Linezolid-Novopharm solution for infusion 2 mg/ml 300 ml package

Instructions Linezolid-Novopharm solution for infusion 2 mg/ml package 300 ml

Composition

active ingredient: linezolid;

1 ml of solution contains 2 mg of linezolid;

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

Dosage form

Solution for infusion.

Main physicochemical properties: transparent colorless or yellow solution.

Pharmacotherapeutic group

Antibacterials for systemic use. ATX code J01X X08.

Pharmacological properties

Pharmacodynamics

General characteristics.

Linezolid is a synthetic antibacterial drug belonging to a 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 through a unique mechanism of action. It binds directly to bacterial ribosomes (23S of 50S subunits) and prevents the formation of a functional 70S initiation complex (an important component of the translation process).

The prevalence of acquired resistance may vary geographically and over time for individual species, therefore it is advisable to rely on local information on resistance patterns, particularly in the treatment of severe infections. Expert advice should be sought when the local prevalence of resistance is such that the benefit of the medicinal product in at least some types of infections is questionable.

Sensitive 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 influenza, Moraxella catarrhalis, Neisseria species, Enterobacteriaceae, Pseudomonas species.

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

Although linezolid demonstrates some in vitro activity against Legionella, Chlamydia pneumoniae, and Mycoplasma pneumoniae, there are insufficient data to support 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, and penicillin- and erythromycin-resistant streptococci) show that linezolid is generally active against organisms 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. Peak plasma concentrations are 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 without regard to food intake. The time to peak concentration is increased from 1.5 to 2.2 hours and Cmax is decreased by approximately 17% when linezolid is administered with a high-fat meal. However, the overall exposure, as assessed by AUC0-¥, is similar in both cases.

Distribution

Pharmacokinetic studies have shown that linezolid is rapidly distributed into well-perfused tissues. Approximately 31% of linezolid is bound to plasma proteins, 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 were determined in various fluids in a limited number of subjects in Phase 1 studies following multiple linezolid administration. The saliva to plasma ratio of linezolid was 1.2:1 and the sweat to plasma ratio was 0.55:1.

Metabolism

Linezolid is primarily metabolized by oxidation of the morpholine ring to form two inactive ring-opened carboxylic acid derivatives: the aminoethoxyacetic acid metabolite (A) and the hydroxyethylglycine metabolite (B). Metabolite A is thought to be formed enzymatically, while the formation of metabolite B is mediated by a non-enzymatic mechanism involving chemical oxidation in vitro. In vitro studies have shown that linezolid is minimally metabolized, with possible involvement of the human cytochrome P450 system. However, the metabolic pathways for linezolid are not fully understood.

Extrarenal clearance accounts for approximately 65% of the total clearance of linezolid. At steady state, approximately 30% of the dose is recovered in the urine as linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min, representing net tubular reabsorption. Linezolid is virtually undetectable in the feces, while approximately 6% of the dose is recovered in the feces as metabolite B and 3% as metabolite A.

A slight 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 small 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 major metabolites of linezolid accumulate in patients with renal impairment, with accumulation increasing in patients with greater severity of renal dysfunction. The pharmacokinetics of linezolid and its two metabolites have also been studied in patients with end-stage renal disease (ESRD) undergoing hemodialysis. In the ESRD study, 14 patients received 600 mg of linezolid every 12 hours for 14.5 days. Since similar plasma concentrations of linezolid were achieved regardless of renal function, no dosage adjustment is recommended for patients with renal impairment. However, given the lack of information on the clinical significance of accumulation of the major metabolites, the use of linezolid in patients with renal insufficiency should be considered in light of the potential risk of accumulation of these metabolites. Both linezolid and the two metabolites are removed by haemodialysis. There is no information on the effect of peritoneal dialysis on the pharmacokinetics of linezolid.

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, no dose adjustment is recommended for patients with mild to moderate hepatic impairment. Pharmacokinetics in patients with severe hepatic impairment have not been evaluated.

