Xgeva

Denosumab (XGEVA) is a sterile, preservative-free, clear, colorless to pale yellow solution.
Denosumab (XGEVA) is a human IgG2 monoclonal antibody that binds to human RANKL.
Denosumab has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.
Each single use vial of denosumab (XGEVA) contains denosumab, sorbitol, glacial acetic acid, polysorbate 20, sodium hydroxide and water for injection.

Pharmacology: Mechanism of Action: Denosumab (XGEVA) binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption, thereby modulating calcium release from bone. Increased osteoclast activity, stimulated by RANKL, is a mediator of bone pathology in solid tumors with osseous metastases. Similarly, giant cell tumors of bone consist of stromal cells expressing RANKL and osteoclast-like giant cells expressing RANK receptor, and signaling through the RANK receptor contributes to osteolysis and tumor growth. Denosumab (XGEVA) prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts, their precursors, and osteoclast-like giant cells.
Pharmacodynamics: In patients with breast cancer and bone metastases, the median reduction in uNTx/Cr was 82% within 1 week following initiation of denosumab (XGEVA) 120 mg administered subcutaneously. In Studies 20050136, 20050244, and 20050103, the median reduction in uNTx/Cr from baseline to Month 3 was approximately 80% in 2075 denosumab (XGEVA)-treated patients.
In a phase 3 study of patients with newly diagnosed multiple myeloma who received SC doses of denosumab (XGEVA) 120 mg every 4 weeks (Q4W), median reductions in uNTx/Cr of approximately 75% were observed by week 5. Reductions in bone turnover markers were maintained, with median reductions of 74% to 79% for uNTx/Cr from weeks 9 to 49 of continued 120 mg Q4W dosing.
Clinical Trials: Bone Metastasis from Solid Tumors: The safety and efficacy of denosumab (XGEVA) for the prevention of skeletal-related events in patients with bone metastases from solid tumors was demonstrated in three international, randomized (1:1), double-blind, active-controlled, noninferiority trials comparing denosumab (XGEVA) with zoledronic acid. In all three trials, patients were randomized to receive 120 mg denosumab (XGEVA) subcutaneously every 4 weeks or 4 mg zoledronic acid intravenously (IV) every 4 weeks (dose adjusted for reduced renal function). Patients with creatinine clearance less than 30 mL/min were excluded. In each trial, the main outcome measure was demonstration of noninferiority of time to first skeletal-related event (SRE) as compared to zoledronic acid. Supportive outcome measures were superiority of time to first SRE and superiority of time to first and subsequent SRE; testing for these outcome measures occurred if the main outcome measure was statistically significant. An SRE was defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression.
Study 20050136 enrolled 2046 patients with advanced breast cancer and bone metastasis. Randomization was stratified by a history of prior SRE (yes or no), receipt of chemotherapy within 6 weeks prior to randomization (yes or no), prior oral bisphosphonate use (yes or no), and region (Japan or other countries). Forty percent of patients had a previous SRE, 40% received chemotherapy within 6 weeks prior to randomization, 5% received prior oral bisphosphonates, and 7% were enrolled from Japan. Median age was 57 years, 80% of patients were White, and 99% of patients were women. The median number of doses administered was 18 for denosumab and 17 for zoledronic acid.
Study 20050244 enrolled 1776 adults with solid tumors other than breast and castrate-resistant prostate cancer with bone metastasis and multiple myeloma. Randomization was stratified by previous SRE (yes or no), systemic anticancer therapy at time of randomization (yes or no), and tumor type (non-small cell lung cancer, myeloma, or other). Eighty-seven percent were receiving systemic anticancer therapy at the time of randomization, 52% had a previous SRE, 64% of patients were men, 87% were White, and the median age was 60 years. A total of 40% of patients had non-small cell lung cancer, 10% had multiple myeloma, 9% had renal cell carcinoma, and 6% had small cell lung cancer. Other tumor types each comprised less than 5% of the enrolled population. The median number of doses administered was 7 for both denosumab and zoledronic acid.
Study 20050103 enrolled 1901 men with castrate-resistant prostate cancer and bone metastasis. Randomization was stratified by previous SRE, PSA level (less than 10 ng/mL or 10 ng/mL or greater) and receipt of chemotherapy within 6 weeks prior to randomization (yes or no). Twenty-six percent of patients had a previous SRE, 15% of patients had PSA less than 10 ng/mL, and 14% received chemotherapy within 6 weeks prior to randomization. Median age was 71 years and 86% of patients were White. The median number of doses administered was 13 for denosumab and 11 for zoledronic acid.
Denosumab (XGEVA) delayed the time to first SRE following randomization as compared to zoledronic acid in patients with breast or castrate-resistant prostate cancer (CRPC) with osseous metastases (see Table 1). In patients with bone metastasis due to other solid tumors or lytic lesions due to multiple myeloma, denosumab (XGEVA) was noninferior to zoledronic acid in delaying the time to first SRE following randomization.
Overall survival and progression-free survival were similar between arms in all three trials. (See Table 1.)

