Version May 2024
The FDA is adding a Boxed Warning to the Prolia (denosumab) prescribing information concerning the significant risk of developing severe hypocalcemia in patients with advanced chronic kidney disease (CKD), particularly patients on dialysis. Severe hypocalcemia appears to be more common in patients with CKD who also have mineral and bone disorder. In patients with advanced CKD taking Prolia, severe hypocalcemia resulted in serious harm, including hospitalization, life-threatening events, and death. Severe hypocalcemia can be asymptomatic or may present as confusion; seizures; arrhythmias; fainting; face twitching; uncontrolled muscle spasms; or weakness, tingling, or numbness in parts of the body. In addition to the Boxed Warning, the prescribing information will be updated to include information on how to reduce the risk of hypocalcemia, including appropriate patient selection for Prolia treatment, monitoring of calcium levels, and other strategies. The updated safety information will also be incorporated into the Medication Guide and the Prolia Risk Evaluation and Mitigation Strategy (REMS).
Further information can be found at https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease
Dosage guidance:
Clinical considerations: Correct hypocalcemia and vitamin D deficiency (eg, to a 25-hydroxyvitamin D level ≥20 ng/mL [≥50 nmol/L]), when appropriate, before initiation, and ensure adequate calcium and vitamin D intake during therapy (Ref).
Bone metastases from solid tumors (prevention of skeletal-related events; Xgeva): SUBQ: 120 mg every 4 weeks (Ref).
Giant cell tumor of bone (Xgeva): SUBQ: 120 mg once every 4 weeks; during the first month, give an additional 120 mg on days 8 and 15 (Ref).
Hypercalcemia of malignancy (albumin-corrected serum calcium ≥12 mg/dL [≥3 mmol/L]) (alternative agent):
Note: For use in patients with hypercalcemia that is refractory to bisphosphonates, or in patients in whom bisphosphonates cannot be taken. Asymptomatic or mildly symptomatic patients with chronic hypercalcemia may not require immediate treatment unless albumin-corrected serum calcium level is >14 mg/dL (>3.5 mmol/L) (Ref).
SUBQ (Xgeva): 120 mg once weekly for up to 3 doses; if the cause of hypercalcemia persists, may continue at 120 mg every 4 weeks starting 2 weeks after the initial 3 weekly doses (Ref). Note: In patients with contraindications to bisphosphonates (eg, severe kidney impairment, bisphosphonate allergy), some experts administer a single dose of 60 mg; monitor carefully in patients with kidney impairment due to high risk of hypocalcemia in this setting (Ref).
Osteoporosis/bone loss (Prolia):
Androgen deprivation therapy-induced bone loss in males with prostate cancer, treatment: SUBQ: 60 mg once every 6 months (Ref).
Aromatase inhibitor-induced bone loss in females with breast cancer, treatment: SUBQ: 60 mg once every 6 months (Ref).
Osteoporosis, fracture risk reduction (males and postmenopausal females) (alternative agent):
Note: For use in patients in whom first-line therapies are ineffective or cannot be used, or as an alternative antiresorptive agent following anabolic therapy (Ref). Therapy following discontinuation must be well-coordinated; avoid use in patients who have difficulty adhering to medication or appointment schedules (Ref). Prior to use, evaluate and treat any potential causes of secondary osteoporosis (eg, severe vitamin D deficiency) (Ref).
SUBQ: 60 mg once every 6 months.
Duration of therapy: The optimal duration of therapy has not been established. If fracture risk remains high after 5 to 10 years of therapy, consider extending therapy or switching to alternative therapy (eg, a bisphosphonate); there are no data on use beyond 10 years (Ref).
Discontinuation/interruption of therapy: Discontinuation or interruption (eg, >1 month beyond next scheduled dose) of denosumab should not occur without subsequent antiresorptive therapy (eg, with a bisphosphonate) due to increased risk of vertebral fracture; drug holidays are not recommended (Ref).
Missed dose: If a dose is missed, administer as soon as possible; fracture risk may be increased if dose is not administered within 7 months of prior dose (Ref). Thereafter, schedule doses every 6 months from the date of the last injection.
Osteoporosis, glucocorticoid-induced (males and females): SUBQ: 60 mg once every 6 months (Ref).
Bone destruction caused by rheumatoid arthritis (off-label use; based on limited data): SUBQ: 60 mg or 180 mg as a single dose and repeated at 6 months (in combination with continued methotrexate); a total of 2 doses was administered in the study (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Monitor patients with severe impairment (CrCl <30 mL/minute or on dialysis) closely, as significant and prolonged hypocalcemia (incidence of 29% and potentially lasting weeks to months) and marked elevations of serum parathyroid hormone are serious risks in this population (Ref). Ensure adequate calcium and vitamin D intake/supplementation.
Altered kidney function:
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute:
Prolia: No dosage adjustment necessary; use in conjunction with guidance from patient's nephrology team, as osteoporosis is difficult to distinguish from chronic kidney disease mineral and bone disorder (Ref). The risk of Prolia administration must be weighed against the accuracy of the diagnosis of the underlying bone disease (Ref).
