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linezolid 600 mg tablet generic zyvox

Out of Stock Manufacturer ASCEND LABORATO 67877041920
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Uses

Linezolid is used for the treatment of community-acquired pneumonia, nosocomial pneumonia, and uncomplicated or complicated skin and skin structure infections caused by certain susceptible staphylococci or streptococci. Linezolid also is used for the treatment of infections caused by vancomycin-resistant Enterococcus faecium.

Linezolid is not indicated for the treatment of infections caused by gram-negative bacteria. It is imperative that an anti-infective active against gram-negative bacteria be used concomitantly if documented or presumed pathogens include gram-negative bacteria.

Respiratory Tract Infections

Community-acquired Pneumonia

Linezolid is used for the treatment of community-acquired pneumonia (CAP), including infections associated with concurrent bacteremia, caused by susceptible Staphylococcus aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or Streptococcus pneumoniae). Although not labeled by FDA for the treatment of CAP caused by methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA), linezolid is one of several anti-infectives that have been recommended for the treatment of these infections.

Initial treatment of CAP generally involves use of an empiric anti-infective regimen based on the most likely pathogens and local susceptibility patterns; treatment may then be changed (if possible) to provide a more specific regimen (pathogen-directed therapy) based on results of in vitro culture and susceptibility testing. The most appropriate empiric regimen varies depending on the severity of illness at the time of presentation, whether outpatient treatment or hospitalization in or out of an intensive care unit (ICU) is indicated, and the presence or absence of cardiopulmonary disease and other modifying factors that increase the risk of certain pathogens (e.g., MRSA, penicillin-resistant S. pneumoniae, multidrug-resistant S. pneumoniae [MDRSP], enteric gram-negative bacilli, Pseudomonas aeruginosa).

For information regarding the treatment of CAP, including infections caused by MRSA, the current clinical practice guidelines from the Infectious Diseases Society of America (IDSA) available at http://www.idsociety.org should be consulted.

Clinical Experience

In 2 randomized clinical studies in patients 13 years of age or older with CAP, cure rates with linezolid (600 mg every 12 hours for 7-14 days given IV or orally initially, then orally) were approximately 90% and were similar to those achieved with oral cefpodoxime proxetil (200 mg every 12 hours for 10-14 days) or IV ceftriaxone (1 g every 12 hours) followed by oral cefpodoxime proxetil (200 mg every 12 hours) for 7-14 days. In a subset of hospitalized patients with CAP and associated S. pneumoniae bacteremia, linezolid was substantially more effective than a regimen of IV ceftriaxone (cure rate of 93 versus 70%, respectively).

Efficacy and safety of linezolid for the treatment of CAP in pediatric patients is supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic studies in pediatric patients, an uncontrolled study in pediatric patients 8 months through 12 years of age, and additional data from a randomized, open-label, comparator-controlled study of documented or suspected gram-positive bacterial infections in neonates and pediatric patients through 11 years of age.

Nosocomial Pneumonia

Linezolid is used for the treatment of nosocomial pneumonia caused by susceptible S. aureus (including MRSA) or S. pneumoniae.

For empiric treatment of hospital-acquired bacterial pneumonia, including healthcare-associated and ventilator-associated pneumonia in patients with risk factors for multidrug-resistant bacteria, the American Thoracic Society (ATS) and IDSA recommend use of anti-infectives that have a broad spectrum of activity against gram-positive, gram-negative, and anaerobic bacteria. An anti-infective active against MRSA (e.g., vancomycin, linezolid) should be included in the initial empiric regimen in hospitals where MRSA is common or if there are other factors that increase the risk for these strains.

For information regarding the diagnosis and management of nosocomial pneumonia, including infections caused by MRSA, the current IDSA clinical practice guidelines available at http://www.idsociety.org should be consulted.

Clinical Experience

In a randomized, double-blind study in adults with nosocomial bacterial pneumonia, the cure rate in clinically evaluable patients was 57% in those treated with linezolid (600 mg every 12 hours IV for 7-21 days) compared with 60% in those treated with vancomycin (1 g every 12 hours IV for 7-21 days). Both treatment groups also received concomitant therapy with aztreonam (1-2 g every 8 hours IV) for gram-negative coverage. In clinically evaluable patients with ventilator-associated pneumonia, the cure rate was 47% in those who received linezolid and 40% in those who received vancomycin. When results were stratified according to causative organism, linezolid was effective in 59% of infections caused by MRSA and 100% of infections caused by S. pneumoniae.

Efficacy and safety of linezolid for the treatment of nosocomial bacterial pneumonia in pediatric patients is supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic studies in pediatric patients, and additional data from a randomized, open-label, comparator-controlled study of documented or suspected gram-positive bacterial infections in neonates and pediatric patients through 11 years of age. In the comparator-controlled study in pediatric patients with documented or suspected gram-positive infections, the cure rate in pediatric patients with nosocomial pneumonia (intent-to-treat analysis) was 72% in those treated with linezolid and 92% in those treated with vancomycin; the cure rate in clinically evaluable pediatric patients with nosocomial pneumonia was 100% in both groups.