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Multiple Myeloma: The efficacy of denosumab (XGEVA) for the prevention of skeletal-related events in newly diagnosed multiple myeloma patients with treatment through disease progression, was evaluated in Study 20090482, an international, randomized (1:1), double-blind, active-controlled, noninferiority trial comparing denosumab (XGEVA) with zoledronic acid. In this trial, patients were randomized to receive 120 mg denosumab (XGEVA) subcutaneously every 4 weeks or 4 mg zoledronic acid intravenously (IV) every 4 weeks (dose adjusted for reduced renal function). Patients with creatinine clearance less than 30 mL/min were excluded. In this trial, the main efficacy outcome measure was noninferiority of time to first skeletal-related event (SRE). Additional efficacy outcome measures were superiority of time to first SRE, time to first and subsequent SRE, and overall survival. An SRE was defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression.
Study 20090482 enrolled 1718 newly diagnosed multiple myeloma patients with bone lesions. Randomization was stratified by a history of prior SRE (yes or no), the anti-myeloma agent being utilized/planned to be utilized in first-line therapy (novel therapy-based or non-novel therapy-based [novel therapies include bortezomib, lenalidomide, or thalidomide]), intent to undergo autologous PBSC transplantation (yes or no), stage at diagnosis (International Staging System I or II or III) and region Japan (yes or no). At study enrollment, 96% of the patients were receiving or planning to receive novel therapy based first-line anti-myeloma therapy, 55% of the patients intended to undergo autologous PBSC transplantation, 61% of patients had a previous SRE, 32% were at ISS stage I, 38% were at ISS stage II and 29% were at ISS Stage III, and 2% were enrolled from Japan. Median age was 63 years, 82% of patients were White, and 46% of patients were women. The median number of doses administered was 16 for denosumab (XGEVA) and 15 for zoledronic acid.
Denosumab (XGEVA) was noninferior to zoledronic acid in delaying the time to first SRE following randomization (HR = 0.98, 95% CI, 0.85-1.14). The results for overall survival (OS) were comparable between denosumab (XGEVA) and zoledronic acid treatment groups with a hazard ratio of 0.90 (95% CI: 0.70, 1.16). (See Table 2.)

