Linezolid

Pronunciation

Pronunciation: lin-AYZ-oh-lid
Class: Oxazolidinone, Anti-infective

Trade Names

Zyvox
- Tablets 400 mg (sodium content is 1.95 mg per 400 mg tablet [0.1 mEq/tablet])
- Tablets 600 mg (sodium content is 2.92 mg per 600 mg tablet [0.1 mEq/tablet])
- Powder for oral suspension 100 mg per 5 mL (sodium content is 8.52 mg per 5 mL [0.4 mEq per 5 mL])
- Injection 2 mg/mL (sodium content is 0.38 mg/mL [5 mEq per 300 mL bag, 3.3 mEq per 200 mL bag, 1.7 mEq per 100 mL bag])

Zyvoxam (Canada)
Zyvoxam IV (Canada)

Pharmacology

Prevents the formation of a functional 70S initiation complex, which is essential to the bacterial translation process.

Slideshow: 10 Things to Know About Antibiotic Resistance

Pharmacokinetics

Absorption

Rapidly and extensively absorbed after oral dosing. T max is 1 to 2 h. Absolute bioavailability is approximately 100% (no dose adjustment needed from IV to oral). Food does not affect absorption; however, T max is delayed from 1.5 to 2.2 h and C max is decreased 17% when high-fat food is given.

Distribution

Readily distributed to well-perfused tissues; 31% protein bound. Vd at steady state is 40 to 50 L.

Metabolism

Primarily metabolized by oxidation of the morpholine ring. Metabolites are aminoethoxyacetic acid (A) and hydroxyethyl glycine (B).

Elimination

Approximately 65% nonrenal Cl. Approximately 30% of dose appears in urine as linezolid (40% as metabolite B, 10% as metabolite A). Renal Cl is 40 mL/min.

Special Populations

Renal Function Impairment

Pharmacokinetics of linezolid are not altered in patients with renal insufficiency. Metabolites A and B may accumulate in patients with renal insufficiency; the significance of this accumulation is not known. Approximately 30% of a dose is eliminated in a 3-h dialysis session; give linezolid after hemodialysis.

Hepatic Function Impairment

The pharmacokinetics of linezolid are not altered in patients with mild to moderate hepatic insufficiency. Pharmacokinetics in patients with severe hepatic impairment have not been studied.

Elderly

Pharmacokinetics are not significantly altered in elderly patients.

Children

C max and Vd are similar regardless of age in children. Cl varies as a function of age. Cl is most rapid in children older than 1 wk of age to 11 y of age, resulting in lower AUC and shorter half-life compared with adults. By adolescence, mean Cl values approach those observed in the adult population.

Gender

Women have slightly lower Vd, higher plasma concentrations, and lower mean oral Cl compared with men. No significant difference is seen in mean apparent elimination-rate constant or half-life. No dose adjustment is necessary based on gender.

Indications and Usage

Treatment of vancomycin-resistant Enterococcus faecium , including cases with concurrent bacteremia; treatment of nosocomial pneumonia, complicated and uncomplicated skin and skin structure infections (including diabetic foot infections without concomitant osteomyelitis), and community-acquired pneumonia caused by susceptible strains of specific organisms.

Contraindications

Concomitant use or use within 14 days of any medicinal product that inhibits MAO-A or MAO-B; hypersensitivity to linezolid or any of the other product components.

Unless carefully observed for potential increases in BP, use is contraindicated in patients with uncontrolled hypertension, pheochromocytoma, and/or thyrotoxicosis; use is also contraindicated in patients with carcinoid syndrome or in patients taking directly and indirectly acting sympathomimetic agents, vasopressive agents, dopaminergic agents, serotonin reuptake inhibitors, tricyclic antidepressants, serotonin 5-HT 1 receptor agonists, meperidine, or buspirone, unless carefully observed for signs and/or symptoms of serotonin syndrome.

Dosage and Administration

Methicillin-Resistant Staphylococcus aureus
Adults

PO / IV 600 mg every 12 h.

Nosocomial Pneumonia, Complicated Skin and Skin Structure Infections, Community-Acquired Pneumonia, Including Concomitant Bacteremia
Adults and Children 12 y of age and older

PO / IV 600 mg every 12 h for 10 to 14 days.