Skin and Skin Structure Infections

Linezolid is used for the treatment of uncomplicated skin and skin structure infections caused by susceptible S. aureus (methicillin-susceptible strains only) or S. pyogenes (group A β-hemolytic streptococci, GAS). The drug also is used for the 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, GBS). The use of linezolid in the treatment of decubitus ulcers has not been studied.

Pending results of in vitro culture and susceptibility testing, coverage against MRSA is recommended for empiric treatment of purulent cellulitis in outpatients or nonpurulent cellulitis in outpatients who do not respond to β-lactam treatment and should be considered for empiric treatment of complicated skin and skin structure infections in hospitalized patients. Linezolid is one of several anti-infectives that have been recommended for the treatment of purulent or nonpurulent cellulitis and for the treatment of complicated skin and skin structure infections caused by MRSA.

For information regarding the treatment of skin and skin structure infections, including infections caused by MRSA, the current IDSA clinical practice guidelines available at http://www.idsociety.org should be consulted.

Clinical Experience

In a randomized, double-blind clinical study in adults with complicated skin and skin structure infections, the efficacy rates (clinical, microbiologic, and overall outcomes) were similar for linezolid (600 mg every 12 hours IV initially, with an option to convert to oral administration) or oxacillin (2 g every 6 hours IV) with an option to switch to oral dicloxacillin (500 mg every 6 hours) for 10-21 days. Patients in both treatment groups received concomitant aztreonam (1-2 g every 6-8 hours IV) if empiric gram-negative coverage was considered necessary. The cure rate in clinically evaluable patients was 90% in those treated with linezolid and 85% in those treated with oxacillin. When results for treatment of these complicated skin and skin structure infections were stratified according to causative organism, linezolid was effective in 88% of infections caused by S. aureus, 67% of infections caused by MRSA, 69% of infections caused by S. pyogenes, and 100% of infections caused by S. agalactiae.

In a randomized clinical study in patients 13 years of age or older with known or suspected MRSA skin and skin structure infections, efficacy (clinical, microbiologic, and overall outcomes) was similar for therapy with linezolid (600 mg every 12 hours IV initially, with an option to convert to oral administration) or vancomycin (1 g every 12 hours IV) for 14-28 days. In an open-label, randomized study in hospitalized adults with documented or suspected MRSA skin and skin structure infections who received 7-28 days of treatment with linezolid (600 mg every 12 hours given IV initially, then orally) or vancomycin (1 g every 12 hours IV) given with or without concomitant aztreonam or gentamicin if clinically indicated, the cure rate in microbiologically evaluable patients was 79% in those treated with linezolid and 73% in those treated with vancomycin.

In a randomized, multicenter open-label comparative study in adults with diabetic foot infections, efficacy rates (clinical and microbiologic outcomes) were similar in patients receiving linezolid (600 mg every 12 hours IV or orally) or an aminopenicillin (ampicillin sodium and sulbactam sodium 1.5-3 g every 6 hours IV, amoxicillin and clavulanate potassium 500-875 mg every 8-12 hours orally, or amoxicillin and clavulanate potassium 0.5-2 g every 6 hours IV [IV preparation not commercially available in the US]) for 14-28 days. Patients in both treatment groups received concomitant aztreonam (1-2 g every 8-12 hours IV) if gram-negative pathogens were isolated from the infection site and patients receiving an aminopenicillin also were treated with vancomycin (1 g every 12 hours IV) if MRSA was isolated from the foot infection. Most patients also received appropriate adjunctive treatment usually required for the treatment of diabetic foot infections (e.g., debridement). When results for treatment of these diabetic foot infections were stratified according to causative organism, linezolid was effective in 78% of infections caused by S. aureus, 71% of infections caused by MRSA, and 86% of infections caused by S. agalactiae.

Efficacy and safety of linezolid for the treatment of complicated skin and skin structure infections in pediatric patients is supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic studies in pediatric patients, and additional data from a randomized, comparator-controlled study of documented or suspected gram-positive bacterial infections in neonates and pediatric patients through 11 years of age. In the comparator-controlled study in pediatric patients with documented or suspected gram-positive infections, the cure rate in pediatric patients with complicated skin and skin structure infections (intent-to-treat analysis) was 85% in those treated with linezolid and 91% in those treated with vancomycin; the cure rate in clinically evaluable pediatric patients with complicated skin and skin structure infections was 94 and 96%, respectively.

Efficacy and safety of linezolid for the treatment of uncomplicated skin and skin structure infections in pediatric patients caused by S. aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or S. pyogenes is supported by data from a comparator-controlled study in pediatric patients 5-17 years of age.

Vancomycin-resistant Enterococcus faecium Infections

Linezolid is used for the treatment of vancomycin-resistant E. faecium infections, including infections associated with concurrent bacteremia.

Linezolid has been used in some patients for the treatment of native valve or prosthetic valve infective endocarditis caused by vancomycin-resistant or multidrug-resistant E. faecium. The American Heart Association (AHA) states that patients with infective endocarditis attributable to enterococci resistant to penicillins, aminoglycosides, and vancomycin should be managed by a team of specialists in infectious disease, cardiology, cardiovascular surgery, clinical pharmacy, and, if necessary, pediatrics.

