Linezolid

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINEZOLID

Composition:

Active substance: linezolid;

1 tablet contains 600 mg of linezolid;

Excipients: hydroxypropylcellulose, corn starch, microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate, hypromellose, polyethylene glycol 400 (macrogol 400), titanium dioxide (E 171), carnauba wax.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: film-coated, elongated tablets of white or almost white color, with convex edges, having a score line on one side.

Pharmacotherapeutic group

Antibacterials for systemic use. ATC code J01X X08.

Pharmacological Properties

Pharmacodynamics

General characteristics

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

The post-antibiotic effect (PAE) of linezolid against Staphylococcus aureus in vitro is approximately 2 hours. In animal models, the in vivo PAE was 3.6 and 3.9 hours for Staphylococcus aureus and Streptococcus pneumoniae, respectively. In animal studies, the key pharmacodynamic parameter of efficacy was the duration of time during which plasma concentrations of linezolid exceeded the minimum inhibitory concentration (MIC) for the infecting organism.

Breakpoints

The minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for staphylococci and enterococci are: susceptible ≤ 4 mg/L and resistant > 4 mg/L. For streptococci (including S. pneumoniae), the breakpoints are susceptibility ≤ 2 mg/L and resistance > 4 mg/L.

Non-species-specific MIC breakpoints are defined as susceptible at ≤ 2 mg/L and resistant at > 4 mg/L. Non-species-specific breakpoints were primarily determined based on PK/PD data and do not depend on the MIC distribution for specific species. They are intended only for organisms for which species-specific breakpoints have not been established, and not for species for which susceptibility testing is not recommended.

Susceptibility

The prevalence of acquired resistance may vary over time and by geographical region, as well as among individual species; therefore, local information on resistance patterns is desirable, especially when treating severe infections. Expert advice should be sought if local resistance prevalence renders the utility of the medicinal product at least questionable for certain types of infections.

Category

Susceptible Organisms 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.

Resistance

Cross-resistance

The mechanism of action of linezolid differs from that of other classes of antibiotics. In vitro studies with clinical isolates (including methicillin-resistant staphylococci, vancomycin-resistant enterococci, and 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.

As documented with other antibiotics, during treatment with linezolid in patients with difficult-to-treat infections and/or prolonged therapy, sudden reduction in susceptibility has been observed. Resistance to linezolid has been reported in enterococci, Staphylococcus aureus, and coagulase-negative staphylococci. This is usually associated with prolonged courses of therapy and the presence of prosthetic materials or undrained abscesses. When antibiotic-resistant microorganisms are identified in a hospital setting, it is important to emphasize infection control policies.

Clinical trial information

Pediatric studies

In an open-label study, the efficacy of linezolid (10 mg/kg every 8 hours) was compared with vancomycin (10–15 mg/kg every 6–24 hours) in treating infections caused by suspected or confirmed resistant Gram-positive pathogens (including nosocomial pneumonia, complicated skin and soft tissue infections, catheter-related bacteremia, bacteremia of unknown origin, and other infections) in children aged from birth to 11 years. The clinical cure rate in the clinically evaluable population was 89.3% (134/150) and 84.5% (60/71) for linezolid and vancomycin, respectively (95% CI: -4.9, 14.6).

Preclinical safety data

Linezolid reduced fertility and reproductive function in male rats at exposure levels approximately equal to those in humans. In sexually mature animals, these effects were reversible. However, these effects were not reversible in young animals that received linezolid throughout nearly the entire period of sexual maturation. Abnormal sperm morphology was observed in the testes of adult male rats, along with hypertrophy and hyperplasia of epithelial cells in the epididymides.

Linezolid likely affected sperm maturation in rats. Additional testosterone administration did not influence the fertility effects mediated by linezolid.

Epididymal hypertrophy was not observed in dogs treated for 1 month, although changes in the vas deferens, prostate gland, testes, and epididymis were evident.

