Denosumab is a subcutaneous fully human, highly specific, monoclonal antibody against receptor activator of nuclear factor kappa-beta ligand (RANKL). The protein is produced in genetically engineered mammalian (Chinese hamster ovary) cells. Denosumab blocks osteoclast activation, thereby resulting in decreased bone resorption (less bone breakdown) and modification of the release of calcium from the bone. The drug lowers serum calcium via this mechanism. Denosumab decreases bone resorption in patients at high risk for osteoclast-mediated bone loss, including certain patients with bone metastases due to malignancy, and postmenopausal women with osteopenia. In a phase 3 clinical trial conducted in women with postmenopausal osteoporosis, patients receiving denosumab had increases in bone mineral density of 9.2% in the lumbar spine and 6% in the total hip, and decreased relative risk of fracture of 68% for new vertebral fractures (RR = 0.32, 95% CI, 0.26 to 0.41, p less than 0.001), 20% for non-vertebral fractures (RR = 0.8, 95% CI, 0.67 to 0.95, p = 0.01), and 40% for hip fractures (RR = 0.6, 95% CI, 0.37 to 0.97, p = 0.04). Due to the potential for serious adverse events associated with denosumab, the approved use in osteoporosis is limited to postmenopausal women with a history of fractures, a high risk of fractures, or intolerance to or failure of other osteoporosis therapy. Denosumab delays the time to a first skeletal event (e.g., surgery, fracture, spinal cord compression, or radiation to the bone) in oncology patients with multiple myeloma or in patients with bone metastases due to solid tumors. Indication-specific denosumab products are available, and it is essential that clinicians choose the right product for use. Prolia and Jubbonti are used for osteoporosis treatment and prophylaxis in selected patients. Xgeva is used for prevention of skeletal-related events in patients with multiple myeloma or with bone metastases due to solid tumors, for the treatment of refractory hypercalcemia of malignancy, and for adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. Denosumab therapy is contraindicated in patients with pre-existing hypocalcemia. Based on study results, denosumab therapy is associated with an increased risk of hypocalcemia in patients with advanced chronic kidney disease, especially those on dialysis, and a substantial risk of hypocalcemia with serious outcomes. Denosumab osteoporosis formulations (Prolia and Jubbonti) have a boxed warning for the risk of severe hypocalcemia in patients with advanced chronic kidney disease. Consider the benefit-risk profile when administering denosumab to patients with severe renal impairment or with renal failure receiving dialysis. Frequent clinical monitoring of calcium concentrations is highly recommended in these patients. Advise patients on dialysis to seek immediate medical care if they experience symptoms of hypocalcemia.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Denosumab is available as more than one indication-specific brand name product (e.g., Prolia, Jubbonti, Xgeva). Avoid duplications. Prior to administration, ensure that the right product has been selected for the individual patient.
-Denosumab should only be administered via the subcutaneous route. Do not administer intravenously, intramuscularly, or intradermally.
-Visually inspect the solution for particulate matter or discoloration before administration; Prolia and Jubbonti solutions are clear and colorless to light yellow. A small amount of tiny, white or opalescent particles may be present and is acceptable. Jubbonti is a clear to slightly opalescent solution that is colorless to slightly yellow or brown. Do not use if discolored, cloudy, or if foreign particulate matter is present.
-For patients receiving Prolia or Jubbonti regimens, ensure adequate intake of calcium and vitamin D to reduce the risk of treatment-related hypocalcemia.
Subcutaneous Administration
-Denosumab should be administered by a health care professional.
-Prior to administration, denosumab may be removed from the refrigerator and brought to room temperature; this generally takes 15 to 30 minutes. Do NOT warm this medication in any other manner. Once removed from the refrigerator, the Prolia and Xgeva must not be exposed to temperatures above 25 degrees C (77 degrees F) or direct light and must be used within 14 days. Jubbonti must not be exposed to temperatures above 25 degrees C (77 degrees F) or direct light and must be used within 30 days following removal from refrigeration.
-Do not vigorously shake denosumab.
Administration using prefilled syringe with needle safety guard:
-Leave green needle safety guard (Prolia) and safety guard wings (Jubbonti) in original position until after dosage administration; sliding the guard or touching the safety guard wings prior to administration will prevent injection.
-Remove and discard needle cap immediately prior to dose administration.
-Administer full contents of denosumab prefilled syringe subcutaneously in the upper arm, the upper thigh, or the abdomen.
-Immediately following injection, point needle away from people and gently slide green safety guard over needle (Prolia) or release the plunger until the needle is covered by the safety guard (Jubbonti).
-Discard all used supplies as appropriate.
Administration using single-use vials:
-Use a 27-gauge needle to withdraw and inject the denosumab dose.
-Administer subcutaneously in the upper arm, upper thigh, or abdomen.
-Do NOT re-insert needle into vial. Discard any unused medication and all used supplies as appropriate.
Infection, some serious, was reported with a higher incidence in denosumab-treated patients as compared to placebo in clinical trials of osteoporotic patients , while similar incidences of infection and serious infection were noted among both denosumab-treated and zoledronic acid-treated patient groups in a published phase 3 trial involving oncology patients. In a clinical study of postmenopausal women with osteoporosis, the incidence of serious infections resulting in death was the same in both placebo and denosumab treatment groups (0.2%). However, the incidence of nonfatal serious infections was higher in the denosumab group (4%) than with placebo (3.3%). Further, hospitalizations due to serious infections were higher in those receiving denosumab vs. placebo; infection sites with respective incidences include abdomen (0.9%), urinary tract (0.7%), ear (0.1%), and skin, including erysipelas and cellulitis (0.4%). Endocarditis was reported in 3 patients receiving denosumab. The total incidence of infection in denosumab treated patients with osteoporosis (regardless of severity) included cystitis (5.9%), upper respiratory tract infection (4.9%), pharyngitis (2.3%), and herpes zoster (2%). Use of denosumab is not recommended for osteoporosis patients with an active infection including chronic, localized, or systemic infections such as sepsis or influenza. In a clinical trial involving oncology patients, 46.4% of denosumab-treated patients as compared to 48.8% of zoledronic acid-treated patients experienced an infectious adverse event, while 7% vs. 8.2% experienced a serious infectious event respectively; sites or types of infection were not stated. In an open-label, single-arm trial of patients with hypercalcemia of malignancy (n = 33), 6% of patients experienced grade 3 or greater infection. The adverse reaction profile of denosumab in patients with giant cell tumor of bone (GCTB) and hypercalcemia of malignancy was otherwise similar to that reported in randomized clinical trials in patients with bone metastases from solid tumors. Naso-pharyngitis was reported in 10% or greater (per-patient incidence) of adult and skeletally mature adolescents patients (age range, 13 to 83 years) with GCTB who received denosumab in 2 single-arm trials (n = 548); pneumonia was reported in 0.9% of treated patients. Monitor for infection as necessary and advise patients to seek medical attention if they develop signs of symptoms of infection. Consider the risk to benefit profile of continued denosumab therapy in patients with recurrent or serious infection development.