For information on diagnosis and management of infective endocarditis and its complications, including anti-infective treatment of enterococcal endocarditis, the current AHA guidelines available at http://my.americanheart.org/statements should be consulted.

Clinical Experience

In a randomized, double-blind study in adults comparing high-dose linezolid (600 mg every 12 hours IV or orally) with low-dose linezolid (200 mg every 12 hours IV or orally) for 7-28 days, cure rates for patients with documented vancomycin-resistant E. faecium at any infection site were 67 or 52% for those treated with high- or low-dose linezolid, respectively, based on intent-to-treat analysis. Some patients received concomitant therapy with aztreonam or aminoglycosides. Compared with patients in the high-dose group, there were more adverse events and more deaths among patients in the low-dose group.

Efficacy and safety of linezolid for the treatment of vancomycin-resistant E. faecium infections in pediatric patients is supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic studies in pediatric patients, and additional data from a randomized, open-label, comparator-controlled study of documented or suspected gram-positive bacterial infections in neonates and pediatric patients through 11 years of age. Data from the open-label, comparator-controlled study indicate that the cure rate was 75% in the 8 microbiologically evaluable pediatric patients with vancomycin-resistant E. faecium infections who received linezolid.

Catheter-related Bloodstream Infections

Although linezolid has been investigated for the treatment of intravascular catheter-related bloodstream infections, linezolid is not labeled by FDA for the treatment of catheter-related bacteremia or catheter-site infections and is not indicated for the treatment of gram-negative bacterial infections.

Data from an open-label, randomized study in patients with intravascular catheter-related bloodstream infections indicated that mortality was higher in patients receiving linezolid than in patients receiving comparator anti-infectives. In this study, seriously ill patients with intravascular catheter-related bloodstream infections were randomized to receive linezolid or vancomycin (patients randomized to vancomycin were switched to dicloxacillin or oxacillin if the pathogen was oxacillin-susceptible); patients could receive concomitant therapy for gram-negative infection. Although there was no difference in mortality between linezolid and the comparator regimens in patients with only gram-positive bacteria identified in the baseline culture, mortality was higher in linezolid-treated patients who had gram-negative bacterial infections, mixed gram-negative and gram-positive bacterial infections, or no pathogen identified at baseline.

CNS Infections

Linezolid has been recommended as an alternative to vancomycin for the treatment of CNS infections caused by MRSA (e.g., meningitis, brain abscess, subdural empyema, spinal epidural abscess). The manufacturer states that linezolid is not recommended for empiric treatment of CNS infections in pediatric patients (see Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions).

For information regarding the treatment of CNS infections caused by MRSA, the current IDSA clinical practice guidelines available at http://www.idsociety.org should be consulted.

Dosage and Administration

Reconstitution and Administration

Linezolid is administered orally or by IV infusion.

Oral Administration

Orally administered linezolid may be given without regard to meals. However, large quantities of foods or beverages with high tyramine content should be avoided during linezolid treatment.(See Monoamine Oxidase Inhibition under Warnings/Precautions: Warnings, in Cautions.)

Linezolid powder for oral suspension should be reconstituted at the time of dispensing with the amount of water specified on the bottle to provide a suspension containing 100 mg/5 mL. After tapping the bottle gently to loosen the powder, the water should be added in 2 portions and the suspension agitated well after each addition.

The reconstituted oral suspension should be stored at room temperature and used within 21 days. Prior to administration of each dose, the suspension should be gently mixed by inverting the bottle 3-5 times but should not be shaken.

IV Administration

Linezolid premixed injection for IV administration in single-use flexible containers is administered by IV infusion without further dilution.

Linezolid premixed solutions should be inspected visually for particulate matter prior to administration and should not be used if visible particles are evident. The solution may exhibit a yellow color that can intensify over time without adversely affecting potency. The bags should be squeezed firmly to check for minute leaks. If leaks are detected, the solution should be discarded since sterility may be impaired.

Linezolid premixed injection for IV administration in single-use flexible infusion bags should not be used in series connections, and additives should not be introduced into the solution.

Linezolid is compatible with 5% dextrose, 0.9% sodium chloride, and lactated Ringer's injection.

During simulated Y-site administration, linezolid was physically incompatible with amphotericin B, chlorpromazine hydrochloride, co-trimoxazole, diazepam, erythromycin lactobionate, pentamidine isethionate, and phenytoin sodium. In addition, linezolid is chemically incompatible with ceftriaxone sodium.

Rate of Administration

Linezolid premixed injection for IV administration in single-use flexible containers should be administered by IV infusion over 30-120 minutes.

Dosage

When clinically appropriate, patients treated initially with IV linezolid may be switched to oral linezolid without dosage adjustment.

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

Adult Dosage

Respiratory Tract Infections

The usual adult oral or IV dosage of linezolid for the treatment of community-acquired pneumonia (CAP) caused by susceptible Staphylococcus aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or Streptococcus pneumoniae is 600 mg every 12 hours for 10-14 days. If linezolid is used for the treatment of CAP caused by susceptible methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA), an oral or IV dosage of 600 mg twice daily for 7-21 days has been recommended.

The usual adult oral or IV dosage of linezolid for the treatment of nosocomial pneumonia caused by susceptible S. aureus (including MRSA) or S. pneumoniae is 600 mg every 12 hours for 10-14 days. IDSA recommends a duration of 7-21 days for the treatment of healthcare-associated pneumonia caused by MRSA.

