Nezolid

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

Composition:

Active substance: linezolid;

1 film-coated tablet contains 600 mg of linezolid;

Excipients: colloidal anhydrous silicon dioxide, microcrystalline cellulose, crospovidone, magnesium stearate, purified talc, Opadry white.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white in color, capsule-shaped, with a score line on one side and smooth on the other.

Pharmacotherapeutic group.

Antibacterials for systemic use. ATC code J01X X08.

Pharmacological properties.

Pharmacodynamics.

Linezolid is a synthetic antibacterial agent belonging to a new class of antimicrobial drugs — oxazolidinones.

It exhibits in vitro activity against aerobic Gram-positive bacteria and anaerobic microorganisms.

Linezolid selectively inhibits protein synthesis in bacterial cells 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 (a key component of the translation process).

Susceptibility.

The prevalence of acquired resistance in specific species may vary geographically and over time; therefore, it is advisable to refer to local information on 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 sp.

Resistant microorganisms: Haemophilus influenzae, Moraxella catarrhalis, Neisseria sp., Enterobacteriaceae, Pseudomonas sp.

* Clinical efficacy has been demonstrated for susceptible strains in approved indications.

Although linezolid demonstrates some in vitro activity against Legionella, Chlamydia pneumoniae, and Mycoplasma pneumoniae, there is insufficient data to confirm clinical efficacy in these cases.

Cross-resistance.

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

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

Pharmacokinetics.

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

Absorption

Linezolid is rapidly 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.

The medicinal product can be administered regardless of food intake. Time to maximum concentration increases from 1.5 to 2.2 hours, and Cmax decreases by approximately 17% when linezolid is taken with a high-fat meal. However, total exposure, assessed by AUC0–∞, is similar in both cases.

Distribution

Pharmacokinetic studies have shown that linezolid rapidly distributes into well-perfused tissues. The extent of plasma protein binding is approximately 31% and is independent of drug concentration. The volume of distribution at steady state in healthy adult volunteers averages 40–50 L.

In Phase 1 studies involving a limited number of healthy volunteers, linezolid concentrations were measured in various body fluids after multiple dosing. The ratios of linezolid concentration in saliva and sweat to plasma concentration were 1.2:1 and 0.55:1, respectively.

Metabolism

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

Elimination

Non-renal clearance accounts for approximately 65% of total linezolid clearance. At steady state, approximately 30% of the dose is excreted in urine as unchanged 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, while approximately 6% of the dose is excreted in feces as metabolite B and 3% as metabolite A.

Minor nonlinearity in clearance was observed with increasing linezolid doses, likely due to reduced renal and non-renal clearance at higher drug concentrations. However, this difference in clearance was minor and did not affect the apparent half-life.

Pharmacokinetics in specific patient populations.

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) on 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 similar regardless of renal function, dose adjustment is not recommended for patients with renal impairment. However, due to the lack of information on the clinical significance of accumulation of the main metabolites, the appropriateness of using linezolid in patients with renal impairment and the potential risks of metabolite accumulation should be carefully considered. Both linezolid and its metabolites are removed by hemodialysis. Data on the effect of peritoneal dialysis on linezolid pharmacokinetics are 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.

For the treatment of infections caused by susceptible strains of anaerobic or aerobic Gram-positive microorganisms, including infections associated with bacteremia, such as:

• 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. The use of linezolid for the treatment of pressure ulcers has not been studied;
• uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes;
• infections caused by enterococci, including vancomycin-resistant strains of Enterococcus faecium and faecalis.

LINEZOLID is not indicated for the treatment of infections caused by Gram-negative microorganisms. In case of suspected or confirmed Gram-negative pathogens, specific Gram-negative therapy should be initiated immediately.

Contraindications.

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

Concomitant use with medicinal products that inhibit monoamine oxidase A and B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide), as well as use within 2 weeks after discontinuation of such agents.

Except when close observation and monitoring of blood pressure are possible, the drug should not be administered to patients with the following concomitant clinical conditions or during concomitant use of the following medications:

• uncontrolled hypertension, thyrotoxicosis, pheochromocytoma, carcinoid, 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 with the medicinal product (see section "Use during 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 monitoring and observation of the patient are possible (see sections "Contraindications" and "Special precautions for use").

Potential interactions leading to increased blood pressure.

