Linezolid krka

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINEZOLID KRKA

Composition:

Active substance: linezolid;

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

Excipients: sodium citrate dihydrate, citric acid, glucose monohydrate, hydrochloric acid*, sodium hydroxide*, water for injections.

* Used in the manufacturing process to adjust the pH of the solution within the range of 4.6–5.2.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless to yellow or yellowish-brown solution.

Pharmacotherapeutic group. Antibacterials for systemic use. Other antibacterials. ATC code J01X X08.

Pharmacological Properties.

Pharmacodynamics.

Linezolid is an antibacterial agent.

A thorough investigation of the QT interval was conducted by comparing linezolid and placebo following a single intravenous infusion of linezolid at a dose of 600 mg administered over 1 hour; a single 1200 mg dose administered as a 1-hour intravenous infusion; as well as administration of placebo and a single oral dose of linezolid for comparison. No significant effect of linezolid on the QT interval was observed at the maximum plasma concentration of linezolid or at any other time following administration of 600 mg or 1200 mg doses.

Pharmacokinetics.

Mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous administrations of linezolid are presented in Table 1.

Table 1.

Mean (standard deviation) pharmacokinetic parameters of linezolid in adults

1AUC for single dose = AUC0-∞; for multiple dose = AUC0-τ.

2Data normalized to a dose of 375 mg.

3Data normalized to a dose of 625 mg; intravenous dose administered by infusion over 0.5 hour.

Cmax – maximum plasma concentration of the drug; Cmin – minimum plasma concentration of the drug; Tmax – time to reach Cmax; AUC – area under the concentration-time curve; t1/2 – elimination half-life; CL – systemic clearance.

Absorption

Linezolid is extensively absorbed after oral administration. Peak plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing, and absolute bioavailability is approximately 100%. Therefore, linezolid can be administered orally or intravenously without dose adjustment.

Linezolid may be administered regardless of food intake. Time to reach Cmax increases from 1.5 to 2.2 hours, and Cmax is reduced by approximately 17% when linezolid is administered with a high-fat meal. However, overall exposure, as assessed by AUC0–∞, is similar in both cases.

Distribution

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

Linezolid concentrations have been measured in various fluids in limited numbers of participants in Phase I studies after multiple dosing. 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 by oxidation of the morpholine ring, resulting in two inactive ring-opened carboxylic acid metabolites: 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 in vitro. In vitro studies have shown that linezolid undergoes minimal metabolism, with no apparent involvement of the human cytochrome P450 enzyme system. However, metabolic pathways of linezolid have not been fully characterized.

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 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 hardly detectable in feces, whereas approximately 6% of the 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 elimination half-life.

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 soft tissue infections, including infections associated with diabetic foot without concomitant osteomyelitis, caused by Staphylococcus aureus (both 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 soft tissue infections caused by Staphylococcus aureus (only methicillin-susceptible isolates) or Streptococcus pyogenes;
• Vancomycin-resistant infections caused by strains of Enterococcus faecium, including infections associated with bacteremia.

If the causative pathogens include gram-negative microorganisms, combination therapy is clinically indicated.

Contraindications.

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

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

Except in cases where close monitoring and blood pressure surveillance are possible, the medicinal product Linezolid KRKA must not be administered to patients with the following concomitant clinical conditions or concomitant use of the following medicinal products:

• Uncontrolled hypertension, pheochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute episodes of dizziness;
• Serotonin reuptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 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 during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Monoamine oxidase (MAO) inhibitors

Linezolid is a non-selective, reversible inhibitor of MAO. In drug interaction studies 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 and patient 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 enhances the blood pressure increase caused by pseudoephedrine and phenylpropanolamine hydrochloride. Combined 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 linezolid is used concomitantly with these agents.

Potential serotonergic interactions

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

Post-marketing experience: one report has been received of symptoms resembling serotonin syndrome in a patient taking linezolid and dextromethorphan; these symptoms resolved after discontinuation of both medicinal products.