Xgeva: There are no specific dosage adjustments recommended. Guidelines suggest dosage adjustment is not necessary; close monitoring for hypocalcemia is recommended (Ref).
Hemodialysis, intermittent (thrice weekly): Unlikely to be removed by hemodialysis (Ref); dose as for patients with CrCl <30 mL/minute; use with caution and monitor calcium levels closely, with appropriate adjustment in dialysate calcium concentration in addition to adequate calcium and active vitamin D supplementation (Ref).
Peritoneal dialysis: Unlikely to be removed by peritoneal dialysis (Ref); dose as for patients with CrCl <30 mL/minute; use with caution and monitor calcium levels closely.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Refer to adult dosing.
(For additional information see "Denosumab: Pediatric drug information")
Dosage guidance:
Clinical considerations: Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia.
Giant cell tumor of the bone, treatment: Xgeva: Adolescents (skeletally mature) weighing ≥45 kg: SubQ: 120 mg once every 4 weeks; during the first month, give an additional dose of 120 mg on days 8 and 15 (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Monitor patients with severe impairment (CrCl <30 mL/minute or on dialysis) due to increased risk of hypocalcemia.
Xgeva: There are no dosage adjustments provided in the manufacturer's labeling; however, in studies of patients with varying degrees of renal impairment, the degree of renal impairment had no effect on denosumab pharmacokinetics or pharmacodynamics.
There are no dosage adjustments provided in manufacturer's labeling (has not been studied).
Atypical femur fracture (AFF) has been reported in patients receiving denosumab for both treatment of osteoporosis as well as in cancer settings (Ref). The fractures may occur anywhere along the femoral shaft (may be bilateral) and commonly occur with minimal to no trauma to the area. Some patients experience prodromal thigh or groin pain weeks or months before the fracture occurs. Contralateral limb should be assessed if AFF occurs. Multiple vertebral column fracture has been reported following discontinuation of therapy (Ref).
Mechanism: Time-related; exact mechanism is not fully understood (Ref).
AFF: AFF are considered stress or insufficiency fractures that develop over time. Antiresorptive agents, including denosumab, suppress bone remodeling which results in increased skeletal fragility and may allow stress fractures to grow to critical size (Ref).
Multiple vertebral column fracture: Discontinuation of therapy results in a rapid, profound increase of bone resorption and loss of bone mineral density, which has been associated with increased risk of rebound-associated multiple vertebral fractures (Ref).
Onset: Delayed; according to the manufacturer, multiple vertebral column fracture has been reported an average of 17 months (range: 7 months to 43 months) after the last dose. Similarly, a few studies report a range of 8 months to 16 months after the last dose (Ref).
Risk factors:
AFF:
• Duration of therapy; in general, long durations (eg, >5 years) of antiresorptive medications are associated with an increased risk of AFF (Ref). The duration of denosumab therapy associated with an increased risk has not been fully elucidated; treatment up to 10 years continues to be associated with a favorable skeletal benefit/risk profile (Ref)
• Prior history of AFF (Ref)
• Patients of Asian descent (Ref)
• Bowed femora (Ref)
• Varus femoral neck/shaft angle (Ref)
• Presence of prodromal symptoms (eg, thigh or groin pain) or signs of early fracture line or periosteal reaction on image of femur (Ref)
• Concurrent use of glucocorticoids for >6 months (Ref)
• Prior long-term use of oral or IV bisphosphonates (Ref)
• Active rheumatoid arthritis (Ref)
• Females (Ref)
• Low serum hydroxyl-vitamin D concentrations (eg, <16 ng/mL) (Ref)
Vertebral column fracture:
• Prior history of vertebral fracture
• Discontinuation of therapy
Denosumab may cause or exacerbate hypocalcemia; severe hypocalcemia (symptomatic cases, including fatalities) has been reported (Ref). Patients may experience a single hypocalcemic episode or recurrent hypocalcemia with subsequent doses (Ref). Resolution (with calcium supplementation) usually occurs within ~30 days (Ref).
Mechanism: Dose-related; related to the pharmacologic action. Denosumab inhibits osteoclastic bone resorption which causes an imbalance of osteoclast and osteoblastic activity reducing the amount of skeletal calcium released into circulation (Ref).
Onset: Varied; Usually occurs ~1 to 2 weeks after treatment initiation; however, a delayed onset (several months after treatment initiation) has also occurred (Ref). Hypocalcemia may appear after the first dose of denosumab (Ref).
Risk factors:
• Preexisting hypocalcemia
• Kidney dysfunction; risk increases with degree of impairment (especially patients with CrCl <30 mL/minute and/or on dialysis with inadequate/no calcium supplementation) (Ref). These patients may also develop marked elevations of serum parathyroid hormone. Concomitant use of calcimimetic medications may worsen hypocalcemia.
