Zyvox

Zyvox

linezolid

Manufacturer:

Pfizer
Full Prescribing Info
Contents
Linezolid.
Description
Each film-coated tablet also contains the following inactive ingredients: Cornstarch, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide and carnauba wax. Each tablet has a sodium content of 2.92 mg (0.1 mEq).
Zyvox injection also contains the following inactive ingredients: Sodium citrate, citric acid and dextrose in an aqueous vehicle. The sodium content is 0.38 mg/mL (5 mEq/300-mL bag, 3.3 mEq/200-mL bag and 1.7 mEq/100-mL bag).
Linezolid, a synthetic antibacterial agent of the oxazolidinone class, is (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-acetamide. The empirical formula is C16H20FN3O4 and the molecular weight is 337.35.
Action
Pharmacology: Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of the other bacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotic is unlikely to happen. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the majority of strains.
Clinical Studies: Adults: Vancomycin-Resistant Enterococcal Infections: Adult patients with documented or suspected vancomycin-resistant enterococcal infection were enrolled in a randomized, multicenter, double-blind trial comparing a high dose of Zyvox (600 mg) with a low dose of Zyvox (200 mg) given every 12 hrs either IV or orally for 7-28 days. Patients could receive concomitant aztreonam or aminoglycosides. There were 79 patients randomized to high-dose linezolid and 66 patients to low-dose linezolid. The intent-to-treat (ITT) population with documented vancomycin-resistant enterococcal infection at baseline consisted of 65 patients in the high-dose arm and 52 patients in the low-dose arm.
The cure rates for the ITT population with documented vancomycin-resistant enterococcal infection at baseline are presented in Table 1 by source of infection. These cure rates do not include patients with missing or indeterminate outcomes. The cure rate was higher in the high-dose arm than in the low-dose arm, although the difference was not statistically significant at the 0.05 level. (See Table 1.)


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Nosocomial Pneumonia: Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a randomized, multicenter, double-blind trial. Patients were treated for 7-21 days. One (1) group received Zyvox IV injection 600 mg every 12 hrs, and the other group received vancomycin 1 g every 12 hrs IV. Both groups received concomitant aztreonam (1-2 g every 8 hrs IV), which could be continued if clinically indicated. There were 203 linezolid-treated and 193 vancomycin-treated patients enrolled in the study. One hundred twenty-two (122) (60%) linezolid-treated patients and 103 (53%) vancomycin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 57% for linezolid-treated patients and 60% for vancomycin-treated patients. The cure rates in clinically evaluable patients with ventilator-associated pneumonia were 47% for linezolid-treated patients and 40% for vancomycin-treated patients. A modified intent-to-treat (MITT) analysis of 94 linezolid-treated patients and 83 vancomycin-treated patients included subjects who had a pathogen isolated before treatment. The cure rates in the MITT analysis were 57% in linezolid-treated patients and 46% in vancomycin-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 2. (See Table 2.)


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Pneumonia Caused by Multi-Drug Resistant Streptococcus pneumoniae (MDRSP*): Zyvox was studied for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) due to MDRSP by pooling clinical data from 7 comparative and non-comparative Phase 2 and Phase 3 studies involving adult and pediatric patients. The pooled MITT population consisted of all patients with S. pneumoniae isolated at baseline; the pooled ME population consisted of patients satisfying criteria for microbiologic evaluability. The pooled MITT population with CAP included 15 patients (41%) with severe illness (risk classes IV and V) as assessed by a prediction rule. The pooled clinical cure rates for patients with CAP due to MDRSP were 35/48 (73%) in the MITT and 33/36 (92%) in the ME populations, respectively. The pooled clinical cure rates for patients with HAP due to MDRSP were 12/18 (67%) in the MITT and 10/12 (83%) in the ME populations, respectively. (See Table 3.)


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Complicated Skin and Skin Structure Infections: Adult patients with clinically documented complicated skin and skin structure infections were enrolled in a randomized, multicenter, double-blind, double-dummy trial comparing study medications administered IV followed by medications given orally for a total of 10-21 days of treatment. One group of patients received Zyvox IV injection 600 mg every 12 hrs followed by Zyvox tablets 600 mg every 12 hrs; the other group received oxacillin 2 g IV every 6 hrs followed by dicloxacillin 500 mg every 6 hrs orally. Patients could receive concomitant aztreonam if clinically indicated. There were 400 linezolid-treated and 419 oxacillin-treated patients enrolled in the study. Two hundred forty-five (245) (61%) linezolid-treated patients and 242 (58%) oxacillin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 90% in linezolid-treated patients and 85% in oxacillin-treated patients. A MITT analysis of 316 linezolid-treated patients and 313 oxacillin-treated patients included subjects who met all criteria for study entry. The cure rates in the MITT analysis were 86% in linezolid-treated patients and 82% in oxacillin-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 4.


