Linezolidin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINEZOLIDIN (LINEZOLIDIN)

Composition:

Active substance: linezolid;

1 tablet contains linezolid equivalent to 100% substance 600 mg;

Excipients: microcrystalline cellulose; maize starch; hydroxypropylcellulose; sodium starch glycolate (type A); magnesium stearate; coating mixture "Aquarius Preferred HSP BPP218011" containing hypromellose, titanium dioxide (E 171), copovidone, polydextrose, polyethylene glycol, medium-chain triglycerides.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical characteristics: film-coated tablets of white or almost white color, oval-shaped, with a biconvex surface.

Pharmacotherapeutic group. Antibacterials for systemic use.

ATC code J01XX08.

Pharmacological properties.

Pharmacodynamics.

General characteristics.

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

The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, 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 shows some in vitro activity against Legionella, Chlamydia pneumoniae, and Mycoplasma pneumoniae, there is insufficient data to confirm clinical efficacy in these cases.

Cross-resistance

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

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

Pharmacokinetics.

The medicinal product Linezolidin contains linezolid, which is the biologically active substance and is metabolized to inactive derivatives.

Absorption

Linezolid is extensively absorbed after oral administration. Maximum plasma concentration is reached approximately within 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 administered regardless of food intake. The time to reach maximum concentration increases from 1.5 to 2.2 hours, and Cmax decreases by approximately 17% when linezolid is administered with a high-fat meal. However, total exposure, assessed by AUC0–∞, is similar in both cases.

Distribution

Pharmacokinetic studies have shown that linezolid rapidly distributes into well-perfused tissues. Approximately 31% of linezolid is protein-bound in plasma, and this binding is independent of drug concentration. The volume of distribution of linezolid at steady state in healthy adult volunteers averages 40–50 L. After multiple dosing, linezolid concentrations were measured in various fluids in a limited number of volunteer participants in phase 1 studies. The ratio of linezolid concentration in saliva to plasma concentration was 1.2:1, and the ratio of linezolid concentration in sweat to plasma concentration was 0.55:1.

Metabolism

Linezolid is primarily metabolized via oxidation of the morpholine ring, forming two inactive open-ring carboxylic acid derivatives: the aminoethoxyacetic acid metabolite (A) and the hydroxyethylglycine metabolite (B). Metabolite A is thought to be formed via an enzymatic pathway, whereas formation of metabolite B is mediated by a non-enzymatic mechanism involving chemical oxidation in vitro. In vitro studies have demonstrated that linezolid undergoes minimal metabolism, possibly involving the human cytochrome P450 system. However, the metabolic pathways of linezolid are not fully understood.

Elimination

Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. At steady state, approximately 30% of the dose is excreted in urine as linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min, indicating tubular reabsorption. Linezolid is virtually undetectable in feces, whereas approximately 6% of the dose is excreted in feces as metabolite B and 3% as metabolite A. Slight non-linearity in clearance was observed with increasing linezolid doses, apparently due to lower renal and non-renal clearance of the drug at higher concentrations. However, this difference in clearance was minor and did not affect the apparent half-life.

Patients with renal impairment. 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 greater 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 the ESRD study, 14 patients received 600 mg of linezolid every 12 hours for 14.5 days. Since plasma concentrations of linezolid were achieved regardless of renal function, dose adjustment is not recommended for patients with renal impairment. However, due to the lack of information on the clinical significance of accumulation of the main metabolites, the benefit-risk balance of using linezolid in patients with renal impairment and the potential risks of metabolite accumulation should be carefully considered. Both linezolid and its two metabolites are removed by hemodialysis. Information on the effect of peritoneal dialysis on linezolid pharmacokinetics is lacking.

Patients with hepatic impairment. The pharmacokinetics of linezolid were not altered in 7 patients with mild to moderate hepatic impairment (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 specified microorganisms in the following conditions:

• Hospital-acquired pneumonia;

• Community-acquired pneumonia;
• Complicated skin and skin structure infections, including infections associated with diabetic foot without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae; Linezolid has not been studied in the treatment of ulcerative pressure sores.
• 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. If Gram-negative pathogens are suspected or identified, specific Gram-negative therapy should be initiated immediately.

