Clinical Policy Title: Infusible agents for osteoporosis Policy contains: Clinical Policy Number: 00.02.05 Effective Date: Initial Review Date: Most Recent Review Date: Next Review Date:

March 1, 2014 December 18, 2013 January 21, 2015 January 2016

RELATED POLICIES: CP # 236.00 PerformRx Prior Authorizations of Medications AmeriHealth VIP Care Utilization Management Program Description

• • • • •

Ibandronate (Boniva) IV. Zoledronic acid (Reclast, Zometa) IV. Pamidronate (Aredia) IV. PerformRx Prior Authorization of Medications. Paget’s bone disease/Medication.

ABOUT THIS POLICY: Keystone First has developed clinical policies to assist with making coverage determinations. Keystone First clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of “medically necessary,” and the specific facts of the particular situation are considered by Keystone First when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Keystone First clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Keystone First clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Keystone First will update its clinical policies as necessary. Keystone First clinical policies are not guarantees of payment.

Coverage Policy Keystone First considers the use of the Infusible agents, Ibandronate and Zoledronic Acid for treatment of Postmenopausal Osteoporosis to be clinically proven and therefore, medically necessary when the following criteria are met: A. Osteoporosis in men and postmenopausal women: 1. The member has new fractures or significant loss of bone mineral density despite previous treatment, contraindication, or intolerance with an oral bisphosphonate; OR 2. Osteoporosis in a post-menopausal woman with a failure, contraindication, or intolerance to TWO preferred osteoporosis therapies [oral bisphosphonates (e.g. alendronate, ibandronate), selective estrogen receptor modulator (SERM) (e.g. raloxifene), calcitonin, or teriparatide; OR 3. Osteoporosis in a man with a failure, contraindication, or intolerance to TWO preferred osteoporosis therapies [oral bisphosphonates (e.g. alendronate, ibandronate), calcitonin, or teriparatide; OR

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4. Bone loss in a man receiving androgen deprivation therapy for non-metastatic prostate cancer; OR 5. Bone loss in a woman receiving adjuvant aromatase inhibitor therapy for breast cancer. B. Osteoporosis Prophylaxis in postmenopausal women: 1. The member is a postmenopausal female. 2. The member has new fractures or significant loss of bone mineral density despite previous treatment, contraindication, or intolerance with an oral bisphosphonate. 3. The member has had previous treatment, contraindication, or intolerance to zoledronic acid. C. Glucocorticoid induced Osteoporosis in men and women taking systemic glucocorticoids: 1. The member has a diagnosis of glucocorticoid induced osteoporosis or is either initiating or continuing systemic glucocorticoids with a daily dosage equivalent of 7.5 mg or greater of prednisone and is expected to remain on glucocorticoids for at least 12 months; AND 2. The member has new fractures or significant loss of bone mineral density despite previous treatment, contraindication, or intolerance with an oral bisphosphonate; AND 3. The member has had previous treatment, contraindication, or intolerance to Zoledronic acid (applies to requests for brand only). D. Unusual metabolic conditions in children: a. Unusual conditions such as osteogenesis imperfecta or other metabolic conditions may warrant special considerations. Keystone First considers the use of Pamidronate to be investigational and therefore, not medically necessary for the treatment, of any of the following because its effectiveness for these indications has not been established • Post-menopausal Osteoporosis; OR • Osteoporosis or osteopenia associated with androgen deprivation. • Glucocorticoid-induced osteoporosis.

Limitations: All other uses of Ibandronate (Boniva) and Zoledronic acid (Reclast, Zometa) are not medically necessary. Keystone First covers the above medications for the prevention and treatment of Osteoporosis. Zoledronic Acid (ZA) (Reclast) is a bisphosphonate drug that was developed initially for treatment of postmenopausal osteoporosis; however, it is currently being evaluated for treatment of bone loss due to other causes. A. Although the FDA approved zoledronic acid in 2007 to treat osteoporosis, the medicine was already available under the name Zometa® for use in cancer patients with certain bone conditions. The FDA first approved zoledronic acid as Zometa® in 2001. B. For the purpose of this policy, the reference to Zoledronic Acid (ZA) (Reclast) is related to the treatment of Osteoporosis, Paget’s Bone Disease.

