NDC 57664-683 Linezolid

Linezolid

NDC Product Code 57664-683

NDC CODE: 57664-683

Proprietary Name: Linezolid What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Linezolid What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Linezolid is an antibiotic used to treat certain serious bacterial infections. It works by stopping the growth of bacteria. This antibiotic treats only bacterial infections. It will not work for viral infections (such as common cold, flu). Using any antibiotic when it is not needed can cause it to not work for future infections. Linezolid also belongs to a class of drugs known as MAO inhibitors. It can increase the levels of certain natural substances in the body (such as dopamine, norepinephrine, serotonin) which can increase the chance of certain side effects and food and drug interactions. See How to Use, Side Effects, and Drug Interactions sections for more details.

NDC Code Structure

  • 57664 - Sun Pharmaceutical Industries, Inc.

NDC 57664-683-57

Package Description: 10 BAG in 1 BOX > 300 mL in 1 BAG (57664-683-31)

NDC Product Information

Linezolid with NDC 57664-683 is a a human prescription drug product labeled by Sun Pharmaceutical Industries, Inc.. The generic name of Linezolid is linezolid. The product's dosage form is injection, solution and is administered via intravenous form.

Labeler Name: Sun Pharmaceutical Industries, Inc.

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Linezolid Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • LINEZOLID 600 mg/300mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • TRISODIUM CITRATE DIHYDRATE (UNII: B22547B95K)
  • ANHYDROUS CITRIC ACID (UNII: XF417D3PSL)
  • DEXTROSE MONOHYDRATE (UNII: LX22YL083G)
  • TRISODIUM CITRATE DIHYDRATE (UNII: B22547B95K)
  • ANHYDROUS CITRIC ACID (UNII: XF417D3PSL)
  • DEXTROSE MONOHYDRATE (UNII: LX22YL083G)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Oxazolidinone Antibacterial - [EPC] (Established Pharmacologic Class)
  • Oxazolidinones - [CS]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Sun Pharmaceutical Industries, Inc.
Labeler Code: 57664
FDA Application Number: ANDA207354 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 02-01-2017 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Information for Patients

Linezolid Injection

Linezolid Injection is pronounced as (li ne' zoh lid)

Why is linezolid injection medication prescribed?
Linezolid injection is used to treat infections, including pneumonia, and infections of the skin and blood. Linezolid is in a class of antibacterials called oxazolidinone...
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* Please review the disclaimer below.

Linezolid Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

Linezolid injection is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. Linezolid injection is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [

see

Warnings and Precautions (5.4)].

1.1 Pneumonia

Nosocomial pneumoniacaused by

Staphylococcus aureus(methicillin-susceptible and -resistant isolates) or

Streptococcus pneumoniae[

see

Clinical Studies (14)].

Community-acquired pneumoniacaused by

Streptococcus pneumoniae, including cases with concurrent bacteremia, or

Staphylococcus aureus(methicillin-susceptible isolates only) [

see

Clinical Studies (14)].

1.2 Skin And Skin Structure Infections

Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by

Staphylococcus aureus(methicillin-susceptible and -resistant isolates),

Streptococcus pyogenes, or

Streptococcus agalactiae. Linezolid injection has not been studied in the treatment of decubitus ulcers [

see

Clinical Studies (14)].

Uncomplicated skin and skin structure infectionscaused by

Staphylococcus aureus(methicillin-susceptible isolates only) or

Streptococcus pyogenes[

see

Clinical Studies (14)].

1.3 Vancomycin-Resistant Enterococcus Faeciuminfections

Vancomycin-resistant

Enterococcus faeciuminfections,

including cases with concurrent bacteremia [

see

Clinical Studies (14)].

1.4 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of linezolid injection and other antibacterial drugs, linezolid injection should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.The safety and efficacy of linezolid injection given for longer than 28 days have not been evaluated in controlled clinical trials.

2.1 General Dosage And Administration

The recommended dosage for linezolid injection for the treatment of infections is described in Table 1.Table 1. Dosage Guidelines for Linezolid Injection Dosage, Route and Frequency of AdministrationRecommended Duration of Treatment (consecutive days)Infection

Due to the designated pathogens [seeIndications and Usage (1)]Pediatric Patients

Neonates less than 7 days: Most pre-term neonates less than 7 days of age (gestational age less than 34 weeks) have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. These neonates should be initiated with a dosing regimen of 10 mg/kg every 12 hours. Consideration may be given to the use of 10 mg/kg every 8 hours regimen in neonates with a sub-optimal clinical response. All neonatal patients should receive 10 mg/kg every 8 hours by 7 days of life [seeUse in Specific Populations (8.4)andClinical Pharmacology (12.3)].(Birth through 11 Years of Age)

