RECLAST, Zoledronic Acid ZOMETA, Zoledronic Acid Form

Zoledronic acid (Reclast®) is a bisphosphonate. FDA Approved Indication(s) Reclast is indicated:
• For the treatment of osteoporosis in postmenopausal women (PMO). In postmenopausal women with osteoporosis, diagnosed by bone mineral density (BMD) or prevalent vertebral fracture, Reclast reduces the incidence of fractures (hip, vertebral, and non-vertebral osteoporosis-related fractures). In patients at high risk of fracture, defined as a recent low- trauma hip fracture, Reclast reduces the incidence of new clinical fractures; • For the prevention of osteoporosis in postmenopausal women (PMO); • For the treatment to increase bone mass in men with osteoporosis; • For the treatment and prevention of GIO in men and women who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who are expected to remain on glucocorticoids for at least 12 months; • For the treatment of Paget's disease of bone in men and women with elevations in serum alkaline phosphatase (ALP) of two times or higher than the upper limit of the age-specific normal reference range, or those who are symptomatic, or those at risk for complications from their disease. Limitation(s) of use: The safety and effectiveness of Reclast for the treatment of osteoporosis is based on clinical data of three years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically. Zoledronic acid (formerly Zometa®) is indicated: • For the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL (3.0 mmol/L);
• For the treatment of patients with multiple myeloma (MM); • :For the treatment of patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. Page 1 of 11

CLINICAL POLICY
Zoledronic Acid Limitation(s) of use: The safety and efficacy of zoledronic acid in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions have not been established. 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.
Index I. Initial Approval Criteria
A. Osteoporosis B. Paget Disease of Bone C. Hypercalcemia of Malignancy D. Multiple Myeloma or Solid Tumor E. Prostate/Breast Cancer - Fracture Prevention (off-label) F. Systemic Mastocytosis (off-label) G. Histiocytic Neoplasms – Langerhans Cell Histiocytosis (off-label) H. Other diagnoses/indications
II. Continued Therapy A. Osteoporosis and Paget Disease of Bone B. All Oncology Indications C. 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 zoledronic acid is
medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Osteoporosis (must meet all):

1. Prescribed for one of the following uses (a or b): a. Treatment or prevention of PMO or GIO; b. Treatment of male osteoporosis;
2. Age ≥ 18 years or documentation of closed epiphyses on x-ray;
   
   3. Failure of a 12-month trial of an oral bisphosphonate (see Appendix B; generic alendronate is preferred) at up to maximally indicated doses, unless all are contraindicated or clinically significant adverse effects are experienced; Prior authorization may be required for oral bisphosphonates

3. Dose does not exceed 5 mg. Approval duration: Medicaid/HIM –
   • Osteoporosis treatment: 12 months (one infusion) • Osteoporosis prevention: 24 months (one infusion)
   Page 2 of 11

   CLINICAL POLICY
   Zoledronic Acid Commercial – 6 months or to the member’s renewal date, whichever is longer B. Paget Disease (must meet all):

4. Diagnosis of Paget disease of the bone;
   2. Age ≥ 18 years or documentation of closed epiphyses on x-ray;
   3. Dose does not exceed 5 mg. Approval duration: Medicaid/HIM – 12 months (one infusion) Commercial – 6 months or to the member’s renewal date, whichever is longer C. Hypercalcemia of Malignancy (must meet all):
   4. Diagnosis of hypercalcemia of malignancy:
   5. Prescribed by or in consultation with an oncologist;
   6. Age ≥ 18 years or documentation of closed epiphyses on x-ray;
   7. Albumin-corrected calcium ≥ 12 mg/dL;
   8. Dose does not exceed 4 mg. Approval duration:
      Medicaid/HIM – 1 week (one infusion) Commercial – 6 months or to the member’s renewal date, whichever is longer
      D. Multiple Myeloma or Solid Tumor (must meet all):
5. 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. Bony metastasis from solid tumor (e.g., breast, kidney, lung, prostate, thyroid);
6. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years or documentation of closed epiphyses on x-ray;
   4. Dose does not exceed 4 mg. Approval duration:
      Medicaid/HIM – 3 months (one infusion every 3 weeks) Commercial – 6 months or to the member’s renewal date, whichever is longer E. Prostate/Breast Cancer - Fracture Prevention (off-label) (must meet all):
7. Diagnosis of one of the following (a or b): a. Prostate cancer, and member is receiving androgen deprivation therapy (e.g., leuprolide (Lupron®), bicalutamide (Casodex®), 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®));

8. Prescribed by or in consultation with an oncologist;

   3. Age ≥ 18 years or documentation of closed epiphyses on x-ray;
   4. Request meets one of the following (a or b): a. Dose does not exceed 4 mg; 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. Page 3 of 11