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C. See PerformRx policy below to view other uses the medications listed in this policy are approved for. ( Appendix A)

Alternative Covered Services: A. Medications approved for Osteoporosis that are prescribed not by infusion but by other routes: 1. Alendronate Sodium or Alendronate Sodium plus Vitamin D3 (Fosamax® and Fosamax Plus D)-Tablet. 2. Ibandronate 150 mg tablet. 3. Risedronate Sodium or Risedronate Sodium with Calcium Carbonate (Actonel®, Actonel® with Calcium and AtelviaTM) - Tablet. 4. Calcitonin-Salmon (Fortical® and Miacalcin®) -Nasal Spray. 5. Denosumab (Prolia) - Injection. 6. Raloxifene (Evista®) - Tablet. 7. Teriparatide Parathyroid Hormone (PTH) (1-34) (Forteo®) - Self-administer injection. 8. Estrogen Therapy (ET) and Hormone Therapy (HT) (Multiple brands available) - tablet or skin (transdermal) patch.

Bisphosphonates: Several bisphosphonates are approved for the prevention or treatment of osteoporosis. These medications reduce the activity of cells that cause bone loss. Parathyroid hormone: A form of human parathyroid hormone (PTH) is approved for postmenopausal women and men with osteoporosis who are at high risk for having a fracture. Use of the drug for more than 2 years is not recommended. RANK ligand (RANKL) inhibitor: A RANK ligand (RANKL) inhibitor is approved for postmenopausal women with osteoporosis who are at high risk for fracture. Estrogen agonists/antagonists: An estrogen agonist/ antagonist (also called a selective estrogen receptor modulator or SERM) is approved for the prevention and treatment of osteoporosis in postmenopausal women. SERMs are not estrogens, but they have estrogen-like effects on some tissues and estrogenblocking effects on other tissues. Calcitonin: Calcitonin is approved for the treatment of osteoporosis in women who are at least 5 years beyond menopause. Calcitonin is a hormone involved in calcium regulation and bone metabolism. Estrogen and hormone therapy: Estrogen and combined estrogen and progestin (hormone therapy) are approved for the prevention of postmenopausal osteoporosis as well as the treatment of moderate to severe hot flashes and vaginal dryness that may accompany menopause. Estrogen without an added progestin is recommended only for women who have had a hysterectomy (surgery to remove the uterus), because estrogen increases the risk of developing cancer of the uterine lining and progestin reduces that risk.

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Results of the NIH-sponsored Women’s Health Initiative, a large, long-term study of disease prevention strategies in postmenopausal women, suggest that, in most women, the harmful effects of long-term use of hormone therapy are likely to outweigh the disease prevention benefits.