Skin and Skin Structure Infections

For the treatment of uncomplicated skin and skin structure infections caused by susceptible S. aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or S. pyogenes (group A β-hemolytic streptococci, GAS), the usual adult oral dosage of linezolid is 400 mg every 12 hours for 10-14 days. For purulent or nonpurulent cellulitis caused by MRSA, IDSA recommends that outpatients receive an oral dosage of 600 mg twice daily for 5-10 days; treatment duration should be based on clinical response.

The usual adult oral or IV dosage of linezolid for the treatment of complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by susceptible S. aureus (including MRSA), S. pyogenes (group A β-hemolytic streptococci), or S. agalactiae (group B streptococci, GBS) is 600 mg every 12 hours for 10-14 days. IDSA recommends a duration of 7-14 days for the treatment of complicated skin and skin structure infections caused by MRSA; treatment duration should be based on clinical response.

Vancomycin-resistant Enterococcus faecium Infections

The usual adult oral or IV dosage of linezolid for the treatment of vancomycin-resistant Enterococcus faecium infections, including infections with concurrent bacteremia, is 600 mg every 12 hours for 14-28 days.

CNS Infections

If linezolid is used in adults for the treatment of CNS infections caused by MRSA(See Uses: CNS Infections), IDSA recommends an oral or IV dosage of 600 mg twice daily.

Pediatric Dosage

General Dosage for Neonates

In premature neonates younger than 7 days of age, the manufacturer recommends an initial linezolid dosage of 10 mg/kg every 12 hours; a dosage of 10 mg/kg every 8 hours may be considered in those with an inadequate response to the lower dosage. The manufacturer recommends that all neonates 7 days of age or older receive a linezolid dosage of 10 mg/kg every 8 hours.

When linezolid is used in neonates 7 days of age or younger, the American Academy of Pediatrics (AAP) recommends an IV dosage of 10 mg/kg every 12 hours in those weighing 2 kg or less and 10 mg/kg every 8 hours in those weighing more than 2 kg. For neonates 8-28 days of age, AAP recommends an IV dosage of 10 mg/kg every 8 hours, regardless of weight.

General Dosage for Infants and Children

The manufacturer usually recommends that infants and children through 11 years of age receive oral or IV linezolid in a dosage of 10 mg/kg every 8 hours and that adolescents 12 years of age or older receive 600 mg every 12 hours.

When linezolid is used in pediatric patients beyond the neonatal period, AAP recommends an oral or IV dosage of 10 mg/kg 3 times daily in children younger than 12 years of age and a dosage of 600 mg twice daily in adolescents 12 years of age or older.

Respiratory Tract Infections

The usual oral or IV dosage of linezolid for the treatment of CAP caused by susceptible S. aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or S. pneumoniae is 10 mg/kg every 8 hours in pediatric patients 7 days of age through 11 years of age and 600 mg every 12 hours in adolescents 12 years of age or older. The recommended duration of treatment is 10-14 days.

The usual oral or IV dosage of linezolid for the treatment of nosocomial pneumonia caused by susceptible S. aureus (including MRSA) or S. pneumoniae is 10 mg/kg every 8 hours in pediatric patients 7 days through 11 years of age and 600 mg every 12 hours in adolescents 12 years of age or older. The recommended duration of treatment is 10-14 days.

IDSA recommends a duration of 7-21 days for the treatment of CAP or healthcare-associated pneumonia caused by MRSA.

Skin and Skin Structure Infections

For the treatment of uncomplicated skin and skin structure infections caused by susceptible S. aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or S. pyogenes in pediatric patients, the usual oral dosage of linezolid is 10 mg/kg every 8 hours in those younger than 5 years of age, 10 mg/kg every 12 hours in those 5 through 11 years of age, and 600 mg every 12 hours in adolescents 12 years of age or older. The recommended duration of treatment is 10-14 days.

The usual oral or IV dosage of linezolid for the treatment of complicated skin and skin structure infections caused by susceptible S. aureus (including MRSA), S. pyogenes, or S. agalactiae is 10 mg/kg every 8 hours in pediatric patients 7 days of age through 11 years of age and 600 mg every 12 hours in adolescents 12 years of age or older. The recommended duration of treatment is 10-14 days.

Vancomycin-resistant Enterococcus faecium Infections

The usual oral or IV dosage of linezolid for the treatment of vancomycin-resistant E. faecium infections is 10 mg/kg every 8 hours in pediatric patients 7 days of age through 11 years of age and 600 mg every 12 hours in adolescents 12 years of age or older. The recommended duration of treatment is 14-28 days.

CNS Infections

If linezolid is used in pediatric patients for the treatment of CNS infections caused by MRSA(See Uses: CNS Infections), IDSA recommends an oral or IV dosage of 10 mg/kg (up to 600 mg) every 8 hours.

Special Populations

Hepatic Impairment

Dosage adjustments are not necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A or B). Data are not available regarding the pharmacokinetics of linezolid in patients with severe hepatic impairment.