Osteonecrosis of the jaw (ONJ) has been reported with denosumab therapy. Perform a dental examination with appropriate preventive dentistry prior to treatment with in patients with risk factors for ONJ such as invasive dental procedures (e.g. tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant therapies (e.g. chemotherapy, corticosteroids angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g. periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). In patients who require invasive dental procedures, the physician and/or oral surgeon should use clinical judgment to guide the management plan of each patient based on an individual benefit-risk assessment. Symptoms of ONJ include jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, dental pain (toothache), gingival ulceration (oral ulceration), or gingival erosion. In a pooled analysis of 3 randomized clinical trials, ONJ occurred in 1.8% of patients with bone metastases from solid tumors who received treatment with denosumab (median drug exposure, 12 months; range, 0.1 to 40.5 months). Of patients who developed ONJ, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance. Two trials included an open-label extension phase in which patients were offered denosumab 120 mg every 4 weeks (median overall exposure 14.9 months; range 0.1 to 67.2 months). The patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year, 3.7% in the second, and 4.6% per year thereafter. The median time to ONJ was 20.6 months (range 4 to 53 months). In a placebo-controlled trial with an extension phase evaluating Xgeva for the prevention of bone metastases in patients with non-metastatic prostate cancer (off-label use), with treatment exposure of up to 7 years, the patient-year adjusted incidence of ONJ was 1.1% during the first year of treatment, 3% in the second, and 7.1% per year thereafter. The adverse reaction profile of denosumab in patients with giant cell tumor of bone (GCTB) was similar to that reported in randomized clinical trials in patients with bone metastases; ONJ occurred in 3.6% of adult and skeletally mature adolescent patients (age range, 13 to 83 years) with GCTB who received Xgeva (n = 548) in 2 single-arm trials. In this analysis, confirmed ONJ was reported in 6.6% of patients. Toothache occurred in 10% or more of patients treated with Xgeva. Advise patients to maintain good oral hygiene, to inform all dental health care providers of denosumab therapy prior to dental work/procedures, and to report persistent pain and/or slow healing of the mouth or jaw following dental work/procedures. If ONJ develops or is suspected, patients should be evaluated by a dentist or oral surgeon; extensive dental surgery may exacerbate ONJ.
Patients should be monitored for possible new primary malignancy as the full effects of denosumab-induced RANKL inhibition within the immune system are not known and neoplastic disease has been reported during clinical trials. In clinical trials of osteoporotic patients, denosumab was associated with a higher incidence of new-onset neoplastic disease as compared to placebo (4.8% vs. 4.3%, respectively). Reports among patients on denosumab and those on placebo include malignancy of the breast (0.9% vs. 0.7%), reproductive system (0.5% vs. 0.2%), and gastrointestinal systems (0.9% vs. 0.6%). Incidence rates of new onset primary malignancy were identical (0.5%) between the denosumab treatment group (n = 1,020) and the zoledronic acid treatment group (n = 1,013) in a published phase 3 trial involving patients with breast cancer. Causality to denosumab exposure has not been established.
In clinical trials of osteoporotic patients, use of denosumab was associated with a higher incidence and severity of pancreatitis as compared to patients receiving placebo (incidence: 0.2% vs 0.1%, respectively); further, all 8 of the cases in the denosumab treatment group were considered serious events including 1 death, while only 1 of the 4 cases in the placebo-treated group was considered serious and none were fatal. According to the manufacturer, the timing of pancreatitis onset was variable. Pancreatitis was not specifically reported in pre-marketing studies of oncology patients.
Electrolyte imbalances have been reported with denosumab therapy. Severe symptomatic hypocalcemia resulting in hospitalization, life-threatening events, and fatal cases has been reported in postmarketing surveillance of denosumab. Correct hypocalcemia prior to starting denosumab therapy. Results from a long-term safety study have suggested an increased risk of hypocalcemia with denosumab use in patients with advanced chronic kidney disease (CKD) and osteoporosis. In addition, an internal FDA study showed a substantial risk of severe and symptomatic hypocalcemia resulting in hospitalization and death in patients on dialysis who were treated with denosumab for osteoporosis, resulting in the addition of a boxed warning for the risk of hypocalcemia. Consider the benefit-risk profile when administering denosumab to patients with severe renal impairment or with renal failure receiving dialysis due to the potential for severe hypocalcemia. Frequent clinical monitoring of calcium concentrations is highly recommended in these patients. Advise patients on dialysis to seek immediate medical care if they experience symptoms of hypocalcemia. At the month 1 visit, hypocalcemia (serum calcium less than 8.4 mg/dL) was reported in 2.4% of patients who received Prolia in a randomized, double-blind study in men with prostate cancer receiving androgen deprivation therapy. Additionally, hypocalcemia (defined as serum calcium concentration less than 8.5 mg/dL) occurred in 1.7% of postmenopausal women with osteoporosis who received Prolia; calcium nadirs occurred at approximately day 10 in patients with normal renal function. In a study of postmenopausal women with osteoporosis, the mean percent change in serum calcium from baseline to day 10 after Prolia administration was -5.5% in women with a CrCl less than 30 mL/minute and -3.1% in women with a CrCl or 30 mL/minute or greater. Patients with CrCl less than 30 mL/minute were excluded from studies evaluating Xgeva. In a pooled analysis of 3 randomized clinical trials, treatment with Xgeva resulted in an 18% per-patient incidence of hypocalcemia and a 32% per-patient incidence of hypophosphatemia in patients with bone metastases from solid tumors. Severe hypocalcemia (defined as a corrected serum calcium concentration less than 7 mg/dL or less than 1.75 mmol/L) and severe hypophosphatemia (defined as a serum phosphorus concentration less than 2 mg/dL or less than 0.6 mmol/L) were reported in 3.1% and 15.4% of these patients, respectively. The adverse reaction profile of denosumab (Xgeva) in patients with giant cell tumor of bone (GCTB) and hypercalcemia of malignancy was similar to that reported in randomized clinical trials in patients with bone metastases from solid tumors. Moderate to severe hypocalcemia (defined as corrected serum calcium less than 8 mg/dL or less than 2 mmol/L) was reported in 5% of adult and skeletally mature adolescents patients (age range, 13 to 83 years) with GCTB who received denosumab (n = 548) in 2 single-arm trials; severe hypophosphatemia (defined as a serum phosphorus less than 2 to 1 mg/dL or less than 0.6 to 0.3 mmol/L) was reported in 20% of patients in this study. Hypophosphatemia of all severities was reported in 10% or more patients treated with Xgeva. In the pooled safety population, 0.7% of patients experienced serious adverse events of hypercalcemia more than 30 days following treatment discontinuation that was recurrent in some patients. In a separate trial (n = 33), grade 3 or higher electrolyte abnormalities reported by patients with hypercalcemia of malignancy included hypomagnesemia (3%), hypokalemia (3%), and hypophosphatemia (76%). Marked elevation in serum parathyroid hormone in patients with renal impairment (CrCl less than 30 mL/minute) or patients receiving