Background Osteoporosis is a progressive bone disease that is characterized by a decrease in bone mass and density which can lead to an increased risk of fracture. In osteoporosis, the bone mineral density (BMD) is reduced, bone microarchitecture deteriorates, and the amount and variety of proteins in bone are altered. Osteoporosis is defined by the World Health Organization (WHO) as a bone mineral density of 2.5 standard deviations or more below the mean peak bone mass (average of young, healthy adults) as measured by dual-energy X-ray absorptiometry; the term “established osteoporosis” included the presence of a fragility fracture. The disease may be classified as primary type 1, primary type 2, or secondary. The form of osteoporosis most common in women after menopause is referred to as primary type1 or postmenopausal osteoporosis. Primary type 2 osteoporosis or senile osteoporosis occurs after age 75 and is seen in both females and males at a ratio of 2:1. Secondary osteoporosis may arise at any age and affect men and women equally. This form results from chronic predisposing medical problems or disease or prolonged use of medications such as glucocorticoids, when the disease is called steroid-or glucocorticoid induced osteoporosis. Osteoporosis, a silent disease until it is complicated by fractures, is the most common bone disease in humans. Based on data from the National Health and Nutrition Examination Survey III (NHANES III, NOF), estimates that 10 million American -8 million women and 2 million men- have osteoporosis and almost 34 million more have low bone density of the hip. Osteoporosis is common, costly and often become a chronic burden on individuals and society. In 2005 osteoporosis caused more than two million fractures in men and women over age 50. By 2025, it is estimated there will be more than three million fractures. The $19 billion of annual direct costs for these fractures are estimated to climb to more than $25 billion. Effective diagnosis and treatment of osteoporosis has prevented millions of fractures and the pain and disability that follow them. However, more fractures still occur than are prevented. For fragile patients with severe osteoporosis, slowing bone loss with antiresorptive drugs may be insufficient to protect against fracture. An anabolic agent that increases bone formation can represent a more effective option. Currently, one bone anabolic is FDA approved for treatment of osteoporosis, teriparatide, a recombinant form of endogenous human parathyroid hormone (PTH 1-34). In research, teriparatide and other variants of PTH have shown remarkable potential for increasing bone density and strength. Federal and state legislation has been introduced in an effort to increase funding for medical research on osteoporosis, expand bone health and osteoporosis education programs and improve access and reimbursement for tests to diagnose the disease. At least thirty-four states and Puerto Rico have enacted laws relating to osteoporosis, the majority of which establish statewide education, public awareness and prevention programs. At least fourteen states—California, Florida, Georgia, Illinois, Kansas, Kentucky, Louisiana, Maryland, Missouri, New York, North Carolina, Oklahoma, Tennessee and Texas—mandate insurance coverage for osteoporosis-related diagnostic and treatment services, including technologies approved by the Federal Drug Administration (FDA) and bone density measurement.

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Although there is no cure for osteoporosis, it is treatable and preventable. Several medications are available to help stop or slow bone loss, to help form new bone, and to reduce the risk of fractures. Among the nonnitrogen-containing bisphosphonates, there are three main alternatives – clodronate, etidronate, and tiludronate. Among the nitrogen-containing bisphosphonates, aside from ibandronate, there are six basic alternatives – alendronate, neridronate, olpadronate, pamidronate, risedronate, and zoledronate. The bisphosphonates available in an IV formulation include ibandronate, pamidronate, and zoledronate. However, only ibandronate IV is approved for the treatment of postmenopausal osteoporosis; the other IV formulations are used for the treatment of cancer patients. Other clinical alternatives include the following: calcium and vitamin D supplementation; calcitonin, a naturally occurring hormone involved in calcium regulation and bone metabolism; estrogen/progestin therapy; raloxifene, a selective estrogen receptor modulator; teriparatide, an injectable form of human parathyroid hormone; and combination therapy.

Methods Searches: Keystone First searched PubMed and the databases of: • UK National Health Services Centre for Reviews and Dissemination. • Agency for Healthcare Research and Quality’s National Guideline Clearinghouse and other evidence-based practice centers. • The Centers for Medicare & Medicaid Services. Searches were conducted on December 2, 2013using the terms “Osteoporosis” and “infusible agents” Included were: • Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidencegrading hierarchies. • Guidelines based on systematic reviews. • Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes — sometimes referred to as efficiency studies — which also rank near the top of evidence hierarchies.

Findings Ibandronate (Boniva) In summary, IV ibandronate injections (3 mg/3 mL) administered every 3 months are at least as effective and similarly well tolerated as an established regimen of daily oral ibandronate (2.5 mg), in postmenopausal women with osteoporosis. IV administration of ibandronate is likely to be advantageous for patients who cannot tolerate oral bisphosphonates and for patients who have difficulty complying with oral treatment. This route of administration could improve patient compliance and persistence with bisphosphonate therapy for PMO. Zoledronic acid (Reclast, Zometa) Results of the available studies provide consistent evidence that ZA therapy prevents or reduces bone loss during breast cancer chemotherapy with agents such as letrozole, anastrozole, tamoxifen, and goserelin. Although the available studies provide strong evidence that some patients undergoing antiestrogen therapy should undergo concomitant treatment with ZA, the studies do not provide sufficient evidence to determine which patients should undergo ZA therapy. For instance, in the study by Bundred et al. (2008), 67% of women had normal BMD at baseline and BMD remained normal 5