Indication

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

̵ nosocomial pneumonia;

̵ community-acquired pneumonia;

- Complicated skin and skin structure infections, including diabetic foot infections without associated 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 infections of the skin and its structures caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes;

̵ vancomycin-resistant infections caused by strains of Enterococcus faecium, including infections accompanied by bacteremia.

Linezolid is not indicated for the treatment of infections caused by Gram-negative organisms. If a Gram-negative pathogen is suspected or identified, specific Gram-negative therapy should be initiated immediately.

Contraindication

Known hypersensitivity to the active substance and/or to other excipients of the medicinal product.

Linezolid should not be used in patients taking any drugs that inhibit monoamine oxidase A and B (e.g. phenelzine, isocarboxazid, selegiline, moclobemide), or within two weeks of taking such drugs.

Unless close observation and monitoring of blood pressure are possible, linezolid should not be administered to patients with the following concomitant clinical conditions or concomitant use of the following medicinal products:

̵ uncontrolled arterial 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 compounds (dopamine, dobutamine), pethidine or buspirone.

Breastfeeding should be discontinued during use of the medicinal product (see section “Use during pregnancy or breast-feeding”).

Interaction with other medicinal products and other types of interactions

Monoamine oxidase inhibitors

Linezolid is a non-selective, reversible inhibitor of monoamine oxidase (MAO). There are very limited data from drug interaction studies and safety studies of linezolid in patients receiving concomitant medications that pose a risk of MAO inhibition. Therefore, linezolid is not recommended in these circumstances unless close observation and monitoring of the patient is possible (see sections 4.3 and 4.4).

In normotensive healthy volunteers, linezolid increased the blood pressure increase induced by pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant administration of linezolid and pseudoephedrine or phenylpropanolamine hydrochloride resulted in an average increase in systolic blood pressure of 30–40 mm Hg compared with 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 patients. It is recommended that doses of drugs with vasopressor effects, including dopaminergic drugs, be carefully titrated to achieve the desired effect when linezolid is coadministered with these drugs.

Potential serotonergic interactions

The potential for interactions between linezolid and dextromethorphan was investigated in a study in healthy volunteers. Subjects received dextromethorphan (two 20 mg doses 4 hours apart) with or without linezolid. No serotonin syndrome (confusion, delirium, restlessness, tremor, flushing, diaphoresis, hyperpyrexia) was observed in healthy volunteers receiving linezolid and dextromethorphan.

Post-marketing experience: There has been one report of serotonin syndrome-like events in a patient receiving linezolid and dextromethorphan; these events resolved after discontinuation of both drugs.

Cases of serotonin syndrome have been reported during clinical use of linezolid and serotonergic medicinal products, including antidepressants (such as selective serotonin reuptake inhibitors (SSRIs)). Therefore, although the combined use of these medicinal products is contraindicated (see section 4.3), the management of patients for whom treatment with both linezolid and serotonergic medicinal products is essential is described in section 4.4.

Use in combination with tyramine-rich foods

No significant vasopressor effect was observed in patients receiving linezolid and tyramine at doses less than 100 mg. This suggests that only excessive consumption of foods and beverages high in tyramine (namely, mature cheeses, yeast extracts, undistilled alcoholic beverages, and fermented soybean 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 of the clinically relevant human cytochrome P450 isoforms (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 drugs metabolized by CYP450.

Rifampicin

The effect of rifampicin on the pharmacokinetics of linezolid was studied in 16 healthy adult male volunteers who received linezolid (600 mg twice daily for 2.5 days) with and without rifampicin (600 mg once daily for 8 days). Rifampicin decreased linezolid Cmax and AUC by a mean of 21% (90% CI 15, 27) and a mean of 32% (90% CI 27, 37), respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin

When warfarin was added to linezolid therapy at steady state, a 10% decrease in mean maximum INR (International Normalized Ratio) was observed with concomitant use, with a 5% decrease in INR AUC. There are insufficient data in patients receiving warfarin and linezolid concomitantly to assess the clinical significance of these findings.

