LINEZOLIDIN

INSTRUCTIONS for medical use of the medicinal product LINEZOLIDIN (LINEZOLIDIN)

Composition:

Active substance: linezolid;

1 ml of solution contains 2 mg of linezolid;

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

Pharmaceutical form. Infusion solution.

Main physicochemical characteristics: clear, colorless or pale yellow liquid.

Pharmacotherapeutic group. Antibacterial agents for systemic use.

ATC code J01X X08.

Pharmacological properties.

Pharmacodynamics.

General characteristics.

Linezolid is a synthetic antibacterial agent belonging to a new class of antimicrobials – the oxazolidinones. It exhibits in vitro activity against aerobic gram-positive bacteria and anaerobic microorganisms. Linezolid selectively inhibits bacterial protein synthesis through a unique mechanism of action. It directly binds to bacterial ribosomes (23S portion of the 50S subunit) 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 regarding 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, Chlamydia pneumoniae, and Mycoplasma pneumoniae, there is insufficient data to confirm clinical efficacy in these cases.

Cross-resistance

The mechanism of action of linezolid differs from that of other classes of antibiotics. In vitro studies of clinical isolates (methicillin-resistant staphylococci, vancomycin-resistant enterococci, as well as penicillin- and erythromycin-resistant streptococci) show that linezolid is generally active against microorganisms resistant to one or more other classes of antimicrobial agents.

Resistance to linezolid is associated with point mutations in the 23S rRNA.

Pharmacokinetics.

The medicinal product Linezolidin contains linezolid, which is the biologically active substance and is metabolized into 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. Time to maximum concentration increases from 1.5 to 2.2 hours, and C_max decreases by approximately 17% when linezolid is administered with a high-fat meal. However, total exposure, assessed by AUC_0–∞, 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 were measured in various fluids involving a limited number of participants in Phase 1 studies after multiple doses of linezolid. The ratio of linezolid concentration in saliva to plasma concentration was 1.2:1, and the ratio of linezolid concentration in sweat to plasma concentration was 0.55:1.

Metabolism

Linezolid is primarily metabolized via oxidation of the morpholine ring, resulting in two inactive ring-opened carboxylic acid metabolites: the metabolite of aminoethoxyacetic acid (A) and the metabolite of hydroxyethylglycine (B). Formation of metabolite A is thought to occur via an enzymatic pathway, whereas formation of metabolite B is mediated by a non-enzymatic mechanism involving chemical oxidation under in vitro conditions. In vitro studies have demonstrated that linezolid undergoes minimal metabolism, with possible involvement of the human cytochrome P450 system. However, the metabolic pathways of linezolid 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 dose is recovered in urine as unchanged linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min, indicating net tubular reabsorption. Linezolid is virtually undetectable in feces, whereas approximately 6% of the dose is recovered in feces as metabolite B and 3% as metabolite A.

A slight nonlinearity in clearance was observed with increasing linezolid doses, apparently due to lower renal and non-renal clearance at higher concentrations. However, this difference in clearance was minor and did not affect the apparent elimination half-life.

Patients with renal impairment. The pharmacokinetics of linezolid are not altered in patients with any degree of renal impairment; however, the two main metabolites of linezolid accumulate in patients with renal impairment, with 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 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 appropriateness of linezolid use 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. The pharmacokinetics of linezolid in patients with severe hepatic impairment have not been evaluated.

Clinical characteristics.

Indications.

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

• nosocomial 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;

linezolid 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 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 any other component of the drug.

Linezolid should not be administered to patients receiving any drugs that inhibit monoamine oxidase A and B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide), or within two weeks after discontinuation of such drugs.

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

• uncontrolled arterial 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 compounds (dopamine, dobutamine), meperidine, or buspirone.

Breastfeeding should be discontinued during treatment (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). During drug interaction studies and safety trials of linezolid, very limited data have been obtained on the use of linezolid in patients receiving concomitant therapy with drugs that pose certain risks due to MAO inhibition. Therefore, the use of linezolid in such circumstances is not recommended unless careful monitoring and observation of the patient are possible (see sections "Contraindications" and "Special precautions").

Potential interactions leading to increased blood pressure.

In healthy volunteers with normal blood pressure, linezolid enhances the increase in blood pressure caused by pseudoephedrine and phenylpropanolamine hydrochloride. Combined 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 arterial hypertension have not been conducted. Careful dose selection of drugs with vasopressor effects, including dopaminergic agents, is recommended to achieve the desired outcome when linezolid is used concomitantly with these drugs.

Potential serotonergic interactions.

Potential drug interactions were studied in a trial involving healthy volunteers. Participants received dextromethorphan (two doses of 20 mg each, 4 hours apart) with or without linezolid. In healthy volunteers receiving 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 linezolid and dextromethorphan; symptoms resolved after discontinuation of both drugs.

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

Use in combination with tyramine-rich foods.

In patients receiving linezolid and tyramine in amounts less than 100 mg, no significant pressor effect was observed. This indicates that only excessive consumption of foods and beverages high in tyramine (such as 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, 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 adult volunteers who received linezolid (600 mg twice daily for 2.5 days) alone and in combination with rifampicin (600 mg once daily for 8 days). Rifampicin reduced Cmax and AUC of linezolid by an average of 21% (90% CI 15, 27) and 32% (90% CI 27, 37), respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin.

