Xgeva

Xgeva

denosumab

Manufacturer:

Amgen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Denosumab.
Description
Each vial contains 120 mg denosumab in 1.7 mL solution (70 mg/mL).
Excipients/Inactive Ingredients: Sorbitol, Glacial acetic acid*, Polysorbate 20, Sodium hydroxide, Water for Injection.
* Acetate buffer is formed by mixing acetic acid with sodium hydroxide.
Sterile, preservative-free, clear, colorless to slightly yellow solution, pH 5.2.
Before administration, XGEVA should be inspected for particulate matter and discoloration. The solution should not be used if cloudy or discolored.
The solution may contain trace amounts of translucent to white proteinaceous particles.
Action
Pharmacology: Mechanism of Action: Denosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity and specificity to RANKL preventing RANKL from activating its only receptor, RANK, found on the surface of osteoclasts and their precursors. RANK ligand exists as a transmembrane or soluble protein. RANK ligand is essential for the formation, function and survival of osteoclasts, the sole cell type responsible for bone resorption. Increased osteoclast activity, stimulated by RANK ligand, is a key mediator of bone destruction in bone disease in metastatic tumors and multiple myeloma. Prevention of RANK ligand-RANK interaction results in reduced osteoclast numbers and function, and thereby decreases bone resorption and cancer-induced bone destruction.
Giant cell tumors of bone are characterized by stromal cells expressing RANK ligand and osteoclast-like giant cells expressing RANK. In patients with giant cell tumor of bone, denosumab binds to RANK ligand, significantly reducing or eliminating osteoclast-like giant cells. Consequently, osteolysis is reduced and proliferative tumor stroma is replaced with non-proliferative, differentiated, densely woven new bone.
Pharmacodynamics: In a phase 2 study of patients with breast cancer and bone metastases who had not previously received IV bisphosphonate therapy, SC doses of XGEVA 120 mg every 4 weeks (Q4W) caused a rapid reduction in markers of bone resorption (uNTX/creatinine, and serum CTx) with median reduction of 82% for uNTX/Cr within 1 week. Reductions in bone turnover markers were maintained, with median uNTX/Cr reductions of 74% to 82% from weeks 2 to 25 of continued 120 mg Q4W dosing. In phase 3 studies of patients with advanced cancer, median reductions of approximately 80% in uNTx/Cr from baseline after 3 months of treatment were observed across 2,075 XGEVA-treated advanced cancer patients (breast, prostate, multiple myeloma or other solid tumors).
Similarly, in patients with advanced cancer and bone metastases (including subjects with multiple myeloma and bone disease) who were receiving IV bisphosphonate therapy, yet had uNTX/Cr levels > 50 nM/mM, multiple SC dosing of XGEVA administered either every 4 weeks or every 12 weeks caused an approximate 80% reduction in uNTX/Cr from baseline after 3 and 6 months of treatment. Overall, 97% of patients in the XGEVA groups had at least 1 uNTX/Cr value < 50 nM/mM up to week 25 of the study.
In a phase 3 study of patients with newly diagnosed multiple myeloma who received SC doses of 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.
In a phase 2 study of patients with giant cell tumor of bone who received SC doses of XGEVA 120 mg every 4 weeks (Q4W) with loading doses on days 8 and 15, median reductions in uNTx/Cr and sCTx of approximately 80% were observed by week 9.
Reductions in bone turnover markers were maintained, with median reductions of 56% to 77% for uNTx/Cr and 79% to 83% for sCTx from weeks 5 to 25 of continued 120 mg Q4W dosing.
Clinical Data: Prevention of Skeletal-Related Events in Adults with Advanced Malignancies Involving Bone: The efficacy and safety of XGEVA in the prevention of Skeletal-Related Events (SREs) were evaluated in patients with advanced malignancies and bone lesions in three randomized, double-blind, active-controlled studies. Each study evaluated denosumab (120 mg administered subcutaneously) with zoledronic acid (4 mg administered intravenously, dose-adjusted for reduced renal function) once every 4 weeks. The primary and secondary endpoints evaluated the occurrence of one or more SREs defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone or spinal cord compression.
