Zoilid

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOILID (ZOILID)

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 physicochemical properties: isotonic, clear, colorless or slightly yellow solution, free from visible particles.

Pharmacotherapeutic group. Antibacterials for systemic use.

ATC code J01X X08.

Pharmacological Properties

Pharmacodynamics

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

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

Susceptible microorganisms

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

Gram-positive anaerobic microorganisms: Clostridium perfringens, Peptostreptococcus anaerobius, Peptostreptococcus species.

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

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

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

Cross-resistance

The mechanism of action of linezolid differs from that of other classes of antibiotics. In vitro studies of clinical strains (methicillin-resistant staphylococci, vancomycin-resistant enterococci, as well as penicillin- and erythromycin-resistant streptococci) show that linezolid is generally active against microorganisms resistant to one or more other classes of antimicrobial agents.

Resistance to linezolid is associated with point mutations in the 23S rRNA.

Pharmacokinetics

The medicinal product Zoilid contains linezolid, which is the biologically active substance and is metabolized to inactive derivatives.

Absorption

Linezolid is extensively absorbed after oral administration. Maximum plasma concentration (Cmax) is reached approximately 1–2 hours after administration, and the absolute bioavailability of the drug is approximately 100%. Therefore, linezolid can be administered orally or intravenously without dose adjustment.

Linezolid can be administered regardless 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, 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 of linezolid at steady state in healthy adult volunteers averages 40–50 L.

Linezolid concentrations were measured in various fluids involving a limited number of participants in Phase 1 studies after multiple doses of linezolid. The ratio of linezolid concentration in saliva to plasma concentration was 1.2:1, and the ratio of linezolid concentration in sweat to plasma concentration was 0.55:1.

Metabolism

Linezolid is primarily metabolized via oxidation of the morpholine ring, forming two inactive ring-opened carboxylic acid derivatives: the metabolite of aminoethoxyacetic acid (A) and the metabolite of hydroxyethylglycine (B). Formation of metabolite A is believed 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 in this process. However, the metabolic pathways for linezolid are not fully understood.

Elimination

Non-renal clearance accounts for approximately 65% of total linezolid clearance. At steady state, approximately 30% of the dose is 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 virtually undetectable 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 doses of linezolid, apparently due to lower renal and non-renal clearance of the drug at higher concentrations. However, this difference in clearance was minor and did not affect the apparent half-life.

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 increased accumulation observed in patients with more severe renal dysfunction. The pharmacokinetics of linezolid and its two metabolites were also studied in patients with end-stage renal disease (ESRD) undergoing hemodialysis. In an ESRD study, 14 patients received 600 mg of linezolid every 12 hours for 14.5 days. Plasma concentrations of linezolid were achieved independent of renal function; therefore, dose adjustment is not recommended for patients with renal impairment. However, given the lack of information on the clinical significance of accumulation of the main metabolites, the appropriateness 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 of linezolid in patients with severe hepatic impairment have not been evaluated.

Clinical characteristics

Indications

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

• Hospital-acquired pneumonia;
• Community-acquired pneumonia;
• Complicated skin and skin structure infections, including infections associated with diabetic foot without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae (Zyolid has not been studied in the treatment of pressure ulcers);
• Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes;
• Vancomycin-resistant infections caused by Enterococcus faecium strains, including infections associated with bacteremia.

Zyolid 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.

Zyolid must not be used during treatment with any drugs that inhibit monoamine oxidase A and B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide), or within two weeks after discontinuation of such drugs.

Except in cases where careful observation and monitoring of blood pressure are possible, Zyolid should not be administered to patients with any of the following concomitant clinical conditions or concurrently with the following medications:

• 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.

Women should discontinue breastfeeding during the period of drug administration (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors (MAO)

Linezolid is a reversible, non-selective inhibitor of MAO. In drug interaction and safety studies of linezolid, very limited data are available on the use of linezolid in patients receiving concomitant therapy with drugs that pose certain risks due to MAO inhibition. Therefore, the use of linezolid is not recommended unless careful monitoring of the patient's condition is possible (see sections "Contraindications" and "Special precautions").

Potential interactions leading to increased blood pressure

In healthy volunteers with normal blood pressure, linezolid enhances the blood pressure increase caused by pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant administration of linezolid with pseudoephedrine or phenylpropanolamine hydrochloride results in an average increase in systolic blood pressure of 30–40 mm Hg, compared to an increase of 11–15 mm Hg with linezolid alone, 14–18 mm Hg with pseudoephedrine or phenylpropanolamine alone, and 8–11 mm Hg with placebo. Similar studies in patients with hypertension have not been conducted. Careful dose titration of vasoactive agents, including dopaminergic agents, is recommended to achieve the desired effect when linezolid is used concomitantly with these drugs.