Adults and Adolescents (12 Years and Older)Nosocomial pneumonia   Community-acquired pneumonia, including concurrent bacteremia10 mg/kg intravenously or oral

Oral dosing using either linezolid tablets or oral suspension.every 8 hours

600 mg intravenously or oralevery 12 hours10 to 14Complicated skin and skin structure infectionsVancomycin-resistant

Enterococcus faeciuminfections, including concurrent bacteremia

10 mg/kg intravenously or oralevery 8 hours600 mg intravenously or oralevery 12 hours14 to 28Uncomplicated skin and skin structure infectionsless than 5 yrs: 10 mg/kg oralevery 8 hours

5-11 yrs: 10 mg/kg oralevery

12 hours

Adults: 400 mg oralevery

12 hours

Adolescents: 600 mg oralevery 12 hours

10 to 14No dose adjustment is necessary when switching from intravenous to oral administration.

2.2 Intravenous Administration

Linezolid injection is supplied in single-use, ready-to-use infusion bags. Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired. Keep the infusion bags in the overwrap until ready to use. Store at room temperature. Protect from freezing. Linezolid injection may exhibit a yellow color that can intensify over time without adversely affecting potency.Linezolid injection should be administered by intravenous infusion over a period of 30 to 120 minutes.

Do not use this intravenous infusion bag in series connections. Additives should not be introduced into this solution. If linezolid injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product.

If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of linezolid injection with an infusion solution compatible with linezolid injection and with any other drug(s) administered via this common line.

2.3 Compatibilities

Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer's Injection, USP.

2.4 Incompatibilities

Physical incompatibilities resulted when linezolid injection was combined with the following drugs during simulated Y-site administration: amphotericin B, chlorpromazine HCl, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium, and trimethoprim-sulfamethoxazole. Additionally, chemical incompatibility resulted when linezolid injection was combined with ceftriaxone sodium.

3 Dosage Forms And Strengths

Linezolid injection: 100-mL (200 mg linezolid) and 300-mL (600mg linezolid) single-use, ready-to-use flexible plastic infusion bags in a foil laminate overwrap. The infusion bags and ports are not made with natural rubber latex.

4.1 Hypersensitivity

Linezolid injection formulations are contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components.

4.2 Monoamine Oxidase Inhibitors

Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product.

5.1 Myelosuppression

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression.

5.2 Peripheral And Optic Neuropathy

Peripheral and optic neuropathies have been reported in patients treated with linezolid injection, primarily in those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Visual blurring has been reported in some patients treated with linezolid injection for less than 28 days. Peripheral and optic neuropathy has also been reported in children.If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking linezolid injection for extended periods (≥ 3 months) and in all patients reporting new visual symptoms regardless of length of therapy with linezolid injection. If peripheral or optic neuropathy occurs, the continued use of linezolid injection in these patients should be weighed against the potential risks.

5.3 Serotonin Syndrome

Spontaneous reports of serotonin syndrome including fatal cases associated with the co-administration of linezolid injection and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported.Unless clinically appropriate and patients are carefully observed for signs and/or symptoms of serotonin syndrome or neuroleptic malignant syndrome-like (NMS-like) reactions, linezolid should not be administered to patients with carcinoid syndrome and/or patients taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), meperidine, bupropion, or buspirone [

see

Drug Interactions (7)and

Clinical Pharmacology (12.3)].

In some cases, a patient already receiving a serotonergic antidepressant or buspirone may require urgent treatment with linezolid. If alternatives to linezolid are not available and the potential benefits of linezolid outweigh the risks of serotonin syndrome or NMS-like reactions, the serotonergic antidepressant should be stopped promptly and linezolid administered. The patient should be monitored for two weeks (five weeks if fluoxetine was taken) or until 24 hours after the last dose of linezolid, whichever comes first. Symptoms of serotonin syndrome or NMS-like reactions include hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes that include extreme agitation progressing to delirium and coma. The patient should also be monitored for discontinuation symptoms of the antidepressant (see package insert of the specified agent(s) for a description of the associated discontinuation symptoms).

An imbalance in mortality was seen in patients treated with linezolid relative to vancomycin/dicloxacillin/oxacillin in an open-label study in seriously ill patients with intravascular catheter-related infections [78/363 (21.5%) vs. 58/363 (16.0%); odds ratio 1.426, 95% CI 0.970, 2.098]. While causality has not been established, this observed imbalance occurred primarily in linezolid-treated patients in whom either Gram-negative pathogens, mixed Gram-negative and Gram-positive pathogens, or no pathogen were identified at baseline, but was not seen in patients with Gram-positive infections only.Linezolid is not approved and should not be used for the treatment of patients with catheter-related bloodstream infections or catheter-site infections.Linezolid has no clinical activity against Gram-negative pathogens and is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [

see

Indications and Usage (1)].