When warfarin was added to linezolid treatment at steady state, a 10% decrease in mean peak INR was observed, with a simultaneous 5% decrease in INR AUC during co-administration. Data on patients receiving 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 drugs are administered concomitantly.

Gentamicin. The pharmacokinetics of linezolid or gentamicin are not altered when these drugs 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 therapy compared to younger patients. Patients with severe renal insufficiency (regardless of whether they are undergoing dialysis) may have an increased incidence of thrombocytopenia. 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 insufficiency; 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 of treatment 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 white blood cell count, and differential leukocyte count) is recommended in all patients receiving linezolid, regardless of baseline blood parameters.

In compassionate use studies involving unapproved use of the drug, patients receiving linezolid for more than 28 days (the maximum recommended treatment duration) showed an increased incidence of severe anemia. 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 of anemia, 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.

Mortality imbalance in a clinical study involving patients with catheter-related bloodstream infections caused by Gram-positive pathogens.

In an open-label study of patients with serious catheter-related bloodstream infections, an increased mortality rate 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 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 in the linezolid treatment group, the mortality rate was significantly higher (p=0.0162) in patients with any additional pathogen or no pathogen 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 established or suspected concomitant Gram-negative infection, linezolid should be used only if no other treatment options are available (see section "Indications"). In such circumstances, concomitant 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 initiated immediately. In such cases, the use of drugs that inhibit peristalsis is contraindicated.

Lactic acidosis

Cases of lactic acidosis have 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. In case of lactic acidosis, the benefit of continuing linezolid therapy versus potential risks should be carefully considered.

Mitochondrial dysfunction

Linezolid inhibits mitochondrial protein synthesis. As a result of this inhibition, adverse reactions such as lactic acidosis, anemia, and neuropathy (peripheral and optic nerve) may occur. These events are more common with treatment durations exceeding 28 days.

Potential interactions leading to 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 drugs, including antidepressants (such as selective serotonin reuptake inhibitors (SSRIs)), have been received. Therefore, concomitant use of linezolid and serotonergic drugs is contraindicated (see "Contraindications"), except in cases where the use of both linezolid and concomitant serotonergic drugs is deemed essential. In such cases, the patient should be under close surveillance 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 drug.

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 linezolid therapy. Such 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 ophthalmologic evaluation is recommended, if necessary. If a patient is receiving linezolid for more than the recommended 28 days, regular vision testing is required.

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

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 linezolid therapy. In most cases, a risk factor such as a history of seizures was reported. Patients should inform their physicians if they have previously experienced seizures.

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO). However, at doses used for antibacterial therapy, it does not exhibit antidepressant effects. Very limited data on the use of linezolid for primary disease treatment 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 monitoring and patient surveillance 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 during treatment with linezolid, a reversible, non-selective MAO inhibitor. Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. Although a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be warned of the potential for hypoglycemic reactions during linezolid therapy.

If hypoglycemia occurs, a reduction in insulin or oral hypoglycemic agent dosage, or discontinuation of the oral hypoglycemic agent, insulin, or linezolid may be necessary.

Hypotension 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 linezolid. If signs and symptoms of hyponatremia and/or SIADH occur, the drug should be discontinued and appropriate supportive measures taken.

Superinfection

The effect of linezolid on normal flora has not been 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 during clinical trials developed drug-related candidiasis. 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 insufficiency (see section "Dosage and administration").

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

No dosage adjustment is necessary based on patient gender.

Impairment of fertility

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

Clinical trials

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

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

Excipients

1 ml of solution contains 50.24 mg (i.e., 15.072 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 1.64 mg (492 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. There are no adequate data on the use of linezolid in pregnant women. Animal studies have demonstrated reproductive toxicity. There is a potential risk for humans. Linezolid should not be used during pregnancy except when the expected benefit outweighs the potential risk.

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

Ability to affect reaction speed when driving or operating machinery.

Patients should be warned of the possible development of dizziness or visual disturbances (see sections "Special precautions for safety" and "Adverse reactions") during linezolid therapy 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 for duration of therapy provided below were applied in clinical studies. A shorter duration of treatment may be appropriate for certain types of infections; however, 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 may be switched to oral linezolid. In such cases, dosage adjustment is not required, as the bioavailability of linezolid after oral administration is nearly 100%.

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

†Newborns aged <7 days. Most preterm newborns aged <7 days (<34 weeks gestation) have lower systemic clearance of linezolid and higher AUC values compared to most term newborns and older children. Treatment of such newborns should be initiated with a dose of 10 mg/kg every 12 hours. For newborns showing inadequate clinical response to the drug, administration of a dose of 10 mg/kg every 8 hours may be considered. All patients aged up to 7 days should receive a dose of 10 mg/kg every 8 hours.

‡ Another pharmaceutical form with appropriate dosing should be used.

Instructions for use. Do not use packages with compromised integrity.

Intravenous infusion should be administered over 30–120 minutes.

