Linezolid-novopharm
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINEZOLID-NOVOFARM
Composition:
Active substance: linezolid;
1 ml of solution contains 2 mg of linezolid;
Excipients: sodium citrate dihydrate; citric acid anhydrous; glucose monohydrate; sodium hydroxide; hydrochloric acid concentrated; water for injections.
Pharmaceutical form. Infusion solution.
Main physicochemical properties: clear colorless or yellow solution.
Pharmacotherapeutic group. Antibacterial agents for systemic use. ATC code J01X X08.
Pharmacological properties.
Pharmacodynamics.
General characteristics.
Linezolid is a synthetic antibacterial agent belonging to the new class of antimicrobial agents – oxazolidinones. It exhibits in vitro activity against aerobic Gram-positive bacteria and anaerobic microorganisms. Linezolid selectively inhibits bacterial protein synthesis via a unique mechanism of action. It directly binds to bacterial ribosomes (23S 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, it is advisable to refer to local information regarding microbial resistance, especially when treating severe infections. If necessary, when the local prevalence of microbial resistance is such that the benefit of using the medicinal product, at least for certain types of infections, is questionable, expert consultation should be sought.
Susceptible microorganisms
Gram-positive aerobic microorganisms: Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Group C streptococci, Group G streptococci.
Gram-positive anaerobic microorganisms: Clostridium perfringens, Peptostreptococcus anaerobius, Peptostreptococcus species.
Resistant microorganisms: Haemophilus influenzae, Moraxella catarrhalis, Neisseria species, Enterobacteriaceae, Pseudomonas species.
* Clinical efficacy has been demonstrated for susceptible strains according to approved indications.
Although linezolid demonstrates some in vitro activity against Legionella, Chlamydia pneumoniae, and Mycoplasma pneumoniae, there is insufficient data to confirm clinical efficacy in these cases.
Cross-resistance
The mechanism of action of linezolid differs from that of other classes of antibiotics. In vitro studies of clinical isolates (methicillin-resistant staphylococci, vancomycin-resistant enterococci, as well as penicillin- and erythromycin-resistant streptococci) show that linezolid is generally active against microorganisms resistant to one or more other classes of antimicrobial agents. Resistance to linezolid is associated with point mutations in the 23S rRNA.
Pharmacokinetics.
Linezolid is a biologically active substance and is metabolized to inactive derivatives.
Absorption
Linezolid is extensively absorbed after oral administration. Maximum plasma concentration is reached approximately 1–2 hours after dosing, and the absolute bioavailability of the drug is about 100%. Therefore, linezolid can be administered orally or intravenously without dose adjustment.
Linezolid can be administered regardless of food intake. The time to reach maximum concentration increases from 1.5 to 2.2 hours, and Cmax decreases by approximately 17% when linezolid is taken with a high-fat meal. However, total exposure, assessed by AUC0–∞, is similar in both cases.
Distribution
Pharmacokinetic studies have shown that linezolid rapidly distributes into well-perfused tissues. Approximately 31% of linezolid is protein-bound in plasma, and this is independent of drug concentration. The volume of distribution of linezolid at steady state in healthy adult volunteers averages 40–50 L.
Linezolid concentrations have been measured in various fluids with a limited number of participants in Phase 1 studies after multiple doses of linezolid. The ratio of linezolid concentration in saliva to plasma concentration was 1.2:1, and the ratio of linezolid concentration in sweat to plasma concentration was 0.55:1.
Metabolism
Linezolid is primarily metabolized via oxidation of the morpholine ring, forming two inactive ring-opened carboxylic acid derivatives: the aminoethoxyacetic acid metabolite (A) and the hydroxyethylglycine metabolite (B). The formation of metabolite A is thought to occur via an enzymatic pathway, whereas the formation of metabolite B is mediated by a non-enzymatic mechanism involving chemical oxidation in vitro. In vitro studies have demonstrated that linezolid is minimally metabolized, with no significant involvement of the human cytochrome P450 system. However, the metabolic pathways of linezolid are not fully understood.
Excretion
Extrarenal clearance accounts for approximately 65% of the total clearance of linezolid. At steady state, approximately 30% of the dose is excreted in urine as linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min, indicating net tubular reabsorption. Linezolid is virtually undetectable in feces, while approximately 6% of the dose is excreted in feces as metabolite B and 3% as metabolite A.
Minor nonlinearity 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.