Contraindications.

Known hypersensitivity to linezolid or to any of the excipients of the medicinal product.

Linezolid must not be administered to patients receiving any medicinal products that inhibit monoamine oxidase A and B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide) or within 2 weeks of discontinuation of such agents.

Except in cases where careful monitoring of blood pressure is possible, Linezolid should not be administered to patients with the following concomitant clinical conditions or concomitant medications:

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

Breastfeeding should be discontinued during treatment (see section "Use in pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO). In drug interaction and safety studies of linezolid, very limited data are available on the use of linezolid in patients receiving concomitant medications that pose certain risks due to MAO inhibition. Therefore, the use of Linezolid under such circumstances is not recommended unless careful patient monitoring is possible (see sections "Contraindications" and "Special precautions for use").

Potential interactions leading to increased blood pressure

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

Potential serotonergic interactions

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

Post-marketing experience: one report has been received of symptoms resembling serotonin syndrome in a patient taking linezolid and dextromethorphan, which resolved after discontinuation of both drugs.

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

Concomitant use with tyramine-rich foods

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

Drugs metabolized by cytochrome P450

Linezolid is not metabolized by the cytochrome P450 enzyme system and does not inhibit the function of any clinically significant human cytochrome P450 isoenzymes (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Similarly, linezolid does not induce cytochrome P450 isoenzymes in rats. Therefore, 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 male volunteers who received linezolid (600 mg twice daily for 2.5 days) alone and in combination with rifampicin (600 mg once daily for 8 days). Rifampicin reduced 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 maximum INR was observed with concomitant administration, while INR AUC decreased by 5%. Data in patients receiving both warfarin and linezolid are insufficient to assess clinical significance, if any.

Antibiotics

Aztreonam. The pharmacokinetics of linezolid or aztreonam are not altered when these agents are administered concomitantly.

Gentamicin. The pharmacokinetics of linezolid or gentamicin are not altered when these agents are administered concomitantly.

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

Antioxidants

Dose adjustment of linezolid is not recommended when administered concomitantly with vitamin C or vitamin E.

Special precautions for use.

Myelosuppression

Cases of myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) have been reported in some patients receiving linezolid. Data suggest that hematological parameters returned to pre-treatment levels after discontinuation of linezolid. The risk of developing these effects is likely related to the duration of treatment. Elderly patients may have a higher risk of developing blood abnormalities when treated with linezolid compared to younger patients. In patients with severe renal insufficiency (regardless of whether they are undergoing dialysis), the incidence of thrombocytopenia may be increased. 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 capable of reducing hemoglobin levels, decreasing blood cell counts, or negatively affecting platelet number or functional activity; 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 is deemed absolutely necessary. In such situations, careful monitoring of complete blood count parameters and implementation of appropriate treatment strategies are required.

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

In compassionate use studies where patients received linezolid for 28 days (the maximum recommended treatment duration), an increased incidence of severe anemia was observed. Such 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 who received linezolid for longer than 28 days.

Additionally, cases of sideroblastic anemia have been reported in the post-marketing period. Among cases with known onset of treatment, 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 trial involving patients with catheter-related bloodstream infections caused by Gram-positive pathogens

In an open-label study involving 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 out of 363 (21.5%) vs. 58 out 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 absence of pathogens 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 treatment group acquired Gram-negative infections during the study and died from infections caused by Gram-negative pathogens or polymicrobial infections. Therefore, in complicated skin and soft tissue infections in patients with confirmed or suspected concomitant Gram-negative infection, linezolid should be used only when no other treatment options are available (see section "Indications"). In such circumstances, concomitant treatment for Gram-negative infection should be initiated.

Antibiotic-associated diarrhea and 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. Therefore, it is 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, antibacterial therapy (including linezolid) should be discontinued and appropriate therapeutic measures should be initiated immediately. In such situations, the use of agents that inhibit peristalsis is contraindicated.

