Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Denosumab (Prolia®, Xgeva®), Romosozumab-aqqg (Evenity™)

Policy #:08.00.94m



The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

MEDICALLY NECESSARY

DENOSUMAB (PROLIA®)
Denosumab (Prolia®) is considered medically necessary and, therefore, covered for the following indications:
  • For the treatment of postmenopausal females with a documented diagnosis of osteoporosis (defined as T-score less than or equal to -2.5 for osteoporosis or documented history of an osteoporotic non-collision fracture [e.g., vertebral, hip, nonvertebral]) when either of the criteria listed below are met:
    • The individual has risk factors for fracture (e.g., endocrine disorders, gastrointestinal disorders, use of medications associated with low bone mass or bone loss [e.g., systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to remain on glucocorticoids for at least 6 months])
    • The individual has or has had one of the following:
      • Documented intolerance to at least one other osteoporosis medicine (e.g., oral or injectable bisphosphonates, calcitonin, estrogens) due to side effects
      • Documented inadequate response after a trial of 12 months from at least one other available osteoporosis medicine (e.g., oral or injectable bisphosphonates, calcitonin, estrogens)
      • A severely deteriorated condition indicating that the osteoporosis is so significant that a trial of bisphosphonates is not medically warranted
      • Documented renal insufficiency
  • For the treatment of males 50 years of age and older with a documented diagnosis of osteoporosis (defined as T-score less than or equal to -2.5 for osteoporosis or documented history of an osteoporotic non-collision fracture [e.g., vertebral, hip, nonvertebral]) when either of the criteria listed below are met:
    • The individual has multiple risk factors for fracture (e.g., endocrine disorders, gastrointestinal disorders, use of medications associated with low bone mass or bone loss [e.g., systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to remain on glucocorticoids for at least 6 months])
    • The individual has or has had one of the following:
      • Documented intolerance to at least one other osteoporosis medicine (e.g., oral or injectable bisphosphonates, calcitonin, estrogens) due to side effects
      • Documented inadequate response from at least one other available osteoporosis medicine (e.g., oral or injectable bisphosphonates, calcitonin, estrogens) after a trial of 12 months
      • A severely deteriorated condition indicating that the osteoporosis is so significant that a trial of bisphosphonates is not medically warranted
      • Documented renal insufficiency
  • For the treatment of individuals less than 50 years of age with documented diagnosis of glucocorticoid-induced osteoporosis and history of an osteoporotic non-collision fracture contributing to high risk for fracture when both of the following criteria are met:
    • The individual is initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to remain on glucocorticoids for at least 6 months
    • The individual has or has had one of the following:
      • Documented intolerance to at least one other osteoporosis medicine (e.g., oral or injectable bisphosphonates, calcitonin, estrogens) due to side effects
      • Documented inadequate response from at least one other available osteoporosis medicine (e.g., oral or injectable bisphosphonates, calcitonin, estrogens) after a trial of 12 months
      • A severely deteriorated condition indicating that the osteoporosis is so significant that a trial of bisphosphonates is not medically warranted
      • Documented renal insufficiency
  • For the treatment of osteopenia (defined as T-score less than -1.0, but greater than -2.5), when the individual meets either of the following criteria:
    • Receiving adjuvant aromatase inhibitor therapy for breast cancer
    • Receiving androgen deprivation therapy for nonmetastatic prostate cancer
  • For postmenopausal females or males 50 years of age and older with a diagnosis of osteopenia (defined as T-score less than -1.0 but greater than -2.5) when the individual meets both of the following criteria:
    • The individual has or has had one of the following:
      • Documented intolerance to at least one other osteoporosis medicine (e.g., oral or injectable bisphosphonates, calcitonin, estrogens) due to side effects
      • Documented inadequate response from at least one other available osteoporosis medicine (e.g., oral or injectable bisphosphonates, calcitonin, estrogens) after a trial of 12 months
      • Documented renal insufficiency not receiving dialysis or diagnosed with stage 5 kidney disease
    • The individual has either of the following:
      • The US- adapted World Health Organization (WHO) 10-year probability of a hip fracture based on the FRAX assessment is 3 percent or more
      • The 10-year fracture probability of any major osteoporosis-related fracture based on the FRAX assessment is 20 percent or more