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 increasing accumulation 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. Since plasma concentrations of linezolid were achieved independently of renal function, dose adjustment is not recommended for patients with renal impairment. However, given the lack of information on the clinical significance of accumulation of the 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 the pharmacokinetics of linezolid is lacking.
Patients with hepatic impairment. The pharmacokinetics of linezolid were not altered in 7 patients with mild to moderate hepatic impairment (Child-Pugh class A or B). Based on available data, dose adjustment is not recommended for patients with mild to moderate hepatic impairment. The pharmacokinetics in patients with severe hepatic impairment have not been evaluated.
Clinical characteristics.
Indications.
Treatment of infections caused by susceptible strains of specific 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 (methicillin-susceptible isolates only) or Streptococcus pyogenes;
- vancomycin-resistant infections caused by strains of Enterococcus faecium, including infections associated with bacteremia.
Linezolid is not indicated for the treatment of infections caused by gram-negative microorganisms. In cases of suspected or confirmed gram-negative pathogens, specific gram-negative therapy should be initiated immediately.
Contraindications.
Known hypersensitivity to the active substance and/or to any of the excipients of the medicinal product.
Linezolid should not be administered to patients taking any medicinal products that inhibit monoamine oxidase A and B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide), or within two weeks of discontinuation of such medicinal products.
Except in cases where close monitoring and blood pressure surveillance are possible, linezolid should not be prescribed 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;
- selective serotonin reuptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), direct and indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine, phenylpropanolamine), vasopressors (epinephrine, norepinephrine), dopaminergic agents (dopamine, dobutamine), meperidine, or buspirone.
Breastfeeding should be discontinued during treatment with the medicinal product (see section "Use during pregnancy or breastfeeding").
Interaction with other medicinal products and other forms of interaction.
Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO). In drug interaction and safety studies of linezolid, very limited data are available on the use of linezolid in patients receiving concomitant therapy with medicinal products that pose certain risks due to MAO inhibition. Therefore, the use of linezolid under such circumstances is not recommended unless close patient monitoring and surveillance are possible (see sections "Contraindications" and "Special precautions for use").
Potential interactions leading to increased blood pressure
In healthy volunteers with normal blood pressure, linezolid 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 selection 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 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 linezolid and dextromethorphan, no symptoms of serotonin syndrome (confusion, hallucinations, agitation, tremor, pathological flushing, diaphoresis, hyperpyrexia) were observed.
Post-marketing experience: one report of symptoms resembling serotonin syndrome was received in a patient taking linezolid and dextromethorphan; 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)), cases of serotonin syndrome have been reported. Thus, although concomitant use of these medicinal products is contraindicated (see section "Contraindications"), treatment of patients for whom therapy with both linezolid and serotonergic medicinal products is essential is described in the section "Special precautions for use."
Concomitant use with tyramine-rich foods
In patients receiving linezolid and tyramine in amounts less than 100 mg, no significant pressor effect was observed. This indicates that only excessive consumption of foods and beverages high in tyramine (i.e., aged cheeses, yeast extracts, non-distilled alcoholic beverages, and fermented soy products such as soy sauce) should be avoided.
Medicinal products 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, no effect of linezolid on the pharmacokinetics of other medicinal products metabolized by CYP450 is expected.
Rifampicin
The effect of rifampicin on the pharmacokinetics of linezolid was studied in 16 healthy male volunteers who received linezolid (600 mg twice daily for 2.5 days) in combination with rifampicin (600 mg once daily for 8 days) and without. Rifampicin reduced Cmax and AUC values of linezolid by an average of 21% (90% CI 15, 27) and by an average of 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 at steady state, a 10% decrease in mean maximum INR (International Normalized Ratio) was observed during concomitant administration, while AUC of INR decreased by 5%. Data on patients receiving warfarin and linezolid concomitantly are insufficient to assess the clinical significance of these findings.
Antibiotics
Aztreonam. The pharmacokinetics of linezolid and aztreonam are not altered when administered concomitantly.
Gentamicin. The pharmacokinetics of linezolid or gentamicin are not altered when administered concomitantly.
In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampicin, imipenem-cilastatin, aztreonam, ampicillin, streptomycin.