Renal Impairment

Dosage adjustments are not necessary in patients with renal impairment. However, the 2 principal metabolites of linezolid may accumulate in patients with renal impairment and the clinical importance of accumulation of these metabolites has not been determined.(See Renal Impairment under Cautions: Specific Populations.)

Because linezolid is removed by hemodialysis, patients undergoing hemodialysis should receive linezolid doses after the dialysis session.

Geriatric Patients

Dosage adjustments are not necessary in geriatric patients.

Cautions

Contraindications

Linezolid is contraindicated in patients with known hypersensitivity to linezolid or any ingredient in the formulation.

Linezolid should not be used in patients who are receiving (or have received within the last 2 weeks) drugs that inhibit monoamine oxidase (MAO) A or B, including MAO inhibitor antidepressants (e.g., isocarboxazid, phenelzine).(See Drug Interactions: Monoamine Oxidase Inhibitors.)

Warnings/Precautions

Hematologic Effects

Myelosuppression (e.g., anemia, leukopenia, pancytopenia, thrombocytopenia) has been reported in patients receiving linezolid.

Toxicity studies in adult and juvenile dogs and rats indicate myelosuppression (bone marrow hypocellularity/decreased hematopoiesis; decreased extramedullary hematopoiesis in spleen and liver; decreased levels of circulating erythrocytes, leukocytes, and platelets) and lymphoid depletion in thymus, lymph nodes, and spleen.

Complete blood cell counts (CBCs) should be monitored weekly during linezolid treatment, especially in patients receiving the drug for more than 2 weeks and in those who have preexisting myelosuppression, are receiving concomitant drugs that produce bone marrow suppression, or have a chronic infection that was or is being treated with concomitant anti-infective therapy.

Discontinuance of linezolid should be considered if myelosuppression develops or worsens. Hematologic parameters generally have increased toward pretreatment values following discontinuance of the drug.

Peripheral and Optic Neuropathy

Peripheral and optic neuropathies have been reported in adults and children receiving linezolid; these events have occurred principally in patients receiving the drug for longer than the maximum recommended duration of treatment (28 days). Optic neuropathy sometimes progressed to loss of vision when linezolid was used for longer than 28 days. Blurred vision has been reported in some patients who received the drug for less than 28 days.

If a patient experiences symptoms of visual impairment (e.g., changes in visual acuity or color vision, blurred vision, or visual field defect), an ophthalmic evaluation should be performed promptly. All patients receiving linezolid for extended periods of time (i.e., 3 months or longer) should have their visual function monitored. In addition, all patients reporting a new visual symptom, regardless of the length of linezolid treatment, should have their visual function monitored.

If peripheral or optic neuropathy occurs, the potential benefits of linezolid should be weighed against the potential risks of continued treatment with the drug.

Serotonin Syndrome

Serotonin syndrome (including some fatalities) has been reported in patients receiving linezolid concomitantly with serotonergic drugs. 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.

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

Linezolid should not be used in patients with carcinoid syndrome or in patients receiving SSRIs, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), meperidine, bupropion, or buspirone unless concomitant therapy is considered clinically appropriate and patients can be carefully monitored for signs and/or symptoms of serotonin syndrome or neuroleptic malignant syndrome-like (NMS-like) reactions.(See Drug Interactions: Monoamine Oxidase Inhibitors and see Drug Interactions: Serotonergic Drugs.)

Mortality

In a study in seriously ill patients with intravascular catheter-related infections, mortality was higher in linezolid-treated patients than in those treated with a comparator anti-infective (vancomycin, dicloxacillin, oxacillin).(See Uses: Catheter-related Bloodstream Infections.)

Monoamine Oxidase Inhibition

Linezolid is a weak, nonselective, reversible inhibitor of monoamine oxidase (MAO). The drug potentially may interact with MAO inhibitors and adrenergic and serotonergic agents.(See Drug Interactions: Monoamine Oxidase Inhibitors, Drug Interactions: Sympathomimetic Agents, and Drug Interactions: Serotonergic Drugs.)

A significant pressor response has been reported when tyramine doses exceeding 100 mg were used in adults receiving linezolid. Patients should be instructed to avoid large quantities of foods or beverages with high tyramine content during linezolid treatment. Foods high in tyramine include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor (e.g., aged cheeses, fermented or air-dried meat, sauerkraut, soy sauce, tap beer, red wine). Tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated. For additional information on interactions in patients receiving MAO inhibitors and foods containing large amounts of tyramine,

Risk of Hypertension

Unless patients are monitored for potential increases in blood pressure, linezolid should not be used in patients with uncontrolled hypertension, pheochromocytoma, or thyrotoxicosis or in patients receiving direct- or indirect-acting sympathomimetic agents (e.g., pseudoephedrine), vasopressor agents (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine).(See Drug Interactions: Sympathomimetic Agents.)

Lactic Acidosis

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

Seizures

Seizures have been reported in patients receiving linezolid. Some cases were reported in patients with a history of seizures or risk factors for seizures.

Hypoglycemia

Symptomatic hypoglycemia has been reported in patients with diabetes mellitus receiving linezolid concomitantly with insulin or oral antidiabetic agents.(See Drug Interactions: Antidiabetic Agents.)

Although a causal relationship between linezolid and hypoglycemia has not been established, patients with diabetes mellitus should be cautioned about the potential for hypoglycemia during linezolid treatment.

