Linezolid Tablets Instructions

Approval date: September 12, 2006
Date of revision: June 08, 2009; December 21, 2009; April 30, 2010; May 05, 2011
November 28, 2011; June 15, 2012; August 23, 2013; February 13, 2015
 Linezolid Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician.
 Drug Name】Generic Name: Linezolid Tablets
Trade name: Svor® / Zyvox®
English Name: Linezolid Tablets
Hanyu Pinyin: Linaizuoan Pian
 Ingredients
The main ingredient of this product is linezolid.
Chemical name: (S)-N[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
Chemical structure formula.
Molecular formula: C16H20FN3O4
Molecular weight: 337.35
The excipients are corn starch, microcrystalline cellulose, hydroxypropyl cellulose, sodium hydroxymethyl starch, magnesium stearate, hydroxypropyl methyl cellulose, polyethylene glycol, titanium dioxide, and palm wax. The sodium ion content is 1.95 mg per tablet for 400 mg and 2.92 mg per tablet for 600 mg (equivalent to 0.1 mEq per tablet).
 【Properties】.
This product is a white or off-white film-coated tablet.
 Indications
This product is used for the treatment of the following infections caused by specific microbial susceptible strains.
Nosocomial acquired pneumonia, caused by Staphylococcus aureus (methicillin-susceptible and resistant strains) or Streptococcus pneumoniae.
Community-acquired pneumonia, community-acquired pneumonia caused by Streptococcus pneumoniae, including concomitant bacteremia, or community-acquired pneumonia caused by Staphylococcus aureus (methicillin-susceptible strains only).
Complex skin and skin soft tissue infections, including uncomplicated diabetic foot infections with osteomyelitis, complex skin and skin soft tissue infections caused by Staphylococcus aureus (methicillin-susceptible and resistant strains), Streptococcus pyogenes, or Streptococcus lactis. No studies are available on the use of linezolid for the treatment of decubitus ulcers.
Uncomplicated skin and soft tissue skin infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.
Vancomycin-resistant Enterococcus faecalis infections, including concomitant bacteraemia.
To reduce the incidence of bacterial resistance and to ensure the efficacy of linezolid and other antimicrobial agents, linezolid should be used only for the treatment of infections due to confirmed or highly suspected sensitive organisms. If bacterial culture and drug sensitivity results are available, consideration should be given to selecting or adjusting antimicrobial therapy accordingly. In the absence of these data, local epidemiologic information and drug susceptibility status may be helpful in the selection of empirical therapy.
The safety and efficacy of linezolid preparations applied for more than 28 days have not been evaluated in controlled clinical studies.
Linezolid is not indicated for the treatment of Gram-negative bacterial infections. If combined Gram-negative infection is confirmed or suspected, it is important to initiate immediate targeted anti-Gram-negative therapy (see WARNINGS).
 Specification
600mg
 Dosage]
The recommended dose of this product for the treatment of infections is shown in Table 1.
Table 1 Recommended dose of linezolid
 Infection* Dose and route of administration Recommended duration of treatment
(Number of consecutive treatment days)Pediatric patients†
(birth to 11 years of age) Adults and adolescents
(12 years and older) Nosocomial acquired pneumonia Every 8 hours, 10 mg/kg
Intravenous or oral‡ 600 mg every 12 hours
IV or oral‡10 to 14 community-acquired pneumonia, including associated bacteremiaComplex skin and soft tissue skin infectionsVancomycin-resistant Enterococcus faecalis infections, including associated bacteremia10 mg/kg every 8 hours
Intravenous or oral‡ 600 mg every 12 hours
Intravenously or orally‡ 14 to 28
Uncomplicated skin and soft tissue skin infections under 5 years of age: 10 mg/kg orally every 8 hours‡
5-11 years: 10 mg/kg orally every 12 hours‡ Adults: 400 mg orally every 12 hours‡
Adolescents: oral‡600 mg every 12 hours10 to 14* Refers to infections caused by specific pathogens (see [Indications])
† Neonates less than 7 days old: Most preterm infants born less than 7 days old (less than 34 gestational weeks) have lower systemic clearance of linezolid than full-term infants and other older infants, and have greater AUC values.
The AUC values are greater. The initial dose for these newborns should be 10 mg/kg every 12 hours, and when clinical outcomes are poor, consideration should be given to dosing at 10 mg/kg every 8 hours. All newborns 7 days of age or older should be administered at a dose of 10 mg/kg every 8 hours (see [Pharmacokinetics], Special Populations, [Pediatric Dosing]).
‡ Oral dosing refers to linezolid tablets or linezolid oral suspension.
 Adult patients with MRSA infection should be treated with linezolid 600 mg every 12 hours.
In limited clinical experience, five of six pediatric patients (83%) with a minimum inhibitory concentration of 4 μg/ml of linezolid against their infecting gram-positive pathogens were clinically cured by linezolid treatment. However, the range of variation in linezolid clearance and systemic drug exposure (AUC) was wider in pediatric patients compared to adults. When clinical efficacy is not optimal in pediatric patients, especially for pathogens with a minimum linezolid inhibitory concentration of 4 μg/ml, their lower systemic exposure to the drug, the site of infection and its severity, and their underlying disease should be considered when making efficacy assessments (see [Pharmacokinetics] – Special Populations, Children and [Pediatric Dosing]).
In controlled clinical studies, the duration of therapy set by the study protocol for the treatment of all infections ranged from 7 to 28 days. The total duration of therapy was determined by the treating physician based on the site and severity of the infection and the patient’s response to treatment.
No dose adjustment was required when switching from intravenous to oral administration. Patients treated with linezolid injection at the start of treatment may be given linezolid tablets or oral suspension to continue treatment, depending on clinical status.
 Adverse reactions]
Because of the varying conditions under which clinical trials are conducted, the rate of adverse reactions observed in clinical trials of one drug is not directly comparable to the rate of adverse reactions observed in clinical trials of another drug and may not reflect the rate of adverse reactions observed in clinical practice.
 Adult Patients
In seven phase III positive drug-controlled clinical studies of up to 28 days duration, 2046 patients were enrolled to evaluate the safety of linezolid.
Among patients treated for uncomplicated skin and soft tissue skin infections (uSSSI), 25.4% of patients using linezolid and 19.6% of patients using the control drug experienced at least one drug-related adverse event. For all other indications, 20.4% of patients using linezolid and 14.3% of patients using the control drug had at least one drug-related adverse event.
In these studies, 85% of linezolid adverse events were mild to moderate by severity of adverse event. Table 2 shows the adverse events with an incidence of more than 2%. The most common adverse events with linezolid were diarrhea (incidence 2.8% to 11.0% across studies), headache (incidence 0.5% to 11.3% across studies), and nausea (incidence 3.4% to 9.6% across studies).
Table 2 Linezolid-positive drug-controlled clinical studies in adult patients
Incidence³ 2% of adverse events
Event
Events linezolid
(n=2046) All control drugs*
(n=2001) Diarrhea 8.3 6.3 Headache 6.5 5.5 Nausea 6.2 4.6 Vomiting 3.7 2.0 Insomnia 2.5 1.7 Constipation 2.2 2.1 Rash 2.0 2.2 Dizziness 2.0 1.9 Fever 1.6 2.1 *Controls included cefpodoxime 200 mg orally every 12 hours; ceftriaxone 1 g intravenously every 12 hours; clarithromycin 250 mg orally every 12 hours; dicloxacillin 500 mg orally every 6 hours; benzocillin 2 g intravenously every 6 hours; and vancomycin 1 g intravenously every 12 hours.
 Other adverse events reported in Phase II and Phase III studies included oral candidiasis, vaginal candidiasis, hypertension, dyspepsia, local abdominal pain, pruritus, and tongue discoloration.
Table 3 shows the incidence of adverse events with any causal relationship that occurred with treatment in adult patients with an incidence greater than 1% in positive drug-controlled clinical studies with different doses of linezolid.
 Table 3: Treatment-emergent adverse events with any causal relationship in adult patients in linezolid positive drug-controlled clinical studies
Adverse reactions with an incidence greater than 1%
 Adverse reactions Uncomplicated skin and soft tissue skin infections All other indications Linezolid
400 mg orally
every 12 hours
(n=548) Clarithromycin
250 mg orally
Every 12 hours
(n=537) Linezolid
600 mg
Every 12 hours
(n=1498) 
 All other control drugs*
(n=1464) Headache 8.8 8.4 5.7 4.4 Diarrhea 8.2 6.1 8.3 6.4 Nausea 5.1 4.5 6.6 4.6 Vomiting 2.0 1.5 4.3 2.3 Dizziness 2.6 3.0 1.8 1.5 Rash 1.1 1.1 2.3 2.6 Anemia 0.4 0 2.1 1.4 Altered taste 1.8 2.0 1.0 0.3 Vaginal candidiasis 1.8 1.3 1.1 0.5 Oral candidiasis 0.5 0 1.7 1.0 Abnormal liver function tests 0.40.2 1.6 0.8 Fungal infections
1.5 0.2 0.3 0.2 Tongue discoloration 1.3 0 0.3 0 Limited abdominal pain 1.3 0.6 1.2 0.8 Diffuse abdominal pain 0.9 0.4 1.2 1.0 *Controls include cefpodoxime 200 mg orally every 12 hours; ceftriaxone 1 g every 12 hours by sedation; dicloxacillin 500 mg orally every 6 hours; benzocillin 2 g every 6 hours by sedation once every 6 hours; vancomycin 1g every 12 hours.
 Among patients treated for uSSSI, 3.5% of patients on linezolid and 2.4% of patients on the control drug discontinued treatment due to drug-related adverse events. For all other indications, 2.1% of patients using linezolid and 1.7% of patients using control drugs discontinued treatment due to drug-related adverse events. The most common drug-related adverse events for which treatment was discontinued were nausea, headache, diarrhea, and vomiting.
     The table below lists the adverse drug reactions that occurred with a frequency of ≥0.1% or were considered serious in the clinical studies. A total of 2,000 adult patients were enrolled in these studies and given the recommended dose of linezolid for up to 28 days.
     Adverse reactions occurred in approximately 22% of patients; the most common were headache (2.1%), diarrhea (4.2%), nausea (3.3%), and candidiasis (particularly oral candidiasis [0.8%] and vaginal candidiasis [1.1%], see table below). The most common drug-related adverse events leading to treatment discontinuation were headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to the occurrence of drug-related adverse events.
     The frequency category for other post-marketing reported adverse reactions in the table below is “unknown” because the actual frequency cannot be estimated based on available data.
     The following adverse reactions were observed and reported during treatment with linezolid and were categorized by the following frequencies: extremely common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/ 10,000), unknown (cannot be estimated from available data).
