Linezolid Injection

Linezolid injection is used to treat infections, including pneumonia, and infections of the skin and blood. Linezolid is in a class of antibacterials called oxazolidinones. It works by stopping the growth of bacteria. Antibiotics will not kill viruses that can cause colds, flu, or other infections.

Before using linezolid injection,

• tell your doctor and pharmacist if you are allergic to linezolid, any other medications, or any of the ingredients in linezolid injection. Ask your pharmacist for a list of the ingredients .
• tell your doctor if you are taking buspirone (Buspar); dobutamine; dopamine; epinephrine (EpiPen, others); medications for migraine such as almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex), and zolmitriptan (Zomig); meperidine (Demerol); norepinephrine; pseudoephedrine (in some common cold or decongestant medications);selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem, Symbyax), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and vilazodone (Vilbyrd); serotonin norepinephrine reuptake inhibitors (SNRIs) such as desvenlafaxine (Pristiq), duloxetine (Cymbalta), and venlafaxine (Effexor); and tricyclic antidepressants such as amitriptyline (Elavil), amoxapine (Asendin), clomipramine (Anafranil), desipramine (Norpramin), doxepin (Adapin, Sinequan), imipramine (Tofranil), nortriptyline (Aventyl, Pamelor), protriptyline (Vivactil), and trimipramine (Surmontil). Also tell your doctor or pharmacist if you are taking the following medications or have stopped taking them within the past two weeks: isocarboxazid (Marplan) phenelzine (Nardil). rasagiline(Azilect), selegiline (Eldepryl), and tranylcypromine (Parnate). Your doctor will probably tell you not to use linezolid injection if you are taking one or more of these medications.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: amphetamine (Adderal, Desoxyn, Vyvanase, in some diet pills or stimulants);carbamazepine; cold remedies or decongestantscontaining phenylpropanolamine; other antibiotics; phenobarbital; phenytoin; and rifampin (Rifadin,Rimactance, in Rifamate in Rifater )Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with linezolid injection, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor if you have carcinoid syndrome (a condition in which a tumor secretes serotonin). Your doctor will probably tell you not to use linezolid injection.
• tell your doctor if you have or have ever had a chronic (long-lasting) infection, high blood pressure, hyperthyroidism (an overactive thyroid), immune suppression (problems with your immune system), pheochromocytoma (a tumor of the adrenal gland), seizures, or kidney disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while using linezolid injection, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are using linezolid injection.

• Zyvox^®

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Some products that may interact with this drug include: apraclonidine, atomoxetine, bethanidine, bupropion, buspirone, carbamazepine, cyclobenzaprine, dextromethorphan, certain antihistamines (azatadine, carbetapentane, chlorpheniramine), herbal products (e.g., ephedra/ma huang, ginseng, tryptophan), indoramin, levodopa, maprotiline, methyldopa, certain narcotic pain relievers (fentanyl, meperidine, methadone, tapentadol), papaverine, drugs for Parkinson's disease (such as entacapone, tolcapone), rifampin, sympathomimetics (e.g., ephedrine, methylphenidate), tetrabenazine, tricyclic antidepressants (such as amitriptyline, doxepin), other drugs which depress the bone marrow (e.g., cancer chemotherapy).Taking other MAO inhibitors with this medication may cause a serious (possibly fatal) drug interaction. Avoid taking other MAO inhibitors (isocarboxazid, methylene blue, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine) during treatment with this medication. Most MAO inhibitors should also not be taken for two weeks before and after treatment with this medication. Ask your doctor when to start or stop taking this medication.The risk of serotonin syndrome/toxicity increases if you are also taking other drugs that increase serotonin. Examples include street drugs such as MDMA/"ecstasy," St. John's wort, certain antidepressants (including mirtazapine, trazodone, SSRIs such as fluoxetine/paroxetine, SNRIs such as duloxetine/venlafaxine), tramadol, "triptans" used to treat migraine headaches (such as eletriptan, sumatriptan), tryptophan, among others. The risk of serotonin syndrome/toxicity may be more likely when you start or increase the dose of these drugs.Check the labels on all your medicines (e.g., cough-and-cold products, diet aids) because they may contain ingredients that could increase your heart rate or blood pressure. Avoid these products while using this medication. Ask your pharmacist for additional information.Limit your tyramine intake while using this medication and for 2 days after stopping treatment. Also avoid foods or drinks with high tyramine content during use because the combination may cause a serious rise in your blood pressure.Foods high in tyramine include those that may change as a result of aging, fermentation, pickling, or smoking. The tyramine content of any protein-rich food (meats, fish and dairy products) may increase if stored for long periods or improperly refrigerated. Some foods high in tyramine include aged cheeses (0 to 15 milligrams per ounce); fermented or air-dried meats (0.1 to 8 milligrams per ounce); sauerkraut (8 milligrams per 8 ounces); soy sauce (5 milligrams per 1 teaspoon); tap beers (4 milligrams per 12 ounces); red wines (0 to 6 milligrams per 8 ounces). Total intake of tyramine should be less than 100 milligrams per meal.Tell your doctor or pharmacist immediately if you notice symptoms of high blood pressure such as fast or pounding heartbeat, vomiting, sweating or headache, chest pain, sudden vision changes, weakness on one side of the body or slurred speech.Contact your healthcare professional (e.g., doctor, pharmacist or dietician) for more information, including recommendations for your diet.Although most antibiotics probably do not affect hormonal birth control such as pills, patch, or ring, some antibiotics may decrease their effectiveness. This could cause pregnancy. Examples include rifamycins such as rifampin or rifabutin. Be sure to ask your doctor or pharmacist if you should use additional reliable birth control methods while using this antibiotic.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Upset stomach or throwing up.
• Loose stools (diarrhea).