If hypoglycemia occurs, dosage reduction of insulin or oral antidiabetic agents or discontinuance of linezolid, insulin, or oral antidiabetic agents may be necessary.

Sensitivity Reactions

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

Tooth Discoloration

Superficial tooth discoloration and tongue discoloration have been reported in patients receiving linezolid. In cases with known outcome, tooth discoloration was removable with professional dental cleaning (manual descaling).

Phenylketonuria

Individuals who must restrict their intake of phenylalanine should be warned that linezolid for oral suspension contains aspartame, which is metabolized in the GI tract following oral administration, to provide 20 mg of phenylalanine per 5 mL of suspension.

Linezolid tablets do not contain aspartame and 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.

Superinfection/Clostridium difficile-associated Diarrhea and Colitis

Use of linezolid may result in emergence and overgrowth of nonsusceptible organisms. Appropriate therapy should be instituted if superinfection occurs.

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all anti-infectives, including linezolid, and may range in severity from mild diarrhea to fatal colitis.C. difficile produces toxins A and B which contribute to the development of CDAD; 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.

CDAD should be considered in the differential diagnosis of patients who develop diarrhea during or after anti-infective therapy. Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued whenever possible. Patients should be managed with 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.

Selection and Use of Anti-infectives

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

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

Safety and efficacy of linezolid given for longer than 28 days have not been evaluated in controlled clinical trials.(See Dosage and Administration: Dosage.)

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

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

Specific Populations

Pregnancy

Category C.

In studies in mice, rats, and rabbits, linezolid was not teratogenic; however, embryo and fetal toxicities were reported. These nonteratogenic effects included increased postimplantational embryo death, decreased fetal body weights, and increased incidence of costal cartilage fusion in mice; decreased fetal body weights, reduced ossification of sternebrae, and decreased survival of pups in rats; and reduced fetal body weight in rabbits. Linezolid should be used during pregnancy only if potential benefits justify potential risk to the fetus.

Lactation

Linezolid and its metabolites are distributed into milk in rats; it is not known whether the drug and metabolites are distributed into human milk.

Linezolid should be used with caution in nursing women.

Pediatric Use

Safety and efficacy of linezolid for the treatment of community-acquired pneumonia (CAP), nosocomial pneumonia, complicated skin and skin structure infections, or vancomycin-resistant Enterococcus faecium 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. Safety and efficacy of the drug for the treatment of CAP in pediatric patients also is supported by evidence from an uncontrolled study in patients 8 months through 12 years of age.

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

While some pharmacokinetic parameters (i.e., peak plasma concentration, volume of distribution) are similar in children of all ages, linezolid clearance varies with age. Excluding neonates younger than 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, the clearance of linezolid decreases and clearance values in adolescents approach those observed in adults. Systemic exposure (mean daily area under the plasma concentration-time curve [AUC]) in pediatric patients younger than 12 years of age receiving linezolid every 8 hours generally is similar to that in adults and adolescents receiving the drug every 12 hours. There is wider intraindividual variability in linezolid clearance and in systemic drug exposure in all pediatric age groups relative to adults.

The manufacturer states that linezolid is not recommended for empiric treatment of CNS infections in pediatric patients; therapeutic concentrations of the drug were not consistently achieved or maintained in CSF of pediatric patients with ventriculoperitoneal shunts.

Inadequate systemic exposure, site and severity of infection, and underlying medical conditions should be considered in children with a suboptimal response to linezolid, especially those with infections caused by gram-positive bacteria that have minimum inhibitory concentrations (MICs) of 4 mcg/mL.

Geriatric Use

No overall differences in safety, efficacy, or pharmacokinetics have been observed in geriatric adults 65 years of age or older compared with younger adults. Other clinical experience has not revealed age-related differences in response, but the possibility of greater sensitivity in some older patients cannot be ruled out.

Renal Impairment

Linezolid pharmacokinetics are not altered in patients with renal impairment. However, the 2 principal metabolites of linezolid may accumulate in patients with impaired renal function and the amount of accumulation increases with the severity of renal impairment. Because the clinical importance of accumulation of linezolid metabolites has not been determined, the potential benefits of linezolid in patients with renal impairment should be weighed against the potential risks of accumulation of the metabolites.(See Renal Impairment under Dosage and Administration: Special Populations.)

Hepatic Impairment

Linezolid pharmacokinetics are not altered in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); pharmacokinetics of the drug have not been evaluated in patients with severe hepatic impairment.

Common Adverse Effects

Adverse effects occurring in 2% or more of adults receiving linezolid include GI effects (diarrhea, nausea, vomiting), headache, anemia, rash, and dizziness. Adverse effects reported in 2% or more of pediatric patients receiving linezolid in clinical studies include GI effects (diarrhea, nausea, vomiting, localized or generalized abdominal pain, loose stools), headache, anemia, and thrombocytopenia.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Linezolid is minimally metabolized (possibly mediated by cytochrome P-450 [CYP] enzymes), does not induce CYP enzymes, and does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4.

Linezolid is not expected to affect the pharmacokinetics of other drugs metabolized by CYP isoenzymes.

