Linezolid krka

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

Composition:

Active substance: linezolid;

1 film-coated tablet contains 600 mg of linezolid;

Excipients: microcrystalline cellulose, maize starch, sodium starch glycolate (type A), hydroxypropylcellulose, magnesium stearate;

coating: hypromellose, titanium dioxide (E 171), polyethylene glycol 6000, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: white to almost white, oval, slightly biconvex film-coated tablets.

Pharmacotherapeutic group. Antibacterials for systemic use.

ATC code J01XX08.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Linezolid is a synthetic antibacterial agent belonging to a new class of antimicrobial agents – oxazolidinones. It is active in vitro against aerobic gram-positive bacteria, some gram-negative bacteria, and anaerobic microorganisms. Linezolid selectively inhibits protein synthesis in bacterial cells via a unique mechanism of action. Specifically, it binds to a site on the bacterial ribosome (23S subunit of the 50S) and prevents the formation of the functional initiating 70S complex, which is an essential component of the translation process.

The in vitro post-antibiotic effect (PAE) of linezolid against Staphylococcus aureus is approximately 2 hours. In in vivo animal models, the PAE was 3.6 and 3.9 hours against Staphylococcus aureus and Streptococcus pneumoniae, respectively. In in vivo studies, the key pharmacodynamic efficacy parameter was the duration of time during which the plasma concentration of linezolid exceeded the minimum inhibitory concentration (MIC) for the infecting organism.

Susceptibility

The prevalence of acquired resistance in certain species, especially when treating severe infections, may vary geographically and over time. If local resistance prevalence is such that the benefit of the agent, at least for certain types of infections, is questionable, expert consultation is recommended.

Susceptible organisms

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 organisms

Haemophilus influenzae Moraxella catarrhalis Neisseria species Enterobacteriaceae Pseudomonas species

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

Linezolid has shown some in vitro activity against Legionella, Chlamydia pneumoniae, and Mycoplasma pneumoniae; however, data are insufficient to confirm clinical efficacy.

Resistance

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 usually 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.

Reduced susceptibility to linezolid has been observed in patients with difficult-to-treat infections and/or prolonged treatment duration. Resistance to linezolid has been reported in enterococci, Staphylococcus aureus, and coagulase-negative staphylococci. This has generally been associated with prolonged courses of therapy and the presence of prosthetic materials or untreated abscesses. In cases of emergence of antibiotic-resistant bacteria in a hospital setting, appropriate measures to prevent the spread of these strains should be followed.

Pharmacokinetics.

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

Table 1

Mean (standard deviation) pharmacokinetic parameters of linezolid in adults

Linezolid dose	Cmax μg/ml	Cmin μg/ml	Tmax h	AUC 1 μg•h/ml	t1/2 h	CL ml/min
400 mg tablets single dose every 12 hours	8.1 (1.83) 11 (4.37)	--- 3.08 (2.25)	1.52 (1.01) 1.12 (0.47)	55.1 (25) 73.4 (33.5)	5.2 (1.5) 4.69 (1.7)	146 (67) 110 (49)
600 mg tablets single dose every 12 hours	12.7 (3.96) 21.2 (5.78)	--- 6.15 (2.94)	1.28 (0.66) 1.03 (0.62)	91.4 (39.3) 138 (42.1)	4.26 (1.65) 5.4 (2.06)	127 (48) 80 (29)
600 mg, intravenous injection3 single dose every 12 hours	12.9 (1.6) 15.1 (2.52)	--- 3.68 (2.36)	0.5 (0.1) 0.51 (0.03)	80.2 (33.3) 89.7 (31)	4.4 (2.4) 4.8 (1.7)	138 (39) 123 (40)
600 mg, oral suspension single dose	11 (2.76)	---	0.97 (0.88)	80.8 (35.1)	4.6 (1.71)	141 (45)

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. Maximum plasma concentrations are reached approximately 1–2 hours after dosing, and the absolute bioavailability of the drug is approximately 100%. Therefore, linezolid may be administered orally or intravenously without dose adjustment.

Linezolid may be administered irrespective of food intake. The time to reach maximum concentration increases from 1.5 to 2.2 hours, and Cmax decreases by approximately 17% when linezolid is administered with a high-fat meal. However, total 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 bound to plasma proteins, 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 volunteers in Phase 1 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). 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 under in vitro conditions. In vitro studies have demonstrated that linezolid undergoes minimal metabolism, with possible involvement of the human cytochrome P450 enzyme 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 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 active 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.

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 observed elimination half-life.

Clinical characteristics.

Indications.

