Linezolid (Systemic)


VA CLASSIFICATION
Primary: AM900

Commonly used brand name(s): Zyvox™.

Another commonly used name is:
U-100766 PNU-10076 Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antibacterial (systemic) —

Indications

General considerations
Time-kill studies demonstrated that linezolid is bacteriostatic against enterococci and staphylococci and bactericidal against the majority of strains of streptococci.{01}

Linezolid is a synthetic antibacterial agent.{01} Linezolid belongs to a new antibiotic class called the oxazolidinones.{01}

The mode of action of linezolid is different from that of other classes of antibacterials.{01}

During clinical trials, resistance to linezolid developed in 6 patients with an infection caused by Enterococcus faecium.{01} During compassionate use of linezolid, resistance developed in 8 patients infected with Enterococcus faecium and one patient infected with Enterococcus faecalis.{01} Resistance may have developed due to use of a lower than recommended dose of linezolid, a retained prosthetic device, or an undrained abscess.{01}


Accepted

Pneumonia, community-acquired (treatment)—Intravenous and oral linezolid is indicated in the treatment of community acquired pneumonia caused by penicillin-susceptible strains of Streptococcus pneumoniae or methicillin-susceptible strains of Staphylococcus aureus.{01}

Pneumonia, nosocomial (treatment)—Intravenous and oral linezolid is indicated in the treatment of nosocomial pneumonia caused by methicillin-susceptible and methicillin-resistant Staphylococcus aureus or penicillin-susceptible strains of Streptococcus pneumoniae. {01}

Skin and soft tissue infections, complicated (treatment)—Intravenous and oral linezolid is indicated in the treatment of complicated skin and soft tissue infections caused by Staphylococcus aureus (methicillin-susceptible and methicillin-resistant), Streptococcus pyogenes, or Streptococcus agalactiae .{01} Patients with diabetic foot ulcers and decubitus ulcers were not included in the clinical trials. {01}

Skin and soft tissue infections, uncomplicated (treatment)—Oral linezolid is indicated in the treatment of uncomplicated skin and soft tissue infections caused by methicillin-susceptible strains of Staphylococcus aureus or Streptococcus pyogenes.{01}

Vancomycin-resistant Enterococcus faecium infections—Intravenous and oral linezolid is indicated in the treatment of vancomycin-resistant Enterococcus faecium infections. {01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Linezolid is a synthetic antibacterial agent.{01}

Chemical group—
    Oxazolidinone{01}
Molecular weight—
    337.35{01}

Mechanism of action/Effect:

The mechanism of action for linezolid is different than that of other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely.{01} Linezolid acts via inhibition of protein synthesis. {01} It binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex. {01} This step is essential for the bacterial translation process. {01}

Absorption:

Well absorbed after oral administration; absolute bioavailability approximately 100%. {01}

Distribution:

Distributed to well-perfused tissues; volume of distribution slightly lower in women than men. {01}

Vol D(steady state)—40 to 50 L. {01}

Protein binding:

Low {01}

Biotransformation:

Linezolid is primarily metabolized via oxidation of the morpholine ring. {01} Two inactive metabolites are formed: the aminoethoxyacetic acid metabolite and the hydroxyethyl glycine metabolite. {01}The hydroxyethyl glycine metabolite is formed via a non-enzymatic chemical oxidation mechanism in vitro. {01}

In vitro studies have not shown that linezolid is metabolized by human cytochrome P450 enzymes{01} Linezolid does not inhibit the cytochrome P450 enzymes.{01}


Elimination–

400 mg tablet every 12 hours-4.69 hours{01}

600 mg tablet every 12 hours-5.4 hours{01}

600 mg oral suspension (single dose)-4.6 hours{01}

600 mg intravenous injection every 12 hours-4.8 hours {01}

Peak serum concentration:

After administration of the 600 mg tablet and injection every 12 hours, the peak concentration was 21.2 mcg/mL and 15.1 mcg/mL, respectively. {01}

After a single dose of the oral suspension, the peak concentration was 11 mcg/mL. {01}

