Zyvox Information
Zyvox (Linezolid)
Zyvox (Linezolid) Description
Zyvox (Linezolid) I.V. Injection, Zyvox (Linezolid) Tablets, and Zyvox (Linezolid) for Oral Suspension contain linezolid, which is a synthetic antibacterial agent of the oxazolidinone class. The chemical name for linezolid is (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
The empirical formula is CHFNO. Its molecular weight is 337.35, and its chemical structure is represented below:
Zyvox (Linezolid) I.V. Injection is supplied as a ready-to-use sterile isotonic solution for intravenous infusion. Each mL contains 2 mg of linezolid. Inactive ingredients are sodium citrate, citric acid, and dextrose in an aqueous vehicle for intravenous administration. The sodium (Na) content is 0.38 mg/mL (5 mEq per 300-mL bag; 3.3 mEq per 200-mL bag; and 1.7 mEq per 100-mL bag).
Zyvox (Linezolid) Tablets for oral administration contain 400 mg or 600 mg linezolid as film-coated compressed tablets. Inactive ingredients are corn starch, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, and carnauba wax. The sodium (Na) content is 1.95 mg per 400-mg tablet and 2.92 mg per 600-mg tablet (0.1 mEq per tablet, regardless of strength).
Zyvox (Linezolid) for Oral Suspension is supplied as an orange-flavored granule/powder for constitution into a suspension for oral administration. Following constitution, each 5 mL contains 100 mg of linezolid. Inactive ingredients are sucrose, citric acid, sodium citrate, microcrystalline cellulose and carboxymethylcellulose sodium, aspartame, xanthan gum, mannitol, sodium benzoate, colloidal silicon dioxide, sodium chloride, and flavors (see ). The sodium (Na) content is 8.52 mg per 5 mL (0.4 mEq per 5 mL).
Zyvox (Linezolid) Clinical Pharmacology
The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous (IV) doses are summarized in Table 1. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours (q12h) are shown in Figure 1.
Figure 1. Plasma Concentrations of Linezolid in Adults at Steady-State Following Oral Dosing Every 12 Hours (Mean ± Standard Deviation, n=16)
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 bacteria 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 (4 patients received 200 mg q12h, lower than the recommended dose, and 2 patients received 600 mg q12h). In a compassionate use program, resistance to linezolid developed in 8 patients with and in 1 patient with. All patients had either unremoved prosthetic devices or undrained abscesses. Resistance to linezolid occurs in vitro at a frequency of 1 x 10 to 1 x 10 . 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 has been a report of (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 spp., including .
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 in the section.
The following in vitro data are available, . 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.
Enterococcus faecalis
Enterococcus faecium
Staphylococcus epidermidis
Staphylococcus haemolyticus
Pasteurella multocida
NOTE:
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.
Zyvox (Linezolid) Indications And Usage
Zyvox (Linezolid) formulations are indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms (see and and ). Linezolid is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected (see ).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zyvox (Linezolid) and other antibacterial drugs, Zyvox (Linezolid) should be used only to treat or prevent 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. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Zyvox (Linezolid) Contraindications
Zyvox (Linezolid) formulations are contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components.
Zyvox (Linezolid) 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 longer than two weeks, those with pre-existing 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 (see ).
Zyvox (Linezolid) Precautions
Patients should be advised that:
Patients should be counseled that antibacterial drugs including Zyvox (Linezolid) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Zyvox (Linezolid) 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 (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Zyvox (Linezolid) or other antibacterial drugs in the future.
(see also )
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 aberration 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 non-viable. 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 drug as juveniles, mildly decreased fertility was observed following treatment with linezolid through most of their period of sexual development (50 mg/kg/day from days 7 to 36 of age, and 100 mg/kg/day from days 37 to 55 of age), with exposures up to 1.7-fold greater than mean AUCs observed in pediatric patients aged 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 to 21), or to juvenile exposure (postnatal days 22 to 35). Reversible reductions in sperm motility and altered sperm morphology were observed in rats treated from postnatal day 22 to 35.
The safety and effectiveness of Zyvox (Linezolid) for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years (see and ):
The safety and effectiveness of Zyvox (Linezolid) for the treatment of pediatric patients with the following infection have been established in a comparator-controlled study in pediatric patients ranging in age from 5 through 17 years (see ):
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.
The C and the volume of distribution (V) of linezolid are similar regardless of age in pediatric patients. However, linezolid clearance is a function of age. Excluding neonates less than a week of age, clearance is most rapid in the youngest age groups ranging from >1 week old to 11 years, resulting in lower single-dose systemic exposure (AUC) and shorter half-life as compared with adults. As age of pediatric patients increases, the clearance of linezolid gradually decreases, and by adolescence, mean clearance values approach those observed for the adult population. There is wider inter-subject variability in linezolid clearance and in systemic drug exposure (AUC) across all pediatric age groups as compared with adults.
Similar mean daily AUC values were observed in pediatric patients from birth to 11 years of age dosed q8h relative to adolescents or adults dosed q12h. Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg q8h. Pediatric patients 12 years and older should receive 600 mg q12h.