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• If you need to store linezolid injection at home, talk with your doctor, nurse, or pharmacist about how to store it.

General Dosage and Administration

The recommended dosage for linezolid formulations for the treatment of infections is described in Table 1.

Table 1. Dosage Guidelines for Linezolid Injection

* Due to the designated pathogens [see Indications and Usage (1)] † Neonates less than 7 days: Most pre-term neonates less than 7 days of age (gestational age less than 34 weeks) have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. These neonates should be initiated with a dosing regimen of 10 mg/kg every 12 hours. Consideration may be given to the use of 10 mg/kg every 8 hours regimen in neonates with a suboptimal clinical response. All neonatal patients should receive 10 mg/kg every 8 hours by 7 days of life [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].
Infection*	Dosage and Route of Administration		Recommended Duration of Treatment (consecutive days)
	Pediatric Patients† (Birth through 11 Years of Age)	Adults and Adolescents (12 Years and Older)
Nosocomial pneumonia	10 mg/kg intravenously every 8 hours	600 mg intravenously every 12 hours	10 to 14
Community-acquired pneumonia, including concurrent bacteremia
Complicated skin and skin structure infections
Vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia	10 mg/kg intravenously every 8 hours	600 mg intravenously every 12 hours	14 to 28

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

Intravenous Administration

Linezolid Injection is supplied in single-use, ready-to-use container (VisIV™ Container). Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired. Keep the containers in the overwrap until ready to use. Store at room temperature. Protect from freezing. Linezolid Injection may exhibit a yellow color that can intensify over time without adversely affecting potency.

Linezolid Injection should be administered by intravenous infusion over a period of 30 to 120 minutes. Do not use this intravenous container in series connections. Additives should not be introduced into this solution. If Linezolid Injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product.

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

Compatibilities

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

Incompatibilities

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

Clinical Trials Experience

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

Adults

The safety of linezolid formulations was evaluated in 2046 adult patients enrolled in seven Phase 3 comparator-controlled clinical trials, who were treated for up to 28 days.

For all indications, 20.4% of linezolid-treated and 14.3% of comparator-treated patients experienced at least one drug-related adverse event.

Table 2 shows the incidence of all-causality, treatment-emergent adverse reactions reported in at least 1% of adult patients in these trials by dose of linezolid.