in 79% of these women during treatment with letrozole and without ZA. Since ZA therapy has been associated with bone pain and other risks, it may not be appropriate to administer this agent to women until they develop mild or severe osteopenia. This concern is reinforced by results of the study by Gnant et al. (2008), which suggest that BMD tends to recover spontaneously after cessation of antiestrogen therapy. Additional studies are necessary to determine patient selection criteria for ZA therapy in women who are undergoing chemotherapy for breast cancer.

Summary of Clinical Evidence Citation

Content, Methods, Recommendations

Delmas et al. (2006)

Comparing IV ibandronate with oral ibandronate. • In this study, any adverse events were reported by 81.5%, 76.1%, and 77.4% of patients in the 2 mg IV ibandronate every 2 months group, the 3 mg IV ibandronate every 3 months group, and the 2.5 mg daily oral ibandronate group, respectively. • Similarly, the incidence of treatment-related adverse events (33% to 44%) and treatment-related adverse events that led to withdrawal (4.5% to 6.6%) was similar for the 3 treatment groups. • The most frequently reported treatment-related adverse events involved the GI and musculoskeletal systems, consisting primarily of dyspepsia (3.4% to 4.1%), upper abdominal pain (3.0% to 3.6%), arthralgia (2.4% to 3.6%), and flu-like illness (0.9% to 4.1%). • No cases of avascular necrosis of the jaw were reported. Four deaths occurred, but none were considered related to the study medication.

Stakkestad et al. (2003)

Study of IV ibandronate for the prevention of PMO. Stakkestad et al. (2003) investigated the safety and efficacy of IV ibandronate for the prevention of PMO in a multicenter, double-blind, randomized placebo controlled trial (n=629). • All patients were postmenopausal. Patients with osteoporosis (BMD T-score ≤ 2.5 SD) were excluded. • All patients were stratified according to their baseline lumbar BMD. Patients were treated with 0.5, 1, or 2 mg IV ibandronate or placebo every 3 months. • All women also received daily calcium supplementation. After 1 year, injections of 0.5, 1, and 2 mg IV ibandronate given every 3 months produced dose-dependent increases in mean lumbar spine BMD of 1.0%, 1.8%, and 2.5%, respectively, relative to baseline. • In contrast, mean lumbar spine BMD decreased in the placebo group (-0.4 %), relative to baseline. • All three ibandronate treatment groups produced significantly greater gains in lumbar spine BMD compared with placebo (P≤0.0001). Highest BMD gains occurred in women with osteopenia receiving 2 mg ibandronate. • At the hip, all three doses of ibandronate produced significantly better gains in BMD than placebo (P3% or a 10 year major osteoporosis-related fracture probability >20% based on the US-adapted WHO absolute fracture risk model. The patient has a documented (consistent with pharmacy claims data) treatment failure after receiving an adequate trial of the following therapies (including dates of treatment at maximum recommended doses of therapy) or has a documented medical reason (intolerance, hypersensitivity, contraindication, etc.) for not utilizing these therapies to manage their medical condition: o An oral bisphosphonate. The patient is taking adequate Calcium and Vitamin D supplementation. If the request is for Forteo (teriparatide [rDNA origin] injection), there must be a documented trial and failure or intolerance to Boniva Injection (ibandronate sodium), Reclast (zoledronic acid), or Prolia (denosumab) in females or Reclast (zoledronic acid) or Prolia (denosumab) in males. If the request is for Reclast, documentation of patients serum creatinine and creatinine clearance > 35mL/min must be submitted. The medication requested has a FDA approved indication for use in patients with osteoporosis and is being recommended and prescribed at a FDA approved dosage.

