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Horizon BCBSNJ
Uniform Medical Policy ManualSection:Drugs
Policy Number:079
Effective Date: 07/13/2020
Original Policy Date:06/22/2010
Last Review Date:06/09/2020
Date Published to Web: 07/19/2010
Subject:
Denosumab (Prolia, Xgeva)

Description:
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IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.

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Denosumab is the first RANK (receptor activator of nuclear factor kappa-B) ligand inhibitor to receive FDA approval. Denosumab binds to the transmembrane or soluble protein, RANKL, and prevents the activation of the RANK receptor. This essentially inhibits osteoclast formation, function and survival and decreases bone resorption while increasing bone mass and strength in the cortical and trabecular bone. Prolia (denosumab) was FDA approved in June 2010 for the treatment of postmenopausal women with osteoporosis at high risk for fracture or in patients who have failed or are intolerant to other osteoporosis therapy. In November 2010, FDA approved Xgeva (denosumab) for the prevention of skeletal-related events in patients with bone metastases from solid tumors. In September 2011, the FDA approved two new indications for Prolia: as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer and as a treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for non-metastatic prostate cancer. In June 2015, the Warnings and Precautions section in the prescribing information was updated for both Prolia and Xgeva; Prolia to include the risk of hypocalcemia and osteonecrosis of the jaw and Xgeva to include the risk of musculoskeletal pain. In January 2018, the FDA approved a new indication for Xgeva: prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors. Also in January 2018, the Warnings and Precautions section in the prescribing information was updated for Xgeva to include risk of embryo-fetal toxicity.

For Prolia: An international, randomized, double-blind Phase III study was conducted in 7,868 patients to assess the safety and efficacy of denosumab in the reduction of fracture risk in postmenopausal subjects with osteoporosis. Patients were women between the ages of 60-90 years with a bone mineral density T score of < -2.5 at the lumbar spine or total hip. Patients were excluded if they had conditions that influence bone metabolism or had taken oral bisphosphonates for more than 3 years. If patients took bisphosphonates for less than 3 years, they were eligible after 12 months without treatment. Other exclusion criteria were if patients had used intravenous bisphosphonates, fluoride, or strontium for osteoporosis within the past 5 years or use of parathyroid hormone or its derivatives, corticosteroids, systemic hormone-replacement therapy, selective estrogen-receptor modulators, or tibolone, calcitonin, or calcitriol within 6 weeks before study enrollment. Patients were randomized to receive either denosumab 60 mg (n= 3,902) or placebo (3,906) subcutaneously every 6 months. The primary endpoint was the reduction in the number of new vertebral fractures at 36 months and the secondary endpoints involved assessment of time to first non-vertebral and first hip fractures. On an annual basis, lateral spine radiographs were taken and assessed for new vertebral fractures by a semi-quantitative grading scale. A new vertebral fracture was defined as an increase of at least 1 grade in a vertebral body that was normal at baseline. Denosumab reduced the risk of new radiographic vertebral fracture with a cumulative incidence of 2.3% in the denosumab group vs. 7.2% in the placebo group (RR: 0.32, CI: 0.26-0.41). Denosumab reduced the risk of nonvertebral fracture with a cumulative incidence of 6.5% in the denosumab group vs. 8.0% in the placebo group and reduced the risk of hip fracture with a cumulative incidence of 0.7% in the denosumab group vs. 1.2% in the placebo group. The incidence of adverse events did not differ between the denosumab and placebo-treated group( 92.8% and 93.1%, respectively). Based on the pivotal study, the incidence of new vertebral fracture (primary endpoint), bone density and markers of bone turnover were all measured at different time points (baseline, 6, 12, 18, 24, 30 or 36 months) during the 36-month treatment timeframe. The incidence of new vertebral fracture was about 0.75% with denosumab vs. 2% in the placebo-treatment group during 0-12 months of therapy, 0.5% with denosumab vs. 3% in the placebo group during 12-24 months of therapy and 3% incidence with denosumab vs. 0.80% in the placebo group during 24-36 months of therapy. The 36-month cumulative incidence of a new radiographic vertebral fracture was 2.3% in the desonumab group and 7.2% in the placebo group, with a risk reduction of 68% (p<0.001). The reduction of risk of nonvertebral fracture had a cumulative incidence of 6.5% in the denosumab group vs. 8% in the placebo group (HR: 0.80, CI: 0.67-0.95, p = 0.01). In comparison to placebo, the patients in the denosumab group had a relative increase of 9.2% in bone mineral density at the lumbar spine and 6% at the total hip. Denosumab also decreased serum C-telopeptide levels by 86% at 1 month and by 72% before treatment was administered by 6 months and by 72% at 36 months. At the same time points, the levels of PINP (bone formation marker) were 18%, 50%, and 76% below those of placebo, respectively.