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A separate study provided additional experience with the use of linezolid in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. This was a randomized, open-label trial in hospitalized adult patients with documented or suspected MRSA infection.
One group of patients received Zyvox IV injection 600 mg every 12 hrs followed by Zyvox tablets 600 mg every 12 hrs. The other group of patients received vancomycin 1 g IV every 12 hrs. Both groups were treated for 7-28 days, and could receive concomitant aztreonam or gentamicin if clinically indicated. The cure rates in microbiologically evaluable patients with MRSA skin and skin structure infection were 26/33 (79%) for linezolid-treated patients and 24/33 (73%) for vancomycin-treated patients.
Diabetic Foot Infections: Adult diabetic patients with clinically documented complicated skin and skin structure infections (diabetic foot infections) were enrolled in a randomized (2:1 ratio), multi-center, open-label trial comparing study medications administered IV or orally for a total of 14-28 days of treatment. One (1) group of patients received Zyvox 600 mg IV or orally every 12 hrs; the other group received ampicillin/sulbactam 1.5-3 g IV or amoxicillin/clavulanate 500-875 mg every 8-12 hrs orally. In countries where ampicillin/sulbactam is not marketed, amoxicillin/clavulanate 500 mg to 2 g every 6 hrs was used for the IV regimen. Patients in the comparator group could also be treated with vancomycin 1 g IV every 12 hrs if MRSA was isolated from the foot infection. Patients in either treatment group who had Gram-negative bacilli isolated from the infection site could also receive aztreonam 1-2 g IV every 8-12 hrs. All patients eligible to receive appropriate adjunctive treatment methods eg, debridement and off-loading, as typically required in the treatment of diabetic foot infections, and most patients received these treatments. There were 241 linezolid-treated and 120 comparator-treated patients in the intent-to-treat (ITT) study population. Two hundred twelve (212) (86%) linezolid-treated patients and 105 (85%) comparator-treated patients were clinically evaluable. In the ITT population, the cure rates were 68.5% (165/241) in linezolid-treated patients and 64% (77/120) in the comparator-treated patients, where those with indeterminated and missing outcomes were considered failures. The cure rates in the clinically evaluable patients (excluding those with indeterminate and missing outcomes) were 83% (159/192) and 73% (74/101) in the linezolid- and comparator-treated patients, respectively. A clinical post-hoc analysis focused on 121 linezolid-treated and 60 comparator-treated patients who had a gram-positive pathogen isolated from the site of infection or from blood, who had less evidence of underlying osteomyelitis than the overall study population, and who did not receive prohibited antimicrobials. Based upon that analysis, the cure rates were 71% (86/121) in the linezolid-treated patients and 63% (38/60) in the comparator-treated patients. None of the previously mentioned analyses were adjusted for the use of adjunctive therapies. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 5. (See Table 5.)


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Microbiology: Linezolid is a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones, which has clinical utility in the treatment of infections caused by aerobic gram-positive bacteria. The in vitro spectrum of activity of linezolid also includes certain gram-negative and anaerobic bacteria. Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the majority of strains.
In clinical trials, resistance to linezolid developed in 6 patients infected with E. faecium (4 patients received 200 mg every 12 hrs, lower than the recommended dose, and 2 patients received 600 mg every 12 hrs). In a compassionate use program, resistance to linezolid developed in 8 patients with E. faecium and in 1 patient with E. faecalis. All patients had either unremoved prosthetic devices or undrained abscesses. Resistance to linezolid occurs in vitro at a frequency of 1 x 10-9 to 1 x 10-11. In vitro studies have shown that point mutations in the 23S rRNA are associated with linezolid resistance. Reports of vancomycin-resistant E. faecium becoming resistant to linezolid during its clinical use have been published. In one report, nosocomial spread of vancomycin- and linezolid-resistant E. faecium occurred. There have been reports of Staphylococcus aureus (methicillin-resistant) developing resistance to linezolid during its clinical use. The linezolid resistance in these organisms was associated with a point mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism. When antibiotic-resistant organisms are encountered in the hospital, it is important to emphasize infection control policies. Resistance to linezolid has not been reported in Streptococcus spp, including S. pneumoniae.
In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampin, imipenem-cilastatin, aztreonam, ampicillin or streptomycin.
Linezolid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections, as described under Indications.
Aerobic and Facultative Gram-Positive Microorganisms: Enterococcus faecium (vancomycin-resistant strains only); Staphylococcus aureus (including methicillin-resistant strains); Streptococcus agalactiae; Streptococcus pneumoniae [including multi-drug resistant isolates (MDRSP)*]; Streptococcus pyogenes.
The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for linezolid. However, the safety and effectiveness of linezolid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Aerobic and Facultative Gram-Positive Microorganisms: Enterococcus faecalis (including vancomycin-resistant strains); Enterococcus faecium (vancomycin-susceptible strains); Staphylococcus epidermidis (including methicillin-resistant strains); Staphylococcus haemolyticus; Viridans group streptococci.
Aerobic and Facultative Gram-Negative Microorganisms: Pasteurella multocida.
*MDRSP refers to isolates resistant to ≥2 of the following antibiotics: Penicillin, 2nd-generation cephalosporins, macrolides, tetracycline and trimethoprim/sulfamethoxazole.
Susceptibility Testing: Note: Susceptibility testing by dilution methods requires the use of linezolid susceptibility powder.
When available, the results of in vitro susceptibility tests should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of linezolid powder. The MIC values should be interpreted according to criteria provided in Table 6.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with linezolid 30 mcg to test the susceptibility of microorganisms to linezolid. The disk diffusion interpretive criteria are provided in Table 6. (See Table 6.)