If all of the above conditions are met, the request for Forteo will be approved for 6-month duration and for all other medications the request will be approved for 12-month duration; if all of the above criteria are not met, the request is referred to a Medical Director for medical necessity review. PRIOR AUTHORIZATION CRITERIA FOR RE-APPROVAL FOR USE IN OSTEOPOROSIS: • The patient has documentation of clinical benefit from the medication. • The patient is taking adequate Calcium and Vitamin D supplementation. • If the request is for Forteo (teriparatide [rDNA origin] injection): O The prescribed dosage is within the FDA approved dosage range and does not exceed the therapy maximum of 2 years as indicated below under dosage and administration. O The medication requested has a FDA approved indication for use in patients with osteoporosis and is being recommended and prescribed at a FDA approved dosage. • If the request is for Reclast, documentation of patients serum creatinine and creatinine clearance >35mL/min must be submitted. If all of the above conditions are met, the request for Forteo will be approved for 6-month duration and for all other medications the request will be approved for 12-month duration; if all of the above criteria are not met, the request is referred to a Medical Director for medical necessity review. PRIOR AUTHORIZATION CRITERIA FOR APPROVAL FOR USE IN THE TREATMENT OR PREVENTION OF OSTEOPOROSIS DUE TO GLUCOCORTICOID THERAPY: • Documentation, including for what indication the patient will be, or is currently utilizing glucocorticoid therapy for a minimum of 12 months. • Documentation that the dosage of the glucocorticoid therapy is equivalent to a dose > 7.5 mg of prednisone daily if the request is for Reclast or >5 mg if the request is for Forteo. • Documentation (consistent with pharmacy claims data) of treatment failure after receiving an adequate trial of the following therapies (including dates of treatment at maximum recommended doses of therapy) or a documented medical reason (intolerance, hypersensitivity, contraindication, etc.) for not utilizing an oral bisphosphonate to manage their medical condition. 17

• If the request is for Reclast, documentation of patients serum creatinine and creatinine clearance > 35mL/min must be submitted • The medication requested has a FDA approved indication for use in patients for the treatment or prevention of osteoporosis and is being recommended and prescribed at a FDA approved dosage. If all of the above conditions are met, the request for Forteo will be approved for 6-month duration and Reclast will be approved for 12-month duration; if all of the above criteria are not met, the request is referred to a Medical Director for medical necessity review. PRIOR AUTHORIZATION CRITERIA FOR RE - APPROVAL FOR USE IN THE TREATMENT OR PREVENTION OF OSTEOPOROSIS DUE TO GLUCOCORTICOID THERAPY: • The patient has documentation of clinical benefit from the medication. • Documentation that the dosage of the glucocorticoid therapy is equivalent to a dose > 7.5 mg of prednisone daily if the request is for Reclast or >5 mg if the request is for Forteo. • If the request is for Reclast, documentation of patients serum creatinine and creatinine clearance > 35mL/min must be submitted • The medication requested is being recommended and prescribed at a FDA approved dosage. If all of the above conditions are met, the request for Forteo will be approved for 6-month duration and Reclast will be approved for 12-month duration; if all of the above criteria are not met, the request is referred to a Medical Director for medical necessity review. PRIOR AUTHORIZATION CRITERIA FOR INITIAL APPROVAL IN PATIENTS WITH PAGET’S DISEASE: • Documentation of a confirmed diagnosis of Paget’s disease. • Documentation (consistent with pharmacy claims data) of treatment failure after receiving an adequate trial of the following therapies (including dates of treatment at maximum recommended doses of therapy) or the patient has a documented medical reason (intolerance, hypersensitivity, contraindication, etc.) for not utilizing an oral bisphosphonate to manage their medical condition. • Documentation (from within 60 days of the request) that the patient has a serum alkaline phosphatase level of > two times the upper limit of normal OR the patient is symptomatic OR the patient is at risk for complication from Paget’s disease. • The patient is taking adequate Calcium and Vitamin D supplementation. • If the request is for Reclast, documentation of patients serum creatinine and creatinine clearance > 35mL/min must be submitted • The medication requested has a FDA approved indication for use in patients with Paget’s disease and is being recommended and prescribed at a FDA approved dosage. If all of the above conditions are met, the request will be approved; if all of the above criteria are not met, the request is referred to a Medical Director for medical necessity review. PRIOR AUTHORIZATION CRITERIA FOR RE - APPROVAL IN PATIENTS WITH PAGET’S DISEASE: • Documentation of a confirmed diagnosis of Paget’s disease. • The patient is taking adequate Calcium and Vitamin D supplementation. • If the patient is in need of redosing less than 6 months after their initial treatment: documentation (from within 60 days of the request) that the patient’s serum alkaline phosphatase level has risen to > two times the upper limit of normal and/or never normalized after the initial treatment OR the patient is suffering from symptoms of Paget’s disease is required. 18