For Xgeva: In a randomized, double-blind, international trial, denosumab was compared to zolendronic acid for the prevention of skeletal-related adverse events (SREs: pathologic fractures, radiation therapy to bone, surgery to bone, or spinal cord compression). The study enrolled 2,046 men and women with breast adenocarcinoma and evidence of bone metastases. Patients were excluded if they had a creatinine clearance < 30 mL/min. Denosumab significantly delayed time to first on-study SREs by 18% compared with zolendronic acid. Denosumab also resulted in statistically significant greater suppression of bone turnover markers uNTx/Cr and BSAP at week 13. Overall survival and disease progression were similar in the two groups. Of note, denosumab has not been studied at the dose of 120 mg every four weeks in patients with creatinine clearance < 30 mL/min or on dialysis.

For Xgeva: bone metastasis from solid tumors: The safety and efficacy of denosumab for the prevention of skeletal-related events in patients with bone metastases from solid tumors was demonstrated in three international, randomized (1:1), double-blind, active-controlled, non-inferiority trials comparing denosumab with zoledronic acid. In all three trials, patients were randomized to receive 120 mg denosumab subcutaneously every 4 weeks or 4 mg zoledronic acid IV every 4 weeks. Patients were excluded if they had a CrCl < 30 mL/min, if they received IV bisphosphonates, had a prior history of osteonecrosis or osteomyelitis of the jaw, had an active dental or jaw condition requiring oral surgery, had non-healed dental/oral surgery, or any planned invasive dental procedure. In each trial, the main outcome measure was demonstration of noninferiority of time to first skeletal-related event (SRE) as compared to zoledronic acid. An SRE was defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. Denosumab delayed the time to first SRE following randomization as compared to zoledronic acid in patients with breast or castrate-resistant prostate cancer (CRPC) with osseous metastases. In patients with bone metastasis due to other solid tumors or lytic lesions due to multiple myeloma, denosumab was noninferior to zoledronic acid in delaying the time to first SRE. Overall survival and progression-free survival were similar between arms in all three trials. The most common adverse reactions in patients (incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation of denosumab were osteonecrosis (occurred in 1.8% of patients) and hypocalcemia (occurred in 3.1% patients).

For Xgeva: multiple myeloma: The efficacy of denosumab for the prevention of skeletal-related events in newly diagnosed multiple myeloma patients with treatment through disease progression was evaluated in an international, randomized (1:1), double-blind, active-controlled, noninferiority trial comparing denosumab with zoledronic acid. In this trial, patients were randomized to receive 120 mg denosumab subcutaneously every 4 weeks or 4 mg zoledronic acid IV every 4 weeks. Patients were excluded if they had a CrCl < 30 mL/min, if they received IV bisphosphonates, had a prior history of osteonecrosis or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. The main efficacy outcome measure was noninferiority of time to first skeletal-related event (SRE). An SRE was defined as any of the following pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. Denosumab was noninferior to zoledronic acid in delaying the time to first SRE. The results for overall survival were comparable between denosumab and zoledronic acid treatment groups. The most common adverse reactions were diarrahea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. The most common serious adverse reaction was pneumonia. The most common adverse reaction resulting in discontinuation of Xgeva was osteonecrosis of the jaw..

