Linezolid

Pronunciation

Class: Oxazolidinones
VA Class: AM900
Molecular Formula: C16H20FN3O4
CAS Number: 165800-03-3
Brands: Zyvox

Introduction

Antibacterial; synthetic oxazolidinone.1 2 3 4 5

Uses for Linezolid

Vancomycin-resistant Enterococcus faecium Infections

Treatment of infections caused by susceptible vancomycin-resistant Enterococcus faecium (VRE), including infections associated with concurrent bacteremia.1 2 3 4

Respiratory Tract Infections

Treatment of community-acquired pneumonia (CAP), including infections associated with concurrent bacteremia, caused by susceptible Streptococcus pneumoniae (including multidrug-resistant S. pneumoniae [MDRSP] resistant to ≥2 of the following anti-infectives: penicillin, second-generation cephalosporins, macrolides, tetracycline, co-trimoxazole).1 2 3 4 19 31

Treatment of CAP caused by susceptible Staphylococcus aureus (methicillin-susceptible [oxacillin-susceptible] strains only).1 2 3 4 Also recommended for treatment of CAP caused by methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA).19 31 32

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Treatment of nosocomial pneumonia caused by susceptible S. aureus (including MRSA) or susceptible S. pneumoniae (including MDRSP).1 2 3 4 11

Vancomycin, linezolid, or clindamycin usually recommended for treatment of CAP or healthcare-associated pneumonia known or suspected to be caused by MRSA.19 21 31 32 For additional information regarding treatment of pneumonia, including infections caused by MRSA, consult current IDSA clinical practice guidelines available at .19 31 32

Not indicated for treatment of respiratory tract infections caused by gram-negative bacteria.1 It is imperative that an anti-infective active against gram-negative bacteria be used concomitantly if the documented or presumptive pathogens also include gram-negative bacteria.1

Skin and Skin Structure Infections

Treatment of uncomplicated skin and skin structure infections caused by susceptible S. aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or susceptible S. pyogenes (group A β-hemolytic streptococci).1 2 3 4 10

Treatment of complicated skin and skin structure infections, including diabetic foot infections, without concurrent osteomyelitis, caused by susceptible S. aureus (including MRSA), S. pyogenes, or S. agalactiae (group B streptococci).1 2 3 4 10 26

Use in the treatment of decubitus ulcers has not been studied.1 3

Clindamycin, co-trimoxazole, a tetracycline (doxycycline or minocycline), or linezolid usually recommended for treatment of purulent cellulitis caused by MRSA; vancomycin, linezolid, daptomycin, telavancin, or clindamycin usually recommended for treatment of complicated skin and skin structure infections caused by MRSA.32 For additional information regarding treatment of skin and skin structure infections, including infections caused by MRSA, consult current IDSA clinical practice guidelines available at .22 26 32

Not indicated for treatment of skin and skin structure infections caused by gram-negative bacteria.1 It is imperative that an anti-infective active against gram-negative bacteria be used concomitantly if the documented or presumptive pathogens also include gram-negative bacteria.1

CNS Infections

Treatment of CNS infections caused by MRSA (e.g., meningitis, brain abscess, subdural empyema, spinal epidural abscess);32 recommended by IDSA as an alternative to vancomycin.32 (See Pediatric Use under Cautions.) For additional information regarding treatment of CNS infections caused by MRSA, consult current IDSA clinical practice guidelines available at .32

Linezolid Dosage and Administration

Administration

Administer orally or by IV infusion.1 2 3 4

When clinically appropriate, IV route may be switched to oral without dosage adjustment.1 3

Avoid large quantities of foods or beverages with high tyramine content during linezolid therapy.1 3 4 (See Monoamine Oxidase Inhibition under Cautions.)

Oral Administration

Administer orally without regard to meals.1

Reconstitution

Reconstitute powder for oral suspension at time of dispensing by adding amount of water specified on bottle to provide a suspension containing 100 mg/5 mL.1 After tapping bottle gently to loosen the powder, add water in 2 portions and agitate well after each addition.1

Prior to administration of each dose, gently mix suspension by inverting bottle 3–5 times; do not shake.1

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Single-use containers of linezolid injection for IV infusion should be administered without further dilution.1 Do not use the containers in series connections; do not introduce additives into the solution.1 3

Rate of Administration

Administer by IV infusion over 30–120 minutes.1 3

Dosage

Manufacturer states safety and efficacy of >28 days of linezolid treatment not evaluated in controlled clinical trials.1

Pediatric Patients

General Dosage for Neonates <7 Days of Age
Oral or IV

10 mg/kg every 12 hours initially; consider 10 mg/kg every 8 hours in neonates with inadequate response to the lower dosage.1 By 7 days of age, all neonates should receive 10 mg/kg every 8 hours.1