• If the request is for Reclast, documentation of patients serum creatinine and creatinine clearance > 35mL/min must be submitted • The medication requested has a FDA approved indication for use in patients with Paget’s disease and is being recommended and prescribed at a FDA approved dosage. If all of the above conditions are met, the request will be approved; if all of the above criteria are not met, the request is referred to a Medical Director for medical necessity review. FDA INDICATION: Indication Osteoporosis in postmenopausal women Osteoporosis in men

Boniva Injection

Forteo

Prolia

Reclast

X

X

X

X

X

X

X

Treatment of osteoporosis due to glucocorticoid therapy

X

X

Prevention of osteoporosis due to glucocorticoid therapy

X

Paget’s disease

X

To increase bone mass in men at risk for fracture receiving androgen deprivation therapy for prostate cancer To increase bone mass in women at risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer

X

X

FDA INDICATION: Boniva injection is indicated for: • Treatment of osteoporosis in postmenopausal women. Reclast is indicated for: • The treatment of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, Reclast reduces the incidence of fractures (hip, vertebral, and non-vertebral osteoporosis- related fractures). • The prevention of osteoporosis in postmenopausal women. • The treatment to increase bone mass in men with osteoporosis. • The treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoids in a daily dosage > 7.5 mg per day of prednisone and who are expected to remain on glucocorticoids for at least 12 months. • The treatment of Paget’s disease of bone in men and women. Treatment is indicated for patient’s wit Paget’s disease of bone with elevations in serum 19

alkaline phosphatase of two times or higher than the upper limit of the agespecific normal reference range, or those who are symptomatic, or those at risk for complications from their disease. Forteo injection is indicated: • For the treatment of postmenopausal women with osteoporosis who are at high risk for fracture, or who have failed or are intolerant of previous osteoporosis therapy. • To increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture. These include men with a history of osteoporotic fracture, or who have multiple risk factors for fracture, or who have failed or are intolerant to previous osteoporosis therapy. • Treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy (daily dosage equivalent to 5 mg or greater of prednisone) at high risk for fracture, 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 Prolia is indicated for: • For the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors 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 • Treatment to increase bone mass in men with osteoporosis • The treatment of increase bone mass in men with osteoporosis at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer. • Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.

DOSAGE AND ADMINISTRATION: Boniva: • Osteoporosis in Postmenopausal Women: The recommended dose is 3 mg IV given once every 3 months Forteo: • Osteoporosis in Postmenopausal Women/Men & Treatment and Prevention of GlucocorticoidInduced Osteoporosis: The recommended dosage is 20 mcg once a day administered as a subcutaneous injection into the thigh or abdominal wall. The length of therapy should be no longer than 2 years. Prolia: • Osteoporosis in Men & Postmenopausal Women, Bone Loss in Men receiving Androgen Deprivation Therapy for Prostate Cancer & Bone Loss in Women Receiving Adjuvant Aromatase Inhibitor Therapy for Breast Cancer: The recommended dose is 60 mg administered as a single subcutaneous injection once every 6 months administered via subcutaneous injection in the upper 20

