ZYVOX, Linezolid Form

Linezolid (Zyvox®) is an oxazolidinone-class antibacterial agent. FDA Approved Indication(s) Zyvox is indicated in adults and children for the treatment of the following infections caused by susceptible gram-positive bacteria:
• Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and - resistant isolates) or Streptococcus pneumoniae • Community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only)
• Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis caused by Staphylococcus aureus (methicillin-susceptible and - resistant isolates), 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 isolates only) or Streptococcus pyogenes • Vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia Limitation(s) of use: • Zyvox 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 • The safety and efficacy of Zyvox formulations given for longer than 28 days have not been evaluated in controlled clinical trials.
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 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. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
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CLINICAL POLICY Linezolid It is the policy of health plans affiliated with Centene Corporation® that Zyvox is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. All FDA-Approved Indications (must meet all):

1. Diagnosis is an FDA-approved indication;
2. Member meets one of the following (a or b): a. Request is for continuation of therapy initiated in an acute care hospital from which member was discharged; b. Both of the following (i and ii):
   i. Culture and sensitivity (C&S) report for the current infection shows isolated pathogen is a gram-positive bacteria susceptible to linezolid, unless provider submits documentation that obtaining a C&S report is not feasible; ii. Member meets one of the following (a, b, or c): a) Failure of ≥ 2 formulary antibiotics to which the isolated pathogen is susceptible (if available) per C&S report, unless clinically significant adverse effects are experienced or all are contraindicated;
   b) C&S report shows resistance or lack of susceptibility of the isolated pathogen to all formulary antibiotics FDA-approved for member’s diagnosis;
   c) If provider documents that obtaining a C&S report is not feasible: Failure of ≥ 2 formulary antibiotics indicated for member’s diagnosis (if available), unless clinically significant adverse effects are experienced or all are contraindicated;
   3. Dose does not exceed both of the following (a and b):
      a. 1,200 mg per day;
      b. 2 tablets, 2 vials, or 60 mL suspension per day. Approval duration: Duration of request or up to 28 days of total treatment, whichever is less B. Pulmonary Multi-Drug Resistant Tuberculosis and Extensively Drug Resistant Tuberculosis (off-label) (must meet all):

3. Diagnosis of pulmonary multi-drug resistant tuberculosis (MDR-TB) or extensively drug resistant tuberculosis (XDR-TB);

   2. Prescribed by or in consultation with an infectious disease specialist, pulmonologist , or expert in the treatment of tuberculosis (e.g., state or county public health department, specialists affiliated with TB Centers of Excellence as designated by the CDC, infectious disease specialists managing TB clinics);
   3. Dose does not exceed both of the following (a and b):
      a. 1,200 mg per day;
      b. 2 tablets per day. Approval duration: 6 months Page 2 of 10

   CLINICAL POLICY Linezolid C. Other diagnoses/indications (must meet 1 or 2):

   1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
   2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
      II. Continued Therapy A. All FDA-Approved Indications (must meet all):
4. Member meets one of the following (a, b, or c): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B); c. Request is for continuation of therapy initiated in an acute care hospital from which member was discharged;
5. Member is responding positively to therapy;
6. Member has not received ≥ 28 days of therapy for current infection;
7. If request is for a dose increase, new dose does exceed both of the following (a and b):
   a. 1,200 mg per day;
   b. 2 tablets, 2 vials, or 60 mL suspension per day. Approval duration: Up to 28 days of total treatment B. Pulmonary Multi-Drug Resistant Tuberculosis and Extensively Drug Resistant Tuberculosis (off-label) (must meet all):
8. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);