Vancomycin-resistant Enterococcus faecium Infections
Oral or IV

Children 7 days through 11 years of age: 10 mg/kg every 8 hours for 14–28 days.1

Adolescents ≥12 years of age: 600 mg every 12 hours for 14–28 days.1

Respiratory Tract Infections
Community-acquired or Nosocomial Pneumonia
Oral or IV

Children 7 days through 11 years of age: 10 mg/kg every 8 hours for 10–14 days.1

Adolescents ≥12 years of age: 600 mg every 12 hours for 10–14 days.1

CAP or healthcare-associated pneumonia caused by MRSA: IDSA recommends 7–21 days of treatment.32

Skin and Skin Structure Infections
Uncomplicated Skin and Skin Structure Infections
Oral

Children 7 days through 4 years of age: 10 mg/kg every 8 hours for 10–14 days.1

Children 5–11 years of age: 10 mg/kg every 12 hours for 10–14 days.1

Adolescents ≥12 years of age: 600 mg every 12 hours for 10–14 days.1

Complicated Skin and Skin Structure Infections
Oral or IV

Children 7 days through 11 years of age: 10 mg/kg every 8 hours for 10–14 days.1

Adolescents ≥12 years of age: 600 mg every 12 hours for 10–14 days.1

CNS Infections Caused by MRSA
Oral or IV

10 mg/kg (up to 600 mg) every 8 hours recommended by IDSA.32

Adults

Vancomycin-resistant Enterococcus faecium Infections
Oral or IV

600 mg every 12 hours for 14–28 days.1

Respiratory Tract Infections
Community-acquired or Nosocomial Pneumonia
Oral or IV

600 mg every 12 hours for 10–14 days.1

CAP or healthcare-associated pneumonia caused by MRSA: IDSA recommends 7–21 days of treatment.32

Skin and Skin Structure Infections
Uncomplicated Skin and Skin Structure Infections
Oral

400 mg every 12 hours for 10–14 days.1

Purulent or nonpurulent cellulitis caused by MRSA: IDSA recommends 600 mg twice daily for 5–10 days; duration depends on clinical response.32

Complicated Skin and Skin Structure Infections
Oral or IV

600 mg every 12 hours for 10–14 days.1

Complicated infections caused by MRSA: IDSA recommends 7–14 days of treatment; duration depends on clinical response.32

CNS Infections Caused by MRSA
Oral or IV

600 mg every 12 hours recommended by IDSA.32

Special Populations

Hepatic Impairment

Dosage adjustments not required in mild to moderate hepatic impairment (Child-Pugh class A or B).1 Data not available regarding pharmacokinetics in severe hepatic impairment.1

Renal Impairment

Dosage adjustments not required.1 Use caution in severe renal impairment.5 (See Renal Impairment under Cautions.)

For hemodialysis patients, administer after dialysis session.1 4

Geriatric Patients

Dosage adjustments not required.1

Cautions for Linezolid

Contraindications

  • Known hypersensitivity to linezolid or any ingredient in the formulation.1 3

  • Patients who are receiving (or have received within the last 2 weeks) drugs that inhibit MAO A or B (e.g., isocarboxazid, phenelzine).1 (See Specific Drugs under Interactions.)

  • Unless patients are monitored for potential increases in BP, do not use in patients with uncontrolled hypertension, pheochromocytoma, or thyrotoxicosis or in patients receiving directly or indirectly acting sympathomimetic agents (e.g., pseudoephedrine), vasopressive agents (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine).1 (See Specific Drugs under Interactions.)

  • Unless patients are carefully monitored for signs and/or symptoms of serotonin syndrome, do not use in patients with carcinoid syndrome.1

  • Because of risk of serotonin syndrome, generally should not be used in patients receiving SSRIs, SNRIs, tricyclic antidepressants, MAO inhibitors, or other serotonergic drugs.1 28 (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Hematologic Effects

Myelosuppression (anemia, leukopenia, pancytopenia, thrombocytopenia) reported.1 6

Toxicity studies in adult and juvenile dogs and rats indicate myelosuppression, reduced extramedullary hematopoiesis in spleen and liver, and lymphoid depletion of thymus, lymph nodes, and spleen.1

Monitor CBCs weekly during linezolid therapy, especially in those receiving the drug for >2 weeks and in those who have preexisting myelosuppression, are receiving concomitant drugs associated with bone marrow suppression, or have a chronic infection that was or is being treated with concomitant anti-infective therapy.1 6