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

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 indicates that only excessive consumption of foods and beverages high in tyramine (i.e., aged cheeses, yeast extracts, non-distilled alcoholic beverages, and fermented soybean products such as soy sauce) should be avoided.

Drugs metabolized by cytochrome P450

Linezolid is not a cytochrome P450 (CYP450) inducer. In addition, linezolid does not inhibit the activity of clinically significant CYP isoforms (e.g., 1A2, 2C9, 2C19, 2D6, 2E1, 3A4) in humans. Similarly, linezolid does not cause induction of cytochrome P450 isoenzymes in rats. Therefore, an effect of linezolid on the pharmacokinetics of other medicinal products metabolized by these major enzymes is not expected.

Rifampicin. The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen healthy adult 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 values of linezolid by an average of 21% (90% CI 15, 27) and 32% (90% CI 27, 37), respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin. When warfarin was added to a course of linezolid treatment at steady state, a 10% reduction in mean maximum INR (International Normalized Ratio) was observed during concomitant administration, while INR AUC decreased by 5%. 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 by concomitant administration of these agents.

Gentamicin. The pharmacokinetics of linezolid or gentamicin are not altered by concomitant administration of these agents.

Antioxidants

No dose adjustment of linezolid is 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. After discontinuation of linezolid, blood parameters returned to values observed prior to treatment initiation. The risk of these effects is likely related to the duration of treatment. Elderly patients may be at greater risk of hematological abnormalities when treated with linezolid compared to younger patients. In patients with severe renal insufficiency (regardless of whether they are undergoing dialysis) and in patients with moderate hepatic insufficiency, an increased incidence of thrombocytopenia may occur. 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 or moderate to severe hepatic 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, careful monitoring of complete blood count parameters and appropriate therapeutic interventions 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.

In patients treated with linezolid for more than 28 days (the maximum recommended treatment duration), an increased incidence of severe anemia has been 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 also been reported. Among cases with known treatment onset, most patients had received linezolid for more than 28 days. After discontinuation of linezolid, most patients recovered fully or partially with or without treatment for anemia.

Mortality in patients with catheter-related bloodstream infections caused by gram-positive pathogens

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

In an open-label study involving patients with serious catheter-related bloodstream infections, an increased mortality rate was observed in the group treated with linezolid compared to the groups treated with vancomycin/dicloxacillin/oxacillin (78 of 363 [21.5%] vs. 58 of 363 [16.0%]). The primary factor influencing mortality was the presence of gram-positive infection at baseline. Mortality rates in patients with infections caused exclusively by gram-positive organisms were similar (relative risk 0.96; 95% confidence interval 0.58–1.59), but in the linezolid treatment group, the mortality rate was significantly higher (p=0.0162) in patients with any additional pathogen or no pathogen identified at baseline (relative risk 2.48; 95% confidence interval: 1.38–4.46). The greatest imbalance occurred during treatment and within 7 days after discontinuation of the investigational drug. Most patients in the linezolid group developed gram-negative infections during the study and died from infections caused by gram-negative or polymicrobial pathogens. Therefore, in complicated skin and soft tissue infections in patients with confirmed or suspected concomitant gram-negative infections, linezolid should be used only when no other treatment options are available (see section "Indications"). In such cases, concomitant therapy 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 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, antibacterial therapy (including linezolid) should be discontinued and appropriate therapeutic measures initiated immediately. In such cases, the use of drugs that inhibit peristalsis is contraindicated.

Potential interactions causing increased blood pressure

Except when close monitoring for possible increases in blood pressure is feasible, linezolid should not be prescribed to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, and/or those receiving concomitant medications such as direct and indirect sympathomimetics (e.g., pseudoephedrine), vasopressors (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine).

Lactic acidosis

Cases of lactic acidosis have been reported during treatment with linezolid. Patients who develop symptoms and signs of metabolic acidosis during linezolid therapy, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels, or hyperventilation, should seek immediate medical attention. If lactic acidosis develops, the benefits 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.

