(den OH sue mab)
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Subcutaneous [preservative free]:
Prolia: 60 mg/mL (1 mL) [contains mouse (murine) and/or hamster protein]
Xgeva: 120 mg/1.7 mL (1.7 mL)
Brand Names: U.S.
- Bone-Modifying Agent
- Monoclonal Antibody
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)
Time to Peak
Serum: 10 days (range: 3 to 21 days)
Duration of Action
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)
~25 to 28 days
Use: Labeled Indications
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 women at high risk of fracture; treatment of osteoporosis (to increase bone mass) in men at high risk of fracture; treatment of bone loss in men receiving androgen-deprivation therapy (ADT) for nonmetastatic prostate cancer; treatment of bone loss in women receiving aromatase inhibitor (AI) therapy for breast cancer.
Off Label Uses
Bone destruction caused by rheumatoid arthritis
Data from a multicenter, randomized, double-blind, placebo-controlled, phase II study supports the use of denosumab (with ongoing methotrexate administration) in the treatment of bone destruction caused by rheumatoid arthritis [Cohen 2008]. Additional data may be necessary to further define the role of denosumab in this condition.
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
Note: Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia
Bone metastases from solid tumors (prevention of skeletal-related events; Xgeva): SubQ: 120 mg every 4 weeks (Fizazi 2011; Henry 2011; Stopeck 2010)
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 (Blay 2011; Thomas 2010)
Hypercalcemia of malignancy (Xgeva): SubQ: 120 mg every 4 weeks; during the first month, give an additional 120 mg on days 8 and 15 (Hu 2014)
Multiple myeloma (prevention of skeletal-related events; Xgeva): SubQ: 120 mg every 4 weeks (Raje 2017). Denosumab has a reversible mechanism of action and therefore should not be discontinued abruptly (ASCO [Anderson 2018]).
Osteoporosis/bone loss (Prolia):
Treatment of androgen deprivation-induced bone loss in men with prostate cancer: SubQ: 60 mg as a single dose, once every 6 months (Smith 2009)
Treatment of aromatase inhibitor-induced bone loss in women with breast cancer: SubQ: 60 mg as a single dose, once every 6 months (Ellis 2008)
Treatment of osteoporosis in men or in postmenopausal women: SubQ: 60 mg as a single dose, once every 6 months
Bone destruction caused by rheumatoid arthritis (off-label use): SubQ: 60 mg or 180 mg as a single one time dose and repeated at 6 months (in combination with continued methotrexate); a total of 2 doses was administered in the study (Cohen 2008). Additional data may be necessary to further define the role of denosumab in this condition.
Refer to adult dosing.
Note: Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia
Giant cell tumor of bone (Xgeva): Adolescents (skeletally mature) 13 to 17 years: SubQ: 120 mg once every 4 weeks; during the first month, give an additional 120 mg on days 8 and 15
Dosing: Renal Impairment
Monitor patients with severe impairment (CrCl <30 mL/minute or on dialysis) closely due to increased risk of hypocalcemia.
Prolia: No dosage adjustment necessary.
Xgeva: There are no dosage adjustments provided in the manufacturer's labeling. Guidelines suggest dosage adjustment is not necessary; close monitoring for hypocalcemia is recommended (ASCO [Anderson 2018]; ASCO/CCO [Van Poznak 2017]; Gravalos 2016).
Dosing: Hepatic Impairment
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
SubQ: Denosumab is intended for subcutaneous route only and should not be administered 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.
Prolia: If a dose is missed, administer as soon as possible, then continue dosing every 6 months from the date of the last injection.
Ensure adequate calcium and vitamin D intake to prevent or treat hypocalcemia. Calcium 1000 mg/day and vitamin D ≥400 units/day is recommended in product labeling (Prolia). If dietary intake is inadequate, dietary supplementation is recommended. Women and men should consume:
Calcium: 1000 mg/day (men: 50 to 70 years) or 1200 mg/day (women ≥51 years and men ≥71 years) (IOM 2011; NOF 2014)
Vitamin D: 800 to 1000 units/day (men and women ≥50 years) (NOF 2014). Recommended Dietary Allowance (RDA): 600 units/day (men and women ≤70 years) or 800 units/day (men and women ≥71 years) (IOM 2011).
Store in original carton at 2°C to 8°C (36°F to 46°F). Do not freeze. Prior to use, bring to room temperature of 25°C (77°F) in original container (usually takes 15 to 30 minutes); do not use any other methods for warming. Use within 14 days once at room temperature. Protect from direct heat and light; do not expose to temperatures >25°C (77°F). Avoid vigorous shaking.
Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination
Immunosuppressants: Denosumab may enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Exceptions: Cytarabine (Liposomal). Monitor therapy
Percentages noted with Prolia (60 mg every 6 months) unless specified as Xgeva (120 mg every 4 weeks):
Cardiovascular: Hypertension (11%, Lewiecki 2007)
Central nervous system: Fatigue (Xgeva: ≤45%), headache (Xgeva: 13% to 24%), peripheral edema (5%; Xgeva: 24%)
Dermatologic: Dermatitis (4% to 11%), eczema (4% to 11%), skin rash (3% to 11%)
Endocrine & metabolic: Hypophosphatemia (Xgeva: 32%), hypocalcemia (2%; Xgeva: 3% to 18%)
Gastrointestinal: Nausea (Xgeva: 31%), decreased appetite (Xgeva: 24%), vomiting (Xgeva: 24%), constipation (Xgeva: 21%), diarrhea (Xgeva: 20%)
Hematologic & oncologic: Anemia (Xgeva: 21%)
Infection: Influenza (11%, Lewiecki 2007)
Neuromuscular & skeletal: Weakness (Xgeva: ≤45%), arthralgia (7% to 14%), limb pain (10% to 12%), back pain (8% to 12%)
Respiratory: Dyspnea (Xgeva: 21% to 27%), cough (Xgeva: 15%)
1% to 10%:
Cardiovascular: Angina pectoris (3%)
Central nervous system: Sciatica (5%)
Endocrine & metabolic: Hypercholesterolemia (7%)
Gastrointestinal: Flatulence (2%)
Hematologic & oncologic: Malignant neoplasm (new; 3% to 5%)
Infection: Serious infection (4%)
Neuromuscular & skeletal: Musculoskeletal pain (6%), ostealgia (4%), myalgia (3%), osteonecrosis (jaw; ≤2%; Xgeva ≤2%)
Ophthalmic: Cataract (≤5%)
Respiratory: Nasopharyngitis (7%), upper respiratory tract infection (5%)
<1%, postmarketing, and/or case reports: Anaphylaxis (both formulations), antibody development (both formulations), endocarditis, erythema, facial swelling, femur fracture (both formulations; diaphyseal, subtrochanteric), hearing loss (FDA Safety Alert June 6, 2016), hypercalcemia (Xgeva, following discontinuation), hypersensitivity (both formulations), hypotension, pancreatitis, severe hypocalcemia (symptomatic; both formulations), urticaria
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 bisphosphonate therapy (IV or oral; dependent on the patient’s underlying indication for bone modifying therapy) is suggested to mitigate decline in bone mineral density (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) may occur in patients with growing skeletons weeks to months following discontinuation of denosumab therapy. Monitor for signs/symptoms of hypercalcemia (eg, nausea, vomiting, headache, decreased alertness) 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 (creatinine clearance <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, or other conditions which 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]). 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.
• 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 bone-modifying agents (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).
• 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).
Concomitant drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Dosage form specific issues:
• Latex: Packaging may contain natural latex rubber.
• 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.
• Appropriate use: Postmenopausal osteoporosis: For use in women 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 women 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.
Recommend monitoring of 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 and symptoms of hypocalcemia, especially in patients predisposed to hypocalcemia (severe renal impairment, thyroid/parathyroid surgery, malabsorption syndromes, hypoparathyroidism); signs/symptoms of hypercalcemia (following discontinuation in patients with growing skeletons); infection, or dermatologic reactions; routine oral exam (prior to treatment); dental exam if risk factors for ONJ; monitor for sings/symptoms of hypersensitivity
Osteoporosis: Bone mineral density (BMD) should be re-evaluated every 2 years (or more frequently) after initiating therapy (NOF 2014); annual measurements of height and weight, assessment of chronic back pain; serum calcium and 25(OH)D; may consider monitoring biochemical markers of bone turnover
Use of Prolia is contraindicated in pregnant women. Based on data from animal reproduction studies and the mechanism of action, denosumab may cause fetal harm if administered to a pregnant woman. In females of reproductive potential, pregnancy status should be verified prior to treatment initiation. Denosumab is a human IgG monoclonal antibody; fetal exposure to monoclonal antibodies is expected to increase as pregnancy progresses. Women of reproductive potential should be advised to use effective contraception during denosumab treatment and for at least 5 months following the last dose. Studies of denosumab when used for osteoporosis/bone loss in 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; however, exposure from seminal fluid of men receiving denosumab for other indications and higher doses is unknown and; therefore, their pregnant partners should be counseled regarding this potential risk.
Women exposed to denosumab during pregnancy should contact the Amgen Pregnancy Surveillance Program (800-772-6436).
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience headache, constipation, lack of appetite, nausea, vomiting, diarrhea, back pain, common cold symptoms, pharyngitis, rhinitis, or painful extremities. Have patient report immediately to prescriber signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of infection, signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), mouth sores, groin, hip, or thigh pain; swelling of arms or legs, jaw pain or edema, severe loss of strength and energy, severe muscle pain, severe joint pain, severe bone pain, shortness of breath, severe dizziness, passing out, bruising, bleeding, signs of high calcium (weakness, confusion, fatigue, headache, nausea and vomiting, constipation, or bone pain), severe skin irritation, bladder pain, painful urination, change in amount of urine passed, or polyuria (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
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- Drug class: miscellaneous bone resorption inhibitors