ROMOSOZUMAB-AQQG (EVENITY™)
Romosozumab-aqqg (Evenity™) for a limited duration of 12 monthly doses is considered medically necessary and, therefore, covered for the following indications:
  • For the treatment of postmenopausal females with a documented diagnosis of osteoporosis (defined as T-score less than or equal to -2.50 for osteoporosis or documented history of an osteoporotic non-collision fracture [e.g., vertebral, hip, nonvertebral]) when both of the criteria listed below are met:
    • The individual has risk factors for fracture (e.g., endocrine disorders, gastrointestinal disorders, use of medications associated with low bone mass or bone loss [e.g., systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to remain on glucocorticoids for at least six months])
    • The individual has or has had both of the following:
      • Documented intolerance due to side effects, or inadequate response after a trial of 12 months to at least one other osteoporosis medicine (e.g., oral or injectable bisphosphonates, calcitonin, estrogens) .
      • Documented intolerance due to side effects, or inadequate response after a trial of 12 months to RANK ligand inhibitor (e.g., denosumab [Prolia®])
  • For individuals with a severely deteriorated condition indicating that the osteoporosis is so significant (i.e., T score less than -3.5 or a T score less than -2.5 with a history of fragility fractures) that a trial bisphosphonates and RANK ligand inhibitor (e.g., denosumab [Prolia®]) is not medically warranted.

Romosozumab-aqqg (Evenity™) is not recommended for individuals with a history of a myocardial infarction or stroke within the preceding year; (consider benefit versus risk in individuals with other cardiovascular risk factors).

Note:
The anabolic effect of romosozumab wanes after 12 monthly doses of therapy. Therefore, the duration of EVENITY use is limited to 12 monthly doses. If osteoporosis therapy remains warranted after medical necessary romosozumab-aqqg (Evenity™), continued therapy with an anti-resorptive agent (e.g., demosumab [Prolia®], alendronate [Fosamax®, Binosto®]) should be considered.

DENOSUMAB (XGEVA®)
Denosumab (Xgeva®) is considered medically necessary and, therefore, covered for the following indications:
  • The prevention of skeletal-related events (i.e., pathologic fracture, need for radiation therapy to bone, need for surgery to bone, or spinal cord compression) in individuals with bone metastases from solid tumors. These include, but are not limited to, the following malignancy-related conditions:
    • Invasive breast cancer:
      • Used with calcium and vitamin D supplementation in addition to chemotherapy or endocrine therapy for bone metastases in individuals with expected survival of three months or greater and adequate renal function
    • Non-small cell lung cancer: Supportive therapy in individuals with bony metastases
    • Prostate cancer:
      • Individuals with bone metastases of castration-recurrent prostate cancer (metastatic prostate cancer that has stopped responding to androgen deprivation therapy and continues to grow) with creatinine clearance greater than 30 mL/min
    • Thyroid cancer:
      • Individuals with bone metastases from any of the following thyroid cancer types: follicular, Hurthle cell, medullary, papillary carcinoma
      • Palliative care for bone metastases in individuals with anaplastic carcinoma
    • Kidney cancer: As a component of best supportive care for individuals with bony metastases
  • The prevention of skeletal-related events (i.e., pathologic fracture, need for radiation therapy to bone, need for surgery to bone, or spinal cord compression) in individuals with multiple myeloma
    • Used in combination with primary myeloma therapy. According to the National Comprehensive cancer Network (NCCN), this is considered a preferred agent in individuals with renal insufficiency
  • The treatment of adult and skeletally mature (i.e., at least one mature long bone [e.g., closed epiphyseal growth plate of the humerus]) adolescent individuals with a giant cell tumor of the bone (GCTB) in the following circumstances:
    • When the GCTB is unresectable or where surgical resection is likely to result in severe morbidity
    • As therapy as a single agent or combined with interferon alfa/peginterferon or radiation therapy for localized disease
    • Treatment as a single agent for metastatic disease
  • The treatment of individuals with hypercalcemia of malignancy (i.e., albumin-corrected serum calcium level greater than 12.5 mg/dL [3.1 mmol/L]) refractory to bisphosphonate therapy
  • The treatment of individuals with systemic mastocytosis as a second-line therapy for osteopenia/osteoporosis in individuals with bone pain not responding to bisphosphonates or for individuals who are not candidates for bisphosphonates because of renal insufficiency.

EXPERIMENTAL/INVESTIGATIONAL

All other uses for denosumab (Prolia®, Xgeva®) and romosozumab-aqqg (Evenity™) are considered experimental/investigational and, therefore, not covered, unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.
Guidelines

According to the FDA-approved label, individuals with severe renal impairment (creatinine clearance less than 30mL/min) or receiving dialysis has a significant risk of developing hypocalcemia following denosumab (Prolia®, Xgeva®) administration.

BLACK BOX WARNINGS

Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings.

DENOSUMAB (PROLIA®, XGEVA®)

Because Prolia® and Xgeva® have the same active ingredient and can be used for different indications, they should not be used in combination.