Antioxidants
No dose adjustment of linezolid is 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 developing these effects is likely related to the duration of treatment. Elderly patients may have a higher risk of hematological abnormalities during linezolid therapy compared to younger patients. Patients with severe renal insufficiency (regardless of whether they are undergoing dialysis procedures) may have an increased incidence of thrombocytopenia. 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 capable of reducing hemoglobin levels, decreasing blood cell counts, or negatively affecting platelet number or function; patients with severe renal impairment; and patients receiving treatment for more than 10–14 days. Linezolid should be used in such patients only with careful monitoring of hemoglobin levels, complete blood count, and, if possible, platelet count.
If significant myelosuppression develops during treatment with linezolid, therapy should be discontinued, except in cases where continuation is considered absolutely necessary. In such situations, careful monitoring of complete blood count parameters should be performed, and appropriate treatment strategies implemented.
Furthermore, weekly monitoring of complete blood count (including hemoglobin levels, platelet count, total leukocyte count, and differential white blood cell count) is recommended in all patients receiving linezolid, regardless of initial blood test results.
In compassionate use studies involving patients treated with linezolid for more than 28 days (the maximum recommended treatment duration), an increased incidence of severe anemia was observed. Such patients more frequently required blood transfusions. Cases of anemia requiring blood transfusion have also been reported in the post-marketing period. This type of anemia occurred more frequently in patients treated with linezolid for more than 28 days.
Cases of sideroblastic anemia have been reported in the post-marketing period. Among cases with known timing of anemia onset, most patients had received linezolid for more than 28 days. After discontinuation of linezolid, most patients recovered fully or partially with treatment for anemia or even without treatment.
Imbalance in mortality rates in a clinical study involving patients with catheter-related bloodstream infections caused by Gram-positive pathogens
In an open-label study involving patients with serious intravascular infections due to catheter use, an increased mortality rate was observed in the group treated with linezolid compared to the vancomycin/dicloxacillin/oxacillin treatment groups (78 out of 363 (21.5%) vs. 58 out of 363 (16.0%)). The primary factor influencing mortality was the presence of Gram-positive infection at baseline. Mortality rates in patients with infections caused exclusively by Gram-positive organisms were similar (relative risk 0.96; 95% confidence interval 0.58–1.59), but in the linezolid treatment group, the rate of fatal outcomes 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 pathogens or polymicrobial infections. Therefore, in complicated skin and soft tissue infections in patients with established or suspected concomitant Gram-negative infections, linezolid should be used only if 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, including pseudomembranous colitis and Clostridium difficile-associated diarrhea (CDAD), have been reported with the use of nearly all antibiotics, including linezolid, with severity ranging from mild diarrhea to fatal colitis. It is therefore important to consider this diagnosis in patients who develop diarrhea during or after treatment with linezolid. If antibiotic-associated diarrhea or colitis is suspected or confirmed, current antibacterial therapy (including linezolid) should be discontinued and appropriate therapeutic measures initiated immediately. In such situations, the use of drugs that inhibit intestinal motility is contraindicated.
Lactic acidosis
Cases of lactic acidosis have been reported during treatment with linezolid. Patients who develop symptoms and signs of metabolic acidosis during linezolid therapy, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels, or hyperventilation, should seek immediate medical attention. If lactic acidosis develops, the benefit of continuing linezolid therapy versus potential risks should be carefully evaluated.
Mitochondrial dysfunction
Linezolid inhibits mitochondrial protein synthesis. As a result of this inhibition, adverse reactions such as lactic acidosis, anemia, and neuropathy (peripheral and optic nerve) may occur. These events are more common when the drug is used for more than 28 days.
Potential interactions causing increased blood pressure
Except in cases where patients can be monitored for possible increases in blood pressure, linezolid should not be prescribed to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, and/or concomitant use of drugs such as direct and indirect sympathomimetics (e.g., pseudoephedrine), vasopressors (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 drugs, including antidepressants (such as selective serotonin reuptake inhibitors (SSRIs)), have been received. Therefore, concomitant use of linezolid and serotonergic drugs is contraindicated (see section "Contraindications"), except when use of both linezolid and serotonergic drugs is deemed essential. In such cases, patients should be closely monitored for symptoms of serotonin syndrome, such as cognitive disturbances, hyperpyrexia, hyperreflexia, and impaired coordination. If such symptoms occur, the physician should consider discontinuing one or both drugs. After discontinuation of the serotonergic drug, withdrawal symptoms may occur.
Peripheral neuropathy and optic neuropathy
Cases of peripheral neuropathy, optic neuropathy, and optic neuritis, sometimes progressing to vision loss, have been reported in patients receiving linezolid therapy. These reports primarily involved patients treated for more than 28 days (the maximum recommended treatment duration).
