PROLIA, Denosumab XGEVA, Denosumab Form

Denosumab (Prolia®, Xgeva®) is a receptor activator of nuclear factor kappa-B ligand inhibitor. FDA Approved Indication(s) Prolia is indicated: • For the treatment of postmenopausal women with osteoporosis (PMO) at high risk for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, Prolia reduces the incidence of vertebral, nonvertebral, and hip fractures. • For the treatment to increase bone mass in men with osteoporosis at high risk for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. • For the treatment of glucocorticoid-induced osteoporosis (GIO) in men and women at high risk of fracture who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to ≥ 7.5 mg of prednisone and expected to remain on glucocorticoids for ≥ 6 months.
• For treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer. In these patients Prolia also reduced the incidence of vertebral fractures. • For treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. __ High risk of fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. Xgeva is indicated:
• For the prevention of skeletal-related events in patients with multiple myeloma (MM) and in patients with bone metastases from solid tumors. • For the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. • For the treatment of hypercalcemia of malignancy refractory to bisphosphonate 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 Denosumab Index I. Initial Approval Criteria
A. Osteoporosis (Prolia) B. Prostate/Breast Cancer - Fracture Prevention (Prolia) C. Multiple Myeloma or Solid Tumor (Xgeva) D. Giant Cell Tumor of Bone (Xgeva) E. Hypercalcemia of Malignancy (Xgeva) F. Systemic Mastocytosis (off-label) (Xgeva) G. Other diagnoses/indications
II. Continued Therapy A. All Indications in Section I (Prolia and Xgeva) B. Other diagnoses/indications III. Diagnoses/Indications for which coverage is NOT authorized IV. Appendices/General Information V. Dosage and Administration
VI. Product Availability
VII. References It is the policy of health plans affiliated with Centene Corporation® that Prolia and Xgeva are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Osteoporosis (must meet all):

1. Request is for Prolia;
2. Diagnosis of PMO, GIO, or male osteoporosis and one of the following (a or b): a. Member is at very high risk for fracture as evidenced by one of the following (i, ii, or iii): i. Recent osteoporotic fracture (within the past 12 months) ii. Bone mineral density (BMD) T-score at hip or spine ≤ -3.0; iii. BMD T-score at hip or spine ≤ -2.5 AND major osteoporotic fracture (i.e., hip, spine, forearm, wrist, humerus); b. Member has completed a 3-year trial of bisphosphonate therapy (see Appendix B; generic alendronate is preferred) at up to maximally indicated doses unless one of the following (i-v): i. All bisphosphonates are contraindicated; ii. Clinically significant adverse effects are experienced to both IV and PO formulations (see Appendix D); iii. Member has experienced a loss of BMD while receiving bisphosphonate therapy; iv. Member has experienced a lack of BMD increase after ≥ 12 months of bisphosphonate therapy; v. Member experienced an osteoporotic fracture or fragility fracture while receiving bisphosphonate therapy; Prior authorization may be required for bisphosonates.
   3. Age ≥ 18 years or documentation of closed epiphyses on x-ray;

3. Prolia is not prescribed concurrently with Xgeva; Page 2 of 13

   CLINICAL POLICY Denosumab

   5. Dose does not exceed 60 mg every 6 months. Approval duration:
      Medicaid/HIM – 12 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. Prostate/Breast Cancer - Fracture Prevention (must meet all):
   6. Request is for Prolia;
4. Diagnosis of one of the following (a or b): a. Prostate cancer, and member is receiving ADT (e.g., leuprolide (Lupron®), bicalutamide (Casodex®) or nilutamide (Nilandron®)); b. Breast cancer, and member is receiving adjuvant endocrine therapy (e.g., tamoxifen or aromatase inhibitors such as anastrozole (Arimidex®), exemestane (Aromasin®) or letrozole (Femara®));
   3. Prescribed by or in consultation with an oncologist;
5. Age ≥ 18 years or documentation of closed epiphyses on x-ray;
6. Member meets one of the following (a, b, or c): a. For breast cancer, failure of zoledronic acid (Zometa) or pamidronate, at up to maximally indicated doses unless clinically significant adverse effects are experienced or both are contraindicated (see Appendices B and D); Prior authorization may be required. b. For prostate cancer, failure of zoledronic acid (Zometa) at up to maximally indicated doses unless contraindicated or clinically significant adverse effects are experienced (see Appendices B and D); *Prior authorization may be required.
   c. Request is for the treatment associated with stage IV or metastatic cancer for a state with regulations against step therapy in advanced oncology settings (see Appendix E);
   6. Prolia is not prescribed concurrently with Xgeva;
7. Dose does not exceed 60 mg every 6 months. Approval duration:
   Medicaid/HIM – 12 months Commercial – 6 months or to the member’s renewal date, whichever is longer C. Multiple Myeloma or Solid Tumor (must meet all):
   