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A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Quality Control: Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard linezolid powder should provide the following range of values noted in Table 7. (See Table 7.)
Note: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains used for microbiological quality control are not clinically significant.


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Pharmacokinetics: The mean pharmacokinetic parameters of linezolid after single and multiple oral and IV doses are summarized in Table 8. (See Table 8.)


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Absorption: Linezolid is rapidly and extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1-2 hrs after dosing and the absolute bioavailability is approximately 100%. Therefore, linezolid may be given orally or IV without dose adjustment.
Linezolid may be administered without regard to the timing of meals. The time to reach the maximum concentration is delayed from 1.5-2.2 hrs and Cmax is decreased by about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC0-∞ values is similar under both conditions.
Distribution: Animal and human pharmacokinetic studies have demonstrated that linezolid readily distributes to well-perfused tissues. The plasma protein-binding of linezolid is approximately 31% and is concentration-independent. The volume of distribution of linezolid at steady state averaged 40-50 L in healthy adult volunteers. Linezolid concentrations have been determined in various fluids from a limited number of subjects in Phase 1 volunteer studies following multiple dosing of linezolid. The ratio of linezolid in saliva relative to plasma was 1.2:1 and for sweat relative to plasma was 0.55:1.
Metabolism: Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in 2 inactive ring-opened carboxylic acid metabolites: The aminoethoxyacetic acid metabolite (A), and the hydroxyethyl glycine metabolite (B). Formation of metabolite B is mediated by a non-enzymatic chemical oxidation mechanism in vitro. Linezolid is not an inducer of cytochrome P-450 (CYP450) in rats, and it has been demonstrated from in vitro studies that linezolid is not detectably metabolized by human CYP450 and it does not inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4).
Excretion: Nonrenal clearance accounts for approximately 65% of the total clearance of linezolid. Under steady-state conditions, approximately 30% of the dose appears in the urine as linezolid, 40% as metabolite B and 10% as metabolite A. The renal clearance of linezolid is low (average 40 mL/min) and suggests net tubular reabsorption. Virtually no linezolid appears in the feces, while approximately 6% of the dose appears in the feces as metabolite B and 3% as metabolite A.
A small degree of nonlinearity in clearance was observed with increasing doses of linezolid, which appears to be due to lower renal and nonrenal clearance of linezolid at higher concentrations. However, the difference in clearance was small and was not reflected in the apparent elimination half-life.
Special Populations: Elderly: The pharmacokinetics of linezolid are not significantly altered in elderly patients (≥65 years). Therefore, dose adjustment for geriatric patients is not necessary.
Gender: Females have a slightly lower volume of distribution of linezolid than males. Plasma concentrations are higher in females than in males, which is partly due to body weight differences. After a 600-mg dose, mean oral clearance is approximately 38% lower in females than in males. However, there are no significant gender differences in mean apparent elimination rate constant or half-life. Thus, drug exposure in females is not expected to substantially increase beyond levels known to be well-tolerated. Therefore, dose adjustment by gender does not appear to be necessary.
Renal Insufficiency: The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any degree of renal insufficiency; however, the 2 primary metabolites of linezolid may accumulate in patients with renal insufficiency, with the amount of accumulation increasing with the severity of renal dysfunction (see Table 9). However, there was no increase in AUC of parent drug. The clinical significance of accumulation of these 2 metabolites has not been determined in patients with severe renal insufficiency. Because similar plasma concentrations of linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal insufficiency. However, given the absence of information on the clinical significance of accumulation of the primary metabolites, use of linezolid in patients with renal insufficiency should be weighed against the potential risks of accumulation of these metabolites. Both linezolid and the 2 metabolites are eliminated by dialysis. Although there is some removal of the major metabolites of linezolide by hemodialysis than those observed in patients with normal renal function or mild to moderate renal insufficiency. Approximately 30% of a dose was eliminated in a 3-hr dialysis session beginning 3 hrs after the dose of linezolid was administered; therefore, linezolid should be given after hemodialysis. The clinical significance of these observations has not been established as limited safety data are currently available.