All patients should be advised to report symptoms of visual disturbances, such as changes in visual acuity, color vision changes, blurred vision, or visual field defects. In such cases, prompt ophthalmological 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 benefit of continuing linezolid therapy versus potential risks should be carefully evaluated.
The risk of neuropathies may be increased when linezolid is used to treat patients who are receiving or have recently received antituberculosis antibacterial therapy.
Seizures
Cases of seizures have been reported in patients receiving linezolid therapy. In most cases, a history of seizures was reported as a risk factor. 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 exhibit antidepressant effects. Very limited data on the use of linezolid for treating the primary condition and/or concomitant use of drugs that may carry certain risks due to MAO inhibition have been obtained from drug interaction and safety studies. Therefore, use of linezolid under such circumstances is not recommended unless close patient monitoring and surveillance are possible (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
Concomitant use with tyramine-rich foods
Patients should be advised to avoid consuming large amounts of tyramine-rich foods (see section "Interaction with other medicinal products and other forms of interaction").
Hypoglycemia
Post-marketing reports indicate cases of symptomatic hypoglycemia in diabetic patients receiving insulin or oral hypoglycemic agents while being treated with linezolid, a non-selective, reversible MAO inhibitor. Hypoglycemic episodes have been associated with some MAO inhibitors in diabetic patients receiving insulin or hypoglycemic agents. Although a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be warned of the potential for hypoglycemic reactions during treatment.
If hypoglycemia occurs, dose reduction of insulin or oral hypoglycemic agent, or discontinuation of the oral hypoglycemic agent, insulin, or linezolid may be required.
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 fatal outcomes. Regular monitoring of serum sodium levels is recommended in elderly patients, patients taking diuretics, and other patients at risk of hyponatremia and/or SIADH during treatment with the drug. 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 insufficiency and only when the expected benefit outweighs the potential risk (see section "Dosage and administration").
Linezolid should be used in patients with severe hepatic insufficiency only when the expected benefit outweighs the theoretical risk (see section "Dosage and administration").
Dose adjustment based on patient sex 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 is unknown.
Clinical trials
The safety and efficacy of linezolid when used for more than 28 days have not been established.
Patients with pressure ulcers, ischemic lesions, severe burns, or gangrene were not included in controlled clinical trials. Therefore, experience with the use of linezolid for treating these conditions is limited.
Excipients
1 ml of solution contains 45.7 mg (i.e., 13.7 g/300 ml) of glucose. This should be taken into account when treating patients with diabetes mellitus or other conditions associated with glucose intolerance.
1 ml of solution contains 0.38 mg (114 mg/300 ml) of sodium. Sodium content should be considered in patients on a sodium-restricted diet.
Use during pregnancy or breastfeeding.
Use during pregnancy. Data on the use of linezolid in pregnant women are limited. 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 throughout the entire period of linezolid use.
Ability to affect reaction speed when driving or operating machinery.
Patients should be warned of the possible development of dizziness or visual disturbances during treatment with linezolid (see sections "Special precautions for use" and "Undesirable effects") and advised not to drive or operate machinery if these symptoms occur.
Dosage and Administration.
The duration of treatment depends on the causative pathogen, site and severity of infection, as well as the clinical response.
Therapy 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.
Maximum duration of treatment is 28 days. The safety and efficacy of linezolid administered for longer than 28 days have not been established.
There is no need to increase the recommended doses or duration of treatment in cases of infections associated with bacteremia.
Patients who were initially treated with intravenous linezolid infusions may be switched to oral linezolid therapy. In such cases, dose adjustment is not required, as the oral bioavailability of linezolid is nearly 100%.
Dosage recommendations according to indications are provided in the table below.