dialysis has been reported with postmarketing use of denosumab (Prolia). In some postmarketing reports, hypocalcemia persisted for weeks to months, required frequent monitoring, and intravenous and/or calcium replacement, with or without vitamin D. Monitor calcium and mineral concentrations (phosphorus and magnesium) 10 to 14 days after Prolia or Jubbonti injection in patients predisposed to hypocalcemia or disturbances of mineral metabolism (e.g., hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, or treatment with other calcium-lowering medications). Patients with advanced CKD [i.e., eGFR less than 30 mL/min/1.73m2], including dialysis-dependent patients, are at a greater risk for severe hypocalcemia following Prolia or Jubbonti administration. Severe hypocalcemia resulting in hospitalization, life-threatening events, and fatal cases have been reported. The presence of underlying CKD-mineral bone disorder (CKD-MBD, renal osteodystrophy) markedly increases the risk of hypocalcemia. Concomitant use of calcimimetic medications may also worsen hypocalcemia risk. To minimize the risk of hypocalcemia in these patients, evaluate for the presence of chronic kidney disease mineral and bone disorder with intact parathyroid hormone (iPTH), serum calcium, 25(OH) vitamin D, and 1,25(OH)2 vitamin D prior to deciding on Prolia or Jubbonti treatment. Also consider assessing bone turnover status (serum markers of bone turnover or bone biopsy) to evaluate the underlying bone disease that may be present. Monitor serum calcium weekly for the first month after Prolia or Jubbonti administration and monthly thereafter. For all patients receiving denosumab, monitor calcium, and other electrolytes (e.g., phosphorus, magnesium); advise patients to report signs and symptoms of hypocalcemia (e.g., muscle cramps/spasms, twitching, tetany, paresthesias or numbness of fingertips, toes, or perioral area). Adequately supplement patients with calcium and vitamin D and magnesium. Assess serum calcium periodically, reevaluate the patient's supplementation requirements and manage patients clinically as appropriate. Clinically significant hypercalcemia requiring hospitalization and complicated with acute renal injury has been reported in denosumab-treated patients with GCTB with growing skeletons and pediatric patients with osteogenesis imperfecta. Denosumab is only recommended for treatment of skeletally mature adolescents with GCTB. Hypercalcemia was reported in the first year after discontinuation of treatment. After treatment is discontinued, monitor patients for signs and symptoms of hypercalcemia (e.g., nausea, vomiting, headache, and decreased alertness); assess serum calcium periodically, reevaluate the patient's calcium and vitamin D supplementation requirements and manage patients clinically as appropriate.
Allergic and dermatologic reactions have been reported with denosumab use. In clinical trials involving postmenopausal women with osteoporosis, denosumab use was associated with a statistically significant higher incidence of dermal adverse events (10.8%) as compared to placebo. Rash (unspecified) (2.5%), pruritus (2.2%), atopic dermatitis, and eczema were reported among patients receiving denosumab. Cutaneous reactions were not limited to the administration site. Hypersensitivity, including anaphylaxis, may occur. Allergic reactions included anaphylactoid reactions, facial angioedema, erythema, rash, facial and upper airway edema (laryngeal edema), dyspnea or wheezing, throat tightness, hypotension, pruritus, and urticaria have been reported postmarketing. Advise patients to seek medical attention if they develop such reactions. If a patient develops a clinically significant allergic reaction, discontinue use of the drug and administer appropriate therapy to treat the reaction. Cutaneous and mucosal lichenoid drug eruptions (lichen planus-like eruption), alopecia, vasculitis (ANCA positive vasculitis and leukocytoclastic vasculitis), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been observed during postmarketing experience. DRESS typically presents as fever, rash, and/or lymphadenopathy in conjunction with other organ system involvement including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Early manifestations such as fever and lymphadenopathy may be present without evidence of a rash. Discontinue denosumab in patients presenting with such signs and symptoms in whom an alternative etiology cannot be identified.
Acute phase reactions, including a flu-like syndrome of fever, chills, flushing, bone pain, arthralgia, and myalgia occurring within the first 3 days after dose administration, as well as other musculoskeletal and nervous system pain have been reported with denosumab therapy. Oncology patients who received denosumab had a lower incidence of acute phase reactions (10.4%) than did those who received zoledronic acid (27.3%). In clinical trials, the following additional adverse events were reported in osteoporosis patients receiving denosumab at rates higher than with placebo: back pain (34.7%), extremity pain (11.7%), musculoskeletal pain (7.6%), bone pain (3.7%), myalgia (2.9%), spinal osteoarthritis (2.1%), headache, and sciatica, a neuropathic pain (4.6%). These reactions occurred at a lower rate in breast cancer patients administered denosumab vs. those receiving zoledronic acid in clinical studies. Severe and occasionally incapacitating musculoskeletal pain, including bone, joint, and/or muscle pain, has been reported with postmarketing use of denosumab for the treatment of osteoporosis (Prolia); the time to onset of these symptoms varied from 1 day to several months. Consider discontinuing denosumab if severe musculoskeletal pain develops. In a pooled analysis of 3 randomized clinical trials, headache occurred in 13% of patients with bone metastases from solid tumors who received treatment with denosumab (Xgeva); headache was reported in 24% of patients with hypercalcemia of malignancy treated with denosumab (Xgeva) in a separate open-label, single-arm trial. The adverse reaction profile of Xgeva in patients with giant cell tumor of bone (GCTB) and hypercalcemia of malignancy was otherwise similar to that reported in randomized clinical trials in patients with bone metastases from solid tumors. Arthralgia, back pain, musculoskeletal pain, and extremity pain were each reported in 10% or greater (per-patient incidence) of adult and skeletally mature adolescents patients (age range, 13 to 83 years) with GCTB who received Xgeva in 2 single-arm trials (n = 548). Serious back pain was reported in 0.9% of patients who received denosumab and headache was reported in 10% or greater (per-patient incidence) of patients evaluated in this analysis.
Abdominal pain (3.3%, flatulence (2.2%), and gastroesophageal reflux disease (2.1%) were reported more often with denosumab (Prolia) compared with placebo in postmenopausal women with osteoporosis in a randomized, double-blind study. Additionally, constipation was one of the most common adverse reactions that led to denosumab therapy discontinuation in osteoporotic women. In a pooled analysis of 3 randomized clinical trials, nausea (31%) and diarrhea (20%) were reported in patients with bone metastases from solid tumors who received treatment with denosumab (Xgeva). The adverse reaction profile of denosumab in patients with giant cell tumor of bone (GCTB) and hypercalcemia of malignancy was similar to that reported in randomized clinical trials in patients with bone metastases from solid tumors. Nausea, vomiting, constipation, and diarrhea were reported in 10% or greater (per-patient incidence) of adult and skeletally mature adolescent patients (age range, 13 to 83 years) with GCTB who received denosumab in 2 single-arm trials. In an open-label, single-arm trial of patients with hypercalcemia of malignancy, additional gastrointestinal adverse events included anorexia (24%), vomiting (24%), constipation (21%), and diarrhea (21%).
