Linezolid euro

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINEZOLID EURO (LINEZOLID EURO)

Composition:

Active substance: linezolid;

1 ml of solution contains 2 mg of linezolid; 300 ml of infusion solution in a bag contains 600 mg of linezolid;

Excipients: glucose monohydrate; sodium citrate; citric acid anhydrous; hydrochloric acid concentrated; sodium hydroxide; water for injections.

Pharmaceutical form. Infusion solution.

Main physico-chemical characteristics: isotonic, clear, colorless or slightly yellow solution without visible particles.

Pharmacotherapeutic group. Antibacterial agents for systemic use.

ATC Code J01XX08.

Pharmacological Properties

Pharmacodynamics

General characteristics

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

The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, local information on microbial resistance should be taken into account, especially when treating severe infections. If necessary, when the local prevalence of resistance is such that the benefit of using the medicinal product, at least for certain types of infections, is questionable, consultation with an expert is recommended.

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. In vitro studies of clinical isolates (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 Euro 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 (C_max) is reached approximately 1–2 hours after dosing, 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 maximum concentration increases from 1.5 to 2.2 hours, and C_max is reduced by approximately 17% when linezolid is administered with a high-fat meal. However, total exposure, assessed by AUC_0–∞, 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 at steady state in healthy adult volunteers averages 40–50 L.

Linezolid concentrations have been 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 aminoethoxyacetic acid metabolite (A) and the hydroxyethylglycine metabolite (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 under in vitro conditions. In vitro studies have demonstrated that linezolid undergoes minimal metabolism, with possible involvement of the human cytochrome P450 system. However, the metabolic pathways of linezolid are not fully characterized.

Elimination

Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. At steady state, approximately 30% of the dose is excreted in urine as linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min, indicating net tubular reabsorption. Linezolid is not significantly detected in feces, whereas approximately 6% of the dose is excreted in feces as metabolite B and 3% as metabolite A.

Minor non-linearity in clearance was observed with increasing linezolid doses, likely due to lower renal and non-renal clearance at higher concentrations. However, this difference in clearance was minor and did not affect the apparent elimination 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, due to the lack of information on the clinical significance of accumulation of the main metabolites, the benefit-risk balance of using linezolid in patients with renal impairment and the potential risks of metabolite accumulation should be carefully considered. Both linezolid and its two metabolites are removed by hemodialysis. Information on the effect of peritoneal dialysis on linezolid pharmacokinetics is lacking.

Patients with hepatic impairment. The pharmacokinetics of linezolid were not altered in 7 patients with mild to moderate hepatic 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 Euro has not been studied in the treatment of pressure ulcer infections;
• 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 Euro 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.

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

Linezolid Euro must not be administered to patients receiving any monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, isocarboxazid, selegiline, moclobemide) or within two weeks of discontinuation of such agents.

Except in cases where careful monitoring and blood pressure surveillance are possible, Linezolid Euro must not be prescribed 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 should be discontinued during treatment with this medicinal product (see section "Use in pregnancy or breastfeeding").

Interaction with other medicinal products and other types of interactions.

Monoamine oxidase inhibitors (MAOIs)

Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO). Very limited data on the use of linezolid in patients receiving concomitant therapy with drugs that pose certain risks due to MAO inhibition have been obtained from drug interaction and safety studies. Therefore, linezolid use is not recommended unless careful patient monitoring and surveillance 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 increases the blood pressure elevation 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 vasoactive agents, including dopaminergic drugs, 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 given 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 receiving 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. Thus, 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 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 (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 sixteen healthy male volunteers who received linezolid (600 mg twice daily for 2.5 days) alone and in combination with rifampicin (600 mg once daily for 8 days). Rifampicin reduced the Cmax and area under the concentration-time curve (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. When warfarin was added to a stable regimen of linezolid treatment, a 10% reduction in the mean maximum international normalized ratio (INR) was observed during concomitant use, with a 5% reduction in INR AUC. 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 these drugs are administered concomitantly.

Gentamicin. The pharmacokinetics of linezolid or gentamicin are not altered when these drugs are 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.

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 may have a higher risk of developing blood abnormalities when treated with linezolid compared to younger patients. In patients with severe renal impairment (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 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.

Furthermore, 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 baseline blood parameters.

In compassionate use studies involving 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.

Cases of sideroblastic anemia have been reported in the post-marketing period. Among cases with known onset time, 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 due to catheter use, increased mortality was observed in the group receiving linezolid compared to the vancomycin/dicloxacillin/oxacillin treatment groups (78 out of 363 [21.5%] vs. 58 out of 363 [16.0%]). The primary factor influencing mortality was the presence of Gram-positive infection at baseline.

Mortality rates in patients with infections caused exclusively by Gram-positive organisms were similar (primary odds ratio 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 identified at baseline (primary odds ratio 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 or 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, concomitant treatment for Gram-negative infection should be initiated.

Diarrhea and antibiotic-associated colitis

Diarrhea and antibiotic-associated 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 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 considered.