Lactic acidosis

Lactic acidosis has been reported during treatment with linezolid. Patients who develop symptoms and signs of metabolic acidosis during treatment with linezolid, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels, or hyperventilation, should seek immediate medical attention. If lactic acidosis develops, the benefit of continuing linezolid therapy versus potential risks should be carefully 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 when the drug is used for longer than 28 days.

Potential interactions causing increased blood pressure

Except in cases where patients can be monitored for elevated blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, and/or concomitant use of medications such as direct and indirect sympathomimetics (e.g., pseudoephedrine), vasopressors (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine).

Serotonin syndrome

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

Peripheral neuropathy and optic neuropathy

Peripheral neuropathy and optic neuropathy, sometimes progressing to vision loss, have been reported in patients receiving linezolid therapy. These reports primarily involved patients who received treatment for 28 days (the maximum recommended treatment duration).

All patients should be advised to report symptoms of visual disturbances, such as changes in visual acuity, changes in color perception, blurred vision, or visual field defects. In such cases, prompt ophthalmological evaluation is recommended, if necessary. Patients receiving linezolid for longer than the recommended 28 days should have regular vision testing.

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

The risk of neuropathy may increase when linezolid is used in patients who are taking or have recently taken antibacterial agents for the treatment of tuberculosis.

Seizures

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

Monoamine oxidase inhibitors

Linezolid is a non-selective, reversible inhibitor of monoamine oxidase (MAO). However, at doses used for antibacterial therapy, it does not exhibit antidepressant effects. Very limited data are available from drug interaction and safety studies regarding the use of linezolid in patients with underlying conditions and/or concomitant medications that pose certain risks due to MAO inhibition. Therefore, the use of linezolid under such circumstances is not recommended unless careful patient monitoring is 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 when linezolid, a non-selective reversible MAO inhibitor, was used in diabetic patients receiving insulin or oral hypoglycemic agents. Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. Although a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be warned about the potential for hypoglycemic reactions during treatment with linezolid.

If hypoglycemia occurs, dose reduction of insulin or oral hypoglycemic agent, or discontinuation of the oral hypoglycemic 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 (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 appear, the drug should be discontinued and appropriate supportive measures should be taken.

Superinfection

The effect of linezolid on normal flora has not been studied in clinical trials.

Antibiotic use may sometimes lead to overgrowth of non-susceptible organisms. For example, approximately 3% of patients receiving linezolid at recommended doses in clinical trials developed candidiasis associated with the drug. Appropriate measures should be taken if superinfection occurs during treatment.

Special patient groups

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

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

Gender

No dosage adjustment of the drug is necessary based on gender.

Impairment of fertility

Linezolid reduced fertility and caused morphological abnormalities in sperm quality in healthy adult male rats at exposure levels approximately similar to those expected in humans. These changes were reversible.

The potential effect of linezolid on male reproductive function is unknown.

Clinical trials

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

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

Emergence of drug-resistant bacteria

It is unlikely that prescribing linezolid in the absence of a diagnosed bacterial infection or for prophylactic purposes will harm the patient or increase the risk of emergence of drug-resistant bacteria.

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 about the possibility of developing dizziness or symptoms of visual disturbances (see sections "Special precautions for safety" and "Adverse reactions") during treatment with linezolid and advised not to drive or operate machinery if such symptoms occur.

Method of administration and dosage.

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

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

Maximum duration of treatment is 28 days. The safety and efficacy of linezolid administered for longer than 28 days have not been studied.

There is no need to increase the recommended doses or duration of treatment in cases of infections associated with bacteremia.

Dosage recommendations according to indications are presented in the table below.

Patients who were initially treated with intravenous linezolid infusions may be switched to oral linezolid therapy. Dose adjustment is not required in such cases, as the bioavailability of linezolid following oral administration is nearly 100%.