Policy:

(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance)

The requirements of the Horizon BCBSNJ Denosumab (Prolia, Xgeva) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).

1. Denosumab (Prolia, Xgeva) should be administered by a healthcare professional AND the prescriber is a specialist in the area of the patient’s diagnosis (e.g. endocrinologist, rheumatologist, oncologist) or has consulted with a specialist in the area of the patient’s diagnosis.

2. Prolia (denosumab) is considered medically necessary for the following FDA approved indications:

    A. Treatment of postmenopausal women with osteoporosis at high risk for fracture when ALL of the following are met:
      • Patient age at least 18 years
      • Patient is postmenopausal with a diagnosis of osteoporosis defined as:
        • T-score -2.5 or below in the lumbar spine, femoral neck, total, and /or 33% (one-third) radius; or
        • Low-trauma spine or hip fracture (regardless of BMD); or
        • Osteopenia or low bone mass (T-score between -1 and -2.5) with a fragility fracture of proximal humerus, pelvis, or possibly distal forearm; or
        • Low bone mass or osteopenia and high FRAX« fracture probability based on country-specific thresholds; AND
      • Patient is at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture (e.g. premature ovarian failure, low body mass, smoking, rheumatoid arthritis, alcohol intake of 3 or more drinks/day, vitamin D deficiency, hyperkyphosis, parental hip fracture, multiple falls, history of oral glucocorticoids ≥ 5 mg/day of prednisone (or equivalent) for > 3 months)
      • Patient has tried and failed or had an inadequate response to a 12 or more months trial of 1 bisphosphonate OR patient is intolerant to or has a contraindication to other oral and IV osteoporosis therapy (e.g. alendronate, risedronate, ibandronate, and zoledronic acid). (Contraindications include esophageal ulceration, esophageal strictures, Barrett's esophagitis, active ulcers and an inability to stand or sit upright for 30 minutes.)
      • Patient has no known contraindications to Prolia including hypocalcemia, pregnancy, and known hypersensitivity to Prolia
      • Patient will be taking a daily supplement of calcium 1000 mg daily and at least 400 IU vitamin D
      • Patient is not concurrently on a bisphosphonate, parathyroid hormone (e.g. Forteo, Tymlos) or Evenity (romosozumab-aqqg) with the requested agent

      [INFORMATIONAL NOTE: As per the 2016 AACE Guidelines for Diagnosis and Treatment of Post-Menopausal Osteoporosis:
      Table 4
      World Health Organization Criteria for Classification of Osteoporosis and Osteopenia
      CategoryT-score
      Normal-1.0 or above
      Low bone mass (osteopenia)*Between -1.0 and -2.5
      Osteoporosis -2.5 or below
      *Fracture rates within this category vary widely. The category of “osteopenia” is useful for epidemiology studies and clinical research but is problematic when applied to individual patients and must be combined with clinical information to make clinical decisions.
          Table 5
          2016 AACE Diagnosis of Osteoporosis in Postmenopausal Women
            1. T-score –2.5 or below in the lumbar spine, femoral neck, total, and/or 33% (one-third) radius

              2. Low-trauma spine or hip fracture (regardless of BMD)

              3. Osteopenia or low bone mass (T-score between –1 and –2.5) with a fragility fracture of proximal humerus, pelvis, or possibly distal forearm