In pre-marketing clinical trials involving postmenopausal women with osteoporosis, angina pectoris was reported in 2.6% of patients receiving denosumab and at rates higher than with placebo. Of note, in this same study, serious cardiovascular effects occurred at a similar incidence in patients receiving denosumab compared to patients receiving placebo including cardiovascular event (4.8% vs. 4.6%, respectively), stroke (1.4%, both), coronary heart disease (0.8%, both), and serious atrial fibrillation episodes (0.7%, both). Cardiovascular events were not specifically reported in pre-marketing studies of oncology patients.
Denosumab use was associated with a higher incidence of hypercholesterolemia as compared to placebo use in clinical trials of osteoporotic postmenopausal women; 7.2% with denosumab developed this condition within the 3-year trial duration. These adverse effects were not specifically reported in the clinical trials involving denosumab treatment of oncology patients.
In clinical trials involving postmenopausal women treated for osteoporosis, vertigo was reported in 5% of patients receiving denosumab and at rates similar to with placebo; this adverse effect was not specifically reported in denosumab clinical trials of oncology patients.
In pre-marketing clinical trials, anemia was reported in 3.3% of postmenopausal osteoporosis patients receiving denosumab and at higher rates vs. placebo. In a separate study, 18.8% of breast cancer patients treated with denosumab (Xgeva) and 22.9% of zoledronic acid-treated patients developed anemia; a causal relationship has not been established. Serious (grade 3 or greater) hematologic adverse events reported among breast cancer study patients included anemia, which was reported in 6.8% of the denosumab treatment group and at rates similar to zoledronic acid, and neutropenia, which was reported in 8.5% of the denosumab treatment group and 9.2% of the zoledronic acid treatment group. Anemia was also reported in 21% of patients treated with denosumab in an open-label, single-arm trial of patients with hypercalcemia of malignancy. The adverse reaction profile of denosumab in patients with giant cell tumor of bone (GCTB) was similar to that reported in randomized clinical trials in patients with bone metastases. The incidence of anemia in adult and skeletally mature adolescent patients (age range, 13 to 83 years) with GCTB who received denosumab (n = 548) was 1.1% in 2 single-arm trials.
Dyspnea was reported in 21% of oncology patients treated with denosumab and 18% of those treated with zoledronic acid in pre-marketing study of oncology patients. In addition, dyspnea was the most common serious adverse reaction in study patients receiving denosumab. Cough was reported in at an equal incidence (15%) in both denosumab and zoledronic acid treatment groups. In an open-label, single-arm trial of patients with hypercalcemia of malignancy, dyspnea was also reported in 27% of patients who received denosumab. Cough was reported in 10% or greater of adult and skeletally mature adolescents patients (age range, 13 to 83 years) with patients with giant cell tumor of bone (GCTB) who received Xgeva in 2 single-arm trials (n =548). These adverse reactions were not specifically reported in pre-marketing clinical trials of osteoporosis patients.
Asthenia was reported in 2.3% of postmenopausal women with osteoporosis who received denosumab (Prolia) and was reported more often than with placebo in clinical trials. In a pooled analysis of 3 randomized clinical trials, fatigue/asthenia occurred in 45% of patients with bone metastases from solid tumors who received treatment with denosumab (Xgeva). The adverse reaction profile of denosumab in patients with giant cell tumor of bone (GCTB) and hypercalcemia of malignancy was similar to that reported in patients with bone metastases from solid tumors. Fatigue was reported in 10% or greater (per-patient incidence) of adult and skeletally mature adolescent patients with GCTB who received densumab in 2 single-arm trials. Severe (grade 3 or greater) fatigue was reported in 3% of patients with hypercalcemia of malignancy who received denosumab and 24% of treated patients experienced peripheral edema.
Bone fractures developing along the femoral shaft (below the lesser trochanter to above the supracondylar flare) have been reported by denosumab recipients, some of whom were receiving concurrent glucocorticoid therapy. These fractures were transverse or short oblique, not comminuted, some were bilateral, and occurred with minimal to no trauma. A definitive causal relationship with denosumab has not been established as fractures of this type are also present in untreated osteoporotic patients. Many patients experience a dull, aching thigh pain weeks to months before the complete fracture occurs, thus, health care providers are advised to rule out an incomplete femur fracture in any patient presenting with thigh or groin pain. Consider treatment interruptions based on the risk-to-benefit assessment of the individual patient. The risk of bone fractures, including multiple vertebral fracture, increases following denosumab (Prolia or Jubbonti) discontinuation in patients treated for osteoporosis. During clinical trials of women with postmenopausal osteoporosis, 6% of women who discontinued denosumab developed new vertebral fractures and 3% developed multiple new vertebral fractures. New vertebral fractures occurred as early as 7 months (average 19 months) after the last denosumab dose. Prior vertebral fractures was a predictor of multiple vertebral fractures after denosumab discontinuation. If denosumab treatment is discontinued, consider transitioning to alternative antiresorptive therapy. The incidence of atypical femoral fracture in patients with giant cell tumor of bone (GCTB) treated with denosumab (Xgeva) during clinical trials was 0.9% (n = 548).
As with all therapeutic proteins, there is the potential for immunogenicity and antibody formation to denosumab. Binding antibodies against denosumab occurred in less than 1% of patients (7 of 2,758) with osseous metastases treated with denosumab doses ranging from 30 to 180 mg subcutaneously every 4 weeks or every 12 weeks for up to 3 years. Three of the 506 patients (0.6%) with giant cell tumor of bone in tested positive for transient binding antibodies following treatment with denosumab. In multiple myeloma patients, 1 out of 199 patients (0.5%) with a post-baseline result, tested positive for binding antibodies against denosumab. No patient with positive binding antibodies tested positive for neutralizing antibodies. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response to denosumab associated with binding antibody development.
Denosumab is available in 3 different marketed products, Prolia, Jubbonti, and Xgeva, which are indicated for different therapeutic uses and are available in different strengths. Patients receiving 1 formulation should not receive other denosumab products concurrently.
Denosumab is contraindicated for use in patients with a history of hypersensitivity to any component of the product. Hypersensitivity reactions have occurred including anaphylaxis, facial swelling/angioedema, hypotension, pruritus, and urticaria. If a patient develops a clinically significant allergic reaction, discontinue denosumab and administer appropriate therapy to treat the reaction.