Potential serotonergic interactions

Potential interactions between linezolid and dextromethorphan were studied in a trial involving healthy volunteers. Participants received dextromethorphan (two 20 mg doses administered 4 hours apart) with or without linezolid. In healthy volunteers receiving both linezolid and dextromethorphan, no symptoms of serotonin syndrome (confusion, hallucinations, agitation, tremor, flushing, diaphoresis, hyperpyrexia) were observed.

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

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

Concomitant use with tyramine-rich foods

In patients receiving linezolid and less than 100 mg of tyramine, no significant pressor effect was observed. This suggests that only excessive consumption of foods and beverages high in tyramine (aged cheeses, yeast extracts, non-distilled alcoholic beverages, and fermented soy products such as soy sauce) should be avoided.

Drugs metabolized by cytochrome P450

Linezolid does not undergo metabolic transformation 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 adult 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 [confidence interval] 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 linezolid treatment at steady state, a 10% decrease in mean maximum international normalized ratio (INR) was observed during concomitant administration, with a 5% decrease in INR AUC. Data on patients receiving warfarin and linezolid concomitantly 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 together.

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

In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampicin, imipenem-cilastatin, aztreonam, ampicillin, streptomycin.

Antioxidants

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

Special precautions for use

Myelosuppression

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 compared to younger patients. In patients with severe renal insufficiency (regardless of whether they are undergoing dialysis), there may be an increased frequency of thrombocytopenia. Therefore, careful monitoring of blood counts is necessary in the following patients: those with pre-existing anemia, granulocytopenia, or thrombocytopenia; patients receiving concomitant medications capable of reducing hemoglobin levels, decreasing blood cell counts, or negatively affecting platelet number or function; patients with severe renal impairment; and patients receiving treatment for longer 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 when continuation is considered absolutely necessary. In such cases, close monitoring of complete blood count parameters and appropriate therapeutic interventions should be implemented.

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 parameters.

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

Cases of sideroblastic anemia have been reported in the post-marketing period. Among cases where the onset of anemia was known, 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.

Bloodstream infections related to catheter use and 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 receiving linezolid compared to the vancomycin/dicloxacillin/oxacillin treatment groups: 78 out of 363 (21.5%) versus 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 microorganisms were similar (relative risk 0.96; 95% CI 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% CI: 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 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 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, 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 linezolid therapy. 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 situations, the use of agents that inhibit peristalsis is contraindicated.

Lactic acidosis

Lactic acidosis has been reported during linezolid therapy. Patients who develop symptoms and signs of metabolic acidosis during linezolid treatment, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels, or hyperventilation, should seek immediate medical attention. If lactic acidosis develops, the benefit of continuing linezolid therapy versus potential risks should be carefully evaluated.

Mitochondrial dysfunction

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

Potential interactions causing increased blood pressure

Except in cases where patients can be monitored for possible increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, and/or those receiving concomitant medications such as direct and indirect sympathomimetics (e.g., pseudoephedrine), vasoconstrictors (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine).

Serotonin syndrome

Spontaneous reports of serotonin syndrome associated with concomitant use of linezolid and serotonergic agents, including antidepressants (such as SSRIs), have been received. Therefore, concomitant use of linezolid and serotonergic agents is contraindicated (see section "Contraindications"), except when the use of both linezolid and serotonergic agents is deemed essential. In such cases, patients 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 agents. Withdrawal symptoms may occur after discontinuation of the serotonergic agent.

Peripheral neuropathy and optic neuropathy

Peripheral neuropathy, optic neuropathy, and optic neuritis, sometimes progressing to vision loss, have been reported in patients receiving the medicinal product Zyolid. These reports primarily involved patients who had received the drug 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, urgent referral to an ophthalmologist for evaluation is recommended. Patients receiving Zyolid for more than 28 recommended days should have regular vision testing.

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

Patients receiving or who have recently received anti-tuberculosis therapy with antibacterial agents have an increased risk of developing neuropathy when treated with linezolid.

Seizures

Seizures have been reported in patients receiving the medicinal product Zyolid. 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 exhibit antidepressant effects. Very limited data on the use of linezolid for the treatment of the primary condition and concomitant therapy with drugs that may carry certain risks due to MAO inhibition have been obtained from drug interaction and safety studies. Therefore, linezolid use 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").

Use in combination 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 cases of symptomatic hypoglycemia have been observed in diabetic patients receiving insulin or oral hypoglycemic agents while being treated with linezolid, a reversible, non-selective 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 linezolid therapy.

If hypoglycemia occurs, dose reduction of insulin or oral hypoglycemic agent, or discontinuation of the oral hypoglycemic agent, insulin, or linezolid may be necessary.

Hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Cases of hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been observed in patients receiving linezolid in the post-marketing period. Signs and symptoms in these cases included confusion, drowsiness, general weakness, and, in severe cases, respiratory failure and even death. Regular monitoring of serum sodium levels is recommended in elderly patients, patients taking diuretics, and other patients at risk of hyponatremia and/or SIADH during treatment with the medicinal product Zyolid. If signs and symptoms of hyponatremia and/or SIADH appear, the drug should be discontinued and appropriate supportive measures taken.