              4. Low bone mass or osteopenia and high FRAX« fracture probability based on country-specific thresholds]
      B. Treatment to increase bone mass in men with osteoporosis at high risk for fracture when ALL of the following are met:
        • Patients age 30 to 85 years,
        • Patient is with bone mineral density (BMD) of -2.5 or below OR -1.0 to -2.5 with prior major osteoporotic fracture
        • Patient is at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture (e.g. hypogonadism, low body mass, smoking, rheumatoid arthritis, alcohol intake of 3 or more drinks/day, vitamin D deficiency, hyperkyphosis, parental hip fracture, multiple falls, history of oral glucocorticoids > 5 mg/day or prednisone for > 3 months)
        • Patient has tried and failed or had an inadequate response to a 12 or more months trial of 1 bisphosphonate OR patient is intolerant to or has a contraindication to other oral and IV osteoporosis therapy (e.g. alendronate, risedronate, ibandronate, and zoledronic acid). (Contraindications include esophageal ulceration, esophageal strictures, Barrett's esophagitis, active ulcers and an inability to stand or sit upright for 30 minutes.)
        • Patient has no known contraindications to Prolia including hypocalcemia and known hypersensitivity to Prolia
        • Patient will be taking a daily supplement of calcium 1000 mg daily and at least 400 IU vitamin D
        • Patient is not concurrently on a bisphosphonate or parathyroid hormone (e.g. Forteo, Tymlos) with the requested agent

        [INFORMATIONAL NOTE: Risk factors for bone fractures are from the 2012 Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis report from the Agency for Healthcare Research and Quality (US)]
      C. Treatment of bone loss in men at high risk for fracture receiving androgen deprivation therapy (ADT) for prostate cancer when ALL of the following are met:
        • Patient is a male with a diagnosis of non-metastatic prostate cancer
        • Patient is expected to continue ADT therapy for > 12 months
        • Patient is at high risk for fracture, defined as a history of osteoporotic fracture, or multiple factors, defined as:
          1. Age > 70 years; OR
          2. Age < 70 years PLUS T score < -1.0;
        • Patient has tried and failed or had an inadequate response to a 12 or more months trial of 1 bisphosphonate OR patient is intolerant to or has a contraindication to other oral and IV osteoporosis therapy (e.g. alendronate, risedronate, ibandronate, and zoledronic acid)
        • Patient has no known contraindications to Prolia including hypocalcemia and known hypersensitivity to Prolia
        • Patient will be taking a daily supplement of calcium 1000 mg daily and at least 400 IU vitamin D
        • Patient is not concurrently on a bisphosphonate or parathyroid hormone (e.g. Forteo) with the requested agent

        [INFORMATIONAL NOTE: Denosumab was studied by Smith et al (2009) for the prevention of bone loss in men receiving androgen deprivation therapy (ADT) for prostate cancer. The study included patients with histologically confirmed prostate cancer who were receiving ADT with an expected duration of treatment for 12 or more months of the study period. Men were 70 years of age or older, or were younger than 70 but had low BMD (T score at lumbar spine, total hip and femoral neck of between -1.0 and 4.0) at baseline or history of osteoporotic fracture. Patients were excluded if they had taken oral bisphosphonates for more than 3 years or were exposed to IV bisphosphonates in the last 5 years, but were included if they had taken oral bisphosphonates previously for 3 months to 3 years, provided they had been bisphosphonate free for > 1 year prior to enrollment. ]
      D. Treatment of bone loss in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer when ALL of the following are met:
        • Patient is a female with a diagnosis of nonmetastatic breast cancer
        • Patient has one or more of the following risk factors for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture (e.g. hypogonadism, low body mass, smoking, rheumatoid arthritis, alcohol intake of 3 or more drinks/day, vitamin D deficiency, hyperkyphosis, parental hip fracture, multiple falls, history of oral glucocorticoids > 5 mg/day or prednisone for > 3 months)
          Documented Hip DXA (femoral neck or total hip) or lumbar spine T-score ≤-1
        • Patient has tried and failed or had an inadequate response to a 12 or more months trial of 1 bisphosphonate OR patient is intolerant to or has a contraindication to other oral and IV osteoporosis therapy (e.g. alendronate, risedronate, ibandronate, and zoledronic acid)
        • Patient has no known contraindications to Prolia including hypocalcemia, pregnancy, and known hypersensitivity to Prolia
        • Patient will be taking a daily supplement of calcium 1000 mg daily and at least 400 IU vitamin D