Mitochondrial dysfunction

Linezolid inhibits mitochondrial protein synthesis. As a result of this inhibition, adverse reactions such as lactic acidosis, anemia, and neuropathy (peripheral and optic nerve) may occur. These events are more common when the drug is used for more than 28 days.

Potential interactions leading to increased blood pressure

Except in cases where patients can be monitored for possible increases in blood pressure, linezolid should not be prescribed to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, and/or concomitant use of drugs such as direct and indirect-acting 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 SSRIs), have been received. Therefore, concomitant use of linezolid and serotonergic drugs is contraindicated (see section "Contraindications"), except when the use of both linezolid and 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. After discontinuation of the serotonergic agent, withdrawal symptoms may occur.

Peripheral neuropathy and optic neuropathy

Cases of peripheral neuropathy, optic neuropathy, and optic neuritis, sometimes progressing to vision loss, have been reported in patients treated with Linezolid Euro. These reports primarily involved patients treated 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, urgent referral to an ophthalmologist for evaluation is recommended if necessary. Patients receiving Linezolid Euro for more than the recommended 28 days should have regular vision checks.

If peripheral neuropathy or optic neuropathy develops, the benefit of continuing treatment with Linezolid Euro versus potential risks should be carefully considered.

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

Seizures

Seizures have been reported in patients treated with Linezolid Euro. 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 MAO inhibitor. 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 of drugs that may carry 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 observation 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 in diabetic patients receiving insulin or oral hypoglycemic agents while being treated with linezolid, a non-selective, reversible MAO inhibitor. 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 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 led to respiratory failure and even death. Regular monitoring of serum sodium levels is recommended in elderly patients, patients taking diuretics, and other patients at risk of hyponatremia and/or SIADH during treatment with Linezolid Euro. If signs and symptoms of hyponatremia and/or SIADH appear, the drug should be discontinued and appropriate supportive measures should be taken.

Superinfection

The effect of linezolid on normal flora 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 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").

Dose adjustment is not necessary based on patient gender.

Fertility impairment

Linezolid reduced fertility and caused morphological abnormalities in sperm quality in healthy adult male rats at exposure levels approximately similar to those expected in humans. These changes were reversible. The potential effect of linezolid on male reproductive function is unknown.

Clinical trials

The safety and efficacy of linezolid 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.

Excipients

1 mL of solution contains 45.7 mg (i.e., 13.7 g/300 mL) of glucose. This should be taken into account when treating patients with diabetes mellitus or other conditions associated with glucose intolerance. 1 mL of solution also contains 0.38 mg (114 mg/300 mL) of sodium. Sodium content should be considered for patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

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

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

Ability to affect reaction speed when driving or operating machinery.

Patients should be warned about the possibility of developing dizziness or visual disturbances (see sections "Special precautions" and "Side effects") 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 agent, site and severity of infection, as well as the clinical response.

The recommendations for duration of therapy 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 studies.

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 were initially treated with Linezolid Euro for intravenous infusion may be switched to Linezolid Euro for oral administration. In such cases, dose adjustment is not required, as the oral bioavailability of linezolid is nearly 100%.

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

Indications	Dosage and route of administration		Recommended duration of treatment (consecutive days)
	Paediatric patients1 (from birth to 11 years of age)	Adults and children (12 years of age and older)
Hospital-acquired pneumonia	10 mg/kg intravenously or orally2 every 8 hours	600 mg intravenously or orally2 every 12 hours	10–14
Community-acquired pneumonia (particularly forms associated with bacteremia)
Complicated skin and skin structure infections
Infections caused by vancomycin-resistant Enterococcus faecium, including infections associated with bacteremia	10 mg/kg intravenously or orally2 every 8 hours	600 mg intravenously or orally2 every 12 hours	14–28
Uncomplicated skin and skin structure infections	Children up to 5 years of age: 10 mg/kg orally2 every 8 hours; children 5–11 years of age: 10 mg/kg orally2 every 12 hours	Adults: 400 mg orally2 every 12 hours; children 12 years of age: 600 mg orally2 every 12 hours	10–14

1Neonates <7 days of age. Most preterm neonates <7 days of age (<34 weeks gestation) have lower systemic clearance and higher AUC values of linezolid than most term neonates and children up to 1 year of age. Treatment of such neonates should be initiated with a dose of 10 mg/kg every 12 hours. For neonates with inadequate clinical response to the drug, a dose of 10 mg/kg every 8 hours may be considered. All patients under 7 days of age should receive a dose of 10 mg/kg every 8 hours.

2 The drug is available in another dosage form allowing appropriate dosing.

Instructions for use

Linezolid Euro for intravenous infusion is supplied in single-use, ready-to-use infusion bags. Immediately before use, remove the aluminum protective overwrap and visually inspect the medicinal product for mechanical particulates; squeeze the bag for approximately 1 minute to ensure its integrity. If the bag leaks, do not use the solution, as sterility may be compromised. Any unused solution should be disposed of according to applicable requirements.

Intravenous infusion should be administered over 30–120 minutes. Do not connect infusion bags in series! Do not add other drugs to this solution.

