Generic Name: (linezolid)
Dosage Type: injection, solution

Generic Name: (linezolid)
Dosage Type: tablet, film coated

Generic Name: (linezolid)
Dosage Type: suspension
Organization: Pharmacia and Upjohn Company

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZYVOX formulations and other antibacterial drugs, ZYVOX should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

ZYVOX I.V. Injection, ZYVOX Tablets, and ZYVOX for Oral Suspension contain linezolid, which is a synthetic antibacterial agent of the oxazolidinone class. The chemical name for linezolid is (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.

The empirical formula is C16H20FN3O4. Its molecular weight is 337.35, and its chemical structure is represented below:

ZYVOX I.V. Injection is supplied as a ready-to-use sterile isotonic solution for intravenous infusion. Each mL contains 2 mg of linezolid. Inactive ingredients are sodium citrate, citric acid, and dextrose in an aqueous vehicle for intravenous administration. The sodium (Na+) content is 0.38 mg/mL (5 mEq per 300-mL bag; 3.3 mEq per 200-mL bag; and 1.7 mEq per 100-mL bag).

ZYVOX Tablets for oral administration contain 400 mg or 600 mg linezolid as film-coated compressed tablets. Inactive ingredients are corn starch, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, and carnauba wax. The sodium (Na+) content is 1.95 mg per 400-mg tablet and 2.92 mg per 600-mg tablet (0.1 mEq per tablet, regardless of strength).

ZYVOX for Oral Suspension is supplied as an orange-flavored granule/powder for constitution into a suspension for oral administration. Following constitution, each 5 mL contains 100 mg of linezolid. Inactive ingredients are sucrose, citric acid, sodium citrate, microcrystalline cellulose and carboxymethylcellulose sodium, aspartame, xanthan gum, mannitol, sodium benzoate, colloidal silicon dioxide, sodium chloride, and flavors (see PRECAUTIONS, Information for Patients). The sodium (Na+) content is 8.52 mg per 5 mL (0.4 mEq per 5 mL).

CLINICAL PHARMACOLOGY

Pharmacokinetics

The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous (IV) doses are summarized in Table 1. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours (q12h) are shown in Figure 1.

Table 1. Mean (Standard Deviation) Pharmacokinetic Parameters of Linezolid in Adults

Dose of Linezolid	Cmax µg/mL	Cmin µg/mL	Tmax hrs	AUC * µg · h/mL	t1/2 hrs	CL mL/min
Cmax = Maximum plasma concentration; Cmin = Minimum plasma concentration; Tmax = Time to Cmax; AUC = Area under concentration-time curve; t1/2 = Elimination half-life; CL = Systemic clearance
* AUC for single dose = AUC0–8; for multiple-dose = AUC0–t † Data dose-normalized from 375 mg ‡ Data dose-normalized from 625 mg, IV dose was given as 0.5-hour infusion.
400 mg tablet   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)
600 mg tablet   single dose   every 12 hours	12.70 (3.96) 21.20 (5.78)	--- 6.15 (2.94)	1.28 (0.66) 1.03 (0.62)	91.40 (39.30) 138.00 (42.10)	4.26 (1.65) 5.40 (2.06)	127 (48) 80 (29)
600 mg IV injection‡   single dose   every 12 hours	12.90 (1.60) 15.10 (2.52)	--- 3.68 (2.36)	0.50 (0.10) 0.51 (0.03)	80.20 (33.30) 89.70 (31.00)	4.40 (2.40) 4.80 (1.70)	138 (39) 123 (40)
600 mg oral suspension   single dose	11.00 (2.76)	---	0.97 (0.88)	80.80 (35.10)	4.60 (1.71)	141 (45)

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

Absorption

Linezolid is rapidly and extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%. Therefore, linezolid may be given orally or intravenously without dose adjustment.

Linezolid may be administered without regard to the timing of meals. The time to reach the maximum concentration is delayed from 1.5 hours to 2.2 hours and Cmax is decreased by about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC0-8 values is similar under both conditions.

Distribution

Animal and human pharmacokinetic studies have demonstrated that linezolid readily distributes to well-perfused tissues. The plasma protein binding of linezolid is approximately 31% and is concentration-independent. The volume of distribution of linezolid at steady-state averaged 40 to 50 liters in healthy adult volunteers.

Linezolid concentrations have been determined in various fluids from a limited number of subjects in Phase 1 volunteer studies following multiple dosing of linezolid. The ratio of linezolid in saliva relative to plasma was 1.2 to 1 and for sweat relative to plasma was 0.55 to 1.

Metabolism

Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic acid metabolite (A), and the hydroxyethyl glycine metabolite (B). Formation of metabolite B is mediated by a non-enzymatic chemical oxidation mechanism in vitro. Linezolid is not an inducer of cytochrome P450 (CYP) in rats, and it has been demonstrated from in vitro studies that linezolid is not detectably metabolized by human cytochrome P450 and it does not inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4).

Excretion

Nonrenal clearance accounts for approximately 65% of the total clearance of linezolid. Under steady-state conditions, approximately 30% of the dose appears in the urine as linezolid, 40% as metabolite B, and 10% as metabolite A. The renal clearance of linezolid is low (average 40 mL/min) and suggests net tubular reabsorption. Virtually no linezolid appears in the feces, while approximately 6% of the dose appears in the feces as metabolite B, and 3% as metabolite A.

