IMBRUVICA, Ibrutinib Form

Ibrutinib (Imbruvica®) is a Bruton tyrosine kinase (BTK) inhibitor. FDA Approved Indication(s) Imbruvica is indicated for the treatment of: • Adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
• Adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with 17p deletion • Adult patients with Waldenström’s macroglobulinemia (WM) • Adult and pediatric patients age 1 year and older with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic 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.
It is the policy of health plans affiliated with Centene Corporation® that Imbruvica 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 Imbruvica requests, member must use generic ibrutinib, if available, unless contraindicated or clinically significant adverse effects are experienced;

2. Prescribed as a single agent;

   6. Request meets one of the following (a, b, c, or d): a. For capsules, dose ≤ 420 mg per day, and prescribed quantity does not exceed 3 capsules per day; b. For tablets, dose is 420 mg per day, and prescribed quantity does not exceed 1 tablet per day; c. For oral suspension, dose does not exceed 420 mg (6 mL) per day; d. 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
      Page 1 of 11

   CLINICAL POLICY Ibrutinib Approval duration:
   Medicaid/HIM – 6 months
   Commercial – 12 months or duration of request, whichever is less B. Waldenström’s Macroglobulinemia (must meet all):

3. Diagnosis of WM or lymphoplasmacytic lymphoma, including symptomatic Bing- Neel syndrome;
4. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. For Imbruvica requests, member must use generic ibrutinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
5. Prescribed as a single agent or in combination with rituximab; Prior authorization may be required
6. Request meets one of the following (a, b, c, or d): a. For capsules, dose ≤ 420 mg per day, and prescribed quantity does not exceed 3 capsules per day; b. For tablets, dose is 420 mg per day, and prescribed quantity does not exceed 1 tablet per day; c. For oral suspension, dose does not exceed 420 mg (6 mL) per day; d. 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 C. Chronic Graft-Versus-Host Disease (must meet all):
7. Diagnosis of cGVHD;
   2. Prescribed by or in consultation with an oncologist, hematologist, or bone marrow transplant specialist;
8. Age ≥ 1 year;
   4. For Imbruvica requests, member must use generic ibrutinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
9. Member has a history of bone marrow/stem cell transplant;
   
   6. Member meets both of the following (a and b):
      a. Failure of a systemic corticosteroid (see Appendix B) at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced;
      b. Failure of a systemic immunosuppressant (see Appendix B) at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced; *Prior authorization may be required

10. Imbruvica is not prescribed concurrently with Jakafi® or Rezurock®;

    8. Request meets one of the following (a, b, c, or d):* a. For capsules, dose ≤ 420 mg per day, and prescribed quantity does not exceed 3 capsules per day; Page 2 of 11

    CLINICAL POLICY Ibrutinib b. For tablets, dose is 420 mg per day, and prescribed quantity does not exceed 1 tablet per day; c. For oral suspension, dose does not exceed any of the following (i or ii): i. 420 mg (6 mL) per day;
    ii. For age 1 to < 12 years: 240 mg/m2 per day; d. 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 D. NCCN Compendium Indications (off-label) (must meet all):

11. Diagnosis of one of the following (a, b, c, or d): a. Primary CNS lymphoma; b. Brain metastases in lymphoma; c. Hairy cell leukemia (HCL); d. B-cell lymphoma subtype (i, ii, iii, iv, v, vi, or vii): i. HIV-related non-germinal center diffuse large B-cell lymphoma (DLBCL); ii. High-grade B-cell lymphoma; iii. Post-transplant lymphoproliferative disorder (PTLD); iv. DLBCL; v. Histologic transformation of CLL/SLL to DLBCL in patients with del(17p)/TP53 mutation; vi. Mantle cell lymphoma (MCL); vii. Marginal zone lymphoma (MZL) subtype (1, 2, 3, or 4):
    1) Gastric MALT lymphoma; 2) Nongastric MALT lymphoma (noncutaneous); 3) Nodal MZL;
    4) Splenic MZL;
12. Prescribed by or in consultation with an oncologist or hematologist;
    3. Age ≥ 18 years;
    4. For Imbruvica requests, member must use generic ibrutinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
13. For oral suspension requests at a dose > 420 mg per day, documentation supports inability to swallow oral capsules/tablets;

14. Member meets one of the following (a, b, c, or d): a. For primary CNS lymphoma, request is for use as either induction therapy or for relapsed or refractory disease;
    b. For brain metastases in lymphoma, request is for initial treatment in select cases (e.g., small asymptomatic brain metastases), or for treatment of recurrent or relapsed brain metastases; c. For B-cell lymphoma, one of the following (i, ii, or iii):
    i. For MCL only: Request is for use as either induction therapy or maintenance therapy;
    ii. For MCL only: Prescribed in combination with rituximab as pretreatment in order to limit the number of cycles of aggressive induction therapy with Page 3 of 11

    CLINICAL POLICY Ibrutinib RHyperCVAD (ritixumab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone); iii. Received ≥ 1 prior line of systemic therapy (see Appendix B), unless contraindicated or clinically significant adverse effects are experienced to all; d. For HCL, member has disease progression after therapy for relapsed/refractory disease (see Appendix B);

15. Request meets one of the following (a, b, c, or d): a. For capsules, dose ≤ 420 mg per day, and prescribed quantity does not exceed 3 capsules per day; b. For tablets, dose ≥ 420 mg per day, and prescribed quantity does not exceed 1 tablet per day; c. For oral suspension, dose does not exceed 420 mg (6 mL) per day; d. 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 E. Other diagnoses/indications (must meet 1 or 2):
16. 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
17. 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):
18. Documentation supports that member is currently receiving Imbruvica for a covered oncology-related indication and has received this medication for at least 30 days;
19. Member is responding positively to therapy;
    3. For Imbruvica requests, member must use generic ibrutinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
20. For oral suspension requests at a dose > 420 mg per day, documentation supports continued inability to swallow oral capsules/tablets;