XGEVA reduced or prevented the risk of developing a SRE, or developing multiple SREs (first or subsequent) in patients with advanced malignancies involving bone. Efficacy results are provided in Table 1. (See Table 1 and Figure 1.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Effect on pain: Pain analyses included evaluation of changes from baseline in BPI-SF worst pain score; evaluations of time to pain worsening, moderate or severe pain, or pain improvement; and the proportions of subjects meeting these criteria. In an ad-hoc analysis of the combined dataset, the median time to worsening pain (> 4-point worst pain score and ≥ 2-point increase from baseline) was longer for XGEVA compared to zoledronic acid (65 versus 59 days and 181 versus 169 days, respectively). In an additional ad-hoc subgroup analysis in patients with mild or no pain at baseline, time to worsening pain (> 4-point worst pain score) was delayed in the XGEVA group compared to the zoledronic acid treatment group (198 versus 143 days). The time to pain improvement (i.e., ≥ 2-point decrease from baseline in BPI-SF worst pain score) was similar for denosumab and zoledronic acid in each study and the integrated analyses.
Overall survival and disease progression: Disease progression was similar between XGEVA and zoledronic acid in all three studies and in the pre-specified analysis of all three studies combined.
In all three studies overall survival was balanced between XGEVA and zoledronic acid in patients with advanced malignancies involving bone: patients with breast cancer (hazard ratio and 95% CI was 0.95 [0.81, 1.11]), patients with prostate cancer (hazard ratio and 95% CI was 1.03 [0.91, 1.17]), and patients with other solid tumors or multiple myeloma (hazard ratio and 95% CI was 0.95 [0.83, 1.08]). An ad-hoc analysis in study 2 (patients with other solid tumors or multiple myeloma) examined overall survival for the 3 tumor types used for stratification (non-small cell lung cancer, multiple myeloma, and other). Overall survival was longer for XGEVA in non-small cell lung cancer (hazard ratio [95% CI] of 0.79 [0.65, 0.95]; n = 702) and longer for zoledronic acid in multiple myeloma (hazard ratio [95% CI] of 2.26 [1.13, 4.50]; n = 180) and similar between the XGEVA and zoledronic acid in other tumor types (hazard ratio [95% CI] of 1.08 (0.90, 1.30); n = 894). This study did not control for prognostic factors and anti-neoplastic treatments for multiple myeloma. In a combined pre-specified analysis from studies 1, 2 and 3, overall survival was similar between XGEVA and zoledronic acid (hazard ratio and 95% CI 0.99 [0.91, 1.07]).
Multiple Myeloma: In Study 4, XGEVA was evaluated in an international, randomized (1:1), double-blind, active-controlled study comparing XGEVA with zoledronic acid in patients with newly diagnosed multiple myeloma.
In this study, 1,718 multiple myeloma patients with at least 1 bone lesion were randomized to receive 120 mg XGEVA subcutaneously every 4 weeks or 4 mg zoledronic acid intravenously (IV) every 4 weeks (dose adjusted for renal impairment and patients with creatinine clearance less than 30 mL/min were excluded based on Zometa prescribing information). The primary outcome measure was demonstration of non-inferiority of time to first skeletal-related event (SRE) as compared to zoledronic acid. Secondary outcome measures included superiority of time to first SRE, superiority of time to first and subsequent SRE, and overall survival. An SRE was defined as any of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.