Antibiotics

Aztreonam: Concomitant administration of linezolid and aztreonam does not alter their pharmacokinetics.

Gentamicin: The pharmacokinetics of linezolid or gentamicin are not altered by their concomitant administration.

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

Antioxidants

When using the drug simultaneously with vitamin C or vitamin E, dose adjustment of linezolid is not recommended.

Application features

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In such cases, the haematological abnormalities have returned to pre-treatment values after discontinuation of linezolid. The risk of these effects appears to be related to the duration of treatment. Elderly patients may be at greater risk of haematological abnormalities when treated with linezolid compared with younger patients. Patients with severe renal impairment (whether or not undergoing dialysis) may be at increased risk of thrombocytopenia. Therefore, close monitoring of blood counts is necessary in the following patients: patients with pre-existing anaemia, granulocytopenia, or thrombocytopenia; Patients receiving concomitant medications that may lower hemoglobin levels, reduce the number of formed blood cells, or adversely affect the number or functional activity of platelets; Patients with severe renal insufficiency; Patients whose course of treatment lasts more than 10-14 days. It is advisable to use linezolid in the treatment of such patients only in combination with careful monitoring of hemoglobin levels, complete blood count, and, if possible, platelet count.

If significant myelosuppression develops during treatment with linezolid, treatment should be discontinued unless continued treatment is considered essential. In such situations, close monitoring of complete blood counts should be performed and appropriate treatment strategies should be implemented.

In addition, weekly monitoring of complete blood counts (including hemoglobin, platelet count, total white blood cell count, and differential white blood cell count) is recommended in patients receiving linezolid, regardless of baseline blood counts.

In studies using an unlicensed medicinal product under a humanitarian program (compassionate use), an increased incidence of severe anemia was observed in patients receiving linezolid for more than 28 days (the maximum recommended duration of treatment). These patients were more likely to require blood transfusions. Cases of anemia requiring blood transfusions have also been reported in the post-marketing period. Such anemia occurred more frequently in patients receiving linezolid for more than 28 days.

Sideroblastic anemia has been reported in the post-marketing setting. Among cases for which the time of onset of anemia was known, the majority of patients had received linezolid for more than 28 days. After discontinuation of linezolid, most patients recovered completely or partially with or without treatment for anemia.

Imbalance in mortality rates in a clinical trial involving patients with catheter-related bloodstream infections caused by gram-positive pathogens

In an open-label study of patients with serious catheter-related intravascular infections, there was an increased mortality in the linezolid group compared with the vancomycin/dicloxacillin/oxacillin groups (78 of 363 (21.5%) vs. 58 of 363 (16.0%). The main factor influencing mortality was the presence of gram-positive infection at baseline. Mortality rates were similar in patients with infections caused exclusively by gram-positive organisms (odds ratio 0.96; 95% confidence interval 0.58–1.59), but the linezolid group had a significantly higher mortality rate (p=0.0162) in patients with any additional pathogen or no pathogens at baseline (odds ratio 2.48; 95% confidence interval 1.38–4.46). The greatest imbalance was observed during treatment and within 7 days of discontinuation of study drug. The majority of patients in the linezolid group acquired gram-negative infections during the study and died from infections caused by gram-negative pathogens and from polymicrobial infections. Therefore, in complicated skin and soft tissue infections in patients with known or suspected concomitant infection due to Gram-negative organisms, linezolid should only be used when no other treatment options are available (see section 4.3). In such circumstances, concurrent treatment for the Gram-negative infection should be initiated.