Serotonin syndrome

Spontaneous reports of serotonin syndrome associated with concomitant use of linezolid and serotonergic agents, including antidepressants (such as SSRIs) and opioids, have been received (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, concomitant use of linezolid and serotonergic agents is contraindicated (see section "Contraindications"), except when the use of both linezolid and concomitant serotonergic agents is deemed essential. In such cases, the patient should be under close surveillance 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 agents. Symptoms of withdrawal may occur after discontinuation of the serotonergic agent.

Rhabdomyolysis

Cases of rhabdomyolysis have been reported with linezolid use. Linezolid should be used with caution in patients with risk factors for rhabdomyolysis. If signs or symptoms of rhabdomyolysis occur, linezolid should be discontinued and appropriate therapy initiated.

Hypotension and syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Hypotension and/or SIADH have been observed in some patients receiving linezolid. Regular monitoring of serum sodium levels is recommended in patients at risk of hyponatremia, such as elderly patients or others receiving medications that may lower serum sodium levels (e.g., thiazide diuretics such as hydrochlorothiazide).

Peripheral neuropathy and optic neuropathy

Peripheral neuropathy, as well as optic neuropathy and optic neuritis, sometimes progressing to vision loss, have been observed in patients receiving linezolid. Most of these patients received 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, 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 testing.

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

The risk of neuropathy may increase when linezolid is used to treat patients who are currently undergoing or have recently received antibacterial therapy for tuberculosis.

Seizures

Cases of seizures have been reported in patients receiving linezolid. 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 reversible, non-selective inhibitor of monoamine oxidase (MAO). However, at doses used for antibacterial therapy, it does not have significant MAO-inhibiting effects. Very limited data are available from drug interaction and safety studies on the use of linezolid in patients with underlying conditions and/or concomitant medications associated with specific risks due to MAO inhibition. Therefore, unless close patient monitoring is possible, linezolid use is not recommended (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").

Superinfection

The effect of linezolid on normal flora has not been studied in 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 trials developed drug-related candidiasis. Appropriate measures should be taken if superinfections occur during treatment.

Special patient groups

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

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

No dose adjustment is necessary based on patient gender.

Effects on fertility

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

Studies

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

Experience with the use of linezolid for treating patients with diabetic foot infections, pressure ulcers, ischemic lesions, severe burns, or gangrene is limited.

Excipients

300 mL of solution contains 13.7 g of glucose. This should be taken into account when treating patients with diabetes mellitus.

300 mL of solution also contains 114 mg of sodium (5 mmol). Sodium content should be considered for patients on a low-sodium diet.

Use during pregnancy or breastfeeding.

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

Ability to affect reaction speed when driving or operating machinery.

Patients should be warned about the possible occurrence of dizziness or visual disturbances (see sections "Special precautions for use" and "Side effects") during linezolid therapy and advised to limit driving and operating machinery if these symptoms occur.

Dosage and Administration

Before using the drug, a skin sensitivity test for linezolid should be performed.

Patients who have started treatment with intravenous infusions of Linezolid KRKA may be switched to oral treatment with Linezolid KRKA. In such cases, dose adjustment is not required, as the bioavailability of linezolid when taken orally is nearly 100%.

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

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

The maximum treatment duration is 28 days. The safety and efficacy of linezolid use beyond 28 days have not been studied.

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

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

Table 2

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

**Use an alternative pharmaceutical form.

Elderly patients

No dose adjustment is required.

Patients with renal impairment (particularly with creatinine clearance < 30 mL/min)

The pharmacokinetics of linezolid are not altered in patients with any degree of renal impairment; however, two major metabolites of linezolid accumulate in patients with renal impairment, with greater accumulation observed in patients with more severe renal dysfunction. Plasma concentrations of linezolid are achieved regardless of renal function; therefore, 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 major metabolites, the use of linezolid in patients with renal impairment should be carefully considered in relation to the potential risks of metabolite accumulation, although concentrations of these metabolites remain significantly higher after dialysis than those observed in patients with normal renal function or mild to moderate renal impairment. Both linezolid and its two metabolites are eliminated by hemodialysis. Information on the effect of peritoneal dialysis on the pharmacokinetics of linezolid is lacking. Since approximately 30% of the administered dose is removed during a 3-hour hemodialysis session, linezolid should be administered after hemodialysis.