Denosumab has been associated with cases of severe, sometimes fatal, hypocalcemia; use is contraindicated with pre-existing hypocalcemia. Correct pre-existing hypocalcemia before initiation of therapy. Patients with advanced chronic renal disease (e.g., chronic renal failure), particularly those on dialysis, may be at an increased risk for developing severe hypocalcemia with serious outcomes, including hospitalization and death; consider the risk:benefit profile of denosumab treatment in these patients. An FDA review determined that the use of denosumab for the treatment of osteoporosis (Prolia or Jubbonti) increased the risk of severe hypocalcemia in patients with advanced chronic kidney disease (CKD), particularly those on dialysis. As a result, a boxed warning was placed in the Prolia and Jubbonti labeling to help reduce the risks of severe hypocalcemia and assist providers in appropriate patient selection and to ensure adequate monitoring. In patients without advanced CKD who are predisposed to hypocalcemia or disturbances of mineral metabolism (e.g., hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, or treatment with other calcium-lowering medications), monitor serum calcium and mineral concentrations (phosphorus and magnesium) 10 to 14 days after Prolia or Jubbonti injection. Patients with advanced CKD [i.e., renal impairment with an eGFR less than 30 mL/min/1.73m2], including dialysis-dependent patients, are at a greater risk for severe hypocalcemia following administration. Severe hypocalcemia resulting in hospitalization, life-threatening events, and fatal cases have been reported. The presence of underlying CKD-mineral bone disorder (CKD-MBD, renal osteodystrophy) markedly increases the risk of hypocalcemia. Concomitant use of calcimimetic medications may also worsen hypocalcemia risk. To minimize the risk of hypocalcemia in these patients, evaluate for the presence of CKD-MBD with intact parathyroid hormone (iPTH), serum calcium, 25(OH) vitamin D, and 1,25(OH)2 vitamin D before choosing treatment with Prolia or Jubbonti. Also consider assessing bone turnover status (serum markers of bone turnover or bone biopsy) to evaluate for underlying bone disease. Monitor serum calcium weekly for the first month after Prolia or Jubbonti administration and monthly thereafter. All patients with advanced CKD (including those who are dialysis-dependent) should be educated about the symptoms of hypocalcemia and the importance of maintaining serum calcium levels with adequate calcium and activated vitamin D supplementation. The use of Prolia or Jubbonti in these patients should be supervised by a health care provider who is experienced in diagnosis and management of CKD-MBD. For patients receiving the Xgeva formulation, calcium concentrations should be monitored throughout therapy, especially in the first weeks of initiating therapy; vitamin D, calcium, and magnesium should be supplemented as necessary. More frequent monitoring is highly recommended in patients with advanced renal disease receiving dialysis and may also be necessary when administering denosumab with other drugs that can lower calcium concentrations. Patients with vitamin D deficiency may require a higher dose of vitamin D supplementation during denosumab treatment. In all patients, ensure adequate intake of calcium and vitamin D. To promote general bone health, guidelines for the prevention and treatment of osteoporosis recommend a target daily intake of 1,200 mg of elemental calcium for females older than 50 years and males older than 70 years. Target daily elemental calcium intake for males 70 years of age or younger is 1,000 mg. Daily vitamin D intake of 20 to 25 mcg (800 to 1,000 international units) is recommended for those 50 years of age and older. Instruct patients to seek prompt medical care if signs or symptoms of hypocalcemia develop.
Do not start denosumab in a patient who has an active infection including chronic, localized, or systemic infections such as sepsis or influenza. Because denosumab is a RANKL inhibitor and RANKL is expressed on activated B-lymphocytes, on activated T-lymphocytes, and in lymph nodes, there is a possibility that use of denosumab may impair immune function and increase the risk of infection. Serious infections resulting in hospitalization and/or death have been reported in clinical study of patients receiving denosumab. Among osteoporotic study patients, the incidence of fatalities resulting from serious infection was the same in both placebo and denosumab study treatment groups (0.2%), while the incidence of nonfatal serious infection was higher in the denosumab treatment group as compared to the placebo treatment group ; rates of reported infection and serious infection were similar in both denosumab and zoledronic acid treatment groups in a published phase 3 trial involving oncology patients (see Adverse Reactions). Consider the risks and benefits of continued denosumab treatment if a serious infection develops during therapy. Patients who have surgery while taking denosumab may be at greater risk for postoperative infections. Monitor all patients for infections during denosumab receipt. As with other monoclonal antibody therapies, carefully consider the benefits and risks of drug therapy in patients with a history of recurrent infections or with underlying conditions that may predispose them to infections (e.g., patients with advanced or uncontrolled diabetes mellitus or immunosuppression), and in those who have lived in tuberculosis or histoplasmosis endemic areas.
In clinical trials of osteoporotic patients, denosumab use was associated with a statistically significant higher incidence of dermal and epidermal adverse events as compared to placebo use (10.8% vs 8.2%, respectively, p < 0.0001) ; no such adverse events were reported in the published phase 3 trial involving oncology patients. It may be prudent to use with caution in patients with pre-existing dermal conditions, including dermatitis, eczema, and/or recurrent rashes, as these disease may be exacerbated by denosumab therapy.
Osteonecrosis of the jaw (ONJ) has been reported in patients receiving denosumab in clinical trials of both osteoporotic and oncology patients. ONJ is typically associated with dental procedures, such as tooth extraction, and local infection with delayed healing; however, cases have appeared spontaneously. If patients require invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan for each patient. A dental examination with appropriate preventive dentistry and correction of dental complications prior to initiating denosumab therapy is recommended for patients with risk factors for ONJ such as invasive dental procedures and dental work (e.g., tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant corticosteroid therapy, concomitant chemotherapy such as treatment with angiogenesis inhibitors, poor oral hygiene, and comorbid conditions such as periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, and ill-fitting dentures. Good oral hygiene practices should be maintained during treatment. Care by a dentist or oral surgeon is recommended if ONJ is suspected or occurs; it should be noted that dental surgery may exacerbate the condition. Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ, and the risk of ONJ may increase with increased duration of treatment with denosumab. Discontinuation of therapy should be considered based on an individual risk-benefit basis assessment.
Patients with a history of pancreatitis may be at an increased risk of recurrence during therapy. In clinical trials involving patients with osteoporosis, use of denosumab was associated with a higher incidence of pancreatitis as compared to patients receiving placebo (0.2% vs 0.1%, respectively); further, all eight of the cases in the denosumab treatment group were considered serious events including 1 death, while only 1 of the 4 cases in the placebo treated group was considered serious and none fatal. According to the manufacturer of denosumab, several patients who experienced pancreatitis during clinical trials had a prior history of the disorder. No cases of pancreatitis were reported in the published phase 3 clinical trial involving oncology patients.