A small degree of nonlinearity in clearance was observed with increasing doses of linezolid, which appears to be due to lower renal and nonrenal clearance of linezolid at higher concentrations. However, the difference in clearance was small and was not reflected in the apparent elimination half-life.

Special Populations

Geriatric

The pharmacokinetics of linezolid are not significantly altered in elderly patients (65 years or older). Therefore, dose adjustment for geriatric patients is not necessary.

Pediatric

The pharmacokinetics of linezolid following a single IV dose were investigated in pediatric patients ranging in age from birth through 17 years (including premature and full-term neonates), in healthy adolescent subjects ranging in age from 12 through 17 years, and in pediatric patients ranging in age from 1 week through 12 years. The pharmacokinetic parameters of linezolid are summarized in Table 2 for the pediatric populations studied and healthy adult subjects after administration of single IV doses.

The Cmax and the volume of distribution (Vss) of linezolid are similar regardless of age in pediatric patients. However, clearance of linezolid varies as a function of age. With the exclusion of pre-term neonates less than one week of age, clearance is most rapid in the youngest age groups ranging from >1 week old to 11 years, resulting in lower single-dose systemic exposure (AUC) and shorter half-life as compared with adults. As age of pediatric patients increases, the clearance of linezolid gradually decreases, and by adolescence mean clearance values approach those observed for the adult population. There is wider inter-subject variability in linezolid clearance and systemic drug exposure (AUC) across all pediatric age groups as compared with adults.

Similar mean daily AUC values were observed in pediatric patients from birth to 11 years of age dosed every 8 hours (q8h) relative to adolescents or adults dosed every 12 hours (q12h). Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg q8h. Pediatric patients 12 years and older should receive 600 mg q12h (see DOSAGE AND ADMINISTRATION).

Table 2. Pharmacokinetic Parameters of Linezolid in Pediatrics and Adults Following a Single Intravenous Infusion of 10 mg/kg or 600 mg Linezolid (Mean: (%CV; [Min, Max Values])

Age Group	Cmax µg/mL	Vss L/kg	AUC * µg • h/mL	t1/2 hrs	CL mL/min/kg
Cmax = Maximum plasma concentration; Vss= Volume of distribution; AUC = Area under concentration-time curve; t1/2 = Apparent elimination half-life; CL = Systemic clearance normalized for body weight
* AUC = Single dose AUC0–8 † In this data set, "pre-term" is defined as <34 weeks gestational age (Note: Only 1 patient enrolled was pre-term with a postnatal age between 1 week and 28 days) ‡ Dose of 10 mg/kg § In this data set, "full-term" is defined as =34 weeks gestational age ¶ Dose of 600 mg or 10 mg/kg up to a maximum of 600 mg # Dose normalized to 600 mg
Neonatal Patients   Pre-term†   < 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§   < 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§   = 1 week to = 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 to < 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 through 11 years‡ (N=59)	15.1 (30%) [6.8, 36.7]	0.69 (28%) [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 through 17 years¶ (N=36)	16.7 (24%) [9.9, 28.9]	0.61 (15%) [0.44, 0.79]	95 (44%) [32, 178]	4.1 (46%) [1.3, 8.1]	2.1 (53%) [0.9, 5.2]
Adult Subjects# (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]

Gender

Females have a slightly lower volume of distribution of linezolid than males. Plasma concentrations are higher in females than in males, which is partly due to body weight differences. After a 600-mg dose, mean oral clearance is approximately 38% lower in females than in males. However, there are no significant gender differences in mean apparent elimination-rate constant or half-life. Thus, drug exposure in females is not expected to substantially increase beyond levels known to be well tolerated. Therefore, dose adjustment by gender does not appear to be necessary.

Renal Insufficiency

The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any degree of renal insufficiency; however, the two primary metabolites of linezolid may accumulate in patients with renal insufficiency, with the amount of accumulation increasing with the severity of renal dysfunction (see Table 3). The clinical significance of accumulation of these two metabolites has not been determined in patients with severe renal insufficiency. Because similar plasma concentrations of linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal insufficiency. However, given the absence of information on the clinical significance of accumulation of the primary metabolites, use of linezolid in patients with renal insufficiency should be weighed against the potential risks of accumulation of these metabolites. Both linezolid and the two metabolites are eliminated by dialysis. No information is available on the effect of peritoneal dialysis on the pharmacokinetics of linezolid. Approximately 30% of a dose was eliminated in a 3-hour dialysis session beginning 3 hours after the dose of linezolid was administered; therefore, linezolid should be given after hemodialysis.