Antibiotic-associated diarrhea and colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhea (CDAD), have been reported with nearly all antibacterial agents, including linezolid, and may range in severity from mild diarrhea to fatal colitis. Therefore, it is 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, ongoing antibacterial therapy (including linezolid) should be discontinued and appropriate therapeutic measures should be initiated immediately. In such situations, the use of drugs that inhibit peristalsis is contraindicated.

Lactic acidosis

Lactic acidosis has been reported with linezolid. Patients who develop symptoms and signs of metabolic acidosis, including recurrent nausea or vomiting, abdominal pain, low bicarbonate, or hyperventilation, while taking linezolid should seek immediate medical attention. If lactic acidosis develops, the benefits of continued linezolid therapy should be weighed against the potential risks.

Mitochondrial dysfunction

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

Potential interactions causing increased blood pressure

Unless patients can be monitored for possible increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or concomitant use of the following types of medicinal products: direct and indirect sympathomimetics (e.g. pseudoephedrine), vasopressors (e.g. epinephrine, norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine).

Serotonin syndrome

Serotonin syndrome has been reported spontaneously with concomitant use of linezolid and serotonergic drugs, including antidepressants (such as selective serotonin reuptake inhibitors (SSRIs)). Therefore, concomitant use of linezolid and serotonergic drugs is contraindicated (see section 4.3), unless both linezolid and the concomitant use of the serotonergic drug are essential. In such cases, the patient should be closely monitored for symptoms of serotonin syndrome, such as cognitive impairment, hyperpyrexia, hyperreflexia, and incoordination. If such symptoms occur, the physician should consider discontinuing the drug. Withdrawal symptoms may occur following discontinuation of the serotonergic drug.

Peripheral neuropathy and optic neuropathy

Peripheral neuropathy, as well as optic neuropathy and optic neuritis, sometimes progressing to vision loss, have been reported in patients treated with linezolid. These reports have primarily occurred in patients treated for more than 28 days (the maximum recommended duration of treatment).

All patients should be advised to report any symptoms of visual impairment, such as changes in visual acuity, changes in colour perception, blurred vision or loss of part of the visual field. In such cases, urgent examination with referral to an ophthalmologist is recommended, if necessary. If the patient is taking linezolid for more than the recommended 28 days, regular visual checks should be performed.

In the event of the development of peripheral neuropathy or optic neuropathy, the benefits of continued linezolid treatment should be weighed against the potential risks.

There may be an increased risk of neuropathy when linezolid is used to treat patients who are receiving or have recently received antibacterial drugs for the treatment of tuberculosis.

Convulsions

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 a history of 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. In drug interaction studies and safety studies of linezolid, very limited data have been obtained on the use of linezolid in the treatment of the underlying disease and/or concomitant treatment with drugs that may carry certain risks due to MAO inhibition. Therefore, the use of linezolid in such circumstances is not recommended unless close supervision and monitoring of the patient's condition is not possible (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Patients should be advised to avoid consuming large amounts of tyramine-rich foods (see section 4.5).

Hypoglycemia

Postmarketing reports have included cases of symptomatic hypoglycemia with linezolid, a nonselective, reversible MAOI, in diabetic patients receiving insulin or oral hypoglycemic agents. Some MAOIs have been associated with hypoglycemic episodes in diabetic patients receiving insulin or oral 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 when using this drug.

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.

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

Cases of hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion have been reported in patients receiving linezolid in the post-marketing setting. In these cases, signs and symptoms have included confusion, somnolence, general weakness, and in severe cases have resulted in respiratory failure and even death. Regular monitoring of serum sodium levels is recommended in the elderly, in patients taking diuretics, and in other patients at risk of hyponatremia and/or CHD during treatment with the drug. If signs and symptoms of hyponatremia and/or CHD develop, the drug should be discontinued and appropriate supportive measures should be taken.

Superinfection

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

The use of antibiotics may occasionally result in overgrowth of nonsusceptible organisms. For example, approximately 3% of patients receiving linezolid at recommended doses experienced drug-related candidiasis during clinical trials. 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 in situations where the expected benefit outweighs the potential risk (see section 4.2).