Elimination:
    Nonrenal clearance is responsible for about 65% of the total clearance of linezolid under steady-state conditions. {01} At steady-state, about 30%, 40%, and 10% of the dose appear in the urine as linezolid, metabolite B, and metabolite A, respectively. {01} The renal clearance of linezolid is low which suggests net tubular reabsorption. {01}
    Almost no parent drug appears in the feces; however, about 6% and 3% of metabolite B and metabolite A appear in the feces. {01}
    With increasing doses, a small degree of nonlinearity in clearance was observed with increasing doses of linezolid; however, the difference in clearance was small and did not affect the elimination half-life. {01}


Precautions to Consider

Carcinogenicity/Tumorigenicity/Mutagenicity

Although lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of linezolid, no mutagenic or clastogenic potential was found in a battery of tests, including the Ames and AS52 assays, an in vitrounscheduled DNA synthesis (UDS) assay, an in vitro chromosome aberration assay in human lymphocytes, and anin vivo mouse micronucleus assay. {01}

Pregnancy/Reproduction
Fertility—
Linezolid did not affect the fertility or reproductive performance of adult female rats. {01} It reversibly decreased fertility and reproductive performance in adult male rats when given at doses ³ 50 mg/kg/day, with exposures approximately equal to or greater than the expected human exposure level (exposure comparisons are based on AUCs). {01} Epithelial cell hypertrophy in the epididymis may have contributed to the decreased fertility by affecting sperm maturation. {01} Similar epididymal changes were not seen in dogs. {01} Although the concentrations of sperm in the testes were in the normal range, the concentrations in the cauda epididymis were decreased, and sperm from the vas deferens had decreased motility. {01}

Mildly decreased fertility occurred in juvenile male rats treated 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 ranging from 0.4–fold to 1.2–fold that expected in humans based on AUCs). {01}No histopathological evidence of adverse effects was observed in the male reproductive tract. {01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done. {01}

Linezolid was not teratogenic in mice or rats at exposure levels 4–fold (in mice) or equivalent to (in rats) the expected human exposure level, based on AUCs. {01}

In mice, embryo and fetal toxicities were seen only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). {01} A dose of 450 mg/kg/day (4–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. {01}

In rats, mild fetal toxicity was observed at 15 and 50 mg/kg/day (exposure levels 0.13– to 0.64–fold 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 body weights. Slight maternal toxicity, in the form of reduced body weight gain, was seen at 50 mg/kg/day. {01}

When female rats were treated with 50 mg/kg/day (.64–fold the estimated human exposure based on AUCs) of linezolid during pregnancy and lactation, survival of pups was decreased on postnatal days 1 to 4. Pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss, with a corresponding decrease in fertility. {01}

FDA Pregnancy Category C. {01}

Breast-feeding

It is not known whether linezolid is distributed into human breast milk. {01}

Linezolid and its metabolites are excreted in the milk of lactating rats. {01} Concentrations of linezolid were similar in milk and maternal plasma of rats. {01}

Pediatrics

Appropriate efficacy studies on the relationship of age to the effects of linezolid have not been performed in the pediatric population. {01} In this population, linezolid clearance is increased resulting in a shorter half-life. {01} A pediatric dosing regimen that provides comparable pharmacokinetic parameters to the adult regimen has not been determined. {01}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of linezolid in the elderly. {01}


Pharmacogenetics

The volume of distribution and mean oral clearance are lower in females than males; however, the mean apparent elimination-rate constant and half-life are not significantly different between genders. {01} Drug exposure in females is not expected to increase beyond levels known to be well tolerated. {01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Aztreonam or
Gentamicin    (the pharmacokinetics of linezolid and these antibiotics were not altered {01})


» Bone marrow depressants, other{02} (see Appendix II)    (leukopenic and/or thrombocytopenic effects of these medications may be increased;{02} weekly monitoring of the complete blood count is recommended during concurrent therapy{02})


Dextromethorphan or    (serotonin syndrome did not occur with concurrent administration; other serotonin re-uptake inhibitors were not studied{01})


Dopamine or
Epinephrine    (initial dose should be reduced and titrated to achieve the desired response {01})


» Pseudoephedrine    (systolic blood pressure increased by 32 mm Hg after administration of linezolid with pseudoephedrine {01})