• Patients predisposed to hypocalcemia or disturbances of mineral metabolism (eg, hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine)
• Bone metastases (especially in patients with prostate cancer or small-cell lung cancer as the primary tumor type); risk increases with the number of bone metastases (Ref)
• Osteoblastic bone metastases (Ref)
• Concurrent use of other calcium-lowering agents
• Patients with high bone turnover (eg, elevated serum alkaline phosphatase, total N-terminal propeptide of type 1 procollagen [P1NP], tartrate-resistant acid phosphatase 5b [TRACP-5b], urinary cross-linked N-telopeptide of type 1 collagen [NTX]) (Ref)
• Males (may be related to higher risk of hypocalcemia in patients with prostate cancer) (Ref)
• No prior zoledronic acid administration (Ref)
An increased incidence of infection (including serious infection) has been demonstrated with denosumab, mainly secondary to an increased risk of ear, nose, and throat infections (eg, pharyngitis, nasopharyngitis, sinusitis, otitis media, labyrinthitis) and GI infections (eg, gastroenteritis, diverticulitis, H. pylori gastritis, cholecystitis, appendicitis, C. difficile-associated disease) (Ref). Cases of kidney and urinary tract infection, serious skin infections, and endocarditis have also been reported (Ref).
Mechanism: Non-dose-related; idiosyncratic; exact mechanism unknown. Denosumab inhibits RANKL which can be found on cells of the immune system including activated T lymphocytes, B cells, dendritic cells, and monocyte-macrophages; therefore, RANKL inhibition may alter immune function (Ref).
Onset: Not well defined. In a meta-analysis of randomized controlled trials, a higher incidence of infection was evident in treatment duration of ≥12 months but not in shorter exposures (Ref). In contrast, an analysis of data from the FREEDOM trial did not find a change in the rate of infection with increasing duration of denosumab treatment (Ref).
Risk factors:
• Impaired immune system
• Concurrent use of immunosuppressive therapy (Ref)
• Venous ulcers (risk factor for skin infection) (Ref)
• Skin wounds (risk factor for skin infection) (Ref)
Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving denosumab and is characterized by nonhealing exposed or necrotic bone in the maxillofacial region (Ref). ONJ may manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth/periodontal infection, toothache, or gingival ulceration/erosion (Ref). Risk of ONJ is increased with intravenous antiresorptive therapy (ie, denosumab) as compared to the risk associated with oral bisphosphonate use (Ref).
Mechanism: Dose- and time-related; exact mechanism unknown. Leading hypotheses include oversuppression of bone turnover or remodeling, inhibition of blood supply, constant microtrauma, and infection/inflammation (Ref).
Onset: Delayed; in one combined analysis of patients with metastatic bone disease receiving antiresorptive therapies reported that ONJ occurred from 4 to 30 months after treatment initiation (median: 14 months). Resolution occurred in 40.4% of patients and median time to resolution was ~8 months (Ref).
Risk factors:
• Invasive dental procedures (eg, tooth extraction, dental implants, oral surgery) (Ref)
• Local infection with delayed healing
• Cancer diagnosis (as compared to patients receiving antiresorptive therapy for osteoporosis, regardless of medication used or dosing schedule) (Ref)
In studies of patients with cancer, a longer duration of denosumab exposure was associated with a higher incidence of ONJ, although a majority of patients had predisposing factors, including a history of poor oral hygiene, tooth extraction, or the use of a dental appliance.
• Duration of therapy (risk may plateau at 2 to 3 years of treatment with denosumab) (Ref)
• Higher doses (eg, doses used in cancer settings) (Ref)
• Concurrent use of certain medications (eg, immunosuppressive therapy, angiogenesis inhibitor therapy, chemotherapy, systemic corticosteroids, hormone therapy, erythropoietin) (Ref)
• Poor oral hygiene (Ref)
• Use of a dental appliance (Ref)
• Ill-fitting dentures (Ref)
• Periodontal and/or other preexisting dental disease
• Diabetes (Ref)
• Anemia (Ref)
• Coagulopathy
• Tobacco use (Ref)
• Hyperthyroidism (Ref)
• Dialysis (Ref)
• Older adults (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Incidences with Prolia (60 mg every 6 months) or Xgeva (120 mg every 4 weeks).
