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 .
Giant Cell Tumor of Bone 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 .
Hypercalcemia of Malignancy Xgeva is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy .
DOSAGE AND ADMINISTRATION : Important Administration Instructions Xgeva is intended for subcutaneous route only and should not be administered intravenously , intramuscularly , or intradermally .
Recommended Dosage : Prevention of Skeletal-Related Events : 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 .
Giant Cell Tumor of Bone : The recommended dose of 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 .
Hypercalcemia of Malignancy : The recommended dose of 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 .
CONTRAINDICATIONS : Hypocalcemia . Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva .
Hypersensitivity . Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva .
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 .
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 . In the postmarketing setting , severe symptomatic hypocalcemia has been reported . Advise patients to contact a healthcare provider for symptoms of hypocalcemia . 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 .
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 . 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 .
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 .
ADVERSE REACTIONS : The following adverse reactions are discussed below and elsewhere in the labeling :
Bone Mets from Solid Tumors ( Trials 1 , 2 , and 3 ) 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 .
Multiple Myeloma The adverse reaction profile of Xgeva in patients with multiple myeloma , was similar to that observed in Trials 1 , 2 , and 3 . 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 .
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Giant Cell Tumor of Bone The adverse reaction profile of Xgeva in patients with giant cell tumor of bone was similar to that reported in Trials 1 , 2 , and 3 . The most common adverse reactions in patients ( per-patient 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 ( per-patient incidence of 0.7 %).
The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis of the jaw ( per-patient incidence of 0.7 %), and tooth abscess or tooth infection ( per-patient 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 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 Trials 4 and 5 , ONJ was confirmed in 4 of 304 ( 1.3 %) patients who received Xgeva . The median time to ONJ was 16 months ( range : 13 to 20 months ) [ see Warnings and Precautions ( 5.4 )].
Hypercalcemia of Malignancy The adverse reaction profile of Xgeva in patients with hypercalcemia of malignancy was similar to that reported in Trials 1 , 2 , 3 , 4 , and 5 . 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 Xgeva therapy .
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 . 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 .
Lactation : Risk Summary : There is no information regarding the presence of Xgeva ( denosumab ) in human milk , the effects on the breastfed infant , 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 . 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 .
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 .
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 . 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 . 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 .
Geriatric Use . Of patients who received Xgeva in Trials 1 , 2 , and 3 , 1260 ( 44 %) were 65 years of age or older . No overall differences in safety or efficacy were observed between these patients 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 .
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