The use of linezolid in patients with severe hepatic impairment is recommended only in situations where the expected benefit outweighs the theoretical risk (see section 4.2).

There is no need to adjust the dose of the drug depending on the patient's gender.

Fertility disorders

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

Clinical trials

The safety and efficacy of linezolid when used for more than 28 days have not been established.

Controlled clinical trials did not include patients with pressure ulcers or ischemic lesions, severe burns, or gangrene. Accordingly, experience with the use of linezolid in 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 contains 0.38 mg (114 mg/300 ml) of sodium. The sodium content should be taken into consideration by patients on a controlled sodium diet.

Use during pregnancy or breastfeeding

Use in pregnancy. Data on the use of linezolid in pregnant women are limited. Animal studies have shown reproductive toxicity. There is a potential risk to humans. Linezolid should not be used during pregnancy unless the expected benefit outweighs the potential risk.

Use during lactation: Animal studies have shown that linezolid and its metabolites may pass into breast milk. Therefore, breastfeeding should be discontinued during the entire period of linezolid administration.

Ability to influence reaction speed when driving vehicles or other mechanisms

Patients should be warned about the possibility of developing dizziness or visual symptoms while taking linezolid (see sections "Special instructions" and "Adverse reactions") and advised not to drive or operate machinery if these symptoms occur.

Method of administration and doses

The duration of therapy recommendations below have been used in clinical trials. For some types of infections, shorter durations of treatment may be appropriate, but have not been evaluated in clinical trials.

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

No increase in recommended doses or duration of treatment is required in cases of infections accompanied by bacteremia.

Patients initiated on intravenous linezolid may be switched to oral linezolid. In this case, no dose adjustment is necessary since oral bioavailability of linezolid is nearly 100%.

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

* Newborns Most premature newborns are

** Linezolid is used in a different dosage form with the possibility of an appropriate dosage.

Use in elderly patients. No dose adjustment is required for such patients.

Use in patients with renal impairment (particularly those with creatinine clearance less than 30 ml/min). No dose adjustment is required. Because the clinical significance of increased concentrations (up to 10-fold) of the two major metabolites of linezolid in patients with severe renal impairment is unknown, linezolid should be used with extreme caution in such patients and only when the expected benefit is considered to outweigh the risk. Since approximately 30% of the dose is removed during a 3-hour hemodialysis session 3 hours after administration, linezolid should be administered to patients receiving such treatment after hemodialysis. The major metabolites of linezolid are removed to some extent by hemodialysis, but the concentrations of these metabolites after dialysis are still significantly higher than those observed in patients with normal renal function or mild to moderate renal impairment.

Therefore, linezolid should be used with extreme caution in patients with severe renal impairment undergoing dialysis, and only if the expected benefit outweighs the potential risk.

There is currently no experience with the use of linezolid in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or alternative treatments for renal failure (other than haemodialysis).

Use in patients with hepatic impairment. No dose adjustment is required. However, clinical data are limited, and it is recommended that linezolid be used in such patients only when the expected benefit outweighs the potential risk.

Instructions for use.

The drug is available in disposable, ready-to-use infusion bags. Immediately before use, remove the drug bag from the secondary packaging (metallized coated bag) and visually inspect the drug for mechanical inclusions; squeeze the bag for approximately 1 minute to ensure its integrity. If the bag leaks, the solution should not be used, as its sterility may be compromised. Any unused solution should be disposed of in accordance with applicable requirements. Intravenous infusion is performed over 30–120 minutes.

Do not connect infusion bags in series! Do not add other medications to this solution.

When this medicinal product is administered concomitantly with other agents, each agent should be administered separately according to the recommended dose and route of administration for each agent. When using the same intravenous line for sequential administration of multiple agents, the line should be primed before and after administration of linezolid to ensure that the