>10%:
Cardiovascular: Peripheral edema (Prolia: 5%; Xgeva: 17%)
Dermatologic: Dermatitis (Prolia: ≤11%), eczema (Prolia: ≤11%), skin rash (≤14%)
Endocrine & metabolic: Hypocalcemia (Prolia: 2%, including severe hypocalcemia; Xgeva: 18%, severe hypocalcemia: 3% (table 1); postmarketing literature suggests a higher incidence of ~40% [Manzaneque 2017]) (table 2), hypophosphatemia (Xgeva: 32%; severe: 15% to 21%)
|
Drug (Denosumab) |
Comparator (Zoledronic acid) |
Dose (Denosumab) |
Dose (Zoledronic acid) |
Indication |
Number of Patients (Denosumab) |
Number of Patients (Zoledronic acid) |
Comment |
|---|---|---|---|---|---|---|---|
|
3% |
1% |
120 mg every 4 weeks |
4 mg/4 weeks |
Bone metastasis from solid tumors |
2,841 |
2,836 |
Severe hypocalcemia was defined as corrected serum calcium <7 mg/dL |
|
Drug (Denosumab) |
Placebo |
Comparator (Zoledronic acid) |
Population |
Dose (Denosumab) |
Dose (Zoledronic acid) |
Indication |
Number of Patients (Denosumab) |
Number of Patients (Placebo or comparator) |
|---|---|---|---|---|---|---|---|---|
|
2% |
0.4% |
N/A |
Female |
60 mg every 6 months |
N/A |
Postmenopausal women with osteoporosis |
N/A |
N/A |
|
2% |
0% |
N/A |
N/A |
60 mg every 6 months |
N/A |
Bone loss in patients receiving androgen deprivation therapy for prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer |
731 |
725 |
|
18% |
N/A |
9% |
N/A |
120 mg every 4 weeks |
4 mg/4 weeks |
Bone metastasis from solid tumors |
2,841 |
2,836 |
Gastrointestinal: Diarrhea (Xgeva: 20% to 34%), nausea (Xgeva: 31% to 32%)
Hematologic & oncologic: Anemia (Xgeva: 22%), thrombocytopenia (Xgeva: 19%)
Nervous system: Fatigue (Xgeva: ≤45%), headache (Prolia: 4%; Xgeva: 11% to 13%)
Neuromuscular & skeletal: Arthralgia (Prolia: 7% to 14%), asthenia (Xgeva: ≤45%), back pain (Prolia: 5% to 12%; Xgeva: 21%), limb pain (Prolia: 10% to 12%)
Respiratory: Cough (Xgeva: 15%), dyspnea (Xgeva: 21%), upper respiratory tract infection (Prolia: 3% to 5%; Xgeva: 15%) (table 3)
|
Drug (Denosumab) |
Placebo |
Comparator (Bisphosphonate) |
Population |
Dose (Denosumab) |
Dose (Bisphosphonate) |
Indication |
Number of Patients (Denosumab) |
Number of Patients (Placebo or comparator) |
|---|---|---|---|---|---|---|---|---|
|
5% |
4% |
N/A |
Female |
60 mg every 6 months |
N/A |
Postmenopausal women with osteoporosis |
3,886 |
3,876 |
|
3% |
N/A |
3% |
N/A |
60 mg every 6 months |
5 mg/day |
Glucocorticoid-induced osteoporosis |
394 |
384 |
1% to 10%:
Cardiovascular: Angina pectoris (Prolia: 3%), hypertension (Prolia: 4%)
Endocrine & metabolic: Hypercholesterolemia (Prolia: 7%)
Gastrointestinal: Constipation (Prolia: 3%), dyspepsia (Prolia: 3%), flatulence (Prolia: 2%), upper abdominal pain (Prolia: 3%), vomiting (Prolia 3%)
Genitourinary: Urinary tract infection (Prolia: 3%) (table 4)
|
Drug (Denosumab) |
Comparator (Bisphosphonate) |
Dose (Denosumab) |
Dose (Bisphosphonate) |
Indication |
Number of Patients (Denosumab) |
Number of Patients (Bisphosphonate) |
|---|---|---|---|---|---|---|
|
3% |
2% |
60 mg every 6 months |
5 mg/day |
Glucocorticoid-induced osteoporosis |
394 |
384 |
Hematologic & oncologic: Malignant neoplasm (Prolia: new; 3% to 5%)
Infection: Serious infection (Prolia: 4%) (table 5)
|
Drug (Denosumab) |
Comparator (Bisphosphonate) |
Dose (Denosumab) |
Dose (Bisphosphonate) |
Indication |
Number of Patients (Denosumab) |
Number of Patients (Bisphosphonate) |
|---|---|---|---|---|---|---|
|
4% |
4% |
60 mg every 6 months |
5 mg/day |
Glucocorticoid-induced osteoporosis |
394 |
384 |
Nervous system: Dizziness (Prolia: 2%), falling (Prolia: 2%), sciatica (Prolia: 5%)
Neuromuscular & skeletal: Musculoskeletal pain (Prolia: 6%), myalgia (Prolia: 3%), ostealgia (Prolia: 4%), osteonecrosis of the jaw (Prolia: <1%; Xgeva: 2%) (table 6), polymyalgia rheumatica (Prolia: 2%), vertebral column fracture (following discontinuation: Prolia: 3% to 6%)
|
Drug (Denosumab) |
Comparator (Zoledronic acid) |
Dose (Denosumab) |
Dose (Zoledronic acid) |
Indication |
Number of Patients (Denosumab) |
Number of Patients (Zoledronic acid) |
|---|---|---|---|---|---|---|
|
2% |
1% |
120 mg every 4 weeks |
4 mg/4 weeks |
Bone metastasis from solid tumors |
2,841 |
2,836 |
Ophthalmic: Cataract (Prolia: 5%)
Respiratory: Bronchitis (Prolia: 4%) (table 7), nasopharyngitis (Prolia: 7%) (table 8), pneumonia (Xgeva: 8%)
|
Drug (Denosumab) |
Comparator (Bisphosphonate) |
Dose (Denosumab) |
Dose (Bisphosphonate) |
Indication |
Number of Patients (Denosumab) |
Number of Patients (Bisphosphonate) |
|---|---|---|---|---|---|---|
|
4% |
3% |
60 mg every 6 months |
5 mg/day |
Glucocorticoid-induced osteoporosis |
394 |
384 |
|
Drug (Denosumab) |
Placebo |
Population |
Indication |
Number of Patients (Denosumab) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
7% |
6% |
Male |
Osteoporosis |
120 |
120 |
<1%:
Cardiovascular: Endocarditis (Prolia) (table 9)
|
Drug (Denosumab) |
Placebo |
Population |
Indication |
Number of Patients (Denosumab) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
0.1% |
0% |
Female |