5.5 Clostridium Difficileassociated Diarrhea

Clostridium difficileassociated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including linezolid injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of

C. difficile.

C. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of

C. difficilecause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.If CDAD is suspected or confirmed, ongoing antibiotic use not directed against

C. difficilemay need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of

C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.6 Potential Interactions Producing Elevation Of Blood Pressure

Unless patients are monitored for potential increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or patients taking any of the following types of medications: directly and indirectly acting sympathomimetic agents (e.g., pseudoephedrine), vasopressive agents (e.g., epinephrine, norepinephrine), dopaminergic agents (e.g., dopamine, dobutamine) [

see

Drug Interactions (7)and

Clinical Pharmacology (12.3)].

5.7 Lactic Acidosis

Lactic acidosis has been reported with the use of linezolid injection. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving linezolid injection should receive immediate medical evaluation.

5.8 Convulsions

Convulsions have been reported in patients when treated with linezolid. In some of these cases, a history of seizures or risk factors for seizures was reported.

5.9 Hypoglycemia

Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with linezolid, a reversible, nonselective MAO inhibitor. Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. While a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be cautioned of potential hypoglycemic reactions when treated with linezolid.If hypoglycemia occurs, a decrease in the dose of insulin or oral hypoglycemic agent, or discontinuation of oral hypoglycemic agent, insulin, or linezolid may be required.

5.10 Development Of Drug-Resistant Bacteria

Prescribing linezolid injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

  • The following adverse reactions have been identified during postapproval use of linezolid injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) [
  • See
  • Warnings and Precautions (5.1)]; sideroblastic anemia.
  • Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision [
  • See
  • Warnings and Precautions (5.2)].
  • Lactic acidosis [
  • See
  • Warnings and Precautions (5.7)]. Although these reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days, these events have also been reported in patients receiving shorter courses of therapy.
  • Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and linezolid injection [
  • See
  • Warnings and Precautions (5.3)].
  • Convulsions [
  • See
  • Warnings and Precautions (5.8)].
  • Anaphylaxis, angioedema, and bullous skin disorders including severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis and Stevens-Johnson syndrome.Superficial tooth discoloration and tongue discoloration have been reported with the use of linezolid. The tooth discoloration was removable with professional dental cleaning (manual descaling) in cases with known outcome.Hypoglycemia, including symptomatic episodes [
  • See
  • Warnings and Precautions (5.9)].

7.1 Monoamine Oxidase Inhibitors

Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. [

see

Contraindications (4.2)and

Clinical Pharmacology (12.3)].

7.2 Adrenergic And Serotonergic Agents

Linezolid has the potential for interaction with adrenergic and serotonergic agents. [

see

Warnings and Precautions (5.3,

5.6)and

Clinical Pharmacology (12.3)].

8.3 Nursing Mothers

Linezolid and its metabolites are excreted in the milk of lactating rats. Concentrations in milk were similar to those in maternal plasma. It is not known whether linezolid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when linezolid injection is administered to a nursing woman.

8.4 Pediatric Use

  • The safety and effectiveness of linezolid injection for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years [
  • See
  • Indications and Usage (1),
  • Clinical Pharmacology (12.3)and
  • Clinical Studies (14)]:
  • Nosocomial pneumoniacomplicated skin and skin structure infectionscommunity-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from 8 months through 12 years)vancomycin-resistant
  • Enterococcus faeciuminfections
  • The safety and effectiveness of linezolid injection for the treatment of pediatric patients with the following infection have been established in a comparator-controlled study in pediatric patients ranging in age from 5 through 17 years [
  • See
  • Clinical Studies (14)]:
  • Uncomplicated skin and skin structure infections caused by
  • Staphylococcus aureus(methicillin-susceptible strains only) or
  • Streptococcus pyogenesPharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended.The pharmacokinetics of linezolid have been evaluated in pediatric patients from birth to 17 years of age. In general, weight-based clearance of linezolid gradually decreases with increasing age of pediatric patients. However, in preterm (gestational age < 34 weeks) neonates < 7 days of age, linezolid clearance is often lower than in full-term neonates < 7 days of age. Consequently, preterm neonates < 7 days of age may need an alternative linezolid dosing regimen of 10 mg/kg every 12 hours [see
  • Dosage and Administration (2.1)and
  • Clinical Pharmacology (12.3)].
  • In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Gram-positive pathogens with minimum inhibitory concentrations (MICs) of 4 mcg/mL treated with linezolid injection had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 mcg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response [
  • See
  • Clinical Pharmacology (12.3)and
  • Dosage and Administration (2)].