Phenytoin or
Warfarin    (drugs metabolized by CYP2C9 may be administered with linezolid without dosage adjustment because linezolid does not affect cytochrome P450 enzymes{01})


» Serotonergics{02} (see Appendix II)     (concurrent use may result in development of signs and symptoms of serotonin syndrome such as cognitive dysfunction or hyperpyrexia;{02} caution is recommended{02})


» Tyramine-containing foods and beverages, such as aged cheese (0 to 15 mg of tyramine per ounce); fermented, pickled, or air-dried meats (0 to 15 mg of tyramine per ounce); red wine (0 to 6 mg of tyramine per 8 ounces); sauerkraut (8 mg of tyramine per 8 ounces); soy sauce (5 mg of tyramine per 1 teaspoon); and tap beer (4 mg of tyramine per 12 ounces){02}    (concurrent use of linezolid with 100 mg or more of tyramine per meal may cause a significant pressor response{02})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Hemoglobin and
Neutrophils and
Platelet count and
White blood count    (values may be decreased during therapy {01})

    (in comparator-controlled phase 3 trials, 2.4% [range 0.3 to 10%] of patients taking linezolid developed substantially low platelet counts [defined as less than 75% of the lower limit of normal and/or baseline] compared with 1.5% [range 0.4 to 7%] of patients taking a comparator medication{02})


Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Amylase and
Aspartate aminotransferase (AST [SGOT] and
Bilirubin, total and
Blood urea nitrogen and
Creatinine and
Lactate dehydrogenase (LDH) and
Lipase     (values may be transiently increased during therapy {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression{02}
» Hypersensitivity to linezolid
» Phenylketonuria    (each 5 mL of the oral suspension contains 20 mg of phenylalanine {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Complete blood count    (weekly monitoring is recommended, especially in patients who receive linezolid for more than 2 weeks, patients who have pre-existing bone marrow depression, patients who concurrently receive medications that produce bone marrow depression, or patients who have a chronic infection and received previous or receive concurrent antibiotic therapy{02})


» Culture and sensitivity test


Side/Adverse Effects

Note: The safety of linezolid was evaluated in 2046 patients enrolled in seven phase 3 comparator-controlled clinical trials.{01} In these studies, 85% of the adverse effects were mild-to-moderate in intensity.{01} During comparator-controlled clinical trials, 2.1% and 3.5% of patients treated with oral linezolid 600 mg and 400 mg every 12 hours, respectively, discontinued therapy.{01}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Diarrhea {01}

Incidence less frequent or rare
    
Anemia {02}(unusual tiredness or weakness)
    
leukopenia {02}(chills; cough; fever; hoarseness; lower back or side pain; painful or difficult urination)
    
oral moniliasis {01} (sore mouth or tongue; white patches in mouth, tongue, or throat)
    
pancytopenia {02}(exertional dyspnea; headache; unusual tiredness or weakness)
    
pseudomembranous colitis {02}(abdominal cramps or pain, severe; diarrhea, severe and watery, may also be bloody; fever)
    
thrombocytopenia {01}(black, tarry stools; blood in urine or stools; pinpoint red spots on skin; unusual bleeding or bruising)
    
vaginal moniliasis {01}(discharge from the vagina ; itching of the vagina)

Note: Mild cases of pseudomembranous colitis usually respond to discontinuation of the medication alone.{02} Moderate to severe cases usually necessitate treatment with fluids and electrolytes, protein supplementation, and an antibacterial agent with activity against Clostridium difficile.{02}
Linezolid-associated thrombocytopenia appears to be dependent on duration of therapy (generally greater than 2 weeks of treatment).{02} For most patients, the platelet count returned to normal or baseline during the follow-up period. {02} No clinical adverse events were identified in clinical trials.{02} In the compassionate use program, bleeding events were identified in patients with thrombocytopenia; however, the role of linezolid in these events cannot be determined.{02}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Nausea {01}