Postmenopausal women with osteoporosis |
3,886 |
3,876 |
Immunologic: Antibody development
Postmarketing (all formulations):
Cardiovascular: Vasculitis (Sanchez 2019)
Dermatologic: Alopecia (Lyakhovitsky 2016), erythema of skin, facial swelling (Gutiérrez-Fernández 2015), lichenoid eruption (King 2018), urticaria (Gutiérrez-Fernández 2015)
Endocrine & Metabolic: Hyperparathyroidism (Mazokopakis 2018)
Hepatic: Hepatotoxicity (Malnick 2017)
Hypersensitivity: Anaphylaxis
Immunologic: Drug reaction with eosinophilia and systemic symptoms (Al-Attar 2019)
Neuromuscular & skeletal: Femur fracture (atypical, diaphyseal, subtrochanteric) (Selga 2016)
Ophthalmic: Epithelial keratopathy (Nguyen 2019)
Renal: Acute interstitial nephritis (Philipponnet 2018)
Prolia: Hypersensitivity (systemic) to denosumab or any component of the formulation; preexisting hypocalcemia; pregnancy
Xgeva: Known clinically significant hypersensitivity to denosumab or any component of the formulation; preexisting hypocalcemia
Concerns related to adverse effects:
• Bone fractures: Atypical femur fractures have been reported in patients receiving denosumab. The fractures may occur anywhere along the femoral shaft (may be bilateral) and commonly occur with minimal to no trauma to the area. Some patients experience prodromal pain weeks or months before the fracture occurs. Because these fractures also occur in osteoporosis patients not treated with denosumab, it is unclear if denosumab therapy is the cause for the fractures; concomitant glucocorticoids may contribute to fracture risk. Advise patients to report new/unusual hip, thigh, or groin pain; and if so, evaluate for atypical/incomplete fracture. Contralateral limb should be assessed if atypical fracture occurs. Consider interrupting therapy in patients who develop an atypical femoral fracture. Following treatment discontinuation, the fracture risk increases, including risk of multiple vertebral fractures; patients with a history of prior fractures or osteoporosis are at higher risk. Vertebral fractures occurred as early as 7 months (average: 19 months) after the last dose of denosumab. Evaluate benefit/risk before initiating denosumab treatment for osteoporosis, especially in patients with prior vertebral fracture. If denosumab is discontinued, evaluate risk for vertebral fracture and consider transitioning to an alternative osteoporosis therapy. Because denosumab is associated with a severe bone turnover rebound following discontinuation, post-denosumab antiresorptive therapy (eg, bisphosphonate therapy or alternative) is suggested to mitigate decline in bone mineral density (ES [Eastell 2019]; Tsourdi 2017). Bisphosphonate therapy following denosumab discontinuation may reduce/prevent bone turnover rebound (Lamy 2017).
• Dermatologic reactions: Dermatitis, eczema, and rash (which are not necessarily specific to the injection site) have been reported. Consider discontinuing if severe symptoms occur.
• Hypersensitivity: Clinically significant hypersensitivity (including anaphylaxis) has been reported. May include throat tightness, facial edema, upper airway edema, lip swelling, dyspnea, pruritus, rash, urticaria, and hypotension. If anaphylaxis or clinically significant hypersensitivity occurs, initiate appropriate management and permanently discontinue.
• Hypercalcemia: Hypercalcemia (clinically significant requiring hospitalization and complicated by acute renal injury) may occur in patients with giant cell tumor of bone and patients with growing skeletons weeks to months following discontinuation of denosumab therapy. Monitor for signs/symptoms of hypercalcemia (eg, nausea, vomiting, headache, decreased alertness), assess serum calcium periodically, and treat accordingly.
• Hypocalcemia: Denosumab may cause or exacerbate hypocalcemia; severe symptomatic cases (including fatalities) have been reported. An increased risk has been observed with increasing renal dysfunction, most commonly severe dysfunction (CrCl <30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels; correct preexisting hypocalcemia prior to therapy. Monitor levels more frequently when denosumab is administered with other drugs that can also lower calcium levels. Use caution in patients with a history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, severe renal impairment/dialysis, treatment with other calcium-lowering agents, or other conditions that would predispose the patient to hypocalcemia; monitor calcium, phosphorus, and magnesium closely during therapy (the manufacturer recommends monitoring within 14 days of injection [Prolia] or during the first weeks of therapy initiation [Xgeva]). Concomitant use of calcimimetic medications may worsen hypocalcemia. Hypocalcemia lasting weeks to months (and requiring frequent monitoring) has been reported in postmarketing analyses. Administer calcium, vitamin D, and magnesium as necessary. Patients with severe renal impairment (CrCl <30 mL/minute) or those on dialysis may also develop marked elevations of serum parathyroid hormone (PTH).