CALCIUM AND VITAMIN D SUPPLEMENTATION

Hypocalcemia should be corrected before initiating therapy with denosumab (Prolia®, Xgeva®) or romosozumab-aqqg (Evenity™) . Supplements of calcium and vitamin D orally once daily are taken when receiving denosumab (Prolia®, Xgeva®) or romosozumab-aqqg (Evenity™) for the treatment of osteoporosis in individuals who are at high risk for fracture or for the prevention of skeletal-related events in individuals with bone metastases from solid tumors (Xgeva®). New-onset or worsening hypocalcemia may result from use of denosumab (Prolia®, Xgeva®) or romosozumab-aqqg (Evenity™) . Clinical monitoring of serum calcium and mineral levels (phosphorus and magnesium) is highly recommended, and symptoms of hypocalcemia should be monitored during therapy with denosumab (Prolia®, Xgeva®) or romosozumab-aqqg (Evenity™) .

The National Osteoporosis Foundation supports the recommendation of the Institute of Medicine that men ages 50-70 consume 1000 mg/day of calcium and women age 51 and older and men age 71 and older consume 1200 mg/day of calcium. In addition, the National Osteoporosis Foundation recommends an intake of 800 to 1000 IU of vitamin D per day for adults age 50 and older.

INABILITY TO TAKE ORAL BISPHOSPHONATES FOR OSTEOPOROSIS

Individuals with any of the following conditions are considered inappropriate candidates for oral bisphosphonate therapy:
  • Difficulty swallowing oral medications
  • Inability to sit upright for 30 to 60 minutes
  • Active esophagitis, gastritis, or gastric ulcer
  • Esophageal stricture
  • Esophageal motility disorder

PEDIATRIC USE OF DENOSUMAB OR ROMOSOZUMAB-AQQG

Xgeva®: The safety and effectiveness of denosumab (Xgeva®) have not been established in pediatric individuals except in skeletally mature adolescents with giant cell tumor of bone.

Prolia®: The safety and effectiveness of denosumab (Prolia®) in pediatric individuals have not been established. Denosumab (Prolia® is not recommended in pediatric individuals.

Evenity™: The safety and effectiveness of romosozumab-aqqg (Evenity™) in pediatric individuals have not been established. Romosozumab-aqqg (Evenity™) is not recommended in pediatric individuals.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, denosumab (Prolia®, Xgeva®) or romosozumab-aqqg (Evenity™) are covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Denosumab (Prolia®) was approved by the FDA on June 1, 2010 for the treatment of postmenopausal women with osteoporosis at high risk for fracture. Supplemental approvals for denosumab (Prolia®) have since been issued by the FDA.

Denosumab (Xgeva®) was approved by the FDA on November 18, 2010 for the prevention of skeletal-related events in individuals with bone metastases from solid tumors. Supplemental approvals for denosumab (Xgeva®) have since been issued by the FDA.

Romosozumab-aqqg (Evenity™) was approved by the FDA on April 09, 2019 for the treatment of postmenopausal women with osteoporosis at high risk for fracture with a limited duration of use to 12 monthly doses.

Description

DENOSUMAB

Denosumab is a human IgG2 monoclonal antibody with affinity and specificity for human receptor activator of nuclear factor kappa-B ligand (RANKL). RANKL is a transmembrane or soluble protein that is essential for osteoclasts, cells that are responsible for bone resorption. Increased osteoclast activity, stimulated by RANKL, is a mediator of bone pathology in solid tumors with bone metastases. Denosumab binds to RANKL, thereby decreasing bone resorption and increasing bone mass and strength.

Hypocalcemia may be exacerbated by the use of denosumab; therefore, pre-existing hypocalcemia must be corrected prior to initiating therapy with denosumab. In individuals who are predisposed to hypocalcemia and disturbances of mineral metabolism (e.g., history of hypoparathyroidism, thyroid surgery, parathyroid surgery, excision of small intestine, severe renal impairment or dialysis, malabsorption syndromes), clinical monitoring of calcium, phosphorus, and magnesium levels is highly recommended.

Denosumab is available under two different FDA--approved trade names: Prolia® and Xgeva®.

PROLIA®

Osteoporosis is characterized by low bone mass, deterioration of bone tissue, disruption of bone architecture, compromised bone strength, and increased risk for fracture. According to the World Health Organization (WHO) diagnostic classification, osteoporosis is operationally defined by measurement of bone mineral density (BMD) at the hip or spine that is less than or equal to 2.5 standard deviations (SD) below the young normal mean reference population. In describing BMD, T-scores compare bone density to the optimal peak bone density for an individual's gender. A T-score is the number of units (standard deviations) above (+) or below (-) what is considered standard. A T-score is within the normal range if it is a positive number, or at least no more negative than -1.0. The more negative the number, the thinner the bones. A T-score less than -1.0 but greater than -2.5 is considered osteopenia, and a risk for developing osteoporosis. A T-score of less than -2.5 is indicative of osteoporosis. The WHO definition applies to postmenopausal women as well as men aged 50 years or older. One-half of all postmenopausal women will have an osteoporosis-related fracture during their lives; of those, 25 percent will develop a vertebral deformity, and 15 percent will sustain a hip fracture. According to the National Osteoporosis Foundation, two million men in the US have osteoporosis and another 12 million are at risk. Osteoporosis and osteoporotic fractures in men remain under-diagnosed and under-treated.

