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Brief Summary: Consult package insert
for complete Prescribing Information
Fracture [see Warnings and Precautions (5.5)], Hypercalcemia following treatment
discontinuation in patients with Giant Cell Tumor of Bone and in patients with growing
skeletons [see Warnings and Precautions (5.6), and Use in Specific Populations (8.4)].
Multiple vertebral fractures (MVF) following treatment discontinuation [see Warnings
and Precautions (5.7)] .
USE IN SPECIFIC POPULATIONS:
Pregnancy: Risk Summary: Based on findings in animals and its mechanism of action,
Xgeva can cause fetal harm when administered to a pregnant woman [see Clinical
Pharmacology (12.1)]. 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
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). 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.
INDICATIONS AND USAGE:
Multiple Myeloma and Bone Metastasis from Solid Tumors
Xgeva is indicated for the prevention of skeletal-related events in patients with multiple
Clinical Trials Experience:
myeloma and in patients with bone metastases from solid tumors.
Bone Mets from Solid Tumors
DOSAGE AND ADMINISTRATION:
The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy
Important Administration Instructions
trials [see Clinical Trials (14.1)] in which a total of 2841 patients with bone metastasis
Xgeva is intended for subcutaneous route only and should not be administered from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from
intravenously, intramuscularly, or intradermally.
multiple myeloma received at least one dose of Xgeva.
Recommended Dosage:
In Studies 20050136, 20050244, and 20050103, patients were randomized
Multiple Myeloma and Bone Metastasis from Solid Tumors:
to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or
The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by
every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to Data: Animal Data: The effects of denosumab on prenatal development have been
studied in both cynomolgus monkeys and genetically engineered mice in which RANK
vitamin D as necessary to treat or prevent hypocalcemia.
11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater.
ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In
CONTRAINDICATIONS:
Patients who had received IV bisphosphonates were excluded, as were patients with cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy
Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition starting at gestational day 20 and at a pharmacologically active dose 25-fold higher
with Xgeva [see Warnings and Precautions (5.3)].
requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental than the recommended human dose of Xgeva based on body weight, there was
Hypersensitivity. Xgeva is contraindicated in patients with known clinically significant procedure. During the study, serum chemistries including calcium and phosphorus increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings
hypersensitivity to Xgeva [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. were monitored every 4 weeks. Calcium and vitamin D supplementation was in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph
recommended but not required. The median duration of exposure to Xgeva was nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental
WARNINGS AND PRECAUTIONS:
12 months (range: 0.1-41) and median duration on-study was 13 months (range: 0.1-41). dysplasia, and tooth malalignment; and decreased neonatal growth. At birth out to
Drug Products with Same Active Ingredient. Xgeva includes the same active
one month of age, infants had measurable blood levels of denosumab (22-621% of
ingredient (denosumab) found in Prolia. Patients receiving Xgeva should not take Prolia. Of patients who received Xgeva, 46% were female. Eighty-five percent were White, maternal levels).
5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range:
Hypersensitivity. Clinically significant hypersensitivity including anaphylaxis has been 18-93). Seventy-five percent of patients who received Xgeva received concomitant
Following a recovery period from birth out to 6 months of age, the effects on bone
reported with use of Xgeva. Reactions may include hypotension, dyspnea, upper airway chemotherapy.
quality and strength returned to normal; there were no adverse effects on tooth
edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically
eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes
significant allergic reaction occurs, initiate appropriate therapy and discontinue Xgeva The most common adverse reactions in patients (incidence greater than or equal to
25%) were fatigue/asthenia, hypophosphatemia, and nausea. The most common remained absent, while mandibular and mesenteric lymph nodes were present, though
therapy permanently [see Contraindications (4.2) and Adverse Reactions (6.2)].
serious adverse reaction was dyspnea. The most common adverse reactions resulting small; and minimal to moderate mineralization in multiple tissues was seen in one
Hypocalcemia. Xgeva can cause severe symptomatic hypocalcemia, and fatal cases in discontinuation of Xgeva were osteonecrosis and hypocalcemia.
recovery animal. There was no evidence of maternal harm prior to labor; adverse
have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment.
maternal effects occurred infrequently during labor. Maternal mammary gland
Monitor calcium levels, throughout Xgeva therapy, especially in the first weeks of Severe Mineral/Electrolyte Abnormalities: Severe hypocalcemia (corrected serum development was normal. There was no fetal NOAEL (no observable adverse effect
initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients level) established for this study because only one dose of 50 mg/kg was evaluated.
