Venetoclax (Venclexta) Form

Venetoclax (Venclexta®) is a B-cell lymphoma 2 protein (BCL-2) inhibitor. FDA Approved Indication(s) Venclexta is indicated: • For the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic • lymphoma (SLL) In combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy 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 Venclexta is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (must meet all):

1. Diagnosis of CLL or SLL;
   2. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. For brand Venclexta requests, member must use generic venetoclax, if available, unless contraindicated or clinically significant adverse effects are experienced;

2. Request meets one of the following (a or b): a. Prescribed as first-line therapy or for relapse if previously used as first-line therapy, in combination with Gazyva®; b. Prescribed as subsequent therapy for relapsed/refractory disease in combination with rituximab or as a single agent (see Appendix B for examples of prior therapy); Prior authorization may be required.

   6. Request meets one of the following (a or b):* a. Dose does not exceed both of the following (i and ii):
      i. 400 mg per day; ii. 4 tablets per day; Page 1 of 11

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   b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). *Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
   Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less B. Myeloid Leukemias (must meet all):

3. Diagnosis of one of the following myeloid leukemias (a or b): a. AML; b. Blastic plasmacytoid dendritic cell neoplasm (BPDCN);
4. Prescribed by or in consultation with an oncologist or hematologist;
   
   3. Age ≥ 18 years;
   4. For brand Venclexta requests, member must use generic venetoclax, if available, unless contraindicated or clinically significant adverse effects are experienced;
5. If diagnosis is AML, one of the following (a, b, or c): a. Disease is newly diagnosed, and (i or ii): i. Age ≥ 60 years; ii. Medical justification supports inability (see Appendix D for examples) to use intensive induction chemotherapy (see Appendix B for examples); b. Disease has relapsed after or is in remission following Venclexta therapy;
   c. Disease has relapsed after or is refractory to induction therapy (see Appendix B for examples);Prior authorization may be required.
6. If diagnosis is BPDCN, one of the following (a or b): a. Disease is systemic, and request is for palliative treatment (e.g., member has low performance and/or nutritional status [i.e., serum albumin < 3.2 g/dL; not a candidate for intensive remission therapy or tagraxofusp-erzs]); b. Disease is relapsed/refractory;
7. Prescribed in combination with azacitidine, decitabine, or low-dose (20 mg/m2) cytarabine;Prior authorization may be required.

8. Request meets one of the following (a, b, or c): a. In combination with azacitidine or decitabine: Dose does not exceed both of the following (i and ii): i. 400 mg per day; ii. 4 tablets per day; b. In combination with low-dose cytarabine: Dose does not exceed both of the following (i and ii): i. 600 mg per day; ii. 6 tablets per day; c. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
   Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less Page 2 of 11

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   C. Mantle Cell Lymphoma (off-label) (must meet all):

9. Diagnosis of mantle cell lymphoma;
   2. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. For brand Venclexta requests, member must use generic venetoclax, if available, unless contraindicated or clinically significant adverse effects are experienced;
10. Member has received ≥ 1 prior therapy (see Appendix B for examples);Prior authorization may be required.
11. Prescribed as a single agent or in combination with rituximab or ibrutinib;
    7. Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
       Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less D. Multiple Myeloma (off-label) (must meet all):
12. Diagnosis of multiple myeloma with t(11;14) translocation;
    2. Prescribed by or in consultation with an oncologist or hematologist;
    3. Age ≥ 18 years;
    4. For brand Venclexta requests, member must use generic venetoclax, if available, unless contraindicated or clinically significant adverse effects are experienced;
13. Member has received ≥ 1 prior therapy (see Appendix B for examples);Prior authorization may be required.
14. Prescribed in combination with dexamethasone;
    7. Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
       Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less E. Additional NCCN Recommended Uses (off-label) (must meet all):
15. Diagnosis of one of the following (a or b): a. Systemic light chain amyloidosis that is relapsed/refractory; b. Waldenström macroglobulinemia/ lymphoplasmacytic lymphoma as a single agent;
16. Prescribed by or in consultation with an oncologist or hematologist;
    3. Age ≥ 18 years;
    4. For brand Venclexta requests, member must use generic venetoclax, if available, unless contraindicated or clinically significant adverse effects are experienced;

17. Member has received ≥ 1 prior therapy (see Appendix B for examples);Prior authorization may be required. Page 3 of 11

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18. Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
    Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less F. Other diagnoses/indications (must meet 1 or 2):
19. 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
20. 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 Indications in Section I (must meet all):
21. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Venclexta for a covered indication and has received this medication for at least 30 days;
22. Member is responding positively to therapy;
    3. For brand Venclexta requests, member must use generic venetoclax, if available, unless contraindicated or clinically significant adverse effects are experienced;
    4. For AML, prescribed in combination with azacitidine, decitabine, or low-dose (20 mg/m2) cytarabine;Prior authorization may be required.