Table 2. Incidence (%) of Treatment-Emergent Adverse Reactions Occurring in > 1% of Adult Patients Treated with Linezolid in Comparator-Controlled Clinical Trials

* Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours.
	Linezolid 600 mg every 12 hours (n = 1498)	All Other Comparators* (n = 1464)
Headache	5.7	4.4
Diarrhea	8.3	6.4
Nausea	6.6	4.6
Vomiting	4.3	2.3
Dizziness	1.8	1.5
Rash	2.3	2.6
Anemia	2.1	1.4
Taste alteration	1.0	0.3
Vaginal moniliasis	1.1	0.5
Oral moniliasis	1.7	1.0
Abnormal liver function tests	1.6	0.8
Fungal infection	0.3	0.2
Tongue discoloration	0.3	0
Localized abdominal pain	1.2	0.8
Generalized abdominal pain	1.2	1.0

Discontinuations due to drug-related adverse events occurred in 2.1% of linezolid-treated and 1.7% of comparator-treated patients. The most common reported drug-related adverse events leading to discontinuation of treatment were nausea, headache, diarrhea, and vomiting.

Pediatric Patients

The safety of linezolid 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 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.

For all indications, 18.8% of linezolid-treated and 34.3% of comparator-treated patients experienced at least one drug-related adverse event.

Table 3 shows the incidence of all-causality, treatment-emergent adverse reactions 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 3. Incidence (%) of Treatment-Emergent Adverse Reactions Occurring in > 1% of Pediatric Patients (and greater than 1 Patient) in Either Treatment Group in Comparator-Controlled Clinical Trials

	Linezolid (n = 215)	Vancomycin (n = 101)
Diarrhea	10.8	12.1
Vomiting	9.4	9.1
Headache	0.9	0
Anemia	5.6	7.1
Thrombocytopenia	4.7	2.0
Nausea	1.9	0
Generalized abdominal pain	0.9	2.0
Localized abdominal pain	0.5	1.0
Loose stools	2.3	3.0
Eosinophilia	1.9	1.0
Pruritus at non-application site	1.4	2.0
Vertigo	0	0

Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously and/or by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6-24 hours, depending on age and renal clearance.

For all indications, discontinuations due to drug-related adverse events occurred in 0.9% of linezolid-treated and 6.1% of comparator-treated patients.

Laboratory Abnormalities

Linezolid 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 linezolid 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 linezolid 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 linezolid and 0.4% with cefadroxil. Thrombocytopenia associated with the use of linezolid 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 linezolid; the role of linezolid in these events cannot be determined [see Warnings and Precautions (5.1)].

Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differences between linezolid 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 4, 5, 6, and 7.

Table 4. Percent of Adult Patients who Experienced at Least One Substantially Abnormal* Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid

* < 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 by mouth every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours.
Laboratory Assay	Linezolid 600 mg every 12 hours	All Other Comparators†
Hemoglobin (g/dL)	7.1	6.6
Platelet count (x 103/mm3)	3.0	1.8
WBC (x 103/mm3)	2.2	1.3
Neutrophils (x 103/mm3)	1.1	1.2

Table 5. Percent of Adult Patients who Experienced at Least One Substantially Abnormal* Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid

* > 2× Upper Limit of Normal (ULN) for values normal at baseline; > 2× ULN and > 2× baseline for values abnormal at baseline. † Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours.
Laboratory Assay	Linezolid 600 mg every 12 hours	All Other Comparators†
AST (U/L)	5.0	6.8
ALT (U/L)	9.6	9.3
LDH (U/L)	1.8	1.5
Alkaline phosphatase (U/L)	3.5	3.1
Lipase (U/L)	4.3	4.2
Amylase (U/L)	2.4	2.0
Total bilirubin (mg/dL)	0.9	1.1
BUN (mg/dL)	2.1	1.5
Creatinine (mg/dL)	0.2	0.6

Table 6. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal* Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid†

* <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 from birth through 11 years of age received linezolid 10 mg/kg intravenously and/or by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6-24 hours, depending on age and renal clearance.
Laboratory Assay	Linezolid	Vancomycin
Hemoglobin (g/dL)	15.7	12.4
Platelet count (x 103/mm3)	12.9	13.4
WBC (x 103/mm3)	12.4	10.3
Neutrophils (x 103/mm3)	5.9	4.3

Table 7. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal* Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid†