 Systematic organ classification common (≥1/100 to <1/10) uncommon (≥1/1000 to <1/100) rare
(≥1/10,000 to <1/1000) very rare
(<1/10000) Unknown (cannot be estimated from available data) Infections and infestations Candidiasis, oral candidiasis, vaginal candidiasis, fungal infections Vaginitis Antibiotic-associated colitis, including pseudomembranous colitis* Blood and lymphatic system abnormalities Leukopenia*, neutropenia, thrombocytopenia*, eosinophilia Bone marrow suppression*, holocytopenia*, anemia* †, iron granulocytic anemia* immune system abnormalities allergic reactions metabolic and nutritional abnormalities lactic acidosis*, hyponatremia psychiatric abnormalities insomnia neurological abnormalities headache, taste inversions (metallic taste in the mouth) dizziness, hyperalgesia, tactile abnormalities 5-hydroxytryptamine syndrome**, convulsions*, peripheral neuropathy* ocular abnormalities* blurred vision* optic neuropathy*, optic neuritis*, visual loss*. Visual acuity changes*, color vision changes*, visual field defect changes* Ear and vagus abnormalities Tinnitus Heart abnormalities Arrhythmia (tachycardia) Vascular abnormalities Hypertension, phlebitis, thrombophlebitis Transient ischemic attack Gastrointestinal abnormalities Diarrhea, nausea, vomiting Pancreatitis, gastritis, limited abdominal pain or total abdominal pain, constipation, dry mouth, dyspepsia, tongue inflammation, loose stools, stomatitis, tongue discoloration or tongue disease Dental surface Discoloration Hepatobiliary abnormalities Abnormal liver function tests; elevated AST, ALT, or alkaline phosphatase Elevated total bilirubin Skin and subcutaneous tissue abnormalities Urticaria, dermatitis, sweating, pruritus, rash Maculopathy manifesting as Stevens-Johnson syndrome and toxic epidermolysis bullosa, angioedema, alopecia areata Renal and urinary system abnormalities Elevated blood urea nitrogen Polyuria, elevated creatinine Renal failure  Reproductive system and breast abnormalities Vulvovaginal disorders Systemic abnormalities and administration site reactions Chills, fatigue, fever, injection site pain, increased thirst, localized pain Laboratory tests Biochemistry
Elevated lactate dehydrogenase, creatine kinase, lipase, amylase, or non-fasting glucose Decreased total protein, albumin, sodium, or calcium. Elevated or decreased potassium or bicarbonate.
 Hematology
Decreased or elevated platelet or white blood cell counts.
Decreased hemoglobin, hematocrit, or red blood cell count. Increased neutrophils or eosinophils. Biochemistry
Elevated sodium or calcium. Decreased non-fasting glucose. Elevated or decreased chloride.
 
 
 
 
 
 
 
 
 
 
 Hematology
Decreased neutrophils.
Reticulocyte count is elevated.   
 * See [Precautions].
** See [Contraindications] and [Precautions].
† See below
 The following are rare serious adverse reactions to linezolid: limited abdominal pain, transient ischemic attack, and hypertension.
     In controlled clinical trials in which linezolid was given for up to 28 days, anemia was reported in less than 0.1% of patients. The percentage of patients with life-threatening infections and underlying comorbidities receiving linezolid in the compassionate use program who developed anemia at ≤28 days was 2.5% (33/1326), compared with 12.3% (53/430) who developed anemia at treatment>28 days. In terms of the percentage of patients reporting drug-related severe anemia and requiring blood transfusion, it was 9% (3/33) among patients treated ≤28 days and 15% (8/53) among patients treated >28 days.
 Pediatric patients
    Safety data from clinical studies based on approximately 500 pediatric patients (from birth to 17 years of age) did not indicate that the safety profile of linezolid differs in pediatric patients from that of adult patients.
The safety of linezolid was evaluated in 215 pediatric patients from birth to 11 years of age and 248 pediatric patients from 5 to 17 years of age (146 of whom were 5 to 11 years of age and 102 of whom were 12 to 17 years of age). Patients were enrolled into two phase III positive drug-controlled clinical studies with a maximum of 28 days of dosing. In the studies, 83% and 99% of the adverse events reported in the linezolid group were classified as mild to moderate, respectively, by severity of adverse event occurrence.
In the study of pediatric patients hospitalized with Gram-positive infections (patients aged newborn to 11 years), patients were randomized 2:1 to two groups (linezolid versus vancomycin), with mortality rates of 6.0% (13/215) and 3.0% (3/101) in the linezolid and vancomycin groups, respectively. Given that all of these patients had severe underlying disease, a causal relationship could not be established. Table 4 shows the adverse events with an incidence of at least 2% in pediatric patients in the linezolid group in the study.
Among pediatric patients treated for uSSSI, 19.2% of patients on linezolid and 14.1% of patients on the control drug had at least one drug-related adverse event. For all other indications, 18.8% of patients using linezolid and 34.3% of patients using the control drug experienced at least one drug-related adverse event.
 Table 4. Incidence in pediatric patients in linezolid-positive drug-controlled clinical studies
≥2% of adverse events
Adverse events Uncomplicated skin and soft tissue skin infections *All other indications** Linezolid
(n = 248) cefadroxil (n = 251) linezolid (n = 215) vancomycin (n = 101) fever 2.93.614.114.1 diarrhea 7.8 8.0 10.8 12.1 vomiting 2.9 6.4 9.4 9.1 sepsis 008.07.1 rash 1.6 1.2 7.0 15.2 headache 6.5 4.0 0.9 0 anemia 0 0 5.6 7.1 Thrombocytopenia 0 0 4.7 2.0 Upper respiratory tract infection 3.75.24.21.0 Nausea 3.7 3.2 1.9 0 Dyspnea 0 0 3.3 1.0 Injection or catheter retention site reaction 003.35.1 Trauma 3.3 4.8 2.8 2.0 Pharyngitis 2.9 1.6 0.5 1.0 Convulsions 0 0 2.8 2.0 Hypokalemia 0 0 2.8 3.0 Pneumonia 0 0 2.8 2.0 Thrombocytosis 0 0 2.8 2.0 Cough 2.4 4.0 0.9 0 Diffuse abdominal pain 2.4 2.8 0.9 2.0 Restricted abdominal pain
2.4 2.8 0.5 1.0 Apnea 0 0 2.3 2.0 Gastrointestinal bleeding 0 0 2.3 1.0 Systemic edema 0 0 2.3 1.0 Scanty stools 1.60.82.33.0 Localized pain 2.01.60.90 Skin lesions 2.000.91.0* Pediatric patients 5 to 11 years of age: linezolid at 10 mg/kg orally every 12 hours or cefadroxil For pediatric patients 12 years of age or older: linezolid at 600 mg orally every 12 hours or cefadroxil at 500 mg orally every 12 hours.
**
Pediatric patients from birth to 11 years of age: linezolid at 10 mg/kg orally or by sedation every 8 hours; vancomycin at 10-15 mg/kg by sedation every 6-24 hours depending on age and renal clearance.
 Table 5 shows the number of adverse events with any causal relationship and an incidence of more than 1% (and more than 1 patient) with treatment in pediatric patients in either treatment group in the phase III positive drug-controlled clinical study.
 Table 5: Adverse reactions in pediatric patients in either treatment group with any causal relationship and an incidence of more than 1% (and more than 1 patient) with treatment in positive drug-controlled clinical studies
 Adverse reactions Uncomplicated skin and skin soft tissue infections* All other indications† Linezolid (n=248) Cefadroxil (n=251) Linezolid (n=215) Vancomycin (n=101) Diarrhea 7.8 8.0 10.8 12.1 Vomiting 2.9 6.4 9.4 9.1 Headache 6.5 4.00.9 0 Anemia 0 0 5.6 7.1 Thrombocytopenia 0 0 4.7 2.0 Nausea 3.7 3.2 1.9 0 Diffuse abdominal pain 2.4 2.8 0.9 2.0 Restricted abdominal pain 2.4 2.8 0.5 1.0 Scanty stools 1.6 0.8 2.3 3.0 Eosinophilia 0.4 0.8 1.9 1.0 Pruritus at non-injection sites 0.8 0.4 1.4 2.0 Vertigo 1.2 0.4 0 0 * Pediatric patients 5 to 11 years of age
† Pediatric patients 12 years of age or older: linezolid at 10 mg/kg orally every 12 hours or cefadroxil at 15 mg/kg orally every 12 hours † Pediatric patients 12 years of age or older: linezolid at 600 mg orally every 12 hours or cefadroxil at 500 mg orally every 12 hours † Pediatric patients 12 years of age or older: linezolid at 600 mg or cefadroxil at 500 mg orally every 12 hours
† Pediatric patients from birth to 11 years of age: linezolid at 10 mg/kg orally or by sedation every 8 hours; vancomycin at 10-15 mg/kg by sedation every 6-24 hours depending on age and renal clearance.
 In pediatric patients treated for uSSSI, 1.6% of patients on linezolid and 2.4% of patients on the control drug discontinued treatment due to drug-related adverse events. For all other indications, 0.9% of patients on linezolid and 6.1% of patients on the control drug discontinued treatment due to drug-related adverse events.
 Changes in Laboratory Tests
Linezolid was associated with thrombocytopenia at doses up to 600 mg every 12 hours for up to 28 days. In a phase III positive drug-controlled clinical study, the percentage of patients with significant thrombocytopenia (defined as less than 75% of normal or basal values) in adults was 2.4% in the linezolid group (range of incidence 0.3-10.0%) and 1.5% in the control group (range of incidence 0.4%-7.0%). In a study of hospitalized pediatric patients from birth to 11 years of age, the percentage of patients who developed significant thrombocytopenia (defined as less than 75% of normal or basal values) was 12.9% in the linezolid group and 13.4% in the vancomycin group. In another study of outpatients aged 5 to 17 years, the percentage of patients presenting with significant thrombocytopenia (defined as less than 75% of normal or basal values) was 0% in the linezolid group and 0.4% in the cefadroxil group. Linezolid-associated thrombocytopenia was shown to be correlated with the course of therapy (usually all courses were longer than 2 weeks). Most patients’ platelet counts returned to normal/basal levels during the follow-up phase. In the phase III clinical study, no clinically relevant adverse events were seen in thrombocytopenic patients. Bleeding events were seen only in thrombocytopenic patients in the linezolid compassionate application program; the role of linezolid in these adverse events could not be determined (see WARNINGS).
Changes in other laboratory findings showed no significant differences between linezolid and control drugs, whether drug-related or not. These changes were generally not clinically significant, did not result in discontinuation of the drug, and were reversible. The percentage of adult and pediatric patients with at least one significant routine blood and blood biochemical abnormality is shown in Tables 6, 7, 8, and 9.
 Table 6. in linezolid-positive drug-controlled clinical studies.