• Infection: Incidence of infections may be increased, including serious skin infections, abdominal, urinary, ear, or periodontal infections. Endocarditis has also been reported following use. Patients should be advised to contact their healthcare provider if signs or symptoms of severe infection or cellulitis develop. Use with caution in patients with impaired immune systems or using concomitant immunosuppressive therapy; may be at increased risk for serious infections. Evaluate the need for continued treatment with serious infection.
• Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving denosumab. ONJ may manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth/periodontal infection, toothache, gingival ulceration/erosion. Risk factors include invasive dental procedures (eg, tooth extraction, dental implants, oral surgery), cancer diagnosis, immunosuppressive therapy, angiogenesis inhibitor therapy, chemotherapy, systemic corticosteroids, poor oral hygiene, use of a dental appliance, ill-fitting dentures, periodontal and/or other preexisting dental disease, diabetes and gingival infections, local infection with delayed healing, anemia, and/or coagulopathy. In studies of patients with cancer, a longer duration of denosumab exposure was associated with a higher incidence of ONJ, although a majority of patients had predisposing factors, including a history of poor oral hygiene, tooth extraction, or the use of a dental appliance. Patients should maintain good oral hygiene during treatment. A dental exam and appropriate preventive dentistry should be performed prior to therapy. The manufacturer's labeling recommends avoiding invasive dental procedures in patients with bone metastases receiving denosumab for prevention of skeletal-related events and to consider temporary discontinuation of therapy in these patients if invasive dental procedure is required. According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), MRONJ has been associated with bisphosphonates and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy; risk is significantly higher in cancer patients receiving antiresorptive therapy compared to patients receiving osteoporosis treatment (regardless of medication used or dosing schedule). MRONJ risk is increased with intravenous antiresorptive therapy compared to the minimal risk associated with oral bisphosphonate use, although risk appears to increase with oral bisphosphonates when duration of therapy exceeds 4 years. The AAOMS suggests that if medically permissible, initiation of denosumab for cancer therapy should be delayed until optimal dental health is attained (if extractions are required, antiresorptive therapy should delayed until the extraction site has mucosalized or until after adequate osseous healing). Once denosumab is initiated for oncologic disease, procedures that involve direct osseous injury and placement of dental implants should be avoided. Patients developing ONJ during therapy should receive care by an oral surgeon (AAOMS [Ruggiero 2014]). According to the manufacturer, discontinuation of denosumab should be considered (based on risk/benefit evaluation) in patients who develop ONJ.
• Musculoskeletal pain: Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported (time to onset of symptoms has varied from one day to several months after initiating therapy). Consider discontinuing use if severe symptoms develop.
Disease-related concerns:
• Breast cancer: The American Society of Clinical Oncology (ASCO)/Cancer Care Ontario (CCO) updated guidelines on the role of bone-modifying agents (BMAs) in metastatic breast cancer patients (ASCO/CCO [Van Poznak 2017]). The guidelines recommend initiating a BMA (denosumab, pamidronate, zoledronic acid) in patients with metastatic breast cancer to the bone. One BMA is not recommended over another (evidence supporting one BMA over another is insufficient). The optimal duration of BMA therapy is not defined; however, the guidelines recommend continuing BMA therapy indefinitely. The analgesic effect of BMAs are modest and BMAs should not be used alone for pain management; supportive care, analgesics, adjunctive therapies, radiation therapy, surgery, and/or systemic anticancer therapy should be utilized.
• Multiple myeloma: The American Society of Clinical Oncology (ASCO) has updated guidelines on the role of BMAs in multiple myeloma (ASCO [Anderson 2018]). The update now includes denosumab as an alternate to zoledronic acid or pamidronate in patients with lytic disease, and as an additional option in adjunctive pain control in patients with pain due to osteolytic disease and patients receiving other interventions for fractures or impending fractures. Denosumab may also be preferred (to zoledronic acid) in patients with renal impairment. The ASCO guidelines recommend continuing the BMA for up to 2 years in multiple myeloma patients; BMAs may then be resumed upon relapse with new onset skeletal-related events. Denosumab has a reversible mechanism of action and therefore should not be discontinued abruptly (refer to Bone fractures [above] for further information).
• Osteoporosis in survivors of adult cancers (nonmetastatic disease): Survivors of adult cancers with nonmetastatic disease who have osteoporosis (T score of -2.5 or lower in femoral neck, total hip, or lumbar spine) or who are at increased risk of osteoporotic fractures, should be offered bone modifying agents (utilizing the osteoporosis-indicated dose) to reduce the risk of fracture. For patients without hormonal responsive cancers, when clinically appropriate, estrogens may be administered along with other bone modifying agents (ASCO [Shapiro 2019]). The choice of bone modifying agent (eg, oral or IV bisphosphonates or subQ denosumab) should be based on several factors (eg, patient preference, potential adverse effects, quality of life considerations, availability, adherence, cost). Adequate calcium and vitamin D intake, exercise (using a combination of exercise types), as well as lifestyle modifications (if indicated), should also be encouraged.