In this study, randomization was stratified by intent to undergo autologous peripheral blood stem cell (PBSC) transplantation (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)], stage at diagnosis (International Staging System I or II or III), previous SRE (yes or no), and region (Japan or other countries). Across both study arms, 54.5% of patients intended to undergo autologous PBSC transplantation, 95.8% patients utilized/planned to utilize a novel anti-myeloma agent in first-line therapy, and 60.7% of patients had a previous SRE. The number of patients across both study arms with ISS stage I, stage II, and stage III at diagnosis were 32.4%, 38.2%, and 29.3%, respectively.
Median age was 63 years, 82.1% of patients were White, and 45.6% of patients were women. The median number of doses administered was 16 for XGEVA and 15 for zoledronic acid. In patients with newly diagnosed multiple myeloma, XGEVA was non-inferior to zoledronic acid in delaying the time to first SRE following randomization (see Figure 2 and Table 2).

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

The hazard ratio between XGEVA and zoledronic acid treatment groups and 95% CI for overall survival (OS) was 0.90 (0.70, 1.16) (see Figure 3). Median progression-free survival (PFS) (95% CI) was 46.1 (34.3, not estimable) months for the XGEVA treatment group and 35.4 (30.2, not estimable) months for the zoledronic acid group (HR [95% CI] of 0.82 [0.68, 0.99]; p-value (multiplicity not adjusted) = 0.036) (see Figure 4).

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Effect on pain: For pain measures based on BPI-SF, the point estimate (95% CI) of the average area under the curve (AUC) of worst pain, relative to baseline, was -1.04 (-1.32, -0.77) for XGEVA and -0.69 (-0.95, -0.43) for zoledronic acid with a point estimate (95% CI) for the treatment difference of -0.35 (-0.73, 0.03) and p = 0.072, and the point estimate (95% CI) of the average AUC of the pain severity score, relative to baseline, was -0.72 (-0.92, -0.51) for XGEVA and -0.40 (-0.59, -0.20) for zoledronic acid, with a point estimate (95% CI) for the treatment difference of -0.32 (-0.60, -0.04) and p = 0.024, other measures showed similar results between XGEVA and zoledronic acid. XGEVA and zoledronic acid showed similar results in time to, and proportion by visit for ≥ 2-point decrease, ≥ 2-point increase, and > 4-point in worst pain score.
Treatment of Giant Cell Tumor of Bone in Adults or Skeletally Mature Adolescents: The safety and efficacy of XGEVA was studied in two phase 2 open-label, single-arm trials (Studies 5 and 6) that enrolled 305 patients with giant cell tumor of bone that was either unresectable or for which surgery would be associated with severe morbidity. Patients received 120 mg XGEVA subcutaneously every 4 weeks with a loading dose of 120 mg on days 8 and 15.
Study 5 enrolled 37 adult patients with histologically confirmed unresectable or recurrent giant cell tumor of bone. The main outcome measure of the trial was response rate, defined as either at least 90% elimination of giant cells relative to baseline (or complete elimination of giant cells in cases where giant cells represent < 5% of tumor cells), or a lack of progression of the target lesion by radiographic measurements in cases where histopathology was not available. Of the 35 patients included in the efficacy analysis, 85.7% (95% CI: 69.7, 95.2) had a treatment response to XGEVA. All 20 patients (100%) with histology assessments met response criteria. Of the remaining 15 patients, 10 (67%) met response criteria based on radiology data.
Study 6 enrolled 282 adult or skeletally mature adolescents with giant cell tumor of bone. Of these patients, 10 were aged 13-17 years (see Precautions). Patients were assigned to one of three cohorts: Cohort 1 included patients with surgically unsalvageable disease (e.g., sacral, spinal, or multiple lesions, including pulmonary metastases); Cohort 2 included patients with surgically salvageable disease whose planned surgery was associated with severe morbidity (e.g., joint resection, limb amputation, or hemipelvectomy); Cohort 3 included patients previously participating in Study 5 and rolled over into this study.
The outcome measures of the study were time to disease progression (based on investigator assessment) for Cohort 1 and proportion of patients without any surgery at month 6 for Cohort 2. Pain outcomes and clinical benefit were also assessed.