Adult patients presenting with
Percentage of patients with at least one significant routine blood abnormality*
Laboratory tests Uncomplicated skin and soft tissue skin infections Other indications Linezolid
400 mg
Clarithromycin every 12 hours
250mg
Linezolid every 12 hours
600mg
All other controls every 12 hours** Hemoglobin (g/dl) 0.9 0.0 7.1 6.6 Platelets (×103/mm3) 0.70.8 3.0 1.8 Leukocytes (×103/mm3) 0.2 0.6 2.2 1.3 Neutrophils (×103/mm3) 0.0 0.2 1.1 1.2 *For those with normal basal values
<75% (<50% for neutrophils) of the lower limit of normal (LLN).
For patients with abnormal basal values, <75% (neutrophils as <50%) of the lower limit of normal and <75% (neutrophils as <50%) of the basal values.
**Controls included cefpodoxime 200 mg orally every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg orally every 6 hours; benzocillin 2 g intravenously every 6 hours; and vancomycin 1 g intravenously every 12 hours.
 Table 7. in linezolid-positive drug-controlled clinical studies.
Adult patients presented with
Percentage of patients with at least one significant abnormal blood biochemical laboratory test*
Laboratory Tests Uncomplicated Skin and Skin Soft Tissue Infections All Other Indications Linezolid
400 mg
Clarithromycin every 12 hours
250mg
Linezolid every 12 hours
600mg
All other controls every 12 hours** AST(U/L) 1.7 1.3 5.0 6.8 ALT(U/L) 1.7 1.7 9.6 9.3 LDH(U/L) 0.2 0.2 1.8 1.5 Alkaline phosphatase(U/L) 0.2 0.2 3.5 3.1 Lipase(U/L) 2.8 2.6 4.3 4.2 Amylase(U/L) 0.2 0.2 2.4 2.0 Total bilirubin (mg/dL) 0.2 0.0 0.9 1.1 BUN (mg/dL) 0.2 0.0 2.1 1.5 Creatinine (mg/dL) 0.2 0.0 0.2 0.6 *For those with normal basal values, >2 times upper limit of normal (ULN)
For those with abnormal basal values, >2 times upper limit of normal and >2 times the basal value
**Controls include cefpodoxime 200 mg orally every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg orally every 6 hours; benzocillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours.
 Table 8. pediatric patients in linezolid-positive drug-controlled clinical studies who developed
Percentage of patients with at least one significant blood abnormality*
Laboratory Tests Uncomplicated Skin and Skin Soft Tissue Infections** All Other Indications*** Linezolid
Cefadroxil linezolid
Vancomycin Hemoglobin (g/dl) 0.0 0.0 15.7 12.4 Platelets (×103/mm3) 0.0 0.4 12.9 13.4 Leukocytes (×103/mm3) 0.8 0.8 12.4 10.3 Neutrophils (×103/mm3) 1.2 0.8 5.9 4.3 * For those with normal basal values, <75% (neutrophils granulocytes for <50%) of the lower limit of normal (LLN).
For patients with abnormal basal values, <75% (neutrophils are <50%) of the lower limit of normal and <75% (if basal values are below normal, neutrophils are <50% and hemoglobin is <90%) of the basal values.
**
Children 5-11 years of age at linezolid 10 mg/kg orally every 12 hours; cefadroxil at 15 mg/kg orally every 12 hours.
For pediatric patients 12 years of age or older linezolid 600 mg orally every 12 hours or cefadroxil 500 mg orally every 12 hours.
***
Linezolid at 10 mg/kg orally every 8 hours in pediatric patients from birth to 11 years of age; vancomycin at 10-15 mg/kg orally every 6 to 24 hours based on age and renal clearance.
 Table 9. pediatric patients in linezolid-positive drug-controlled clinical studies who developed
Percentage of patients with at least one significant blood biochemical abnormality*
 Laboratory tests
Uncomplicated skin and skin soft tissue infections** All other indications*** Linezolid
Cefadroxil linezolid
Vancomycin ALT (U/L) 0.0 0.0 10.1 12.5 Lipase (U/L) 0.4 1.2 — — Amylase (U/L) —— 0.6 1.3 Total bilirubin (mg/dL) — — 6.3 5.2 Creatinine (mg/dL) 0.4 0.0 2.4 1.0 * For those with normal basal values, >2 times the upper limit of normal ( ULN).
For abnormal basal values, >2 times upper limit of normal and >2 times (>1.5 total bilirubin) the basal value.
**
Pediatric patients 5-11 years of age: linezolid at 10 mg/kg orally every 12 hours; cefadroxil at 15 mg/kg orally every 12 hours. pediatric patients 12 years of age or older: linezolid at 600 mg orally every 12 hours or cefadroxil at 500 mg orally every 12 hours.
*** Pediatric patients from birth to 11 years of age: linezolid at 10 mg/kg orally every 8 hours; vancomycin at 10-15 mg/kg orally every 6-24 hours depending on age and renal clearance.
 Post-marketing experience
Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in post-marketing clinical applications of linezolid (see WARNINGS). Peripheral neuropathy and optic neuropathy sometimes progressing to visual loss have been reported. Lactic acidosis has been reported during the application of linezolid. (See [Precautions], General Precautions). Although the above reports have occurred primarily in patients who have been on linezolid for longer than the recommended maximum duration of application (28 days), they have also been reported in patients who have been on the drug for shorter periods of time. 5-hydroxytryptamine syndrome has been reported in patients on linezolid in combination with 5-hydroxytryptamines, including antidepressants such as: selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) (see [Precautions], General Precautions). Convulsions have been reported in the course of linezolid application (see [Precautions], General Precautions). Allergic reactions, angioedema, and cutaneous blistering described as Stevens Johnson syndrome have also been reported. Discoloration of the teeth and tongue has been reported following linezolid use. In cases with known outcomes, tooth discoloration can be removed by professional dental cleaning (manual descaling). Hypoglycemia, including symptomatic episodes, has been reported (see WARNINGS). These adverse events may be listed due to their severity, frequency of reporting, possible correlation with linezolid, or a combination of these factors. Because the above events were reported spontaneously and it is not known from what sample of patient population they originated, their incidence cannot be estimated and their causal relationship with drug administration cannot be accurately determined.
 Contraindications
This product is contraindicated in patients with known hypersensitivity to linezolid or other components of this product.
 Monoamine oxidase inhibitors
Linezolid should not be used in patients who are using any drug that inhibits monoamine oxidase A or B (e.g., phenelzine, isocarbohydrazide), or who have used such drugs within two weeks.
 Potential interactions causing increased blood pressure
Linezolid should not be used in patients with the following potential clinical conditions or with concomitant use of the following types of drugs unless the patient can be monitored for possible elevations in blood pressure.
Patients with uncontrolled hypertension, pheochromocytoma, carcinoid tumors, hyperthyroidism, bipolar depression, schizoaffective disorder, or in an acute state of unconsciousness
Patients on any of the following medications: 5-hydroxytryptamine reuptake inhibitors, tricyclic antidepressants, 5-hydroxytryptamine 5-HT1 receptor agonists (treprostans), direct or indirect sympathomimetic drugs (including epinephrine bronchodilators, pseudoephedrine and norephedrine), vasopressors (e.g., epinephrine, norepinephrine), dopamines (e.g., dopamine, dop phentermine), pethidine or buspirone (see [Precautions], [Drug Interactions]).
Animal data suggest that linezolid and its metabolites can enter breast milk, so breastfeeding should be discontinued prior to and during treatment with this product (see [Use in Pregnant and Lactating Women])
 Potential Interactions with 5-Hydroxytryptamines
Linezolid should not be used in patients with carcinoid syndrome and/or in patients using any of the following drugs: 5-hydroxytryptamine reuptake inhibitors, tricyclic antidepressants, 5-hydroxytryptamine 5-HT1 receptor agonists (treprostinines), pethidine, or buspirone unless the patient is closely observed for signs and/or symptoms of 5-hydroxytryptamine syndrome (see [Precautions], General Precautions, and [Drug Interactions]).
 Precautions]
To reduce the emergence of drug-resistant bacteria and to ensure the efficacy of this and other antibacterial drugs, linezolid should be used only for the treatment or prevention of infectious diseases that have been confirmed or are highly suspected to be caused by bacteria.
Warnings
Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients on linezolid. In cases with known regression, blood picture indicators can rise and return to pre-treatment levels after discontinuation of linezolid. The risk of these effects appears to be related to the course of therapy. Older patients treated with linezolid have a higher risk of developing blood malignancy than younger patients. Thrombocytopenia is more common in patients with severe renal insufficiency (whether or not they are on dialysis).
Weekly complete blood counts should be performed in patients on linezolid, especially those with severe renal insufficiency who have been on the drug for more than two weeks or who have pre-existing anemia, granulocytopenia, thrombocytopenia, myelosuppression, or a combination of other drugs that can lower hemoglobin levels, suppress white blood cell counts, adversely affect platelet counts or function, or can cause myelosuppression; patients receiving Patients treated for more than 10-14 days or patients with chronic infections previously or currently receiving other antibiotics in combination. Linezolid should only be used in these patients if hemoglobin levels, white blood cell counts and platelet counts can be closely monitored.
 Discontinuation of linezolid therapy should be considered in patients who develop or worsen myelosuppression. Unless continued treatment is absolutely necessary, in which case blood counts should be monitored more frequently and appropriate management strategies should be implemented.
     It is also recommended that complete blood counts (including hemoglobin levels, platelets, total white blood cells, and sorted counts) should be monitored weekly in patients receiving linezolid, regardless of their baseline blood counts.
     In compassionate use studies, linezolid treatment beyond the maximum recommended 28 days has been associated with an increased incidence of severe anemia. These patients often required blood transfusions. Cases of anemia requiring transfusion have also been reported post-marketing, with more cases occurring in patients treated with linezolid for more than 28 days.
     Cases of iron granulocytic anemia have been reported post-marketing. Among patients whose duration of onset was known, the majority had a course of linezolid for more than 28 days. Most patients recovered completely or partially after discontinuation of linezolid, with or without anemia treatment.
 Bone marrow suppression, decreased extramedullary hematopoiesis in the spleen and liver, and decreased lymphocytes in the thymus, lymph nodes, and spleen have been observed in adult and immature dogs and rats (see [Pharmacology and Toxicology]).
An imbalance in mortality was found in a study of catheter-associated bloodstream infections including cannula site infections.