The risk of bone fractures, including the risk of multiple vertebral fractures, increases upon discontinuation of denosumab. Patients at higher risk for multiple vertebral fractures include those with risk factors or a history of osteoporosis or prior fractures. If denosumab is discontinued in these patients, consider transitioning to an alternative antiresportive therapy. Discontinuation of denosumab therapy may result in a greater short-term increase in bone loss. After discontinuation of therapy in clinical trials of osteoporotic patients, markers of bone resorption increased to levels 40% to 60% above pretreatment values, returning to baseline levels within 12 months. Measurements of bone mineral density decreased to baseline values within 12 months of therapy discontinuation. Bone fractures developing along the femoral shaft (below the lesser trochanter to above the supracondylar flare) have also been reported by denosumab recipients, some of whom were receiving concurrent glucocorticoid therapy. These fractures were transverse or short oblique, not comminuted, some were bilateral, and occurred with minimal to no trauma. A definitive causal relationship with denosumab has not been established as fractures of this type are also present in untreated osteoporotic patients. Many patients experience a dull, aching thigh pain weeks to months before the complete fracture occurs, thus, health care providers are advised to rule out an incomplete femur fracture in any patient presenting with thigh or groin pain. Consider treatment interruptions based on the risk-to-benefit assessment of the individual patient.
In clinical trials of osteoporotic patients, denosumab use was associated with a higher incidence of new onset neoplastic disease (new primary malignancy) as compared to placebo use (4.8% vs 4.3%, respectively) ; however, in a clinical trial involving oncology patients with pre-existing disease, the incidence of new onset primary malignancy was 0.5% in both denosumab treated patients and zoledronic acid treated patients. A causal relationship has not been established. Reports include higher incidence of malignancy of the breast, reproductive system, and gastrointestinal system among osteoporotic patients receiving denosumab. Denosumab is a monoclonal antibody that blocks the effects of endogenous RANKL (receptor activator of nuclear factor kappa-beta ligand). It is unknown if this activity may affect host defenses against neoplastic disease. Consider the risks and benefits of denosumab before treatment initiation in patients with a history of or current malignancy and before continuation in patients who develop a malignancy.
Denosumab is available as 3 products, Prolia, Jubbonti, and Xgeva. Prolia or Jubbonti use is contraindicated during pregnancy. Xgeva use should be avoided during pregnancy. Denosumab can cause fetal harm when given during pregnancy based on findings in animals. The risk for adverse fetal effects may be greater during second and third trimesters. Monoclonal antibodies cross the placenta linearly, with the greatest amount transferred during the third trimester. If pregnancy occurs during therapy, discontinue treatment; inform the patient of the potential risk to the fetus. Animal studies conducted in cynomolgus monkeys and mice genetically engineered to lack RANKL demonstrated fetal harm. In cynomolgus monkeys dosed throughout gestation at a dose 25-fold higher than the recommended human dose, stillbirths, fetal loss, and postnatal mortality occurred. Other effects included the absence of peripheral (axillary, inguinal, mandibular, and mesenteric) lymph nodes, reduced bone strength, abnormal bone growth, decreased neonatal growth, decreased hematopoiesis, tooth malalignment, and dental dysplasia. Measurable blood concentrations of denosumab, at 22 to 621% of maternal levels, were detected at birth through 1 month of age. The effects of denosumab on bone quality and strength returned to normal during observation through 6 months of age. Tooth eruption was normal; however, dental dysplasia was still present. Small mandibular and mesenteric lymph nodes were present with axillary and inguinal nodes still missing. Mineralization in multiple tissues also occurred in 1 recovery animal. No maternal harm occurred prior to labor and adverse effects during labor were infrequent. In mice, fetal lymph node development was also lacking and postnatal impairment of bone and tooth development occurred.
All females treated with any denosumab formulation should avoid becoming pregnant while taking denosumab and should be informed of the potential reproductive risk should pregnancy occur. Pregnancy testing should occur to verify the pregnancy status prior to initiating denosumab treatment. Discuss contraception requirements with the patient. Females of reproductive potential who receive any denosumab formulation should be instructed to use highly effective contraception during therapy, for at least 5 months after the last dose, and to contact their health care provider if pregnancy occurs or if the patient suspects pregnancy within 5 months of taking the last dose. In a study of 12 healthy male volunteers, denosumab was present in seminal fluid at a concentration approximately 2% of serum exposure. After vaginal intercourse, the amount of drug delivered to a female partner would result in exposures approximately 11,000 times lower than that seen after the recommended dose. Male condom use is not necessary as it is unlikely the partner or fetus would be exposed to pharmacologically relevant concentrations of denosumab via seminal fluid.
Denosumab is not recommended for use during breast-feeding. Either the drug or breast-feeding should be discontinued because of the potential for serious adverse reactions in the breastfed child, taking into account the importance of the drug to the treated patient. It is not known if denosumab is excreted into human milk. Maternal antibodies are known to be present in human milk; however, data are limited regarding use of denosumab during lactation. The drug is a protein and would likely be digested in the gastrointestinal tract of the breastfed infant, but exposure and effects on the nursing infant are not known. Exposure of pediatric patients to denosumab is not recommended as it may impair bone growth and inhibit tooth eruption. Additionally, patients receiving treatment during pregnancy may have impaired lactation postpartum due to drug-induced interruption of mammary gland development; animal studies have demonstrated conflicting results regarding altered maturation of mammary glands. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition.
Denosumab is available as 3 products, Prolia, Jubbonti, and Xgeva. The safety and efficacy of the Prolia and Jubbonti products have not been established in adolescents, children, or infants. Xgeva should only be used in pediatric patients with selected conditions and with close clinical monitoring. Xgeva is recommended for use in the treatment of giant cell tumor of the bone (GCTB) only in skeletally mature adolescents; safety and efficacy in adolescents who are not skeletally mature, children, or infants have not been established. In an analysis that looked at the efficacy of Xgeva in 10 adolescent patients with GCTB, skeletal maturity was defined as having at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus) and a body weight of at least 45 kg. Clinically significant hypercalcemia requiring hospitalization and complicated with acute renal injury has been reported in denosumab-treated pediatric patients with GCTB with growing skeletons and in pediatric patients with osteogenesis imperfecta. Hypercalcemia has been reported within the first year after treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia and treat appropriately. After treatment is discontinued, monitor patients for signs and symptoms of hypercalcemia, assess serum calcium periodically, and reassess calcium and vitamin D supplementation requirements. Denosumab is a monoclonal antibody that inhibits RANKL and thus affects osteoclast activity and bone remodeling; use in pediatric patients may impair bone growth and inhibit tooth eruption. Denosumab administered to adolescent primates at doses of up to 50-times the human equivalent dose resulted in the development of abnormal growth plates consistent with denosumab-activity.
Ensure proper product selection
Denosumab is available in 3 different products, which are indicated for different therapeutic uses and are available in different strengths. Choose the proper dosage form for the indication for use and avoid therapeutic duplication.