In healthy volunteers with normal blood pressure, linezolid 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 vasopressor agents, including dopaminergic drugs, 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 given 4 hours apart) with or without linezolid. In healthy volunteers receiving linezolid and dextromethorphan, no symptoms of serotonin syndrome (confusion, hallucinations, agitation, tremor, pathological flushing, diaphoresis, hyperpyrexia) were observed.

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

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

Concomitant use with tyramine-rich foods.

In patients receiving linezolid and tyramine in amounts less than 100 mg, no significant pressor effect was observed. This indicates that only excessive consumption of foods and beverages high in tyramine (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). Likewise, linezolid does not induce cytochrome P450 isoenzymes in rats. Therefore, an effect of linezolid on the pharmacokinetics of other drugs metabolized by these major enzymes 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) in combination with rifampicin (600 mg once daily for 8 days) and without rifampicin. Rifampicin reduced Cmax and AUC of linezolid by an average of 21% (90% CI [confidence interval] 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% reduction in peak international normalized ratio (INR) was observed, with a 5% reduction in mean INR. Data on patients receiving warfarin and linezolid concomitantly are insufficient to assess clinical significance.

Antibiotics.

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

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

In vitro studies have demonstrated additivity or indifference between the effects of 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. Blood parameters returned to baseline values 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 hematological abnormalities when treated with linezolid compared to younger patients. An increased incidence of thrombocytopenia may occur in patients with severe renal impairment (regardless of whether they are undergoing dialysis) and in patients with moderate hepatic impairment. Therefore, careful monitoring of blood counts is required in the following patients: those 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 function; patients with severe renal impairment or moderate to severe hepatic impairment; and patients receiving treatment for more than 10–14 days. Linezolid should be used 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, close monitoring of complete blood count parameters and implementation of appropriate treatment strategies are required.

Additionally, weekly monitoring of complete blood count (including hemoglobin levels, platelet count, total leukocyte count, and differential leukocyte count) is recommended in all patients receiving linezolid, regardless of initial blood test results.

In studies using an unapproved medicinal product under a compassionate use program, an increased incidence of severe anemia was observed in the group of patients who received linezolid for more than 28 days (the maximum recommended treatment duration). 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.

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

Imbalance in mortality rates in patients with gram-negative bloodstream infections related to catheter use.

In an open-label study involving patients with serious catheter-related bloodstream infections, an increased mortality rate was observed in the group of patients treated with 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 (RR [relative risk] 0.96; 95% CI: 0.58–1.59), but in the linezolid treatment group, the mortality rate was significantly higher (p = 0.0162) in patients with any additional pathogen or no pathogen at baseline (RR 2.48; 95% CI: 1.38–4.46). The greatest imbalance occurred during treatment and within 7 days after discontinuation of the investigational drug. Most patients in the linezolid treatment group developed gram-negative infections during the study—these patients died from infections caused by gram-negative pathogens and polymicrobial infections. Therefore, in complicated skin and soft tissue infections in patients with confirmed or suspected concomitant infection caused by gram-negative pathogens, linezolid should be used only if no other treatment options are available (see section "Indications"). In such circumstances, concomitant therapy for gram-negative infection should be initiated.

Diarrhea and antibiotic-associated colitis.

Diarrhea and colitis, 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, current 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.

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 the event of lactic acidosis, the benefit of continuing linezolid therapy versus potential risks should be carefully evaluated.

Mitochondrial dysfunction.

Linezolid inhibits mitochondrial protein synthesis. As a result of this inhibition, adverse reactions such as lactic acidosis, anemia, and neuropathy (peripheral and optic nerve) may occur. These events are more common 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 possible increases in blood pressure, linezolid should not be prescribed in patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, or when used concomitantly with 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 agents, including antidepressants (such as selective serotonin reuptake inhibitors [SSRIs]) and opioids, have been received. Therefore, the use of linezolid with serotonergic agents is contraindicated (see section "Contraindications"), except when such concomitant use is considered essential. In such cases, the patient should be closely monitored for symptoms of serotonin syndrome, such as cognitive disturbances, hyperpyrexia, hyperreflexia, and motor incoordination. If these symptoms occur, the physician should consider discontinuing one or both agents. Symptoms of withdrawal may occur after discontinuation of the serotonergic agent.

Peripheral neuropathy and optic neuropathy.

Cases of peripheral neuropathy, as well as optic neuropathy and optic neuritis, sometimes leading to vision loss, have been reported in patients receiving linezolid therapy. These reports primarily involved patients treated for more than 28 days (the maximum recommended treatment duration).