In Cohort 1, median time to disease progression was not reached, as only 6 of the 169 treated patients (3.6%) had disease progression. In Cohort 2, XGEVA prolonged the time to surgery, reduced the morbidity of planned surgery, and reduced the proportion of patients undergoing surgery. Sixty-four of the 71 (90.1%; 95% CI: 80.7%, 95.9%) evaluable patients treated with XGEVA had not undergone surgery by month 6. Overall, of 100 patients for whom surgery was planned, 74 patients (74%) had no surgery performed, and 16 patients (16%) underwent a less morbid surgical procedure from that planned at baseline (see Table 3).
In Cohorts 1 and 2 combined, a clinically meaningful reduction in worst pain (i.e., ≥ 2-point decrease from baseline) was reported for 31.4% of patients at risk (i.e., those who had a worst pain score of ≥ 2 at baseline) within 1 week of treatment, and ≥ 50% at week 5. These pain improvements were maintained at all subsequent evaluations. In a post-hoc analysis, at least half of evaluable patients had a ≥ 30% reduction in worst pain score from baseline at all post-baseline time points beginning at week 9.
A retrospective independent review of radiographic imaging data was performed for patients enrolled in Studies 5 and 6. Of the 305 patients enrolled in Studies 5 and 6, 190 had at least 1 evaluable time point response and were included in the analysis (see Table 4).
Patients were evaluated by the following response criteria to determine objective tumor response: • Modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1) to evaluate tumor burden based on computed tomography (CT)/magnetic resonance imaging (MRI),
• Modified European Organization for Research and Treatment of Cancer (EORTC) criteria to evaluate metabolic response using fluorodeoxyglucose positron emission tomography (FDG-PET),
• Modified Inverse Choi criteria to evaluate tumor size and density using Hounsfield units based on CT/MRI (Density/Size).
Overall, XGEVA achieved objective tumor responses in 71.6% (95% CI: 64.6, 77.9) of patients (see Table 4). The median time to response was 3.1 months (95% CI: 2.89, 3.65).
The median duration of response was not estimable, as few patients experienced disease progression, with a median follow-up of 13.4 months. Efficacy results in skeletally mature adolescents appeared to be similar to those observed in adults. (See Tables 3 and 4.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Treatment of Hypercalcemia of Malignancy: The safety and efficacy of XGEVA was studied in a phase 2 open-label, single-arm trial (Study 7) that enrolled 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate. Patients received XGEVA subcutaneously every 4 weeks with additional 120 mg doses on days 8 and 15 of the first month of therapy.
In this study, 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 in the last 7-30 days. The primary endpoint 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 XGEVA administration. XGEVA was associated with rapid and sustained decreases in serum calcium in the majority of patients including those with or without bone metastases (see Figure 5 and Table 5).

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Pharmacokinetics: Following subcutaneous administration, bioavailability was 62% and denosumab displayed non-linear pharmacokinetics with doses over a wide dose range, but approximately dose-proportional increases in exposure for doses of 60 mg (or 1 mg/kg) and higher. In subjects with advanced cancer, who received multiple doses of 120 mg every 4 weeks an approximate 2-fold accumulation in serum denosumab concentrations was observed and steady-state was achieved by 6 months, consistent with time-independent pharmacokinetics. In subjects with multiple myeloma who received 120 mg every 4 weeks, median trough levels varied by less than 8% between months 6 and 12. In subjects with giant cell tumor of bone who received 120 mg every 4 weeks with a loading dose on days 8 and 15, steady-state levels were achieved within the first month of treatment. Between weeks 9 and 49, median trough levels varied by less than 9%. At steady-state, the mean serum trough concentration was 20.6 mcg/mL (range: 0.456 to 56.9 mcg/mL). In subjects who discontinued 120 mg every-4-weeks dosing, the mean half-life was 28 days (range: 14 to 55 days).