Treatment of infections caused by susceptible strains of specified microorganisms in the following conditions:

• Nosocomial pneumonia;

• Community-acquired pneumonia;
• Complicated skin and soft tissue 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 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.

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

Contraindications.

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

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

Except in cases where careful observation and monitoring of blood pressure are possible, Linezolid KRKA must not be prescribed in the following cases:

• Uncontrolled arterial hypertension, pheochromocytoma, carcinoid syndrome, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute episodes of dizziness;
• Concomitant use of 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 in pregnancy or lactation").

Interaction with other medicinal products and other forms of interaction.

Monoamine oxidase inhibitors

Linezolid is a non-selective, reversible inhibitor of monoamine oxidase (MAO). Data on the use of linezolid in patients receiving concomitant therapy with medicinal products that pose certain risks due to MAO inhibition are limited. Therefore, unless close patient monitoring is feasible, linezolid use is not recommended (see sections "Contraindications" and "Special warnings and precautions for use").

Potential interactions leading to increased blood pressure

In healthy volunteers, linezolid potentiates 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 have not been conducted in hypertensive patient populations. Careful dose titration of vasopressor agents, including dopaminergic drugs, is recommended to achieve the desired effect when used concomitantly with linezolid.

Potential serotonergic interactions

Potential interactions between linezolid and dextromethorphan were studied in a trial involving healthy volunteers. Administration of dextromethorphan (two 20 mg doses given 4 hours apart) in combination with linezolid did not result in manifestations of serotonin syndrome (confusion, delirium, agitation, tremor, pathological flushing, diaphoresis, hyperpyrexia).

One case of symptoms resembling serotonin syndrome has been reported in a patient receiving linezolid and dextromethorphan; these symptoms resolved after discontinuation of both drugs.

Cases of serotonin syndrome have been reported during clinical use of linezolid in combination with serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), and opioids. 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 section "Special warnings and 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 suggests that only excessive consumption of foods and beverages high in tyramine (such as aged cheeses, yeast extracts, undistilled 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, linezolid is not expected to affect the pharmacokinetics of other medicinal products metabolized by these major enzymes.

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. A 10% reduction in mean peak INR (International Normalized Ratio) was observed when warfarin was added to a stable regimen of linezolid, with a simultaneous 5% reduction in INR AUC. Data in 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 these agents are administered together.

Gentamicin. The pharmacokinetics of linezolid or gentamicin are not altered when these agents are administered together.

Antioxidants

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

Special precautions.

Myelosuppression

Cases of myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) have been reported in some patients receiving linezolid. Hematological parameters returned to pre-treatment levels after discontinuation of linezolid. The use of linezolid in elderly patients is associated with a higher risk of hematological abnormalities compared to younger patients. The risk of these effects is likely related to the duration of treatment. An increased incidence of thrombocytopenia may occur in patients with severe renal impairment (regardless of whether they are undergoing dialysis) and in patients with moderate hepatic impairment. Therefore, careful monitoring of blood counts is necessary in the following patient groups: patients with pre-existing anemia, granulocytopenia, or thrombocytopenia; patients receiving concomitant medications that may reduce hemoglobin levels, decrease blood cell counts, or negatively affect platelet number or function; patients with severe renal impairment or moderate to severe hepatic impairment; and patients receiving treatment for more than 10–14 days. Linezolid should be used in such patients with careful monitoring of hemoglobin levels, complete blood count, and, when possible, platelet count.

If significant myelosuppression develops during treatment with linezolid, therapy should be discontinued, except in cases where continuation is deemed absolutely necessary. In such situations, careful monitoring of complete blood count parameters and appropriate therapeutic interventions are required.

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

An increased incidence of severe anemia has been observed in patients treated with linezolid for more than 28 days (the maximum recommended treatment duration). Such patients more frequently required blood transfusions.

Cases of sideroblastic anemia have also been reported. After discontinuation of linezolid, most patients recovered fully or partially with or without treatment for anemia.

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

In an open-label study involving patients with serious catheter-related bloodstream infections, 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 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 (odds ratio 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 (odds ratio 2.48; 95% confidence interval: 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 group developed gram-negative infections during the study and died from infections caused by gram-negative organisms or polymicrobial infections. Therefore, in complicated skin and soft tissue infections in patients with known or suspected concomitant gram-negative infections, 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, have been reported with the use of nearly all antibacterial agents, 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, current antibacterial therapy (including linezolid) should be discontinued and appropriate therapeutic measures initiated immediately. In such cases, the use of agents that inhibit peristalsis is contraindicated.