Table 3. Mean (Standard Deviation) AUCs and Elimination Half-lives of Linezolid and Metabolites A and B in Patients with Varying Degrees of Renal Insufficiency After a Single 600-mg Oral Dose of Linezolid

Parameter	Healthy Subjects CLCR> 80 mL/min	Moderate Renal Impairment 30 < CLCR< 80 mL/min	Severe Renal Impairment 10 < CLCR< 30 mL/min	Hemodialysis-Dependent
				Off Dialysis*	On Dialysis
NA = Not applicable
* between hemodialysis sessions
Linezolid
AUC0–8, µg h/mL	110 (22)	128 (53)	127 (66)	141 (45)	83 (23)
t1/2, hours	6.4 (2.2)	6.1 (1.7)	7.1 (3.7)	8.4 (2.7)	7.0 (1.8)
Metabolite A
AUC0–48, µg h/mL	7.6 (1.9)	11.7 (4.3)	56.5 (30.6)	185 (124)	68.8 (23.9)
t1/2, hours	6.3 (2.1)	6.6 (2.3)	9.0 (4.6)	NA	NA
Metabolite B
AUC0–48, µg h/mL	30.5 (6.2)	51.1 (38.5)	203 (92)	467 (102)	239 (44)
t1/2;, hours	6.6 (2.7)	9.9 (7.4)	11.0 (3.9)	NA	NA

Hepatic Insufficiency

The pharmacokinetics of linezolid are not altered in patients (n=7) with mild-to-moderate hepatic insufficiency (Child-Pugh class A or B). On the basis of the available information, no dose adjustment is recommended for patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of linezolid in patients with severe hepatic insufficiency have not been evaluated.

Drug-Drug Interactions

Drugs Metabolized by Cytochrome P450

Linezolid is not an inducer of cytochrome P450 (CYP) in rats. It is not detectably metabolized by human cytochrome P450 and it does not inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, no CYP450-induced drug interactions are expected with linezolid. Concurrent administration of linezolid does not substantially alter the pharmacokinetic characteristics of (S)-warfarin, which is extensively metabolized by CYP2C9. Drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with linezolid without changes in dosage regimen.

Antibiotics

Aztreonam: The pharmacokinetics of linezolid or aztreonam are not altered when administered together.

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

Monoamine Oxidase Inhibition

Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.

Adrenergic Agents: A significant pressor response has been observed in normal adult subjects receiving linezolid and tyramine doses of more than 100 mg. Therefore, patients receiving linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content (see PRECAUTIONS, Information for Patients).

A reversible enhancement of the pressor response of either pseudoephedrine HCl (PSE) or phenylpropanolamine HCl (PPA) is observed when linezolid is administered to healthy normotensive subjects (see PRECAUTIONS, Drug Interactions). A similar study has not been conducted in hypertensive patients. The interaction studies conducted in normotensive subjects evaluated the blood pressure and heart rate effects of placebo, PPA or PSE alone, linezolid alone, and the combination of steady-state linezolid (600 mg q12h for 3 days) with two doses of PPA (25 mg) or PSE (60 mg) given 4 hours apart. Heart rate was not affected by any of the treatments. Blood pressure was increased with both combination treatments. Maximum blood pressure levels were seen 2 to 3 hours after the second dose of PPA or PSE, and returned to baseline 2 to 3 hours after peak. The results of the PPA study follow, showing the mean (and range) maximum systolic blood pressure in mm Hg: placebo = 121 (103 to 158); linezolid alone = 120 (107 to 135); PPA alone = 125 (106 to 139); PPA with linezolid = 147 (129 to 176). The results from the PSE study were similar to those in the PPA study. The mean maximum increase in systolic blood pressure over baseline was 32 mm Hg (range: 20–52 mm Hg) and 38 mm Hg (range: 18–79 mm Hg) during co-administration of linezolid with pseudoephedrine or phenylpropanolamine, respectively.

Serotonergic Agents: The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20-mg doses given 4 hours apart) with or without linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan.

MICROBIOLOGY

Linezolid is a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones, which has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the majority of strains.

In clinical trials, resistance to linezolid developed in 6 patients infected with Enterococcus faecium (4 patients received 200 mg q12h, lower than the recommended dose, and 2 patients received 600 mg q12h). In a compassionate use program, resistance to linezolid developed in 8 patients with E. faecium and in 1 patient with Enterococcus faecalis. All patients had either unremoved prosthetic devices or undrained abscesses. Resistance to linezolid occurs in vitro at a frequency of 1 x 10 -9 to 1 x 10 -11. In vitro studies have shown that point mutations in the 23S rRNA are associated with linezolid resistance. Reports of vancomycin-resistant E. faecium becoming resistant to linezolid during its clinical use have been published.1 In one report nosocomial spread of vancomycin- and linezolid-resistant E. faecium occurred 2. There has been a report of Staphylococcus aureus (methicillin-resistant) developing resistance to linezolid during its clinical use.3 The linezolid resistance in these organisms was associated with a point mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism. When antibiotic-resistant organisms are encountered in the hospital, it is important to emphasize infection control policies.4, 5 Resistance to linezolid has not been reported in Streptococcus spp., including Streptococcus pneumoniae.

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

Linezolid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.

Aerobic and facultative Gram-positive microorganisms

• Enterococcus faecium (vancomycin-resistant strains only)
• Staphylococcus aureus (including methicillin-resistant strains)
• Streptococcus agalactiae
• Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP]1)
• Streptococcus pyogenes

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for linezolid. However, the safety and effectiveness of linezolid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

---

1

MDRSP refers to isolates resistant to two or more of the following antibiotics: penicillin, second-generation cephalosporins, macrolides, tetracycline, and trimethoprim/sulfamethoxazole.