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Giant Cell Tumor of Bone: The safety and efficacy of denosumab (XGEVA) for the treatment of giant cell tumor of bone in adults or skeletally mature adolescents were demonstrated in two open-label trials (Study 20040215 and Study 20062004) that enrolled patients with histologically confirmed measurable giant cell tumor of bone that was either recurrent, unresectable, or for which planned surgery was likely to result in severe morbidity. Patients received 120 mg denosumab (XGEVA) subcutaneously every 4 weeks with additional doses on Days 8 and 15 of the first cycle of therapy.
Study 20040215 was a single arm, pharmacodynamic, and proof of concept trial conducted in 37 adult patients with unresectable or recurrent giant cell tumor of bone. Patients were required to have histologically confirmed giant cell tumor of bone and radiologic evidence of measurable disease from a computed tomography (CT) or magnetic resonance imaging (MRI) obtained within 28 days prior to study enrollment. Patients enrolled in Study 20040215 underwent CT or MRI assessment of giant cell tumor of bone at baseline and quarterly during denosumab (XGEVA) treatment.
Study 20062004 was a parallel-cohort, proof of concept, and safety trial conducted in 282 adult or skeletally mature adolescent patients with histologically confirmed giant cell tumor of bone and evidence of measurable active disease. Study 20062004 enrolled 10 patients who were 13 - 17 years of age [see Use in Children under Precautions]. Patients enrolled into one of three cohorts: Cohort 1 enrolled 170 patients with surgically unsalvageable disease (e.g., sacral or spinal sites of disease, or pulmonary metastases); Cohort 2 enrolled 101 patients with surgically salvageable disease where the investigator determined that the planned surgery was likely to result in severe morbidity (e.g., joint resection, limb amputation, or hemipelvectomy); Cohort 3 enrolled 11 patients who previously participated in Study 20040215. Patients underwent imaging assessment of disease status at intervals determined by their treating physician.
An independent review committee evaluated objective response in 187 patients enrolled and treated in Study 20040215 and Study 20062004 for whom baseline and at least one post-baseline radiographic assessment were available (27 of 37 patients enrolled in Study 20040215 and 160 of 270 patients enrolled in Cohorts 1 and 2 of Study 20062004). The primary efficacy outcome measure was objective response rate using modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
The overall objective response rate (RECIST 1.1) was 25% (95% CI: 19, 32). All responses were partial responses. The estimated median time to response was 3 months. In the 47 patients with an objective response, the median duration of follow-up was 20 months (range: 2-44 months), and 51% (24/47) had a duration of response lasting at least 8 months. Three patients experienced disease progression following an objective response.
Hypercalcemia of Malignancy: The safety and efficacy of denosumab (XGEVA) was demonstrated in an open-label, single-arm trial (Study 20070315) that enrolled 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy. Patients received denosumab (XGEVA) subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy.
In this trial, refractory hypercalcemia of malignancy was defined as an albumin-corrected calcium of >12.5 mg/dL (3.1 mmol/L) despite treatment with intravenous bisphosphonate therapy in 7-30 days prior to initiation of denosumab (XGEVA) therapy. The primary outcome measure was the proportion of patients achieving a response, defined as corrected serum calcium (CSC)
11.5 mg/dL (2.9 mmol/L), within 10 days after denosumab (XGEVA) administration. Efficacy data are summarized in Figure 1 and Table 3. Concurrent chemotherapy did not appear to affect response to denosumab (XGEVA). (See Figure 1 and Table 3.)

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Median time to response (CSC ≤11.5 mg/dL) was 9 days (95% CI: 8, 19), and the median duration of response was 104 days (95% CI: 7, not estimable). Median time to complete response (CSC ≤10.8 mg/dL) was 23 days (95% CI: 9, 36), and the median duration of complete response was 34 days (95% CI: 1, 134).
Pharmacokinetics: Following subcutaneous administration, bioavailability was 62%. Denosumab displayed nonlinear pharmacokinetics at doses below 60 mg, but approximately dose-proportional increases in exposure at higher doses.
With multiple subcutaneous doses of 120 mg once every 4 weeks, up to 2.8-fold accumulation in serum denosumab concentrations was observed and steady state was achieved by 6 months. A mean (± standard deviation) serum steady-state trough concentration of 20.5 (±13.5) mcg/mL was achieved by 6 months. The mean elimination half-life was 28 days.
In patients with newly diagnosed multiple myeloma who received 120 mg every 4 weeks, denosumab concentrations appear to reach steady-state by month 6. In patients with giant cell tumor of bone, after administration of subcutaneous doses of 120 mg once every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy, mean (± standard deviation) serum trough concentrations on Day 8, 15, and one month after the first dose were 19.0 (±24.1), 31.6 (±27.3), 36.4 (±20.6) mcg/mL, respectively. Steady-state was achieved in 3 months after initiation of treatment with a mean serum trough concentration of 23.4 (±12.1) mcg/mL.
Special Populations: Body Weight: A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. Denosumab clearance and volume of distribution were proportional to body weight. The steady-state exposure following repeat subcutaneous administration of 120 mg every 4 weeks to 45 kg and 120 kg subjects were, respectively, 48% higher and 46% lower than exposure of the typical 66 kg subject.
Age, Gender and Race: The pharmacokinetics of denosumab was not affected by age, gender, and race.
Pediatrics: The pharmacokinetics of denosumab in pediatric patients has not been assessed.
Hepatic Impairment: No clinical trials have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of denosumab.
Renal Impairment: In clinical trials of 87 patients with varying degrees of renal dysfunction, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics and pharmacodynamics of denosumab [see Renal Impairment under Precautions].
Drug Interactions: No formal drug-drug interaction trials have been conducted with denosumab (XGEVA). There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy and were not altered by concomitant chemotherapy and/or hormone therapy.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of denosumab has not been evaluated in long-term animal studies. The genotoxic potential of denosumab has not been evaluated.
Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 6.5- to 25-fold higher than the recommended human dose of 120 mg subcutaneously administered once every 4 weeks, based on body weight (mg/kg).
Animal Toxicology and/or Pharmacology: Denosumab is an inhibitor of osteoclastic bone resorption via inhibition of RANKL.
Because the biological activity of denosumab in animals is specific to nonhuman primates, evaluation of genetically engineered (knockout) mice or use of other biological inhibitors of the RANK/RANKL pathway, OPG-Fc and RANK-Fc, provided additional information on the pharmacodynamic properties of denosumab. RANK/RANKL knockout mice exhibited absence of lymph node formation, as well as an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy). Neonatal RANK/RANKL knockout mice exhibited reduced bone growth and lack of tooth eruption. A corroborative study in 2-week-old rats given the RANKL inhibitor OPG-Fc also showed reduced bone growth, altered growth plates, and impaired tooth eruption. These changes were partially reversible in this model when dosing with the RANKL inhibitors was discontinued.