• Renal impairment: Use with caution in patients with renal impairment (CrCl <30 mL/minute) or patients on dialysis; risk of hypocalcemia is increased. Dose adjustment is not needed when administered at 60 mg every 6 months (Prolia); once-monthly dosing has not been evaluated in patients with renal impairment (Xgeva).
Dosage form specific issues:
• Latex: Packaging may contain natural latex rubber (Note: Prior to January 2023, the Prolia prescribing information stated the prefilled syringe gray needle cap contained dry natural rubber).
Special populations:
• Pediatric: May impair bone growth in children with open growth plates or inhibit eruption of dentition. Indicated only for the treatment of giant cell tumor of bone in adolescents who are skeletally mature.
Other warnings/precautions:
• Appropriate use: Postmenopausal osteoporosis: For use in females at high risk for fracture which is defined as a history of osteoporotic fracture or multiple risk factors for fracture. May also be used in females who failed or did not tolerate other therapies.
• Duplicate therapy: Do not administer Prolia and Xgeva to the same patient for different indications.
• Long-term therapy: Denosumab therapy results in significant suppression of bone turnover; the long-term effects of treatment are not known, but may contribute to adverse outcomes such as ONJ, atypical fractures, or delayed fracture healing; monitor.
Prolia prefilled syringe gray needle cap contains dry natural rubber (a derivative of latex).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Subcutaneous [preservative free]:
Xgeva: 120 mg/1.7 mL (1.7 mL)
Solution Prefilled Syringe, Subcutaneous [preservative free]:
Prolia: 60 mg/mL (1 mL)
No
Solution (Xgeva Subcutaneous)
120 mg/1.7 mL (per mL): $2,254.89
Solution Prefilled Syringe (Prolia Subcutaneous)
60 mg/mL (per mL): $2,083.96
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Subcutaneous:
Xgeva: 120 mg/1.7 mL (1.7 mL)
Solution Prefilled Syringe, Subcutaneous:
Prolia: 60 mg/mL (1 mL) [contains mouse (murine) and/or hamster protein]
SUBQ: Denosumab is intended for SUBQ route only and should not be administered IV, IM, or intradermally. Prior to administration, bring to room temperature in original container (allow to stand ~15 to 30 minutes); do not warm by any other method. Solution may contain trace amounts of translucent to white protein particles; do not use if cloudy, discolored (normal solution should be clear and colorless to pale yellow), or contains excessive particles or foreign matter. Avoid vigorous shaking. Administer via SUBQ injection in the upper arm, upper thigh, or abdomen; should only be administered by a health care professional.
SubQ: Administer by SubQ injection only; do not administer intravenously, intramuscularly, or intradermally. Prior to administration, bring to room temperature in original container (allow to stand ~15 to 30 minutes); do not warm by any other method. Solution may contain trace amounts of translucent to white protein particles; do not use if cloudy, discolored (normal solution should be clear and colorless to pale yellow), or contains excessive particles or foreign matter. Avoid vigorous shaking. Administer via SubQ injection in the upper arm, upper thigh, or abdomen; should only be administered by a health care professional.
Xgeva: Use 27 gauge needle to withdraw dose from vial and administer subcutaneously.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Prolia: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125320s210lbl.pdf#page=31
Bone metastases from solid tumors (Xgeva): Prevention of skeletal-related events in patients with bone metastases from solid tumors.
Giant cell tumor of bone (Xgeva): Treatment of giant cell tumor of bone (in adults and skeletally mature adolescents) that is unresectable or where surgical resection is likely to result in severe morbidity.
Hypercalcemia of malignancy (Xgeva): Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.
Multiple myeloma (Xgeva): Prevention of skeletal-related events in patients with multiple myeloma.
Osteoporosis/bone loss (Prolia): Treatment of osteoporosis in postmenopausal females at high risk of fracture; treatment of osteoporosis (to increase bone mass) in males at high risk of fracture; treatment of bone loss (to increase bone mass) in males receiving androgen-deprivation therapy for nonmetastatic prostate cancer; treatment of bone loss (to increase bone mass) in females receiving aromatase inhibitor therapy for breast cancer; treatment of glucocorticoid-induced osteoporosis in patients at high risk of fracture who are initiating or continuing systemic glucocorticoids at a daily dose equivalent to ≥7.5 mg of prednisone for an anticipated duration of at least 6 months (high risk defined as osteoporotic fracture history, multiple risk factors for fracture, or failure of or intolerance to other available osteoporosis therapy).