Consider discontinuing linezolid if myelosuppression develops or worsens.1 6 Hematologic parameters generally have increased toward pretreatment values following discontinuance of the drug.1 6

Mortality

In an investigational study in seriously ill patients with intravascular catheter-related infections, mortality was higher in patients receiving linezolid than in patients receiving a comparator anti-infective (vancomycin, oxacillin, dicloxacillin); patients also could receive concomitant therapy for gram-negative infection.1 23 There was no difference in mortality between linezolid and comparator regimens in patients with only gram-positive bacteria identified in the baseline culture; mortality was higher in linezolid-treated patients with gram-negative bacterial infections, mixed gram-positive and gram-negative infections, or no pathogen identified at baseline.1 23 Causality not established.1

Not approved by FDA for treatment of catheter-related bacteremia or catheter-site infections; not approved for treatment of gram-negative bacterial infections.1 23

Monoamine Oxidase Inhibition

Linezolid is a weak, nonselective, reversible inhibitor of MAO,1 2 3 4 and potentially may interact with MAO inhibitors and adrenergic and serotonergic agents.1 (See Specific Drugs under Interactions.)

Significant pressor response reported when tyramine doses >100 mg were used in adults receiving linezolid.1 Instruct patients to consume <100 mg of tyramine per meal during linezolid therapy.1 3 4 Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor (e.g., aged cheeses: 0–15 mg tyramine/ounce; fermented or air-dried meat: 0.1–8 mg/ounce; sauerkraut: 8 mg/8 ounces; soy sauce: 5 mg/teaspoon; tap beer: 4 mg/12 ounces; red wine: 0–6 mg/8 ounces).1 Consider that tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.1

Serotonin Syndrome

Serotonin syndrome (including some fatalities) reported in patients receiving linezolid concomitantly with serotonergic drugs.1 5 15 16 17 25 28 29 Signs and symptoms of serotonin syndrome include mental changes (confusion, hyperactivity, memory problems), muscle twitching, excessive sweating, shivering, shaking, diarrhea, loss of coordination, and/or fever.28

Most reported cases occurred in patients receiving linezolid concomitantly with SSRIs or SNRIs.30 FDA has not concluded whether concomitant use of linezolid with other drugs with lesser degrees of serotonergic activity (e.g., tricyclic antidepressants, MAO inhibitors) is associated with a risk comparable to that reported with SSRIs or SNRIs.30

FDA states that linezolid generally should not be used in patients receiving serotonergic drugs.28 Certain life-threatening or urgent emergency situations may necessitate immediate linezolid treatment in a patient receiving a serotonergic drug, including when the anti-infective is indicated for treatment of VRE infections, nosocomial pneumonia (including cases caused by MRSA), or complicated skin and skin structure infections (including cases caused by MRSA).28 In such situations, consider availability of alternative anti-infectives and weigh benefits of linezolid against risks of serotonin syndrome.28 If linezolid is initiated, immediately discontinue the serotonergic agent.28 (See Specific Drugs under Interactions.)

Hypoglycemia

Symptomatic hypoglycemia reported in patients with diabetes mellitus receiving linezolid concomitantly with insulin or oral hypoglycemic agents.1

Caution patients with diabetes mellitus about potential for hypoglycemia during linezolid therapy.1 If hypoglycemia occurs, dosage reduction of insulin or oral antidiabetic agents or discontinuance of linezolid, insulin, or oral antidiabetic agents may be necessary.1

Superinfection/Clostridium difficile-associated Diarrhea and Colitis (CDAD)

Possible emergence and overgrowth of nonsusceptible organisms.1 Institute appropriate therapy if superinfection occurs.1

Treatment with anti-infectives can alter normal intestinal flora and may lead to overgrowth of Clostridium difficile.1 35

Clostridium difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with nearly all systemic anti-infectives, including linezolid, and may range in severity from mild diarrhea to fatal colitis.1 35 C. difficile produces toxins A and B which contribute to the development of CDAD;1 hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1

Consider CDAD if diarrhea develops during or after therapy and manage accordingly.1 Obtain careful medical history since CDAD may occur as late as 2 months or longer after anti-infective therapy is discontinued.1

If CDAD is suspected or confirmed, discontinue inciting anti-infective whenever possible.1 35 Initiate appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.1 35

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis, angioedema, and bullous skin disorders, such as those described as Stevens-Johnson syndrome, reported.1

General Precautions

Lactic Acidosis

Lactic acidosis, characterized by recurrent nausea and vomiting, has been reported.1 14 Patients who develop recurrent nausea and vomiting, unexplained acidosis, or a low bicarbonate concentration while receiving linezolid should undergo immediate medical evaluation.1 14