In an open study of linezolid versus vancomycin/dicloxacillin/benzoxacillin in critically ill patients with intravascular catheter-associated infections, an imbalance in mortality was found between the two groups [78/363 (21.5%) in the linezolid group versus 58/363 (16.0%) in the control group; ratio 1.426, 95% confidence interval 0.970, 2.098]. The causality has not been established, and the imbalance in morbidity and mortality occurred mainly in patients in the linezolid group with Gram-negative infections, mixed Gram-negative and Gram-positive infections, or no pathogens isolated at baseline; no imbalance in mortality was found in patients with Gram-positive infections alone. The main factor affecting mortality was gram-positive bacterial infection at baseline. Mortality was similar in patients with Gram-positive infection alone (ratio 0.96; 95% confidence interval: 0.58-1.59), but significantly higher in the linezolid-treated group (p=0.0162) when combined with other pathogens or without pathogenic infection at baseline (ratio 2.48; 95% confidence interval: 1.38-4.46). Mortality was most abnormal during treatment and up to 7 days after discontinuation of the study drug. More patients in the linezolid-treated group were infected with Gram-negative pathogens during the study period and died from infections caused by Gram-negative pathogens and multiple microbial infections. Therefore, linezolid should be used in the treatment of complicated skin and soft tissue infections in patients with known or suspected co-infection with Gram-negative bacteria only when no alternative treatment options are available. In these cases, anti-Gram-negative therapy must be initiated concurrently.
Linezolid is not approved and should not be used to treat patients with catheter-associated bloodstream infections or cannula site infections.
Linezolid has no clinical efficacy against gram-negative pathogens and is not indicated for the treatment of gram-negative bacterial infections. It is important to initiate immediate targeted anti-Gram-negative therapy if a comorbid Gram-negative pathogen infection is confirmed or suspected (see [Indications] and [Dosage]).
Antibiotic-associated diarrhea and colitis
    Pseudomembranous colitis has been reported with the use of almost all antimicrobial agents, including linezolid. Therefore, if a patient develops diarrhea after receiving any antimicrobial drug, a diagnosis of pseudomembranous colitis should be considered. If antibiotic-associated colitis is suspected or confirmed, linezolid may need to be discontinued. Appropriate management measures should be taken.
Antibiotic-associated diarrhea and colitis (including pseudomembranous colitis and Clostridium difficile-associated diarrhea (CDAD)) have been reported with almost all antimicrobial agents (including Swor) and can range in severity from mild diarrhea to fatal colitis. Antimicrobial therapy can alter the normal intestinal flora and lead to the overgrowth of C. difficile.
C. difficile produces toxin A and toxin B, which are associated with the development of CDAD. High-producing strains of C. difficile can lead to increased morbidity and mortality, and such infections are difficult to treat with antibiotics and may require colonic resection. The possibility of CDAD must be considered in patients treated with antibiotics who develop diarrhea.
It has been reported that CDAD may sometimes occur even 2 months after the use of antibacterial drugs, so a detailed history is needed.
Therefore, this diagnosis should be considered if a patient develops severe diarrhea during or after linezolid therapy. If antibiotic-associated diarrhea or CDAD is suspected or confirmed, ongoing antimicrobial therapy (including linezolid) that has no direct activity against C. difficile may need to be discontinued and appropriate therapeutic measures taken immediately. Depending on the clinical indications, appropriate rehydration, maintenance of electrolyte balance and protein supplementation, administration of antibiotic therapy against C. difficile, and surgical evaluation may be indicated. Drugs that inhibit intestinal motility should be contraindicated in this setting.
Hypoglycemia
Symptomatic hypoglycemia has been reported in diabetic patients using linezolid (a reversible, non-selective monoamine oxidase inhibitor) in conjunction with insulin therapy or oral hypoglycemic agents in post-marketing applications. Some monoamine oxidase inhibitors have been associated with episodes of hypoglycemia in diabetic patients receiving insulin or glucose-lowering medications. Although a causal relationship between linezolid use and hypoglycemia has not been established, patients with diabetes should be warned of the potential for hypoglycemic reactions when using linezolid. If hypoglycemia occurs, the dose of insulin or oral hypoglycemic agents should be reduced, or treatment with oral hypoglycemic agents, insulin, or linezolid should be discontinued.
General Precautions
Lactic acidosis
Lactic acidosis has been reported during the application of linezolid. In reported cases, patients have experienced recurrent nausea and vomiting. Patients who experience recurrent nausea or vomiting, abdominal pain, have unexplained acidosis, hypocapnia, or hyperventilation while receiving linezolid require immediate clinical examination. If lactic acidosis develops, the benefits of continued linezolid use should be weighed against the potential risks.
Mitochondrial dysfunction
Linezolid may inhibit mitochondrial protein synthesis. This inhibition may lead to adverse events such as lactic acidosis, anemia, and neuropathy (optic neuropathy and peripheral neuropathy); these events are more common with drug use beyond 28 days.
5-hydroxytryptamine syndrome
Spontaneous reports of 5-hydroxytryptamine syndrome have been reported in patients with linezolid in combination with 5-hydroxytryptamines, including antidepressants, e.g., selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) (see Drug Interactions in [Precautions]). Therefore, the combination of linezolid with 5-hydroxytryptamines is contraindicated (see [Contraindications]).
Unless clinically appropriate and patients are closely monitored for signs and/or symptoms associated with 5-hydroxytryptamine syndrome or malignant syndrome-like (NMS-like) reactions, linezolid should not be used in patients with carcinoid syndrome and/or the application of: 5-hydroxytryptamine reuptake inhibitors, tricyclic antidepressants, 5-hydroxytryptamine 5HT1 receptor agonists (treprostans), pethidine, bupropion, or buspirone.
When linezolid is clinically required in combination with 5-hydroxytryptamines, patients should be closely monitored for signs and symptoms of 5-hydroxytryptamine syndrome, such as cognitive impairment, hyperthermia, hyperreflexia, and ataxia. If any of these signs or symptoms occur, the physician should consider discontinuing 1 or both of the medications.
In some cases, emergency treatment with linezolid may be required for patients already receiving 5-hydroxytryptamine antidepressants or buspirone. If no linezolid alternative is available and the potential benefit of linezolid application outweighs the risk of 5-hydroxytryptamine syndrome or NMS-like reactions, the 5-hydroxytryptamine antidepressant should be discontinued immediately and linezolid administered. Patients should be monitored for two weeks (five weeks if fluoxetine is used) or until 24 hours after the last dose of linezolid, whichever is earlier. Symptoms of 5-hydroxytryptamine syndrome or NMS-like reactions include hyperthermia, tonicity, myoclonus, autonomic dysfunction, and altered mental status (including extreme agitation that progresses to delirium and coma). Patients should be monitored for symptoms of antidepressant withdrawal.
If any of these signs or symptoms are present, the physician should consider discontinuing either or both drugs; discontinuation symptoms may occur if 5-hydroxytryptamines are discontinued (see the drug’s instructions for its associated discontinuation symptoms).
Peripheral neuropathy and optic neuropathy
Peripheral neuropathy, optic neuropathy, and optic neuritis have been reported in patients treated with linezolid, primarily in patients treated beyond the maximum recommended duration of 28 days. In cases where optic neuropathy progressed to visual loss, patients were treated for longer than the longest recommended course of treatment. Blurred vision has been reported in patients treated with linezolid for less than 28 days.
Patients should undergo prompt ophthalmologic examination if they develop symptoms of visual impairment, such as altered visual acuity, altered color vision, blurred vision, or visual field defects. Visual function monitoring should be performed in all patients on linezolid for a long period of time (greater than or equal to 3 months) and in patients reporting new visual symptoms, regardless of the duration of linezolid treatment. If peripheral neuropathy and optic neuropathy occur, an evaluation of the benefits versus potential risks of dosing should be performed to determine whether to continue dosing.
Patients who are currently using or have recently used antibranched-bacterial drugs for the treatment of tuberculosis may be at increased risk of developing neuropathy with concomitant linezolid use.
Convulsions
Convulsions have been reported during linezolid therapy. Some of these cases have a history of seizures or have risk factors for seizures. Patients should inform their physician if they have a history of seizures.
Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective monoamine oxidase inhibitor (MAOI); however, it does not produce antidepressant effects at antimicrobial therapeutic doses. There are very limited safety data on linezolid from drug interaction studies and from patients with underlying disease and/or who are co-administering medications that may have MAO inhibitory effects. Therefore, linezolid is not recommended in these situations unless the patient can be closely observed and monitored.
Secondary Infections
The effect of linezolid therapy on normal flora has not been evaluated in clinical trials.
The application of antibiotics may promote overgrowth of non-sensitive strains of bacteria. For example, drug-associated candidiasis developed in approximately 3% of patients who received the recommended dose of linezolid during clinical trials. Appropriate measures should be taken in the event of a secondary infection during treatment.
Special Populations
Patients with severe renal insufficiency should use this product only if the expected benefit exceeds the theoretical risk and the patient needs to be closely monitored during application.
Linezolid is recommended for use in patients with severe hepatic insufficiency only when the perceived benefit exceeds the theoretical risk.
Linezolid has not been studied in patients with uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, and untreated hyperthyroidism.
Clinical Trials
The safety and efficacy of linezolid preparations applied for more than 28 days have not been evaluated in controlled clinical studies.
Development of drug-resistant bacteria
Prescribing linezolid may not provide benefit to patients without evidence of confirmed or highly suspected bacterial infection or without indications for prophylaxis, and there is an increased risk of drug-resistant bacterial production.
Use when consuming tyramine-rich foods
Patients should be advised to avoid consuming large amounts of tyramine-rich foods.
 Patient Medication Information
The following information should be given:
Linezolid may be taken with or before a meal.
Patients should be informed if they have a history of hypertension
Foods and beverages with high tyramine content should be avoided when linezolid is applied. Foods high in tyramine should be consumed at less than 100 mg per meal. tyramine-rich foods include those that are denatured by storage, fermentation, salting, and smoking for flavor modification, such as aged cheese (0-15 mg tyramine per ounce); fermented or air-dried meats (0.1-8 mg tyramine per ounce); kimchi ( 8 mg tyramine per 8 ounces); soy sauce (5 mg tyramine per teaspoon); draft beer (4 mg tyramine per 12 ounces); red wine (0-6 mg tyramine per 8 ounces). Tyramine levels in any of the protein-rich foods can increase if stored for long periods of time or if improperly refrigerated.
Patients should inform their physician if they are taking medications containing pseudoephedrine hydrochloride or phenylpropanolamine hydrochloride, such as anti-cold medications and medications to relieve congestion.
The physician should be informed if 5-hydroxytryptamine reuptake inhibitors or other antidepressants are being applied.
Phenylketonuria: Linezolid oral suspensions contain 20 mg of phenylalanine per 5 ml of size 100 mg/5 ml. Other linezolid preparations do not contain phenylalanine. Contact your doctor or pharmacist if you have this condition.
A physician should be notified if changes in vision occur.
Patients should inform their doctor if they have a history of seizures.
Diarrhea is a common problem caused by antibiotics and usually stops when the antibiotic is discontinued. Sometimes watery or bloody stools (with or without stomach cramps and fever) may occur after antibiotic therapy has been started, or even 2 months or more after antibiotics have been stopped.
This may occur 2 months or more after stopping antibiotics. If these occur, patients should contact their physician as soon as possible.