Denosumab was originally approved under the trade name of Prolia® in June 2010. Denosumab (Prolia®) is indicated to treat postmenopausal women with osteoporosis who are at risk for bone fractures. In September 2011, denosumab (Prolia®) was approved for treatment of bone loss in men receiving androgen deprivation therapy in prostate cancer and for treatment of bone loss in women receiving adjuvant aromatase inhibitor therapy for breast cancer. A new indication was approved for denosumab (Prolia®) in September 2012 for the treatment to increase bone mass in men with osteoporosis.

The FDA approval of denosumab (Prolia®) for the treatment of osteoporosis in postmenopausal women who are at high risk of fracture is based on a pivotal 3-year, Phase III study involving 7,808 postmenopausal women with osteoporosis who had a baseline BMD T-score between -2.5 and -4.0 at either the lumbar spine or total hip. A subcutaneous injection of denosumab (Prolia®) 60 mg was administered every 6 months. All women in the study received at least 1000 mg calcium orally once daily and at least 400 IU of vitamin D orally once daily. Denosumab (Prolia®) reduced the incidence of vertebral, hip, and nonvertebral fractures. Over 3 years, denosumab (Prolia®) significantly reduced the incidence of new vertebral fractures by 68 percent, reduced the incidence of hip fractures by 40 percent, and reduced the incidence of non-spine fractures by 20 percent.

The approval of denosumab (Prolia®) for the treatment of low bone mass in women at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer is based on a 2-year, randomized, double-blind, placebo-controlled, multinational study that enrolled women with breast cancer. Women in this study had a baseline BMD T-score between -1.0 and -2.5 and had not experienced fracture after age 25. All women received at least 1000 mg calcium and 400 IU vitamin D daily. After two years denosumab (Prolia®) significantly improved BMD in these individuals of 6.2 percent at the lumbar spine, 3.8 percent at the total hip, and 2.8 percent at the femoral neck.

Approval of denosumab (Prolia®) for the treatment of low bone mass in men at high risk for fracture who are receiving androgen-deprivation therapy (ADT) for nonmetastatic prostate cancer is based on a 3-year trial that enrolled 1468 men who had prostate cancer and were required to have a BMD T-score between -1.0 and -4.0, or history of osteoporotic fracture. Denosumab (Prolia®) significantly increased lumbar spine BMD and significantly reduced the incidence of new vertebral fractures.

In September 20, 2012 denosumab (Prolia®) was approved by the FDA for the treatment to increase bone mass in men with osteoporosis based on results from the ADAMO trial 3 (A multicenter, randomized, double-blind, placebo-controlled study to examine the efficacy and safety of DenosumAb [Prolia®] 60 mg every six months vs placebo in Men with Osteoporosis). The pivotal Phase 3 study involved 242 men with low bone mineral density (BMD) of T-score between -2.0 and -3.5 at the lumbar spine or femoral neck or a T-score between -1.0 and -3.5 at the lumbar spine or femoral neck with a history of prior fragility fracture. All men received at least 1000 mg of calcium and at least 800 IU vitamin D daily. In the study, treatment with denosumab (Prolia®) resulted in significantly greater gains at the lumbar spine when compared to placebo (5.7 percent vs. 0.9 percent). Effects of denosumab (Prolia®) on BMD were independent of age, baseline testosterone levels, BMD status, and estimated fracture risk. Safety findings were consistent with those observed in other studies of Prolia® in postmenopausal women with osteoporosis.

In May 2018, denosumab (Prolia®) was approved by the FDA for the treatment of glucocorticoid-induced osteoporosis in men and women at high risk for fracture who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to greater than or equal to 7.5 mg of prednisone and expected to remain on glucocorticoids for at least six months.

The efficacy and safety of denosumab (Prolia®) in the treatment of individuals with glucocorticoid-induced osteoporosis was assessed in the 12 month primary analysis of a two year, randomized, multicenter, double-blind, parallel-group, active-controlled study of 795 individuals (70 percent women and 30 percent men) aged 20 to 94 years (mean age of 63 years) treated with greater than or equal to 7.5 mg/day oral prednisone (or equivalent) for less than three months prior to study enrollment and planning to continue treatment for a total of at least six months (glucocorticoid-initiating subpopulation; n = 290) or greater than or equal to three months prior to study enrollment and planning to continue treatment for a total of at least six months (glucocorticoid-continuing subpopulation, n = 505). Randomization was stratified by gender within each subpopulation. Individuals received at least 1000 mg calcium and 800 IU vitamin D supplementation daily. Enrolled individuals less than 50 years of age were required to have a history of osteoporotic fracture. Enrolled individuals greater than or equal to 50 years of age who were in the glucocorticoid-continuing subpopulation were required to have a baseline BMD T-score of ≤ -2.0 at the lumbar spine, total hip, or femoral neck; or a BMD T-score ≤ -1.0 at the lumbar spine, total hip, or femoral neck and a history of osteoporotic fracture.