arm, the upper thigh, or the abdomen. All patients should receive calcium 1000 mg daily and at least 400 IU vitamin D daily. If a dose of Prolia is missed, administer the injection as soon as the patient is available. Thereafter, schedule injections every 6 months from the date of the last injection. Reclast: • Treatment of Postmenopausal Osteoporosis/ Osteoporosis in Men & the Treatment and Prevention of Glucocorticoid-Induced Osteoporosis: The recommended dose is a 5 mg infusion once a year given intravenously over no less than 15 minutes. Patients must be adequately supplemented with calcium and vitamin D if dietary intake is not sufficient. An average of at least 1200 mg of calcium and 800-1000 IU of vitamin D daily is recommended. • Prevention of Osteoporosis in Postmenopausal Women: The recommended regimen in a 5 mg infusion given once every 2 years intravenously over no less than 15 minutes. Patients must be adequately supplemented with calcium and vitamin D if dietary intake is not sufficient. Postmenopausal women require an average of 1200 mg calcium and 800-1000IU vitamin D daily. • Paget’s Disease of the Bone: The recommended dose is a 5 mg infusion. The infusion must be given over a constant infusion rate of no less than 15 minutes.

PerformRx Reference: 1. Boniva Injection Prescribing Information. GlaxoSmithKline, 04/2013. 2. Forteo® Prescribing Information. Eli Lilly and Company, 03/2012. 3. Prolia™ Prescribing Information. Amgen, 09/2012. 4. Reclast® Prescribing Information. Novartis, 04/2013. 5. Dawson-Hughes B. Lindsay R, Khosla S. Et al. Physician’s Guide to Prevention and treatment of osteoporosis. Developed by the National Osteoporosis Foundation in collaboration with American Academy of Orthopedic Surgeons, American Academy of Physical Medicine and Rehabilitation, American College of Obstetricians and Gynecologists, American College of Radiology, American College of Rheumatology, American Geriatrics Society, American Medical Association, International Society for Physical Medicine and Rehabilitation and The Endocrine Society. Updated 2008. 6. National Osteoporosis Foundation. Physician’s guide to prevention and treatment of osteoporosis. http://www.nof.org/sites/default/files/pdfs/NOF_ClinicianGuide2009_v7.pdf. Accessed February 8, 2011. 7. Black DM, Delmas PD, Eastell R, et al. Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis. N Eng J Med 2007; 356(18): 1809-22. 8. McClung M, Recker R, Miller P, et al. Intravenous Zoledronic Acid 5 mg in the Treatment of Postmenopausal Women with Low Bone Density Previously Treated with Alendronate. Bone 2007; 45: 122-8. 9. Reid IR, Miller P, Lyles K, et al. Comparison of a Single Infusion of Zoledronic Acid with Risedronate for Paget’s disease. N Eng J Med 2005; 353: 898-908. 10. Siris ES, Lyles KW, Singer FR, Meunier PJ. Medical Management of Paget’s disease of Bone: Indications of Treatment and Review of Current Therapies. J Bone and Mineral Research 2006; 21(S2): 94-8. 11. Binkley N. Krueger D. Current osteoporosis prevention and management. Topics in Geriatric Rehabilitation. 2004; 21(1):17-29. 21

12. Olszynski WP, Davison KS, Adachi JD, et al. Osteoporosis in Men: Epidemiology, Diagnosis, Prevention, and Treatment. Clinical Therapeutics 2004; 26(1): 15-28. 13. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20; 361(8):756-65. 14. Smith MR, Egerdie B, Toriz NH, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl Med. 2009 Aug 20; 361(8): 745-55. 15. Ellis, GK, Bone HG, Chlebowski R, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol 2008 Oct 20; 25:4875-82. 16. NCCN Clinical Practice Guidelines in Oncology™: Prostate Cancer; V.2.2013. Update. 17. NCCN Clinical Practice Guidelines in Oncology™: Breast Cancer; V. 3.2013. Update. Revision/Review Date: 8/2013 Associated Policy: Prior Authorization of Medications 236.200

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