Recommendations for the dosage regimen for pre-term neonates less than 7 days of age (gestational age less than 34 weeks) are based on pharmacokinetic data from 9 pre-term neonates. Most of these pre-term neonates have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. Therefore, these pre-term neonates should be initiated with a dosing regimen of 10 mg/kg q12h. Consideration may be given to the use of a 10 mg/kg q8h regimen in neonates with a sub-optimal clinical response. All neonatal patients should receive 10 mg/kg q8h by 7 days of life (see and ).
In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Gram-positive pathogens with MICs of 4 µg/mL treated with Zyvox (Linezolid) had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 µg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response (see and ).
Zyvox (Linezolid) 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.
In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was observed 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. Sensitive morphologic 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 after 6 months of dosing, 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 comparable to spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of common background change.
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.
Zyvox (Linezolid) Adverse Reactions
The safety of Zyvox (Linezolid) formulations was evaluated in 2046 adult patients enrolled in seven 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 (Linezolid) were described as mild to moderate in intensity. Table 6 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 (Linezolid) were diarrhea (incidence across studies: 2.8% to 11.0%), headache (incidence across studies: 0.5% to 11.3%), and nausea (incidence across studies: 3.4% to 9.6%).
Other adverse events reported in Phase 2 and Phase 3 studies included oral moniliasis, vaginal moniliasis, hypertension, dyspepsia, localized abdominal pain, pruritus, and tongue discoloration.
Table 7 shows the incidence of drug-related adverse events reported in at least 1% of adult patients in these trials by dose of Zyvox (Linezolid) .
The safety of Zyvox (Linezolid) formulations was evaluated in 215 pediatric patients ranging in age from birth through 11 years, and in 248 pediatric patients aged 5 through 17 years (146 of these 248 were age 5 through 11 and 102 were age 12 to 17). These patients were enrolled in two Phase 3 comparator-controlled clinical trials and were treated for up to 28 days. In these studies, 83% and 99%, respectively, of the adverse events reported with Zyvox (Linezolid) were described as mild to moderate in intensity. In the study of hospitalized pediatric patients (birth through 11 years) with Gram-positive infections, who were randomized 2 to 1 (linezolid:vancomycin), mortality was 6.0% (13/215) in the linezolid arm and 3.0% (3/101) in the vancomycin arm. However, given the severe underlying illness in the patient population, no causality could be established. Table 8 shows the incidence of adverse events reported in at least 2% of pediatric patients treated with Zyvox (Linezolid) in these trials.
Table 9 shows the incidence of drug-related adverse events reported in more than 1% of pediatric patients (and more than 1 patient) in either treatment group in the comparator-controlled Phase 3 trials.
Zyvox (Linezolid) has been associated with thrombocytopenia when used in doses up to and including 600 mg every 12 hours for up to 28 days. In Phase 3 comparator-controlled trials, the percentage of adult patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 2.4% (range among studies: 0.3 to 10.0%) with Zyvox (Linezolid) and 1.5% (range among studies: 0.4 to 7.0%) with a comparator. In a study of hospitalized pediatric patients ranging in age from birth through 11 years, the percentage of patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 12.9% with Zyvox (Linezolid) and 13.4% with vancomycin. In an outpatient study of pediatric patients aged from 5 through 17 years, the percentage of patients who developed a substantially low platelet count was 0% with Zyvox (Linezolid) and 0.4% with cefadroxil. Thrombocytopenia associated with the use of Zyvox (Linezolid) appears to be dependent on duration of therapy, (generally greater than 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 (Linezolid) ; the role of linezolid in these events cannot be determined (see ).
Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differences between Zyvox (Linezolid) and the comparators. These changes were generally not clinically significant, did not lead to discontinuation of therapy, and were reversible. The incidence of adult and pediatric patients with at least one substantially abnormal hematologic or serum chemistry value is presented in Tables 10, 11, 12, and 13.
Zyvox (Linezolid) 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-hour hemodialysis session beginning 3 hours 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 mg/kg/day and 2000 mg/kg/day, respectively.
Zyvox (Linezolid) Dosage And Administration
The recommended dosage for Zyvox (Linezolid) formulations for the treatment of infections is described in Table 14.
Adult patients with infection due to MRSA should be treated with Zyvox (Linezolid) 600 mg q12h.
In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Gram-positive pathogens with MICs of 4 µg/mL treated with Zyvox (Linezolid) had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 µg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response (see and ).
In controlled clinical trials, the protocol-defined duration of treatment for all infections ranged from 7 to 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 intravenous to oral administration. Patients whose therapy is started with Zyvox (Linezolid) I.V. Injection may be switched to either Zyvox (Linezolid) Tablets or Oral Suspension at the discretion of the physician, when clinically indicated.
Zyvox (Linezolid) How Supplied
Zyvox (Linezolid) Tablets are available as follows:
Zyvox (Linezolid)
Zyvox (Linezolid) Principal Display Panel - Mg Tablet Bottle Label
NDC 21695-399-20
Repackaged by:
Thousand Oaks, CA 91320