Results showed that compared to the active-control, treatment with denosumab (Prolia®) significantly increased lumbar spine bone mineral density (BMD) at one year in the glucocorticoid-initiating subpopulation (p<.001). In the glucocorticoid-continuing subpopulation, treatment with denosumab (Prolia®) was associated with significant increases in lumbar spine BMD compared with active-control (p<.001). The safety of denosumab (Prolia®) was found to be consistent with previous trials (Saag et al, 2018).

ROMOSOZUMAB-AQQG (EVENITY™)

In April 09, 2019, romosozumab-aqqg (Evenity™) was approved by the US Food and Drug Administration (FDA) for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or failed or are intolerant to other available osteoporosis therapy.
Romosozumab-aqqg (Evenity™) is a monoclonal antibody that binds to and inhibits sclerostin (a regulatory factor in bone metabolism), increases bone formation, and to a lesser extent, decreases bone resorption. The FDA based its approval of Romosozumab-aqqg (Evenity™) on the results of two Phase 3 studies.

FRAME (FRActure study in postmenopausal woMen with ostEoporosis) study is a randomized, double-blind, placebo-controlled study that evaluated 7,180 postmenopausal women with osteoporosis. The study evaluated the efficacy of romosozumab-aqqg (Evenity™) treatment (210 mg administered monthly), compared with placebo, in reducing the incidence of new vertebral fractures through 12 months. The study also evaluated the efficacy of treating with romosozumab-aqqg (Evenity™) for 12 months followed by denosumab (Prolia®) for 12 months, compared with placebo followed by denosumab (Prolia®), in reducing the incidence of new vertebral fractures through 24 months. The study showed that individuals randomly assigned to receive a monthly subcutaneous 210 mg dose of romosozumab (Evenity™) experienced a statistically significant 73 percent reduction in the relative risk of a new vertebral (spine) fracture through 12 months, the first co-primary endpoint, compared to those receiving placebo (fracture incidence 0.5 percent versus 1.8 percent, respectively [p<0.001]). Of interest, the data showed that by six months, new vertebral fractures occurred in 14 romosozumab (Evenity™) and 26 placebo individuals, and between six to 12 months, fractures occurred in two additional romosozumab (Evenity™) individuals versus 33 additional placebo individuals.

ARCH (Active-contRolled FraCture Study in Postmenopausal Women with Osteoporosis at High Risk of Fracture) is a Phase 3 multicenter, international, randomized, double-blind, alendronate-controlled study of romosozumab-aqqg (Evenity™) involving 4,093 postmenopausal women with osteoporosis at high risk for fracture based on previous fracture history. The study evaluated 12 months of subcutaneous romosozumab-aqqg (Evenity™) treatment (210 mg administered monthly) followed by at least 12 months of alendronate treatment (70 mg), compared with weekly oral alendronate (70mg) treatment alone, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in ≥330 participants). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated.

Over a period of 24 months, a 48 percent lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2 percent [127 of 2046 individuals]) than in the alendronate-to-alendronate group (11.9 percent [243 of 2047 individuals]) (P<0.001). Clinical fractures occurred in 198 of 2046 individuals (9.7 percent) in the romosozumab-to-alendronate group versus 266 of 2047 individuals (13.0 percent) in the alendronate-to-alendronate group, representing a 27 percent lower risk with romosozumab (P<0.001). The risk of nonvertebral fractures was lower by 19 percent in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 individuals [8.7 percent] vs. 217 of 2047 individuals [10.6 percent]; P=0.04), and the risk of hip fracture was lower by 38 percent (41 of 2046 individuals [2.0 percent] vs. 66 of 2047 individuals [3.2 percent]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year one, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 individulas [2.5 percent] vs. 38 of 2014 individuals [1.9 percent]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (one event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (two events and four events, respectively) were observed. The authors concluded that in postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. The anabolic effect of romosozumab wanes after 12 monthly doses of therapy. Therefore, the duration of romosozumab use should be limited to 12 monthly doses. If osteoporosis therapy remains warranted, continued therapy with an anti-resorptive agent should be considered.