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Hepatic Insufficiency: The pharmacokinetics of linezolid are not altered in patients (n=7) with mild to moderate hepatic insufficiency (Child-Pugh class A or B). On the basis of the available information, no dose adjustment is recommended for patients with mild to moderate hepatic insufficiency. The pharmacokinetics of linezolid in patients with severe hepatic insufficiency have not been evaluated. However, as linezolid is metabolized by a non-enzymatic process, impairment of hepatic function would not be expected to significantly alter its metabolism.
Drug-Drug Interactions: Drugs Metabolized by CYP450: Linezolid is not an inducer of CYP450 in rats. It is not detectably metabolized by human cytochrome P-450 and it does not inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, no CYP450-induced drug interactions are expected with linezolid. Concurrent administration of linezolid does not substantially alter the pharmacokinetic characteristics of (S)-warfarin, which is extensively metabolized by CYP2C9. Drugs eg, warfarin and phenytoin, which are CYP2C9 substrates, may be given with linezolid without changes in dosage regimen.
Antibiotics: Aztreonam: The pharmacokinetics of linezolid or aztreonam are not altered when administered together.
Gentamicin: The pharmacokinetics of linezolid or gentamicin are not altered when administered together.
Rifampicin: The effect of rifampin on the pharmacokinetics of linezolid was studied in sixteen healthy adult male volunteers administered linezolid 600 mg twice daily for 2.5 days with and without rifampin 600 mg once daily for 8 days. Rifampin decreased the linezolid Cmax and AUC by a mean 21% [90% CI, 15, 27] and a mean 32% [90% CI, 27, 37], respectively. The mechanism of this interaction and its clinical significance are unknown.
Monoamine Oxidase Inhibition: Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.
Adrenergic Agents: A significant pressor response has been observed in normal adult subjects receiving linezolid and tyramine doses of >100 mg. Therefore, patients receiving linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content (see Information for Patients under Precautions).
A reversible enhancement of the pressor response of either pseudoephedrine HCl (PSE) or phenylpropanolamine HCl (PPA) is observed when linezolid is administered to healthy normotensive subjects (see Interactions). A similar study has not been conducted in hypertensive patients. The interaction studies conducted in normotensive subjects evaluated the blood pressure and heart rate effects of placebo, PPA or PSE alone, linezolid alone, and the combination of steady-state linezolid (600 mg every 12 hrs for 3 days) with 2 doses of PPA (25 mg) or PSE (60 mg) given 4 hrs apart. Heart rate was not affected by any of the treatments. Blood pressure was increased with both combination treatments. Maximum blood pressure levels were seen 2-3 hrs after the 2nd dose of PPA or PSE, and returned to baseline 2-3 hrs after peak. The results of the PPA study follow, showing the mean (and range) maximum systolic blood pressure in mmHg: Placebo = 121 (103-158); linezolid alone = 120 (107-135); PPA alone = 125 (106-139); PPA with linezolid = 147 (129-176). The results from the PSE study were similar to those in the PPA study. The mean maximum increase in systolic blood pressure over baseline was 32 mmHg (range: 20-52 mmHg) and 38 mmHg (range: 18-79 mmHg) during co-administration of linezolid with pseudoephedrine or phenylpropanolamine, respectively.
Serotonergic Agents: The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20-mg doses given 4 hrs apart) with or without linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan. The effects of other serotonin re-uptake inhibitors have not been studied.
Toxicology: Animal Pharmacology: Target organs of linezolid toxicity were similar in juvenile and adult rats and dogs. Dose and time-dependent myelosuppression, as evidenced by bone marrow hypocellularity/decreased hematopoiesis, decreased extramedullary hematopoiesis in spleen and liver, and decreased levels of circulating erythrocytes, leukocytes and platelets have been seen in animal studies. Lymphoid depletion occurred in thymus, lymph nodes and spleen. Generally, the lymphoid findings were associated with anorexia, weight loss and suppression of body weight gain, which may have contributed to the observed effects. These effects were observed at exposure levels that are comparable to those observed in some human subjects. The hematopoietic and lymphoid effects were reversible, although in some studies, reversal was incomplete within the duration of the recovery period.
Indications/Uses
Treatment of the following infections caused by susceptible strains of the designated microorganisms (see Precautions and Dosage & Administration): Treatment of MRSA and vancomycin-resistant enterococcus (VRE) of the following infections caused by gram-positive bacteria: Nosocomial pneumonia; complicated skin and soft tissue infections including diabetic foot infections without concomitant osteomyelitis caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes or Streptococcus agalacticiae. Zyvox has not been studied in the treatment of decubitus ulcers. Combination therapy may be clinically indicated if the documented or presumptive pathogens include gram-negative organisms.
Linezolid should only be initiated in a hospital environment and after consultation with a relevant specialist.
Linezolid is active against gram-positive bacteria only. Linezolid has no clinical activity against gram-negative pathogens. Specific gram-negative therapy is required if concomitant gram-negative pathogens is documented or suspected.
Consideration should be given to the official guidance on the appropriate use of antibacterial agents.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zyvox and other antibacterial drugs, Zyvox should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.
Dosage/Direction for Use
The recommended dosage for Zyvox formulations for the treatment of infections is described in Table 10.