Although the mechanism of the interaction is unknown and may be related to induction of hepatic enzymes, concomitant use of rifampin and linezolid has resulted in decreased linezolid concentrations. It is possible that concomitant use of other potent inducers of hepatic enzymes (e.g., carbamazepine, phenytoin, phenobarbital) could result in decreased linezolid exposures.

Antidiabetic Agents

Hypoglycemia has been reported in patients with diabetes mellitus receiving linezolid concomitantly with insulin or oral antidiabetic agents. Although a causal relationship has not been established, linezolid is a nonselective, reversible monoamine oxidase (MAO) inhibitor and some MAO inhibitors have been associated with hypoglycemic episodes in patients with diabetes mellitus who were also receiving insulin or oral antidiabetic agents. Patients should be warned of the potential for hypoglycemia. If hypoglycemia occurs, dosage reduction of the antidiabetic agent or discontinuance of linezolid or the antidiabetic agent may be necessary.

Anti-infective Agents

Aminoglycosides

Concomitant use of linezolid and gentamicin does not affect the pharmacokinetics of either drug.

In vitro studies indicate the antibacterial effects of linezolid and gentamicin or streptomycin may be additive or indifferent.

Ampicillin

In vitro studies indicate the antibacterial effects of linezolid and ampicillin may be additive or indifferent.

Aztreonam

Concomitant use of linezolid and aztreonam does not result in clinically important effects on the pharmacokinetics of either drug.

In vitro studies indicate the antibacterial effects of linezolid and aztreonam may be additive or indifferent.

Carbapenems

In vitro studies indicate the antibacterial effects of linezolid and imipenem may be additive or indifferent.

Rifampin

Concomitant use of linezolid (600 mg twice daily for 2.5 days) and rifampin (600 mg once daily for 8 days) resulted in a 21% decrease in peak plasma concentrations of linezolid and a 32% decrease in the area under the plasma concentration-time curve (AUC) of linezolid. The mechanism and clinical importance of this pharmacokinetic interaction are unknown, although the interaction may be related to induction of hepatic enzymes.

In vitro studies indicate the antibacterial effects of linezolid and rifampin may be additive or indifferent.

Vancomycin

In vitro studies indicate the antibacterial effects of linezolid and vancomycin may be additive or indifferent.

Monoamine Oxidase Inhibitors

Linezolid is a weak, nonselective, reversible MAO inhibitor and there is potential for pharmacologic interactions with other MAO inhibitors. Because of the potential for interaction, linezolid should not be used in patients who are receiving (or have received within the last 2 weeks) a drug that inhibits MAO-A or MAO-B (e.g., isocarboxazid, phenelzine, selegiline, tranylcypromine).

Although FDA has not concluded whether the risk of serotonin syndrome associated with concomitant use of linezolid and MAO inhibitors is comparable to that reported when linezolid is used concomitantly with selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), linezolid generally should not be used in patients receiving serotonergic drugs, including MAO inhibitors (e.g., isocarboxazid, phenelzine, selegiline, tranylcypromine).(See Drug Interactions: Serotonergic Drugs.)

Phenytoin

Concomitant use of linezolid and phenytoin is not expected to affect the pharmacokinetics of phenytoin, but may possibly result in decreased linezolid exposures. Dosage adjustments are not required if linezolid and phenytoin are used concomitantly.

Serotonergic Drugs

Concomitant use of linezolid and serotonergic drugs is associated with a risk of serotonin syndrome. There have been postmarketing reports of serotonin syndrome, including some fatalities, in patients who received linezolid concurrently with or shortly after discontinuance of serotonergic agents, particularly SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) or SNRIs (e.g., desvenlafaxine, duloxetine, venlafaxine). While FDA has not received reports of serotonin syndrome with concomitant use of linezolid and vilazodone, the risk is considered comparable to that with SSRIs. It is unclear whether concomitant use of linezolid and other drugs with lesser degrees of serotonergic activity, including tricyclic antidepressants (amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine), MAO inhibitors (isocarboxazid, phenelzine, transdermal selegiline, tranylcypromine), amoxapine, bupropion, buspirone, maprotiline, mirtazapine, nefazodone, and trazodone, is associated with a risk of serotonin syndrome comparable to that reported when linezolid is used concomitantly with SSRIs or SNRIs.

Because of the risk of serotonin syndrome, linezolid should not be used in patients receiving serotonergic drugs, including SSRIs, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), meperidine, bupropion, or buspirone, unless concomitant therapy is considered clinically appropriate and patients can be carefully monitored for signs and/or symptoms of serotonin syndrome or neuroleptic malignant syndrome-like (NMS-like) reactions.

There may be some cases when a patient is already receiving a serotonergic antidepressant or buspirone and requires urgent treatment with linezolid (e.g., life-threatening infections caused by methicillin-resistant Staphylococcus aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA] or vancomycin-resistant Enterococcus faecium). In these situations, if alternatives to linezolid are not available and the potential benefits of linezolid outweigh the risks of serotonin syndrome or NMS-like reactions, the serotonergic antidepressant should be stopped promptly and linezolid administered. The patient should be monitored for manifestations of serotonin syndrome or NMS-like reactions (e.g., hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes that include extreme agitation progressing to delirium and coma) for 2 weeks (5 weeks if fluoxetine was taken) or until 24 hours after the last dose of linezolid, whichever comes first. The patient also should be monitored for symptoms associated with discontinuance of the antidepressant.

