

Packaging.

300 ml of the drug in a polyethylene or polypropylene container. 1 container in a silver bag in a cardboard box.

 

Terms of dispensing. On prescription.

 

 

Date of last update.

29.06.2026