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Adult patients with infection due to MRSA should be treated with Zyvox 600 mg every 12 hrs.
In controlled clinical trials, the protocol-defined duration of treatment for all infections ranged from 7-28 days. Total treatment duration was determined by the treating physician based on site and severity of the infection, and on the patient's clinical response.
No dose adjustment is necessary when switching from IV to oral administration. Patients whose therapy is started with Zyvox IV injection may be switched to Zyvox tablets at the discretion of the physician, when clinically indicated.
Patients with Severe Renal Insufficiency (ie, CrCl <30 mL/min): No dose adjustment is required. Due to the unknown clinical significance of higher exposure (up to 10-fold) to the 2 primary metabolites of linezolid in patients with severe renal insufficiency, linezolid should be used with special caution in these patients and only when the anticipated benefit is considered to outweigh the theoretical risk.
As approximately 30% of a linezolid dose is removed during 3 hrs of hemodialysis, linezolid should be given after dialysis in patients receiving such treatment. The primary metabolites of linezolid are removed to some extent by hemodialysis, but the concentrations of these metabolites are still very considerably higher following dialysis than those observed in patients with normal renal function or mild to moderate renal insufficiency.
Therefore, linezolid should be used with special caution in patients with severe renal insufficiency who are undergoing dialysis and only when the anticipated benefit is considered to outweigh the theoretical risk. To date, there is no experience of linezolid administration to patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or alternative treatments for renal failure (other than hemodialysis).
Patients with Hepatic Insufficiency: No dose adjustment is required. However, there are limited clinical data and it is recommended that linezolid should be used in such patients only when the anticipated benefit is considered to outweigh the theoretical risk.
Elderly: No dose adjustment is required.
IV Administration: Zyvox IV injection is supplied in single-use, ready-to-use infusion bags. Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired.
Zyvox IV injection should be administered by IV infusion over a period of 30-120 min. Do not use this IV infusion bag in series connections. Additives should not be introduced into this solution. If Zyvox IV injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product. In particular, physical incompatibilities resulted when Zyvox IV injection was combined with the following drugs during simulated Y-site administration: Amphotericin B, chlorpromazine HCl, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium and trimethoprim-sulfamethoxazole. Additionally, chemical incompatibility resulted when Zyvox IV injection was combined with ceftriaxone sodium.
If the same IV line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of Zyvox IV injection with an infusion solution compatible with Zyvox IV injection and with any other drug(s) administered via this common line (see Compatible IV Solutions).
Compatible IV Solutions: 5% Dextrose Injection; 0.9% Sodium Chloride Injection; Lactated Ringer's Injection.
Overdosage
In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Hemodialysis may facilitate more rapid elimination of linezolid. In a phase 1 clinical trial, approximately 30% of a dose of linezolid was removed during a 3-hr hemodialysis session beginning 3 hrs after the dose of linezolid was administered. Data are not available for removal of linezolid with peritoneal dialysis or hemoperfusion. Clinical signs of acute toxicity in animals were decreased activity and ataxia in rats and vomiting and tremors in dogs treated with 3000 and 2000 mg/kg/day, respectively.
Contraindications
Patients who have known hypersensitivity to linezolid or any of the other components of Zyvox.
Warnings
Myelosuppression (including anemia, leukopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for >2 weeks, those with preexisting myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression.
In adult and juvenile dogs and rats, myelosuppression, reduced extramedullary hematopoiesis in spleen and liver, and lymphoid depletion of thymus, lymph nodes and spleen were observed.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Zyvox, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of any antibacterial agent.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicated that a toxin produced by Clostridium difficile is a primary cause of antibiotic-associated colitis.
After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial agent clinically effective against Clostridium difficile. Convulsions have been reported to occur rarely in patients when treated with linezolid. In most of these cases, a history of seizures or risk factors for seizures were reported.
Special Precautions
General: Lactic acidosis has been reported with the use of Zyvox. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea and vomiting, unexplained acidosis, or low bicarbonate level while receiving Zyvox should receive immediate medical evaluation.
Peripheral and optic neuropathy have been reported in patients treated with Zyvox, primarily those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progresses to loss of vision, patients were treated for extended periods beyond the maximum recommended duration.
If symptoms of visual impairment appear eg, changes in visual acuity, changes in color vision, blurred vision or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking Zyvox for extended periods (≥3 months) and in all patients reporting new visual symptoms regardless of length of therapy with Zyvox. If peripheral or optic neuropathy occurs, the continued use of Zyvox in these patients should be weighed against the potential risks.
The use of antibiotics may promote the overgrowth of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.
Zyvox has not been studied in patients with uncontrolled hypertension, pheochromocytoma, carcinoid syndrome or untreated hyperthyroidism.
The safety and efficacy of Zyvox formulations given >28 days have not been evaluated in controlled clinical trials.
Prescribing Zyvox in the absence of a proven or strongly suspected bacterial infection or a prophylactic indications is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Information for Patients: Patients should be advised that Zyvox may be taken with or without food. They should inform their physician if they have a history of hypertension.
Large quantities of foods or beverages with high tyramine content should be avoided while taking Zyvox. Quantities of tyramine consumed should be <100 mg/meal. Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling or smoking to improve flavor eg, aged cheeses (tyramine 0-15 mg/oz); fermented or air-dried meats (tyramine 0.1-8 mg/oz); sauerkraut (tyramine 8 mg/8 oz); soy sauce (tyramine/tsp 5 mg); tap beers (tyramine 4 mg/12 oz); red wines (tyramine 0-6 mg/8 oz). The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.
Patients should inform the physician if they are taking medications containing pseudoephedrine HCl or phenylpropanolamine HCl eg, cold remedies and decongestants.
Patients should inform the physician if they are taking serotonin re-uptake inhibitors or other antidepressants.
Patients should inform their physician if they experience changes in vision.
Patients should inform their physician if they have a history of seizures.
Diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
Patients should be counseled that antibacterial drugs including Zyvox should only be used to treat bacterial infections. They do not treat viral infections (eg, the common cold). When Zyvox is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may decrease the effectiveness of the immediate treatment and increase the likelihood that bacteria will develop resistance and will not be treatable by Zyvox or other antibacterial drugs in the future.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of linezolid. Neither mutagenic nor clastogenic potential was found in a battery of tests, including assays for mutagenicity (Ames bacterial reversion and CHO cell mutation), an in vitro unscheduled DNA synthesis (UDS) assay, an in vitro chromosome abberation assay in human lymphocytes and an in vivo mouse micronucleus assay.