Children (birth through 11 y of age)

PO / IV 10 mg/kg every 8 h for 10 to 14 days. Most preterm neonates younger than 7 days of age should start with 10 mg/kg every 12 h; all neonates should receive 10 mg/kg every 8 h by 7 days of life. A dose of 10 mg/kg every 8 h may be considered in neonates with a suboptimal response.

Uncomplicated Skin and Skin Structure Infections
Adults

PO 400 mg every 12 h for 10 to 14 days.

Children 12 to 18 y of age

PO 600 mg every 12 h for 10 to 14 days.

Children 5 to 11 y of age

PO 10 mg/kg every 12 h for 10 to 14 days.

Children younger than 5 y of age

PO 10 mg/kg every 8 h for 10 to 14 days. Most preterm neonates younger than 7 days of age should start with 10 mg/kg every 12 h; all neonates should receive 10 mg/kg every 8 h by 7 days of life. A dose of 10 mg/kg every 8 h may be considered in neonates with a suboptimal response.

Vancomycin-Resistant E. faecium Infections, including Concomitant Bacteremia
Adults and Children 12 y of age and older

PO / IV 600 mg every 12 h for 14 to 28 days.

Children (birth through 11 y of age)

PO / IV 10 mg/kg every 8 h for 14 to 28 days. Most preterm neonates younger than 7 days of age should start with 10 mg/kg every 12 h; all neonates should receive 10 mg/kg every 8 h by 7 days of life. A dose of 10 mg/kg every 8 h may be considered in neonates with a suboptimal response.

General Advice

No dosage adjustment is necessary when switching from IV to PO.

Oral
  • Oral suspension contains phenylalanine 20 mg per 5 mL.
  • Administer tablets and oral suspension without regard to meals. Administer with food if GI upset occurs.
  • Gently mix suspension by inverting bottle 3 to 5 times before each dose. Do not shake suspension. Measure and administer prescribed dose of suspension using dosing syringe, dosing spoon, or dosing cup.
Injection
  • For administration by IV infusion only over a period of 30 to 120 min. Not for intradermal, subcutaneous, IM, continuous IV infusion, IV bolus, or intra-arterial administration.
  • Keep infusion bag in protective overwrap until ready to administer.
  • Do not administer if solution is cloudy, discolored, or contains particulate matter. Solution may exhibit a yellow color, which is normal and does not affect potency.
  • Before administration, check IV bag for minute leaks by firmly squeezing bag. If leaks are detected, discard solution because sterility may be compromised.
  • Do not use IV infusion bag in series connections or add any other medications to infusion bag.
  • If other drugs are being administered through same IV line, flush IV line before and after infusion of linezolid with dextrose 5% injection, sodium chloride 0.9% injection, or Ringer's lactate injection.

Storage/Stability

Oral

Store at 59° to 86°F. Protect from light. Keep bottles tightly closed. Store constituted suspension at 59° to 86°F. Discard any unused suspension after 21 days.

Injection

Store IV infusion bags at 59° to 86°F. Protect from freezing and light.

Drug Interactions

Apraclonidine

Linezolid is a reversible, nonselective MAOI. Apraclonidine is contraindicated in patients receiving MAOIs. The risk of hypertension may be increased. Do not coadminister linezolid and apraclonidine within 14 days of each other.

Atomoxetine

Risk of serious or fatal reactions, including hyperthermia and rapid fluctuations in vital signs, may be increased. Coadministration of linezolid and atomoxetine within 14 days of each other is contraindicated.

Beta-2 agonists (eg, albuterol)

Coadministration of linezolid and beta-2 agonists may result in adverse CV effects characterized by hypertension. Use caution when administering linezolid with or within 14 days of beta-2 agonists. Monitor for potential increases in BP with coadministration of these agents.

Bupropion, cyclobenzaprine, methylphenidate

The risk of hypertensive crisis is increased. Do not coadminister these agents and linezolid within 14 days of each other.