Aerobic and facultative Gram-positive microorganisms

• Enterococcus faecalis (including vancomycin-resistant strains)
• Enterococcus faecium (vancomycin-susceptible strains)
• Staphylococcus epidermidis (including methicillin-resistant strains)
• Staphylococcus haemolyticus
• Viridans group streptococci

Aerobic and facultative Gram-negative microorganisms

• Pasteurella multocida

Susceptibility Testing Methods

NOTE: Susceptibility testing by dilution methods requires the use of linezolid susceptibility powder.

When available, the results of in vitro susceptibility tests should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method 6,7 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of linezolid powder. The MIC values should be interpreted according to criteria provided in Table 4.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 7,8 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 µg of linezolid to test the susceptibility of microorganisms to linezolid. The disk diffusion interpretive criteria are provided in Table 4.

Table 4. Susceptibility Interpretive Criteria for Linezolid

Pathogen	Susceptibility Interpretive Criteria
	Minimal Inhibitory Concentrations (MIC in µg/mL)			Disk Diffusion (Zone Diameters in mm)
	S	I	R	S	I	R
* The current absence of data on resistant strains precludes defining any categories other than "Susceptible." Strains yielding test results suggestive of a "nonsusceptible" category should be retested, and if the result is confirmed, the isolate should be submitted to a reference laboratory for further testing. † These interpretive standards for S. pneumoniae and Streptococcus spp. other than S. pneumoniae are applicable only to tests performed by broth microdilution using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood inoculated with a direct colony suspension and incubated in ambient air at 35°C for 20 to 24 hours. ‡ These zone diameter interpretive standards are applicable only to tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood inoculated with a direct colony suspension and incubated in 5% CO2 at 35°C for 20 to 24 hours.
Enterococcus spp	= 2	4	=8	= 23	21–22	=20
Staphylococcus spp *	=4	---	---	= 21	---	---
Streptococcus pneumoniae*	=2†	---	---	= 21‡	---	---
Streptococcus spp other than S pneumoniae*	=2†	---	---	= 21‡	---	---

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard linezolid powder should provide the following range of values noted in Table 5. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains used for microbiological quality control are not clinically significant.

Table 5. Acceptable Quality Control Ranges for Linezolid to be Used in Validation of Susceptibility Test Results

QC Strain	Acceptable Quality Control Ranges
	Minimum Inhibitory Concentration (MIC in µg/mL)	Disk Diffusion (Zone Diameters in mm)
* This organism may be used for validation of susceptibility test results when testing Streptococcus spp. other than S. pneumoniae. † This quality control range for S. pneumoniae is applicable only to tests performed by broth microdilution using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood inoculated with a direct colony suspension and incubated in ambient air at 35°C for 20 to 24 hours. ‡ This quality control zone diameter range is applicable only to tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood inoculated with a direct colony suspension and incubated in 5% CO2 at 35°C for 20 to 24 hours.
Enterococcus faecalis ATCC 29212	1 – 4	Not applicable
Staphylococcus aureus ATCC 29213	1 – 4	Not applicable
Staphylococcus aureus ATCC 25923	Not applicable	25 – 32
Streptococcus pneumoniae ATCC 49619*	0.50 – 2†	25 – 34‡

INDICATIONS AND USAGE

ZYVOX formulations are indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms (see PRECAUTIONS, Pediatric Use and DOSAGE AND ADMINISTRATION).

Vancomycin-Resistant Enterococcus faecium infections, including cases with concurrent bacteremia (see CLINICAL STUDIES).

Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), or Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]). Combination therapy may be clinically indicated if the documented or presumptive pathogens include Gram-negative organisms (see CLINICAL STUDIES).

Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes, or Streptococcus agalactiae. ZYVOX has not been studied in the treatment of decubitus ulcers. Combination therapy may be clinically indicated if the documented or presumptive pathogens include Gram-negative organisms (see CLINICAL STUDIES).

Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible only) or Streptococcus pyogenes.

Community-acquired pneumonia caused by Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]1), including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible strains only).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZYVOX and other antibacterial drugs, ZYVOX should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CONTRAINDICATIONS

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

WARNINGS

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

In adult and juvenile dogs and rats, myelosuppression, reduced extramedullary hematopoiesis in spleen and liver, and lymphoid depletion of thymus, lymph nodes, and spleen were observed (see ANIMAL PHARMACOLOGY).

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ZYVOX, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of any antibacterial agent.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicated that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis."

After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile.

PRECAUTIONS

General

Lactic Acidosis

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

Serotonin Syndrome

Spontaneous reports of serotonin syndrome associated with the co-administration of ZYVOX and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported (see PRECAUTIONS, Drug Interactions).

Where administration of ZYVOX and concomitant serotonergic agents is clinically appropriate, patients should be closely observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If signs or symptoms occur physicians should consider discontinuation of either one or both agents. If the concomitant serotonergic agent is withdrawn, discontinuation symptoms can be observed (see package insert of the specified agent(s) for a description of the associated discontinuation symptoms).

Peripheral and Optic Neuropathy

Peripheral and optic neuropathy have been reported in patients treated with ZYVOX, primarily those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Visual blurring has been reported in some patients treated with ZYVOX for less than 28 days.

If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking ZYVOX for extended periods (= 3 months) and in all patients reporting new visual symptoms regardless of length of therapy with ZYVOX. If peripheral or optic neuropathy occurs, the continued use of ZYVOX in these patients should be weighed against the potential risks.

