Pretomanid Form

Pretomanid is a nitroimidazooxazine antimycobacterial drug. FDA Approved Indication(s) Limited population: Pretomanid is indicated, as part of a combination regimen with bedaquiline and linezolid for the treatment of adults with pulmonary tuberculosis (TB) that is resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug OR adults with pulmonary TB resistant to isoniazid and rifampin, who are treatment-intolerant or nonresponsive to standard therapy. Approval of this indication is based on limited clinical safety and efficacy data. This drug is indicated for use in a limited and specific population of patients. Limitation(s) of use:
• Pretomanid tablets are not indicated in patients with: o Drug-sensitive (DS) TB
o Latent infection due to Mycobacterium tuberculosis o Extra-pulmonary infection due to Mycobacterium tuberculosis o TB resistant to isoniazid and rifampin who are responsive to standard therapy and not treatment-intolerant o TB with known resistance to any component of the combination • Safety and effectiveness of pretomanid has not been established for its use in combination with drugs other than bedaquiline and linezolid as part of the recommended dosing regimen. 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.
It is the policy of health plans affiliated with Centene Corporation® that pretomanid is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Drug Resistant Tuberculosis (must meet all):

1. Diagnosis of pulmonary TB;

   2. Documentation of one of the following (a or b):
      a. Resistance to isoniazid and rifampin, and member is treatment-intolerant or nonresponsive to standard therapy (see Appendix D); b. Resistance to isoniazid, rifamycins, a fluroquinolone, and a second line injectable antibacterial drug (e.g., amikacin, capreomycin, kanamycin);
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   CLINICAL POLICY Pretomanid

2. Prescribed by or in consultation with an 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. Age ≥ 15 years;
   5. Prescribed in combination with Sirturo® (bedaquiline) and linezolid; *Prior authorization may be required for Sirturo and linezolid.
4. One of the following (a or b): a. Prescribed in combination with moxifloxacin (off-label); b. Documented resistance to fluoroquinolones, unless contraindicated or clinically significant adverse effects are experienced;
5. Dose does not exceed 200 mg (1 tablet) per day. Approval duration: 26 weeks B. Other diagnoses/indications (must meet 1 or 2):
6. 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

7. 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. Drug Resistant Tuberculosis (must meet all):

   1. 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);
   2. Member is responding positively to therapy;
   3. Member meets one of the following (a or b): a. Member continues to receive Sirturo and linezolid in combination with pretomanid; b. Member continues to receive Sirturo and has completed at least 4 weeks of linezolid therapy; Page 2 of 8

   CLINICAL POLICY Pretomanid

8. If request is for treatment beyond 26 weeks, provider attestation of delayed treatment response within the first 8 weeks as assessed by time to culture conversion, persistent culture positivity, clinical response to treatment, and other underlying clinical factors, or modified based on adverse events;
9. If request is for a dose increase, new dose does not exceed 200 mg (1 tablet) per day. Approval duration: up to a total treatment duration of 26 weeks (9 months if evidence of delayed culture conversion) B. Other diagnoses/indications (must meet 1 or 2):
10. 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

11. 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 BPaL: bedaquiline, pretomanid, and linezolid CDC: Centers for Disease Control FDA: Food and Drug Administration 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 Dosing Regimen Dose Limit/ Maximum Dose 4,000 mg/dose pyrazinamide Follow weight-based dosing in prescribing information Page 3 of 8

    CLINICAL POLICY Pretomanid Drug Name Dosing Regimen Dose Limit/ Maximum Dose 1,000 mg/day 1,000 mg/day 20 mg/kg/day capreomycin amikacin/kanamycin cycloserine ethionamide streptomycin 10 to 15 mg/kg PO QD or BID 10 to 20 mg/kg PO QD or BID 15 mg/kg IM or IV QD or 25 mg/kg PO 3 times weekly 15 mg/kg IM or IV QD or 25 mg/kg PO 3 times weekly 15 mg/kg IM or IV QD or 25 mg/kg PO 3 times weekly 8 to 12 g PO BID to TID 500 to 1,000 mg PO or IV QD 400 mg PO or IV QD 600 - 1,200 mg PO QD 400 mg PO QD for the first 2 weeks, followed by 200 mg PO three times per week for remaining 24 weeks. 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. para-amino salicylic acid levofloxacin moxifloxacin linezolid (Zyvox®) Sirturo® (bedaquiline) 12 g/day 1,000 mg/day 400 mg/day 1,200 mg/day 400 mg/day 15 mg/kg/day 1,000 mg/day Appendix C: Contraindications/Boxed Warnings • Contraindication(s): patients who have contraindications to Sirturo and/or linezolid
    • Boxed warning(s): none reported Appendix D: General Information • CDC Centers of Excellence for TB: https://www.cdc.gov/tb/education/tb_coe/default.htm • Standard pulmonary TB therapy consists of 4-month rifapentine-moxifloxacin regimen or 6- or 9- month RIPE (rifamycin, isoniazid, pyrazinamide, and ethambutol) regimen.
    • 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 regimen 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 200 mg/day CLINICAL POLICY Pretomanid V. Dosage and Administration
    Indication Dosing Regimen Drug resistant pulmonary TB Administer in combination with bedaquiline and linezolid in a directly observed therapy (DOT) setting. • Pretomanid: 200 mg PO QD for 26 weeks. • Sirturo: 400 mg PO QD for 2 weeks followed by 200 mg 3 times per week (at least 48 hours between doses) for the remaining 24 weeks (total duration of 26 weeks).
    • Linezolid: 600 mg PO QD for 26 weeks*. Patients 17 years of age or older may continue treatment with Sirturo and pretomanid without linezolid if the patient has previously received a total daily dose of linezolid 1,200 mg for at least 4 weeks.

    • Treatment with the BPaL regimen can be extended beyond 26 weeks up to 9 months (39 weeks) based on delayed treatment response within the first 8 weeks as assessed by time to culture conversion, persistent culture positivity, clinical response to treatment, and other underlying clinical factors, or modified based on adverse events. VI. Product Availability
      Tablets: 200 mg VII.