In reproductive toxicity studies in mice and rats, no signs of teratogenic effects were observed at exposure levels 4 times higher than or equivalent to those in humans, respectively. The same concentrations of linezolid caused maternal toxicity in mice and were associated with increased embryonic mortality, including complete litter loss, reduced fetal body weight, and exacerbation of the normal genetic predisposition to sternal variations in the mouse strain. In rats, slight maternal toxicity was observed at exposures lower than clinical exposures. Moderate fetal toxicity was noted, manifested as reduced fetal body weight, decreased sternal ossification, reduced pup survival, and slight delay in maturation. After mating, these same pups showed reversible, dose-dependent increases in preimplantation losses with corresponding reductions in fertility. In rabbits, reduced fetal body weight was observed only in the presence of maternal toxicity (clinical signs, reduced body weight gain, and food consumption) at low exposure levels of 0.06 times compared to the expected human exposure based on AUC. This species is known to be sensitive to the effects of antibiotics.

Linezolid and its metabolites are excreted in the milk of lactating rats during the lactation period, and observed concentrations were higher than those in maternal plasma.

Linezolid caused reversible myelosuppression in rats and dogs.

In rats receiving oral linezolid for 6 months, irreversible, minimal to moderate axonal degeneration of the sciatic nerves was observed at a dose of 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in one male at this dose level at an interim necropsy after 3 months. Sensitive morphological evaluation of perfusion-fixed tissues was performed to investigate signs of optic nerve degeneration. Minimal or moderate optic nerve degeneration was observed in 2 out of 3 male rats after 6 months of drug administration, but a direct relationship with the drug was questionable due to the acute nature of the observed degeneration and its asymmetric distribution. The observed optic nerve degeneration was microscopically comparable to spontaneous unilateral optic nerve degeneration reported in aging rats and may represent an exacerbation of background changes.

Preclinical data based on standard repeated-dose toxicity and genotoxicity studies revealed no special hazard for humans other than those considered in other sections of this medical instruction. Carcinogenicity/oncogenicity studies were not conducted due to the short dosing period and lack of genotoxicity.

Pharmacokinetics

The medicinal product contains (S)-linezolid, which is the biologically active substance and is metabolized to inactive derivatives.

Absorption

Linezolid is rapidly and extensively absorbed after oral administration. Maximum plasma concentration is reached within 2 hours after dosing. Absolute oral bioavailability of linezolid (after oral and intravenous administration in a crossover study) is complete (approximately 100%).

Food does not significantly affect absorption, and absorption of the oral suspension is similar to that achieved with film-coated tablets.

Cmax and Cmin of linezolid in plasma (mean value and [standard deviation]) at steady state after intravenous administration of 600 mg twice daily were 15.1 [2.5] mg/L and 3.68 [2.68] mg/L, respectively.

In another study, after oral administration of 600 mg twice daily to achieve steady state, Cmax and Cmin were 21.2 [5.8] mg/L and 6.15 [2.94] mg/L, respectively.

Steady state is achieved by the second day of drug administration.

Distribution

The volume of distribution at steady state averages approximately 40–50 liters in healthy adults and is roughly equivalent to total body water. Plasma protein binding is approximately 31% and is independent of concentration.

Linezolid concentrations were measured in various fluids in a limited number of subjects in multiple-dose volunteer studies. The ratio of linezolid in saliva and sweat relative to plasma was 1.2:1.0 and 0.55:1.0, respectively. The ratio between epithelial lining fluid and alveolar cells in the lungs was 4.5:1.0 and 0.15:1.0, respectively, when measuring steady-state Cmax. In a small study involving patients with ventriculoperitoneal shunts and no signs of meningitis, the ratio of linezolid in cerebrospinal fluid to plasma at Cmax was 0.7:1.0 after multiple doses of linezolid.

Biotransformation

Linezolid is primarily metabolized via oxidation of the morpholine ring, forming two inactive open-ring carboxylic acid derivatives: the aminoethoxyacetic acid metabolite (PNU-142300) and the hydroxyethylglycine metabolite (PNU-142586). The hydroxyethylglycine metabolite (PNU-142586) is the predominant metabolite in humans and is believed to be formed via a non-enzymatic pathway.

The aminoethoxyacetic acid metabolite (PNU-142300) is less prevalent. Other minor, inactive metabolites have been characterized.

