Linezolid (Page 4 of 7)


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


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

The empirical formula is C 16 H 20 FN 3 O 4 . Its molecular weight is 337.35, and its chemical structure is represented below:

Structural Formula
(click image for full-size original)

Linezolid tablets for oral administration contain 600 mg linezolid as film-coated tablets. Inactive ingredients are carnauba wax, colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, polacrilin potassium, polyethylene glycol and titanium dioxide.


12.1 Mechanism of Action

Linezolid is an antibacterial drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral doses are summarized in Table 8. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours are shown in Figure 1.

Table 8. Mean (Standard Deviation) Pharmacokinetic Parameters of Linezolid in Adults

AUC for single dose = AUC0 to ∞; for multiple dose = AUC0 to T
Data dose-normalized from 375 mg
Data dose-normalized from 625 mg, intravenous dose was given as 0.5-hour infusion.

Dose of Linezolid

C max mcg/mL

C min mcg/mL

T max hrs

AUC *mcg•h/mL

t 1/2 hrs

CL mL/min

400 mg tablet single dose

8.10 (1.83)

1.52 (1.01)

55.10 (25)

5.20 (1.50)

146 (67)

every 12 hours

11 (4.37)

3.08 (2.25)

1.12 (0.47)

73.40 (33.50)

4.69 (1.70)

110 (49)

600 mg tablet single dose

12.70 (3.96)

1.28 (0.66)

91.40 (39.30)

4.26 (1.65)

127 (48)

every 12 hours

21.20 (5.78)

6.15 (2.94)

1.03 (0.62)

138 (42.10)

5.40 (2.06)

80 (29)

600 mg IV injection single dose

12.90 (1.60)

0.50 (0.10)

80.20 (33.30)

4.40 (2.40)

128 (39)

every 12 hours

15.10 (2.52)

3.68 (2.36)

0.51 (0.03)

89.70 (31)

4.80 (1.70)

123 (40)

600 mg oral suspension single dose

11 (2.76)

0.97 (0.88)

80.80 (35.10)

4.60 (1.71)

141 (45)

C max = Maximum plasma concentration; C min = Minimum plasma concentration; T max = Time to C max ; AUC = Area under concentration-time curve; t 1\2 = Elimination half-life; CL = Systemic clearance

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

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

Linezolid is 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 C max is decreased by about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC 0 to ∞ is similar under both conditions.

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 the ratio of linezolid in sweat relative to plasma was 0.55 to 1.

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 A is presumed to be formed via an enzymatic pathway whereas metabolite B is mediated by a non-enzymatic chemical oxidation mechanism in vitro. In vitro studies have demonstrated that linezolid is minimally metabolized and may be mediated by human cytochrome P450. However, the metabolic pathway of linezolid is not fully understood.

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 mean renal clearance of linezolid is 40 mL/min which 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.

Specific Populations
Geriatric Patients
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 Patients The pharmacokinetics of linezolid following a single intravenous 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 9 for the pediatric populations studied and healthy adult subjects after administration of single intravenous doses.

The C max and the volume of distribution (V ss ) of linezolid are similar regardless of age in pediatric patients. However, plasma clearance of linezolid varies as a function of age. With the exclusion of pre-term neonates less than one week of age, weight-based 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 a shorter half-life as compared with adults. As the age of pediatric patients increases, the weight-based clearance of linezolid gradually decreases, and by adolescence mean clearance values approach those observed for the adult population. There is increased 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 relative to adolescents or adults dosed every 12 hours. Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg every 8 hours. Pediatric patients 12 years and older should receive 600 mg every 12 hours [see Dosage and Administration (2)].

Table 9. 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])

AUC = Single dose AUC0 to ∞
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

Age Group

C max mcg/mL

V ss L/kg

AUC *mcg•h/mL

t ½ hrs

CL mL/min/kg

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 (52%) [0.9, 4]

Full-term § < 1 week (N=10)

11.5 (24%) [8, 18.3]

0.78 (20%) [0.45, 0.96]

55 (47%) [19, 103]

3 (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 (27%) [7.2, 18]

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]

3.8 (53%) [1, 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]

C max = Maximum plasma concentration; V ss = Volume of distribution; AUC = Area under concentration-time curve; t 1/2 = Apparent elimination half-life; CL = Systemic clearance normalized for body weight

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 Impairment The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any degree of renal impairment; however, the two primary metabolites of linezolid accumulate in patients with renal impairment, with the amount of accumulation increasing with the severity of renal dysfunction (see Table 10). The pharmacokinetics of linezolid and its two metabolites have also been studied in patients with end-stage renal disease (ESRD) receiving hemodialysis. In the ESRD study, 14 patients were dosed with linezolid 600 mg every 12 hours for 14.5 days (see Table 11). Because similar plasma concentrations of linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal impairment. However, given the absence of information on the clinical significance of accumulation of the primary metabolites, use of linezolid in patients with renal impairment should be weighed against the potential risks of accumulation of these metabolites. Both linezolid and the two metabolites are eliminated by hemodialysis. 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-hours hemodialysis session beginning 3 hours after the dose of linezolid was administered; therefore, linezolid should be given after hemodialysis.