Convulsions

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

The use of antibiotics may promote the overgrowth of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.

ZYVOX has not been studied in patients with uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, or untreated hyperthyroidism.

The safety and efficacy of ZYVOX formulations given for longer than 28 days have not been evaluated in controlled clinical trials.

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

Information for Patients

Patients should be advised that:

• ZYVOX may be taken with or without food.
• They should inform their physician if they have a history of hypertension.
• Large quantities of foods or beverages with high tyramine content should be avoided while taking ZYVOX. Quantities of tyramine consumed should be less than 100 mg per meal. Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor, such as aged cheeses (0 to 15 mg tyramine per ounce); fermented or air-dried meats (0.1 to 8 mg tyramine per ounce); sauerkraut (8 mg tyramine per 8 ounces); soy sauce (5 mg tyramine per 1 teaspoon); tap beers (4 mg tyramine per 12 ounces); red wines (0 to 6 mg tyramine per 8 ounces). The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.9,10
• They should inform their physician if taking medications containing pseudoephedrine HCl or phenylpropanolamine HCl, such as cold remedies and decongestants.
• They should inform their physician if taking serotonin re-uptake inhibitors or other antidepressants.
• Phenylketonurics: Each 5 mL of the 100 mg/5 mL ZYVOX for Oral Suspension contains 20 mg phenylalanine. The other ZYVOX formulations do not contain phenylalanine. Contact your physician or pharmacist.
• They should inform their physician if they experience changes in vision.
• They should inform their physician if they have a history of seizures.

Patients should be counseled that antibacterial drugs including ZYVOX should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ZYVOX is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ZYVOX or other antibacterial drugs in the future.

Drug Interactions

(see also CLINICAL PHARMACOLOGY, Drug-Drug Interactions)

Monoamine Oxidase Inhibition

Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.

Adrenergic Agents: Some individuals receiving ZYVOX may experience a reversible enhancement of the pressor response to indirect-acting sympathomimetic agents, vasopressor or dopaminergic agents. Commonly used drugs such as phenylpropanolamine and pseudoephedrine have been specifically studied. Initial doses of adrenergic agents, such as dopamine or epinephrine, should be reduced and titrated to achieve the desired response.

Serotonergic Agents: Co-administration of linezolid and serotonergic agents was not associated with serotonin syndrome in Phase 1, 2 or 3 studies. Spontaneous reports of serotonin syndrome associated with co-administration of ZYVOX and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported. Patients who are treated with ZYVOX and concomitant serotonergic agents should be closely observed as described in the PRECAUTIONS, General Section.

Drug-Laboratory Test Interactions

There are no reported drug-laboratory test interactions.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of linezolid. Neither mutagenic nor clastogenic potential was found in a battery of tests including: assays for mutagenicity (Ames bacterial reversion and CHO cell mutation), an in vitro unscheduled DNA synthesis (UDS) assay, an in vitro chromosome aberration assay in human lymphocytes, and an in vivo mouse micronucleus assay.

Linezolid did not affect the fertility or reproductive performance of adult female rats. It reversibly decreased fertility and reproductive performance in adult male rats when given at doses = 50 mg/kg/day, with exposures approximately equal to or greater than the expected human exposure level (exposure comparisons are based on AUCs). The reversible fertility effects were mediated through altered spermatogenesis. Affected spermatids contained abnormally formed and oriented mitochondria and were non-viable. Epithelial cell hypertrophy and hyperplasia in the epididymis was observed in conjunction with decreased fertility. Similar epididymal changes were not seen in dogs.

In sexually mature male rats exposed to drug as juveniles, mildly decreased fertility was observed following treatment with linezolid through most of their period of sexual development (50 mg/kg/day from days 7 to 36 of age, and 100 mg/kg/day from days 37 to 55 of age), with exposures up to 1.7-fold greater than mean AUCs observed in pediatric patients aged 3 months to 11 years. Decreased fertility was not observed with shorter treatment periods, corresponding to exposure in utero through the early neonatal period (gestation day 6 through postnatal day 5), neonatal exposure (postnatal days 5 to 21), or to juvenile exposure (postnatal days 22 to 35). Reversible reductions in sperm motility and altered sperm morphology were observed in rats treated from postnatal day 22 to 35.

Pregnancy

Teratogenic Effects.

Pregnancy Category C

Linezolid was not teratogenic in mice, rats, or rabbits at exposure levels 6.5-fold (in mice), equivalent to (in rats), or 0.5-fold (in rabbits) the expected human exposure level, based on AUCs. However, embryo and fetal toxicities were seen (see Non-teratogenic Effects). There are no adequate and well-controlled studies in pregnant women. ZYVOX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Non-teratogenic Effects

In mice, embryo and fetal toxicities were seen only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). A dose of 450 mg/kg/day (6.5-fold the estimated human exposure level based on AUCs) correlated with increased postimplantational embryo death, including total litter loss, decreased fetal body weights, and an increased incidence of costal cartilage fusion.

In rats, mild fetal toxicity was observed at 15 and 50 mg/kg/day (exposure levels 0.22-fold to approximately equivalent to the estimated human exposure, respectively based on AUCs). The effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a finding often seen in association with decreased fetal body weights. Slight maternal toxicity, in the form of reduced body weight gain, was seen at 50 mg/kg/day.