Neuropathy

Peripheral and optic neuropathy, sometimes progressing to loss of vision, reported; these events have occurred principally in patients receiving the drug for >28 days.1 24 Blurred vision reported in some patients receiving the drug for <28 days.1

If a patient experiences symptoms of visual impairment (e.g., changes in visual acuity or color vision, blurred vision, or visual field defect), promptly perform an ophthalmic evaluation.1 Monitor visual function in all patients receiving linezolid for extended periods of time (i.e., ≥3 months).1 In addition, monitor visual function in all patients reporting a new visual symptom, regardless of length of therapy.1

If peripheral or optic neuropathy occurs, weigh potential benefits versus risks of continued linezolid therapy.1

Seizures

Seizures reported; history of seizures or risk factors for seizures noted in some cases.1

Selection and Use of Anti-infectives

Linezolid is indicated only for treatment of certain infections caused by certain gram-positive bacteria.1 The drug has no clinical activity against gram-negative bacteria and is not indicated for treatment of infections caused by gram-negative bacteria.1

It is imperative that an anti-infective active against gram-negative bacteria be used concomitantly if documented or presumptive pathogens also include gram-negative bacteria.1 (See Uses.)

Manufacturer states that safety and efficacy of linezolid given for >28 days have not been evaluated in controlled clinical trials.1 (See Dosage under Dosage and Administration.)

To reduce development of drug-resistant bacteria and maintain effectiveness of linezolid and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.1

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.1 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.

Phenylketonuria

Oral suspension contains aspartame, which is metabolized in the GI tract to provide 20 mg of phenylalanine per 5 mL of suspension.1 5

Other linezolid preparations do not contain aspartame;1 these other preparations should be used in individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine.1

Other Precautions

Linezolid has not been studied in patients with uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, or untreated hyperthyroidism.1 3 (See Contraindications under Cautions.)

Superficial tooth discoloration and tongue discoloration reported.1 In cases with known outcome, tooth discoloration was removable with professional dental cleaning (manual descaling).1

Specific Populations

Pregnancy

Category C.1

Lactation

Linezolid and its metabolites are distributed into milk in rats; not known whether distributed into human milk.1 Use caution.1

Pediatric Use

Safety and efficacy for treatment of vancomycin-resistant E. faecium infections, community-acquired pneumonia (CAP), nosocomial pneumonia, and complicated skin and skin structure infections in pediatric patients are supported by adequate and well-controlled studies in adults, pharmacokinetic studies in pediatric patients, and additional data from a comparator-controlled study of gram-positive infections in neonates and children through 11 years of age.1 Safety and efficacy for treatment of CAP in pediatric patients also is supported by evidence from an uncontrolled study in patients 8 months through 12 years of age.1

Safety and efficacy for treatment of uncomplicated skin and skin structure infections in pediatric patients established in a comparator-controlled study in pediatric patients 5–17 years of age.1

In children with a suboptimal response to linezolid, especially those with infections caused by pathogens with linezolid MICs of 4 mcg/mL, consider inadequate systemic exposure, site and severity of infection, and underlying medical conditions.1

Manufacturer states not recommended for empiric treatment of CNS infections in pediatric patients.1 (See Distribution under Pharmacokinetics.)

Geriatric Use

Pharmacokinetic, safety, and efficacy profiles similar to those in younger adults.1 2

Hepatic Impairment

Pharmacokinetics not evaluated in patients with severe hepatic impairment.1

Renal Impairment

Although clinical importance not determined, the 2 principal metabolites of linezolid may accumulate in patients with renal impairment, especially severe renal impairment.1 3 Weigh potential benefits against potential risks of accumulation of linezolid metabolites.1 Use with caution in severe renal impairment.5

Common Adverse Effects

GI effects (diarrhea, nausea, vomiting, constipation, localized or generalized abdominal pain), fever, headache, insomnia, rash, dizziness, skin disorder, pharyngitis, cough, upper respiratory tract infection.1

Interactions for Linezolid

Minimally metabolized; possibly by CYP isoenzymes.1

Does not inhibit CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4.1 Does not induce CYP isoenzymes.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potent inducers of hepatic enzymes: Possible reduced linezolid concentrations.1

Specific Drugs

Drug

Interaction

Comments

Aminoglycosides

Gentamicin: Pharmacokinetics of linezolid and gentamicin not affected if the drugs are used concomitantly1 2 3

Gentamicin or streptomycin: In vitro evidence of additive or indifferent antibacterial effects1

Ampicillin

In vitro evidence of additive or indifferent antibacterial effects1

Antidiabetic agents, oral

Potential for hypoglycemia1

Dosage reduction of antidiabetic agent or discontinuance of linezolid or antidiabetic agent may be necessary1