Patients should be informed that antimicrobial drugs, including linezolid, should be used only to treat bacterial infections and should not be used to treat viral infections (e.g., colds). When linezolid is used for bacterial infections, patients should be informed that they should take the medication exactly as prescribed early in treatment, although they will usually feel better. Omissions in dosing or failure to complete the entire course of treatment may (1) reduce the effectiveness of treatment at the time and (2) increase the incidence of bacterial resistance and the potential inability to treat with linezolid or other antibacterial drugs in the future.
 Drug interactions (see [Pharmacology and Toxicology], [Drug Interactions])
Monoamine oxidase inhibition: Linezolid is a reversible, non-selective monoamine oxidase inhibitor. Therefore, linezolid has potential interactions with adrenergic and 5-hydroxytryptamine-like drugs.
 Adrenergic drugs: Some patients receiving linezolid may reversibly increase the pressor effects of non-direct acting sympathomimetic drugs, vasopressors, or dopamines. Its effects have been studied with commonly used drugs such as phenylpropanolamine and pseudoephedrine. The starting dose of adrenergic drugs, such as dopamine or epinephrine, should be reduced and gradually adjusted to a level at which the desired drug effect can be achieved.
 5-Hydroxytryptamines: In phase I, II and III
In phase I, II, and III clinical studies, the combination of linezolid with 5-hydroxytryptamines has not been reported to cause 5-hydroxytryptamine syndrome. Spontaneous reports of 5-hydroxytryptamine syndrome have been reported with linezolid in combination with 5-hydroxytryptamines, including antidepressants, such as selective 5-hydroxytryptamine reuptake inhibitors (SSRIs). Patients receiving linezolid therapy who are also taking 5-hydroxytryptamines should be closely monitored as described in General Precautions.
 Strong CYP450 inducers: In a study in healthy volunteers, the combination of rifampicin and oral linezolid resulted in a 21% reduction in Cmax and a 32% reduction in AUC0-12 of linezolid. The clinical significance of this interaction is unknown. Other strong inducers of liver enzymes (e.g., carbamazepine, phenytoin, phenobarbital), may cause similar or slightly less severe changes (see [Pharmacology and Toxicology], [Drug Interactions]).
 Drug-laboratory interactions
There are no reports that this product may interfere with laboratory tests.
 Pregnant women and nursing mothers
Linezolid and its metabolites can be secreted into the milk of lactating rats. The concentration of the drug in the milk is similar to the plasma drug concentration in the mother. It is not known whether linezolid is secreted into human breast milk. Because many drugs are secreted into human milk, linezolid should be used with caution in lactating women.
Adequate, rigorously controlled clinical studies have not been conducted in pregnant women. It is recommended for use in pregnant women only if the potential benefits outweigh the potential risks to the fetus.
 Pediatric Dosage]
The safety and efficacy of linezolid in the treatment of the following infections in pediatric patients has been confirmed by the following studies, including adequate, rigorously controlled clinical studies in adults, data from pharmacokinetic studies in pediatric patients, and positive drug-controlled clinical studies in children 0-11 years of age with Gram-positive bacterial infections (see [Indications], [Dosage], and [Clinical Studies]).
Nosocomial acquired pneumonia
Complex skin and skin soft tissue infections
Community-acquired pneumonia (supported by additional evidence from an uncontrolled study involving patients 8 months to 12 years of age)
Vancomycin-resistant Enterococcus faecalis infection
A positive controlled study in pediatric patients 5 to 17 years of age confirmed the safety and efficacy of linezolid in the following infections (see [Clinical Studies])
Uncomplicated skin and soft tissue skin infections caused by methicillin-susceptible Staphylococcus aureus and Streptococcus pyogenes
Pharmacokinetic data obtained in pediatric patients undergoing transventricular peritoneal shunts showed that drug concentrations in the cerebrospinal fluid (CSF) varied widely after administration of single or multiple doses of linezolid and did not always achieve or maintain therapeutic concentrations in the CSF. Therefore, linezolid is not recommended for empirical use in pediatric patients with central nervous system infections.
The pharmacokinetics of linezolid have been evaluated in pediatric patients from birth to 17 years of age. In general, weight-based clearance of linezolid decreases with increasing age in pediatric patients. However, in preterm infants born less than 7 days after birth (<34 gestational weeks), linezolid clearance is typically lower than in term infants born less than 7 days after birth. Therefore, alternative linezolid dosing regimens, i.e., 10 mg/kg every 12 hours, are required for preterm infants less than 7 days of age (see [Pharmacokinetics] – Special Populations, Children and [Dosage]).
In limited clinical experience, 5 of 6 pediatric patients (83%) with a minimum inhibitory concentration MIC of 4 mcg/mL of linezolid against their infected gram-positive pathogens were clinically cured by linezolid treatment. However, the clearance and systemic drug exposure (AUC) of linezolid in pediatric patients had a wider range of variation compared to adults. When clinical efficacy is not optimal in pediatric patients, especially for pathogens with a minimum linezolid inhibitory concentration of 4 mcg/ml, their lower systemic exposure, the site of infection and its severity, and their underlying disease should be considered when making an efficacy assessment (see [Pharmacokinetics] – Special Populations, Children and [Dosage]).
 [Geriatric Use].
In the phase III controlled study, 2046 patients were treated with linezolid, 589 (29%) of whom were 65 years of age or older; 253 (12%) were older than or equal to 75 years of age. No differences in safety and efficacy of linezolid were seen between these patients and younger patients.
 [Drug Interactions].
Drugs metabolized by cytochrome P450.
In rats, linezolid is not an inducer of cytochrome enzyme P450 (CYP450). In addition, linezolid does not inhibit the activity of clinically significant human cytochrome isozymes (e.g., 1A2, 2C9; 2C19, 2D6, 2E1, and 3A4). Therefore, linezolid is not expected to affect the pharmacokinetics of drugs that are metabolized by these major cytochrome isozymes. Co-administration with linezolid does not significantly alter the pharmacokinetic properties of (S)-warfarin, which is metabolized primarily by CYP2C9. Drugs such as warfarin and phenytoin, which are substrates of CYP2C9, can be co-administered with linezolid without any change in the dosing regimen.
Antibiotics
Aminotransomide: The pharmacokinetic properties of both linezolid and aminotransomide are unchanged when the two are combined.
Gentamicin: The pharmacokinetic properties of linezolid and gentamicin are unchanged when combined.
Antioxidants
The potential drug interactions of linezolid with the antioxidants vitamin C and vitamin E were studied in healthy volunteers. Subjects received 600 mg of linezolid orally on day 1 and again 600 mg on day 8. on days 2-9, subjects were given vitamin C (1000 mg/day) or vitamin E (800 IU/day). The AUC0-∞ of linezolid increased by 2.3% when combined with vitamin C and by 10.9% when combined with vitamin E. No dose adjustment is required when co-administered with vitamin C or vitamin E.
Strong CYP 3A4 inducers
Rifampicin: The pharmacokinetic effects of rifampicin on linezolid were evaluated in a study conducted in 16 healthy adult male volunteers. Volunteers in the study received oral linezolid 600 mg twice daily for 5 doses with or without rifampicin 600 mg once daily for 8 days. The combination of rifampicin and linezolid resulted in a 21% [90% CI, 15%-27%] decrease in Cmax and a 32% [90% CI, 27%-37%] decrease in AUC0-12 for linezolid. The clinical significance of this interaction is unknown. The mechanism of this interaction is not fully elucidated and may be related to hepatic enzyme induction. Other strong inducers of hepatic enzymes (e.g., carbamazepine, phenytoin, phenobarbital), may cause similar or slightly milder changes.
Monoamine oxidase inhibition
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase. Therefore, linezolid has potential interactions with adrenergic drugs or 5-hydroxytryptamine-like agents.
Adrenergic drugs
    Some patients receiving linezolid may reversibly increase the pressor effects of non-direct acting sympathomimetic drugs, vasopressors, or dopamines. Its effects have been studied with commonly used drugs such as phenylpropanolamine and pseudoephedrine. The starting dose of adrenergic drugs such as dopamine or epinephrine should be reduced and gradually adjusted to a level at which the desired drug effect can be achieved.
    Tyramine: When healthy adult subjects received both linezolid and more than 100 mg of tyramine, a significant pressor response was seen. Therefore, patients on linezolid should avoid foods or beverages with high tyramine levels.
Pseudoephedrine hydrochloride or phenylpropanolamine hydrochloride: A reversible increase in the pressor effect of pseudoephedrine (PSE), phenylpropanolamine hydrochloride (PPA) was observed with linezolid given to healthy volunteers with normal blood pressure (see Drug Interactions in [Precautions]). Similar studies have not been conducted in hypertensive patients. The effects of linezolid, PSE, PPA, and placebo alone, and linezolid at steady state (600 mg every 12 hours for 3 days) in combination with PSE or PPA (PPA, 25 mg or PSE, 60 mg at two doses each, administered 4 hours apart) on blood pressure and heart rate were studied in healthy volunteers with normal blood pressure. Heart rate was not affected by any of the dosing regimens. The combination of linezolid with either PPA or PSE resulted in an increase in blood pressure. The highest blood pressure values were observed 2-3 hours after the second dose of PPA or PSE; 2-3 hours after reaching the peak, blood pressure returned to basal levels. results of the PPA study showed that the mean (range) maximum systolic blood pressure expressed in mmHg was: placebo = 121 (103 -158), linezolid alone = 120 (107-135); PPA alone = 125 (106-139), and PPA in combination with linezolid = 147 (129-176).The results of the PSE study were similar to those of the PPA study results were similar. When linezolid was combined with PSE or PPA, the mean maximum increase over basal systolic blood pressure was 32 mmHg (range: 20-52 mmHg) and 38 mmHg (range: 18-79 mmHg), respectively.
5-Hydroxytryptamines
Dextromethorphan: A study of potential drug interactions between linezolid and dextromethorphan was conducted in healthy volunteers. Volunteers were given dextromethorphan (two doses, 20 mg each, 4 hours apart) with or without linezolid. No effects of 5-hydroxytryptamine syndrome (confusion, extreme euphoria, restlessness, tremors, flushing, sweating, and elevated body temperature) were observed in normotensive volunteers receiving dextromethorphan and linezolid.
 Drug overdose]
In the event of an overdose, supportive therapy is recommended to maintain glomerular filtration. Hemodialysis accelerates the clearance of linezolid. In phase I clinical studies, 30% of the dose was cleared by 3 hours of hemodialysis after 3 hours of linezolid administration. No information is available on the clearance of linezolid by peritoneal dialysis or hemofiltration. When linezolid was given at 3000 mg/kg/day and 2000 mg/kg/day, respectively, the clinical signs of acute toxicity in animals were decreased mobility and dyskinesia in rats and vomiting and tremors in dogs.