* > 2 x Upper Limit of Normal (ULN) for values normal at baseline; > 2× ULN and > 2 (> 1.5 for total bilirubin) × baseline for values abnormal at baseline. † Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6-24 hours, depending on age and renal clearance.
Laboratory Assay	Linezolid	Vancomycin
ALT (U/L)	10.1	12.5
Amylase (U/L)	0.6	1.3
Total bilirubin (mg/dL)	6.3	5.2
Creatinine (mg/dL)	2.4	1.0

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of linezolid. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported during postmarketing use of linezolid [see Warnings and Precautions (5.1)]. Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision, have been reported in patients treated with linezolid [see Warnings and Precautions (5.2)]. Lactic acidosis has been reported with the use of linezolid [see Warnings and Precautions (5.7)]. Although these reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days, these events have also been reported in patients receiving shorter courses of therapy. Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and linezolid [see Warnings and Precautions (5.3)]. Convulsions have been reported with the use of linezolid [see Warnings and Precautions (5.8)]. Anaphylaxis, angioedema, and bullous skin disorders such as those described as Stevens-Johnson syndrome have been reported. Superficial tooth discoloration and tongue discoloration have been reported with the use of linezolid. The tooth discoloration was removable with professional dental cleaning (manual descaling) in cases with known outcome. Hypoglycemia, including symptomatic episodes, has been reported [see Warnings and Precautions (5.9)].

Mechanism of Action

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

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.

Pharmacokinetics

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

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

*   AUC for single dose = AUC0-∞; for multiple dose = AUC0-τ †   Data dose-normalized from 375 mg ‡   Data dose-normalized from 625 mg, intravenous dose was given as 0.5-hour infusion. 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
Dose of Linezolid	Cmax mcg/mL	Cmin mcg/mL	Tmax hrs	AUC* mcg•h/mL	t1/2 hrs	CL mL/min
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)

Absorption

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 Cmax is decreased by about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC0-∞ 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 the ratio of linezolid in 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 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.

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 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 Cmax and the volume of distribution (Vss) 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-∞ **   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) *** In this data set, “full-term” is defined as ≥ 34 weeks gestational age †     Dose of 10 mg/kg ‡     Dose of 600 mg or 10 mg/kg up to a maximum of 600 mg §     Dose normalized to 600 mg 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
Age Group	Cmax mcg/mL	Vss L/kg	AUC* mcg•h/mL	t1/2 Hrs	CL mL/min/kg
Neonatal Patients
Pre-term**    <1 week (N = 9)†    Full-term***    <1 week (N = 10)†    Full-term***    ≥1 week to ≤28 days (N = 10)†	12.7 (30%) [9.6, 22.2] 11.5 (24%) [8.0, 18.3] 12.9 (28%) [7.7, 21.6]	0.81 (24%) [0.43, 1.05] 0.78 (20%) [0.45, 0.96] 0.66 (29%) [0.35, 1.06]	108 (47%) [41, 191] 55 (47%) [19, 103] 34 (21%) [23, 50]	5.6 (46%) [2.4, 9.8] 3.0 (55%) [1.3, 6.1] 1.5 (17%) [1.2, 1.9]	2.0 (52%) [0.9, 4.0] 3.8 (55%) [1.5, 8.8] 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 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-hour 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

1    Metabolite B is the major metabolite 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
LINEZOLID
AUC0-∞, mcg h/mL	110 (22)	128 (53)	127 (66)
t1/2, hours	6.4 (2.2)	6.1 (1.7)	7.1 (3.7)
METABOLITE A
AUC0-48, mcg h/mL	7.6 (1.9)	11.7 (4.3)	56.5 (30.6)
t1/2, hours	6.3 (2.1)	6.6 (2.3)	9.0 (4.6)
METABOLITE B1
AUC0-48, mcg h/mL	30.5 (6.2)	51.1 (38.5)	203 (92)
t1/2, hours	6.6 (2.7)	9.9 (7.4)	11.0 (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

1    between hemodialysis sessions 2    Metabolite B is the major metabolite of linezolid.
Parameter	ESRD Subjects1
LINEZOLID
AUC0-12, mcg h/mL (after last dose)	181 (52.3)
t1/2, h (after last dose)	8.3 (2.4)
METABOLITE A
AUC0-12, mcg h/mL (after last dose)	153 (40.6)
t1/2, h (after last dose)	15.9 (8.5)
METABOLITE B2
AUC0-12, mcg h/mL (after last dose)	356 (99.7)
t1/2, 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.