Multiple Myeloma and Bone Metastasis from Solid Tumors: Denosumab (XGEVA) is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors.
Giant Cell Tumor of Bone: Denosumab (XGEVA) is indicated for the treatment of 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 [see Pharmacology: Pharmacodynamics: Clinical Trials: Multiple Myeloma under Actions].
Hypercalcemia of Malignancy: Denosumab (XGEVA) is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

Important Administration Instructions: Denosumab (XGEVA) is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally.
Multiple Myeloma and Bone Metastasis from Solid Tumors: The recommended dose of denosumab (XGEVA) is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen.
Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia [see Hypocalcemia under Precautions].
Giant Cell Tumor of Bone: The recommended dose of denosumab (XGEVA) is 120 mg administered every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen.
Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia [see Hypocalcemia under Precautions].
Hypercalcemia of Malignancy: The recommended dose of denosumab (XGEVA) is 120 mg administered every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen.
Preparation and Administration: Visually inspect denosumab (XGEVA) for particulate matter and discoloration prior to administration. Denosumab (XGEVA) is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter.
Prior to administration, denosumab (XGEVA) may be removed from the refrigerator and brought to room temperature (up to 25°C) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm denosumab (XGEVA) in any other way.
Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-dose or entry.

There is no experience with overdosage of denosumab (XGEVA).

Hypocalcemia: Pre-existing hypocalcemia must be corrected prior to initiating therapy with denosumab (XGEVA) [see Hypocalcemia under Precautions].
Hypersensitivity: Denosumab (XGEVA) is contraindicated in patients with known clinically significant hypersensitivity to denosumab (XGEVA) [see Hypersensitivity under Precautions and Postmarketing Experience under Adverse Reactions].