 [Clinical study
Adults
Nosocomial acquired pneumonia
Adult patients with clinically and radiologically confirmed nosocomial acquired pneumonia were enrolled in a randomized, multicenter, double-blind study. Patients were treated for 7-21 days. Patients in one group were given linezolid IV 600 mg every 12 hours and the other group was given vancomycin IV 1 g every 12 hours. Both groups received a combination of amineptine (1 to 2 g IV every 8 hours), which could be extended if clinically indicated. 203 patients were enrolled in the linezolid group and 193 patients in the vancomycin group. 122 (60%) patients in the linezolid group and 103 (53%) patients in the vancomycin group were available for clinical evaluation. The cure rate among clinically evaluable patients was 57% in the linezolid-treated group and 60% in the vancomycin-treated group. Among clinically evaluable patients with ventilator-associated pneumonia, the cure rate was 47% in the linezolid-treated group. In the vancomycin-treated group, the cure rate was 40 percent. Adjusted intention-to-treat (MITT) patients included 94 patients in the linezolid-treated group and 83 patients in the vancomycin-treated group, including patients in whom the causative strain had been isolated prior to treatment. the cure rate for patients in the MITT analysis was 57% in the linezolid-treated group and 46% in the vancomycin-treated group. The cure rates for different pathogens in microbiologically assessable patients are shown in Table 10.
 Table 10 Cure rates at follow-up of cure testing in adult patients with microbiologically assessable nosocomial acquired pneumonia
Pathogen cure
Cure linezolid n /N (%) Vancomycin n /N (%) Staphylococcus aureus 23/38 (61) 14/23 (61) Methicillin-resistant Staphylococcus aureus 13/22 (59) 7/10 (70) Streptococcus pneumoniae 9/9 (100) 9/10 (90) 
 Complex skin and soft tissue skin infections
Adult patients with complicated skin and skin soft tissue infections were enrolled in a randomized, multicenter, double-blind, double-mock study to compare the efficacy and safety of the trial drug when administered intravenously and then switched to oral administration for a total duration of 10 to 21 days. Patients in one group were given linezolid intravenously 600 mg every 12 hours and then switched to linezolid oral 600 mg tablets every 12 hours; in the other group, benzocillin was given intravenously 2 g every 6 hours and then switched to dicloxacillin oral 500 mg every 6 hours. If clinically indicated, patients may be given concomitant aminotransomide. Patients enrolled in this study had 400 cases in the linezolid-treated group and 419 cases in the dicloxacillin-treated group. Clinical evaluation was available for 245 patients (61%) in the linezolid group and 242 patients (58%) in the benzocillin group. The cure rate of clinically evaluable patients was 90% in the linezolid-treated group and 85% in the benzocillin group. The adjusted intention-to-treat (MITT) analysis included those subjects who met the inclusion criteria, 316 in the linezolid-treated group and 313 in the benzocillin group. The MITT analysis cure rate was 86% for patients in the linezolid-treated group and 82% in the benzocillin-treated group. The cure rates for different pathogens in microbiologically evaluable patients are shown in Table 11.
 Table 11 Cure rates at follow-up of microbiologically evaluable patients with complicated skin and skin soft tissue infections for cure testing
Pathogen cure
Cure linezolid n/N (%) benzocillin/dicloxacillin n/N (%) Staphylococcus aureus 73/83 (88) 72/84 (86) Methicillin-resistant Staphylococcus aureus 2/3 (67) 0/0 (-) Lactococcus aureus 6/6 (100) 3/6 (50) Streptococcus pyogenes 18/26 (69) 21/28 (75) 
 Another trial provided experience with linezolid in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. This was a randomized, open trial with patients who were adult inpatients with confirmed or suspected MRSA infection.
One group of patients received linezolid administered intravenously 600 mg every 12 hours and then switched to linezolid tablets administered orally 600 mg every 12 hours. The other group of patients received vancomycin administered intravenously 1 g every 12 hours. Patients in both groups are treated for 7-28 days. If clinically indicated, patients may be treated with a combination of amineptine or gentamicin. The cure rate for microbiologically evaluable patients with MRSA skin and skin soft tissue infections was 26/33 (79%) in the linezolid-treated group and 24/33 (73%) in the vancomycin group.
 Diabetic foot infections
Adult diabetic patients with clinically proven complex skin and skin soft tissue infections (diabetic foot infections) were randomized (in a 2:1 ratio) to a multicenter, open, controlled clinical study with intravenous or oral administration of the trial drug for a total duration of 14 to 28 days. In one group, linezolid was administered intravenously or orally at 600 mg every 12 hours; in the other group, ampicillin/sulbactam was administered intravenously at 1.5 to 3 g or amoxicillin/clavulanic acid was administered orally at 500 mg to 875 mg every 8 to 12 hours (q8-12h). In countries where ampicillin/sulbactam is not available, intravenous administration of amoxicillin/clavulanic acid 500 mg to 2 g every 6 hours (q6h) is the drug of choice. Patients in the control group who had MRSA detected at the site of foot infection could be given vancomycin 1 g every 12 hours intravenously. In patients in both groups, if Gram-negative bacilli are isolated at the site of infection, aminoglutethimide 1 g to 2 g every 8 to 12 hours may be given. All patients could receive appropriate adjuvant therapy with typical measures for the treatment of diabetic foot infections such as debridement and load shedding, and the vast majority of patients received such therapy. The intention-to-treat (ITT) population consisted of 241 linezolid-treated and 120 control drug-treated patients. 212 (86%) patients in the linezolid-treated group and 105 (85%) patients in the control drug-treated group served as clinically evaluable patients. the cure rate in the ITT population was 68.5% (165/241) in the linezolid-treated group and 64% (77/120) in the control drug group. 64% (77/120), and outcomes that could not be adjudicated and were missing at the time of evaluation were classified as treatment failure. The cure rate among clinically evaluable patients (excluding those with undetermined and missing outcomes) was 83% (159/192) in the linezolid-treated group and 73% (74/101) in the control drug group. In an important post-hoc analysis of patients with Gram-positive organisms isolated from the site of infection or blood, 121 in the linezolid group and 60 in the control group, these patients had less evidence of concomitant osteomyelitis and were not on a prohibited antibiotic than the overall study population. According to this analysis, the cure rate was 71% (86/121) in the linezolid-treated patients and 63% (38/60) in the control drug group. No adjustment was made for the above analysis based on adjuvant therapy. The cure rates for different pathogens in microbiologically assessable patients are shown in Table 12.
Table 12 Cure rates at follow-up of microbiologically assessable cure tests in adult patients with diabetic foot infections
Pathogen cure
Cure linezolid n/N (%) Control drug n/N (%) Staphylococcus aureus 49/63 (78) 20/29 (69) Methicillin-resistant Staphylococcus aureus 12/17 (71) 2/3 (67) Lactococcus aureus 25/29 (86) 9/16 (56) 
 Vancomycin-resistant enterococcal infections
Adult patients with definite or suspected vancomycin-resistant enterococcal infections were enrolled in a randomized, multicenter, double-blind controlled study and treated with high-dose linezolid (600 mg every 12 hours orally or intravenously) or low-dose linezolid (200 mg every 12 hours or intravenously) for 7-28 days. Patients may be combined with aminoglycoside antibiotics. 79 patients were randomized to the high-dose group and 66 patients were randomized to the low-dose group. The Intent-to-treat (ITT) population for vancomycin-resistant enterococcal infections identified at baseline included 65 in the high-dose group and 52 in the low-dose group.
Cure rates for different infections in the ITT population with vancomycin-resistant enterococcal infections identified at baseline are shown in Table 13. These cure rates do not include patients with missing or inconclusive results. Patients in the high-dose group had higher cure rates than those in the low-dose group, but this difference was not statistically significant at the 0.05 test level.
Table 13 Cure rates in adult ITT patients with vancomycin-resistant enterococcal infections identified at baseline, at cure test follow-up
 Source of infection cure
Cure linezolid
600 mg every 12 hours n/N (%) Linezolid
200 mg every 12 hours n/N (%) All sites 39/58 (67) 24/46 (52) All sites with associated bacteremia 10/17 (59) 4/14 (29) Bacteremia of unknown origin 5/10 (50) 2/7 (29) Skin soft tissue 9/13 (69) 5/5 (100) Urinary tract 12/19 (63) 12/20 ( 60) Pneumonia 2/3(67) 0/1(0) Other* 11/13(85) 5/13(39) *Including sources of infection such as: liver abscess, biliary sepsis, gallbladder necrosis, peri-intestinal abscess, pancreatitis, and duct-related infections.
 Pediatric patients
Infections due to gram-positive microorganisms
A clinical study provided experience with the safety and efficacy of linezolid for the treatment of infections due to gram-positive organisms, including methicillin-resistant and sensitive Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis causing nosocomial-acquired pneumonia, complicated skin and skin soft tissue infections, and other infections in pediatric patients. Pediatric patients, ranging in age from newborn to 11 years, had infections that were confirmed or suspected to be caused by Gram-positive bacteria, and patients were enrolled into a randomized, open, positive drug-controlled clinical study. One group of patients received linezolid at 10 mg/kg intravenously every 8 hours, followed by a change to oral linezolid suspension at 10 mg/kg every 8 hours. Patients in the second group received vancomycin by intravenous infusion at 10-15 mg/kg every 6-24 hours, depending on age and renal clearance. Patients with confirmed vancomycin-resistant enterococcal infections were enrolled in the third group and received linezolid at 10 mg/kg IV or oral every 8 hours. All patients were treated for 10-28 days, and antibiotics targeting Gram-negative infections could be combined if clinically indicated. Of the intent-to-treat (ITT) population, 206 patients were randomized to the linezolid group and 102 patients were randomized to the vancomycin group. 117 (57%) patients in the linezolid group and 55 (54%) patients in the vancomycin group were clinically evaluable. Among intention-to-treat patients, cure rates were 81% and 83% (95% confidence interval; -13%, 8%) in the linezolid and vancomycin groups, respectively. Among clinically evaluable patients, the cure rate was 91% (95% confidence interval; -11%, 11%) in both the linezolid and vancomycin groups. Adjusted intent-to-treat patients, i.e., intent-to-treat patients in whom gram-positive organisms were isolated from the patient’s site of infection or blood at enrollment, had cure rates of 80% and 90% (95% confidence interval; -23%, 3%) in the linezolid and vancomycin groups, respectively. Cure rates in intention-to-treat patients, adjusted intention-to-treat patients, and clinically evaluable patients are shown in Table 14. 13 additional patients aged 4 days to 16 years entered the open extension period of the study at the end of the study and were enrolled into the VRE arm of this study. The clinical cure rates for each pathogen among microbiologically evaluable patients, including patients with vancomycin-resistant Enterococcus faecalis infection enrolled in the extension study, are shown in Table 15.
Table 14. cure rates at cure testing follow-up among intent-to-treat pediatric patients, adjusted intent-to-treat pediatric patients, and clinically evaluable pediatric patients in the overall population.