XGEVA®
Weakened bones due to cancer metastases can lead to fractures and compression of the spinal cord. They necessitate procedures such as surgery and radiation, which are designed to prevent or manage bone complications. The primary goal of treatment for bone metastases is to prevent the occurrence of debilitating bone complications that can affect an individual's quality of life. The major cancer types that tend to metastasize to the bone include breast, lung, prostate, thyroid, and kidney.

In January 2018, denosumab received a Supplemental Biologic License Application approval under denosumab (Xgeva®) for prevention of skeletal-related events (SREs) in individuals with multiple myeloma. The efficacy was evaluated in an international, randomized double-blinded, active controlled, noninferiority trial comparing denosumab (Xgeva®) with zoledronic acid in 1718 newly diagnosed individuals with multiple myeloma. The main efficacy outcome measure was noninferiority of time to first skeletal-related event. Denosumab (Xgeva®) was significantly noninferior to zolendronic acid in delaying the time to the first SRE.

In November 2010, denosumab received a Supplemental Biologic License Application approval under denosumab (Xgeva®) for prevention of skeletal-related events (SREs) in individuals with bone metastases from solid tumors, which are abnormal masses of tissue that usually do not contain cysts or liquid areas. In 2013, denosumab (Xgeva®) was approved for use in adults and skeletally mature adolescents for the treatment of giant cell tumor of bone (GCTB) that is unresectable or where surgical resection is likely to result in severe morbidity. In December 2014, denosumab (Xgeva®) received FDA approval for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

The safety and effectiveness of Denosumab (Xgeva®) was confirmed in three randomized, double-blind studies of 5723 individuals, comparing Denosumab (Xgeva®) with zoledronic acid (Zometa®). One study involved individuals with breast cancer, the second study involved individuals with prostate cancer, and the third study involved individuals with a variety of other cancers. The studies were designed to measure the time until the occurrence of an SRE. SREs include pathological fracture, spinal cord compression due to cancer, or the need for radiation therapy or surgery to bone. In each trial, denosumab (Xgeva®) was noninferior to zoledronic acid (Zometa®) for the delay of time-to-first SRE in patients with bone metastasis from solid tumors. Supportive outcome measures were superiority of time-to-first SRE and superiority of time-to-first and subsequent SRE; testing for these outcome measures occurred if the main outcome measure was statistically significant.

In June 2013, denosumab (Xgeva®) was granted FDA approval for treatment of Giant Cell Tumor of Bone (GCTB), a rare and usually non-cancerous tumor usually occurring in adults between the ages of 20 and 40 years of age. Most of the time, GCTB does not spread to other areas of the body, but destroys normal bone as it grows, which causes pain, limited range of motion, and bone fractures. On rare occasion, GCTB can transform into a cancerous tumor that spreads to the lungs.

Denosumab (Xgeva®) is intended for persons with GCTB who are not surgical candidates or when surgery would result in severe morbidity. The safety and effectiveness of denosumab (Xgeva®) for use in GCTB is based on two open-label trials 187 persons who had tumors that could be measured; of this group, 47 individuals experienced a reduction in the size of their tumors. In a follow-up, occurring on average 20 months later, re-growth of GCTB occurred in 3 individuals whose tumors had originally become smaller during the treatment phase.

The approval of denosumab (Xgeva®) for individuals with hypercalcemia was based on an open-label, single-arm trial that assessed safety and effectiveness in 33 individuals with hypercalcemia of malignancy refractory to bisphosphonate therapy. In the trial refractory hypercalcemia of malignancy was defined as an albumin-corrected calcium of greater than 12.5 mg/dL despite treatment with intravenous bisphosphonate therapy in 7 to 30 days prior to denosumab (Xgeva®) therapy. The median time of complete response was 23 days with a median duration of complete response of 34 days.

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
References


American College of Rheumatology. Position Statements. Bone Mineral Density Measurement and the Role of Rheumatologists in the Management of Osteoporosis. 08/2017. Available at: https://www.rheumatology.org/Portals/0/Files/Bone-Density-Measurement-Rheumatologist-Role-Position-Statement.pdf. Accessed February 08, 2019.

Amgen. Press Release: FDA approves Amgen's Xgeva® (denosumab) for the prevention of skeletal-related events in patients with bone metastases from solid tumors. [Amgen Web site]. 11/18/10. Available at: http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1498709. Accessed February 08, 2019.

Amgen. Press Release: FDA approves Amgen's Xgeva® (denosumab) for the treatment of Giant Cell Tumor of bone. [Amgen Web site]. 6/13/2013. Available at: http://www.amgen.com/media/media_pr_detail.jsp?year=2013&releaseID=1829715. Accessed February 08, 2019.

Black D, Rosen C. Postmenopausal osteoporosis. New Engl J Med. 2016;374:254-62.