Drug Products with Same Active Ingredient: Denosumab (XGEVA) includes the same active ingredient (denosumab) found in denosumab (Prolia). Patients receiving denosumab (XGEVA) should not take denosumab (Prolia).
Hypersensitivity: Clinically significant hypersensitivity including anaphylaxis has been reported with use of denosumab (XGEVA). Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue denosumab (XGEVA) therapy permanently [see Hypersensitivity under Contraindications and Postmarketing Experience under Adverse Reactions].
Hypocalcemia: Denosumab (XGEVA) can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to denosumab (XGEVA) treatment. Monitor calcium levels, throughout denosumab (XGEVA) therapy, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when denosumab (XGEVA) is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare provider for symptoms of hypocalcemia [see Hypocalcemia under Contraindications and Adverse Reactions].
An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake [see Clinical Trials Experience under Adverse Reactions, Renal Impairment under Precautions, and Pharmacology: Pharmacokinetics under Actions].
Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) has been reported in patients receiving denosumab (XGEVA), manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with cancer, the incidence of ONJ was higher with longer duration of exposure [see Clinical Trials Experience under Adverse Reactions]. Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections. Similarly, for denosumab (XGEVA) patients with multiple myeloma that developed ONJ, 58% had a history of invasive dental procedures as a predisposing factor.
Perform an oral examination and appropriate preventive dentistry prior to the initiation of denosumab (XGEVA) and periodically during denosumab (XGEVA) therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with denosumab (XGEVA). Consider temporary discontinuation of denosumab (XGEVA) therapy if an invasive dental procedure must be performed. There are no data available to suggest the optimal duration of treatment interruption.
Patients who are suspected of having or who develop ONJ while on denosumab (XGEVA) should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Clinical judgment of the treating healthcare provider should guide the management plan of each patient based on individual risk/benefit assessment.
Atypical Subtrochanteric and Diaphyseal Femoral Fracture: Atypical femoral fracture has been reported with denosumab (XGEVA) [see Clinical Trial Experience under Adverse Reactions]. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.
Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.
During denosumab (XGEVA) treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of denosumab (XGEVA) therapy should be considered, pending a risk/benefit assessment, on an individual basis.
Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in Patients with Growing Skeletons: Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury has been reported in denosumab (XGEVA)-treated patients with giant cell tumor of bone and patients with growing skeletons. Hypercalcemia has been reported within the first year after treatment discontinuation. After treatment is discontinued, monitor patients for signs and symptoms of hypercalcemia, assess serum calcium periodically, reevaluate the patient's calcium and vitamin D supplementation requirements and manage patients as clinically appropriate [see Adverse Reactions and Use in Children as follows].
Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation: Multiple vertebral fractures (MVF) have been reported following discontinuation of treatment with denosumab. Patients at higher risk for MVF include those with risk factors for or a history of osteoporosis or prior fractures.
When denosumab (XGEVA) treatment is discontinued, evaluate the individual patient's risk for vertebral fractures.
Embryo-Fetal Toxicity: Based on data from animal studies and its mechanism of action, denosumab (XGEVA) can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of denosumab to cynomolgus monkeys throughout pregnancy at a dose 25-fold higher than the recommended human dose of denosumab (XGEVA) based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth and decreased neonatal growth.
Verify the pregnancy status of females of reproductive potential prior to the initiation of denosumab (XGEVA). Advise pregnant women and females of reproductive potential that exposure to denosumab (XGEVA) during pregnancy or within 5 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of denosumab (XGEVA) [see Use in Pregnancy & Lactation and Pharmacology: Mechanism of Action under Actions].
Renal Impairment: Two clinical trials were conducted in patients without cancer and with varying degrees of renal function.
In one study, patients (N=55) with varying degrees of renal function (ranging from normal through end-stage renal disease requiring dialysis) received a single 60 mg subcutaneous dose of denosumab. In a second study, patients (N=32) with severe renal dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis) were given two 120 mg subcutaneous doses of denosumab. In both studies, greater risk of developing hypocalcemia was observed with increasing renal impairment, and with inadequate/no calcium supplementation. Hypocalcemia was mild to moderate in severity in 96% of patients. Monitor calcium levels and calcium and vitamin D intake [see Hypocalcemia previously, Clinical Trial Experience under Adverse Reactions, and Pharmacology: Pharmacokinetics under Actions].
Use in Children: The safety and efficacy of denosumab (XGEVA) have not been established in pediatric patients except in skeletally mature adolescents with giant cell tumor of bone. Denosumab (XGEVA) is recommended only for treatment of skeletally mature adolescents with giant cell tumor of bone [see Giant Cell Tumor of Bone under Indications]. Clinically significant hypercalcemia after treatment discontinuation has been reported in pediatric patients with growing skeletons who received denosumab for giant cell tumor of bone or for unapproved indications [see Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in Patients with Growing Skeletons under Precautions and Postmarketing Experience under Adverse Reactions].
Denosumab (XGEVA) was studied in an open-label trial that enrolled a subset of 10 adolescent patients (aged 13-17 years) with giant cell tumor of bone who had reached skeletal maturity, defined by at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus), and had a body weight ≥45 kg [see Giant Cell Tumor of Bone under Indications and Pharmacology: Pharmacodynamics: Clinical Trials: Giant Cell Tumor of Bone under Actions]. A total of two of six (33%) evaluable adolescent patients had an objective response by retrospective independent assessment of radiographic response according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria. The adverse reaction profile and efficacy results appeared to be similar in skeletally mature adolescents and adults [see Clinical Trials Experience under Adverse Reactions and Pharmacology: Pharmacodynamics: Clinical Trials: Giant Cell Tumor of Bone under Actions].
Treatment with denosumab (XGEVA) may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of denosumab (XGEVA) therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab.
Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth [see Use in Pregnancy & Lactation].
Use in the Elderly: Of the total number of patients in clinical studies that received denosumab (XGEVA) (n=2841) in Studies 20050136, 20050244, and 20050103, 1271 (44%) were ≥65 years old, while 473 patients (17%) were ≥75 years old. Of the 859 patients in Study 20090482 that received denosumab (XGEVA), 387 patients (45%) were ≥65 years old, while 141 patients (16%) were ≥75 years old. No overall differences in safety or efficacy were observed between older and younger patients.

