Linezolid-hetero

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINEZOLID-HETERO (LINEZOLID-HETERO)

Composition:

Active substance: linezolid;

One film-coated tablet contains 600 mg of linezolid;

Excipients: lactose monohydrate, corn starch, hydroxypropylcellulose, sodium starch glycolate, magnesium stearate, Opadry White 03B58895.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: white or almost white, oval, biconvex tablets with beveled edges, film-coated, marked with a score line, bearing the inscription "H" on one side and inscriptions "L" and "8" separated by the score line on the reverse side.

The tablet can be divided into two equal parts.

Pharmacotherapeutic group. Antibacterials for systemic use.
ATC code: J01XX08.

Pharmacological properties.

Pharmacodynamics.

General characteristics.

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 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 data 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 species.

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

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

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

Cross-resistance

The mechanism of action of linezolid differs from that of other classes of antibiotics. In vitro studies of clinical 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 Linezolid-Hetero contains linezolid, which is a biologically active substance and is metabolized to inactive derivatives.

Absorption

Linezolid is rapidly 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. 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. Approximately 31% of linezolid is protein-bound in plasma, independent of drug concentration. The volume of distribution 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 phase 1 study volunteers. 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). 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 total linezolid clearance. At steady state, approximately 30% of the dose is recovered in urine as unchanged linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min, indicating tubular reabsorption. Linezolid is virtually undetectable in feces, whereas approximately 6% of the dose is recovered in feces as metabolite B and 3% as metabolite A.

Minor non-linearity in clearance was observed with increasing linezolid doses, apparently due to lower renal and non-renal clearance at higher concentrations. However, this difference in clearance was minor and did not affect the apparent 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 similar regardless of renal function, dose adjustment is not recommended for patients with renal impairment. However, given the lack of information on the clinical significance of accumulation of the major metabolites, the appropriateness of linezolid use in patients with renal impairment and the potential risks of metabolite accumulation should be carefully considered. Both linezolid and its two metabolites are removed by hemodialysis. Information on the effect of peritoneal dialysis on linezolid pharmacokinetics is lacking.

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

• Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes;

• Vancomycin-resistant infections caused by Enterococcus faecium strains, including infections associated with bacteremia.

Linezolid is not indicated for the treatment of infections caused by gram-negative microorganisms. In case of suspicion or identification of a gram-negative pathogen, specific gram-negative therapy should be initiated immediately.

Contraindications.

Known hypersensitivity to linezolid or to any other component of the medicinal product.

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

Except in cases where close observation and monitoring of blood pressure are possible, linezolid must not be administered to patients with the following concomitant clinical conditions or concurrently with the following medicinal products:

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

Breastfeeding must 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 non-selective, reversible 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 therapy with medicinal products that pose certain risks due to MAO inhibition. Therefore, the use of linezolid under such circumstances is not recommended unless close monitoring of the patient is possible (see sections "Contraindications" and "Special precautions").

Potential interactions leading to increased blood pressure

In healthy volunteers with normal blood pressure, linezolid potentiates the increase in blood pressure caused by pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant administration of linezolid and 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 agents with vasopressor activity, including dopaminergic agents, is recommended to achieve the desired effect when linezolid is used concomitantly with such 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 volunteers receiving both 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 taking linezolid and dextromethorphan; symptoms resolved after discontinuation of both drugs.

During clinical use of linezolid in combination with serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids, cases of serotonin syndrome have been reported. Thus, although concomitant use of these agents 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 vasopressor effect was observed. This indicates that only excessive consumption of foods and beverages rich 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) in combination with rifampicin (600 mg once daily for 8 days) and without. Rifampicin reduced Cmax and AUC of linezolid by 21% (90% CI 15, 27) and 32% (90% CI 27, 37), respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin. A 10% reduction in mean maximum INR (international normalized ratio) was observed when warfarin was added to a course of linezolid treatment at steady state, with a concurrent 5% reduction in INR AUC. Data on patients receiving warfarin and linezolid concomitantly are insufficient to assess clinical significance, if any.

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

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

Special precautions for use.

Myelosuppression

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

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

During clinical studies, in patients treated with linezolid for more than 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. This type of anemia occurred more frequently in patients treated with linezolid for more than 28 days.

In the post-marketing period, cases of sideroblastic anemia have also been reported in patients, most of whom received linezolid for more than 28 days. After discontinuation of linezolid, most patients recovered fully or partially with treatment for anemia or even without treatment.

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

In an open-label study 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 of 363 (21.5%) vs. 58 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; however, in the linezolid treatment group, the mortality rate was significantly higher in patients with any additional pathogen or no pathogen identified at baseline. The greatest imbalance occurred during treatment and within 7 days after discontinuation of the study drug. Most patients in the linezolid group developed gram-negative infections during the study and died from infections caused by gram-negative pathogens or polymicrobial infections. Therefore, in complicated skin and soft tissue infections in patients with confirmed or suspected concomitant infection caused by gram-negative pathogens, 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.

Diarrhea and antibiotic-associated colitis

Diarrhea and colitis associated with antibiotic use, including pseudomembranous colitis and Clostridium difficile-associated diarrhea (CDAD), have been reported with the use of nearly all antibiotics, including linezolid, with severity ranging from mild diarrhea to fatal colitis. It is therefore important to consider this diagnosis in patients who develop diarrhea during or after treatment with linezolid. If antibiotic-associated diarrhea or colitis is suspected or confirmed, ongoing antibacterial therapy (including linezolid) should be discontinued and appropriate therapeutic measures initiated immediately. In such situations, the use of drugs that inhibit peristalsis is contraindicated.

