Linecoc

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINECOCK (LINEcoc)

Composition:

Active ingredient: linezolid;

1 tablet contains 600 mg of linezolid;

Excipients: poloxamer 407, sodium starch glycolate (type A), povidone K30, colloidal anhydrous silicon dioxide, microcrystalline cellulose (type 102), lactose monohydrate, talc, magnesium stearate;

film coating Opadry White YS-1-18202-A: hypromellose (E464), titanium dioxide (E171), macrogol (MW 400) / polyethylene glycol;

blue printing ink: ethanol, water, purified shellac (E904), propylene glycol, FD&C Blue No.1 (E133 Brilliant Blue FCF), ammonium hydroxide (E527).

Medicinal form. Film-coated tablets.

Main physicochemical properties: white, oval, biconvex tablets with the inscription "600" on one side.

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 antimicrobials — 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 (a key component in the translation process).

The prevalence of acquired resistance in specific species may vary geographically and over time; therefore, local information on microbial resistance should be taken into account, especially when treating severe infections. If necessary, when the local prevalence of microbial resistance raises doubts about the benefit of using the medicinal product, at least for certain types of infections, consultation with an expert should be sought.

Susceptible microorganisms

Aerobic gram-positive microorganisms: Enterococcus faecalis, Enterococcus faecium*, Staphylococcus aureus*, coagulase-negative staphylococci, Streptococcus agalactiae*, Streptococcus pneumoniae*, Streptococcus pyogenes*, Group C streptococci, Group G streptococci.

Anaerobic gram-positive microorganisms: Clostridium perfringens, Peptostreptococcus anaerobius, Peptostreptococcus species.

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

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

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

Cross-resistance

The mechanism of action of linezolid differs from that of other classes of antibiotics. Studies of clinical strains (methicillin-resistant staphylococci, vancomycin-resistant enterococci, as well as penicillin- and erythromycin-resistant streptococci) in vitro 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 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 (Cmax) is reached approximately 1–2 hours after administration, and absolute bioavailability is approximately 100%. Therefore, linezolid can be administered orally or intravenously without dose adjustment. Linezolid can be administered regardless of food intake. Time to reach Cmax 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 the area under the concentration-time curve (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. Linezolid concentrations were measured in various fluids in a limited number of participants in phase 1 studies after multiple doses of linezolid. The ratio of linezolid concentration in saliva to plasma concentration was 1.2:1, and the ratio of linezolid concentration in sweat to plasma concentration was 0.55:1.

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

Excretion. Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. At steady state, approximately 30% of the administered dose is recovered in urine as unchanged linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min, indicating net tubular reabsorption. Linezolid is hardly detectable in feces, whereas approximately 6% of the administered dose is recovered 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.

Special patient groups

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

Patients with hepatic impairment. The pharmacokinetics of linezolid were not altered in 7 patients with mild to moderate hepatic dysfunction (Child-Pugh class A or B). Based on available data, dose adjustment is not recommended for patients with mild to moderate hepatic impairment. The pharmacokinetics in patients with severe hepatic impairment have not been evaluated.

Clinical Characteristics

Indications

For the treatment of infections caused by susceptible strains of specified microorganisms:

• Hospital-acquired pneumonia;

• Community-acquired pneumonia;

• Complicated skin and skin structure infections, including diabetic foot infections without accompanying osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae. The use of linezolid in 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;

• Vancomycin-resistant infections caused by strains of Enterococcus faecium, 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 anti-gram-negative therapy should be initiated immediately.

Contraindications

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

Linezolid should not be used during treatment with any medicinal products that inhibit monoamine oxidase A and B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide), or within 2 weeks after discontinuation of such agents.

Except in cases where careful observation and monitoring of blood pressure are possible, linezolid should not be administered to patients with the following conditions:

• Uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute episodes of dizziness;
• Concomitant use of 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 this medicinal product (see section "Use in pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors (MAO)

Linezolid is a reversible non-selective inhibitor of MAO. In drug interaction and safety studies of linezolid, 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 careful monitoring of the patient's condition is possible (see sections "Contraindications" and "Special precautions").

Potential interactions leading to increased blood pressure

In healthy volunteers with normal blood pressure, linezolid enhances 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 patients with hypertension have not been conducted. Careful dose titration of medicinal products with vasopressor effects, including dopaminergic agents, is recommended to achieve the desired outcome when used concomitantly with linezolid.

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 linezolid and dextromethorphan, no symptoms of serotonin syndrome (confusion, hallucinations, agitation, tremor, flushing, diaphoresis, hyperpyrexia) were observed.

Post-marketing experience: one report of symptoms resembling serotonin syndrome was received in a patient taking linezolid and dextromethorphan; symptoms resolved after discontinuation of both drugs. During clinical use of linezolid with serotonergic agents, including antidepressants (such as selective serotonin reuptake inhibitors [SSRIs]), cases of serotonin syndrome have been reported. Therefore, although concomitant 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".