Buspirone, meperidine, selective 5-HT 1 receptor agonists (eg, sumatriptan), serotonin reuptake inhibitors (eg, fluoxetine, paroxetine, sertraline, venlafaxine), tricyclic antidepressants (eg, amitriptyline)

Unless patients are carefully observed for signs and symptoms of serotonin syndrome, do not coadminister linezolid with these agents. Serotonin syndrome requires immediate medical attention, including withdrawal of the serotonergic agent and supportive care.

Catechol-O-methyl-transferase inhibitors (eg, entacapone)

Coadministration of linezolid and catechol-O-methyl-transferase (COMT) inhibitors may result in inhibition of the majority of pathways responsible for normal catecholamine metabolism. Excessive sympathetic stimulation may result. Use of linezolid with COMT inhibitors is not recommended.

Dopaminergic agents (eg, dobutamine, dopamine), sympathomimetic agents (eg, pseudoephedrine), vasopressive agents (eg, epinephrine, norepinephrine)

Unless patients are monitored for increases in BP, do not coadminister linezolid with dopaminergic agents.

Ginseng

Use of linezolid with ginseng may produce unexpected toxic effects (eg, headache, manic-like symptoms). Avoid concomitant use of linezolid and ginseng.

Levodopa

Linezolid may increase the pharmacologic and toxic effects (flushing, headache, and hypertension) of levodopa. Hypertensive crisis may occur. Avoid coadministration of levodopa and linezolid. If inadvertently given and hypertension occurs, administer phentolamine.

MAOIs (eg, phenelzine)

Linezolid is a reversible, nonselective MAOI; do not coadminister with any medicinal product that inhibits MAO-A or MAO-B or within 2 wk of administering such products.

Propoxyphene

A severe reaction potentially involving the respiratory, cardiac, and central nervous systems may occur shortly after administering propoxyphene to patients receiving linezolid. Because of the potential seriousness of the consequences, use propoxyphene with caution in patients receiving linezolid.

Rifamycins (eg, rifampin)

Linezolid C max and AUC (exposure) may be reduced, decreasing the pharmacologic effects. Monitor the response of the patient and adjust therapy as needed.

Sibutramine

The risk of serotonin syndrome may be increased. Serotonergic effects of these agents may be additive. MAOIs are contraindicated in patients receiving sibutramine.

Tetrabenazine

The combination of linezolid and tetrabenazine may produce severe unexpected toxicity (eg, behavioral changes, confusion, restlessness). Coadministration of linezolid and tetrabenazine is contraindicated.

Tryptophan

The risk of serotonin syndrome may be increased. Serotonergic effects of these agents may be additive. Carefully monitor patients for adverse reactions, including signs and symptoms of serotonin syndrome. Serotonin syndrome requires immediate medical attention, including withdrawal of the serotonergic agent and supportive care.

Adverse Reactions

CNS

Headache (7%); convulsions, insomnia (3%); dizziness (2%); vertigo (1%); peripheral neuropathy (postmarketing).

Dermatologic

Rash (7%); skin disorder (2%); bullous skin disorders (postmarketing).

EENT

Pharyngitis (3%); optic neuropathy sometimes progressing to vision loss (postmarketing).

GI

Diarrhea (11%); vomiting (9%); nausea (6%); altered taste, constipation, generalized and localized abdominal pain, GI bleeding, loose stools (2%); oral moniliasis, tongue discoloration (1%).

Genitourinary

Vaginal moniliasis (2%).

Hematologic

Anemia (6%); thrombocytopenia (5%); thrombocythemia (3%); eosinophilia (1%); leukopenia, pancytopenia (postmarketing).

Lab Tests

Abnormal Hgb (16%); abnormal platelets (13%); abnormal WBC (12%); abnormal ALT (10%); abnormal neutrophils, abnormal total bilirubin (6%); abnormal AST (5%); abnormal alkaline phosphatase, abnormal lipase (4%); abnormal amylase, BUN, creatinine, and LDH (2%).

Local

Injection- or catheter-site reactions (3%).

Metabolic

Hypokalemia (3%); generalized edema (2%); lactic acidosis (postmarketing).

Respiratory

Upper respiratory tract infection (4%); dyspnea, pneumonia (3%); apnea, cough (2%).