All patients should be instructed to inform their physician if they experience symptoms of visual disturbances, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defects. In such cases, prompt ophthalmologic evaluation is recommended, with referral to an ophthalmologist if necessary. Patients receiving linezolid for longer than the recommended 28 days should have regular vision assessments.

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

The risk of developing neuropathies may increase in patients receiving or who have recently received treatment with antituberculosis antibiotics.

Seizures.

Seizures have been reported in patients receiving linezolid therapy. Most of these patients had a risk factor such as a history of seizures. Patients should be advised to inform their physicians if they have a history of seizures.

Monoamine oxidase inhibitors.

Linezolid is a reversible, non-selective monoamine oxidase (MAO) inhibitor. However, at doses used for antibacterial therapy, it does not exhibit antidepressant effects. Very limited data on the use of linezolid in patients with underlying conditions and/or concomitant use of drugs associated with certain risks due to MAO inhibition have been obtained from drug interaction and safety studies. Therefore, the 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").

Use in combination 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.

Cases of symptomatic hypoglycemia have been reported in the post-marketing period 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 treatment and hypoglycemia has not been established, diabetic patients should be warned about the potential for hypoglycemic reactions during linezolid therapy.

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

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

Cases of hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been observed in patients receiving linezolid in the post-marketing period. These cases were associated with confusion, somnolence, general weakness, and, in severe cases, respiratory failure and death. Regular monitoring of serum sodium levels is recommended in patients at risk of hyponatremia, such as elderly patients, patients taking medications that may reduce serum sodium (e.g., thiazide diuretics such as hydrochlorothiazide), and other patients at risk of SIADH. If signs and symptoms of hyponatremia and/or SIADH occur, the drug NEZOLID should be discontinued and appropriate therapeutic measures should be taken.

Superinfection.

The effect of linezolid on normal flora has not been studied during clinical trials. Antibiotic use may sometimes lead to overgrowth of non-susceptible organisms. For example, approximately 3% of patients receiving linezolid at recommended doses developed drug-related candidiasis. Appropriate measures should be taken if superinfection occurs during treatment.

Special patient groups.

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

Linezolid is recommended for use in patients with severe hepatic impairment only when the expected benefit outweighs the theoretical risk (see section "Dosage and administration").

Gender.

No dosage adjustment of the medicinal product is required based on patient gender.

Impairment of fertility.

Linezolid decreased fertility and caused morphological changes 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.

Duration of use.

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

Specific diseases.

There is no experience with the use of linezolid for the treatment of patients with pressure ulcers, ischemic lesions, severe burns, or gangrene.

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.

Pregnancy.

Data on the use of linezolid in pregnant women are limited. Animal studies have demonstrated reproductive toxicity. There is a potential risk for humans. NEZOLID should not be used during pregnancy except when the expected benefit outweighs the potential risk.

Breastfeeding.

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

Ability to affect reaction speed when driving or operating machinery. Patients should be warned about the possible development of dizziness or visual disturbances (see sections "Special precautions for use" and "Adverse reactions") during linezolid therapy and advised not to drive or operate machinery if these symptoms occur.

Method of administration and dosage.

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

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 are based on clinical studies. For certain types of infections, a shorter duration of treatment may be appropriate, although 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 studied.

When treating infections associated with bacteremia, dose escalation or prolongation of the recommended treatment duration is not required.

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

Table 2

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

Patients who have been initially treated with intravenous infusions of linezolid may be switched to oral linezolid. In such cases, dose adjustment is not required, as the oral bioavailability of linezolid is nearly 100%.

Use in elderly patients. Dose adjustment is not necessary.

Use in patients with renal impairment (particularly those with creatinine clearance < 30 mL/min): the pharmacokinetics of linezolid are not altered in patients with any degree of renal impairment; however, two major metabolites of linezolid accumulate in patients with renal impairment, and the accumulation is greater in patients with more severe renal dysfunction. Plasma concentrations of linezolid are similar regardless of renal function; therefore, dose adjustment is not recommended for patients with renal impairment. However, given the lack of information on the clinical significance of accumulation of the major metabolites, this should be taken into consideration when administering linezolid to patients with renal impairment and potential risks associated with accumulation of these metabolites. Both linezolid and its two metabolites are removed by hemodialysis. Information on the effect of peritoneal dialysis on the pharmacokinetics of linezolid is lacking. Since approximately 30% of the administered dose is eliminated during a 3-hour hemodialysis session, linezolid should be administered after hemodialysis.