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 (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 influence of linezolid on the pharmacokinetics of other drugs metabolized by CYP450 is expected.

Rifampicin. The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen healthy male 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 the Cmax and area under the concentration-time curve (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. A 10% decrease in mean peak international normalized ratio (INR) was observed when warfarin was added to a stable linezolid regimen, with a 5% reduction in INR AUC during concomitant administration. Data on patients receiving both warfarin and linezolid are insufficient to assess the clinical significance of these findings.

Antibiotics

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

Gentamicin. The pharmacokinetics of linezolid or gentamicin are not altered when administered concomitantly. In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampicin, imipenem-cilastatin, aztreonam, ampicillin, streptomycin.

Antioxidants

No dose adjustment of linezolid is recommended when administered concomitantly with vitamin C or vitamin E.

Special precautions for use

Myelosuppression

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In such cases, hematological parameters returned to pre-treatment levels after discontinuation of linezolid. The risk of these effects is likely related to the duration of treatment. Elderly patients have a higher risk of developing blood abnormalities when receiving linezolid compared to younger patients. In patients with severe renal insufficiency (regardless of whether they are undergoing dialysis), there may be an increased frequency of thrombocytopenia. Therefore, careful monitoring of blood counts is necessary 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 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 considered absolutely necessary. In such situations, close monitoring of complete blood count parameters and appropriate therapeutic interventions are required.

Furthermore, it is recommended to perform weekly monitoring of complete blood count (including hemoglobin levels, platelet count, total leukocyte count, and differential leukocyte count) in all patients receiving linezolid, regardless of baseline blood parameters.

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

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

Imbalance in mortality rates in a clinical study involving patients with catheter-related bloodstream infections caused by Gram-positive pathogens

In an open-label study involving patients with serious intravascular infections caused by catheter use, 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 main 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% CI 0.58–1.59), but in the linezolid treatment group, the frequency of fatal outcomes was significantly higher (p = 0.0162) in patients with any additional pathogen or no pathogen at baseline (relative risk 2.48; 95% CI: 1.38–4.46). The greatest imbalance occurred during treatment and within 7 days after discontinuation of the study drug. Most patients in the linezolid treatment group developed Gram-negative infections during the study and died from infections caused by Gram-negative pathogens and polymicrobial infections. Therefore, in complicated skin and soft tissue infections in patients with established or suspected concomitant Gram-negative infection, linezolid should be used only when no other treatment options are available (see section "Indications"). In such circumstances, concurrent treatment for Gram-negative infection should be initiated.

Diarrhea and antibiotic-associated colitis

Diarrhea and colitis associated with antibiotic use, including pseudomembranous colitis and Clostridium difficile-associated diarrhea (CDAD), have been reported with the use of nearly all antibiotics, including linezolid. The severity of these conditions may range 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 drugs 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. In case 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 more 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 prescribed in cases of uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, and/or concomitant use of drugs such as direct and indirect-acting 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), have been received. Therefore, concomitant use of linezolid and serotonergic drugs is contraindicated (see section "Contraindications"), except in cases where the use of both linezolid and concomitant serotonergic agents is deemed 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 such symptoms occur, the physician should consider discontinuing one or both drugs. Withdrawal symptoms may occur after discontinuation of the serotonergic agent.

Peripheral neuropathy and optic neuropathy

Peripheral neuropathy, as well as optic neuropathy and optic neuritis, sometimes progressing to vision loss, have been reported in patients receiving Linexoc. These disorders occurred primarily in patients receiving treatment for more than 28 days (the maximum recommended treatment duration).

All patients should be advised to report symptoms of visual disturbances, such as changes in visual acuity, changes in color perception, blurred vision, or visual field defects. In such cases, prompt ophthalmological examination is recommended, with referral to an ophthalmologist if necessary. Patients receiving Linexoc for more than the recommended 28 days should have regular vision checks.

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

The risk of neuropathy may be increased when linezolid is used to treat patients who are receiving or have recently received anti-tuberculosis therapy.

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 physicians if they have previously experienced seizures.

MAO 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 on the use of linezolid for treating the primary condition and/or concomitant use with agents that may carry certain risks due to MAO inhibition have been obtained from drug interaction and safety studies. Therefore, use of linezolid under such circumstances is not recommended unless close monitoring and patient surveillance can be ensured (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Use with tyramine-rich products

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 while being treated with linezolid, a non-selective, reversible MAO inhibitor. Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. Although a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be warned 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 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. 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 Linexoc. If symptoms of hyponatremia and/or SIADH occur, the drug should be discontinued and appropriate supportive measures taken.