For the treatment of osteoporosis in men and postmenopausal women at high risk for fracture, as well as for glucocorticoid-induced osteoporosis:
Subcutaneous dosage (Prolia or Jubbonti):
Adults: 60 mg subcutaneously once every 6 months. All patients should receive a minimum of 1,000 mg of calcium and at least 10 mcg (400 international units) of vitamin D daily. If a dose is missed, administer the dose as soon as possible and schedule future injections every 6 months from that date. Patients at a high risk for fracture are those with a history of osteoporotic fracture, those with multiple risk factors for fracture, those who have failed or are intolerant to other available osteoporosis therapy, or those initiating or continuing systemic glucocorticoids (i.e., 7.5 mg/day or more of prednisone or equivalent) and expected to remain on glucocorticoids for at least 6 months. Denosumab is an alternative first-line treatment for postmenopausal women at high risk of fracture or who are unable to tolerate oral bisphosphonates. There is no limit to duration of treatment with denosumab. Do not stop or delay treatment with denosumab past 7 months without follow-up treatment to prevent bone loss and vertebral fractures. Subsequent treatment with a bisphosphonate is recommended to prevent bone loss. Switching from denosumab to an anabolic agent (i.e., teriparatide or abaloparatide) may result in loss of hip bone mineral density and is not recommended.
For the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors:
Subcutaneous dosage (Xgeva):
Adults: 120 mg subcutaneously once every 4 weeks. To treat or prevent hypocalcemia, administer calcium and vitamin D as necessary. In a published clinical trial, study patients were encouraged to supplement with calcium greater than or equal to 500 mg and vitamin D greater than or equal to 400 units daily. In clinical trials, the definition of "skeletal-related events" was the occurrence of pathologic fracture, radiation therapy to the bone, surgery to the bone, or spinal cord compression.
For osteoporosis prophylaxis in men at high risk for bone fractures after receiving androgen deprivation therapy for nonmetastatic prostate cancer and in women at high risk for bone fractures after receiving adjuvant aromatase inhibitor therapy for breast cancer:
Subcutaneous dosage (Prolia or Jubbonti):
Adults: 60 mg subcutaneously once every 6 months. All patients should receive 1,000 mg of calcium and at least 10 mcg (400 international units) of vitamin D daily. If a dose is missed, administer the dose as soon as possible and schedule future injections every 6 months from that date. CLINICAL STUDIES: Approval was based on the results of 2 studies. The first was a clinical study of men with prostate cancer in which the differences in bone mineral density (BMD) between denosumab vs. placebo at the 3 year treatment period were 7.9% (6.8% denosumab, -1.2% placebo) at the lumbar spine, 5.7% (3.2% denosumab, -2.6% placebo) at the total hip, and 4.9% (3% denosumab, -1.8% placebo) at the femoral neck. In women with breast cancer, where the differences in BMD for denosumab vs. placebo at the 2 year treatment period were 7.6% (6.2% denosumab, -1.4% placebo) at the lumbar spine, 4.7% (3.8% denosumab, -1% placebo) at the total hip, and 3.6% (2.8% denosumab, -0.8% placebo) at the femoral neck.
For the treatment of giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity:
Subcutaneous dosage (Xgeva):
Adults and Adolescents (who have reached skeletal maturity): 120 mg subcutaneously once every 4 weeks; give 2 additional denosumab 120 mg doses on day 8 and 15 of the first month of therapy only. To treat or prevent hypocalcemia, give calcium and vitamin D as necessary. The objective response rate (ORR) was evaluated by an independent review committee (using a modified RECIST criteria) in 187 patients with giant cell tumor of the bone (GCTB) who received denosumab and had a baseline and at least 1 additional radiographic assessment in 2 open-label studies. In this analysis, the ORR was 25% (all partial responses) and the estimated median time to response was 3 months. At a median follow-up of 20 months (range, 2 to 44 months), 51% of responding patients (n = 24 of 47) had a response duration of 8 months. In an open-label study, a tumor response (defined as the elimination of at least 90% of giant cells or no radiological progression of the target lesion up to week 25) was achieved in 30 of 35 evaluable adult patients (86%) with recurrent or unresectable GCTB. All patients received supplementation with calcium 500 mg/day and vitamin D 400 international units/day. No concomitant treatment for GCTB was allowed during the study. In a second open-label study, denosumab treatment was evaluated in patients with GCTB who had surgically unsalvageable disease (e.g., sacral or spinal disease, pulmonary metastases) or surgically salvageable disease but planned surgery was likely to result in severe morbidity (e.g., joint resection, limb amputation, or hemipelvectomy). Ten patients in this study were skeletally mature adolescents (age range, 13 to 17 years) defined as having at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus) and a body weight of at least 45 kg. An ORR was achieved in 33% of skeletally mature adolescents.
For the treatment of hypercalcemia of malignancy that is refractory to bisphosphonate therapy:
Subcutaneous dosage (Xgeva):
Adults: 120 mg subcutaneously on days 1, 8, and 15 initially, then 120 mg subcutaneously every 4 weeks beginning on day 29. Patients with hypercalcemia of malignancy (with or without bone metastases) refractory to intravenous bisphosphonate therapy were treated with denosumab in an open-label, single-arm clinical trial (n = 33); refractory was defined as an albumin-corrected calcium of greater than 12.5 mg/dL within 7 to 30 days of receiving intravenous bisphosphonate therapy. Within 10 days of treatment with denosumab, 63.6% (95% CI, 45.1% to 79.6%) achieved a corrected serum calcium level less than or equal to 11.5 mg/dL and 36.4% (95% CI, 20.4% to 54.9%) achieved a corrected serum calcium level less than or equal to 10.8 mg/dL. By day 57, 69.7% (95% CI, 51.3% to 84.4%) and 63.7% (95% CI, 45.1% to 79.6%) had achieved responses, respectively.
Maximum Dosage Limits:
-Adults
Treatment and prevention of osteoporosis (Prolia or Jubbonti): 60 mg/dose subcutaneously.
Prevention of skeletal-related events in patients with bone metastases from solid tumors (Xgeva): 120 mg/dose subcutaneously.
Treatment of unresectable giant cell tumor of the bone (Xgeva): 120 mg/dose subcutaneously.
-Geriatric
Treatment and prevention of osteoporosis (Prolia or Jubbonti): 60 mg/dose subcutaneously.
Prevention of skeletal-related events in patients with bone metastases from solid tumors (Xgeva): 120 mg/dose subcutaneously.
Treatment of unresectable giant cell tumor of the bone (Xgeva): 120 mg/dose subcutaneously.
-Adolescents
Treatment and prevention of osteoporosis (Prolia or Jubbonti): safety and efficacy have not been established.
Prevention of skeletal-related events in patients with bone metastases from solid tumors (Xgeva): safety and efficacy have not been established.