Patients with hepatic impairment

Clinical data are limited; therefore, linezolid should be prescribed only when the expected benefit outweighs the potential risk.

Instructions for use. For single use only. Immediately before use, remove the foil protective packaging and visually inspect the medicinal product for the presence of 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. Do not use packages with compromised integrity.

The recommended dosage regimen of linezolid is twice daily intravenous administration.

Intravenous infusion should be administered over 30–120 minutes.

Infusion bags must not be connected in series!

When administering linezolid infusion solution concomitantly with another medicinal product, each medicinal product should be administered separately, in accordance with the recommended dose and route of administration for each agent.

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

Compatible infusion solutions: 0.9% sodium chloride injection solution, 5% dextrose injection solution, Ringer's lactate injection solution (Hartmann's injection solution).

Major cases of incompatibility

Physical incompatibility occurred when linezolid infusion solution was administered via a Y-connector simultaneously with the following drugs: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, sodium phenytoin, and sulfamethoxazole/trimethoprim. In addition, the drug is chemically incompatible with ceftriaxone sodium.

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 provides exposure approaching that achieved in adults receiving 600 mg twice daily.

In neonates aged up to 1 week, 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, higher systemic exposure to the drug is observed on the first day of life. However, excessive accumulation of the drug is not expected with this dosing regimen during the first week of life (due to the rapidly increasing clearance of the drug during the first 7 days 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 600 mg. Thus, in adolescents receiving 600 mg every 12 hours, exposure will be the same as in adult patients receiving the same dose.

Overdose.

No specific antidote is known.

No cases of overdose have been reported.

In case of overdose, symptomatic treatment with measures to support glomerular filtration is indicated. Approximately 30% of the administered dose is removed during a 3-hour hemodialysis session, but there are no data on the elimination of linezolid during peritoneal dialysis or hemoperfusion procedures. The two primary metabolites of linezolid are also eliminated by hemodialysis.

Adverse Reactions

The table below lists adverse reactions with their frequency, observed during clinical studies involving 6000 adult patients who received the recommended doses of Linezolid KRKA for up to 28 days.

The most commonly reported adverse reactions were diarrhea (8.9%), nausea (6.9%), vomiting (4.0%), and headache (6.5%). The most frequent adverse reactions leading to discontinuation of the medicinal product were headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to adverse drug reactions.

Adverse reactions reported after marketing authorization of the medicinal product are included in the list below, with their frequency listed as "frequency not known", since the frequency cannot be estimated from the available data.

The frequency of adverse reactions is defined as follows: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (> 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

1See section "Special warnings and precautions for use".

2See sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction".

3The frequency of adverse reactions is assessed using "The Rule of 3".

4In 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 patients treated for >28 days. The proportion of reported cases of severe anemia attributed to the medicinal product that required blood transfusion was 9% (3 out of 33) in patients treated for ≤28 days and 15% (8 out of 53) in patients treated for >28 days.

Reporting of suspected adverse reactions.

Reporting of 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 any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

After opening: the solution is chemically and physically stable for 24 hours at room temperature in the primary packaging after removal of the secondary packaging. From a microbiological standpoint, the solution should be used immediately. If not used immediately, the storage times and conditions prior to use are the responsibility of the user.

Storage conditions. Store in the original (primary and secondary) packaging to protect from light at a temperature not exceeding 30°C. Keep out of the reach of children.

Packaging.

300 ml in an intravenous administration system; 1 intravenous administration system in a laminated foil pouch; 1 or 10 pouches in a carton.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto, Slovenia/KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and location of operations.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.