In rabbits, reduced fetal body weight occurred only in the presence of maternal toxicity (clinical signs, reduced body weight gain and food consumption) when administered at a dose of 15 mg/kg/day (0.5-fold the estimated human exposure based on AUCs).

When female rats were treated with 50 mg/kg/day (approximately equivalent to the estimated human exposure based on AUCs) of linezolid during pregnancy and lactation, survival of pups was decreased on postnatal days 1 to 4. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss.

Nursing Mothers

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

Pediatric Use

The safety and effectiveness of ZYVOX for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years (see INDICATIONS AND USAGE and CLINICAL STUDIES):

• nosocomial pneumonia
• complicated skin and skin structure infections
• community-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from 8 months through 12 years)
• vancomycin-resistant Enterococcus faecium infections

The safety and effectiveness of ZYVOX for the treatment of pediatric patients with the following infection have been established in a comparator-controlled study in pediatric patients ranging in age from 5 through 17 years (see CLINICAL STUDIES):

• uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes

Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended.

The Cmax and the volume of distribution (Vss) of linezolid are similar regardless of age in pediatric patients. However, linezolid clearance is a function of age. Excluding neonates less than a week of age, clearance is most rapid in the youngest age groups ranging from >1 week old to 11 years, resulting in lower single-dose systemic exposure (AUC) and shorter half-life as compared with adults. As age of pediatric patients increases, the clearance of linezolid gradually decreases, and by adolescence, mean clearance values approach those observed for the adult population. There is wider inter-subject variability in linezolid clearance and in systemic drug exposure (AUC) across all pediatric age groups as compared with adults.

Similar mean daily AUC values were observed in pediatric patients from birth to 11 years of age dosed q8h relative to adolescents or adults dosed q12h. Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg q8h. Pediatric patients 12 years and older should receive 600 mg q12h.

Recommendations for the dosage regimen for pre-term neonates less than 7 days of age (gestational age less than 34 weeks) are based on pharmacokinetic data from 9 pre-term neonates. Most of these pre-term neonates have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. Therefore, these pre-term neonates should be initiated with a dosing regimen of 10 mg/kg q12h. Consideration may be given to the use of a 10 mg/kg q8h regimen in neonates with a sub-optimal clinical response. All neonatal patients should receive 10 mg/kg q8h by 7 days of life (see CLINICAL PHARMACOLOGY, Special Populations, Pediatric and DOSAGE AND ADMINISTRATION).

In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Gram-positive pathogens with MICs of 4 µg/mL treated with ZYVOX had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 µg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response (see CLINICAL PHARMACOLOGY, Special Populations, Pediatric and DOSAGE AND ADMINISTRATION).

Geriatric Use

Of the 2046 patients treated with ZYVOX in Phase 3 comparator-controlled clinical trials, 589 (29%) were 65 years or older and 253 (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

ANIMAL PHARMACOLOGY

Target organs of linezolid toxicity were similar in juvenile and adult rats and dogs. Dose- and time-dependent myelosuppression, as evidenced by bone marrow hypocellularity/decreased hematopoiesis, decreased extramedullary hematopoiesis in spleen and liver, and decreased levels of circulating erythrocytes, leukocytes, and platelets have been seen in animal studies. Lymphoid depletion occurred in thymus, lymph nodes, and spleen. Generally, the lymphoid findings were associated with anorexia, weight loss, and suppression of body weight gain, which may have contributed to the observed effects.

In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was observed in males dosed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in 1 male at this dose level at a 3-month interim necropsy. Similar changes were not observed in female rats. Sensitive morphologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 male rats after 6 months of dosing, but the direct relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical distribution. The nerve degeneration observed was microscopically compatible to spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of common background change.

These effects were observed at exposure levels that are comparable to those observed in some human subjects. The hematopoietic and lymphoid effects were reversible, although in some studies, reversal was incomplete within the duration of the recovery period.

ADVERSE REACTIONS

Adult Patients

The safety of ZYVOX formulations was evaluated in 2046 adult patients enrolled in seven Phase 3 comparator-controlled clinical trials, who were treated for up to 28 days. In these studies, 85% of the adverse events reported with ZYVOX were described as mild to moderate in intensity. Table 6 shows the incidence of adverse events reported in at least 2% of patients in these trials. The most common adverse events in patients treated with ZYVOX were diarrhea (incidence across studies: 2.8% to 11.0%), headache (incidence across studies: 0.5% to 11.3%), and nausea (incidence across studies: 3.4% to 9.6%).

Table 6. Incidence (%) of Adverse Events Reported in =2% of Adult Patients in Comparator-Controlled Clinical Trials with ZYVOX

Event	ZYVOX (n=2046)	All Comparators * (n=2001)
* Comparators included cefpodoxime proxetil 200 mg PO q12h; ceftriaxone 1 g IV q12h; clarithromycin 250 mg PO q12h; dicloxacillin 500 mg PO q6h; oxacillin 2 g IV q6h; vancomycin 1 g IV q12h.
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

Other adverse events reported in Phase 2 and Phase 3 studies included oral moniliasis, vaginal moniliasis, hypertension, dyspepsia, localized abdominal pain, pruritus, and tongue discoloration.