Miscellaneous

Fever (14%); sepsis (8%); trauma (3%); fungal infections, localized pain (2%); anaphylaxis, angioedema, serotonin syndrome, superficial tooth discoloration, tongue discoloration (postmarketing).

Precautions

Monitor

Monitor CBCs weekly, particularly in patients who receive linezolid longer than 2 wk, have preexisting myelosuppression, receive concomitant drugs that produce bone marrow suppression, or who have a chronic infection and have received previous or concomitant antibiotic therapy. Closely observe patients for signs and symptoms of serotonin syndrome when linezolid is administered with a serotonergic agent. Monitor visual function in all patients taking linezolid for 3 mo or more and in all patients with new visual symptoms, regardless of length of therapy.


Pregnancy

Category C .

Lactation

Undetermined.

Children

See dosing recommendations. The use of linezolid for the empiric treatment of children with CNS infections is not recommended.

Special Risk Patients

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

Catheter-related infections

An imbalance in mortality was seen in patients with intravascular catheter-related infections treated with linezolid. Linezolid is not approved for and should not be used in the treatment of patients with catheter-related bloodstream infections or catheter-site infections.

Clostridium difficile –associated diarrhea

May range from mild diarrhea to fatal colitis. Consider in all patients who present with diarrhea after linezolid use.

Convulsions

Have been reported, in some cases in patients with a history of seizures or risk factors for seizures.

Duration of therapy

Safety and efficacy for linezolid given for more than 28 days have not been evaluated in controlled clinical trials.

Lactic acidosis

May occur.

Myelosuppression

Myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia, has been reported in patients receiving linezolid.

Peripheral and optic neuropathy

Have been reported, including cases progressing to loss of vision, primarily in patients treated for longer than the maximum recommended duration of 28 days.

Phenylketonurics

Oral suspension contains phenylalanine; use with caution in patients with phenylketonuria.

Resistance

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

Serotonin syndrome

Has been associated with coadministration of linezolid and serotonergic agents, including SSRIs.

Superinfection

Use of antibiotics may promote overgrowth of nonsusceptible organisms. Should superinfection occur during therapy, take appropriate measures.

Overdosage

Symptoms

None well documented.

Patient Information

  • Advise patient or caregiver that injection will be prepared by a health care provider, administered in a health care setting, and oral therapy will be started as soon as possible.
  • Advise patient to take each dose without regard to meals but to take with food if stomach upset occurs.
  • Advise patient or caregiver to gently mix suspension by inverting bottle 3 to 5 times before measuring dose, then measure and administer prescribed dose using a dosing syringe, dosing spoon, or dosing cup.
  • Advise patients with phenylketonuria that oral suspension contains phenylalanine and to contact health care provider before using.
  • Advise patient of the need to take exactly as prescribed and complete entire course of therapy, even if symptoms of infection have disappeared. Caution patient or caregiver that skipping doses or not completing the full course of therapy may cause the infection to worsen and increase the possibility that the bacteria will become resistant to the antibiotic and may cause infections that will not be treatable in the future.
  • Instruct patient to avoid foods and beverages with high tyramine content. Review common foods known to have high tyramine content (eg, aged cheeses, fermented or air-dried meats, red wines, sauerkraut, soy sauce, tap beers).
  • Advise patient that diarrhea, headache, and nausea are most common adverse reactions and to inform health care provider if they occur and are intolerable.
  • Advise patient to discontinue therapy and contact health care provider immediately if changes in vision, general body discomfort, generalized stomach distress, hives, itching, muscle aches, progressive drowsiness, skin rash, or unexplained rapid breathing or shortness of breath occurs.
  • Advise patient to report the following signs of superinfection to health care provider: black, furry tongue; foul-smelling stools; white patches in the mouth; vaginal itching or discharge.
  • Warn patient that diarrhea containing blood or pus may be a sign of a serious disorder and to seek medical care if noted and not to treat at home, even if diarrhea starts after stopping the antibiotic.
  • Caution patient not to take any OTC cold products containing decongestants (eg, pseudoephedrine) unless advised by health care provider.

Copyright © 2009 Wolters Kluwer Health.

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