List by selected diagnosis at enrollment
 Population Intent-to-Treat Patients Adjusted Intent-to-Treat Patients* Clinically Evaluable Patients Linezolid
n/N (%) Vancomycin
n/N (%) Linezolid
n/N (%) Vancomycin
n/N (%) Linezolid
n/N (%) Vancomycin
n/N (%) Any diagnosis
 
 150/186 (81)
 69/83
(83)
 86/108
(80)
 44/49
(90)
 106/117 (91)
 49/54
(91)
 Complex skin and skin soft tissue infections 61/72
(85) 31/34
(91) 37/43
(86) 22/23
(96) 46/49
(94) 26/27
(96) Nosocomial acquired pneumonia
13/18
(72)
11/12
(92)
5/6
(83)
4/4
(100)
7/7
(100)
5/5
(100)
*Adjusted intention-to-treat patients (MITT) = patients with intention-to-treat (ITT) in whom gram-positive pathogens were isolated at the time of enrollment
 Table 15. microbiologically evaluable pediatric patients with gram-positive pathogen infections
Cure rate at cure test follow-up
 Pathogens microbiologically assessable linezolid n/N (%) Vancomycin n/N (%) Vancomycin-resistant Enterococcus faecalis 6/8 (75) *0/0 (-) Staphylococcus aureus 36/38 (95) 23/24 (96) Methicillin-resistant Staphylococcus aureus 16/17 (94) 9/9 (100) Streptococcus pyogenes 2/2 (100) 1/2 ( 50) *
Includes 7 patients enrolled from the open extension period of this study
 Pharmacodynamics
In a randomized, positive-controlled and placebo-controlled crossover study of the full QT interval, 40 healthy subjects received linezolid 600 mg IV for 1 hour as a single dose and linezolid 1200 mg IV for 1 hour as a single dose, placebo and a single oral positive control dose. There was no significant effect of linezolid at peak plasma concentrations or at any other time on the QTc interval for both the 600 mg and 1200 mg doses.
 Pharmacology and Toxicology
Pharmacological effects
Linezolid belongs to the oxazolidinone class of synthetic antibiotics, which can be used to treat infections caused by aerobic gram-positive bacteria. The in vitro antibacterial spectrum of linezolid also includes some gram-negative bacteria and anaerobic bacteria. Linezolid binds to sites on the 23S ribosomal RNA of the bacterial 50S subunit, thereby preventing the formation of a functional 70S initiation complex, which is a very important component of bacterial reproduction. The results of the time-bactericidal curve study indicate that linezolid is an inhibitor of enterococci and staphylococci. Linezolid is a bactericidal agent for most strains of Streptococcus.
In vitro studies have shown that point mutations in 23S rRNA are associated with the development of linezolid resistance. Reports of vancomycin-resistant Enterococcus faecium developing resistance to linezolid during clinical use have been published. In one report, there was intra-hospital transmission of vancomycin with linezolid-resistant Enterococcus faecalis. There is another report of (methicillin-resistant) Staphylococcus aureus resistance occurring during clinical administration of linezolid. The resistance of these organisms to linezolid was associated with a point mutation in their 23S rRNA (substitution of guanine by thymine at position 2576). Microorganisms resistant to oxazolidinone through mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins (L3 and L4) are usually cross-resistant to linezolid. Staphylococcal resistance to linezolid mediated by methyltransferases has also been reported. This resistance is mediated by the cfr gene (flucloxacillin resistance gene), which hosts a plasmid that can be transferred between staphylococci.
 Interaction with other antibacterial drugs
In vitro studies have shown that linezolid has additive or unrelated effects with vancomycin, gentamicin, rifampicin, imipenem-cistatin, aminoglutethimide, ampicillin or streptomycin.
 Both in vitro and clinical results indicate that this product has antibacterial activity against most strains of the following microorganisms
: – The following
 Aerobic and parthenogenic Gram-positive pathogenic bacteria.
Enterococcus faecalis (vancomycin-resistant strains only)
Staphylococcus aureus (including methicillin-resistant strains)
Streptococcus lactis-free
Streptococcus pneumoniae
Streptococcus pyogenes
 At least 90% of the following strains have in vitro minimum inhibitory concentrations (MICs) below or equal to the sensitivity range for linezolid, which is only available from in vitro studies and the clinical significance of which is unclear.
 Aerobic and parthenogenic gram-positive pathogens
Enterococcus faecalis (including vancomycin-resistant strains)
Enterococcus faecalis (vancomycin-susceptible strains)
Staphylococcus epidermidis (including methicillin-resistant strains)
Staphylococcus haemolyticus
Streptococcus straw green
 Aerobic and parthenogenic gram-negative pathogenic bacteria
Pasteurella multocida
 Toxicological studies
Genotoxicity
No teratogenic or mutagenic potential was found in the linezolid gene mutation test (Ames bacterial revertant mutation test and Chinese hamster ovary cell chromosome aberration test), in vitro unconventional DNA synthesis (UDS) test, in vitro chromosome defect analysis of human lymphocytes and in vivo micronucleus test in mice.
Reproductive Toxicity
Linezolid did not affect the fertility or reproductive behavior of adult female rats. When administered to adult male rats at ≥50 mg/kg/day (a dose equivalent to or greater than that administered to humans, as extrapolated from the AUC), it reversibly reduced fertility and reproductive behavior in male rats. The reversible effect on reproductive function is mediated by altered sperm production. Affected sperm cells contain morphologically and orientationally abnormal mitochondria and are non-viable. The observed hypertrophy and hyperplasia of epithelial cells in the epididymis is associated with reduced fertility. Similar epididymal changes were not seen in dogs.
Linezolid administered to immature male rats during the vast majority of their sexual development (50 mg/kg/day from days 7-36 of birth; 100 mg/kg/day from days 37-55 of birth, equivalent to 1.7 times the dose administered to children from 3 months to 11 years of age in humans, extrapolated from the mean AUC) was found to mildly reduce sexually mature male rats’ fertility. No effect of shorter treatment periods on fertility was observed in observations of drug exposure at conception and early neonatal period (equivalent to day 6 of conception to day 5 postpartum), neonatal period (5 to 21 days postpartum), or immature period (22 to 35 days postpartum). Reversible reductions in sperm motility and alterations in sperm morphology were observed in rats administered between 22 and 35 days of life.
No teratogenic effects were seen in mice, rats, or rabbits at linezolid exposures equivalent to 6.5 times (mice), or equivalent (rats), or 0.06 times (rabbits) the expected human exposure, respectively, as extrapolated from the AUC. However, embryonic and fetal toxicity was seen.
In mice, embryonic and fetal toxicity was found only at doses that resulted in maternal toxicity (clinical signs and reduced body weight gain). At a dose of 450 mg/kg/day (6.5 times the estimated human exposure based on AUC), increased post-implantation embryonic mortality was seen, including whole litter loss, reduced litter weight, and increased incidence of rib cartilage fusion.
In rats, mild fetal toxicity was seen at doses of 15 and 50 mg/kg/day (approximately 0.22 times the estimated human exposure based on AUC), respectively. Effects included reduced fetal body weight and reduced sternal ossification, the latter of which was frequently observed in conjunction with reduced fetal body weight. At a dose of 50 mg/kg/day, mild maternal toxicity was seen, as evidenced by reduced body weight gain.
In rabbits, reduced fetal body weight occurred only at a dose of 15 mg/kg/day (0.06 times the estimated human exposure based on AUC), when maternal toxicity (clinical signs, reduced body weight gain and reduced food intake) was present.
In female rats given 50 mg/kg/d (equivalent to human dose in terms of AUC) between gestation and lactation, the number of surviving pups decreased 1-4 days after delivery. An increase in the number of non-fertilized embryos was seen in surviving female or male pups mated to sexual maturity.
Linezolid and its metabolites are secreted through the milk of lactating rats, and the concentrations in milk are similar to those in maternal plasma. It is not known whether linezolid is secreted in human milk.
Carcinogenicity
Lifetime survival studies in animals have not been conducted to assess the potential carcinogenicity of linezolid.
Other
The toxic target organs of linezolid were similar in immature and adult rats and dogs. The effect on myelosuppression was time- and dose-dependent, manifested in animal studies by reduced myelocytopenic hematopoiesis, reduced extramedullary hematopoiesis in the spleen and liver, and decreased peripheral blood erythrocyte, leukocyte, and platelet levels. Lymphatic tissue deficiency was observed in the thymus, lymph nodes and spleen. In conclusion, signs of lymphoid tissue were associated with a possible observed decrease in appetite, weight loss and suppression of weight gain.
Irreversible, mild to mild axial degeneration of the sciatic nerve was seen in males in the 80 mg/kg/day dose group when rats were given linezolid orally for 6 consecutive months; mild degeneration of the sciatic nerve was also found in 1 male in this dose group at mid-3 month necropsy. Sensitive morphological assessment of perfused fixed tissue was performed to investigate evidence of optic nerve degeneration. Slight to moderate optic nerve degeneration was seen in 2 male rats 6 months after drug administration, but its direct correlation with the drug is unclear because the abnormal finding was an acute change with an asymmetric distribution. This neurodegeneration found on microscopic examination is similar to spontaneous unilateral optic nerve degeneration in aged rats and may be an exacerbation of common background changes.
The doses of action described above are comparable to those observed in some human subjects. The effects on the blood and lymphatic systems were reversible, although not fully recovered during the recovery period of some studies.
 Pharmacokinetics]
The mean pharmacokinetic parameters following single or multiple oral and sedative doses of linezolid in adults are shown in Table 17. The plasma concentrations of linezolid after steady-state administration of linezolid 600 mg orally every 12 hours are shown in Figure 1 .
Table 17 Mean (standard deviation) pharmacokinetic parameters of linezolid in adults
Dose Cmax of linezolid
mg/mlCmin
mg/mlTmax
hrs AUC*
mg h/mlt1/2
hrs CL
ml/min 400mg tablets
Single dose**
 
 Every 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) 600mg tablets
Single Dose
 
 Every 12 hours
 12.7
(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) 600mg intravenous solution***
Single dose
 
 Every 12 hours
 12.9
(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) 600mg oral suspension
Single Dose
 11.00
(2.76) 
 -Coronary
 0.97
(0.88) 
 80.80
(35.10) 
 4.60
(1.71) 
 141
(45) *
AUC for a single dose = AUC0-¥
; AUC for multiple doses = AUC0-τ
**
Data normalized from 375 mg
***
Data normalized from 625 mg, administered intravenously as an infusion over 30 minutes
Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; Tmax = time to peak
AUC = area under the drug-time curve; t1/2 = elimination half-life; CL = systemic elimination rate
 
Figure 1. Plasma concentrations of linezolid at steady state at 600 mg orally every 12 hours (mean ± standard deviation, n = 16)
Absorption: After oral administration, linezolid was rapidly and completely absorbed. Peak plasma concentrations are reached about 1-2 hours after administration, and the absolute bioavailability is about 100%. Therefore, no dose adjustment is required for oral or intravenous administration of linezolid.