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

When using a single intravenous line for sequential administration of multiple drugs, the line must be flushed before and after administration of Linezolidin for intravenous infusion with an infusion solution compatible with both Linezolidin and the other drug being administered through the same 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 injection was administered through a Y-site connector together with the following drugs: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, sodium phenytoin, and trimethoprim-sulfamethoxazole. In addition, linezolid for intravenous injection was chemically incompatible with ceftriaxone sodium.

Use in elderly patients. Dose adjustment is not required.

Use in patients with renal impairment (including creatinine clearance < 30 mL/min). 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.

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

In newborns aged less than 1 week, systemic clearance of linezolid (per kg body weight) increases rapidly during the first week of life. Therefore, in newborns receiving the drug at a dose of 10 mg/kg every 8 hours daily, higher systemic exposure to the drug is observed on the first day after birth. However, excessive accumulation of the drug is not expected with this dosing regimen during the first week of life (due to rapidly increasing clearance of the drug during the first 7 days of life) (see section «Dosage and administration»).

In children aged 12 to 17 years, the pharmacokinetics of linezolid are similar to those in adults receiving the drug at a dose of 600 mg. Thus, in children receiving the drug at a dose of 600 mg every 12 hours daily, exposure will be the same as 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 with measures to support glomerular filtration is indicated. Approximately 30% of the administered dose is eliminated during 3 hours of hemodialysis, but there are no data on the elimination of linezolid during peritoneal dialysis or hemoperfusion. Two primary metabolites of linezolid are also eliminated by hemodialysis.

Adverse Reactions

The frequency of adverse reactions is defined as follows: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (> 1/10,000, < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated from the available data).

Infections and infestations: common – candidiasis, oral candidiasis, vaginal candidiasis, fungal infections; uncommon – vaginitis; rare – antibiotic-associated colitis, including pseudomembranous colitis*.

Blood and lymphatic system disorders: common – anemia*†; uncommon – leukopenia*, neutropenia, thrombocytopenia*, eosinophilia; rare – pancytopenia*; frequency not known – myelosuppression*, sideroblastic anemia*.

Immune system disorders: frequency not known – anaphylaxis.

Metabolism and nutrition disorders: uncommon – hyponatremia; frequency not known – lactic acidosis*.

Psychiatric disorders: common – insomnia.

Nervous system disorders: common – headache, taste disturbances (metallic taste), dizziness; uncommon – seizures*, hypoesthesia, paraesthesia; frequency not known – serotonin syndrome**, peripheral neuropathy*.

Eye disorders: uncommon – blurred vision*; rare – visual field defect*; frequency not known – optic neuropathy*, optic neuritis*, vision loss*, change in visual sensation*, change in color perception*.

Ear and labyrinth disorders: uncommon – tinnitus.

Cardiac disorders: uncommon – arrhythmia (tachycardia).

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

Gastrointestinal disorders: common – diarrhea, nausea, vomiting, localized or generalized abdominal pain, constipation, dyspepsia; uncommon – pancreatitis, gastritis, abdominal distension, dry mouth, glossitis, frequent loose stools, stomatitis, disturbances or change in tongue color; rare – discoloration of tooth surfaces.

Hepatobiliary disorders: common – abnormalities in liver function tests, increased levels of ALT, AST or alkaline phosphatase; uncommon – increased total bilirubin.

Skin and subcutaneous tissue disorders: common – pruritus, rash; uncommon – urticaria, dermatitis, excessive sweating; frequency not known – bullous skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, alopecia.

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

Reproductive system and breast disorders: uncommon – vulvovaginal disorders.

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

Investigations. Biochemistry: common – increased lactate dehydrogenase, creatine kinase, lipase, amylase, or postprandial (non-fasting) glucose levels; decreased total protein, albumin, sodium, and calcium; increased or decreased potassium or bicarbonate; uncommon – increased sodium or calcium, decreased glucose without fasting, increased or decreased chloride. Hematology: common – increased 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 warnings and precautions for use".

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

† During controlled clinical trials in which linezolid was administered for up to 28 days, anemia was reported 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 out of 1,326), compared with 12.3% (53 out of 430) in those treated for > 28 days. The proportion of documented cases of severe anemia requiring blood transfusion attributed to the drug 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, which were assessed in rare cases as severe reactions: localized abdominal pain, transient ischemic attack, and arterial hypertension.

During the post-marketing period, cases of symptomatic hypoglycemia have been reported in diabetic patients receiving insulin or oral hypoglycemic agents while being 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 secretion of antidiuretic hormone (SIADH) have been observed. Signs and symptoms in these cases included confusion, drowsiness, general weakness, and in severe cases led to respiratory insufficiency and even death.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the local reporting system.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging until use. Do not store in the refrigerator and do not freeze. Keep out of reach of children.

Packaging.

300 ml in a bottle, one bottle per carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Halychpharm".

Manufacturer's address.

6/8 Opryshkivska St., Lviv, 79024, Ukraine.

Marketing Authorization Holder. JSC "Halychpharm".

Address of the Marketing Authorization Holder.

6/8 Opryshkivska St., Lviv, 79024, Ukraine.