Elimination

In patients with normal renal function or mild to moderate renal impairment, linezolid is excreted in urine at steady state primarily as PNU-142586 (40%), parent active substance (30%), and PNU-142300 (10%). The parent active substance is practically undetectable in feces, while approximately 6% and 3% of each dose are excreted as PNU-142586 and PNU-142300, respectively. The half-life of linezolid averages approximately 5–7 hours.

Non-renal clearance accounts for approximately 65% of total linezolid clearance. A slight degree of non-linearity in clearance is observed with increasing linezolid dose. This is likely due to lower renal and non-renal clearance at higher linezolid concentrations.

However, the difference in clearance is minor and does not affect the apparent half-life.

Special populations

Patients with renal impairment

After a single 600 mg dose, a 7–8-fold increase in plasma exposure of the two primary metabolites of linezolid was observed in patients with severe renal impairment (i.e., creatinine clearance < 30 mL/min). However, no increase in AUC of the parent active substance was observed. Despite some removal of the main metabolites of linezolid by hemodialysis, plasma levels of metabolites after a single 600 mg dose remained significantly higher after dialysis than in patients with normal renal function or mild to moderate renal impairment.

In 24 patients with severe renal impairment, 21 of whom were on regular hemodialysis, peak plasma concentrations of the two main metabolites after multiple dosing were approximately 10 times higher than in patients with normal renal function. Peak plasma levels of linezolid were unchanged.

The clinical significance of these observations is not established, as safety data are limited (see sections "Dosage and administration" and "Special precautions").

Patients with hepatic impairment

Limited data indicate that the pharmacokinetics of linezolid, PNU-142300, and PNU-142586 are not altered in patients with mild to moderate hepatic impairment (i.e., Child-Pugh class A or B). The pharmacokinetics of linezolid in patients with severe hepatic impairment (i.e., Child-Pugh class C) have not been evaluated. However, since linezolid is metabolized via a non-enzymatic pathway, hepatic dysfunction is not expected to significantly alter its metabolism (see sections "Dosage and administration" and "Special precautions").

Children (< 18 years)

Data on the safety and efficacy of linezolid in children and adolescents (under 18 years of age) are insufficient; therefore, the use of linezolid in this age group is not recommended (see section "Dosage and administration"). Further studies are required to establish safe and effective dosing recommendations. Pharmacokinetic studies indicate that after single and multiple doses in children (from 1 week to 12 years of age), linezolid clearance (per kg body weight) was higher in children than in adults but decreased with increasing age.

In children aged 1 week to 12 years, administration of 10 mg/kg every 8 hours daily provided exposure approaching that achieved with 600 mg twice daily in adults.

In neonates under 1 week of age, systemic clearance of linezolid (per kg body weight) increases rapidly during the first week of life. Thus, neonates receiving 10 mg/kg every 8 hours will have the highest systemic exposure on the first day after birth. However, excessive accumulation during the first week of life is not expected with this dosing regimen, as clearance increases rapidly during this period.

In adolescents (aged 12 to 17 years), the pharmacokinetics of linezolid were similar to those in adults after administration of a 600 mg dose. Thus, adolescents receiving 600 mg every 12 hours will have exposure similar to that observed in adults receiving the same dose.

In pediatric patients with ventriculoperitoneal shunts receiving linezolid at 10 mg/kg every 12 or 8 hours, variable concentrations of linezolid were observed in cerebrospinal fluid (CSF) after single or multiple doses.

Therapeutic concentrations in cerebrospinal fluid were not achieved or consistently maintained. Therefore, the use of linezolid for empirical treatment of pediatric patients with central nervous system infections is not recommended.

Elderly patients:

the pharmacokinetics of linezolid are not significantly altered in elderly patients aged 65 years and older.

Female patients:

in females, the volume of distribution is slightly smaller than in males, and the mean clearance (adjusted for body weight) is reduced by approximately 20%. Plasma concentrations in females are higher, which can be partially explained by differences in body weight. However, since the mean half-life of linezolid in males and females does not differ significantly, plasma concentrations in females are not expected to substantially exceed those known to be well tolerated, and thus dose adjustment is not required.

Clinical characteristics

Indications

Nosocomial pneumonia.