Pregnancy: Risk Summary: Based on findings in animals and its mechanism of action, denosumab (XGEVA) can cause fetal harm when administered to a pregnant woman [see Pharmacology: Mechanism of Action under Actions]. There are insufficient data with denosumab use in pregnant women to inform any drug associated risks for adverse developmental outcomes. In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab throughout pregnancy at a dose 25-fold higher than the recommended human dose of denosumab (XGEVA) based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality; and absent lymph nodes, abnormal bone growth, and decreased neonatal growth [see Data as follows].
Apprise pregnant women of the potential risk to the fetus.
The background rate of major birth defects and miscarriage is unknown for the indicated population. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data: Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a "knockout mouse"). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy starting at gestational day 20 and at a pharmacologically active dose 25-fold higher than the recommended human dose of denosumab (XGEVA) based on body weight, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia, and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels).
Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated.
In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation [see Females and Males of Reproductive Potential as follows and Pharmacology: Nonclinical Toxicology: Animal Toxicology and/or Pharmacology under Actions].
Lactation: Risk Summary: There is no information regarding the presence of denosumab (XGEVA) in human milk, the effects on the breastfed child, or the effects on milk production. Denosumab was detected in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤0.5% milk:serum ratio) and maternal mammary gland development was normal, with no impaired lactation. However, pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation [see Pregnancy previously and Pharmacology: Nonclinical Toxicology: Animal Toxicology and/or Pharmacology under Actions]. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for denosumab (XGEVA) treatment and any potential adverse effects on the breastfed child from denosumab (XGEVA) or from the underlying maternal condition.
Females and Males of Reproductive Potential: Based on findings in animals and its mechanism of action, denosumab (XGEVA) can cause fetal harm when administered to a pregnant woman [see Pregnancy previously].
Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating denosumab (XGEVA) treatment.
Contraception: Females: Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of denosumab (XGEVA).

The following adverse reactions are discussed as follows and elsewhere in the labeling: Hypersensitivity [see Hypersensitivity under Precautions].
Hypocalcemia [see Hypocalcemia, Renal Impairment under Precautions].
Osteonecrosis of the Jaw [see Osteonecrosis of the Jaw (ONJ) under Precautions].
Atypical Subtrochanteric and Diaphyseal Femoral Fracture [see Atypical Subtrochanteric and Diaphyseal Femoral Fracture under Precautions].
Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in Patients with Growing Skeletons [see Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in Patients with Growing Skeletons and Use in Children under Precautions].
Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation [see Precautions].
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Bone Metastasis from Solid Tumors: The safety of denosumab (XGEVA) was evaluated in three randomized, double-blind, double-dummy trials [see Pharmacology: Pharmacodynamics: Clinical Trials: Bone Metastasis from Solid Tumors under Actions] in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of denosumab (XGEVA). In Studies 20050136, 20050244, and 20050103, patients were randomized to receive either 120 mg of denosumab (XGEVA) every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.
The median duration of exposure to denosumab (XGEVA) was 12 months (range: 0.1-41) and median duration on-study was 13 months (range: 0.1-41). Of patients who received denosumab (XGEVA), 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18-93). Seventy-five percent of patients who received denosumab (XGEVA) received concomitant chemotherapy.
The most common adverse reactions in patients (incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 4). The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation of denosumab (XGEVA) were osteonecrosis and hypocalcemia. (See Table 4.)

