SIRTURO, Bedaquiline Fumarate Form

Bedaquiline (Sirturo®) is a diarylquinoline antimycobacterial drug. FDA Approved Indication(s) Sirturo is indicated as part of combination therapy in the treatment of adult and pediatric patients (5 years and older and weighing at least 15 kg) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve Sirturo for use when an effective treatment regimen cannot otherwise be provided. Limitation(s) of use:
• Do not use Sirturo for the treatment of: o Latent infection due to Mycobacterium tuberculosis o Drug-sensitive tuberculosis o Extra-pulmonary tuberculosis
o Infections caused by non-tuberculous mycobacteria
• The safety and efficacy of Sirturo in the treatment of HIV infected patients with MDR-TB have not been established as clinical data are limited. This indication is approved under accelerated approval based on time to sputum culture conversion. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 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 Sirturo is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Multi-Drug Resistant Tuberculosis without Pretomanid (must meet all):

1. Diagnosis of MDR-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);

2. Age ≥ 5 years;

   4. Weight ≥ 15 kg; Page 1 of 10

   CLINICAL POLICY Bedaquiline

3. Prescribed in combination with at least 3 other anti-tuberculosis agents (Appendix B);
   6. Dose does not exceed one of the following (a or b): a. Weight ≥ 30 kg: 400 mg per day for the first 2 weeks, followed by 200 mg three times per week; b. Weight 15 to 29 kg: 200 mg per day for the first 2 weeks, followed by 100 mg three times per week. Approval duration: 24 weeks B. Multi-Drug Resistant Tuberculosis with Pretomanid (must meet all):
4. Diagnosis of pulmonary MDR-TB or XDR-TB;
   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);
5. Age ≥ 15 years;
   4. Prescribed in combination with pretomanid and linezolid; *Prior authorization may be required for pretomanid and linezolid.
6. 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;
7. Dose does not exceed 400 mg per day for the first 2 weeks, followed by 200 mg three times per week. Approval duration: 26 weeks C. Other diagnoses/indications (must meet 1 or 2):
8. 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
9. 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. Multi-Drug Resistant Tuberculosis without Pretomanid (must meet all):

10. Member meets one of the following (a or b): Page 2 of 10

    CLINICAL POLICY Bedaquiline 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 has not received more than 24 weeks of Sirturo therapy;
    4. If request is for a dose increase, new dose does not exceed one of the following (a or b): a. Weight ≥ 30 kg: 200 mg three times per week; b. Weight 15 to 29 kg: 100 mg three times per week. Approval duration: up to a total duration of 24 weeks B. Multi-Drug Resistant Tuberculosis with Pretomanid (must meet all):
11. 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 pretomanid and linezolid in combination with Sirturo; b. Member continues to receive pretomanid and has completed at least 4 weeks of linezolid therapy;
12. 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;
13. If request is for a dose increase, new dose does not exceed 200 mg three times per week. Approval duration: up to a total treatment duration of 26 weeks (9 months if evidence of delayed culture conversion) C. Other diagnoses/indications (must meet 1 or 2):

14. 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: Page 3 of 10

    CLINICAL POLICY Bedaquiline CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

15. 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 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 Dosing Regimen amikacin/kanamycin capreomycin cycloserine ethambutol ethionamide imipenem-cilastatin levofloxacin linezolid meropenem moxifloxacin para-aminosalicylic acid pyrazinamide streptomycin 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 10 to 15 mg/kg PO QD or BID Follow weight-based dosing in prescribing information 10 to 20 mg/kg PO QD or BID 1,000 mg IV BID 500 to 1,000 mg PO or IV QD 600 mg PO or IV QD 2,000 mg IV BID or TID 400 mg PO or IV QD 8 to 12 g PO BID or TID Follow weight-based dosing in prescribing information 15 mg/kg IM or IV QD or 25 mg/kg PO 3 times weekly Page 4 of 10 Dose Limit/ Maximum Dose 15 mg/kg/day 1,000 mg/day 1,000 mg/day 4,000 mg/dose 1,000 mg/day 2,000 mg/day 1,000 mg/day 600 mg/day 6,000 mg/day 400 mg/day 12 g/day 4,000 mg/dose 20 mg/kg/day

    CLINICAL POLICY Bedaquiline Drug Name Dosing Regimen pretomanid 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. *Amoxicillin-clavulanic acid should be coadministered with every dose of imipenem-cilastatin or meropenem but is not counted as a separate agent and should not be used as a separate agent. 200 mg PO QD for 26 weeks. 600 - 1,200 mg PO QD Dose Limit/ Maximum Dose 200 mg/day 1,200 mg/day Appendix C: Contraindications/Boxed Warnings • Contraindication(s): none reported • Boxed warning(s): increased mortality, QT prolongation Appendix D: General Information For MDR-TB: • Sirturo should only be used in combination with at least 3 other drugs to which the patient’s MDR-TB isolate has been shown to be susceptible in vitro. If in vitro testing results are unavailable, Sirturo treatment may be initiated in combination with at least 4 other drugs to which the patient’s MDR-TB isolate is likely susceptible. • Laboratory confirmation of multi-drug resistant TB must show TB with an isolate showing genotypic or phenotypic resistance to isoniazid and rifampin. For MDR-TB or XDR-TB with pretomanid: • 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.
    V. Dosage and Administration
    Indication MDR-TB Dosing Regimen Weight ≥ 30 kg: 400 mg PO QD for the first 2 weeks, followed by 200 mg PO three times per week (with at Maximum Dose Weight ≥ 30 kg: 400 mg/dose Page 5 of 10

    CLINICAL POLICY Bedaquiline Indication Dosing Regimen least 48 hours between doses) for 22 weeks (total duration of 24 weeks). Maximum Dose Weight 15 to 29 kg: 200 mg/dose MDR-TB or XDR-TB with pretomanid 400 mg/dose Weight 15 to 29 kg: 200 mg PO QD for the first 2 weeks, followed by 100 mg PO three times per week (with at least 48 hours between doses) for 22 weeks (total duration of 24 weeks). Sirturo should be administered by directly observed therapy (DOT) Administer in combination with pretomanid and linezolid (BPaL regimen) 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: 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
      Tablet: 20 mg, 100 mg VII.