A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. This analysis showed no notable difference in pharmacokinetics with age (18 to 87 years), race, body weight (36 to 174 kg), or across patients with solid tumors, multiple myeloma, and giant cell tumor of bone. Denosumab pharmacokinetics and pharmacodynamics were similar in men and women and in patients transitioning from IV bisphosphonate therapy. Denosumab pharmacokinetics and pharmacodynamics were not affected by the formation of binding antibodies to denosumab.
Special Populations: Gender: The pharmacokinetics of denosumab were not different in men and women.
Geriatrics: The pharmacokinetics of denosumab were not affected by age from 18 years to 87 years.
Pediatrics: The pharmacokinetics of denosumab in pediatric patients have not been assessed.
Race: The pharmacokinetics of denosumab were not affected by race.
Hepatic Impairment: No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of denosumab.
Renal Impairment: In studies of denosumab (60 mg, N = 55 and 120 mg, N = 32) in patients without advanced cancer, but with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics and pharmacodynamics of denosumab; therefore dose adjustment for renal impairment is not necessary.
Toxicology: Preclinical Safety Data/Nonclinical Toxicology: Carcinogenicity: The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.
Mutagenicity: The genotoxic potential of denosumab has not been evaluated.
Impairment of Fertility: Denosumab had no effect on female fertility or male reproductive organs in monkeys at exposures that were 9.5- to 16-fold higher, respectively, than the human exposure at 120 mg SC administered once every 4 weeks.
Animal Pharmacology: Denosumab has been shown to be a potent inhibitor of bone resorption via inhibition of RANK ligand.
Since 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, such as OPG-Fc and RANK-Fc, were used to evaluate the pharmacodynamic properties of denosumab in rodent models. In mouse bone metastasis models of estrogen receptor positive and negative human breast cancer, prostate cancer, and non-small cell lung cancer, OPG-Fc reduced osteolytic, osteoblastic, and osteolytic/osteoblastic lesions, delayed formation of de novo bone metastases, and reduced skeletal tumor growth. When OPG-Fc was combined with hormonal therapy (tamoxifen) or chemotherapy (docetaxel) in these models, there was additive inhibition of skeletal tumor growth in breast, and prostate, or lung cancer respectively. In a mouse model of mammary tumor induction, RANK-Fc delayed tumor formation.
The role of osteoclast-mediated hypercalcemia was evaluated in 2 murine models of humoral hypercalcemia of malignancy through the use of osteoprotegerin (OPG), an endogenous decoy receptor that binds and neutralizes RANKL. In one model, mice were inoculated with syngeneic colon adenocarcinoma cells, and in the other mice were injected with high-dose parathyroid hormone-related protein (PTHrP) (0.5 mg/kg, SC, twice per day). In both models, a single injection of OPG caused more rapid reversal of established hypercalcemia and longer lasting suppression of hypercalcemia than high-dose bisphosphonates.
Adolescent primates dosed with denosumab at 15 times (50 mg/kg dose) and 2.7 times (10 mg/kg dose) the area under the curve (AUC) exposure in adult humans dosed at 120 mg subcutaneously every 4 weeks had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. In neonatal cynomolgus monkeys exposed in utero to denosumab at 50 mg/kg, there was increased postnatal mortality; abnormal bone growth resulting in reduced bone strength, reduced hematopoiesis, and tooth malalignment; absence of peripheral lymph nodes; and decreased neonatal growth. Following a recovery period from birth out to 6 months of age, the effects on bone returned to normal. Minimal to moderate mineralization in multiple tissues was seen in one recovery animal. Maternal mammary gland development was normal. Tissue distribution studies indicated that denosumab does not bind to tissues known for expression of other member of the TNF superfamily, including TNF-related apoptosis-inducing ligand (TRAIL).