Treatment with serotonergic drugs should not be initiated in a patient receiving linezolid; when necessary, the serotonergic drug may be started or reinitiated 24 hours after the last linezolid dose.

For further information on serotonin syndrome, including manifestations and treatment,

Sympathomimetic Agents

Concomitant use of linezolid and indirect-acting sympathomimetic agents (e.g., phenylpropanolamine, pseudoephedrine), vasopressor agents (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine) may result in a reversible enhancement of the pressor response to these agents.

Unless patients are monitored for potential increases in blood pressure, linezolid should not be used in patients receiving direct- or indirect-acting sympathomimetic agents (e.g., pseudoephedrine), vasopressor agents (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine).

If an adrenergic agent (e.g., dopamine, epinephrine) is initiated in a patient receiving linezolid, lower initial doses of the adrenergic agent should be used and dosage titrated to achieve the desired response.

Vitamins

Concomitant use of linezolid (600 mg orally on day 1 and day 8) and ascorbic acid (1 g daily on days 2-9) or vitamin E (800 units daily on days 2-9) increased the AUC of linezolid by 2.3 or 10.9%, respectively.

Adjustment of linezolid dosage is not needed if the drug is used concomitantly with ascorbic acid or vitamin E.

Warfarin

Linezolid does not have a substantial effect on the pharmacokinetics of warfarin; dosage adjustments are not required if linezolid and warfarin are used concomitantly.

Pharmacokinetics

Absorption

Bioavailability

Linezolid is rapidly and extensively absorbed after oral administration; absolute oral bioavailability of the drug is approximately 100%.

Peak plasma concentrations of linezolid are attained within 1-2 hours following oral administration.

Food

The time to peak concentrations is delayed and peak concentrations are decreased when linezolid is administered with a high-fat meal, but the extent of absorption is not affected. This effect is not considered clinically important.

Distribution

Extent

Linezolid is readily distributed into well-perfused tissues.

In adults with CNS infections, IV administration of linezolid (600 mg twice daily) resulted in steady-state mean peak CSF concentrations that were 36-58% of mean peak plasma concentrations; the time to peak CSF concentrations was approximately 3-4 hours after a dose.

In pediatric patients with ventriculoperitoneal shunts receiving single or multiple doses of linezolid, therapeutic concentrations of the drug were not consistently achieved or maintained in CSF.

Linezolid and its metabolites are distributed into milk in rats; it is not known whether the drug and metabolites are distributed into human milk.

Plasma Protein Binding

Linezolid is approximately 31% bound to plasma proteins.

Elimination

Metabolism

Linezolid is metabolized principally by oxidation of the morpholine ring to 2 inactive metabolites, an aminoethoxyacetic acid metabolite (A) and a hydroxyethyl glycine metabolite (B). Although metabolite A is presumed to be formed via an enzymatic pathway, in vitro studies indicate metabolite B is formed by nonenzymatic chemical oxidation. In vitro studies indicate linezolid is minimally metabolized and this may be mediated by the cytochrome P-450 (CYP) enzyme system.

Elimination Route

Approximately 65% of a linezolid dose is eliminated via nonrenal clearance. Under steady-state conditions, approximately 30% of a linezolid dose is eliminated in urine as unchanged drug, 10% is eliminated as metabolite A, and 40% is eliminated as metabolite B. Mean renal clearance of linezolid is 40 mL/minute, suggesting net tubular reabsorption.

Almost no linezolid is found in feces as unchanged drug; approximately 3 and 6% of a dose is eliminated in feces as metabolite A and metabolite B, respectively.

Linezolid and its metabolites are removed by hemodialysis. Approximately 30% of a linezolid dose is removed by a 3-hour hemodialysis session started 3 hours after the dose.

It is not known whether linezolid and its metabolites are removed by peritoneal dialysis.

Half-life

The mean elimination half-life of linezolid is 4.3-6.4 hours in adults.

In neonates, the mean elimination half-life of linezolid is 5.6 hours in preterm neonates younger than 1 week of age, 3 hours in full-term neonates younger than 1 week of age, and 1.5 hours in neonates 1 week to 28 days of age.

In infants and children, the mean elimination half-life of linezolid is 1.8 hours in infants older than 28 days through 2 months of age and 2.9 hours in infants and children 3 months through 11 years of age.

In adolescents 12 through 17 years of age, the mean elimination half-life of linezolid is 4.1 hours.

Special Populations

Linezolid pharmacokinetics in patients 65 years of age or older are similar to the pharmacokinetics in younger adults.

In pediatric patients, clearance of linezolid varies with age and there is wide intraindividual variability. Excluding neonates younger than 7 days 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.

Linezolid pharmacokinetics are not affected by mild to moderate hepatic impairment (Child-Pugh class A or B); pharmacokinetics of the drug have not been studied in patients with severe hepatic impairment.

Pharmacokinetics of linezolid are not affected by renal impairment. However, the 2 principal metabolites of the drug accumulate in patients with impaired renal function and the amount of accumulation increases with the severity of renal impairment.

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