Bone destruction caused by rheumatoid arthritis
Denosumab may be confused with daclizumab, daratumumab, dinutuximab, dupilumab, durvalumab
Prolia may be confused with Udenyca
Xgeva may be confused with Jevtana, Xofigo, Xtandi, Zometa, Zytiga
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
Duplicate therapy issues: Prolia contains denosumab, which is the same ingredient contained in Xgeva; patients receiving Xgeva should not be treated with Prolia
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Calcimimetic Agents: Denosumab may enhance the hypocalcemic effect of Calcimimetic Agents. Risk C: Monitor therapy
Corticosteroids (Systemic): Denosumab may enhance the immunosuppressive effect of Corticosteroids (Systemic). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and systemic corticosteroids. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Immunosuppressants (Cytotoxic Chemotherapy): Denosumab may enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and cytotoxic chemotherapy. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Immunosuppressants (Miscellaneous Oncologic Agents): Denosumab may enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Immunosuppressants (Therapeutic Immunosuppressant Agents): May enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification
Methotrexate: Denosumab may enhance the immunosuppressive effect of Methotrexate. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants, such as methotrexate. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Evaluate pregnancy status prior to use in females of reproductive potential. Females of reproductive potential should be advised to use effective contraception during denosumab treatment and for at least 5 months following the last denosumab dose. Studies of denosumab following a single 60 mcg subcutaneous dose in healthy men demonstrated that denosumab is present in the semen in low concentrations (~2% of serum exposure) and therefore unlikely that a female partner or fetus would be exposed during unprotected sex to pharmacologically relevant denosumab concentrations via seminal fluid (Sohn 2016).
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to denosumab may cause fetal harm. Denosumab is a humanized monoclonal antibody (IgG2). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009). Use of Prolia is contraindicated during pregnancy.
Data collection to monitor pregnancy and infant outcomes following exposure to denosumab is ongoing. Health care providers are encouraged to enroll females exposed to denosumab during pregnancy in the Amgen Pregnancy Surveillance Program (1-800-772-6436).
It is not known if denosumab is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Ensure adequate calcium and vitamin D intake to prevent or treat hypocalcemia. Calcium 1,000 mg/day and vitamin D ≥400 units/day is recommended in product labeling (Prolia). If dietary intake is inadequate, dietary supplementation is recommended. Patients should consume:
Calcium: 1,000 mg/day (males: 50 to 70 years of age) or 1,200 mg/day (females ≥51 years of age and males ≥71 years of age) (IOM 2011; NOF 2014).
Vitamin D: 800 to 1,000 units/day (age ≥50 years) (NOF 2014). Recommended dietary allowance (RDA): 600 units/day (age ≤70 years) or 800 units/day (age ≥71 years) (IOM 2011).
Serum creatinine, serum calcium, phosphorus and magnesium (especially within the first 14 days of therapy [Prolia] or during the first weeks of therapy initiation [Xgeva]), pregnancy test (prior to treatment initiation in females of reproductive potential); signs/symptoms of hypocalcemia, especially in patients predisposed to hypocalcemia (severe renal impairment, thyroid/parathyroid surgery, malabsorption syndromes, hypoparathyroidism); signs/symptoms of hypercalcemia, including periodic serum calcium (following discontinuation in patients with giant cell tumor of the bone and patients with growing skeletons); infection, or dermatologic reactions; routine oral exam (prior to treatment); dental exam if risk factors for ONJ; signs/symptoms of hypersensitivity.
Osteoporosis: Serial bone mineral density (BMD) should be evaluated at baseline and every 1 to 3 years (usually at ~2 years following initiation of therapy, then more or less frequently depending on patient-specific factors and stability of BMD) (AACE/ACE [Camacho 2020]; ES [Eastell 2019]; NOF [Cosman 2014]); may consider monitoring biochemical markers of bone turnover (eg, fasting serum CTX or urinary NTX) at baseline, 3 months, and 6 months, to assess treatment response (ES [Eastell 2019]).
Patients with cancer: The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Denosumab is a monoclonal antibody with affinity for nuclear factor-kappa ligand (RANKL). Osteoblasts secrete RANKL; RANKL activates osteoclast precursors and subsequent osteolysis which promotes release of bone-derived growth factors, such as insulin-like growth factor-1 (IGF1) and transforming growth factor-beta (TGF-beta), and increases serum calcium levels. Denosumab binds to RANKL, blocks the interaction between RANKL and RANK (a receptor located on osteoclast surfaces), and prevents osteoclast formation, leading to decreased bone resorption and increased bone mass in osteoporosis. In solid tumors with bony metastases, RANKL inhibition decreases osteoclastic activity leading to decreased skeletal related events and tumor-induced bone destruction. In giant cell tumors of the bone (which express RANK and RANKL), denosumab inhibits tumor growth by preventing RANKL from activating its receptor (RANK) on the osteoclast surface, osteoclast precursors, and osteoclast-like giant cells.
Onset of action: Decreases markers of bone resorption by ~85% within 3 days; maximal reductions observed within 1 month.
Hypercalcemia of malignancy: Time to response (median): 9 days; Time to complete response (median): 23 days (Hu 2014).
Duration: Markers of bone resorption return to baseline within 12 months of discontinuing therapy.
Hypercalcemia of malignancy: Duration of response (median): 104 days; Duration of complete response (median): 34 days (Hu 2014).
Bioavailability: SUBQ: 62%.
Half-life elimination: ~25 to 28 days.
Time to peak, serum: 10 days (range: 3 to 21 days).
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