Potential interactions leading to increased blood pressure

Except in cases where close monitoring for possible increases in blood pressure is feasible, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, and/or concomitantly with direct and indirect sympathomimetic agents (e.g., pseudoephedrine), vasopressors (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine).

Hypoglycemia

Post-marketing reports have indicated cases of symptomatic hypoglycemia when linezolid, a non-selective reversible monoamine oxidase inhibitor (MAO), was used in diabetic patients receiving insulin or oral hypoglycemic agents. Hypoglycemic episodes have been associated with the use of 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, a reduction in the dose of insulin or oral hypoglycemic agent, or discontinuation of the oral hypoglycemic agent, insulin, or linezolid may be necessary.

Lactic acidosis

Lactic acidosis has been reported during treatment with linezolid. Patients who develop symptoms and signs of metabolic acidosis during treatment with linezolid, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels, or hyperventilation, should seek immediate medical attention. 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, adverse reactions such as lactic acidosis, anemia, and neuropathy (peripheral and optic) may occur. These effects are more common when the drug is used for longer than 28 days.

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 (see section "Interaction with other medicinal products and other types of interactions"). Therefore, concomitant use of linezolid and serotonergic agents is contraindicated (see section "Contraindications"), except in cases where both linezolid and concomitant serotonergic agents are clinically indicated. In such cases, the patient should be closely monitored for symptoms of serotonin syndrome, such as cognitive disturbances, hyperpyrexia, hyperreflexia, and movement incoordination. If 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 the use of linezolid. 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.

Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Hyponatremia 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 other patients receiving medications that may reduce 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 therapy. Most such patients received treatment for longer than 28 days (the maximum recommended treatment duration).

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 ophthalmological evaluation is recommended. Patients receiving linezolid KRKA for more than 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 neuropathies may increase when linezolid is used to treat patients who are currently or recently undergoing anti-tuberculosis therapy with antibacterial agents.

Seizures

Cases of seizures have been reported in patients receiving linezolid therapy. Most of these patients had a history of seizures; therefore, patients should inform their physicians if they have previously experienced seizures.

Monoamine oxidase inhibitors

Linezolid is a non-selective, reversible inhibitor of monoamine oxidase (MAO). However, at doses used for antibacterial therapy, it does not exert significant MAO-inhibitory 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, if close patient monitoring is not feasible, the use of linezolid is not recommended (see sections "Contraindications" and "Interaction with other medicinal products and other types of interactions").

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 types of interactions").

Superinfection

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

Antibiotic use may occasionally lead to overgrowth of resistant organisms. For example, approximately 3% of patients receiving linezolid at recommended doses in clinical trials developed candidiasis associated with the drug. Appropriate measures should be taken if superinfection occurs 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 impairment (see sections "Pharmacokinetics" and "Dosage and administration").

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

Gender

Dose adjustment based on gender is not necessary.

Impairment of fertility

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

Clinical trials

The safety and efficacy of linezolid for treatment durations exceeding 28 days have not been established.

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

Emergence of drug-resistant bacteria

It is unlikely that the use of linezolid KRKA for the treatment of undiagnosed bacterial infections or for prophylactic purposes would harm the patient or increase the risk of emergence of drug-resistant bacteria.

Pregnancy or breastfeeding.

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

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of administration and dosage.

Patients who have initiated treatment with Linezolid KRKA for intravenous infusion may be switched to Linezolid KRKA for oral administration. In such cases, dose adjustment is not required, as the bioavailability of linezolid after oral administration 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 applied in clinical studies. For certain types of infections, a shorter treatment duration may be appropriate, although this has not been evaluated in clinical trials.

Maximum treatment duration is 28 days. The safety and efficacy of linezolid administered for longer than 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

Indications	Dosage and method of administration	Recommended duration of treatment (consecutive days)
	Adults and children (aged 12 years and older)
Nosocomial pneumonia	600 mg orally every 12 hours	10–14
Community-acquired pneumonia (including forms associated with bacteremia)
Complicated skin and soft tissue infections
Infections caused by vancomycin-resistant Enterococcus faecium, including infections associated with bacteremia	600 mg orally every 12 hours	14–28
Uncomplicated skin and soft tissue 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 dosage form allowing appropriate dosing.

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

Use in elderly patients: no dose adjustment is required.

Use in patients with renal impairment (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.

Plasma concentrations of linezolid are achieved independent 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 should be carefully considered in patients with renal impairment who are at risk of metabolite accumulation. Linezolid and its two metabolites are removed by hemodialysis, but concentrations of these metabolites remain significantly higher after dialysis than those observed in patients with normal renal function or mild to moderate renal impairment. Information on the effect of peritoneal dialysis on the pharmacokinetics of linezolid is not available. Since approximately 30% of the administered dose is eliminated during a 3-hour hemodialysis session, linezolid should be administered after hemodialysis.