Knockout mice lacking RANK or RANKL (1) had an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy) (2) exhibited impairment of lymph node formation (3) exhibited reduced bone growth, altered growth plates and lack of tooth eruption. Reduced bone growth, altered growth plates, and impaired tooth eruption were seen in studies of neonatal rats administered RANKL inhibitors, and these changes were partially reversible when dosing of RANKL inhibitors was discontinued.
Indications/Uses
Skeletal-related Events: 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 the Bone: XGEVA is indicated for the treatment of giant cell tumor of bone in adults or skeletally mature adolescents (see Pharmacology: Pharmacodynamics: Clinical Data under Actions).
Hypercalcemia of Malignancy: XGEVA is indicated for the treatment of hypercalcemia of malignancy that is refractory to intravenous bisphosphonate (see Pharmacology: Pharmacodynamics: Clinical Data under Actions).
Dosage/Direction for Use
Subcutaneous Injection: Administration should be performed by an individual who has been trained in injection techniques. Patients should receive adequate calcium and vitamin D supplementation. No dose adjustment is required for patients with renal impairment.
Skeletal-related Events: 120 mg subcutaneous injection once every 4 weeks.
Giant Cell Tumor of the Bone: 120 mg subcutaneous every 4 weeks with additional 120 mg doses on days 8 and 15 of the first month of therapy.
Hypercalcemia of Malignancy: 120 mg subcutaneous every 4 weeks with additional 120 mg doses on days 8 and 15 of the first month of therapy.
Overdosage
There is no experience with overdosage in human clinical trials.
Contraindications
Clinically significant hypersensitivity to denosumab or any components of XGEVA.
Warnings
This drug may cause harm. It must be used under a physician's control only.
Special Precautions
Hypocalcemia: Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA. Supplementation of calcium and vitamin D is required in all patients, unless hypercalcemia is present. Hypocalcemia can occur during therapy with XGEVA. Monitoring of calcium levels is recommended during treatment, especially in the first weeks of initiating therapy.
In the post-marketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). If hypocalcemia occurs, additional short-term calcium supplementation may be necessary (see Renal Impairment as follows and Adverse Reactions).
Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) has occurred in patients treated with denosumab. In clinical trials, the incidence of ONJ was higher with longer duration of exposure (see Adverse Reactions).
Poor oral hygiene, invasive dental procedures (e.g., tooth extraction), treatment with anti-angiogenic medication, local gum or oral infection were risk factors for ONJ in patients receiving XGEVA in clinical trials.
A dental examination with appropriate preventive dentistry is recommended prior to treatment with XGEVA, especially in patients with risk factors for ONJ. Good oral hygiene practices should be maintained during treatment with XGEVA.
Avoid invasive dental procedures during treatment with XGEVA. For patients in whom invasive dental procedures cannot be avoided, the clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. In patients who develop ONJ during treatment with XGEVA, a temporary interruption of treatment should be considered based on individual risk/benefit assessment until the condition resolves.
Atypical Femoral Fractures: Atypical femoral fracture has been reported with XGEVA. Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur and may be bilateral. Specific radiographic findings characterize these events. Atypical femoral fractures have also been reported in patients with certain comorbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with use of certain pharmaceutical agents (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred without antiresorptive therapy. During XGEVA treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture, and the contralateral femur should also be examined.
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 XGEVA-treated patients with giant cell tumor of bone and patients with growing skeletons weeks to months following treatment discontinuation. After treatment is discontinued, monitor patients for signs and symptoms of hypercalcemia, consider periodic assessment of serum calcium as clinically indicated, and reevaluate the patients' calcium and vitamin D supplementation requirements. Manage hypercalcemia as clinically appropriate (see Hepatic Impairment as follows and Adverse Reactions).
Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation: Multiple vertebral fractures (MVF), not due to bone metastases, may occur following discontinuation of treatment with XGEVA, particularly in patients with risk factors such as osteoporosis or prior fractures.