Aztreonam

Pharmacokinetics of linezolid and aztreonam not affected if the drugs are used concomitantly1 2 3

In vitro evidence of additive or indifferent antibacterial effects1

Carbamazepine

Possible decreased linezolid concentrations1

Carbapenems

Imipenem: In vitro evidence of additive or indifferent antibacterial effects1

Insulin

Potential for hypoglycemia1

Dosage reduction of insulin or discontinuance of linezolid or insulin may be necessary1

MAO inhibitors (isocarboxazid, phenelzine, selegiline, tranylcypromine)

Potential pharmacologic interaction1

Increased risk of CNS toxicity, including serotonin syndrome1 28

Do not use linezolid in patients who are receiving (or have received within the last 2 weeks) an MAO inhibitor1 (see Serotonergic Drugs under Specific Drugs)

Phenobarbital

Possible decreased linezolid concentrations1

Phenytoin

Effect on phenytoin pharmacokinetics unlikely;1 possible decreased linezolid concentrations1

Dosage adjustments not required1

Rifampin

Decreased peak plasma concentration and AUC of linezolid1

Mechanism of the interaction and clinical importance unknown1

Serotonergic drugs (SSRIs, SNRIs, tricyclic antidepressants, amoxapine, bupropion, buspirone, maprotiline, mirtazapine, nefazodone, trazodone, vilazodone)

Increased risk of serotonin syndrome, particularly with SSRIs and SNRIs;1 3 4 5 15 16 17 25 28 30 unclear whether risk associated with other serotonergic drugs is comparable to that reported with SSRIs and SNRIs30

Do not use concurrently;28 if a life-threatening or urgent emergency situation necessitates immediate linezolid treatment in a patient receiving a serotonergic drug, consider availability of alternative anti-infectives and weigh benefit of linezolid against risk of serotonin syndrome28

If emergency use of linezolid is considered necessary, immediately discontinue the serotonergic drug; monitor closely for symptoms of CNS toxicity (e.g., mental changes, muscle twitching, excessive sweating, shivering/shaking, diarrhea, loss of coordination, fever) for 2 weeks (5 weeks if the patient was receiving fluoxetine) or until 24 hours after the last linezolid dose, whichever comes first28

If nonemergency use of linezolid is planned, withhold the serotonergic drug for at least 2 weeks (5 weeks if the patient was receiving fluoxetine) prior to initiating linezolid;28 serotonergic drug may be resumed 24 hours after last linezolid dose28

Do not initiate serotonergic drug in patients receiving linezolid; when necessary, initiate 24 hours after last linezolid dose28

Sympathomimetic agents

Potential pharmacologic interaction (enhanced vasopressor effects) with sympathomimetic agents, vasopressor agents, or dopaminergic agents1

Manufacturer of linezolid states that, unless patients are monitored for potential increases in BP, do not use in patients receiving directly or indirectly acting sympathomimetic agents (e.g., pseudoephedrine), vasopressor agents (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine)1

If an adrenergic agent (e.g., dopamine, epinephrine) is used in a patient receiving linezolid, use lower initial doses of the adrenergic agent and titrate dosage to achieve desired response1

Vancomycin

In vitro evidence of additive or indifferent antibacterial effects1

Warfarin

No substantial effect on warfarin pharmacokinetics1

Dosage adjustments not required1

Linezolid Pharmacokinetics

Absorption

Bioavailability

Rapidly and extensively absorbed after oral administration.1 Absolute oral bioavailability is approximately 100%.1 18

Peak plasma concentrations attained within 1–2 hours following oral administration.1

Food

Time to peak concentrations is delayed and peak concentration decreased when administered with a high-fat meal,1 but extent of absorption is not affected.1 Not considered clinically important.1

Distribution

Extent

Readily distributed into well-perfused tissues.1

Adults with CNS infections: IV administration of linezolid (600 mg twice daily) resulted in steady-state mean peak CSF concentrations 36–58% of mean peak plasma concentrations;33 34 time to peak CSF concentrations was approximately 3–4 hours after a dose.34

Pediatric patients with ventriculoperitoneal shunts: Therapeutic concentrations not consistently achieved or maintained in CSF after single or multiple doses.1

Linezolid and its metabolites are distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

Approximately 31%.1

Elimination

Metabolism

Principally metabolized by oxidation of the morpholine ring to 2 inactive metabolites.1 Minimally metabolized; possibly mediated by CYP enzyme system.1