Monitor levels more frequently when Xgeva is administered with other drugs that can treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients Mammary gland histopathology at 6 months of age was normal in female offspring
also lower calcium levels. Advise patients to contact a healthcare provider for symptoms who experienced severe hypocalcemia, 33% experienced 2 or more episodes of exposed to denosumab in utero; however, development and lactation have not been
of hypocalcemia [see Contraindications (4.1), Adverse Reactions (6.1, 6.2), and Patient severe hypocalcemia and 16% experienced 3 or more episodes [see Warnings and fully evaluated.
Counseling Information (17)]. An increased risk of hypocalcemia has been observed in Precautions (5.3) and Use in Specific Populations (8.6)]. Severe hypophosphatemia
clinical trials of patients with increasing renal dysfunction, most commonly with severe (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused
dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic fetal lymph node agenesis and led to postnatal impairment of dentition and bone
with inadequate/no calcium supplementation. Monitor calcium levels and calcium and acid. Osteonecrosis of the Jaw (ONJ). In the primary treatment phases of Studies growth. Pregnant RANKL knockout mice showed altered maturation of the maternal
vitamin D intake [see Adverse Reactions (6.1), Use in Specific Populations (8.6), and 20050136, 20050244, and 20050103, ONJ was confirmed in 1.8% of patients in the mammary gland, leading to impaired lactation [see Use in Specific Populations (8.3)
Xgeva group (median exposure of 12.0 months; range: 0.1-40.5) and 1.3% of patients and Nonclinical Toxicology (13.2)].
Clinical Pharmacology (12.3)].
in the zoledronic acid group. The trials in patients with breast (Study 20050136) or
Osteonecrosis of the Jaw. Osteonecrosis of the jaw (ONJ) has been reported in prostate (Study 20050103) cancer included an Xgeva open label extension treatment Lactation: Risk Summary: There is no information regarding the presence of Xgeva
patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, phase where patients were offered Xgeva 120 mg once every 4 weeks (median overall (denosumab) 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
tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. exposure of 14.9 months; range: 0.1-67.2).
to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio) and maternal
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 The patient-year adjusted incidence (number of events per 100 patient years) of mammary gland development was normal, with no impaired lactation. However,
was higher with longer duration of exposure [see Adverse Reactions (6.1)]. Seventy-nine confirmed ONJ was 1.1% during the first year of treatment, 3.7% in the second year, pregnant RANKL knockout mice showed altered maturation of the maternal mammary
percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use and 4.6% per year thereafter. The median time to ONJ was 20.6 months (range: 4-53) gland, leading to impaired lactation [see Use in Specific Populations (8.1) and Nonclinical
Toxicology (13.2)]. Consider the developmental and health benefits of breastfeeding
of a dental appliance as a predisposing factor. Other risk factors for the development [see Warnings and Precautions (5.4)].
of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, In a placebo-controlled clinical trial with an extension treatment phase evaluating along with the mother’s clinical need for Xgeva treatment and any potential adverse
systemic corticosteroids, diabetes, and gingival infections. Similarly, for Xgeva patients Xgeva for the prevention of bone metastases in patients with non-metastatic prostate effects on the breastfed child from Xgeva or from the underlying maternal condition.
with multiple myeloma that developed ONJ, 58% had a history of invasive dental cancer (a patient population for which Xgeva is not indicated), with longer treatment
Females and Males of Reproductive Potential. Based on findings in animals and
procedures as a predisposing factor.
exposure of up to 7 years, the patient-year adjusted incidence (number of events per its mechanism of action, Xgeva can cause fetal harm when administered to a pregnant
Perform an oral examination and appropriate preventive dentistry prior to the initiation 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3.0% woman [see Use in Specific Populations (8.1)].
of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene in the second year, and 7.1% per year thereafter.
Pregnancy Testing: Verify the pregnancy status of females of reproductive potential
practices. Avoid invasive dental procedures during treatment with Xgeva. Consider Atypical Subtrochanteric and Diaphyseal Fracture
temporary discontinuation of Xgeva therapy if an invasive dental procedure must be Atypical femoral fracture has been reported with Xgeva [see Warnings and Precautions (5.5)]. prior to initiating Xgeva treatment.
performed. There are no data available to suggest the optimal duration of treatment
Contraception: Females: Advise females of reproductive potential to use effective
Multiple Myeloma
interruption.
contraception during therapy, and for at least 5 months after the last dose of Xgeva.