9. Member is responding positively to therapy; Page 3 of 10

   CLINICAL POLICY Linezolid

   3. If request is for a dose increase, new dose does not exceed both of the following (a and b):
      a. 1,200 mg per day; b. 2 tablets per day.
      Approval duration: Up to a total treatment duration of 24 months C. Other diagnoses/indications (must meet 1 or 2):
   4. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
   5. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
      III. Diagnoses/Indications for which coverage is NOT authorized:
      A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid or evidence of coverage documents.
      IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key C&S: culture and sensitivity CDC: Centers for Disease Control and Prevention FDA: Food and Drug Administration MDR-TB: multi-drug resistant tuberculosis
      XDR-TB: extensively drug resistant tuberculosis
      Appendix B: Therapeutic Alternatives
      This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
      Drug Name Dose Limit/ Maximum Dose Therapeutic alternatives include formulary antibiotics that are indicated for member’s diagnosis and have sufficient activity against the offending pathogen at the site of the infection. Dosing Regimen Page 4 of 10

   CLINICAL POLICY Linezolid Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Appendix C: Contraindications/Boxed Warnings • Contraindication(s):
   o Known hypersensitivity to linezolid or any of the other product components o Patients taking any monoamine oxidase inhibitors (MAOI) within two weeks of taking an MAOI • Boxed warnings(s): none reported Appendix D: General Information For MDR-TB or XDR-TB with pretomanid: • Centers for Disease Control and Prevention (CDC) Centers of Excellence for TB: https://www.cdc.gov/tb/education/tb_coe/default.htm • Pretomanid should only be used in combination with Sirturo and linezolid.
   • Dosing of the combination regimen of pretomanid, Sirturo, and linezolid can be extended beyond 26 weeks if necessary, to a maximum of 9 months, in patients with delayed culture conversion.
   o Delayed culture conversion: two consecutive negative sputum cultures following an initial positive culture.
   • Laboratory confirmation of multi-drug resistant TB must show TB with an isolate showing genotypic or phenotypic resistance to isoniazid and rifampin. • Laboratory confirmation of extensively drug resistant TB must show TB with an isolate showing genotypic or phenotypic resistance to isoniazid, rifampin, fluoroquinolones, as well as second-line injectable agents such as aminoglycosides or capreomycin. • Linezolid starting dose of 1,200 mg daily for 26 weeks may be managed as follows: o Adjusted to 600 mg daily and further reduced to 300 mg daily as necessary for adverse reactions of myelosuppression, peripheral neuropathy, and optic neuropathy.
   o Doses of the regiment missed for safety reasons can be made up at the end of treatment; does of linezolid alone missed due to adverse reactions should not be made up.
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   Maximum Dose Adults and adolescents age ≥ 12 years: 1,200 mg/day Age 1 – 11 years: 10 mg/kg/dose PO or IV every 8 hours (max: 600 mg/dose) Infants and neonates: 10 mg/kg/dose PO or IV every 8 hours 1,200 mg/day CLINICAL POLICY Linezolid V. Dosage and Administration
   Indication Pediatrics (birth – age 11 years) Nosocomial pneumonia 10 mg/kg IV or PO every Community-acquired 8 hours pneumonia, including concurrent bacteremia Complicated skin and skin structure infections Vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia Uncomplicated skin and skin structure infections 10 mg/kg IV or PO every 8 hours Age < 5 years: 10 mg/kg PO every 8 hours Dosing Regimen Adults and Adolescents (age ≥ 12 years) 600 mg IV or PO every 12 hours Duration (consecutive days) 10 to 14 14 to 28 10 to 14 600 mg IV or PO every 12 hours Adults: 400 mg PO every 12 hours MDR-TB or XDR-TB with pretomanid (off-label) Adolescents: 600 mg PO every 12 hours Age 5 – 11 years: 10 mg/kg PO every 12 hours Administer in combination with Sirturo and pretomanid in a directly observed therapy (DOT) setting. • Sirturo: 400 mg PO QD for the first 2 weeks, followed by 200 mg PO three times per week (with at least 48 hours between doses) for 24 weeks (total duration of 26 weeks). • Pretomanid: 200 mg PO QD for 26 weeks. • Linezolid: 1,200 mg PO QD for 26 weeks. Page 6 of 10

   CLINICAL POLICY Linezolid VI. Product Availability
   Injection: 200 mg/100 mL and 600mg /300 mL • • Tablets: 600 mg
   • Oral suspension: 100 mg/5 mL VII.