        [INFORMATIONAL NOTE: Denosumab was studied by Ellis et al (2008) for the prevention of bone loss in women receiving aromatase inhibitor therapy oir nonmetastatic breast cancer. The study included patients who were > 18 years with early-stage histologically or cytologically confirmed breast cancer that was hormone-receptor positive, had evidence of low bone mass (lumbar spine, total hip, or femoral neck BMD corresponding to T score of -1.0 to -2.5. Patients with T score < -2.5, current use of bisphosphonates or prior vertebral fracture were excluded. 63% of patients had been on aromatase inhibitor therapy for > 6 months prior to enrollment. 63% of patients had been on aromatase inhibitor therapy for > 6 months prior to enrollment.
          There are many safety concerns with denosumab. In a trial of over 7,800 post menopausal women with osteoporosis, the incidence of nonfatal serious infection was 4.0% in the denosumab group and 3.3% in the placebo. Patients receiving denosumab has a statistically significant greater number of skin and soft tissue related adverse events than placebo at 10.8% vs. 8.2%, respectively. Pancreatitis was reported in 4 patients (0.1%) in the placebo and 8 patients (0.2%) in the Prolia group. There was also an increase incidence of cancer during a three year trial period and the long term carcinogenic effect of denosumab has not been established.]
        E. Treatment of glucocorticoid-induced osteoporosis in men and women at high risk for fracture when ALL of the following are met:
            • Patient age at least 18 years
            • Patient is with a diagnosis of osteoporosis with documented bone mineral density (BMD) T-score < -2.5.
            • Patient has one or more of the following risk factors for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture (e.g. hypogonadism, low body mass index (BMI), smoking, rheumatoid arthritis, alcohol intake of 3 or more drinks/day, vitamin D deficiency, hyperkyphosis, parental hip fracture, multiple falls, history of oral glucocorticoids > 5 mg/day or prednisone for > 3 months)
            • Patient will be initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone
            • Patient will be on systemic glucocorticoid therapy for at least 6 months
            • Patient has tried and failed or had an inadequate response to a 12 or more months trial of 1 bisphosphonate OR patient is intolerant to or has a contraindication to other oral and IV osteoporosis therapy (e.g. alendronate, risedronate, ibandronate, and zoledronic acid). (Contraindications include esophageal ulceration, esophageal strictures, Barrett's esophagitis, active ulcers and an inability to stand or sit upright for 30 minutes.)
            • Patient has no known contraindications to Prolia including hypocalcemia, pregnancy (in women), and known hypersensitivity to Prolia
            • Patient will be taking a daily supplement of calcium 1000 mg daily and at least 400 IU vitamin
            • Patient is not concurrently on a bisphosphonate or parathyroid hormone (e.g. Forteo) with the requested agent
      3. Xgeva (denosumab) is considered medically necessary for the following FDA approved indications and when ALL of the following are met:
        A. Prevention of skeletal-related events in patients with bone metastases from solid tumors
          • Patient is ≥ 18 years of age
          • Pre-existing hypocalcemia has already been addressed and corrected
          • For patient diagnosed with bone metastases secondary to solid tumor (other than breast cancer or castrate-recurrent prostate cancer), patient has an inadequate response, contraindication, or intolerance to zoledronic acid

        B. Treatment of adults and skeletally mature adolescents > 13 years old with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity
          • Pre-existing hypocalcemia has already been addressed and corrected
        C. Hypercalcemia of malignancy
          • Patients must be > 18 years old; AND
          • Patient must have a diagnosis of cancer (malignancy); AND
          • Patient must have a diagnosis of refractory hypercalcemia of malignancy defined as an albumin-corrected calcium of >12.5 mg/dL (3.1 mmol/L) despite treatment with a minimum seven (7) day trial on previous therapy with intravenous (IV) bisphosphonate such as zoledronic acid; OR
          • Patient has a documented contraindication or intolerance to intravenous (IV) bisphosphonate such as zoledronic acid