Table 2

Indications	Dosage and administration			Recommended duration of treatment (number of days)
	Adults and children aged 12 years and older
Nosocomial pneumonia	600 mg intravenously* or orally every 12 hours			10–14
Community-acquired pneumonia (including bacteremic forms)
Complicated skin and skin structure infections
Infections caused by vancomycin-resistant Enterococcus faecium, including bacteremic infections	600 mg intravenously* or orally every 12 hours			14–28
Uncomplicated skin and skin structure infections	Adults: 400 mg orally every 12 hours* Children aged 12 years and older: 600 mg orally every 12 hours			10–14

* Use the drug in another pharmaceutical form allowing appropriate dosing.

The maximum dose for adults and children should not exceed 600 mg twice daily.

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 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 insufficiency. No dose adjustment is required (see section "Pharmacological properties. Pharmacokinetics").

Children

The drug in this pharmaceutical form is indicated for children aged 12 years and older.

Overdose

No specific antidote is known.

Cases of overdose have not been reported.

In case of overdose, symptomatic treatment with measures to support glomerular filtration should be administered. Approximately 30% of the administered dose of the drug is removed during 3 hours of hemodialysis; however, there are no data on the elimination of linezolid during peritoneal dialysis or hemoperfusion procedures. Two primary metabolites of linezolid are also eliminated by hemodialysis.

Side effects

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

The most commonly reported side effects leading to discontinuation of the medicinal product were headache, diarrhoea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to drug-related adverse reactions.

Additional adverse reactions reported after marketing authorization are listed below with their frequency categorized as "frequency unknown", since the frequency cannot be estimated from the available data.

Adverse reactions reported during treatment are listed below according to the following frequency classification: very common (≥ 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (> 1/10000), 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 – anaemia*†; uncommon – leucopenia*, neutropenia, thrombocytopenia*, eosinophilia; rare – pancytopenia*; frequency not known – myelosuppression*, sideroblastic anaemia*.

Immune system disorders: frequency not known – anaphylaxis.

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

Psychiatric disorders: common – insomnia.

Nervous system disorders: common – headache, taste disturbances (metallic taste), dizziness; uncommon – seizures*, hypoaesthesia, 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 colour perception*.

Ear and labyrinth disorders: uncommon – tinnitus.

Cardiac disorders: uncommon – arrhythmia (tachycardia).

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

Gastrointestinal disorders: common – diarrhoea, nausea, vomiting, localized or generalized abdominal pain, constipation, dyspepsia; uncommon – pancreatitis, gastritis, abdominal distension, dry mouth, glossitis, frequent loose stools, stomatitis, disorders or change in tongue colour; rare – discolouration of tooth surface.

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 – pyrexia, localized pain; uncommon – chills, fatigue, injection site pain, thirst.

Investigations. Chemistry: common – increased lactate dehydrogenase, creatine kinase, lipase, amylase, or postprandial (non-fasting) glucose levels; decreased total protein, albumin, sodium, and calcium; increased or decreased potassium or bicarbonate; uncommon – increased sodium or calcium, decreased glucose (non-fasting), increased or decreased chloride. Hematology: common – increased neutrophils or eosinophils, decreased haemoglobin, haematocrit, or erythrocyte count, increased or decreased platelet or leukocyte count; uncommon – increased reticulocyte count, decreased neutrophil count.

* See section "Special precautions".

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

† During controlled clinical trials in which linezolid was administered for up to 28 days, anaemia was observed in 2.0% of patients. In a compassionate use program involving patients with life-threatening infections and concomitant illnesses, the percentage of patients who developed anaemia 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 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, which were assessed as severe in rare cases, include localized abdominal pain, transient ischaemic attack, and arterial hypertension.

During the post-marketing period, cases of symptomatic hypoglycaemia have been reported in diabetic patients treated with insulin or oral hypoglycaemic agents when receiving linezolid, a non-selective, reversible monoamine oxidase (MAO) inhibitor. Hypoglycaemic episodes have been associated with the use of some MAO inhibitors in diabetic patients receiving insulin or hypoglycaemic agents.

Cases of hyponatraemia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been observed in patients receiving linezolid during the post-marketing period. Signs and symptoms in these cases included confusion, drowsiness, general weakness, and in severe cases, led to respiratory depression and even death.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization 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 in accordance with the local reporting system.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging. 10 tablets in a blister pack, 1 blister pack in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and place of business.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.