Treatment of unresectable giant cell tumor of the bone (Xgeva): 120 mg/dose subcutaneously (in skeletally mature adolescents only).
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Patients with renal impairment may be at increased risk of severe hypocalcemia.
*non-FDA-approved indication
Albuterol; Budesonide: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Azelastine; Fluticasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Beclomethasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Betamethasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Budesonide: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Budesonide; Formoterol: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Calcitonin: (Moderate) Monitor serum calcium, phosphorus, and magnesium concentrations within 14 days of denosumab injection during concurrent treatment with calcimimetics such as calcitonin. The risk for hypocalcemia and other disturbances of mineral metabolism may increase during coadministration. Monitor serum calcium concentrations closely in patients with severe renal impairment (CrCl less than 30 mL/minute) or renal failure (and/or on dialysis) receiving calcimimetics. An increased risk of hypocalcemia was seen in clinical trials involving patients with renal dysfunction. Instruct patients to seek medical care if symptoms of hypocalcemia develop.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciclesonide: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Cinacalcet: (Moderate) Monitor serum calcium, phosphorus, and magnesium concentrations within 14 days of denosumab injection during concurrent treatment with calcimimetics such as cinacalcet. The risk for hypocalcemia and other disturbances of mineral metabolism may increase during coadministration. Monitor serum calcium concentrations closely in patients with severe renal impairment (CrCl less than 30 mL/minute) or renal failure (and/or on dialysis) receiving calcimimetics. An increased risk of hypocalcemia was seen in clinical trials involving patients with renal dysfunction. Instruct patients to seek medical care if symptoms of hypocalcemia develop.
Corticosteroids: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Cortisone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Deflazacort: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Dexamethasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Etelcalcetide: (Moderate) Monitor serum calcium, phosphorus, and magnesium concentrations within 14 days of denosumab injection during concurrent treatment with calcimimetics such as etelcalcetide. The risk for hypocalcemia and other disturbances of mineral metabolism may increase during coadministration. Monitor serum calcium concentrations closely in patients with severe renal impairment (CrCl less than 30 mL/minute) or renal failure (and/or on dialysis) receiving calcimimetics. An increased risk of hypocalcemia was seen in clinical trials involving patients with renal dysfunction. Instruct patients to seek medical care if symptoms of hypocalcemia develop.
Fludrocortisone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Flunisolide: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Fluticasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Fluticasone; Salmeterol: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Fluticasone; Vilanterol: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Formoterol; Mometasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Hydrocortisone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Lenalidomide: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection and/or osteonecrosis of the jaw, a rare condition that has been reported during denosumab therapy.
Methylprednisolone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Mometasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Olopatadine; Mometasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Pomalidomide: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection and/or osteonecrosis of the jaw, a rare condition that has been reported during denosumab therapy.
Prednisolone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Prednisone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Thalidomide: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection and/or osteonecrosis of the jaw, a rare condition that has been reported during denosumab therapy.
Triamcinolone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Denosumab neutralizes the biologic activity of receptor activator of nuclear factor kappa-B ligand (RANKL) by binding to it and blocking its interaction with cell surface receptors known as receptor activator of nuclear factor-kappa-beta (RANK). Endogenous RANKL, a transmembrane or soluble protein, is expressed on the surface of both precursor and mature osteoclasts and is essential for their formation, function, and survival. RANKL inhibition by denosumab (Prolia and Jubbonti) decreases RANKL activation of RANK receptors on the surface of osteoclasts resulting in a down regulation of osteoclast activity and thus a reduction of bone resorption; an increase in bone mass and strength in both cortical and trabecular bone is seen. By blocking RANKL from activating RANK, denosumab (Xgeva) inhibits the increased osteoclast activity that leads to bone pathology in solid tumor with osseous metastases. Additionally, denosumab prevents osteolysis and tumor growth in giant cell tumors of the bone containing stromal cells that express RANKL and osteoclast-like giant cells that express the RANK receptor.
Denosumab is given by subcutaneous injection. Then mean volume of distribution of denosumab is 5.2 L (SD = 1.7 L). After reaching Cmax, serum concentrations of denosumab decrease over a period of 4 to 5 months. The mean terminal half-life is approximately 25.4 days (+/- 8.5 days) after a single-dose administration of 60 mg and approximately 28 days with repeat dosing of 120 mg every 4 weeks.
Affected cytochrome P450 isoenzymes or drug transporters: None
-Route-Specific Pharmacokinetics
Subcutaneous Route
The bioavailability after subcutaneous administration was 62% in one pharmacokinetic trial. After a single 60-mg subcutaneous dose to fasted, healthy adults (n = 73, age range: 18 to 64 years), a maximum serum concentration of 6.75 (+/- 1.89) mcg/mL was achieved at a median time of 10 days (range: 3 to 21 days). The mean AUC(0 to 16 weeks) of denosumab was 316 mcg x day/mL (SD = 101 mcg x day/mL). Multiple subcutaneous doses of 60 mg given every 6 months did not result in denosumab accumulation or otherwise affect denosumab pharmacokinetics. Doses above 60 mg displayed approximately dose-proportional increases in drug exposure. Up to a 2.8-fold accumulation in serum denosumab has been noted with doses of 120 mg of denosumab administered subcutaneously every 4 weeks to adult cancer patients with bone metastases; steady-state was achieved by 6 months. Following the administration of denosumab 120 mg subcutaneously every 4 weeks with 2 additional 120 mg doses given on day 8 and 15 of the first month of therapy, steady-state levels were achieved in 3 months.
-Special Populations
Hepatic Impairment
Pharmacokinetic study of denosumab has not been undertaken in patients with hepatic impairment.
Renal Impairment
The pharmacokinetics of denosumab was not affected by varying degrees of renal impairment or dialysis treatment (n=55).
Pediatrics
In skeletally-mature adolescent patients (12 to 16 years of age) with giant cell tumor of bone (GCTB) who received denosumab 120 mg subcutaneously every 4 weeks with a 120 mg loading dose on Days 8 and 15, the pharmacokinetics of denosumab were comparable to those observed in adult patients with GCTB.
Geriatric
The pharmacokinetics of denosumab were not affected by age in adults 28 to 87 years.
Gender Differences
Comparing healthy males 50 years and older to postmenopausal women, the pharmacokinetics of denosumab were not affected by gender.
Ethnic Differences
The pharmacokinetics of denosumab was not affected by race.
Obesity
The pharmacokinetics of denosumab were not notably affected by body weight in patients weighing between 36 and 140 kg following a single, subcutaneous 60-mg dose of denosumab (Prolia). In another pharmacokinetic analysis, denosumab (Xgeva) clearance and volume of distribution were found to be proportional to body weight. The steady-state exposure after repeat administration of 120 mg every 4 weeks to study patients who weighed 45 kg and 120 kg were 48% higher and 46% lower, respectively, than exposure of the typical 66 kg patient.