        D. Prevention of skeletal-related events in patients with multiple myeloma patients
          • Patients must be ≥ 18 years old; AND
          • Patient must have a diagnosis of multiple myeloma; AND
          • Pre-existing hypocalcemia has already been addressed and corrected; AND
          • Patient does not have a prior history or current evidence of osteonecrosis/osteomyelitis of the jaw, and does not have any active dental or jaw condition which requires an invasive dental procedure
          • Patient has an inadequate response, contraindication, or intolerance to zoledronic acid unless the patient has renal insufficiency

        [INFORMATIONAL NOTES Based on FDA approved package insert,
        • Patients should be instructed to take calcium 1000 mg daily and at least 400 units of vitamin D daily.
        • Patients with creatinine clearance less than 30 mL/min or receiving dialysis are at risk for hypocalcemia. Adequately supplement with calcium and vitamin D.
        • Xgeva can cause harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects and therefore should not be used in pregnant patients. Females of reproductive potential should use effective contraception in order to prevent the potential risk to the fetus.]

      4. When denosumab is considered medically necessary, initial therapy will be approved for 6 months.
        • Prolia (denosumab) will be eligible at the FDA approved dose of 60 mg administered subcutaneously every 6 months.
        • Xgeva (denosumab) will be eligible at the FDA approved dose of 120 mg administered subcutaneously every four weeks. Giant cell tumor of bone and hypercalcemia of malignancy have additional doses on Days 8 and 15 of the first month of therapy.
      5. Medical necessity for continued therapy will be considered annually if there is improvement and member can tolerate therapy, and there is no sign of unacceptable toxicity such as severe symptomatic hypocalcemia or osteonecrosis of the jaw

      6. Prolia and Xgeva (denosumab) are considered medically necessary for the following off-label indications that are 2A or better recommendations on National Comprehensive Cancer Network (NCCN) compendium. Refer to National Comprehensive Cancer Network: Drugs and Biologics Compendium - Denosumab. Available at: https://www.nccn.org/professionals/drug_compendium/content/.

      7. Other uses of denosumab are considered investigational .

      Medicare Coverage


      There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for this service. Therefore, Medicare Advantage will follow the Horizon Policy.


      Medicaid Coverage

      For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf

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      Horizon BCBSNJ Medical Policy Development Process:

      This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

      ___________________________________________________________________________________________________________________________

      Index:
      Denosumab (Prolia, Xgeva)
      Prolia (Denosumab)
      Xgeva (Denosumab)

      References:
      1. Amgen Inc. Prolia (denosumab) prescribing information. Thousand Oaks, CA. March 2020.

      2. Amgen Inc. Prolia Risk Evaluation and Mitigation Strategy (REMS) Materials (US). Available at: http://wwwext.amgen.com/media/prolia_in_the_news.html

      3. U.S. Department of Health and Human Services (DHHS), Food and Drug Administration (FDA). Background Document for Meeting of Advisory Committee for Reproductive Health Drugs (August 13, 2009) Denosumab. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM176595.pdf

      4. Cummings S, Martin J, McClung M, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. NEJM 2009. 361:756-65.

      5. ClinicalTrials.gov. An open-label, single arm, extension study to evaluate the long term safety of denosumab (AMG 162) in the treatment of bone loss in subjects undergoing androgen-deprivation therapy for non-metastatic prostate cancer. Available from: http://clinicaltrials.gov/ct2/show/NCT00838201?term=denosumab&rank=2