Linezolid did not affect the fertility or reproductive performance of adult female rats. It reversibly decreased fertility and reproductive performance in adult male rats when given at doses ≥50 mg/kg/day, with exposures approximately equal to or greater than the expected human exposure level (exposure comparisons are based on AUCs). The reversible fertility effects were mediated through altered spermatogenesis. Affected spermatids contained abnormally formed and oriented mitochondria and were nonviable. Epithelial cell hypertrophy and hyperplasia in the epididymis was observed in conjunction with decreased fertility. Similar epididymal changes were not seen in dogs.
In sexually-mature male rats exposed to drugs as juveniles, mildly decreased fertility was observed following treatment with linezolid through most of their period of sexual development (50 mg/kg/day from age of 7-36 days, and 100 mg/kg/day from age of 37-55 days), with exposures up to 1.7-fold greater than mean AUCs observed in pediatric patients 3 months to 11 years. Decreased fertility was not observed with shorter treatment periods, corresponding to exposure in utero through the early neonatal period (gestation day 6 through postnatal day 5), neonatal exposure (postnatal days 5-21) or to juvenile exposure (postnatal days 22-35). Reversible reductions in sperm motility and altered sperm morphology were observed in rats treated from postnatal day 22-35.
Use in pregnancy: Teratogenic Effects: Pregnancy Category C: Linezolid was not teratogenic in mice or rats at exposure levels 6.5-fold (in mice) or equivalent to (in rats) the expected human exposure level, based on AUCs. However, embryo and fetal toxicities were seen (see Nonteratogenic Effects as follows). There are no adequate and well-controlled studies in pregnant women. Zyvox should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: In mice, embryo and fetal toxicities were seen only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). A dose of 450 mg/kg/day (6.5-fold the estimated human exposure level based on AUCs) correlated with increased post-implantational embryo death, including total litter loss, decreased fetal body weights and an increased incidence of costal cartilage fusion.
Linezolid was also not teratogenic in rabbits when administered twice daily at total oral doses up to 15 mg/kg/day (0.5 times the clinical exposure, based on AUC). Maternal toxicity (clinical signs, reduced body weight gain and food consumption) occurred at 5 and 15 mg/kg/day, and reduced fetal body weight occurred at 15 mg/kg/day. Linezolid exposures were low due to the characteristic sensitivity of rabbits to antibiotics.
Linezolid produced reversible myelosupression in adult and juvenile rats and dogs.
In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was observed in males dosed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in 1 male at this dose level at a 3-month interim necropsy. Similar changes were not observed in female rats. Sensitive morpohologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 male rats administered linezolid at 80 mg/kg/day for 6 months, but the direct relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical distribution. The nerve degeneration observed was microscopically compatible to a spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of a common background change.
In rats, mild fetal toxicity was observed at 15 and 50 mg/kg/day (exposure levels 0.22-fold to approximately equivalent to the estimated human exposure, respectively, based on AUCs). The effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a finding often seen in association with decreased fetal body weights. Slight maternal toxicity, in the form of reduced body weight gain, was seen at 50 mg/kg/day.
When female rats were treated with 50 mg/kg/day (approximately equivalent to the estimated human exposure based on AUCs) of linezolid during pregnancy and lactation, survival of pups was decreased on postnatal days 1-4. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in pre-implantation loss.
Use in lactation: Linezolid and its metabolites are excreted in the milk of lactating rats. Concentrations in milk were similar to those in maternal plasma. It is not known whether linezolid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Zyvox is administered to a nursing woman.
Use in children: Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended.
Use in the elderly: Of the 2046 patients treated with Zyvox in phase 3 comparator-controlled clinical trials, 589 (29%) were ≥65 years and 253 (12%) were ≥75 years. No overall differences in safety or effectiveness were observed between these patients and younger patients.
Use In Pregnancy & Lactation
Use in pregnancy: Teratogenic Effects: Pregnancy Category C: Linezolid was not teratogenic in mice or rats at exposure levels 6.5-fold (in mice) or equivalent to (in rats) the expected human exposure level, based on AUCs. However, embryo and fetal toxicities were seen (see Nonteratogenic Effects as follows). There are no adequate and well-controlled studies in pregnant women. Zyvox should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: In mice, embryo and fetal toxicities were seen only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). A dose of 450 mg/kg/day (6.5-fold the estimated human exposure level based on AUCs) correlated with increased post-implantational embryo death, including total litter loss, decreased fetal body weights and an increased incidence of costal cartilage fusion.
Linezolid was also not teratogenic in rabbits when administered twice daily at total oral doses up to 15 mg/kg/day (0.5 times the clinical exposure, based on AUC). Maternal toxicity (clinical signs, reduced body weight gain and food consumption) occurred at 5 and 15 mg/kg/day, and reduced fetal body weight occurred at 15 mg/kg/day. Linezolid exposures were low due to the characteristic sensitivity of rabbits to antibiotics.
Linezolid produced reversible myelosupression in adult and juvenile rats and dogs.
In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was observed in males dosed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in 1 male at this dose level at a 3-month interim necropsy. Similar changes were not observed in female rats. Sensitive morpohologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 male rats administered linezolid at 80 mg/kg/day for 6 months, but the direct relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical distribution. The nerve degeneration observed was microscopically compatible to a spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of a common background change.
In rats, mild fetal toxicity was observed at 15 and 50 mg/kg/day (exposure levels 0.22-fold to approximately equivalent to the estimated human exposure, respectively, based on AUCs). The effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a finding often seen in association with decreased fetal body weights. Slight maternal toxicity, in the form of reduced body weight gain, was seen at 50 mg/kg/day.
When female rats were treated with 50 mg/kg/day (approximately equivalent to the estimated human exposure based on AUCs) of linezolid during pregnancy and lactation, survival of pups was decreased on postnatal days 1-4. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in pre-implantation loss.
Use in lactation: Linezolid and its metabolites are excreted in the milk of lactating rats. Concentrations in milk were similar to those in maternal plasma. It is not known whether linezolid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Zyvox is administered to a nursing woman.
Adverse Reactions
The safety of Zyvox formulations was evaluated in 2046 patients enrolled in 7 phase 3 comparator-controlled clinical trials, who were treated for up to 28 days. In these studies, 85% of the adverse events reported with Zyvox were described as mild to moderate in intensity. Table 11 shows the incidence of adverse events reported in at least 2% of patients in these trials. The most common adverse events in patients treated with Zyvox were diarrhea (incidence across studies: 2.8-11%), headache (incidence across studies: 0.5-11.3%) and nausea (incidence across studies: 3.4-9.6%). (See Table 11.)