Elimination Route

Approximately 65% of a dose eliminated via nonrenal clearance; renal clearance is low, suggesting net tubular reabsorption.1 Almost no linezolid is found in feces as unchanged drug.1

Linezolid and its metabolites removed by hemodialysis.1

Not known whether linezolid or its metabolites are removed by peritoneal dialysis.1 3 5

Half-life

Adults: Mean elimination half-life is 4.3–6.4 hours.1 18

Neonates: Mean elimination half-life is 5.6 hours in preterm neonates <1 week of age, 3 hours in full-term neonates <1 week of age, and 1.5 hours in neonates 1 week to 28 days of age.1

Infants and children: Mean elimination half-life is 1.8 hours in infants >28 days through 2 months of age and 2.9 hours in children 3 months through 11 years of age.1

Adolescents 12 through 17 years of age: Mean elimination half-life is 4.1 hours.1

Special Populations

In pediatric patients, clearance varies with age and there is wide intraindividual variability.1 Excluding neonates <1 week of age, clearance is most rapid in the youngest age groups (i.e., those 7 days to 11 years of age); as children age, clearance of linezolid decreases and clearance in adolescents is similar to that observed in adults.1

Pharmacokinetics not affected by mild-to-moderate hepatic impairment (Child-Pugh class A or B).1

Pharmacokinetics of linezolid not affected by renal insufficiency, but the primary metabolites may accumulate.1 Clinical importance unclear.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1 Protect from light.1

For Suspension

25°C (may be exposed to 15–30°C).1 Protect from light.1 After reconstitution, store at room temperature and use within 21 days.1

Parenteral

Injection, for IV Infusion

25°C (may be exposed to 15–30°C); do not freeze.1 Protect from light.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Dextrose 5% in water

Ringer's injection, lactated

Sodium chloride 0.9%

Drug Compatibility
Admixture CompatibilityHID

Compatible

Aztreonam

Cefazolin sodium

Ceftazidime

Ciprofloxacin

Gentamicin sulfate

Levofloxacin

Tobramycin sulfate

Incompatible

Ceftriaxone sodium

Co-trimoxazole

Erythromycin lactobionate

Y-Site CompatibilityHID

Compatible

Acyclovir sodium

Alfentanil HCl

Amikacin sulfate

Aminophylline

Ampicillin sodium

Ampicillin sodium–sulbactam sodium

Anidulafungin

Aztreonam

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Carboplatin

Caspofungin acetate

Cefazolin sodium

Cefotetan disodium

Cefoxitin sodium

Ceftazidime

Ceftriaxone sodium

Cefuroxime sodium

Ciprofloxacin

Cisatracurium besylate

Cisplatin

Clindamycin phosphate

Cyclophosphamide

Cyclosporine

Cytarabine

Dexamethasone sodium phosphate

Dexmedetomidine HCl

Digoxin

Diphenhydramine HCl

Dobutamine HCl

Dopamine HCl

Doripenem

Doxorubicin HCl

Doxycycline hyclate

Droperidol

Enalaprilat

Esmolol HCl

Etoposide phosphate

Famotidine

Fenoldopam mesylate

Fentanyl citrate

Fluconazole

Fluorouracil

Furosemide

Ganciclovir sodium

Gemcitabine HCl

Gentamicin sulfate

Granisetron HCl

Haloperidol lactate

Heparin sodium

Hydrocortisone sodium succinate

Hydromorphone HCl

Hydroxyzine HCl

Ifosfamide

Imipenem–cilastatin sodium

Labetalol HCl

Leucovorin calcium

Levofloxacin

Lidocaine HCl

Lorazepam

Magnesium sulfate

Mannitol

Meperidine HCl

Meropenem

Mesna

Methotrexate sodium

Methylprednisolone sodium succinate

Metoclopramide HCl

Metronidazole

Midazolam HCl

Mitoxantrone HCl

Morphine sulfate

Nalbuphine HCl

Naloxone HCl

Nicardipine HCl

Nitroglycerin

Ondansetron HCl

Paclitaxel

Pentobarbital sodium

Phenobarbital sodium

Piperacillin sodium–tazobactam sodium

Potassium chloride

Prochlorperazine edisylate

Promethazine HCl

Propranolol HCl

Ranitidine HCl

Remifentanil HCl

Sodium bicarbonate

Sufentanil citrate

Theophylline

Tigecycline

Tobramycin sulfate

Vancomycin HCl

Vasopressin

Vecuronium bromide

Verapamil HCl

Vincristine sulfate

Zidovudine

Incompatible

Amphotericin B

Chlorpromazine HCl

Diazepam

Pentamidine isethionate

Phenytoin sodium

Actions and Spectrum

  • Synthetic oxazolidinone anti-infective agent structurally unrelated to other anti-infectives commercially available in the US.1 2 3 4 5

