Cigna Pharmacy Coverage Policy Effective Date . 8/15/2012 Next Review Date . 8/15/2013 Coverage Policy Number . 1123 SubjectLinezolid (Zyvox®) Table of Contents Hyperlink to Related Coverage Policies INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna companies including plans formerly administered by Great-West Healthcare, which is now a part of Cigna. Coverage Policies are intended to provide guidance in interpreting certain standard Cigna benefit plans. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supercedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations. Proprietary information of Cigna. Copyright 2012 Cigna
Coverage Policy Cigna covers linezolid (Zyvox®) as medically necessary for treatment of a gram-positive infection caused by ANY of the following:
• methicillin-resistant Staphylococcus aureus (MRSA) • oxacillin-resistant Staphylococcus aureus (ORSA)
• methicillin-resistant Staphylococcus epidermidis (MRSE) • oxacillin-resistant Staphylococcus epidermidis (ORSE)
• vancomycin-resistant enterococcus (VRE)
When coverage is available and medically necessary, the dosage, frequency, site of administration, and duration of therapy should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to Linezolid (Zyvox®).
FDA Approved Indications Zyvox formulations are indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms. 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.
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• Vancomycin-Resistant Enterococcus (VRE) faecium infections, including cases with concurrent
• Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant
strains), or Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]).
• Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes, or Streptococcus agalactiae. Zyvox has not been studied in the treatment of decubitus ulcers.
• Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-
susceptible only) or Streptococcus pyogenes.
• Community-acquired pneumonia caused by Streptococcus pneumoniae (including MDRSP),
including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible strains only).
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 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. FDA Recommended Dosing Dosage Guidelines for Zyvox Infection Pediatric Patients* (Birth Adults and Adolescents Recommended through 11 Years of Age) (12 Years and Older) Duration of Treatment Dosage and Route of Dosage and Route of (consecutive days) Administration Administration
Complicated skin and skin structure infections Community-acquired
concurrent bacteremia Nosocomial pneumonia Vancomycin-resistant
infections, including concurrent bacteremia Uncomplicated skin
5-11 yrs: 10 mg/kg oral q12h Adolescents: 600 mg oral
Oral dosing using either Zyvox tablets or Zyvox for oral suspension. * Neonates <7 days: Most pre-term neonates < 7 days of age (gestational age < 34 weeks) have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. These neonates should be initiated with a dosing regimen of 10 mg/kg q12h. Consideration may be given to the use of 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. Adult patients with infection due to MRSA should be treated with Zyvox 600 mg q12h.
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Drug Availability Zyvox IV injection is available in single-use, ready-to-use flexible plastic infusion bags in a foil laminate overwrap. The infusion bags are available in the following package sizes: 100 mL bag (200 mg linezolid), 200 mL bag (400 mg linezolid), and 300 mL bag (600 mg linezolid). Zyvox tablets are available as follows: 400 mg (white, oblong, film-coated tablets printed with “ZYVOX 400mg”) in bottles of 100 or 20 tablets, or unit dose packages of 30 tablets; 600 mg (white, capsule-shaped, film-coated tablets printed with “ZYVOX 600 mg”) in bottles of 100 or 20 tablets or in init dose packages of 30 tablets. Zyvox for oral suspension is available as a dry, white to off-white, orange-flavored granule/powder. When constituted as directed, each bottle will contain 150 mL of a suspension providing the equivalent of 100 mg of linezolid per each 5 mL. Oral suspension is supplied as 100 mg/5 mL in 240mL glass bottles. General Background
Pharmacology Linezolid is an oxazolidinone antibiotic that has coverage primarily against aerobic gram-positive organisms, including vancomycin, methicillin, and penicillin-resistant microorganisms. It inhibits protein synthesis by binding to ribosomal RN in the 50S subunit and prevents bacterial translation. Linezolid is rapidly and extensively absorbed after oral dosing with nearly 100% bioavailability. It distributes into well-perfused tissues, where it is 31% plasma protein bound. Linezolid is oxidized into two major inactive carboxylic acid metabolites. Clinical Efficacy Phase III human clinical trials have demonstrated that linezolid was effective in treating VRE infections (including bacteremia), nosocomial and community-acquired pneumonia, as well as complicated and uncomplicated skin/skin structure infections cause by Streptococcus and Staphylococcus organisms. In most studies linezolid was similar to the comparator agent (vancomycin, clarithromycin, or ceftriaxone) in outcomes. In some trials, linezolid was associated with a significantly higher rate of adverse events. Results of a new international phase 4 study of patients with nosocomial pneumonia due to proven methicillin- resistant Staphylococcus aureus (MRSA) demonstrated that the antibiotic Zyvox achieved a statistically significantly higher clinical success rate compared with vancomycin for the primary endpoint. These findings were presented at the 48th annual meeting of the Infectious Diseases Society of America (IDSA). Investigators from 156 centers worldwide randomized 1,225 patients, of whom 448 patients had proven MRSA nosocomial pneumonia; 339 patients also met key protocol criteria at the end of study (per-protocol group) and were included in the primary analysis. Clinical success rates at the end of study were 57.6 percent for patients treated with Zyvox compared with 46.6 percent for patients treated with vancomycin. These results demonstrated that Zyvox achieved a statistically significantly higher clinical success rate compared to vancomycin. Nosocomial pneumonia continues to be a significant cause of illness, and when these infections are due to MRSA, options are limited, as there are few antibiotics that are effective against the resistant organism. These findings, which show a higher cure rate for linezolid compared with vancomycin, provide important information for physicians who treat nosocomial pneumonia caused by MRSA. Adverse Reactions Thrombocytopenia was the most clinically significant adverse effect reported in clinical trials involving patients receiving linezolid. Other common side effects include diarrhea, headache, nausea and vomiting, insomnia, and constipation. Linezolid is a reversible nonselective monoamine oxidase inhibitor and may interact with adrenergic and serotonergic agents. Not all serotonergic psychiatric drugs have an equal capacity to cause serotonin syndrome with linezolid. Most of serotonin syndrome with linezolid occurred in patients taking specific serotonergic psychiatric drugs, namely a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor (SNRI). It is unclear at this time whether linezolid administration in patients receiving other psychiatric drugs with lesser degrees of serotonergic activity poses a comparable risk.
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Note: Zyvox is typically covered under pharmacy benefit plans. Certain prescription drugs require an authorization for coverage to ensure that appropriate treatment regimens are followed. Medical drug coding and diagnosis codes, however, are generally not required for pharmacy claims submissions, therefore, this section is not in use. References
1. Chien JW, Kucia ML, and Salata RA. Use of linezolid, and oxazolidinone, in the treatment of multidrug-
resistant gram-positive bacterial infections. Clinical Infectious Diseases 2000;30: 146-151.
2. McNeil S, Clark N, Chandraseka P, et al. Successful treatment of vancomycin-resistant Enterococcus
faecium bacteremia with linezolid after failure of treatment with Synercid (quinupristin/dalfopristin). Clin Infect Dis 2000;30:403-404.
3. Pharmacia & Upjohn, Inc. Zyvox (linezolid) package insert. Kalamazoo, Michigan: Pharmacia &
4. Rybak M, Hershberger E, Moldovan T, et al. In vitro activities of daptomycin, vancomycin, linezolid, and
quinupristin-dalfopristin against Staphylococci and Enterococci, including vancomycin-intermediate and -resistant strains. Antimicrob Agents Chemother 2000;44(4):1062-1066.
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