Camacho P, Petak S, Binkley N, et. al. American Associated of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the diagnosis and treatment of postmenopausal osteoporosis--2016. Endocrine Practice. 2016;22(Suppl 4):1-42.

Camacho PM, Petak SM, 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-executive summary. Endocr Pract. 2016;22(9):1111-1118.

Cummings SR, San Martin J, McClung SR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-65.

Dawson-Hughes B, Tosteson A, Melton L, et. al. Implications of absolute fracture risk assessment for osteoporosis practice guidelines in the USA. Osteoporosis Int. 2008.

Denosumab. American Hospital Formulary Services (AHFS) Drug Information 2016. [ Lexi-Comp website]. 02/20/2015. Available at: http://online.lexi.com/lco/action/home#[via subscription only]. Accessed February 08, 2019.

Denosumab (Prolia®, Xgeva®). Micromedex® Healthcare Series. DrugDex®. [Micromedex Web site]. Last modified 09/20/2018. Available at: http://www.micromedexsolutions.com/[via subscription only]. Accessed February 08, 2019.

Ellis GK. Effect of denosumab on bone mineral density in women receiving aromatase inhibitors for nonmetastatic breast cancer: subgroup analyses of a phase study. Breast Cancer Res Treat. 2009;118(1):81-7.

Elsevier Gold's Standard Clinical Pharmacology Compendium. Denosumab. [ClinicalKey Web site. 06/13/2018. Available at: https://www.clinicalkey.com/#!/search/Denosumab?scrollTo=%23result-0. [via subscription only]. Accessed February 08, 2019.

Langdahl B, Teglbjaerg C, Ho P, et. al. A 24-month evaluating the efficacy and safety of Denosumab for the treatment of men with low bone mineral density: Results from the ADAMO trial. J Clin Endocrinol Metab. 2015;100(4):1335-1342.

Lewiecki ME. Assessment of fracture risk: clinical risk factors for fracture. [Medscape Web site]. 06/22/05. Available at: http://cme.medscape.com/viewarticle/506083_3 [via subscription only]. Accessed February 08, 2019.

Lexi-Drugs Compendium. Denosumab. [Lexicomp Online Web site]. 06/08/2016. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed February 08, 2019.

National Comprehensive Cancer Network (NCCN). NCCN Guidelines Clinical Practice Guidelines in Oncology: Bone Cancer. V1.2019. [NCCN Web site, login required]. 08/03/2018. Available at: http://www.nccn.org/professionals/physician_gls/pdf/bone.pdf
Accessed February 08, 2019.

National Comprehensive Cancer Network (NCCN). NCCN Guidelines Clinical Practice Guidelines in Oncology: Breast Cancer. V4.2018. [NCCN Web site].12/08/2019. Available at: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via subscription only]. Accessed February 08, 2019.

National Comprehensive Cancer Network (NCCN). NCCN Guidelines Clinical Practice Guidelines in Oncology: Kidney Cancer V3.2019. [NCCN Web site]. 02/02/2019. Available at: https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf [via subscription only]. Accessed February 08, 2019.

National Comprehensive Cancer Network (NCCN). NCCN Guidelines Clinical Practice Guidelines in Oncology.Systemic MastocytosisV2.2019. [NCCN Web site]. 09/20/2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/systemicmastocytosis.pdf [via subscription only]. Accessed February 08, 2019.

National Comprehensive Cancer Network (NCCN). NCCN Guidelines Clinical Practice Guidelines in Oncology: Multiple Myeloma.V2.2019. [NCCN Web site]. 11/16/2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf [via subscription only]. Accessed February 08, 2019.

National Comprehensive Cancer Network (NCCN). NCCN Guidelines Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer V3.2019. [NCCN Web site].10/19/2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf [via subscription only]. Accessed February 08, 2019.

National Comprehensive Cancer Network (NCCN). NCCN Guidelines Clinical Practice Guidelines in Oncology: Prostate Cancer. V4.2018. [NCCN Web site].08/15/2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf [via subscription only]. Accessed February 08, 2019.

National Comprehensive Cancer Network (NCCN). NCCN Guidelines Clinical Practice Guidelines in Oncology: Thyroid Cancer V3.2018. [NCCN Web site]. 12/20/2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf [via subscription only]. Accessed February 08, 2019.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium™. Denosumab (Xgeva®). [NCCN Web site]. 2019. Available at:http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/PrintMatrix.aspx?AID=368 [via subscription only]. Accessed February 08, 2019.

National Cancer Institute. Dictionary of cancer terms. Solid tumor. [National Cancer Institute Web site]. Available at: http://www.cancer.gov/dictionary/?CdrID=45301. Accessed February 08, 2019.