Community-acquired pneumonia.

Linezolid is indicated in adults for the treatment of community-acquired pneumonia and nosocomial pneumonia when it is known or suspected to be caused by susceptible Gram-positive bacteria. When determining the appropriateness of linezolid therapy, microbiological test results or information on the prevalence of resistance to antibacterial agents among Gram-positive bacteria should be taken into account (see section "Pharmacological properties. Pharmacodynamics" regarding relevant microorganisms).

Linezolid is not active against infections caused by Gram-negative pathogens. Specific therapy against Gram-negative microorganisms should be initiated concomitantly if a Gram-negative pathogen is confirmed or suspected.

Complicated skin and soft tissue infections (see section "Special instructions for use").

Linezolid is indicated in adults for the treatment of complicated skin and soft tissue infections only when microbiological testing has confirmed that the infection is caused by susceptible Gram-positive bacteria.

Linezolid is not active against infections caused by Gram-negative pathogens. Linezolid should be used in patients with complicated skin and soft tissue infections with known or possible concurrent Gram-negative microorganism infection only when no alternative treatment options are available (see section "Special instructions for use"). In such circumstances, concomitant therapy for Gram-negative infection should be initiated.

Linezolid therapy should be initiated only in a hospital setting and after consultation with an appropriate specialist, such as a microbiologist or infectious disease expert.

Attention should be paid to official recommendations regarding the appropriate use of antibacterial agents.

Contraindications

Hypersensitivity to linezolid or to any other component of the medicinal product.

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

In the absence of means for careful monitoring and blood pressure surveillance, linezolid must not be administered to patients with the following primary clinical conditions or while taking the following types of concomitant medicinal products:

• patients with uncontrolled hypertension, pheochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder, or acute confusional states;
• patients receiving any of the following medicinal products: serotonin reuptake inhibitors (see section "Special instructions for use"), tricyclic antidepressants, 5-HT1 serotonin receptor agonists (triptans), direct and indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine, and phenylpropanolamine), vasopressor agents (e.g., adrenaline, noradrenaline), dopaminergic agents (e.g., dopamine, dobutamine), meperidine, or buspirone.

Animal data indicate that linezolid and its metabolites may pass into breast milk; therefore, breastfeeding must be discontinued before and during the entire period of treatment with the medicinal product (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other types of interactions

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO). In drug interaction and safety studies, 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 patient monitoring and surveillance can be ensured (see sections "Contraindications" and "Special instructions for use").

Potential interactions leading to increased blood pressure

In healthy volunteers with normal blood pressure, linezolid potentiated the blood pressure increase caused by pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant administration of linezolid with pseudoephedrine or phenylpropanolamine resulted in an average increase in systolic blood pressure of 30–40 mm Hg, compared to an increase of 11–15 mm Hg with linezolid alone, 14–18 mm Hg with pseudoephedrine or phenylpropanolamine alone, and 8–11 mm Hg with placebo. Similar studies in patients with hypertension have not been conducted. Careful dose titration of vasopressor agents, including dopaminergic agents, is recommended to achieve the desired effect when linezolid is used concomitantly with these agents.

Potential serotonergic interactions

Potential interactions between linezolid and dextromethorphan were studied in a trial involving healthy volunteers. Participants received dextromethorphan (two 20 mg doses 4 hours apart) with or without linezolid. In healthy volunteers receiving both linezolid and dextromethorphan, no symptoms of serotonin syndrome (confusion, hallucinations, agitation, tremor, flushing, diaphoresis, hyperpyrexia) were observed.

Post-marketing experience: one report of symptoms resembling serotonin syndrome was received in a patient receiving linezolid and dextromethorphan; symptoms resolved after discontinuation of both agents.

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

Use in combination with tyramine-rich foods

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

Medicinal products 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 medicinal products metabolized by CYP450 is expected.