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Other adverse events reported in phase 2 and 3 studies included oral moniliasis, vaginal moniliasis, hypertension, dyspepsia, localized abdominal pain, pruritus and tongue discoloration. Table 12 shows the incidence of drug-related adverse events reported in at least 1% of patients in these trials by dose of Zyvox. (See Table 12.)


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Laboratory Changes: Zyvox has been associated with thrombocytopenia when used in doses up to and including 600 mg every 12 hrs for up to 28 days. In phase 3 comparator-controlled trials, the percentage of patients who developed a substantially low platelet count (defined as <75% of lower limit of normal and/or baseline) was 2.4% (range among studies: 0.3-10%) with Zyvox and 1.5% (range among studies: 0.4-7%) with a comparator. Thrombocytopenia associated with the use of Zyvox appears to be dependent on duration of therapy, (generally >2 weeks of treatment). The platelet counts for most patients returned to the normal range/baseline during the follow-up period. No related clinical adverse events were identified in phase 3 clinical trials in patients developing thrombocytopenia. Bleeding events were identified in thrombocytopenic patients in a compassionate use program for Zyvox; the role of linezolid in these events cannot be determined (see Warnings).
Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differences between Zyvox and the comparators. These changes were generally not clinically significant, did not lead to discontinuation of therapy, and were reversible. The incidence of patients with at least one substantially abnormal hematologic or serum chemistry value is presented in Tables 13 and 14. (See Tables 13 and 14.)