  • Acts early in bacterial translation; binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents formation of a functional 70S initiation complex.1 2 3

  • Bacteriostatic against enterococci and staphylococci and bactericidal against most streptococci.1 2 4

  • Active in vitro against vancomycin-resistant Enterococcus faecium.1 3 Although clinical importance unknown, also active in vitro against E. faecium (vancomycin-susceptible strains) and E. faecalis (including vancomycin-resistant strains).1

  • Active in vitro against Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA]), Streptococcus agalactiae (group B streptococci), S. pneumoniae (including MDRSP), and S. pyogenes (group A β-hemolytic streptococci).1 Although clinical importance unknown, also active in vitro against S. epidermidis (including methicillin-resistant [oxacillin-resistant] strains), S. haemolyticus, viridans group streptococci, and Pasteurella multocida.1

  • Resistant strains of E. faecium, E. faecalis, and S. aureus have emerged during linezolid therapy.1

  • Cross-resistance between linezolid and other anti-infectives commercially available in the US is unlikely because of the drug’s unique mechanism of action.1 2 3

Advice to Patients

  • Advise patients that antibacterials (including linezolid) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1

  • Importance of completing full course of therapy, even if feeling better after a few days.1

  • Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with linezolid or other antibacterials in the future.1

  • Advise patients that linezolid may be taken orally without regard to meals.1

  • If using the oral suspension, importance of not shaking the bottle vigorously and gently inverting the bottle 3–5 times to resuspend the drug prior to administration of each dose.1

  • Advise patients of the potential risk of serotonin syndrome, particularly if linezolid is used concomitantly with MAO inhibitors, SSRIs, SNRIs, tricyclic antidepressants, or other serotonergic drugs.28 Importance of immediately contacting clinician if signs and symptoms of serotonin syndrome develop (e.g., confusion, hyperactivity, memory problems, muscle twitching, excessive sweating, shivering, shaking, diarrhea, loss of coordination, fever).28 Importance of not discontinuing serotonergic drugs without first consulting clinician.28

  • Advise patients with diabetes mellitus of potential risk of hypoglycemia if receiving linezolid concomitantly with insulin or oral antidiabetic agents.1

  • Importance of avoiding excessive amounts of dietary tyramine (>100 mg per meal) during linezolid therapy.1 4

  • Advise individuals with phenylketonuria that the oral suspension contains aspartame, which is metabolized in the GI tract to provide 20 mg of phenylalanine per 5 mL of suspension.1 4

  • Importance of notifying clinician of any history of hypertension or seizures.1

  • Importance of notifying clinician if any change in vision occurs.1

  • Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.1 Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy including prescription drugs (e.g., antidepressants) and OTC drugs (e.g., pseudoephedrine), as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Linezolid

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

For suspension

100 mg/5 mL

Zyvox

Pfizer

Tablets, film-coated

600 mg

Zyvox

Pfizer

Parenteral

Injection, for IV infusion

2 mg/mL (200 and 600 mg) in sterile isotonic solution

Zyvox Injection (in flexible containers)

Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Zyvox 600MG Tablets (PFIZER U.S.): 20/$1,989.19 or 40/$3,935.04

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 10, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Pfizer. Zyvox (linezolid) injection, tablets, and for oral suspension prescribing information. New York, NY: 2011 Nov.

2. Clemett D, Markham A. Linezolid. Drugs. 2000; 59:815-27. [PubMed 10804037]

3. Pharmacia & Upjohn. Zyvox (linezolid) injection, tablets, and oral suspension comprehensive review. Kalamazoo, Michigan; 2000 April.

4. Anon. Linezolid (Zyvox). Med Lett Drugs Ther. 2000; 42:45-6. [PubMed 10859730]

5. Pharmacia & Upjohn, Kalamazoo, MI: Personal communication.

6. Peterson J. Dear health care professional letter regarding updated labeling for Zyvox (linezolid) on myelosuppression. Peapack, NJ: Pharmacia; (undated).