8.5 Geriatric Use

Of the 2046 patients treated with linezolid in Phase 3 comparator-controlled clinical trials, 589 (29%) were 65 years or older and 253 (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

10 Overdosage

In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Hemodialysis may facilitate more rapid elimination of linezolid. In a Phase 1 clinical trial, approximately 30% of a dose of linezolid was removed during a 3-hour hemodialysis session beginning 3 hours after the dose of linezolid was administered. Data are not available for removal of linezolid with peritoneal dialysis or hemoperfusion. Clinical signs of acute toxicity in animals were decreased activity and ataxia in rats and vomiting and tremors in dogs treated with 3000 mg/kg/day and 2000 mg/kg/day, respectively.

11 Description

Linezolid injection contain linezolid, which is a synthetic antibacterial agent of the oxazolidinone class. The chemical name for linezolid is (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-acetamide.The empirical formula is C

16H

20FN

3O

4. Its molecular weight is 337.35, and its chemical structure is represented below:

Linezolid injection is supplied as a ready-to-use sterile isotonic solution for intravenous infusion. Each mL contains 2 mg of linezolid. Inactive ingredients are sodium citrate, citric acid, and dextrose in an aqueous vehicle for intravenous administration. The sodium (Na

+) content is 0.38 mg/mL (5 mEq/300-mL bag and 1.7 mEq/100-mL bag).

12.1 Mechanism Of Action

Linezolid is an antibacterial drug [see

Microbiology (12.4)].

12.2 Pharmacodynamics

In a randomized, positive- and placebo-controlled crossover thorough QT study, 40 healthy subjects were administered a single linezolid 600 mg dose via a 1 hour IV infusion, a single linezolid 1200 mg dose via a 1 hour IV infusion, placebo, and a single oral dose of positive control. At both the 600 mg and 1200 mg linezolid doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.

12.3 Pharmacokinetics

The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous doses are summarized in Table 8. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours are shown in Figure 1.Table 8. Mean (Standard Deviation) Pharmacokinetic Parameters of Linezolid in AdultsDose of Linezolid

C

maxmcg/mL

C

minmcg/mL

T

maxhrs

AUC

AUC for single dose = AUC 0–∞; for multiple dose = AUC 0–τmcg•h/mL

t

1/2hrs

CL

mL/min

C

max= Maximum plasma concentration; C

min= Minimum plasma concentration; T

max= Time to C

max; AUC = Area under concentration-time curve; t

1/2= Elimination half-life; CL = Systemic clearance

400 mg tabletsingle dose

Data dose-normalized from 375 mgevery 12 hours

8.10

(1.83)

11.00

(4.37)

---

3.08

(2.25)

1.52

(1.01)

1.12

(0.47)

55.10

(25.00)

73.40

(33.50)

5.20

(1.50)

4.69

(1.70)

146

(67)

110

(49)

600 mg tabletsingle dose

every 12 hours

12.70

(3.96)

21.20

(5.78)

---

6.15

(2.94)

1.28

(0.66)

1.03

(0.62)

91.40

(39.30)

138.00

(42.10)

4.26

(1.65)

5.40

(2.06)

127

(48)

80

(29)

600 mg IV injectionData dose-normalized from 625 mg, intravenous dose was given as 0.5-hour infusion.single dose

every 12 hours

12.90

(1.60)

15.10

(2.52)

---

3.68

(2.36)

0.50

(0.10)

0.51

(0.03)

80.20

(33.30)

89.70

(31.00)

4.40

(2.40)

4.80

(1.70)

138

(39)

123

(40)

600 mg oral suspensionsingle dose

11.00

(2.76)

---

0.97

(0.88)

80.80

(35.10)

4.60

(1.71)

141

(45)

Figure 1. Plasma Concentrations of Linezolid in Adults at Steady-State Following Oral Dosing Every 12 Hours (Mean ± Standard Deviation, n=16)

