Brief Summary : Consult package insert for complete Prescribing Information
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 myeloma and in patients with bone metastases from solid tumors .
DOSAGE AND ADMINISTRATION : Important Administration Instructions Xgeva is intended for subcutaneous route only and should not be administered intravenously , intramuscularly , or intradermally .
Recommended Dosage : Multiple Myeloma and Bone Metastasis from Solid Tumors : The recommended dose of 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 .
CONTRAINDICATIONS : Hypocalcemia . Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva [ see Warnings and Precautions ( 5.3 )].
Hypersensitivity . Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva [ see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.2 )].
WARNINGS AND PRECAUTIONS : Drug Products with Same Active Ingredient . Xgeva includes the same active ingredient ( denosumab ) found in Prolia . Patients receiving Xgeva should not take Prolia .
Hypersensitivity . Clinically significant hypersensitivity including anaphylaxis has been reported with use of 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 Xgeva therapy permanently [ see Contraindications ( 4.2 ) and Adverse Reactions ( 6.2 )].
Hypocalcemia . Xgeva can cause severe symptomatic hypocalcemia , and fatal cases have been reported . Correct pre-existing hypocalcemia prior to Xgeva treatment . Monitor calcium levels , throughout Xgeva therapy , especially in the first weeks of initiating therapy , and administer calcium , magnesium , and vitamin D as necessary . Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels . Advise patients to contact a healthcare provider for symptoms of hypocalcemia [ see Contraindications ( 4.1 ), Adverse Reactions ( 6.1 , 6.2 ), and Patient Counseling Information ( 17 )]. 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 Adverse Reactions ( 6.1 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )].
Osteonecrosis of the Jaw . Osteonecrosis of the jaw ( ONJ ) has been reported in patients receiving 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 Adverse Reactions ( 6.1 )]. 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 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 Xgeva and periodically during Xgeva therapy . Advise patients regarding oral hygiene practices . Avoid invasive dental procedures during treatment with Xgeva . Consider temporary discontinuation of 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 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 Xgeva [ see Adverse Reactions ( 6.1 )]. 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 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 Xgeva therapy should be considered , pending a risk / benefit assessment , on an individual basis .
Hypercalcemia Following Treatment Discontinuation in Patients with Growing Skeletons . Clinically significant hypercalcemia has been reported in Xgeva-treated patients with growing skeletons weeks to months following treatment discontinuation . Monitor patients for signs and symptoms of hypercalcemia and treat appropriately .
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 Xgeva treatment is discontinued , evaluate the individual patient ’ s risk for vertebral fractures [ see Patient Counseling Information ( 17 )].
EMBRYO FETAL TOXICITY : Based on data from animal studies and its mechanism of action , 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 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 Xgeva . Advise pregnant women and females of reproductive potential that exposure to 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 Xgeva [ see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )].
ADVERSE REACTIONS : The following adverse reactions are discussed below and elsewhere in the labeling :
Hypersensitivity [ see Warnings and Precautions ( 5.2 )], Hypocalcemia [ see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.6 )], Osteonecrosis of the Jaw [ see Warnings and Precautions ( 5.4 )], Atypical Subtrochanteric and Diaphyseal Femoral Fracture [ see Warnings and Precautions ( 5.5 )], Hypercalcemia following treatment discontinuation in patients with growing skeletons [ see Warnings and Precautions ( 5.6 )], Multiple vertebral fractures ( MVF ) following treatment discontinuation [ see Warnings and Precautions ( 5.7 )].
Clinical Trials Experience : Bone Mets from Solid Tumors The safety of Xgeva was evaluated in three randomized , double-blind , double-dummy trials [ see Clinical Trials ( 14.1 )] 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 Xgeva .
In Studies 20050136 , 20050244 , and 20050103 , patients were randomized to receive either 120 mg of 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 Xgeva was 12 months ( range : 0.1-41 ) and median duration on-study was 13 months ( range : 0.1-41 ).
Of patients who received 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 Xgeva received concomitant chemotherapy .
The most common adverse reactions in patients ( incidence greater than or equal to 25 %) were fatigue / asthenia , hypophosphatemia , and nausea . The most common serious adverse reaction was dyspnea . The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia .
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 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 Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.6 )]. Severe hypophosphatemia ( serum phosphorus less than 2 mg / dL or less than 0.6 mmol / L ) occurred in 15.4 % of patients treated with 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 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 Xgeva open label extension treatment phase where patients were offered 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 Warnings and Precautions ( 5.4 )].
In a 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 Subtrochanteric and Diaphyseal Fracture Atypical femoral fracture has been reported with Xgeva [ see Warnings and Precautions ( 5.5 )].
Print-only content
Multiple Myeloma The safety of Xgeva was evaluated in an international , randomized ( 1:1 ), doubleblind , active-controlled trial of patients with newly diagnosed multiple myeloma with treatment through disease progression [ see Clinical Trials ( 14.2 )]. In this trial , patients received 120 mg 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 Xgeva was 16 months ( range : 1-50 ) and median duration on-study was 17 months ( range : 0.0 – 49 ). Of patients who received 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 Xgeva was 63 years ( range : 29-91 ) and all patients who received Xgeva received concomitant anti-myeloma chemotherapy . The adverse reaction profile of Xgeva in patients with multiple myeloma , Study 2009482 , 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 Xgeva ( ≥ 1.0 %) was osteonecrosis of the jaw .
Postmarketing Experience : The following adverse reactions have been identified during postapproval use of 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 ( 4.1 ) and Warnings and Precautions ( 5.3 )]. Hypersensitivity , including anaphylactic reactions [ see Contraindications ( 4.2 ) and Warnings and Precautions ( 5.2 )]. Musculoskeletal pain , including severe musculoskeletal pain . Positive rechallenge has been reported .
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 below 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 .
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 .
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 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 Use in Specific Populations ( 8.3 ) and Nonclinical Toxicology ( 13.2 )].
Lactation : Risk Summary : There is no information regarding the presence of Xgeva ( 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 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 Use in Specific Populations ( 8.1 ) and Nonclinical Toxicology ( 13.2 )]. Consider the developmental and health benefits of breastfeeding along with the mother ’ s clinical need for Xgeva treatment and any potential adverse effects on the breastfed child from Xgeva or from the underlying maternal condition .
Females and Males of Reproductive Potential . Based on findings in animals and its mechanism of action , Xgeva can cause fetal harm when administered to a pregnant woman [ see Use in Specific Populations ( 8.1 )].
Pregnancy Testing : Verify the pregnancy status of females of reproductive potential prior to initiating 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 Xgeva .
Pediatric Use . The safety and efficacy of Xgeva have not been established in pediatric patients except in skeletally mature adolescents with giant cell tumor of bone . Xgeva is recommended only for treatment of skeletally mature adolescents with giant cell tumor of bone [ see Indications and Usage ( 1.2 )].
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 Indications and Usage ( 1.2 ) and Clinical Trials ( 14.3 )]. 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 Adverse Reactions ( 6.1 ) and Clinical Trials ( 14.3 )]. Treatment with 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 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 Specific Populations ( 8.1 )].
Geriatric Use . Of the total number of patients in clinical studies that received 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 2009482 that received 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 .
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 Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.1 ), and Clinical Pharmacology ( 12.3 )].
Amgen Manufacturing Limited , a subsidiary of Amgen Inc . One Amgen Center Drive Thousand Oaks , California 91320-1799 © 2010-2018 Amgen Inc . All rights reserved . Printed in USA .