Linezolid is administered without regard to the timing of food intake. When linezolid is administered with high-fat foods, the time to peak is delayed from 1.5 hours to 2.2 hours and the peak concentration decreases by approximately 17%. However, the total exposure index AUC0-¥
values were similar in both cases.
Distribution: Pharmacokinetic studies in both animals and humans demonstrate that linezolid is rapidly distributed to well perfused tissues. The plasma protein binding of linezolid is approximately 31% and is non-concentration dependent. In healthy volunteers, the mean volume of distribution of linezolid at steady state is 40-50 L.
In a phase I clinical study investigating multiple dosing of linezolid, linezolid concentrations were measured in multiple body fluids in a limited number of healthy subjects. The ratio of linezolid in saliva to plasma was 1.2 to 1; the ratio in sweat to plasma was 0.55 to 1.
Metabolism: The primary metabolism of linezolid is the oxidation of the morpholine ring, which yields two inactive ring-opening carboxylic acid metabolites, aminoethoxyacetic acid metabolite (A) and hydroxyethylaminoacetic acid metabolite (B). In vitro, metabolite A is presumed to be formed via an enzymatic pathway, while metabolite B is formed via a non-enzymatic-mediated chemical oxidation mechanism. In vitro studies suggest that linezolid may have a very low degree of metabolism mediated by human cytochrome enzyme P450. However, the metabolic pathway of linezolid remains incompletely defined.
Excretion: Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. At steady state, approximately 30% of the drug is excreted as linezolid, 40% as metabolite B, and 10% as metabolite A in the urine. The low renal clearance of linezolid (mean 40 ml/min) is suggestive of renal tubular network reabsorption. In fact, no linezolid is present in the feces, and approximately 6% and 3% of the drug is present in the feces as metabolites B and A, respectively.
A slight nonlinear clearance of linezolid was observed with increasing doses of linezolid, as evidenced by a decrease in renal and non-renal clearance of linezolid at high concentrations. However, changes in clearance were small and not sufficient to affect the apparent elimination half-life of linezolid.
 Special Populations
Elderly: The pharmacokinetic properties of linezolid are not significantly altered in elderly patients (≥65 years). Therefore, no dose adjustment is required in elderly patients.
Children: Pharmacokinetic studies of linezolid administered intravenously in a single dose were conducted in pediatric patients from birth to 17 years of age (including preterm and term born neonates), in healthy adolescents aged 12-17 years, and in pediatric patients from 1 week to 12 years of age after birth. Table 18 provides a summary of the pharmacokinetic parameters of linezolid after single-dose intravenous administration in pediatric patients and healthy adult volunteers who were tested.
Independent of the age of the pediatric patients, the Cmax and volume of distribution (Vss) of linezolid were similar in pediatric patients of all age groups. However, the clearance of linezolid varied among pediatric patients of all age groups. With the exception of preterm infants born less than one week old, the clearance rate was fastest in the youngest pediatric group (i.e., after one week of life to 11 years of age), resulting in lower systemic drug exposure (AUC) and shorter half-life after single-dose administration compared to adults. The clearance rate of linezolid decreases with increasing age in pediatric patients. Clearance rates in adolescent patients were similar to those in adults. There was greater individual variation in clearance versus systemic drug exposure (AUC) in pediatric patients across all age groups compared to adults.
The mean daily AUC values for pediatric patients from newborn to 11 years of age administered every 8 hours were similar to the mean daily AUC values for adolescent and adult patients administered every 12 hours. Therefore, the dose for pediatric patients 11 years of age and younger should be 10 mg/kg every 8 hours, and for pediatric patients 12 years of age and older, 600 mg every 12 hours (see [DOSAGE]).
 Table 18: Pharmacokinetics of linezolid after a single dose of 10 mg/kg IV infusion or 600 mg of linezolid.
Pharmacokinetic parameters in pediatric versus adult patients (mean: ( CV%); [min vs max])
 Age group Cmax
µg/ml Vss
l/kg AUC*
µg-h/ml t1/2
hrsCL
ml/min/kg Neonatal group Preterm infants**
<1 week (N=9)†12.7 (30%)
[9.6, 22.2] 0.81 (24%)
[0.43,1.05] 108 (47%)
[41, 191] 5.6 (46%)
[2.4, 9.8] 2.0 (52%)
[0.9, 4.0] Full-term infants***
<1 week (N=10)† 11.5 (24%)
[8.0, 18.3] 0.78 (20%)
[0.45, 0.96] 55 (47%)
[19, 103] 3.0 (55%)
[1.3, 6.1] 3.8 (55%)
[1.5, 8.8] Full-term baby***
³ week but £28 days (N=10) †12.9 (28%)
[7.7, 21.6] 0.66 (29%)
[0.35, 1.06] 34 (21%)
[23, 50] 1.5 (17%)
[1.2, 1.9] 5.1 (22%)
[3.3, 7.2] Infant patients
>28 days but<3 months (N=12) †11.0 (27%)
[7.2, 18.0] 0.79 (26%)
[0.42, 1.08] 33 (26%)
[17, 48] 1.8 (28%)
[1.2, 2.8] 5.4 (32%)
[3.5, 9.9] Pediatric patients
3 months to 11 years (N=59) †15.1 (30%)
[6.8, 36.7] 0.69 (15%)
[0.31, 1.50] 58 (54%)
[19, 153] 2.9 (53%)
[0.9, 8.0] 3.8 (53%)
[1.0, 8.5] Adolescent subjects and patients
12 to 17 years old (N=36) ‡ 16.7 (24%)
[9.9, 28.9] 0.61 (15%)
[0.44, 0.79] 95 (54%)
[32, 178] 4.1 (46%)
[1.3, 8.1] 2.1 (53%)
[0.9, 5.2] Adult patients
(N=29) §12.5 (21%)
[8.2, 19.3] 0.65 (16%)
[0.45, 0.84] 91 (33%)
[53, 155] 4.9 (35%)
[1.8, 8.3] 1.7 (34%)
[0.9, 3.3] * AUC = single dose AUC0-¥
;.
**
preterm infants were defined as less than 34 gestational weeks at birth in this data set (only one pediatric patient with preterm birth was enrolled between 1 week and 28 days after birth).
***
for this data set, full-term infants were defined as greater than or equal to 34 gestational weeks at birth
†
Dose of 10 mg/kg
‡
Dose of 600 mg or 10 mg/kg, up to 600 mg;
§
Dose normalized to 600 mg
Cmax = maximum plasma concentration; Vss = volume of distribution; AUC = area under the drug-time curve; t1/2 = apparent elimination half-life; CL = weight-normalized systemic elimination rate
Normalized systemic elimination rate by body weight
 
 Gender: The volume of distribution of linezolid is smaller in females compared to males. Plasma concentrations were higher in women than in men, partly due to weight differences. After oral administration of 600 mg, the mean clearance rate was approximately 38% lower in women than in men. However, no significant gender differences were seen in the mean apparent clearance rate constant and half-life. Therefore, drug exposure in women does not significantly exceed the known tolerable levels. Therefore, no gender-specific dose adjustment is required.
 Renal Insufficiency: The pharmacokinetic properties of the prodrug linezolid are not altered in patients with varying degrees of renal insufficiency. In patients with renal insufficiency, accumulation of the two major metabolites may occur, and accumulation increases with the severity of renal insufficiency (see Table 19). The clinical significance of the accumulation of both of these metabolites has not been studied in patients with severe renal insufficiency. Similar plasma drug concentrations of linezolid are obtained in patients regardless of renal function, and therefore no dose adjustment is required in patients with renal insufficiency. Because of the lack of knowledge regarding the clinical significance of the accumulation of the two major metabolites in the body, patients with renal insufficiency should weigh the advantages and disadvantages of linezolid against the potential risk of accumulation of its metabolites. Linezolid and its two metabolites are cleared by dialysis. There is no information on the effect of peritoneal dialysis on the pharmacokinetic properties of linezolid. Dialysis is initiated 3 hours after linezolid administration, and approximately 30% of the drug dose is cleared during a dialysis period of approximately 3 hours. Therefore, linezolid should be administered at the end of hemodialysis.
 Table 19 Oral administration of linezolid at a single dose of 600 mg of linezolid in patients with varying degrees of renal insufficiency, and the AU of linezolid and its
Mean AUC and elimination half-life of metabolites A and B (standard deviation)
Parameter
Number healthy volunteers
ClCR>80
ml/min Those with moderately impaired renal function
30< ClCR
<80
ml/min Severely impaired renal function
10< ClCR
<30
ml/min Hemodialysis-dependent End of hemodialysis * Hemodialysis in progress linezolid AUC0-¥ ,mg-h/ml 110(22) 128(53) 127(66) 141(45) 83(23) t1/2, hour 6.4(2.2) 6.1(1.7) 7.1(3.7) 8.4(2.7) 7.0(1.8) Metabolite AAUC0-48 ,mg-h/ml 7.6(1.9) 11.7(4.3) 56.5(30.6) 185(124) 68.8(23.9) t1/2, h 6.3(2.1) 6.6(2.3) 9.0(4.6) NA NA Metabolite Product BAUC0-48 ,mg-h/ml 30.5(6.2) 51.1(38.5) 203(92) 467(102) 239(44) t1/2, hour 6.6(2.7) 9.9(7.4) 11.0(3.9) NA NA * Between hemodialysis, NA = not applicable
 Hepatic insufficiency: Studies in 7 patients with mild to moderate hepatic insufficiency (Child-Pugh classification A or B) have shown no change in the pharmacokinetic properties of linezolid. Based on the available data, no dose adjustment is required in patients with mild to moderate hepatic insufficiency. The pharmacokinetic properties of linezolid have not been evaluated in patients with severe hepatic insufficiency.
 [Storage].
Keep away from light, tightly closed, at 15-30°C (59-86°F).
Package
10 tablets/box in blister pack; 20 tablets/bottle
Expiration date
24 months
Executive Standard
Imported drug registration standard JX20130142 and meet the requirements of the Chinese Pharmacopoeia, 2015 edition.
Approval number
Imported drug registration certificate number: H20130609
Manufacturer
Company Name: Pfizer Pharmaceuticals LLC
Production Address: Vega Baja, PR 00693, USA
Packaging company: Pfizer Pharmaceuticals LLC
Address
Address: Vega Baja, PR 00693, USA
 Domestic contact address.
Domestic Contact Address: 8-13F, Block B, Minmetals Plaza, 3-7 Chaoyangmen North Street, Dongcheng District, Beijing, China
Postal Code: 100010
Tel: 010-85167000
Product Inquiry Hotline：400 910 0055