| Indications |
Dosage and route of administration |
Recommended duration of treatment (consecutive days) |
|
| Paediatric patients*(from birth to 11 years of age) |
Adults and children (aged 12 years and older) |
||
| Nosocomial pneumonia |
10 mg/kg intravenously or orally** every 8 hours |
600 mg intravenously or orally** every 12 hours |
10–14 |
| Community-acquired pneumonia (particularly cases associated with bacteremia) |
|||
| Complicated skin and soft tissue infections |
|||
| Infections caused by vancomycin-resistant Enterococcus faecium, including infections associated with bacteremia |
10 mg/kg intravenously or orally** every 8 hours |
600 mg intravenously or orally** every 12 hours |
14–28 |
| Uncomplicated skin and soft tissue infections |
Children under Children aged 5–11 years: 10 mg/kg orally** every 12 hours |
Adults: 400 mg orally** every 12 hours. Children aged 12 years and older: 600 mg orally** every 12 hours |
10–14 |
* Neonates < 7 days of age. Most preterm neonates aged < 7 days (< 34 weeks gestation) have lower systemic clearance of linezolid and higher AUC values than most term neonates and children up to 1 year of age. Treatment of such neonates should be initiated with a dose of 10 mg/kg every 12 hours. For neonates with inadequate clinical response to the drug, a dose of 10 mg/kg every 8 hours may be considered. All patients aged up to 7 days should receive a dose of 10 mg/kg every 8 hours.
** Linezolid is available in another pharmaceutical form allowing appropriate dosing.
Use in elderly patients. Dose adjustment is not required in these patients.
Use in patients with renal insufficiency (particularly with creatinine clearance < 30 mL/min). Dose adjustment is not required. Because of the unknown clinical significance of elevated concentrations (up to 10-fold) of two major metabolites of linezolid in patients with severe renal impairment, linezolid should be used with particular caution in such patients and only when the anticipated benefit outweighs the risk. Since approximately 30 % of the dose is eliminated during a 3-hour hemodialysis session, linezolid should be administered to patients undergoing hemodialysis after the dialysis session. The major metabolites of linezolid are partially removed by hemodialysis, but their concentrations after dialysis remain significantly higher than those observed in patients with normal renal function or mild to moderate renal impairment.
Therefore, linezolid should be used with particular caution in patients with severe renal impairment undergoing dialysis, and only when the expected benefit exceeds the potential risk.
Currently, there is no experience with the use of linezolid in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or other alternative treatments for renal failure (other than hemodialysis).
Use in patients with hepatic insufficiency. Dose adjustment is not required. However, clinical data are limited; therefore, linezolid should be used in such patients only when the expected benefit outweighs the potential risk.
Instructions for use.
The medicinal product is supplied in single-use, ready-to-use infusion bags. Immediately before use, remove the bag containing the medicinal product from the secondary packaging (foil pouch) and visually inspect the solution for the presence of particulate matter. Squeeze the bag for approximately 1 minute to ensure its integrity. If the bag leaks, the solution must not be used, as sterility may be compromised. Any unused solution should be disposed of according to applicable requirements. Intravenous infusion should be administered over 30–120 minutes.
Infusion bags must not be connected in series! Other medicinal products must not be added to this solution.
When administering this medicinal product concurrently with other agents, each drug should be administered separately according to the recommended dose and route of administration for each medicinal product. When using a single intravenous system for sequential administration of multiple drugs, the system should be flushed before and after administration of linezolid for intravenous infusion with an infusion solution compatible with both linezolid and the other drug being administered through the same system.
Compatible infusion solutions: 0.9 % sodium chloride injection solution, 5 % dextrose injection solution, lactated Ringer's injection solution.
Main cases of incompatibility. Physical incompatibility occurred when linezolid was administered intravenously via a Y-site connector simultaneously with the following medicinal products: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, sodium phenytoin, and trimethoprim/sulfamethoxazole. In addition, intravenous linezolid was chemically incompatible with sodium ceftriaxone.
Children.
Can be used from the first days of life.
In neonates up to 1 week of age, systemic clearance of linezolid (per kg body weight) increases rapidly during the first week of life. Thus, in neonates receiving the drug at a dose of 10 mg/kg every 8 hours daily, higher systemic exposure to the drug is observed on the first day after birth. However, excessive accumulation of the drug in the body is not expected with this dosing regimen during the first week of life (due to the rapidly increasing clearance of linezolid during the first 7 days of life) (see section "Dosage and administration").
In children aged 1 week to 12 years, administration of linezolid 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 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 linezolid at a dose of 600 mg every 12 hours daily, exposure will be the same as in adult patients receiving the drug at the same dose.
Overdose.
There is no specific antidote.
No cases of overdose have been reported.
In case of overdose, symptomatic treatment should be administered along with measures to support glomerular filtration rate. Approximately 30 % of the administered dose of the drug is eliminated during 3 hours of hemodialysis, but there are no data on the elimination of linezolid during peritoneal dialysis or hemoperfusion procedures. The two major metabolites of linezolid are also eliminated by hemodialysis.