Use in patients with hepatic impairment: no dose adjustment is required. Clinical data in this regard are limited; therefore, linezolid should be prescribed only when the expected benefit of treatment outweighs the potential risks.

Children.

The medicinal product in this dosage form is indicated for children aged 12 years and older.

Overdose.

No specific antidote is known.

No cases of overdose have been reported.

In the event of overdose, symptomatic treatment should be administered, including measures to support glomerular filtration. Approximately 30% of the administered dose is removed during 3 hours of hemodialysis, but there are no data on the elimination of linezolid during peritoneal dialysis or hemoperfusion procedures. The two primary metabolites of linezolid are also removed by hemodialysis.

Adverse reactions.

The table below lists adverse reactions with their frequency, observed during clinical trials 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 (4.3%), and headache (4.2%).

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

Adverse reactions reported in the post-marketing period are included in the list below with the frequency category listed as "frequency not known", since the frequency cannot be estimated based on 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 based on available data).

System Organ Class	Common (> 1/100, < 1/10)	Uncommon (> 1/1000, < 1/100)	Rare (>1/10000, < 1/1000)	Very rare (< 1/10000)	Frequency not known (cannot be estimated based on available data)
Infections and infestations	Candidiasis (including oral and vaginal) or fungal infections	Antibiotic-associated colitis, including pseudomembranous colitis1, vaginitis
Blood and lymphatic system disorders	Anemia1,4, thrombocytopenia1	Pancytopenia1, eosinophilia, leukopenia, neutropenia	Sideroblastic anemia1		Myelosuppression
Immune system disorders			Anaphylaxis
Metabolism and nutrition disorders		Hypotension1	Lactic acidosis1
Psychiatric disorders	Insomnia
Nervous system disorders	Headache, taste disturbances (metallic taste), dizziness	Peripheral neuropathy1, hypoesthesia, paresthesia, seizures1			Serotonin syndrome2
Eye disorders		Blurred vision1, optic neuropathy1	Visual field defect1		Optic neuritis1, vision loss1, change in visual sensation1, change in color perception1
Ear and labyrinth disorders		Tinnitus
Cardiac disorders		Arrhythmia (tachycardia)
Vascular disorders	Hypertension	Phlebitis, thrombophlebitis, transient ischemic attack
Gastrointestinal disorders	Diarrhea, nausea, vomiting, localized or generalized abdominal pain, constipation, dyspepsia	Dry mouth, gastritis, pancreatitis, glossitis, loose stools, stomatitis, disturbances or change in tongue color	Discoloration of tooth surfaces
Hepatobiliary disorders	Abnormal liver function tests, increased levels of alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase	Elevated total bilirubin
Skin and subcutaneous tissue disorders	Itching, rash	Angioedema, dermatitis, excessive sweating, urticaria	Toxic epidermal necrolysis4, Stevens-Johnson syndrome4, hypersensitivity, vasculitis		Alopecia
Musculoskeletal and connective tissue disorders			Rhabdomyolysis
Renal and urinary disorders	Increased blood urea nitrogen	Polyuria, elevated creatinine, renal failure
Reproductive system and breast disorders		Vulvovaginal disorders
General disorders and administration site conditions	Fever, localized pain	Chills, fatigue, increased thirst
Investigations	Biochemistry Elevated lactate dehydrogenase, creatine kinase, lipase, amylase or glucose (non-fasting). Decreased total protein, albumin, sodium and calcium. Increased or decreased potassium or bicarbonate levels. Hematology Elevated neutrophils or eosinophils. Decreased hemoglobin, hematocrit or red blood cell count. Increased or decreased platelet or white blood cell count	Biochemistry Elevated sodium or calcium. Decreased glucose (non-fasting). Increased or decreased chloride levels. Hematology Elevated reticulocyte count. Decreased neutrophil count

1See section "Special precautions".

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 studies where linezolid was administered for up to 28 days, anemia was reported 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 caused by the drug requiring 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.

Children

Safety data obtained from clinical studies involving over 500 children (from birth to 17 years of age) do not indicate that the safety profile of linezolid in children differs from that in adult patients.

Reporting of suspected adverse reactions

Reporting of adverse reactions after medicinal product authorization is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions. No special storage conditions are required for this medicinal product. Keep out of reach and sight of children.

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

Prescription status. Prescription only.

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

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.