Use in patients with hepatic impairment: dose adjustment is not necessary. However, because clinical data are limited, linezolid should be administered to such patients only when the expected benefit outweighs the theoretical risk (see sections "Pharmacological Properties. Pharmacokinetics" and "Special Warnings").

Route of administration: orally.

Film-coated tablets may be taken regardless of food intake.

Children.

This medicinal product in this pharmaceutical form should be administered to children aged 12 years and older.

Overdose.

No specific antidote is known.

No cases of overdose have been reported.

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

Adverse Reactions

The data on adverse reactions presented below were obtained from clinical studies in which adult patients received the recommended doses of linezolid for up to 28 days.

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

The most frequent 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.

In addition to the list below, adverse reactions reported after marketing authorization are included. Since the frequency of these reactions cannot be determined from the available data, they are listed as "frequency unknown."

The following classification was used to define the frequency of adverse reactions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency unknown (cannot be estimated from the available data).

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

Blood and lymphatic system disorders: common — thrombocytopenia*, anemia*†; uncommon — pancytopenia*, eosinophilia, leukopenia*, neutropenia; rare — sideroblastic anemia*; frequency unknown — myelosuppression*.

Immune system disorders: rare — anaphylaxis.

Metalbolism and nutrition disorders: uncommon — hyponatremia; rare — lactic acidosis*.

Psychiatric disorders: common — insomnia.

Nervous system disorders: common — headache, taste perversion (metallic taste), dizziness; uncommon — hypesthesia, paresthesia, seizures*, peripheral neuropathy*; frequency unknown — serotonin syndrome**.

Eye disorders: uncommon — visual impairment, blurred vision*, optic neuropathy*; rare — visual field defect*; frequency unknown — 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 — phlebitis, thrombophlebitis, transient ischemic attack.

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

Hepatobiliary disorders: common — abnormal liver function tests, increased levels of alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase; uncommon — increased total bilirubin.

Skin and subcutaneous tissue disorders: common — pruritus, rash; uncommon — angioedema, dermatitis, hyperhidrosis, urticaria; rare — bullous skin lesions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, allergic vasculitis; frequency unknown — alopecia.

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

Reproductive system and breast disorders: uncommon — vulvovaginal disorders.

General disorders: common — fever, localized pain; uncommon — chills, fatigue, increased thirst.

Investigations. Biochemistry: common — increased levels of AST, ALT, lactate dehydrogenase [LDH], alkaline phosphatase, blood urea nitrogen, creatine kinase, lipase, amylase; decreased levels of total protein, albumin, sodium, calcium; increased or decreased levels of potassium or bicarbonate, postprandial (non-fasting) glucose; uncommon — increased bilirubin, creatinine, sodium, calcium; decreased non-fasting glucose; increased or decreased chloride levels. Hematology: common — increased neutrophil or eosinophil count, decreased hemoglobin, hematocrit or erythrocyte count, increased or decreased platelet or leukocyte count; uncommon — increased reticulocyte count, decreased neutrophil count.

* See section "Special 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 occurred in 2.0% of patients. In a compassionate use program involving patients with life-threatening infections and comorbid conditions, the incidence of anemia after linezolid treatment for ≤ 28 days was 2.5% (33 of 1326), compared to 12.3% (53 of 430) in patients treated for > 28 days. The proportion of documented cases of severe anemia requiring blood transfusion was 9% (3 of 33) in patients treated for ≤ 28 days and 15% (8 of 53) in those treated for > 28 days.

Rarely, adverse reactions associated with linezolid use were severe: localized abdominal pain, transient ischemic attack, and arterial hypertension.

In 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 reversible non-selective monoamine oxidase inhibitor (MAOI). The use of some MAO inhibitors has been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents.

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 led to respiratory failure and even death.

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. 4 or 10 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Zim Laboratories Limited

Address of manufacturer.
B-21/22, MIDC Area, Kalmeshwar, Nagpur, Maharashtra State, 441501, India

Marketing Authorization Holder. AAR PHARMA FZ-LLC

Address of Marketing Authorization Holder.
Premises 702, 7th Floor, Building: DSC Tower, P.O. Box – 478837, Dubai, United Arab Emirates