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.

Antioxidants

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 2-9, subjects were given either Vitamin C (1000 mg/day) or Vitamin E (800 IU/ day). The AUC0-∞ 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 Cmax [90% CI, 15% - 27%] and a 32% decrease in linezolid AUC0-12 [90% CI, 27% - 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: 20-52 mm Hg) and 38 mm Hg (range: 18-79 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.

Microbiology

Mechanism of Action

Linezolid is a synthetic antibacterial agent of the oxazolidinone class, 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 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 essential for bacterial reproduction. 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 isolates.

Mechanisms of Resistance

In vitro studies have shown that point mutations in the 23S rRNA are associated with linezolid resistance. Reports of vancomycin-resistant Enterococcus faecium becoming resistant to linezolid during its clinical use have been published. There are reports of Staphylococcus aureus (methicillin-resistant) developing resistance to linezolid during clinical use. The linezolid resistance in these organisms is associated with a point mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism. Organisms resistant to oxazolidinones via mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins (L3 and L4) are generally cross-resistant to linezolid. Also linezolid resistance in staphylococci mediated by the enzyme methyltransferase has been reported. This resistance is mediated by the cfr (chloramphenicol-florfenicol) gene located on a plasmid which is transferable between staphylococci.

Interaction with Other Antimicrobial Drugs

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. [See Indications and Usage (1)].

Gram-positive bacteria
Enterococcus faecium (vancomycin-resistant isolates only)
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes

Greater than 90% of the following bacteria exhibit an in vitro MIC less than or equal to the linezolid-susceptible breakpoint for organisms of similar genus shown in Table 12. The safety and effectiveness of linezolid in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria
Enterococcus faecalis (including vancomycin-resistant isolates)
Enterococcus faecium (vancomycin-susceptible isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Staphylococcus haemolyticus
Viridans group streptococci

Gram-negative bacteria
Pasteurella multocida

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

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 method1,2 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 12.

Diffusion techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method2,3. This procedure uses paper disks impregnated with 30 mcg linezolid to test the susceptibility of bacteria to linezolid. The disk diffusion interpretive criteria are provided in Table 12.

Table 12. Susceptibility Test Interpretive Criteria for Linezolid

S=susceptible, I=intermediate, R=resistant a    For disk diffusion testing of staphylococcal species, petri plates should be held up to the light source and read with transmitted light. The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth. Any discernible growth within the zone of inhibition is indicative of resistance. Resistant results obtained by the disk diffusion method should be confirmed using an MIC method. b    The current absence of data on resistant isolates precludes defining any categories other than “Susceptible.” Isolates 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.
Pathogen	Susceptibility Interpretive Criteria
	Minimal Inhibitory Concentrations (MIC in mcg/mL)			Disk Diffusion (Zone Diameters in mm)
	S	I	R	S	I	R
Enterococcus spp.	≤2	4	≥8	≥23	21-22	≤20
Staphylococcus spp.a	≤4	---	≥8	≥21	---	≤20
Streptococcus pneumoniaeb	≤2	---	---	≥21	---	---
Streptococcus spp. other than S. pneumoniaeb	≤2	---	---	≥21	---	---

A report of “Susceptible” indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the bacteria 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 product is physiologically concentrated or in situations where a high dosage of the drug product can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test1,2,3. Standard linezolid powder should provide the following range of MIC values noted in Table 13. For the diffusion technique using the 30 mcg linezolid disk, the criteria in Table 13 should be achieved.

Table 13. Acceptable Quality Control Ranges for Linezolid

a    This organism may be used for validation of susceptibility test results when testing Streptococcus spp. other than S. pneumoniae.
	Minimum Inhibitory Ranges (MIC in mcg/mL)	Disk Diffusion Ranges Zone Diameters (mm)
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 49619a	0.25-2	25-34

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015 2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement, CLSI document M100-S25 Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015 3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.