   1. Request is for Xgeva;
8. Diagnosis of one of the following (a or b): a. MM, and member is receiving or initiating therapy (e.g., chemotherapy, transplant) for symptomatic disease; b. Bone metastasis secondary to solid tumor (e.g., breast, kidney, lung, prostate, thyroid);
   3. Prescribed by or in consultation with an oncologist;
9. Age ≥ 18 years or documentation of closed epiphyses on x-ray;

10. For indications other than prostate or breast cancer, member meets one of the following (a or b): a. Failure of zoledronic acid (Zometa) or pamidronate at up to maximally indicated doses, unless clinically significant adverse effects are experienced or both are contraindicated (see Appendices B and D); Page 3 of 13

    CLINICAL POLICY Denosumab *Prior authorization may be required. b. Request is for the treatment associated with stage IV or metastatic cancer for a state with regulations against step therapy in advanced oncology settings (see Appendix E);

    6. Xgeva is not prescribed concurrently with Prolia;
11. Dose does not exceed 120 mg every 4 weeks. Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer D. Giant Cell Tumor of Bone (must meet all):
    
    1. Request is for Xgeva;
12. Diagnosis of giant cell tumor of bone that is characterized as one of the following (a or b): a. Metastatic or unresectable disease; b. Localized disease, and Xgeva is prescribed as a single agent or in combination with interferon alfa or radiation therapy;
13. Prescribed by or in consultation with an oncologist;
14. Age ≥ 18 years or documentation of closed epiphyses on x-ray;
15. Xgeva is not prescribed concurrently with Prolia;
16. Dose does not exceed 120 mg every 4 weeks plus 120 mg on days 8 and 15 of first month of therapy. Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer E. Hypercalcemia of Malignancy (must meet all):
    
    1. Request is for Xgeva;
17. Diagnosis of hypercalcemia of malignancy:
18. Prescribed by or in consultation with an oncologist;
19. Age ≥ 18 years or documentation of closed epiphyses on x-ray;
20. Albumin-corrected calcium > 12.5 mg/dL despite IV bisphosphonate therapy in the last 30 days (see Appendix B); *Prior authorization may be required.
    6. Xgeva is not prescribed concurrently with Prolia;
21. Dose does not exceed 120 mg every 4 weeks plus 120 mg on days 8 and 15 of first month of therapy. Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer F. Systemic Mastocytosis (off-label) (must meet all):
    
    1. Request is for Xgeva;
22. Diagnosis of systemic mastocytosis;
23. Member has osteopenia or osteoporosis with bone pain;
24. Prescribed by or in consultation with an oncologist;

25. Age ≥ 18 years or documentation of closed epiphyses on x-ray; Page 4 of 13

    CLINICAL POLICY Denosumab

    6. Member meets one of the following (a or b): a. Failure of zoledronic acid (Zometa) or pamidronate at up to maximally indicated doses unless clinically significant adverse effects are experienced or both are contraindicated (see Appendices B and D); *Prior authorization may be required. b. Request is for the treatment associated with Stage IV or metastatic cancer for a State with regulations against step therapy in advanced oncology settings (see Appendix E);
    7. Xgeva is not prescribed concurrently with Prolia;

26. 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 – 6 months or to the member’s renewal date, whichever is longer G. 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 Indications in Section I (must meet all):
    3. 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. Documentation supports that member is currently receiving Prolia or Xgeva for a covered cancer-related indication and has received this medication for at least 30 days;
    4. Member is responding positively to therapy; Page 5 of 13

