Description
Zoledronic acid is a bisphosphonate which inhibits osteoclast-mediated bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. Bisphosphonates show selective action on bone due to their high affinity for mineralized bone. Zoledronic acid is drawn to bone in areas of high bone turnover where its main target is the osteoclast. It binds to mineralized bone, targeting the osteoclast. Within the osteoclast, it inhibits the action of the enzyme farnesyl pyrophosphate synthase, resulting in disruption of the osteoclast cytoskeleton and cell death. This action prevents the increased osteoclastic activity and accompanying skeletal calcium release of certain tumors and other conditions.  

Policy 
The indications below, including FDA-approved indications and compendial uses, are considered MEDICALLY NECESSARY.

FDA-Approved Indications

1. Treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greaterthan or equal to 12mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL = Ca in mg/dL + 0.8 (4.0 g/dL — patient albumin [g/dL])
2. Treatment of patients with multiple myeloma and 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 
3. Treatment of documented bone metastases from solid tumors (in conjunction with standard antineoplastic therapy)

Compendial Uses

1. Treatment or prevention of osteoporosis during androgen-deprivation therapy (ADT) in prostate cancer patients with high fracture risk
2. Treatment in postmenopausal patients with breast cancer who are receiving adjuvant therapy to maintain or improve bone mineral density and reduce risk of fractures
3. Treatment for osteopenia or osteoporosis in patients with systemic mastocytosis

   Reclast: 

1. Treatment and prevention of osteoporosis in postmenopausal females 
2. Treatment to increase bone mass in males with osteoporosis
3. Treatment and prevention of glucocorticoid-induced osteoporosis
4. Treatment of Paget disease of bone
    

All other indications are considered NOT MEDICALLY NECESSARY.

BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be medically necessary if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and not medically necessary.

References 

1. Camacho, P.M., Petak, S.M., Binkley, N. et al, American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016. Endocr Pract. 2016; Sep 2; 22 (Suppl 4):1-42.
2. Dhesy-Thind S, Fletcher GG, Blanchette PS, et al.: Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: a Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline. DOI: 10.1200/JCO.2016.70.7257 Journal of Clinical Oncology - published online before print March 6, 2017.
3. Lexi-Comp Online. (2017). AHFS DI. Zoledronic acid. Retrieved October 09, 2017 from Lexi-Comp Online with AHFS.
4. MICROMEDEX Healthcare Series. Drugdex Drug Evaluations. (2017, September). Zoledronic acid. Retrieved October 09, 2017 from MICROMEDEX Healthcare Series.
5. National Comprehensive Cancer Network. (2017). NCCN Drugs & Biologics Compendium™. Zoledronic acid. Retrieved October 09, 2017 from the National Comprehensive Cancer Network.
6. Qaseem A, Forciea MA, McLean RM, Denberg TD; for the Clinical Guidelines Committee of the American College of Physicians. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians (published online May 9, 2017). Ann Intern Med. doi:10.7326/M15-1361.
7. U. S. Food and Drug Administration. (2016, December). Center for Drug Evaluation and Research. Label and Approval History. Zometa® (zoledronic acid). Retrieved October 09, 2017 from https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021223s035lbl.pdf.
8. U. S. Food and Drug Administration. (2017, July). Center for Drug Evaluation and Research. Label and Approval History. Reclast® (zoledronic acid) injection. Retrieved October 09, 2017 from https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021817s027lbl.pdf. 
9. Zometa (package insert). East Hanover, NJ: Novartis Pharmaceuticals Corporation; December 2016.
10. Micromedex Solutions (database online). Ann Arbor, MI: Truven Health Analytics Inc. Updated periodically. www.micromedexsolutions.com (available with subscription). Accessed October 18, 2017.
11. American Society of Health System Pharmacists. AHFS Drug Information (electronic version). Bethesda, MD. Available at: http://online.lexi.com. Accessed October 18, 2017.
12. The NCCN Drugs & Biologics Compendium™ © 2015 National Comprehensive Cancer Network, Inc. http://www.nccn.org. Accessed October 20, 2016.
13. Gralow JR, Biermann S, Farooki A, et al. NCCN Task Force Report: Bone Health in Cancer Care. JNCCN. 2013; 11(Suppl 3):S1-50.
14. World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield. FRAX WHO fracture risk assessment tool. Available at http://www.shef.ac.uk/FRAX/tool.jsp. Accessed October 18, 2017.

Dosage  
Hypercalcemia of malignancy

• 4 mg as a single-use intravenous infusion over no less than 15 minutes
• 4 mg as retreatment after a minimum of 7 days

Multiple myeloma and bone metastasis from solid tumors.

• 4 mg as a single-use intravenous infusion over no less than 15 minutes every 3-4 weeks for patients with creatinine clearance of greater than 60 mL/min
• Reduce the dose for patients with renal impairment
• Co-administer oral calcium supplements of 500 mg and a multiple vitamin containing 400 international units of vitamin D daily

Administer through a separate vented infusion line and do not allow to come in contact with any calcium or divalent cation-containing solutions.

 Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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