      6. Clinical Trials.gov. Study to compare the efficacy and safety of denosumab versus placebo in males with osteoporosis- the ADAMO trial. Available from: http://clinicaltrials.gov/ct2/show/NCT00980174?term=denosumab&rank=4

      7. ClinicalTrials.gov. Study of denosumab in the treatment of hypercalcemia of malignancy in subjects with elevated serum calcium. Available from: http://clinicaltrials.gov/ct2/show/NCT00896454?term=denosumab&rank=10

      8. ClinicalTrials.gov. Study of denosumab as adjuvant treatment for women with high early risk breast cancer receiving neoadjuvant or adjuvant therapy (D-Care). Available from: http://clinicaltrials.gov/ct2/show/NCT01077154?term=denosumab&rank=12

      9. ClinicalTrials.gov. Safety study of denosumab in subjects with recurrent or unresectable giant cell tumor of bone. Available from: http://clinicaltrials.gov/ct2/show/NCT00680992?term=denosumab&rank=13

      10. ClinicalTrials.gov. Study to evaluate the safety and efficacy of denosumab and Actonel« in postmenopausal women transitioned from alendronate therapy. Available from: http://clinicaltrials.gov/ct2/show/NCT00919711?term=denosumab&rank=28

      11. ClinicalTrials.gov. Efficacy, safety and tolerability of denosumab in the treatment of rheumatoid arthritis. Available from: http://clinicaltrials.gov/ct2/show/NCT00095498?term=denosumab&rank=20

      12. ClinicalTrials.gov. AMG 162 in bisphosphonate na´ve metastatic breast cancer. Available from: http://clinicaltrials.gov/ct2/show/NCT00091832?term=denosumab&rank=35

      13. ClinicalTrials.gov. A study comparing denosumab vs. zoledronic acids in treatment of bone metastases in breast cancer subjects. Available from: http://clinicaltrials.gov/ct2/show/NCT00321464?term=denosumab&rank=29

      14. ClinicalTrials.gov. Double-blind study of denosumab compared with zoledronic acid in treatment of bone metastases in subjects with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. Available from: http://clinicaltrials.gov/ct2/show/NCT00330759?term=denosumab&rank=19

      15. ClinicalTrials.gov. Safety and efficacy study of denosumab in subjects with recurrent or unresectable giant cell tumor of bone. Available from: http://clinicaltrials.gov/ct2/show/NCT00396279?term=denosumab&rank=22
      16. ClinicalTrials.gov. Open-label, Phase 2, Proof of concept study in Multiple Myeloma- Denosumab. Available from: http://clinicaltrials.gov/ct2/show/NCT00259740?term=denosumab&rank=24

      17. ClinicalTrials.gov. AMG 162 in the treamtent of bone loss in subjects undergoing androgen-deprivation for non-metastatic prostate cancer. Available from: http://clinicaltrials.gov/ct2/show/NCT00089674?term=denosumab&rank=31

      18. ClinicalTrials.gov. Study on prolonging bone metastasis-free survival in men with hormone refractory prostate cancer. Available from: http://clinicaltrials.gov/ct2/show/NCT00286091?term=denosumab&rank=36

      19. Stopeck A, Body JJ, Fujiwara Y, et al. Denosumab versus zoledronic acid for the treatment of breast cancer patients with bone metastases: results of a randomized phase 3 study. Eur J Can Suppl. 2009; 7(3):2. Abstract 2LBA.

      20. Stopeck A, Body JJ, Fujiwara Y, et al. Denosumab versus zoledronic acid for the treatment of breast cancer patients with bone metastases: results of a randomized phase 3 study. Presented at: 2009 Annual Meeting of the European Cancer Organisation and European Society for Medical Oncology; September 20-24, 2009. Berlin, Germany.

      21. Lipton A, Steger GG, Figueroa J, et al. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol. 2007; 25:4431-4437.

      22. Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol. 2009; 27:1564-1571.

      23. 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. 26: 4875-4882.