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Severe Mineral/Electrolyte Abnormalities: Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with denosumab (XGEVA) and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes [see Hypocalcemia, Renal Impairment under Precautions].
Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with denosumab (XGEVA) and 7.4% of patients treated with zoledronic acid.
Osteonecrosis of the Jaw (ONJ): In the primary treatment phases of Studies 20050136, 20050244, and 20050103, ONJ was confirmed in 1.8% of patients in the denosumab (XGEVA) group (median exposure of 12.0 months; range: 0.1-40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Study 20050136) or prostate (Study 20050103) cancer included an denosumab (XGEVA) open-label extension treatment phase where patients were offered denosumab (XGEVA) 120 mg once every 4 weeks (median overall exposure of 14.9 months; range: 0.1-67.2). The patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3.7% in the second year, and 4.6% per year thereafter. The median time to ONJ was 20.6 months (range: 4-53) [see Osteonecrosis of the Jaw (ONJ) under Precautions].
In a placebo-controlled clinical trial with an extension treatment phase evaluating denosumab (XGEVA) for the prevention of bone metastases in patients with non-metastatic prostate cancer (a patient population for which denosumab (XGEVA) is not indicated), with longer treatment exposure of up to 7 years, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3.0% in the second year, and 7.1% per year thereafter.
Atypical Subtrochanteric and Diaphyseal Fracture: In the clinical trial program, atypical femoral fracture has been reported in patients treated with denosumab (XGEVA) and the risk increased with longer duration of treatment. Events have occurred during treatment and after treatment was discontinued [see Atypical Subtrochanteric and Diaphyseal Femoral Fracture under Precautions].
Multiple Myeloma: The safety of denosumab (XGEVA) was evaluated in an international, randomized (1:1), double-blind, active-controlled trial of patients with newly diagnosed multiple myeloma with treatment through disease progression [see Pharmacology: Pharmacodynamics: Clinical Trials: Multiple Myeloma under Actions]. In this trial, patients received 120 mg denosumab (XGEVA) every 4 weeks as a subcutaneous injection (n = 850) or 4 mg (dose adjusted for renal function) of zoledronic acid intravenously (IV) every 4 weeks by IV infusion (n = 852). Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.
The median duration of exposure to denosumab (XGEVA) was 16 months (range: 1-50) and median duration on-study was 17 months (range: 0.0-49). Of patients who received denosumab (XGEVA), 46% were female, 83% percent were White, 13% Asian, 3% Black or African American, and 4% Hispanic/Latino. The median age of the patients randomized to denosumab (XGEVA) was 63 years (range: 29-91) and all patients who received denosumab (XGEVA) received concomitant anti-myeloma chemotherapy.
The adverse reaction profile of denosumab (XGEVA) in patients with multiple myeloma, Study 20090482, was similar to that observed in Studies 20050136, 20050244, and 20050103. The most common adverse reactions (incidence ≥10%) were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%), and headache (11%). The most common serious adverse reaction (incidence ≥5%) was pneumonia (8%). The most common adverse reaction resulting in discontinuation of denosumab (XGEVA) (≥1.0%) was osteonecrosis of the jaw.
Hypocalcemia and Hypophosphatemia: Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) and severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 2% and 21% patients treated with denosumab (XGEVA), respectively.
Osteonecrosis of the Jaw (ONJ): In the primary treatment phase of Study 20090482, ONJ was confirmed in 4.1% of patients in the denosumab (XGEVA) group (median exposure of 16 months; range: 1-50) and 2.8% of patients in the zoledronic acid group (median 15 months; range: 1-45 months). At the completion of the double-blind treatment phase of Study 20090482, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ in the denosumab (XGEVA) group (median exposure of 19.4 months; range: 1-52) was 2.0% during the first year of treatment, 5.0% in the second year, and 4.5% per year thereafter. The median time to ONJ was 18.7 months (range: 1-44) [see Osteonecrosis of the Jaw under Precautions].
Giant Cell Tumor of Bone: The safety of denosumab (XGEVA) was evaluated in two single arm trials (Study 20062004 and Study 20040215) [see Pharmacology: Pharmacodynamics: Clinical Trials: Giant Cell Tumor in Bone under Actions] in which a total of 304 adult or skeletally mature adolescent patients with giant cell tumor of bone received at least 1 dose of denosumab (XGEVA). Patients received 120 mg denosumab (XGEVA) subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Patients receiving concurrent bisphosphonate therapy were excluded from enrollment in both studies. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure were excluded from enrollment in Study 20040215. During the trial, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.