Rifampicin. The effect of rifampicin on the pharmacokinetics of linezolid was studied in 16 healthy male volunteers who received linezolid (600 mg twice daily for 2.5 days) with and without rifampicin (600 mg once daily for 8 days). Rifampicin reduced Cmax and AUC of linezolid by 21% (90% CI 15, 27) and 32% (90% CI 27, 37), respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin. A 10% reduction in mean peak INR (International Normalized Ratio) was observed when warfarin was added to a stable linezolid regimen, with a 5% reduction in INR AUC. Data on patients receiving warfarin and linezolid concomitantly are insufficient to assess clinical significance, if any.

Special precautions for use

Myelosuppression

Myelosuppression (including anaemia, leucopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, haematological parameters increased to pre-treatment levels after discontinuation of linezolid. The risk of these effects appears to be related to the duration of treatment. Elderly patients receiving linezolid may be at greater risk of developing blood dyscrasias than younger patients. Thrombocytopenia may occur more frequently in patients with severe renal insufficiency, whether or not they are on dialysis, and in patients with moderate to severe hepatic insufficiency. Therefore, careful monitoring of blood counts is recommended in patients who: have anaemia, granulocytopenia, or thrombocytopenia; are receiving concomitant medicinal products that may reduce haemoglobin levels, suppress blood counts, or negatively affect platelet number or function; have acute renal failure or moderate to severe hepatic insufficiency; or are receiving more than 10–14 days of therapy. Linezolid should be administered to such patients only with careful monitoring of haemoglobin levels, complete blood count, and platelet count.

If significant myelosuppression occurs during treatment with linezolid, therapy should be discontinued, except when continuation is considered absolutely necessary; in such cases, intensive monitoring of complete blood count should be performed and appropriate treatment strategies implemented.

Furthermore, it is recommended to perform weekly monitoring of complete blood count (including haemoglobin, platelets, total and differential white blood cell count) in patients receiving linezolid, regardless of initial blood test results.

In compassionate use studies, a higher incidence of severe anaemia was reported in patients who received linezolid beyond the maximum recommended treatment duration (28 days). These patients more frequently required blood transfusions. Cases of anaemia requiring blood transfusion have also been reported in the post-marketing period, with a higher number of cases observed in patients who received linezolid therapy for more than 28 days.

In the post-marketing period, cases of sideroblastic anaemia have been reported. In cases where the onset time was known, most patients had received linezolid for more than 28 days. Most patients recovered fully or partially after discontinuation of linezolid, with or without anaemia treatment.

Mortality imbalance in a clinical trial in patients with catheter-associated infections caused by Gram-positive pathogens

In an open-label study involving critically ill patients with intravascular catheter-associated infections, an increased mortality rate was observed in patients receiving linezolid compared to those receiving vancomycin/dicloxacillin/oxacillin
[78/363 (21.5%) vs 58/363 (16.0%)]. The primary factor influencing mortality rate was the Gram-positive infection status at study entry. Mortality rates were similar in patients with infections caused exclusively by Gram-positive microorganisms (odds ratio 0.96; 95% CI: 0.58–1.59), but were significantly higher (p=0.0162) in the linezolid group among patients with any other pathogen or no pathogen at study entry (odds ratio 2.48; 95% CI: 1.38–4.46). The greatest imbalance occurred during treatment and within 7 days after discontinuation of the investigational medicinal product. Most patients in the linezolid group became infected with Gram-negative pathogens during the study and died from infections caused by Gram-negative organisms and polymicrobial infections. Therefore, in complicated skin and soft tissue infections, linezolid should be administered to patients with known or suspected concomitant Gram-negative microorganism infection only when no alternative treatment options are available (see section "Indications"). In such circumstances, treatment for Gram-negative infection should be initiated concomitantly.

Antibiotic-associated diarrhoea and colitis

Antibiotic-associated diarrhoea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhoea, have been reported with the use of nearly all antibiotics, including linezolid, and may vary in severity from mild diarrhoea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop severe diarrhoea during or after administration of linezolid. If antibiotic-associated diarrhoea or antibiotic-associated colitis is suspected or confirmed, the current antibacterial therapy, including linezolid, should be discontinued and appropriate therapeutic measures initiated immediately. Medicinal products that inhibit peristalsis are contraindicated in this situation.