Superinfection

The effect of linezolid on normal flora was not studied during clinical trials. Antibiotic use may sometimes lead to overgrowth of resistant organisms. For example, approximately 3% of patients receiving linezolid at recommended doses during clinical trials developed candidiasis associated with linezolid use. Appropriate measures should be taken if superinfections occur 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 "Method of administration and dosage").

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

Dose adjustment based on patient gender is not necessary.

Impairment of fertility

Linezolid reduced fertility and caused morphological abnormalities in sperm quality in healthy adult male rats at exposure levels approximately equivalent 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 when used for more than 28 days have not been established.

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

Emergence of drug-resistant bacteria

It is unlikely that prescribing Linexoc in cases of undiagnosed bacterial infection or for prophylactic purposes will harm the patient or increase the risk of emergence of drug-resistant bacteria.

Excipients:

• Each tablet of Linexoc contains 172.8 mg of sodium. Caution is advised when administering to patients on a sodium-controlled diet.
• Each tablet of Linexoc contains 25.2 mg of lactose monohydrate. If a patient has a known intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Use during pregnancy or breastfeeding

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

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

Ability to affect reaction speed when driving or operating machinery

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

Method of Administration and Dosage

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

The treatment duration recommendations provided below are based on results from clinical trials. For certain types of infections, a shorter treatment duration may be appropriate, although 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 established. There is no need to increase the recommended doses or duration of treatment in cases of infections associated with bacteremia.

Patients who have initiated treatment with intravenous linezolid infusions may be switched to oral treatment with Linekox. Dose adjustment is not required in such cases, as the oral bioavailability of linezolid is nearly 100%. Dosage recommendations according to indications are provided in the table below.

* Use another dosage form of the drug 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 impairment. No dose adjustment is required. Since approximately 30% of the dose is removed during a 3-hour hemodialysis session initiated 3 hours after drug administration, linezolid should be administered after hemodialysis in patients receiving such treatment (see section "Pharmacological Properties. Pharmacokinetics").

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

Children

Linexok, film-coated tablets, are indicated for children aged 12 years and older.

Overdose

Symptoms. No cases of overdose have been reported.

Treatment. There is no specific antidote. In case of overdose, symptomatic treatment along with measures to support glomerular filtration rate is indicated. Approximately 30% of the administered dose of the drug 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 main metabolites of linezolid are also removed by hemodialysis.

Adverse Reactions

Data on adverse reactions were obtained from clinical trials in which more than 2000 adult patients received recommended doses of linezolid for up to 28 days.

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

The frequency of adverse reactions reported after linezolid marketing cannot be established from available data and is therefore listed as "frequency unknown."

Adverse reactions are listed below according to the following frequency classification: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency unknown (cannot be estimated from available data).

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

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

Immune system disorders: frequency unknown — anaphylaxis.

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

Psychiatric disorders: common — insomnia.

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

Eye disorders: uncommon — blurred vision*; rare — visual field defect*; frequency unknown — optic neuropathy*, optic neuritis*, vision loss*, altered visual sensation*, change in color perception*.

Ear and labyrinth disorders: uncommon — tinnitus.

Cardiovascular disorders: common — hypertension; uncommon — arrhythmia (tachycardia), transient ischemic attack, phlebitis, thrombophlebitis.

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

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

Skin and subcutaneous tissue disorders: common — pruritus, rash; uncommon — urticaria, dermatitis, excessive sweating; frequency unknown — bullous skin lesions such as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, alopecia.

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

Reproductive system and breast disorders: uncommon — vulvovaginal disorders.

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

Investigations. Chemistry: common — increased lactate dehydrogenase, creatine kinase, lipase, amylase, or postprandial (non-fasting) glucose levels; decreased total protein, albumin, sodium, or calcium; increased or decreased potassium or bicarbonate levels; uncommon — increased sodium or calcium, decreased non-fasting glucose, increased or decreased chloride levels.

Hematology: common — increased neutrophils or eosinophils, decreased hemoglobin, hematocrit, or erythrocyte count, increased or decreased platelet or leukocyte count; uncommon — increased reticulocytes, decreased neutrophil count.

* See section "Special warnings and precautions for use".

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

† In controlled clinical trials where linezolid was administered for up to 28 days, anemia occurred in 2.0% of patients. In patients treated under an unapproved drug program for life-threatening infections and comorbid conditions, the percentage of patients who developed anemia after receiving linezolid for ≤ 28 days was 2.5% (33 of 1326), compared to 12.3% (53 of 430) in those 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.

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

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product registration is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging. 10 tablets in a blister; 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer

FARMATEN S.A.

FARMATEN INTERNATIONAL S.A.

Manufacturer's address and location of operations

Derwenakion 6, Pallini Attica, 15351, Greece

Industrial Park Sapes Prefecture Rodopi, Block No. 5, Rodopi, 69300, Greece