21. For cGVHD, Imbruvica is not prescribed concurrently with Jakafi or Rezurock; Page 4 of 11

    CLINICAL POLICY Ibrutinib

22. If request is for a dose increase, request meets one of the following (a, b, or c): a. CLL/SLL and WM: one of the following (i, ii, or iii): i. For capsules, new dose ≤ 420 mg per day, and prescribed quantity does not exceed 3 capsules per day; ii. For tablets, new dose is 420 mg per day, and prescribed quantity does not exceed 1 tablet per day; iii. For oral suspension, new dose does not exceed 420 mg (6 mL) per day; b. cGVHD: New dose does not exceed any of the following (i, ii, or iii): i. For capsules, new dose ≤ 420 mg per day, and prescribed quantity does not exceed 3 capsules per day; ii. For tablets, new dose is 420 mg per day, and prescribed quantity does not exceed 1 tablet per day; iii. For oral suspension, new dose does not exceed any of the following (1 or 2): 1) 420 mg (6 mL) per day;
    2) For age 1 to < 12 years, 240 mg/m2 per day; c. New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). For oncology indications, prescribed regimen must be FDA-approved or recommended by NCCN
    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):
23. 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

24. 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.
    Page 5 of 11

    CLINICAL POLICY Ibrutinib IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key BTK: Bruton’s tyrosine kinase cGVHD: chronic graft-versus-host disease CLL: chronic lymphocytic leukemia DLBCL: diffuse large B-cell lymphoma FDA: Food and Drug Administration
    HCL: hairy cell leukemia MALT: mucosa-associated lymphoid tissue MCL: mantle cell lymphoma
    MZL: marginal zone lymphoma NCCN: National Comprehensive Cancer Network PTLD: post-transplant lymphoproliferative disorders SLL: small lymphocytic lymphoma
    WM: Waldenström’s macroglobulinemia
    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 Varies Examples of systemic therapies for B-cell lymphomas Bendeka®, Treanda® (bendamustine) ± Rituxan (rituximab) or Gazyva® (obinutuzumab) CHOP + Gazyva (obinutuzumab) EPOCH [etoposide, prednisone, vincristine (Vincasar PFS®), cyclophosphamide, doxorubicin (Adriamycin®)]

    • Rituxan (rituximab) NORDIC [dose-intensified induction immunochemotherapy with Rituxan (rituximab) + cyclophosphamide, vincristine (Vincasar PFS), doxorubicin, predisone] alternating with Rituxan (rituximab) and high-dose cytarabine RCEOP [Rituxan (rituximab), cyclophosphamide, etoposide, vincristine (Vincasar PFS), prednisone] RCEPP [Rituxan (rituximab), cyclosphosphamide, etoposide, prednisone, procarbazine] RCHOP [cyclophosphamide, doxorubicin (Adriamycin®), vincristine (Vincasar PFS), prednisone]/RDHAP RCVP [Rituxan (rituximab), cyclophosphamide, doxorubicin (Adriamycin®), vincristine (Vincasar PFS)] RDHAP [Rituxan (rituximab), dexamethasone, cytarabine, cisplatin] RDHAX [Rituxan (rituximab), dexamethasone, cytarabine, oxaliplatin]
      Revlimid® (lenalidomide) + Rituxan (rituximab) Rituxan (rituximab) Page 6 of 11

    CLINICAL POLICY Ibrutinib Drug Name Dosing Regimen Dose Limit/ Maximum Dose Varies Varies VR-CAP [bortezomib (Velcade®), Rituxan (rituximab), cyclosphosphamide, doxorubicin (Adriamycin®), and prednisone] Examples of systemic corticosteroids and immunosuppressants for cGVHD Systemic corticosteroids (e.g., methylprednisolone, prednisone)
    mycophenolate mofetil (Cellcept®) cyclosporine (Gengraf®, Neoral®, Sandimmune®) tacrolimus (Prograf®) sirolimus (Rapamune®) imatinib (Gleevec®) Jakafi® (ruxolitinib) Rezurock™ (belumosudil) Examples of systemic therapies for primary CNS lymphoma High-dose methotrexate-based regimen [methotrexate (Rheumatrex®) + Rituxan (rituximab) and other agents (e.g., temozolomide, vincristine (Vincasar PFS), procarbazine, cytarabine)] Examples of systemic therapies for relapsed/refractory HCL Tafinlar® (dabrafenib) + Mekinist® (trametinib) (if not previously treated with BRAF inhibitor) Zelboraf® (vemurafenib) ± rituximab (if not previously given) rituximab ± purine analog (e.g., cladribine, pentostatin) Pegasys® (peginterferon alfa-2a) 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. Varies Varies Varies Varies Appendix C: Contraindications/Boxed Warnings None reported V. Dosage and Administration
    Indication Dosing Regimen CLL/SLL, WM cGVHD 420 mg PO QD • Age ≥ 12 years and older: 420 mg PO QD • Age 1 to < 12 years: 240 mg/m2 PO QD, up Maximum Dose 420 mg/day (3 capsules, 1 tablet, or 6 mL per day) 420 mg/day (3 capsules, 1 tablet, or 6 mL per day) to a dose of 420 mg VI. Product Availability
    • Capsules: 70 mg, 140 mg • Tablets: 140 mg, 280 mg, 420 mg • Oral suspension: 70 mg/mL Page 7 of 11

    CLINICAL POLICY Ibrutinib VII.