National Institutes of Health. Clinical trials: Efficacy and safety of romosozumab treatment in postmenopausal women with osteoporosis (FRAME). (NCT01575834). [ClinicalTrials Web site]. 02/19/2019. Available at: https://clinicaltrials.gov/ct2/show/NCT01575834 . Accessed April 09, 2019.

National Institutes of Health. Clinical trials: Study to determine the efficacy and safety of romosozumab in the treatment of postmenopausal women with osteoporosis (ARCH) (NCT01631214). [ClinicalTrials Web site]. 12/17/2018. Available at: https://clinicaltrials.gov/ct2/show/NCT01631214 Accessed April 09, 2019.

National Osteoporosis Foundation (NOF). Clinician's guide to prevention and treatment of osteoporosis. [NOF Web site]. 06/12/2014. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176573/pdf/198_2014_Article_2794.pdf. Accessed February 08, 2019.

North American Menopause Society. Management of osteoporosis in postmenopausal women: 2010 position statement of the north American menopause society. Menopause.2010;17(1):25-54.

Orwoll E. A randomized placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab. 2012;97(9):3161-9.

Prolia® (denosumab). Healthcare Professionals. Amgen, Inc. 2018. Available at:http://www.prolia.com/. Accessed February 08, 2019.

Rao SS, Mudhwar N, Ashfaque A. American Family Physician.Osteoporosis in men. [American Academy of Family Physicians (AAFP) Web site]. 09/01/2010. Available at:
http://www.aafp.org/afp/2010/0901/p503.html. Accessed February 08, 2019.

Saag KG, Wagman RB, Guesens P, et al. Denosumab versus risedronate in glucocorticoid-induced osteoporosis: a multicentre, randomosed, double-blind, active-controlled, double-dummy, non-inferiority study. Lancet Diabetes Endocrinol.2018;6(6):445-454.

Smith MR. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. NEJM. 2009;361(8):745-55.

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http://www.xgeva.com/. Accessed February 08, 2019.




Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

See Attachment A.


HCPCS Level II Code Number(s)



THE FOLLOWING CODE REPRESENTS DENOSUMAB (PROLIA® OR XGEVA®):

J0897 Injection, denosumab, 1 mg


THE FOLLOWING CODE REPRESENTS ROMOSOZUMAB-AQQG (EVENITY™):

J3111 Injection, romosozumab-aqqg, 1 mg



Revenue Code Number(s)

N/A



Coding and Billing Requirements


Cross References

Attachment A: Denosumab (Prolia®, Xgeva®), Romosozumab-aqqg (Evenity™)
Description: ICD-10-CM Codes




Policy History

00.08.94m:
10/01/2019This version of the policy will become effective 10/01/2019.

The following NOC codes have been removed from this policy and is replaced by the following HCPCS code:

REMOVED: J3590 Unclassified biologics
C9399 Unclassified drugs or biologicals

REPLACED WITH: J3111 Injection, romosozumab-aqqg, 1 mg

00.08.94l:
07/15/2019This version of the policy will become effective 07/15/2019

This policy has been updated to communicate the Company’s coverage criteria for Romosozumab-aqqg (Evenity™).

The following ICD-10 CM code has been added to this policy:
M81.0 Age-related osteoporosis without current pathological fracture

The following HCPCS codes have been added to this policy:
C9399 Unclassified drugs or biologicals
J3590 Unclassified biologics

00.08.94k:
04/08/2019This version of the policy will become effective 04/08/2019.

This policy was updated to include the following:
  • Xgeva medically necessary criteria language revised from management of skeletal-related events to prevention of skeletal-related events in accordance with current FDA labeling.
  • Removal of Policy Guidelines statement for limitation of use regarding denosumab (Xgeva®) not indicated for the prevention of skeletal-related events in individuals with multiple myeloma.
  • Addition of definitions for skeletal-related events; skeletally mature; and hypercalcemia of malignancy to policy criteria
  • Addition of denosumab (Prolia®) to policy criteria for the treatment of glucocorticoid-induced osteoporosis in individuals below age of 50 years of age with a history of an osteoporotic fracture
  • The following ICD-10 CM codes have been added to this policy:
      C90.00 Multiple myeloma not having achieved remission (medically necessary)
      C90.02 Multiple myeloma in relapse (medically necessary)
      M81.8 Other osteoporosis without current pathological fracture

00.08.94j
12/31/2018The policy criteria was updated to include the following new indications:

Prolia
  • Osteopenia

Xgeva
  • Anaplastic carcinoma of the thyroid
  • Multiple Myeloma
  • Systemic Mastocytosis

The following diagnosis code was added to the policy: D47.02


00.08.94i
11/22/2017This policy has been reissued in accordance with the Company's annual review process.


Effective 10/05/2017 this policy has been updated to the new policy template format.


Version Effective Date: 10/01/2019
Version Issued Date: 10/03/2019
Version Reissued Date: N/A



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