Table 7 shows the incidence of drug-related adverse events reported in at least 1% of adult patients in these trials by dose of ZYVOX.

Table 7. Incidence (%) of Drug-Related Adverse Events Occurring in >1% of Adult Patients Treated with ZYVOX in Comparator-Controlled Clinical Trials

	Uncomplicated Skin and Skin Structure Infections		All Other Indications
Adverse Event	ZYVOX 400 mg PO q12h (n=548)	Clarithromycin 250 mg PO q12h (n=537)	ZYVOX 600 mg q12h (n=1498)	All Other Comparators* (n=1464)
* Comparators included cefpodoxime proxetil 200 mg PO q12h; ceftriaxone 1 g IV q12h; dicloxacillin 500 mg PO q6h; oxacillin 2 g IV q6h; vancomycin 1 g IV q12h. † The most commonly reported drug-related adverse events leading to discontinuation in patients treated with ZYVOX were nausea, headache, diarrhea, and vomiting.
% of patients with 1 drug-related adverse event	25.4	19.6	20.4	14.3
% of patients discontinuing due to drug-related adverse events†	3.5	2.4	2.1	1.7
Diarrhea	5.3	4.8	4.0	2.7
Nausea	3.5	3.5	3.3	1.8
Headache	2.7	2.2	1.9	1.0
Taste alteration	1.8	2.0	0.9	0.2
Vaginal moniliasis	1.6	1.3	1.0	0.4
Fungal infection	1.5	0.2	0.1	<0.1
Abnormal liver function tests	0.4	0	1.3	0.5
Vomiting	0.9	0.4	1.2	0.4
Tongue discoloration	1.1	0	0.2	0
Dizziness	1.1	1.5	0.4	0.3
Oral moniliasis	0.4	0	1.1	0.4

Pediatric Patients

The safety of ZYVOX formulations was evaluated in 215 pediatric patients ranging in age from birth through 11 years, and in 248 pediatric patients aged 5 through 17 years (146 of these 248 were age 5 through 11 and 102 were age 12 to 17). These patients were enrolled in two Phase 3 comparator-controlled clinical trials and were treated for up to 28 days. In these studies, 83% and 99%, respectively, of the adverse events reported with ZYVOX were described as mild to moderate in intensity. In the study of hospitalized pediatric patients (birth through 11 years) with Gram-positive infections, who were randomized 2 to 1 (linezolid:vancomycin), mortality was 6.0% (13/215) in the linezolid arm and 3.0% (3/101) in the vancomycin arm. However, given the severe underlying illness in the patient population, no causality could be established. Table 8 shows the incidence of adverse events reported in at least 2% of pediatric patients treated with ZYVOX in these trials.

Table 8. Incidence (%) of Adverse Events Reported in =2% of Pediatric Patients Treated with ZYVOX in Comparator-Controlled Clinical Trials

	Uncomplicated Skin and Skin Structure Infections*		All Other Indications†
Event	ZYVOX (n=248)	Cefadroxil (n = 251)	ZYVOX (n = 215)	Vancomycin (n=101)
* Patients 5 through 11 years of age received ZYVOX 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received ZYVOX 600 mg PO q12h or cefadroxil 500 mg PO q12h. † Patients from birth through 11 years of age received ZYVOX 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6–24h, depending on age and renal clearance.
Fever	2.9	3.6	14.1	14.1
Diarrhea	7.8	8.0	10.8	12.1
Vomiting	2.9	6.4	9.4	9.1
Sepsis	0	0	8.0	7.1
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 infection	3.7	5.2	4.2	1.0
Nausea	3.7	3.2	1.9	0
Dyspnea	0	0	3.3	1.0
Reaction at site of injection or of vascular catheter	0	0	3.3	5.1
Trauma	3.3	4.8	2.8	2.0
Pharyngitis	2.9	1.6	0.5	1.0
Convulsion	0	0	2.8	2.0
Hypokalemia	0	0	2.8	3.0
Pneumonia	0	0	2.8	2.0
Thrombocythemia	0	0	2.8	2.0
Cough	2.4	4.0	0.9	0
Generalized abdominal pain	2.4	2.8	0.9	2.0
Localized 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
Generalized edema	0	0	2.3	1.0
Loose stools	1.6	0.8	2.3	3.0
Localized pain	2.0	1.6	0.9	0
Skin disorder	2.0	0	0.9	1.0

Table 9 shows the incidence of drug-related adverse events reported in more than 1% of pediatric patients (and more than 1 patient) in either treatment group in the comparator-controlled Phase 3 trials.