Lactic acidosis

Lactic acidosis has been reported with the use of linezolid. Patients who develop signs and symptoms of metabolic acidosis during linezolid therapy, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels, or hyperventilation, should seek immediate medical attention. If lactic acidosis occurs, the benefits 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 effects such as lactic acidosis, anaemia, and neuropathy (optic and peripheral) may occur; these events are more commonly observed when the drug is used for longer than 28 days.

Serotonin syndrome

There have been spontaneous reports of serotonin syndrome associated with concomitant use of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, concomitant use of linezolid and serotonergic agents is contraindicated (see section "Contraindications"), except in cases where concomitant use of linezolid and concomitant serotonergic agents is essential. In such cases, patients should be under close surveillance for signs and symptoms of serotonin syndrome, such as cognitive dysfunction, hyperpyrexia, hyperreflexia, and incoordination. If signs or symptoms occur, physicians should consider discontinuing one or both agents; if the concomitant serotonergic agent is discontinued, withdrawal symptoms may occur.

Rhabdomyolysis

Cases of rhabdomyolysis have been reported with the use of linezolid. Linezolid should be administered with caution to patients predisposed to rhabdomyolysis. If signs or symptoms of rhabdomyolysis occur, linezolid administration should be discontinued and appropriate therapy initiated.

Hypotonicity and syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Hyponatraemia and/or SIADH have been observed in some patients taking linezolid. Regular monitoring of serum sodium levels is recommended in patients at risk of hyponatraemia, such as elderly individuals or other patients taking medicinal products that may reduce blood sodium levels (e.g., thiazide diuretics such as hydrochlorothiazide).

Peripheral and optic neuropathy

Peripheral neuropathy, as well as optic neuropathy and optic neuritis, sometimes progressing to vision loss, have been reported in patients receiving linezolid therapy; such reports primarily involved patients receiving treatment for more than 28 days (the maximum recommended treatment duration).

All patients should be advised to report symptoms of visual deterioration, such as changes in visual acuity, changes in colour perception, blurred vision, or visual field defects.
In such cases, prompt evaluation and referral to an ophthalmologist, if necessary, is recommended. If any patient receives linezolid for longer than the recommended 28 days, regular monitoring of visual function is required.

If peripheral or optic neuropathy occurs, the benefit of continuing the medicinal product versus potential risks should be carefully considered.

An increased risk of neuropathies may exist when linezolid is used in patients who are currently taking or have recently taken antimycobacterial agents for the treatment of tuberculosis.

Seizures

Seizures have been reported in patients during treatment with linezolid. In most of these cases, a history of seizures or risk factors for seizures was reported. Patients should be advised to inform their physician if they have a history of seizure episodes.

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO); however, at doses used for antibacterial therapy, it does not exert an antidepressant effect. There are very limited interaction study data on the safety of linezolid in patients with concomitant diseases and/or concomitant medicinal products that may pose a risk due to MAO inhibition. Therefore, linezolid is not recommended under such circumstances unless close observation and monitoring of the recipient's condition are possible (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Use with tyramine-rich products

Patients should be advised not to consume large amounts of tyramine-rich foods (see "Interaction with other medicinal products and other forms of interaction").

Superinfection

The impact of linezolid therapy on normal flora has not been evaluated in clinical studies.

Antibiotic use may occasionally lead to overgrowth of resistant organisms. For example, approximately 3% of patients receiving recommended doses of linezolid developed drug-related candidiasis during clinical trials. Appropriate measures should be taken if superinfection occurs during therapy.

Special patient populations

Linezolid should be used with particular caution in patients with severe renal insufficiency and only when the expected benefit outweighs the potential risk (see sections "Dosage and administration" and "Pharmacological properties. Pharmacokinetics").

Linezolid is recommended to be administered to patients with severe hepatic insufficiency only when the expected benefit outweighs the potential risk (see sections "Dosage and administration" and "Pharmacological properties. Pharmacokinetics").

Impairment of fertility

Linezolid reversibly reduced fertility and caused morphological abnormalities in spermatozoa in adult male rats at exposure levels approximately similar to those expected in humans; the potential effect of linezolid on male reproductive function is unknown (see section "Pharmacological properties. Pharmacodynamics").