Incidence less frequent or rare
    
Dizziness {02}
    
dysgeusia (bad taste in the mouth; change in sense of taste; loss of taste)
    
headache {02}
    
tongue discoloration {02}
    
vomiting {02}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Treatment of overdose
There is no known specific antidote to linezolid. {01}Treatment is generally supportive. {01} In a phase 1 clinical trial, approximately 30% of a linezolid dose was removed during a 3–hour hemodialysis session. {01} Hemodialysis was initiated 3 hours after the dose of linezolid. {01} Hemodialysis may facilitate removal of linezolid. {01}No information is available for removal of linezolid with peritoneal dialysis or hemoperfusion. {01}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Linezolid (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to linezolid
Other medications, especially other bone marrow depressants, pseudoephedrine, serotonergics, or tyramine-containing foods or beverages
Other medical problems, especially phenylketonuria

Proper use of this medication
» Importance of receiving medication for full course of therapy and on regular schedule

» Proper administration technique for oral liquid

» Proper dosing
Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses

Proper storage

Precautions while using this medication
» If your symptoms do not improve within a few days or if they become worse, check with your doctor

Caution if bone marrow depression occurs:
» Avoiding exposure to persons with bacterial infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back of side pain, or painful or difficult urination occur

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur
» Avoiding large amounts of tyramine-containing foods and beverages


Side/adverse effects
Signs of potential side effects, especially diarrhea, anemia, leukopenia, oral moniliasis, pancytopenia, pseudomembranous colitis, thrombocytopenia, and vaginal moniliasis


For oral dosing forms:

Diet/Nutrition
Linezolid tablets and suspension may be taken with or without food. {01}

Bioequivalence information
Dosage adjustment is not necessary when switching patients from intravenous to oral linezolid because the oral bioavailability is approximately 100%. {01}

For parenteral dosing forms:
Linezolid injection should be administered as an intravenous infusion over 30 to 120 minutes. {01}

Linezolid intravenous infusion bag should not be used in a series connection. {01}

Additives should not be made to the linezolid infusion bag. {01}

If linezolid injection is given concomitantly with another drug, each drug should be administered separately according to the administration guidelines for each drug.{01}

If the same intravenous line is used for administration of several drugs, the line should be flushed before and after administration of linezolid injection. {01}


Oral Dosage Forms

LINEZOLID TABLETS

Usual Adult Dose
Pneumonia, community-acquired (treatment)
Oral, 600 mg every 12 hours for 10 to 14 days.{01}

Pneumonia, nosocomial (treatment)
Oral, 600 mg every 12 hours for 10 to 14 days.{01}

Skin and soft tissue infections, complicated (treatment)
Oral, 600 mg every 12 hours for 10 to 14 days.{01}

Skin and soft tissue infections, uncomplicated (treatment)
Oral, 400 mg every 12 hours for 10 to 14 days.{01}

Vancomycin-resistant Enterococcus faecium infections
Oral, 600 mg every 12 hours for 14 to 28 days.{01}


Usual adult prescribing limits
Up to 1200 mg daily. {01}

Usual Pediatric Dose
Dosage in patients up to 18 years of age has not been established. {01}

Usual Geriatric Dose
See Usual adult dose.

Usual geriatric prescribing limits
SeeUsual adult prescribing limits.

Note: Dosage adjustment is not necessary for patients with renal insufficiency. Since the the metabolites may accumulate in patients with renal insufficiency, the potential risks should be weighed carefully in this patient population. {01}
Dosage adjustment is not necessary for patients with mild-to-moderate hepatic insufficiency; however, data are not available for patients with severe hepatic insufficiency. {01}


Note: The sodium content is 0.1 mEq per tablet regardless of strength. {01}


Strength(s) usually available
U.S.—


400 mg (Rx) [Zyvox™ ( corn starch) (microcrystalline cellulose) (hydroxypropyl methylcellulose) (sodium starch glycolate) (polyethylene glycol) (titanium dioxide) (carnauba wax)]


600 mg (Rx) [Zyvox™ (corn starch) (microcrystalline cellulose) (hydroxypropyl methylcellulose) (sodium starch glycolate) (polyethylene glycol) (titanium dioxide ) (carnauba wax)]

Packaging and storage:
Store at 25 °C (77 °F); excursions permitted to 15 to 30 °C (59 and 77 °F). Store in a tight, light-resistant container. {01}

Auxiliary labeling:
   • Continue medication for full course of treatment.


LINEZOLID FOR ORAL SUSPENSION

Usual Adult Dose
SeeLinezolid Tablets.