When administering Linezolid Euro for intravenous infusion simultaneously with other medicinal products, each product should be administered separately, in accordance with the recommended dose and route of administration for each medicinal product.

When using a single intravenous system for sequential administration of multiple drugs, the system should be flushed before and after administration of Linezolid Euro for intravenous infusion with an infusion solution compatible with both Linezolid Euro and the other drug being administered through the same system.

Compatible infusion solutions: 0.9% sodium chloride injection, 5% dextrose injection, lactated Ringer's injection.

Major incompatibilities

Physical incompatibility occurred when Linezolid Euro for intravenous infusion was administered via a Y-connector together with the following drugs: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, sodium phenytoin, and trimethoprim/sulfamethoxazole. In addition, Linezolid Euro for intravenous infusion was chemically incompatible with ceftriaxone sodium.

Use in elderly patients. Dose adjustment is not required.

Use in patients with renal impairment. Dose adjustment is not required. Since approximately 30% of the dose is eliminated during a 3-hour hemodialysis session initiated 3 hours after drug administration, linezolid should be administered after hemodialysis in patients undergoing such treatment (see section "Pharmacological properties. Pharmacokinetics").

Use in patients with hepatic impairment. Dose adjustment is not required (see section "Pharmacological properties. Pharmacokinetics").

Children.

Can be used from the first days of life.

In children aged 1 week to 12 years, administration of the drug at a dose of 10 mg/kg every 8 hours daily provides exposure approaching that achieved in adults when the drug is administered at a dose of 600 mg twice daily.

In neonates under 1 week of age, systemic clearance of linezolid (per kg body weight) increases rapidly during the first week of life. Thus, in neonates receiving the drug at a dose of 10 mg/kg every 8 hours daily, higher systemic exposure to the drug is observed on the first day after birth. Due to the rapidly increasing clearance of the drug during the first 7 days of life, excessive accumulation of the drug in the body is not expected with this dosing regimen during the first week of life (see section "Dosage and administration").

In children aged 12 to 17 years, the pharmacokinetics of linezolid are similar to those in adults receiving a 600 mg dose. Therefore, in adolescents receiving the drug at a dose of 600 mg every 12 hours daily, exposure will be the same as in adult patients receiving the drug at the same dose.

Overdose.

There is no specific antidote.

No cases of overdose have been reported.

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

Adverse Reactions.

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

The most frequently reported adverse reactions were diarrhea (8.4%), headache (6.5%), nausea (6.3%), and vomiting (4.0%). The most common adverse reactions leading to discontinuation of the medicinal product were headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to drug-related adverse reactions.

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

The adverse reactions reported during treatment 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 not known (cannot be estimated from the available data).

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

Blood and lymphatic system disorders: common – anemia*3; 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*, hypoaesthesia, paraesthesia; frequency not known – serotonin syndrome**, peripheral neuropathy*.

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

Ear and labyrinth disorders: uncommon – tinnitus.

Cardiac disorders: uncommon – arrhythmia (tachycardia).

Vascular disorders: common – arterial 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, tongue disorders or color changes; 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 reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, alopecia.

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

Reproductive system and breast disorders: uncommon – vulvovaginal disorders.

General disorders and administration site conditions: common – pyrexia, localized pain; uncommon – chills, fatigue, injection site pain, thirst.

Investigations

Biochemistry: common – increased lactate dehydrogenase, creatine kinase, lipase, amylase, or postprandial (non-fasting) glucose levels; decreased total protein, albumin, sodium, and calcium; increased or decreased potassium or bicarbonate; uncommon – increased sodium or calcium, decreased glucose without fasting, increased or decreased chloride.

Hematology: common – increased neutrophils or eosinophils, decreased hemoglobin, hematocrit, or erythrocyte count, increased or decreased platelet or leukocyte count; uncommon – increased reticulocyte count, 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".

3 In controlled clinical trials where linezolid was administered for up to 28 days, anemia was observed in 2.0% of patients. In a compassionate use program involving patients with life-threatening infections and comorbid conditions, the percentage of patients who developed anemia after receiving linezolid for ≤28 days was 2.5% (33 out of 1326), compared to 12.3% (53 out of 430) in those treated for >28 days. The proportion of documented cases of severe anemia requiring blood transfusion due to the medicinal product was 9% (3 out of 33) in patients treated for ≤28 days and 15% (8 out of 53) in those treated for >28 days.

Adverse reactions associated with linezolid use, which were assessed in rare cases 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 reversible non-selective monoamine oxidase inhibitor (MAO). The use of some MAO inhibitors has been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents.

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

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging to protect from light. Do not freeze. Keep out of the reach and sight of children.

The contents of the bag should be used immediately after opening.

Incompatibilities. See section "Dosage and method of administration".

Packaging.

300 ml of solution, packed in a multilayer polyolefin infusion bag with a non-latex port system connector; the bag is enclosed in a foil protective overwrap; 10 bags per cardboard box.

Prescription category. Prescription only.

Manufacturer. Infomed Fluids S.R.L.

Manufacturer's address and location of operations.

Boulevard Theodore Pallady No. 50, Sector 3, Bucharest, 032266, Romania.