Of the 304 patients who received denosumab (XGEVA), 145 patients were treated with denosumab (XGEVA) for ≥1 year, 44 patients for ≥2 years, and 15 patients for ≥3 years. The median number of doses received was 14 (range: 1-60 doses) and the median number of months on study was 11 (range: 0-54 months). Fifty-eight percent of the enrolled patients were women and 80% were White. The median age was 33 years (range: 13-83 years); a total of 10 patients were skeletally mature adolescents (13 to 17 years of age).
The adverse reaction profile of denosumab (XGEVA) in patients with giant cell tumor of bone was similar to that reported in Studies 20050136, 20050244, and 20050103. The most common adverse reactions in patients (incidence ≥10%) were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis (incidence of 0.7%). The most common adverse reactions resulting in discontinuation of denosumab (XGEVA) were osteonecrosis of the jaw (incidence of 0.7%), and tooth abscess or tooth infection (incidence of 0.7%). The adverse reaction profile appeared similar in skeletally mature adolescents and adults.
Hypocalcemia and Hypophosphatemia: Moderate hypocalcemia (corrected serum calcium less than 8 to 7 mg/dL or less than 2 to 1.75 mmol/L) occurred in 2.6% of patients treated with denosumab (XGEVA).
Severe hypophosphatemia (serum phosphorus less than 2 to 1 mg/dL or less than 0.6 to 0.3 mmol/L) occurred in 29 patients (9.5%).
Osteonecrosis of the Jaw (ONJ): In Study 20062004 and Study 20040215, ONJ was confirmed in 4 of 304 (1.3%) patients who received denosumab (XGEVA). The median time to ONJ was 16 months (range: 13-20 months) [see Osteonecrosis of the Jaw (ONJ) under Precautions].
Hypercalcemia of Malignancy: Denosumab (XGEVA) was evaluated in an open-label, single-arm trial (Study 20070315) in which 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy were enrolled [see Pharmacology: Pharmacodynamics: Clinical Trials: Hypercalcemia of Malignancy under Actions].
The adverse reaction profile of denosumab (XGEVA) in patients with hypercalcemia of malignancy was similar to that reported in Studies 20050136, 20050244, 20050103, 20062004, and 20040215. Adverse reactions occurring in greater than 20% of patients were nausea (30%), dyspnea (27%), decreased appetite (24%), headache (24%), peripheral edema (24%), vomiting (24%), anemia (21%), constipation (21%), and diarrhea (21%). The following adverse reactions of Grade 3 or greater severity related to study therapy were reported on study: fatigue (3%) and infection (6%). Grade 3 laboratory abnormalities included hypomagnesemia (3%), hypokalemia (3%), and hypophosphatemia (76%) of patients. No deaths on study were related to denosumab (XGEVA) therapy.
Postmarketing Experience: The following adverse reactions have been identified during post approval use of denosumab (XGEVA). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases [see Contraindications and Precautions].
Hypercalcemia: Severe symptomatic hypercalcemia following treatment discontinuation can occur [see Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in Patients with Growing Skeletons under Precautions and Adverse Reactions].
Hypersensitivity, including anaphylactic reactions [see Contraindications and Precautions].
Musculoskeletal pain, including severe musculoskeletal pain. Positive rechallenge has been reported.
Lichenoid drug eruptions (e.g., lichen planus-like reactions).
Alopecia.
Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to denosumab in the studies described as follows with the incidence of antibodies to other studies or to other products may be misleading.
Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30-180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. None of the 304 patients with giant cell tumor of bone in Study 20062004 and Study 20040215 tested positive for binding antibodies. In multiple myeloma patients in Study 20090482, 1 out of 199 patients with a post baseline result, tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development.

Store in a refrigerator (2°C-8°C). Do not freeze.
Keep the glass vial in the outer carton in order to protect from direct light. Do not shake.
If removed from the refrigerator, denosumab (XGEVA) should be kept at controlled room temperature (up to 25°C) in the original carton and must be used within 30 days.

Agents Affecting Bone Metabolism

M05BX04 - denosumab ; Belongs to the class of other drugs affecting bone structure and mineralization. Used in the treatment of bone diseases.

Rx