Table 9. Incidence (%) of Drug-related Adverse Events Occurring in >1% of Pediatric Patients (and >1 Patient) in Either Treatment Group in Comparator-Controlled Clinical Trials

Event	Uncomplicated Skin and Skin Structure Infections*		All Other Indications†
	ZYVOX (n=248)	Cefadroxil (n = 251)	ZYVOX (n = 215)	Vancomycin (n=101)
* Patients 5 through 11 years of age received ZYVOX 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received ZYVOX 600 mg PO q12h or cefadroxil 500 mg PO q12h † Patients from birth through 11 years of age received ZYVOX 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6–24h, depending on age and renal clearance. ‡ These reports were of 'red-man syndrome', which were coded as anaphylaxis.
% of patients with =1 drug-related adverse event	19.2	14.1	18.8	34.3
% of patients discontinuing due to a drug-related adverse event	1.6	2.4	0.9	6.1
Diarrhea	5.7	5.2	3.8	6.1
Nausea	3.3	2.0	1.4	0
Headache	2.4	0.8	0	0
Loose stools	1.2	0.8	1.9	0
Thrombocytopenia	0	0	1.9	0
Vomiting	1.2	2.4	1.9	1.0
Generalized abdominal pain	1.6	1.2	0	0
Localized abdominal pain	1.6	1.2	0	0
Anemia	0	0	1.4	1.0
Eosinophilia	0.4	0.4	1.4	0
Rash	0.4	1.2	1.4	7.1
Vertigo	1.2	0.4	0	0
Oral moniliasis	0	0	0.9	4.0
Fever	0	0	0.5	3.0
Pruritus at non-application site	0.4	0	0	2.0
Anaphylaxis	0	0	0	10.1‡

Laboratory Changes

ZYVOX has been associated with thrombocytopenia when used in doses up to and including 600 mg every 12 hours for up to 28 days. In Phase 3 comparator-controlled trials, the percentage of adult patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 2.4% (range among studies: 0.3 to 10.0%) with ZYVOX and 1.5% (range among studies: 0.4 to 7.0%) with a comparator. In a study of hospitalized pediatric patients ranging in age from birth through 11 years, the percentage of patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 12.9% with ZYVOX and 13.4% with vancomycin. In an outpatient study of pediatric patients aged from 5 through 17 years, the percentage of patients who developed a substantially low platelet count was 0% with ZYVOX and 0.4% with cefadroxil. Thrombocytopenia associated with the use of ZYVOX appears to be dependent on duration of therapy, (generally greater than 2 weeks of treatment). The platelet counts for most patients returned to the normal range/baseline during the follow-up period. No related clinical adverse events were identified in Phase 3 clinical trials in patients developing thrombocytopenia. Bleeding events were identified in thrombocytopenic patients in a compassionate use program for ZYVOX; the role of linezolid in these events cannot be determined (see WARNINGS).

Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differences between ZYVOX and the comparators. These changes were generally not clinically significant, did not lead to discontinuation of therapy, and were reversible. The incidence of adult and pediatric patients with at least one substantially abnormal hematologic or serum chemistry value is presented in Tables 10, 11, 12, and 13.

Table 10. Percent of Adult Patients who Experienced at Least One Substantially Abnormal* Hematology Laboratory Value in Comparator-Controlled Clinical Trials with ZYVOX

Laboratory Assay	Uncomplicated Skin and Skin Structure Infections		All Other Indications
	ZYVOX 400 mg q12h	Clarithromycin 250 mg q12h	ZYVOX 600 mg q12h	All Other Comparators†
* <75% (<50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; <75% (<50% for neutrophils) of LLN and of baseline for values abnormal at baseline. † Comparators included cefpodoxime proxetil 200 mg PO q12h; ceftriaxone 1 g IV q12h; dicloxacillin 500 mg PO q6h; oxacillin 2 g IV q6h; vancomycin 1 g IV q12h.
Hemoglobin (g/dL)	0.9	0.0	7.1	6.6
Platelet count (x 103/mm3)	0.7	0.8	3.0	1.8
WBC (x 103/mm3)	0.2	0.6	2.2	1.3
Neutrophils (x 103/mm3)	0.0	0.2	1.1	1.2

Table 11. Percent of Adult Patients who Experienced at Least One Substantially Abnormal* Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with ZYVOX

Laboratory Assay	Uncomplicated Skin and Skin Structure Infections		All Other Indications
	ZYVOX 400 mg q12h	Clarithromycin 250 mg q12h	ZYVOX 600 mg q12h	All Other Comparators†
* >2 x Upper Limit of Normal (ULN) for values normal at baseline; >2 x ULN and >2 x baseline for values abnormal at baseline. † Comparators included cefpodoxime proxetil 200 mg PO q12h; ceftriaxone 1 g IV q12h; dicloxacillin 500 mg PO q6h; oxacillin 2 g IV q6h; vancomycin 1 g IV q12h.
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

Table 12. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal* Hematology Laboratory Value in Comparator-Controlled Clinical Trials with ZYVOX

Laboratory Assay	Uncomplicated Skin and Skin Structure Infections†		All Other Indications‡
	ZYVOX	Cefadroxil	ZYVOX	Vancomycin
* <75% (<50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; <75% (<50% for neutrophils) of LLN and <75% (<50% for neutrophils, <90% for hemoglobin if baseline <LLN) of baseline for values abnormal at baseline. † Patients 5 through 11 years of age received ZYVOX 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received ZYVOX 600 mg PO q12h or cefadroxil 500 mg PO q12h. ‡ Patients from birth through 11 years of age received ZYVOX 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6–24h, depending on age and renal clearance.
Hemoglobin (g/dL)	0.0	0.0	15.7	12.4
Platelet count (x 103/mm3)	0.0	0.4	12.9	13.4
WBC (x 103/mm3)	0.8	0.8	12.4	10.3
Neutrophils (x 103/mm3)	1.2	0.8	5.9	4.3

Table 13. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal* Ser