Usual adult prescribing limits
See Linezolid Tablets

Usual Pediatric Dose
SeeLinezolid Tablets

Usual Geriatric Dose
See Linezolid Tablets.

Usual geriatric prescribing limits
See Linezolid Tablets.

Note: The sodium content is 0.4 mEq per 5 mL. {01}


Strength(s) usually available
U.S.—


100 mg of linezolid per 5 mL (when reconstituted according to manufacturer's instructions) (Rx) [Zyvox™ ( sucrose) (citric acid) ( sodium citrate) (microcrystalline cellulose) (carboxymethylcellulose sodium) (aspartame ) (xanthan gum) (mannitol ) (sodium benzoate) ( colloidal silicon dioxide) (sodium chloride) (flavors)]

Packaging and storage:
Store at 25 °C (77 °F); excursions permitted to 15 to 30 °C (59 and 77 °F). Store in a tight, light-resistant container. {01}

Preparation of dosage form:
To prepare the oral suspension, add 123 mL of distilled water in two portions. After adding the first half, shake vigorously. Then add the second portion and shake vigorously to obtain a uniform suspension. {01}

Stability:
Suspension retains its potency for 21 days from date of reconstitution when stored at room temperature. {01}

Auxiliary labeling:
   • Continue medication for full course of treatment.
   • Do not shake.
   • Beyond-use date.



Parenteral Dosage Forms

LINEZOLID INJECTION

Usual Adult Dose
Pneumonia, community-acquired (treatment)
Intravenous, 600 mg every 12 hours for 10 to 14 days.{01}

Pneumonia, nosocomial (treatment)
Intravenous, 600 mg every 12 hours for 10 to 14 days.{01}

Skin and soft tissue infections, complicated (treatment)
Intravenous, 600 mg every 12 hours for 10 to 14 days.{01}

Vancomycin-resistant Enterococcus faecium infections
Intravenous, 600 mg every 12 hours for 14 to 28 days.{01}


Usual adult prescribing limits
Up to 1200 mg daily. {01}

Usual Pediatric Dose
Dosage in patients up to 18 years of age has not been established. {01}

Usual Geriatric Dose
See Usual adult dose.

Usual geriatric prescribing limits
SeeUsual adult prescribing limits.

Note: Dosage adjustment is not necessary for patients with renal insufficiency. Since the the metabolites may accumulate in patients with renal insufficiency, the potential risks should be weighed carefully in this patient population. {01}
Dosage adjustment is not necessary for patients with mild-to-moderate hepatic insufficiency; however, data are not available for patients with severe hepatic insufficiency. {01}


Note: The sodium content is 5 mEq, 3.3 mEq, and 1.7 mEq for the 300-mL bag, 200-mL bag, and the 100-mL bag, respectively. {01}


Strength(s) usually available
U.S.—


200 mg of linezolid per 100 mL (Rx) [Zyvox™ (sodium citrate) (citric acid) (dextrose)]


400 mg of linezolid per 200 mL (Rx) [Zyvox™ ( sodium citrate) (citric acid) ( dextrose)]


600 mg of linezolid per 300 mL (Rx) [Zyvox™ ( sodium citrate) (citric acid) ( dextrose)]

Packaging and storage:
Store at 25 °C (77 °F); excursions permitted to 15 to 30 °C (59 and 77 °F). Protect from freezing. Store infusion bags in the overwrap until ready to use. {01}

Incompatibilities:
When administered via simulated Y-site injection, linezolid was incompatible with amphotericin B, ceftriaxone sodium, chlorpromazine HCl, diazepam, erythromycin lactobionate, pentamidine isothionate, phenytoin sodium, and trimethoprim-sulfamethoxazole. If other drugs are administered via the same intravenous line, the line should be flushed before and after administering linezolid. {01}



Developed: 08/17/2000
Revised: 05/02/2001



References
  1. Product Information: Zyvox(TM), linezolid. Pharmacia & Upjohn Company, Kalamazoo, Michigan, (PI revised 04/2000) reviewed 7/2000.
  1. Product Information: Zyvox™, linezolid. Pharmacia & Upjohn Company, Kalamazoo, MI, (PI revised 01/2001) reviewed 04/2001.
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