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 diabetic foot infections, pressure ulcers, ischaemic lesions, severe burns, or gangrene. Therefore, experience with the use of linezolid for the treatment of these conditions is limited.

Excipients

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Use during pregnancy. Data on the use of linezolid in pregnant women are limited. Animal studies have shown reproductive toxicity (see section "Pharmacological properties. Pharmacodynamics"). There is a potential risk for humans. Linezolid should not be used during pregnancy except in cases of extreme necessity when the expected benefit outweighs the potential risk.

Use during breastfeeding. Animal studies have shown that linezolid and its metabolites may pass into breast milk; therefore, breastfeeding should be discontinued before and throughout the entire period of medicinal product use.

Fertility. In animal studies, linezolid caused reduced fertility (see section "Pharmacological properties. Pharmacodynamics").

Ability to affect reaction speed when driving or operating machinery

Patients should be warned about the possibility of experiencing dizziness or symptoms of visual disturbances (see sections "Special precautions for use" and "Adverse reactions") during linezolid administration, and should refrain from driving or operating machinery if any of these symptoms occur.

Dosage and Administration

Linezolid in the form of an infusion solution, film-coated tablets, or oral suspension may be used as initial therapy. Patients who begin treatment with the parenteral formulation may be switched to the oral formulation when clinically indicated. In such cases, dose adjustment is not required, as the oral bioavailability of linezolid is approximately 100%.

Recommended dosage and duration of treatment for adults

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

The treatment duration recommendations provided below correspond to those used in clinical studies. Shorter treatment regimens may be appropriate for certain types of infections, but have not been evaluated in clinical trials.

The maximum duration of treatment is 28 days. The safety and efficacy of linezolid administered for periods longer than 28 days have not been established (see section "Special precautions for use").

There is no need to increase the recommended dose or duration of treatment for infections associated with concomitant bacteremia.

Dosage recommendations for the infusion solution and for tablets/oral suspension granules are identical and are provided below:

Infections	Dosage	Duration of treatment
Nosocomial pneumonia	600 mg twice daily	10-14 consecutive days
Community-acquired pneumonia
Complicated skin and soft tissue infections	600 mg twice daily

Geriatric patients

Dose adjustment is not required.

Renal impairment

Dose adjustment is not required (see sections “Special precautions for use” and “Pharmacological properties. Pharmacokinetics”).

Severe renal impairment (i.e. CLCr < 30 mL/min)

Dose adjustment is not required. Due to the lack of information on the clinical significance of increased exposure (up to 10-fold) to two major metabolites of linezolid in patients with severe renal impairment, linezolid should be used with particular caution in such patients and only when the expected benefit outweighs the potential risk.

Since approximately 30% of the dose of linezolid is removed during 3 hours of hemodialysis, linezolid should be administered after dialysis in patients undergoing this treatment. The main metabolites of linezolid are partially removed by hemodialysis, but their concentrations after dialysis are still significantly higher than in patients with normal renal function or mild to moderate renal impairment.

Therefore, linezolid should be used with particular caution in patients with severe renal impairment undergoing dialysis, and only when the expected benefit outweighs the potential risk.

Currently, there is no experience with the use of linezolid in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or other alternative treatments for renal failure (other than hemodialysis).

Hepatic impairment

Dose adjustment is not required. However, clinical data are limited; therefore, linezolid should be used in such patients only when the expected benefit outweighs the potential risk (see sections “Special precautions for use” and “Pharmacological properties”).

Method of administration

The recommended dose of linezolid should be administered orally twice daily.

Route of administration: oral.

Film-coated tablets may be taken with or without food.

Children

The safety and efficacy of linezolid in children under 18 years of age have not been established. Current available data are described in sections “Adverse reactions” and “Pharmacological properties”, but no dosage recommendations can be provided.

Overdose

No specific antidote is known.

There have been no reported cases of overdose.

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

Signs of toxicity in rats after administration of linezolid at a dose of 3000 mg/kg/day included decreased activity and ataxia, whereas vomiting and tremor were observed in dogs receiving a dose of 2000 mg/kg/day.

Adverse Reactions

The information provided is based on data obtained from clinical studies in which more than 6,000 adult patients received the recommended doses of linezolid for up to 28 days.