Advise patients not to interrupt XGEVA therapy without their physician's advice. When XGEVA treatment is discontinued, evaluate the individual patient's risk for vertebral fractures.
Drugs with Same Active Ingredient: XGEVA contains the same active ingredient as found in PROLIA (denosumab). Patients being treated with XGEVA should not receive PROLIA.
Effects on Ability to Drive and Use Machines: No studies on the effect on the ability to drive or use heavy machinery have been performed in patients receiving denosumab.
Renal Impairment: No dosage adjustment is necessary in patients with renal impairment.
There is no need for renal monitoring with XGEVA dosing.
In clinical studies of subjects without advanced cancer with varying degrees of renal function (including patients with severe renal impairment [creatinine clearance < 30 mL/min] or receiving dialysis), there was a greater risk of developing hypocalcemia with increasing degree of renal impairment and in the absence of calcium supplementation. Monitoring calcium levels and adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis (see Hypocalcemia in the previous text).
Hepatic Impairment: No clinical studies were conducted in subjects with hepatic impairment.
Use in Children: The safety and efficacy of XGEVA have not been established in pediatric patients other than skeletally mature pediatric patients with giant cell tumor of bone.
XGEVA is not recommended for use in pediatric patients other than skeletally mature pediatric patients with giant cell tumor of bone. Clinically significant hypercalcemia after treatment discontinuation has been reported in the post-marketing setting in pediatric patients with growing skeletons who received denosumab for giant cell tumor of bone or for unapproved indications (see Hypercalcemia as previously mentioned).
XGEVA was studied in a phase 2 open-label trial that enrolled a subset of 10 pediatric patients (aged 12-17 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 body weight ≥ 45 kg (see Indications and Pharmacology: Pharmacodynamics: Clinical data under Actions).
Adolescent primates dosed with denosumab at 2.8 and 15 times (10 and 50 mg/kg dose) the clinical exposure based on AUC had abnormal growth plates. In neonatal cynomolgus monkeys exposed in utero to denosumab at 50 mg/kg, there was increased postnatal mortality; abnormal bone growth resulting in reduced bone strength, reduced hematopoiesis, and tooth malalignment; absence of peripheral lymph nodes; and decreased neonatal growth. Following a recovery period from birth out to 6 months of age, the effects on bone returned to normal; there were no adverse effects on tooth eruption; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. In neonatal rats, inhibition of RANK ligand (target of denosumab therapy) was associated with inhibition of bone growth, altered growth plates and inhibited tooth eruption, and these changes were partially reversible upon cessation of RANKL inhibition. Therefore, treatment with denosumab may impair bone growth in children with open growth plates and may inhibit eruption of dentition (see Pharmacology: Toxicology: Animal Pharmacology under Actions).
Use in the Elderly: No overall differences in safety or efficacy were observed between older patients and younger patients. Controlled clinical studies of XGEVA in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 revealed similar efficacy and safety in older and younger patients.
Use In Pregnancy & Lactation
Pregnancy: The safety and efficacy of XGEVA in pregnant women has not been established.
XGEVA is not recommended for use in pregnant women. Women should be advised not to become pregnant during and for at least 5 months after treatment with XGEVA.
At AUC exposures up to 16-fold higher than the human exposure (120 mg every 4 weeks), denosumab showed no evidence of impaired fertility in female cynomolgus monkeys.
In a study of cynomolgus monkeys dosed with denosumab during the period equivalent to the first trimester at AUC exposures up to 10-fold higher than the human dose (120 mg every 4 weeks), there was no evidence of maternal or fetal harm. In this study, fetal lymph nodes were not examined.
In another study of cynomolgus monkeys dosed with denosumab throughout pregnancy at AUC exposures 12-fold higher than the human dose (120 mg every 4 weeks), there were increased stillbirths and postnatal mortality; abnormal bone growth resulting in reduced bone strength, reduced hematopoiesis, and tooth malalignment; absence of peripheral lymph nodes; and decreased neonatal growth. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal.