The safety of Xgeva was evaluated in an international, randomized (1:1), double-
Patients who are suspected of having or who develop ONJ while on Xgeva should
blind, active-controlled trial of patients with newly diagnosed multiple myeloma with Pediatric Use. The safety and efficacy of Xgeva have not been established in pediatric
receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery
treatment through disease progression [see Clinical Trials (14.2)]. In this trial, patients patients except in skeletally mature adolescents with giant cell tumor of bone. Xgeva
to treat ONJ may exacerbate the condition. Clinical judgment of the treating healthcare
received 120 mg Xgeva every 4 weeks as a subcutaneous injection (n = 850) or is recommended only for treatment of skeletally mature adolescents with giant cell
provider should guide the management plan of each patient based on individual risk/
4 mg (dose adjusted for renal function) of zoledronic acid intravenously (IV) every tumor of bone [see Indications and Usage (1.2)]. Clinically significant hypercalcemia
benefit assessment.
4 weeks by IV infusion (n = 852). Entry criteria included serum calcium (corrected) from after treatment discontinuation has been reported in pediatric patients with growing
Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. skeletons who received denosumab for giant cell tumor of bone or for unapproved
fracture has been reported with Xgeva [see Adverse Reactions (6.1)]. These fractures Patients who had received IV bisphosphonates were excluded, as were patients with indications [see Adverse Reactions (6.2) and Warnings and Precautions (5.6)].
can occur anywhere in the femoral shaft from just below the lesser trochanter to above prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition
the supracondylar flare and are transverse or short oblique in orientation without requiring oral surgery, non-healed dental/oral surgery, or any planned invasive Xgeva was studied in an open-label trial that enrolled a subset of 10 adolescent
evidence of comminution. Atypical femoral fractures most commonly occur with dental procedure. During the study, serum chemistries including calcium and patients (aged 13-17 years) with giant cell tumor of bone who had reached skeletal
minimal or no trauma to the affected area. They may be bilateral and many patients phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation maturity, defined by at least 1 mature long bone (e.g., closed epiphyseal growth plate
report prodromal pain in the affected area, usually presenting as dull, aching thigh was recommended but not required. The median duration of exposure to Xgeva of the humerus), and had a body weight ≥ 45 kg [see Indications and Usage (1.2)
pain, weeks to months before a complete fracture occurs. A number of reports note was 16 months (range: 1-50) and median duration on-study was 17 months and Clinical Trials (14.3)]. A total of two of six (33%) evaluable adolescent patients
that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at (range: 0.0 – 49). Of patients who received Xgeva, 46% were female, 83% percent had an objective response by retrospective independent assessment of radiographic
the time of fracture. During Xgeva treatment, patients should be advised to report new were White, 13% Asian, 3% Black or African American, and 4% Hispanic/Latino. The response according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain median age of the patients randomized to Xgeva was 63 years (range: 29-91) and all criteria. The adverse reaction profile and efficacy results appeared to be similar in
should be suspected of having an atypical fracture and should be evaluated to rule patients who received Xgeva received concomitant anti-myeloma chemotherapy. The skeletally mature adolescents and adults [see Adverse Reactions (6.1) and Clinical Trials
out an incomplete femur fracture. Patient presenting with an atypical femur fracture adverse reaction profile of Xgeva in patients with multiple myeloma, Study 2009482, (14.3)]. Treatment with Xgeva may impair bone growth in children with open growth
should also be assessed for symptoms and signs of fracture in the contralateral was similar to that observed in Studies 20050136, 20050244, and 20050103. plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the
limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit The most common adverse reactions (incidence ≥ 10%) were diarrhea (34%), target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at
assessment, on an individual basis.
nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral 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
Hypercalcemia Following Treatment Discontinuation in Patients with Giant edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%), 50 mg/kg dose) higher than the recommended human dose of 120 mg administered
Cell Tumor of Bone and in Patients with Growing Skeletons. Clinically significant and headache (11%). The most common serious adverse reaction (incidence ≥ 5%) once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates,
hypercalcemia requiring hospitalization and complicated by acute renal injury has was pneumonia (8%). The most common adverse reaction resulting in discontinuation considered to be consistent with the pharmacological activity of denosumab.
been reported in Xgeva-treated patients with giant cell tumor of bone and patients of Xgeva (≥ 1.0%) was osteonecrosis of the jaw.
Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities,
with growing skeletons. Hypercalcemia has been reported within the first year after Postmarketing Experience:
reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an
treatment discontinuation. After treatment is discontinued, monitor patients for signs The following adverse reactions have been identified during postapproval use of absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone
and symptoms of hypercalcemia, assess serum calcium periodically, reevaluate the Xgeva. Because these reactions are reported voluntarily from a population of uncertain abnormalities recovered once exposure was ceased following birth; however, axillary
patient’s calcium and vitamin D supplementation requirements and manage patients as size, it is not always possible to reliably estimate their frequency or establish a causal and inguinal lymph nodes remained absent 6 months post-birth [see Use in Specific
clinically appropriate [see Adverse Reactions (6) and Use in Specific Populations (8.4)]. relationship to drug exposure. Hypocalcemia: Severe symptomatic hypocalcemia, Populations (8.1)].
Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation. including fatal cases [see Contraindications (4.1) and Warnings and Precautions
Multiple vertebral fractures (MVF) have been reported following discontinuation of (5.3)]. Hypercalcemia: severe symptomatic hypercalcemia following treatment Geriatric Use. Of the total number of patients in clinical studies that received Xgeva
treatment with denosumab. Patients at higher risk for MVF include those with risk discontinuation can occur [see Adverse Reactions (6.0) and Warnings and Precautions (n = 2841) in Studies 20050136, 20050244, and 20050103, 1271 (44%) were
(5.6)]. Hypersensitivity, including anaphylactic reactions [see Contraindications ≥ 65 years old, while 473 patients (17%) were ≥ 75 years old. Of the 859 patients in
factors for or a history of osteoporosis or prior fractures.
(4.2) and Warnings and Precautions (5.2)]. Musculoskeletal pain, including severe Study 2009482 that received Xgeva, 387 patients (45%) were ≥ 65 years old, while
When Xgeva treatment is discontinued, evaluate the individual patient’s risk for
141 patients (16%) were ≥ 75 years old. No overall differences in safety or efficacy
musculoskeletal pain. Positive rechallenge has been reported.
vertebral fractures [see Patient Counseling Information (17)].
were observed between older and younger patients.
Immunogenicity
EMBRYO FETAL TOXICITY: Based on data from animal studies and its mechanism As with all therapeutic proteins, there is potential for immunogenicity. The detection Renal Impairment. Two clinical trials were conducted in patients without cancer and
of action, Xgeva can cause fetal harm when administered to a pregnant woman. In of antibody formation is highly dependent on the sensitivity and specificity of the with varying degrees of renal function. In one study, patients (N = 55) with varying
animal reproduction studies, administration of denosumab to cynomolgus monkeys assay. Additionally, the observed incidence of antibody (including neutralizing degrees of renal function (ranging from normal through end-stage renal disease
throughout pregnancy at a dose 25-fold higher than the recommended human dose of antibody) positivity in an assay may be influenced by several factors including assay requiring dialysis) received a single 60 mg subcutaneous dose of denosumab. In a
Xgeva based on body weight resulted in increased fetal loss, stillbirths, and postnatal methodology, sample handling, timing of sample collection, concomitant medications, second study, patients (N = 32) with severe renal dysfunction (creatinine clearance less
mortality, along with evidence of absent peripheral lymph nodes, abnormal bone and underlying disease. For these reasons, comparison of the incidence of antibodies than 30 mL/minute and/or on dialysis) were given two 120 mg subcutaneous doses
growth and decreased neonatal growth. Verify the pregnancy status of females of to denosumab in the studies described below with the incidence of antibodies to other of denosumab. In both studies, greater risk of developing hypocalcemia was observed
reproductive potential prior to the initiation of Xgeva. Advise pregnant women and studies or to other products may be misleading.
with increasing renal impairment, and with inadequate/no calcium supplementation.
females of reproductive potential that exposure to Xgeva during pregnancy or within
Hypocalcemia was mild to moderate in severity in 96% of patients. Monitor calcium
5 months prior to conception can result in fetal harm. Advise females of reproductive Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) levels and calcium and vitamin D intake [see Warnings and Precautions (5.3), Adverse
potential to use effective contraception during therapy, and for at least 5 months of patients with osseous metastases treated with denosumab doses ranging from Reactions (6.1), and Clinical Pharmacology (12.3)].
after the last dose of Xgeva [see Use in Specific Populations (8.1, 8.3) and Clinical 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
Pharmacology (12.1)].
and Study 20040215 tested positive for binding antibodies. In multiple myeloma
ADVERSE REACTIONS: The following adverse reactions are discussed below and patients in Study 20090482, 1 out of 199 patients with a post baseline result, tested Amgen Manufacturing Limited, a subsidiary of Amgen Inc.
elsewhere in the labeling:
positive for binding antibodies. No patient with positive binding antibodies tested One Amgen Center Drive
Hypersensitivity [see Warnings and Precautions (5.2)], Hypocalcemia [see Warnings positive for neutralizing antibodies as assessed using a chemiluminescent cell-based Thousand Oaks, California 91320-1799
and Precautions (5.3) and Use in Specific Populations (8.6)], Osteonecrosis of the Jaw in vitro biological assay. There was no evidence of altered pharmacokinetic profile, ©2010-2018 Amgen Inc. All rights reserved.
Printed in USA.
[see Warnings and Precautions (5.4)], Atypical Subtrochanteric and Diaphyseal Femoral toxicity profile, or clinical response associated with binding antibody development.