The most frequently reported adverse reactions were diarrhea (8.9%), nausea (6.9%), vomiting (4.3%), and headache (4.2%).

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

Adverse reactions reported during the post-marketing period are listed below, categorized with a frequency term of "frequency not known," as the frequency cannot be estimated based on available data.

Adverse reactions reported during treatment are listed below, classified according to the following frequency categories: 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 based on available data).

System Organ Classes	Common (> 1/100, < 1/10)	Uncommon (> 1/1000, < 1/100)	Rare (> 1/10000, < 1/1000)	Very rare (> 1/10000)	Frequency not known (cannot be estimated from available data)
Infections and infestations	candidiasis, oral candidiasis, vaginal candidiasis, fungal infections	antibiotic-associated colitis, including pseudomembranous colitis*, vaginitis
Blood and lymphatic system disorders	thrombocytopenia*, anemia*†	pancytopenia*, leukopenia*, neutropenia, eosinophilia	sideroblastic anemia*		myelosuppression*
Immune system disorders			anaphylaxis
Metabolism and nutrition disorders		hyponatremia	lactic acidosis*.
Psychiatric disorders	insomnia
Nervous system disorders	headache, taste disturbance (metallic taste), dizziness	seizures*, peripheral neuropathy*, hypesthesia, paresthesia			serotonin syndrome**
Eye disorders		optic neuropathy*, blurred vision*	visual field defect*		optic neuritis*, vision loss*, change in visual acuity*, change in color perception*
Ear and labyrinth disorders		tinnitus
Cardiac disorders		arrhythmia (tachycardia).
Vascular disorders	hypertension	transient ischemic attack, phlebitis, thrombophlebitis
Gastrointestinal disorders	diarrhea, nausea, vomiting, localized or generalized abdominal pain, constipation, dyspepsia	pancreatitis, gastritis, bloating, dry mouth, glossitis, frequent loose stools, stomatitis, disturbances or change in tongue color	discoloration of tooth surface
Hepatobiliary disorders	abnormal liver function tests, increased levels of ALT, AST or alkaline phosphatase	increased total bilirubin
Skin and subcutaneous tissue disorders	pruritus, rash	angioedema, urticaria, dermatitis, bullous skin lesions, hyperhidrosis	toxic epidermal necrolysis, Stevens-Johnson syndrome, allergic vasculitis		alopecia
Musculoskeletal and connective tissue disorders			rhabdomyolysis*
Renal and urinary disorders	increased blood urea nitrogen	renal failure, increased creatinine, polyuria
Reproductive system and breast disorders		vulvovaginal disorders
General disorders and administration site conditions	fever, localized pain	chills, fatigue, injection site pain, thirst
Investigations	Biochemistry: increased lactate dehydrogenase, creatine kinase, lipase, amylase, or postprandial (non-fasting) glucose level; decreased total protein, albumin, sodium, and calcium; increased or decreased potassium or bicarbonate Hematology: increased neutrophils or eosinophils; decreased hemoglobin, hematocrit, or red blood cell count; increased or decreased platelets or white blood cells	Biochemistry: increased sodium or calcium, decreased glucose without fasting, increased or decreased chloride Hematology: increased reticulocyte count, decreased neutrophil count

* See section "Special precautions".

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

† 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 concomitant diseases, the percentage of patients who developed anemia after receiving linezolid for ≤ 28 days was 2.5% (33 out of 1326), compared to 12.3% (53 out of 430) in those treated for > 28 days. The proportion of documented cases of severe anemia caused by the medicinal product, 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 administration, which were considered rare but severe, include localized abdominal pain, transient ischemic attack, and arterial hypertension.

Children

Safety data from clinical trials involving more than 500 children (from birth to 17 years of age) do not indicate any difference in the safety profile of linezolid in children compared to adults.

Reporting of suspected adverse reactions

Reporting of adverse reactions after medicinal product registration is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions

Store in original packaging at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging

5 or 10 tablets per blister; 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer

JSC "Tekhnolohiya".

Manufacturer's address and location of its business activity

8 Stara Prorina Street, Uman, Cherkasy Oblast, 20300, Ukraine