      24. Ellis GK, Bone HG, Chlebowski R, et al. Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer : subgroup analyses of a phase 3 study. Breast Cancer Res Treat. 2009; 118: 81-87.

      25. Smith MR, Egerdie B, Hernandez Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. NEJM 2009; 361: 745-755.

      26. Smith MR. Saad F, Egerdie B, et al. Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer. J Urol. 2009; 182: 2670-2676.

      27. Henry D, von Moos R, Vadhan-Raj S, et al. A double-blind, randomized study of denosumab versus zoledronic acid for the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. Eur J Can Suppl. 2009; 7(3): 11. Abstract 20LBA.

      28. Cohen S, Dore R, Lane N, et al. Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis. Arthritis & Rheumatism. 58(5): 1299-1309.

      29. Sharp JT, Tsuji W, Ory P, et al. Denosumab prevents metacarpal shaft cortical bone loss in patients with erosive rheumatoid arthritis. Arthritis Care Res. 2010; 62: 537-544.

      30. National Institute of Clinical Health and Excellence. Denosumab for the prevention of osteoporotic fractures in postmenopausal women: appraisal consultation document. Available online at: http://guidance.nice.org.uk/TA/Wave20/75/Consultation/DraftGuidance. Last viewed June 2010.

      31. Cummings SR, et al. Twice Yearly Denosumab, a Monoclonal Antibody to RANK-ligand, for Prevention of Fractures in Postmenopausal Women with Osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756-65.

      32. Kendler D, Roux C, Benhamou C, et al. Effects of Denosumab on Bone Mineral Density Turnover in Postmenopausal women transitioning from Alendronate Therapy. Journal of Bone and Minderal Research. 2010 Jan; vol 25, No.1:72-81.

      33. Brown J, Prince R, Deal C, et al. Comparison of the Effect of Denosumab and alendronate on BMI and biochemical markers of Bone turnover in Postmenopausal Women with Low Bone Mass: A Randomized, Blinded, Phase 3 Trial. J Bone Miner Res 2009;24:153-161.

      34. Bone H, Bolognese M, Yuen C, et al. Effects of Denosumab on Bone Mineral Density and Bone Turnover in Postmenopausal Women. J.Clin Endocrinol. Metab. 2008;93:2149-2157.

      35. Lafleur J, McAdam-Marx C, Kirkness C, et al. Clinical Risk Factors for Fracture in Postmenopausal Osteoporotic Women: A Review of the Recent Literature. The Annals of Pharmacotherapy. 2008 March; 42 [published online.]

      36. Stopeck AT, Lipton A, Body JJ, et al. Denosumab Compared with Zolendronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study. J Clin Oncol. 2010;28: 1-10.

      37. Amgen, Inc. Xgeva [prescribing information]. Thousand Oaks, CA. March 2016. Updated February 2020.

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      40. Smith M, Egerdie B, Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med, 2009;361(8):745-55.

      41. 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; 26:4875-4882.

      42. Orwoll E., Teglbjaerg CS., Langdahl BL., et al. A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab, September 2012, 97(9):3161-3169.

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      47. Bone HG, Bolognese MA, Yuen CK, et al: Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab 2008.

      48. Crandall CJ, Newberry SJ, Diamant A, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: Update of a 2007 Report [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Mar. (Comparative Effectiveness Reviews, No. 53.).

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      50. Gnant M, Pfeiler G, Dubsky PC,et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Aug 1;386(9992):433-43.

      51. Henry D, Costa L, Goldwasser F, et al. Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma. J Clin Oncol. 2011;29:1125-1132.

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      53. Buckley L, Guyatt G, Fink HA, et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis & Rhetumatology 2017; Vol 69, No. 8, pp 1521-1537. DOI 10.1002/art.40137

      54. Evenity [package insert]. Thousand Oaks, Ca: Amgen Inc ; April 2019.

      Codes:
      (The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

      CPT*

        HCPCS
          J0897

        * CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

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