   CLINICAL POLICY
   Zoledronic Acid Approval duration:
   Medicaid/HIM – 12 months (one infusion for prostate cancer, two infusions for breast cancer) Commercial – 6 months or to the member’s renewal date, whichever is longer F. Systemic Mastocytosis (off-label) (must meet all):

9. Diagnosis of systemic mastocytosis;
   2. Member has osteopenia or osteoporosis with bone pain;
   3. Prescribed by or in consultation with an oncologist;
   4. Age ≥ 18 years or documentation of closed epiphyses on x-ray;
   5. Request meets one of the following (a or b): a. Dose does not exceed 4 mg; 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 – 3 months (one infusion every 3 weeks) Commercial – 6 months or to the member’s renewal date, whichever is longer G. Histiocytic Neoplasms – Langerhans Cell Histiocytosis (off-label) (must meet all):
10. Diagnosis of Langerhans cell histiocytosis;
    2. Member has multifocal bone disease;
    3. Prescribed by or in consultation with an oncologist;
    4. Age ≥ 18 years or documentation of closed epiphyses on x-ray;
    5. Request meets one of the following (a or b): a. Dose does not exceed 4 mg; 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 – 3 months (one infusion every 4 weeks) Commercial – 6 months or to the member’s renewal date, whichever is longer H. Other diagnoses/indications (must meet 1 or 2):

11. 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 Page 4 of 11

    CLINICAL POLICY
    Zoledronic Acid

12. 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. Osteoporosis and Paget Disease of Bone (must meet all):
13. 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. If request is for a dose increase, new dose does not exceed 5 mg. Approval duration:
       Medicaid/HIM –
       • Osteoporosis treatment and Paget disease: 12 months (one infusion) • Osteoporosis prevention: 24 months (one infusion)
       Commercial – 6 months or to the member’s renewal date, whichever is longer B. Oncology-Related Indications (must meet all):
14. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving zoledronic acid for a covered indication and has received this medication for at least 30 days;
    2. Member is responding positively to therapy;
    3. If request is for a dose increase, request meets one of the following (a or b): a. New dose does not exceed 4 mg; b. New 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 –
       • Hypercalcemia of malignancy: 1 week (one infusion) • Prostate cancer and breast cancer: 12 months (one infusion for prostate cancer, two infusions for breast cancer) • All other indications: 12 months (one infusion every 3 weeks) Commercial – 6 months or to the member’s renewal date, whichever is longer C. Other diagnoses/indications (must meet 1 or 2):

15. 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: Page 5 of 11

    CLINICAL POLICY
    Zoledronic Acid 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

16. 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 ALP: alkaline phosphatase BMD: bone mineral density cCa: corrected calcium FDA: Food and Drug Administration Appendix B: Therapeutic Alternatives
    GIO: glucocorticoid-induced osteoporosis MM: multiple myeloma PMO: postmenopausal osteoporosis This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent and may require prior authorization.
    Drug Name Dosing Regimen Dose Limit/ Maximum Dose Varies Oral bisphosphonates alendronate (Fosamax®) Fosamax® Plus D (alendronate / cholecalciferol) risedronate (Actonel®, Atelvia®) ibandronate (Boniva®)
    Treatment/prevention: PMO Treatment: GIO, male osteoporosis See prescribing information for dose. Treatment: PMO, male osteoporosis See prescribing information for dose. Actonel: Treatment/prevention: PMO, GIO Treatment: male osteoporosis Atelvia: Treatment: PMO See prescribing information for dose. Treatment/prevention: PMO See prescribing information for dose. Page 6 of 11

    CLINICAL POLICY
    Zoledronic Acid 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 Hypersensitivity to any product component o Reclast: hypocalcemia, creatinine clearance < 35 mL/min, acute renal impairment • Boxed warning(s): none reported V. Dosage and Administration Drug Name Indication Zoledronic acid (Reclast) Zoledronic acid (formerly Zometa) Treatment: PMO, male osteoporosis Treatment/prevention: GIO Prevention: PMO Paget disease
    Hypercalcemia of malignancy MM Solid tumor - bone metastasis Dosing Regimen 5 mg IV once a year Maximum Dose 5 mg/year 5 mg 5 mg IV once every 2 years 5 mg/2 years 5 mg IV once; retreatment may be considered
    4 mg as a single-use IV infusion; may re-treat with 4 mg after a minimum of 7 days 4 mg as a single-use IV infusion every 3 to 4 weeks 4 mg/3 weeks 4 mg/infusion VI. Product Availability Drug Name Zoledronic acid (Reclast) Zoledronic acid (formerly Zometa) Availability Ready-to-infuse solution: 5 mg/100 mL Ready-to-infuse solution: 4 mg/100 mL Single-use vial concentrate: 4 mg/5 mL VII.