Adverse Reactions
The information provided is based on data from clinical trials in which more than 2000 adult patients received the recommended doses of linezolid 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 medicinal product were headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to drug-related adverse reactions.
The frequency of adverse reactions is defined 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 based on available data.
Infections and infestations: common – candidiasis, oral candidiasis, vaginal candidiasis, fungal infections; uncommon – vaginitis; rare – antibiotic-associated colitis, including pseudomembranous colitis*.
Blood and lymphatic system disorders: common – anemia*†; uncommon – leukopenia*, neutropenia, thrombocytopenia*, eosinophilia; rare – pancytopenia*; frequency not known – myelosuppression*, sideroblastic anemia*.
Immune system disorders: frequency not known – anaphylaxis.
Metabolism and nutrition disorders: uncommon – hyponatremia; frequency not known – lactic acidosis*.
Psychiatric disorders: common – insomnia.
Nervous system disorders: common – headache, taste perversion (metallic taste), dizziness; uncommon – convulsions*, hypoesthesia, paraesthesia; frequency not known – serotonin syndrome**, peripheral neuropathy*.
Eye disorders: uncommon – blurred vision*; rare – visual field defect*; frequency not known – optic neuropathy*, optic neuritis*, vision loss*, change in visual sensation*, change in color perception*.
Ear and labyrinth disorders: uncommon – tinnitus.
Cardiac disorders: uncommon – arrhythmia (tachycardia).
Vascular disorders: common – arterial hypertension; uncommon – transient ischemic attack, phlebitis, thrombophlebitis.
Gastrointestinal disorders: common – diarrhea, nausea, vomiting, localized or generalized abdominal pain, constipation, dyspepsia; uncommon – pancreatitis, gastritis, abdominal distension, dry mouth, glossitis, frequent loose stools, stomatitis, disorders or color change of the tongue; rare – discoloration of tooth surfaces.
Hepatobiliary disorders: common – abnormal liver function test results, increased levels of ALT, AST, or alkaline phosphatase; uncommon – increased total bilirubin.
Skin and subcutaneous tissue disorders: common – pruritus, rash; uncommon – urticaria, dermatitis, hyperhidrosis; frequency not known – bullous skin lesions such as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, alopecia.
Renal and urinary disorders: common – increased blood urea nitrogen; uncommon – renal failure, increased creatinine, polyuria.
Reproductive system and breast disorders: uncommon – vulvovaginal disorders.
General disorders and administration site conditions: common – fever, localized pain; uncommon – chills, fatigue, injection site pain, thirst.
Investigations. Biochemistry: common – increased lactate dehydrogenase, creatine kinase, lipase, amylase, or postprandial (non-fasting) glucose levels; decreased total protein, albumin, sodium, and calcium; increased or decreased potassium or bicarbonate; uncommon – increased sodium or calcium, decreased glucose (non-fasting), increased or decreased chloride. 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 Warnings and Precautions for Use".
** See sections "Contraindications" and "Interaction with Other Medicinal Products and Other Forms of Interaction".
† In controlled clinical trials where linezolid was administered for up to 28 days, anemia occurred 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 of 1326), compared to 12.3% (53 of 430) in those treated for > 28 days. The proportion of documented cases of severe anemia requiring blood transfusion due to drug administration was 9% (3 of 33) in patients treated for ≤ 28 days and 15% (8 of 53) in those treated for > 28 days.
Adverse reactions associated with linezolid use that were rarely assessed as severe reactions: localized abdominal pain, transient ischemic attack, and arterial hypertension.
During the post-marketing period, cases of symptomatic hypoglycemia have been reported when linezolid, a non-selective, reversible MAO inhibitor, 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.
In patients receiving linezolid during the post-marketing period, cases of hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been observed. Signs and symptoms in these cases included confusion, drowsiness, general weakness, and in severe cases, respiratory failure and even fatal outcomes.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and 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 at a temperature not exceeding 25 °C. Keep out of the reach of children. The contents of the bag should be used immediately after opening.
Incompatibilities. See section "Dosage and Administration".
Packaging.
300 ml in a bag; 1 bag in a metallized pouch.
Prescription status. Prescription only.
Manufacturer.
Limited liability company "Novopharm-Biosyntez".
Manufacturer's address and place of business. 38 Zhитомирska St., Zviahel, Zviahel district, Zhytomyr region, 11700, Ukraine.