    CLINICAL POLICY Denosumab

    3. If request is for a dose increase, new dose does not exceed (a or b): a. Prolia: 60 mg every 6 months; b. Xgeva: 120 mg every 4 weeks 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 – 12 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. 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 ADT: androgen deprivation therapy BMD: bone mineral density FDA: Food and Drug Administration GIO: glucocorticoid-induced osteoporosis MM: multiple myeloma PMO: postmenopausal osteoporosis 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.
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    CLINICAL POLICY Denosumab Drug Name Dosing Regimen IV bisphosphonates ibandronate (Boniva®)
    zoledronic acid (Reclast®; Zometa) pamidronate Oral bisphosphonates alendronate (Fosamax®) Fosamax® Plus D (alendronate / cholecalciferol) risedronate (Actonel®, Atelvia®) Treatment: PMO Hypercalcemia of malignancy (off-label) Reclast: Treatment/prevention: PMO, GIO Treatment: male osteoporosis Zometa:
    MM Bone metastasis from solid tumors
    Hypercalcemia of malignancy Systemic mastocytosis (off-label) Fracture prevention - breast/prostate cancer (off-label) MM
    Bone metastasis from breast cancer Hypercalcemia of malignancy Systemic mastocytosis (off-label) Fracture prevention – breast/prostate cancer (off-label) Treatment: PMO Treatment: GIO, male osteoporosis Treatment: PMO, male osteoporosis Dose Limit/ Maximum Dose Varies
    See prescribing information and compendia for dosing. Varies See prescribing information and compendia for dosing. Actonel: Treatment: PMO, GIO
    Treatment: male osteoporosis Atelvia: Treatment: PMO ibandronate (Boniva®)
    Treatment/prevention: PMO 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 Prolia: hypocalcemia, pregnancy, known hypersensitivity to Prolia o Xgeva: hypocalcemia, known clinically significant hypersensitivity to Xgeva • Boxed warning(s): none reported Page 7 of 13

    CLINICAL POLICY Denosumab Appendix D: IV/PO Bisphosphonates: Examples of Contraindications and Adverse Effects Bisphosphonates
    Oral Formulations IV Formulations Contraindications Hypocalcemia Increased risk of aspiration Hypersensitivity to product component
    Inability to stand/sit upright for at least 30 minutes Creatinine clearance < 35 mL/min or evidence of acute renal impairment Esophagus abnormalities which delay emptying such as stricture or achalasia Clinically significant warnings or adverse side effects Pregnancy Eye inflammation Acute renal failure Osteonecrosis of the jaw
    Atypical femoral shaft fracture Drug interactions (product-specific) Severe or incapacitating musculoskeletal pain X X X X

    • X X X X X X X X X
    • X
    • X
    • X X X X X X X Appendix E: States with Regulations against Redirections in Stage III, IV or Metastatic Cancer State Step Therapy Prohibited? Yes Yes FL GA IA LA NV OH OK PA TN TX Yes Yes Yes Yes Yes Yes Yes Yes Notes For stage 4 metastatic cancer and associated conditions. For stage 4 metastatic cancer. Redirection does not refer to review of medical necessity or clinical appropriateness. For standard of care stage 4 cancer drug use, supported by peer- reviewed, evidence-based literature, and approved by FDA. For stage 4 advanced, metastatic cancer or associated conditions. Exception if “clinically equivalent therapy, contains identical active ingredient(s), and proven to have same efficacy. Stage 3 and stage 4 cancer patients for a prescription drug to treat
      the cancer or any symptom thereof of the covered person Applies to Commercial and HIM requests only For stage 4 metastatic cancer and associated conditions Applies to HIM requests only For advanced metastatic cancer and associated conditions For stage 4 advanced, metastatic cancer For advanced metastatic cancer and associated conditions For stage 4 advanced, metastatic cancer and associated conditions Page 8 of 13

    CLINICAL POLICY Denosumab V. Dosage and Administration
    Drug Name Indication Denosumab (Prolia) Denosumab (Xgeva) Treatment: PMO, GIO, male osteoporosis Oncology: fracture prevention

    • Men at high risk for fracture receiving ADT for nonmetastatic prostate cancer
    • Women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer
      MM Solid tumor - bone metastasis Giant cell tumor of bone Hypercalcemia of malignancy Dosing Regimen 60 mg SC once every 6 months Maximum Dose 60 mg/dose 120 mg SC once every 4 weeks 120 mg SC every 4 weeks plus 120 mg on Days 8 and 15 of first month of therapy 20 mg/dose 120 mg/dose VI. Product Availability
      Drug Name Denosumab (Prolia) Denosumab (Xgeva) Availability Injection (single-use prefilled syringe): 60 mg/mL Injection (single-use vial): 120 mg/1.7 mL (70 mg/mL) VII.