Lactic acidosis

Cases of lactic acidosis have 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 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 closely monitored for possible increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, and/or concomitant use of drugs such as direct and indirect sympathomimetics (e.g., pseudoephedrine), vasoconstrictors (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, concomitant use of linezolid and serotonergic agents is contraindicated (see section "Contraindications"), except when use of both linezolid and concomitant serotonergic agents is deemed essential. In such cases, the patient should be under close observation for signs and symptoms of serotonin syndrome, such as cognitive disturbances, hyperpyrexia, hyperreflexia, and motor incoordination. If signs or symptoms occur, the physician should consider discontinuing one or both agents. Withdrawal symptoms may occur after discontinuation of the serotonergic agent.

Peripheral neuropathy and optic neuropathy

Cases of peripheral neuropathy, optic neuropathy, and optic neuritis, sometimes progressing to vision loss, have been reported in patients receiving linezolid therapy. 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, color vision changes, blurred vision, or visual field defects. In such cases, prompt ophthalmologic evaluation is recommended, if necessary. Patients receiving linezolid for more than the recommended 28 days should have regular vision monitoring.

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 be increased in patients receiving or who have recently received antibacterial agents for the treatment of tuberculosis.

Seizures

Cases of seizures have been reported in patients receiving Linezolid-Hetero. In most cases, a risk factor such as a history of seizures was reported. Patients should inform their physicians if they have previously experienced seizures.

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO). However, at doses used for antibacterial therapy, it does not exhibit antidepressant effects. Very limited data are available from drug interaction and safety studies on the use of linezolid for the treatment of the primary condition and/or concomitant use with drugs that may carry certain risks due to MAO inhibition. Therefore, use of linezolid under such circumstances is not recommended unless close monitoring and observation of the patient are possible (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use with tyramine-rich foods

Patients should be advised to avoid consuming large amounts of tyramine-rich foods (see section "Interaction with other medicinal products and other forms of interaction").

Hypoglycemia

Post-marketing reports indicate cases of symptomatic hypoglycemia with linezolid, a reversible non-selective MAO inhibitor, in diabetic patients taking insulin or oral hypoglycemic agents. Hypoglycemic episodes have been associated with some MAO inhibitors in diabetic patients receiving insulin or hypoglycemic agents. Although a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be warned of the potential for hypoglycemic reactions during 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, somnolence, general weakness, and, in severe cases, respiratory insufficiency and even fatal outcomes. 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-Hetero. If signs and symptoms of hyponatremia and/or SIADH occur, the drug should be discontinued and appropriate supportive measures taken.

Superinfection

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

Antibiotic use may occasionally lead to overgrowth of non-susceptible organisms. For example, approximately 3% of patients receiving linezolid at recommended doses in clinical studies developed drug-related candidiasis. Appropriate measures should be taken if superinfections occur 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 should be used in patients with severe hepatic impairment only when the expected benefit outweighs the theoretical risk (see section "Dosage and administration").

No dosage adjustment is necessary based on patient gender.

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 use beyond 28 days have not been established.

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

Pregnancy. Data on the use of linezolid in pregnant women are limited. Animal studies have demonstrated reproductive toxicity. The potential risk to humans exists. Linezolid 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 may pass into breast milk. Therefore, breastfeeding should be discontinued during treatment with the drug.

Ability to affect reaction rate when driving or operating machinery

Patients should be warned of the possibility of developing dizziness or visual disturbances during treatment with linezolid and advised not to drive or operate machinery if these symptoms occur.

Administration and Dosage

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

The treatment duration recommendations provided below were used in 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 established.

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

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

Patients who have initiated treatment with intravenous linezolid (Linezolid-Hetero for infusion) may be switched to oral linezolid (Linezolid-Hetero for oral administration) without dose adjustment, as the oral bioavailability of linezolid is nearly 100%.

Indications	Dosage and route of administration	Recommended duration of treatment (consecutive 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 forms associated with bacteremia)
Complicated skin and skin structure infections
Infections caused by Enterococcus faecium , vancomycin-resistant, including infections associated with bacteremia	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 with 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 removed during a three-hour hemodialysis session initiated three 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 can be administered to children aged 12 years and older.

Overdose.

Specific antidote is unknown.

There have been no reported cases of overdose.

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

Adverse Reactions

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

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

Additional adverse reactions reported after marketing of the drug are listed below, categorized with the frequency term "frequency not known," as the frequency cannot be estimated from the available data.

Adverse reactions reported during treatment are listed below, classified by frequency as follows: 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 not known – frequency cannot be estimated from the available data.

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

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

Immune system disorders: frequency not known – anaphylaxis.

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

Psychiatric disorders: common – insomnia.

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

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

Ear and labyrinth disorders: uncommon – tinnitus.

Cardiac disorders: uncommon – arrhythmia (tachycardia).

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

Gastrointestinal disorders: common – diarrhea, nausea, vomiting, localized or generalized abdominal pain, constipation, dyspepsia; uncommon – pancreatitis, gastritis, abdominal distension, dry mouth, glossitis, frequent loose stools, stomatitis, disorders or changes in tongue color; rare – discoloration 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 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: common – fever, localized pain; uncommon – chills, fatigue, thirst.

Investigations. Biochemistry: 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 levels, decreased glucose levels without fasting, 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 was observed in 2.0% of patients.

Adverse reactions associated with linezolid use, which have been rarely assessed as severe reactions: 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 when treated with linezolid, a non-selective, reversible monoamine oxidase inhibitor (MAOI). Some MAO inhibitors have 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 insufficiency and even fatal outcomes.

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C, in a place inaccessible to children.

Packaging. Tablets 600 mg; 10 tablets in a blister pack, 1 or 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and location of business activity.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.