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of linezolid. Neither mutagenic nor clastogenic potential was found in a battery of tests including: assays for mutagenicity (Ames bacterial reversion and CHO cell mutation), an in vitro unscheduled DNA synthesis (UDS) assay, an in vitro chromosome aberration assay in human lymphocytes, and an in vivo mouse micronucleus assay.Linezolid did not affect the fertility or reproductive performance of adult female rats. It reversibly decreased fertility and reproductive performance in adult male rats when given at doses ≥ 50 mg/kg/day, with exposures approximately equal to or greater than the expected human exposure level (exposure comparisons are based on AUCs). The reversible fertility effects were mediated through altered spermatogenesis. Affected spermatids contained abnormally formed and oriented mitochondria and were non-viable. Epithelial cell hypertrophy and hyperplasia in the epididymis was observed in conjunction with decreased fertility. Similar epididymal changes were not seen in dogs.In sexually mature male rats exposed to drug as juveniles, mildly decreased fertility was observed following treatment with linezolid through most of their period of sexual development (50 mg/kg/day from days 7 to 36 of age, and 100 mg/kg/day from days 37 to 55 of age), with exposures up to 1.7-fold greater than mean AUCs observed in pediatric patients aged 3 months to 11 years. Decreased fertility was not observed with shorter treatment periods, corresponding to exposure in utero through the early neonatal period (gestation day 6 through postnatal day 5), neonatal exposure (postnatal days 5 to 21), or to juvenile exposure (postnatal days 22 to 35). Reversible reductions in sperm motility and altered sperm morphology were observed in rats treated from postnatal day 22 to 35.

13.2 Animal Toxicology And/Or Pharmacology

Target organs of linezolid toxicity were similar in juvenile and adult rats and dogs. Dose- and time-dependent myelosuppression, as evidenced by bone marrow hypocellularity/decreased hematopoiesis, decreased extramedullary hematopoiesis in spleen and liver, and decreased levels of circulating erythrocytes, leukocytes, and platelets have been seen in animal studies. Lymphoid depletion occurred in thymus, lymph nodes, and spleen. Generally, the lymphoid findings were associated with anorexia, weight loss, and suppression of body weight gain, which may have contributed to the observed effects.In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was observed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in 1 male at this dose level at a 3-month interim necropsy. Sensitive morphologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 male rats after 6 months of dosing, but the direct relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical distribution. The nerve degeneration observed was microscopically comparable to spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of common background change.These effects were observed at exposure levels that are comparable to those observed in some human subjects. The hematopoietic and lymphoid effects were reversible, although in some studies, reversal was incomplete within the duration of the recovery period.

15 References

  • Clinical and Laboratory Standards Institute (CLSI).
  • Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – Tenth Edition.CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
  • Clinical and Laboratory Standards Institute (CLSI).
  • Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement. CLSI document M100-S25, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
  • Clinical and Laboratory Standards Institute (CLSI).
  • Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard – Twelfth Edition.CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

16.1 Injection

Linezolid injection is available in single-use, ready-to-use flexible plastic infusion bags in a foil laminate overwrap. The infusion bags and ports are not made with natural rubber latex. The infusion bags are available in the following package sizes:100 mL bag (200 mg linezolid)            NDC 57664-682-30300 mL bag (600 mg linezolid)            NDC 57664-683-31300 mL bag (600 mg linezolid) × 10    NDC 57664-683-57

16.4 Storage And Handling

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [

see USP Controlled Room Temperature]. Protect from light. It is recommended that the infusion bags be kept in the overwrap until ready to use. Protect infusion bags from freezing.

17 Patient Counseling Information

  • Patients should be counseled that antibacterial drugs including linezolid injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When linezolid injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by linezolid injection or other antibacterial drugs in the future.Patients should be advised that:Linezolid injection may be taken with or without food.They should inform their physician if they have a history of hypertension.Large quantities of foods or beverages with high tyramine content should be avoided while taking linezolid injection. Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor, such as aged cheeses ,fermented or air-dried meats ,sauerkraut , soy sauce, tap beers, and red wines. The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.They should inform their physician if taking medications containing pseudoephedrine HCl or phenylpropanolamine HCl, such as cold remedies and decongestants.They should inform their physician if taking serotonin re-uptake inhibitors or other antidepressants.They should inform their physician if they experience changes in vision.They should inform their physician if they have a history of seizures.Diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.Inform patient, particularly those with diabetes mellitus that hypoglycemic reactions, such as diaphoresis and tremulousness, along with low blood glucose measurements may occur when treated with linezolid. If such reactions occur, patients should contact a physician or other health professional for proper treatment.Distributed by:
  • Sun Pharmaceutical Industries, Inc.Cranbury, NJ 08512
  • Manufactured by:
  • Nang Kuang Pharmaceutical Co., Ltd.No. 1001, Zhongshan Rd., Xinhua Dist,
  • Tainan City 71423, Taiwan
  • Issued: 021418-04
  • 2620000000U563

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