Table 10. Mean (Standard Deviation) AUCs and Elimination Half-lives of Linezolid and Metabolites A and B in Patients with Varying Degrees of Renal Impairment After a Single 600 mg Oral Dose of Linezolid

Metabolite B is the major metabolite of linezolid.


Healthy Subjects CL CR > 80 mL/min

Moderate Renal Impairment 30 < CL CR < 80 mL/min

Severe Renal Impairment 10 < CL CR < 30 mL/min


AUC 0-∞ , mcg h/mL

110 (22)

128 (53)

127 (66)

t 1/2 , hours

6.4 (2.2)

6.1 (1.7)

7.1 (3.7)


AUC 0-48 , mcg h/mL

7.6 (1.9)

11.7 (4.3)

56.5 (30.6)

t 1/2 , hours

6.3 (2.1)

6.6 (2.3)

9 (4.6)


AUC 0-48 , mcg h/mL

30.5 (6.2)

51.1 (38.5)

203 (92)

t 1/2 , hours

6.6 (2.7)

9.9 (7.4)

11 (3.9)

Table 11. Mean (Standard Deviation) AUCs and Elimination Half-lives of Linezolid and Metabolites A and B in Subjects with End-Stage Renal Disease (ESRD) After the Administration of 600 mg Linezolid Every 12 Hours for 14.5 Days

between hemodialysis sessions
Metabolite B is the major metabolite of linezolid.


ESRD Subjects *


AUC 0-12 , mcg h/mL (after last dose)

181 (52.3)

t 1/2 , h (after last dose)

8.3 (2.4)


AUC 0-12 , mcg h/mL (after last dose)

153 (40.6)

t 1/2 , h (after last dose)

15.9 (8.5)


AUC 0-12 , mcg h/mL (after last dose)

356 (99.7)

t 1/2 , h (after last dose)

34.8 (23.1)

Hepatic Impairment
The pharmacokinetics of linezolid are not altered in patients (n=7) with mild-to-moderate hepatic impairment (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 impairment. The pharmacokinetics of linezolid in patients with severe hepatic impairment have not been evaluated.

Drug Interactions
Drugs Metabolized by Cytochrome P450
Linezolid is not an inducer of cytochrome P450 (CYP450) in rats. In addition, linezolid does not inhibit the activities of clinically significant human CYP isoforms (e.g., 1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, linezolid is not expected to affect the pharmacokinetics of other drugs metabolized by these major enzymes. 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.

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.

The potential for drug-drug interactions with linezolid and the antioxidants Vitamin C and Vitamin E was studied in healthy volunteers. Subjects were administered a 600 mg oral dose of linezolid on Day 1, and another 600 mg dose of linezolid on Day 8. On Days 2 to 9, subjects were given either Vitamin C (1000 mg/day) or Vitamin E (800 IU/ day). The AUC 0 to ∞ of linezolid increased 2.3% when co-administered with Vitamin C and 10.9% when co-administered with Vitamin E. No linezolid dose adjustment is recommended during co-administration with Vitamin C or Vitamin E.

Strong CYP 3A4 Inducers
Rifampin: The effect of rifampin on the pharmacokinetics of linezolid was evaluated in a study of 16 healthy adult males. Volunteers were administered oral linezolid 600 mg twice daily for 5 doses with and without rifampin 600 mg once daily for 8 days. Co-administration of rifampin with linezolid resulted in a 21% decrease in linezolid C max [90% CI, 15% to 27%] and a 32% decrease in linezolid AUC 0 to 12 [90% CI, 27% to 37%]. The clinical significance of this interaction is unknown. The mechanism of this interaction is not fully understood and may be related to the induction of hepatic enzymes. Other strong inducers of hepatic enzymes (e.g. carbamazepine, phenytoin, phenobarbital) could cause a similar or smaller decrease in linezolid exposure.

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 linezolid 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.

Tyramine: 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 Patient Counseling Information (17)].

Pseudoephedrine HCl or phenylpropanolamine HCl: 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 Warnings and Precautions (5.6) and Drug Interactions (7)]. 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 every 12 hours 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 to 52 mm Hg) and 38 mm Hg (range: 18 to 79 mm Hg) during co-administration of linezolid with pseudoephedrine or phenylpropanolamine, respectively.

Serotonergic Agents
Dextromethorphan: 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.

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