Studies in mice suggest absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum.
Lactation: It is not known if denosumab is excreted in human milk. Because denosumab has the potential to cause adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug.
Adverse Reactions
The adverse reactions identified in the clinical trials and from post-marketing experience with XGEVA are presented in table as follows.
Frequency is provided by CIOMS category [e.g., Very common (≥ 10%), common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%), rare (≥ 0.01% and < 0.1%), and very rare (< 0.01%)]. (See Table 6.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Drug Hypersensitivity Events: In clinical trials in patients with advanced malignancies involving bone, drug hypersensitivity events were reported rarely in subjects treated with XGEVA. In the post-marketing setting, hypersensitivity, including anaphylactic reactions has been reported.
Hypocalcemia: In the post-marketing setting, severe symptomatic hypocalcemia (including fatal cases) has been reported.
Musculoskeletal Pain: In the post-marketing setting, musculoskeletal pain, including severe cases has been reported.
Osteonecrosis of the Jaw (ONJ): In three phase 3 active-controlled clinical trials in patients with advanced malignancies involving bone, ONJ was confirmed in 1.8% of patients in the 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 or prostate cancer included an XGEVA extension treatment phase (median overall exposure of 14.9 months; range 0.1-67.2) (see Pharmacology: Pharmacodynamics: Clinical Data under Actions). 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).
In a phase 3 double-blind, active-controlled clinical trial in patients with newly diagnosed multiple myeloma, ONJ was confirmed in 4.1% of patients in the XGEVA group (median exposure of 15.8 months; range 1-49.8) and 2.8% of patients in the zoledronic acid group. At the completion of the double-blind treatment phase of this trial, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ in the 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).
In a phase 3 placebo-controlled clinical trial with an extension treatment phase evaluating XGEVA for the prevention of bone metastases in patients with non-metastatic prostate cancer (a patient population for which 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 Femoral Fracture: In the clinical trial program, atypical femoral fracture has been reported uncommonly in patients treated with XGEVA 120 mg and the risk increased with longer duration of treatment. Events have occurred during treatment and up to 9 months after treatment was discontinued.
Lichenoid Drug Eruptions: In the post-marketing experience, lichenoid drug eruptions (e.g., lichen planus-like reactions) have been observed.
Immunogenicity: In clinical studies, neutralizing antibodies have not been observed for XGEVA. Using a sensitive immunoassay, < 1% of patients treated with denosumab tested positive for non-neutralizing binding antibodies, with no evidence of altered pharmacokinetics, pharmacodynamic response or toxicity.
Drug Interactions
No formal drug-drug interaction studies have been conducted with XGEVA.
In clinical trials, XGEVA has been administered in combination with standard anti-cancer treatment and in subjects previously receiving bisphosphonates. The pharmacokinetics and pharmacodynamics of denosumab were not altered, by concomitant chemotherapy and/or hormone therapy nor by previous intravenous bisphosphonate exposure.
Caution For Usage
Special Instructions for Use and Handling: Do not shake.
Single-use Vial: Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial.
Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: This medicinal product must not be mixed with other medicinal products.
Storage
Store in a refrigerator (2°C - 8°C) in the original carton.
Once removed from the refrigerator, XGEVA must not be exposed to temperature above 25°C/77°F and must be used within 30 days. If not used within the 30 days, XGEVA should be discarded. Do not use XGEVA after the expiry date printed on the label.
Prior to administration, XGEVA may be allowed to reach room temperature (up to 25°C/77°F) in the original container.
Do not freeze.
Protect from direct light and heat.
ATC Classification
M05BX04 - denosumab ; Belongs to the class of other drugs affecting bone structure and mineralization. Used in the treatment of bone diseases.
Presentation/Packing
Inj (vial) 120 mg/1.7 mL (70 mg/mL) (clear, colorless to slightly yellow solution) x 1's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in