7. Tsiodras S, Gold HS, Sakoulas G et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet. 2001; 358:207-8. [IDIS 467414] [PubMed 11476839]

8. Prystowsky J, Siddiqui F, Chosay J et al. Resistance to linezolid: characterization of mutations in rRNA and comparison of their occurrences in vancomycin-resistant enterococci. Antimicrob Agents Chemother. 2001; 45:2154-6. [PubMed 11408243]

9. Kaatz GW, Seo SM. In vitro activities of oxazolidinone compounds U100592 and U100766 against Staphylococcus aureus and Staphylococcus epidermidis. Antimicrob Agents Chemother. 1996; 40:799-801. [PubMed 8851617]

10. Stevens DL, Smith LG, Bruss JB et al. Randomized comparison of linezolid (PNU-100766) versus oxacillin-dicloxacillin for treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother. 2000; 44:3408-13. [IDIS 455666] [PubMed 11083648]

11. Rubinstein E, Cammarata SK, Oliphant TH et al. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis. 2001; 32:402-12. [IDIS 466030] [PubMed 11170948]

12. Moellering RC. Linezolid: the first oxazolidinone antimicrobial. Ann Intern Med. 2003; 138:135-42. [IDIS 491830] [PubMed 12529096]

13. Lipsky BA, Armstrong D, Acin F et al. Treating diabetic foot infections with linezolid vs. aminopenicillins: a randomized international multicenter trial. Presented at the 40th annual meeting of the Infectious Diseases Society of America. Chicago, IL: 2002 October 24-27. Abstract No. 189.

14. Apodaca AA, Rakita RM. Linezolid-induced lactic acidosis. N Engl J Med. 2003; 348:86-7. [IDIS 491223] [PubMed 12510056]

15. Wigen CL, Goetz MB. Serotonin syndrome and linezolid. Clin Infect Dis. 2002; 34:1651-2. [IDIS 482703] [PubMed 12032904]

16. Bernard L, Stern R, Lew D et al. Serotonin syndrome after concomitant treatment with linezolid and citalopram. Clin Infect Dis. 2003; 36:1197. [IDIS 511356] [PubMed 12715317]

17. Hachem RY, Hicks K, Huen A et al. Myelosuppression and serotonin syndrome associated with concurrent use of linezolid and selective serotonin reuptake inhibitors in bone marrow transplant recipients. Clin Infect Dis. 2003; 37:e8-11. [IDIS 512019] [PubMed 12830431]

18. Fung HB, Kirschenbaum HL, Ojofeitimi BO. Linezolid: an oxazolidinone antimicrobial agent. Clin Ther. Mar; 23:356-91.

19. Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007; 44 Suppl 2:S27-72. [PubMed 17278083]

20. Anon. Choice of Antibacterial Drugs. Treat Guidel Med Lett. 2007; 5:33-50.

21. American Thoracic Society and the Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005; 171:388-416. [PubMed 15699079]

22. Stevens DL, Bisno AL, Chambers HF et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005; 41:1373-406. [PubMed 16231249]

23. Food and Drug Administration. Information for Healthcare Professionals: Linezolid (marketed as Zyvox). 2007 Mar 16. From FDA website ().

24. McKinley SH, Foroosan R. Optic neuropathy associated with linezolid treatment. J Neuroophthalmol. 2005; 25:18-21. [PubMed 15756127]

25. Steinberg M, Morin AK. Mild serotonin syndrome associated with concurrent linezolid and fluoxetine. Am J Health-Syst Pharm. 2007; 64:59-62. [PubMed 17189581]

26. Lipsky BA, Berendt AR, Deery HG et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2004; 39:885-910. [PubMed 15472838]

28. Food and Drug Administration. Drug Safety Communication: Serious CNS reactions possible when linezolid (Zyvox) is given to patients taking certain psychiatric medications. 2011 Jul 26. From FDA website.

29. Clark DB, Andrus MR, Byrd DC. Drug interactions between linezolid and selective serotonin reuptake inhibitors: case report involving sertraline and review of the literature. Pharmacotherapy. 2006; 26:269-76. [PubMed 16466332]

30. Food and Drug Administration. Drug Safety Communication: Updated information about the drug interaction between linezolid (Zyvox) and serotonergic pyschiatric medications. 2011 Oct 20. From FDA website.

31. Bradley JS, Byington CL, Shah SS et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011; 53:e25-76.

32. Liu C, Bayer A, Cosgrove SE et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011; 52:285-92. [PubMed 21217178]

33. Myrianthefs P, Markantonis SL, Vlachos K et al. Serum and cerebrospinal fluid concentrations of linezolid in neurosurgical patients. Antimicrob Agents Chemother. 2006; 50:3971-6. [PubMed 16982782]

34. Beer R, Engelhardt KW, Pfausler B et al. Pharmacokinetics of intravenous linezolid in cerebrospinal fluid and plasma in neurointensive care patients with staphylococcal ventriculitis associated with external ventricular drains. Antimicrob Agents Chemother. 2007; 51:379-82. [PubMed 17043116]

35. Cohen SH, Gerding DN, Johnson S et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010; 31:431-55. [PubMed 20307191]

HID. Trissel LA. Handbook of injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013:710-4.

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