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Drug Interactions
(See also Pharmacokinetics: Drug-Drug Interactions under Actions.)
Monoamine Oxidase Inhibition: Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.
Adrenergic Agents: Some individuals receiving Zyvox may experience a reversible enhancement of the pressor response to indirect-acting sympathomimetic agents, vasopressor or dopaminergic agents. Commonly used drugs eg, phenylpropanolamine and pseudoephedrine have been specifically studied. Initial doses of adrenergic agents eg, dopamine or epinephrine, should be reduced and titrated to achieve the desired response.
Serotonergic Agents: Co-administration of linezolid and serotonergic agents was not associated with serotonin syndrome in phase 1, 2 or 3 studies. Spontaneous reports of serotonin syndrome occurring with co-administration of Zyvox and serotonergic agents have occurred. Physicians should be alert to the possibility of signs and symptoms of serotonin syndrome (hyperreflexia, incoordination, hyperpyrexia and cognitive dysfunction) in patients receiving concomitant serotonergic agents.
Drug-Laboratory Test: There are no reported drug-laboratory test interactions.
Caution For Usage
Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired.
Keep the infusion bags in the overwrap until ready to use. Zyvox IV injection may exhibit a yellow color that can intensify over time without adversely affecting potency.
Storage
Film-Coated Tablet: Store at temperature below 30°C.
Solution for Infusion: Store below 25°C. Do not freeze. Sensitive to light. Keep bags in foil overwrap and carton until ready to use. Store at room temperature. Protect from freezing Zyvox IV. Injection may exhibit a yellow color that can intensify over time without adversely affecting potency.
Shelf-Life: 36 months.
MIMS Class
ATC Classification
J01XX08 - linezolid ; Belongs to the class of other antibacterials. Used in the systemic treatment of infections.
Presentation/Packing
FC tab 600 mg (white to off-white, compressed, printed with "ZYVOX 600 mg") x 10's. Infusion 2 mg/mL (single-use, ready-to-use, sterile, isotonic soln) x 300 mL x 1's.
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