Superinfection

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

Antibiotic use may sometimes lead to overgrowth of resistant organisms. For example, approximately 3% of patients receiving linezolid at recommended doses during clinical trials developed 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 based on patient gender is not necessary.

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 effect of linezolid on male reproductive function is unknown.

Clinical trials

The safety and efficacy of linezolid when used for longer 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 the treatment of 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 if the patient is on a sodium-restricted diet.

Use during pregnancy or breastfeeding

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

Breastfeeding. Animal studies have shown that linezolid and its metabolites can pass into breast milk. Therefore, women should discontinue breastfeeding during treatment with the drug.

Ability to affect reaction speed when driving or operating machinery. Patients should be warned about the possible development of dizziness or visual disturbances (see sections "Special precautions for use" and "Side effects") during linezolid therapy and advised not to drive or operate machinery if these symptoms occur.

Dosage and Administration

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

The treatment duration recommendations provided below are based on 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 duration of treatment is 28 days. The safety and efficacy of linezolid administration beyond 28 days have not been established.

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

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

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

1Neonates < 7 days of age. Most preterm neonates aged < 7 days (< 34 weeks gestation) have lower systemic clearance of linezolid and higher AUC values compared to most term neonates and children up to 1 year of age. 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 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.

2 Administer the drug in another pharmaceutical form allowing appropriate dosing.

Instructions for use

Zyolid for intravenous injection is supplied in ready-to-use single-dose infusion bags. Immediately before use, remove the foil overwrap and visually inspect the medicinal product for particulate matter. Squeeze the bag for approximately 1 minute to ensure its integrity. If the bag leaks, do not use the solution, as its 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 the infusion solution of Zyolid for intravenous injection concurrently with other medicinal products, each drug should be administered separately, according to 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 the Zyolid infusion solution with an infusion solution compatible with both Zyolid and the other drug being administered through the same line.

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

Major cases of incompatibility

Physical incompatibility occurred when the Zyolid infusion solution for intravenous injection was administered through a Y-connector together with the following drugs: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, sodium phenytoin, and trimethoprim/sulfamethoxazole. Additionally, the Zyolid infusion solution for intravenous injection 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 (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 receiving the drug at a dose of 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 daily, higher systemic exposure to the drug is observed on the first day after birth. Due to the rapid increase in drug clearance 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 the drug at a dose of 600 mg. Thus, in adolescents receiving the drug at a dose of 600 mg every 12 hours daily, exposure will be comparable to that in adult patients receiving the same dose.

Overdose

No specific antidote is available.

No cases of overdose have been reported.

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

Side effects

Data on adverse reactions were obtained from clinical studies in which more than 2000 adult patients received the recommended doses of the medicinal product Zoylid for up to 28 days.

The most commonly reported adverse reactions were diarrhea (8.4%), headache (6.5%), nausea (6.3%), and vomiting (4.0%). The most frequent adverse reactions leading to discontinuation of the drug 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 included in the list below with the frequency category "frequency not known", since the frequency cannot be estimated from the available data.

Adverse reactions reported during treatment are listed below, classified by frequency as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (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*1; 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 perversion (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 ischaemic 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 surfaces.

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

Skin and subcutaneous tissue disorders: common — pruritus, rash; uncommon — urticaria, dermatitis, increased 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 levels of lactate dehydrogenase, creatine kinase, lipase, amylase, or postprandial (non-fasting) glucose; decreased levels of total protein, albumin, sodium, and calcium; increased or decreased levels of potassium or bicarbonate; uncommon — increased levels of sodium or calcium, decreased glucose level without fasting, increased or decreased chloride levels.

Hematology: common — increased neutrophil or eosinophil count, decreased hemoglobin, hematocrit, or erythrocyte count, increased or decreased platelet or leukocyte count; uncommon — increased reticulocyte count, decreased neutrophil count.

* See section "Special precautions".

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

1 During controlled clinical trials in which linezolid was administered for up to 28 days, anemia occurred in 2.0% of patients. In compassionate use studies involving patients with life-threatening infections and comorbidities, 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 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 that were assessed as severe in rare cases: localized abdominal pain, transient ischemic attack, and arterial hypertension.

In the post-marketing period, cases of symptomatic hypoglycemia have been reported when linezolid, a reversible non-selective monoamine oxidase inhibitor (MAO), was administered to 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.

Hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported in patients receiving linezolid in the post-marketing period. Signs and symptoms in these cases included confusion, drowsiness, general weakness, and in severe cases, respiratory insufficiency and even death.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: 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 reach of children.

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

Incompatibilities. See section "Dosage and administration".

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

Prescription status. Prescription only.

Manufacturer. Infomed Fluids S.R.L.

Manufacturer's address and place of business. Bulevardul Teodor Pallady No. 50, Sector 3, Bucharest, 032266, Romania.