23. If request is for a dose increase, request meets one of the following (a, b, or c):
    a. CLL, SLL, or in combination with azacitidine or decitabine for AML: New dose does not exceed both of the following (i and ii): i. 400 mg per day; ii. 4 tablets per day; b. In combination with low-dose cytarabine for AML: New dose does not exceed both of the following (i and ii):
    i. 600 mg per day; ii. 6 tablets per day; Page 4 of 11

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    c. New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).
    Approval duration:
    Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less B. Other diagnoses/indications (must meet 1 or 2):

24. 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

25. 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 AML: acute myeloid leukemia BCL-2: B-cell lymphoma 2 protein BPDCN: blastic plasmacytoid dendritic cell neoplasm CLL: chronic lymphocytic leukemia FDA: Food and Drug Administration NCCN: National Comprehensive Cancer Network SLL: small lymphocytic lymphoma 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 Varies CLL/SLL Varies Page 5 of 11

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    Drug Name Dosing Regimen Dose Limit/ Maximum Dose Examples of first-line, second-line and subsequent therapies: • FCR (fludarabine, cyclophosphamide, rituximab) • HDMP (high-dose methylprenisolone) + rituximab Single-agent examples: Imbruvica® (ibrutinib); Brukinsa® (zanubrutinib), Campath® (alemtuzumab) ± rituximab; Gazyva; Copiktra® (duvelisib); Calquence® (acalabrutinib) ± Gazyva; Revlimid® (lenalidomide) ± rituximab; Arzerra® (ofatumumab) ± FC (fludarabine, cyclophosphamide); Leukeran® (chlorambucil) + rituximab; Zydelig® (idelalisib) ± rituximab AML cytarabine with idarubicin or daunorubicin cytarabine with idarubicin or daunorubicin or mitoxantrone Mantle cell lymphoma Examples of induction/chemoimmuno- therapy: • RDHA (rituximab, dexamethasone, cytarabine) + platinum therapy (e.g., carboplatin, cisplatin, oxaliplatin) • Alternating RCHOP/RDHAP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)/(rituximab, Age < 60 years: example of intensive induction therapy: cytarabine 100 – 200 mg/m2 continuous IV infusion x 7 days with idarubicin 12 mg/m2 IV or daunorubicin 60-90 mg/m2 IV x 3 days Age ≥ 60 years: example of intensive induction therapy: cytarabine 100 – 200 mg/m2 continuous IV infusion x 7 days with idarubicin 12 mg/m2 IV or daunorubicin 60-90 mg/m2 IV x 3 days or mitoxantrone 12 mg/m2 x 3 days Varies Varies Varies Page 6 of 11

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    Drug Name Dosing Regimen dexamethasone, cytarabine, cisplatin) Multiple myeloma Examples of primary therapy: • Bortezomib/lenalidomide/dexameth Varies Dose Limit/ Maximum Dose Varies asone • Bortezomib/cyclophosphamide or lenalidomide/dexamethasone • Carfilzomib or ixazomib/lenalidomide/ dexamethasone • Daratumumab/lenalidomide/ dexamethasone ± bortezomib • Lenalidomide/dexamethasone • Daratumumab/bortezomib/ mephalan/prednisone • Daratumumab/cyclophosphamide /bortezomib/dexamethasone Examples of maintenance therapy: • Lenalidomide • Ixazomib • Bortezomib Systemic light chain amyloidosis Examples of primary therapy: • Darzalex Faspro® (daratumumab and hyaluronidase-fihj)/ bortezomib/cyclophosphamide/ dexamethasone, bortezomib ± dexamethasone, bortezomib/ cyclophosphamide/dexamethasone, melphalan/dexamethasone Waldenström macroglobulinemia / lymphoplasmacytic lymphoma Examples of primary therapy: • Brukinsa® (zanubrutinib), Imbruvica® (ibrutinib) ± rituximab, bendamustine/rituximab, bortezomib/dexamethasone/ rituximab Varies Varies Varies Varies 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. Page 7 of 11

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    Appendix C: Contraindications/Boxed Warnings • Contraindication(s): concomitant use of Venclexta with strong inhibitors of CYP3A at initiation and during ramp-up phase in patients with CLL/SLL • Boxed warning(s): none reported
    Appendix D: General Information Patient or disease state characteristics that may preclude use of intensive induction therapy include but are not limited to the following examples:
    • Limited functional status as indicated by an Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2 • Significant comorbidity (e.g., severe cardiac, pulmonary or renal disease) • AML without favorable cytogenetics or molecular markers • AML secondary to prior antineoplastic therapy • AML preceded by a hematologic disorder such as myelodysplastic syndrome V. Dosage and Administration Indication Dosing Regimen CLL and SLL
    Venclexta 5-week dose ramp-up schedule:
    20 mg PO QD for one week followed by 50 mg PO QD for one week, 100 mg PO QD for one week, 200 mg PO QD for one week, then 400 mg PO QD Maximum Dose 400 mg/day Venclexta in combination with Gazyva:
    On Cycle 1 Day 22, start Venclexta according to the 5-week ramp-up schedule. Continue Venclexta 400 mg QD from Cycle 3 Day 1 until the last day of Cycle 12. Venclexta in combination with rituximab:
    Administer rituximab after the 5-week ramp-up schedule with Venclexta. Continue Venclexta 400 mg QD for 24 months from Cycle 1 Day 1 of rituximab. Venclexta as monotherapy: 400 mg PO QD after the patient has completed the 5-week dose ramp-up schedule until disease progression or unacceptable toxicity PO QD in combination with azacitidine, decitabine, or low- dose cytarabine: • Day 1: 100 mg/day
    • Day 2: 200 mg/day
    • Day 3: 400 mg/day
    • Day 4 and beyond, until disease progression or unacceptable toxicity:
    o In combination with azacitidine or decitabine: 400 mg/day
    AML 400 mg/day with azacitidine or decitabine; 600 mg/day with cytarabine
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    Indication Dosing Regimen Maximum Dose o In combination with low-dose cytarabine: 600 mg/day VI. Product Availability Tablets: 10 mg, 50 mg, 100 mg
    VII.