Data from FDA - Curated by Marshall Pearce - Last updated 07 November 2017

Indication(s)

1 INDICATIONS AND USAGE Xgeva is a RANK ligand (RANKL) inhibitor indicated for: Prevention of skeletal-related events in patients with bone metastases from solid tumors (1.1) 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 (1.2, 14.2) Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy (1.3) L imitation of u se: Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma 1.1 Bone Metastasis from Solid Tumors Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Limitation of Use: Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma [see Clinical Trials ( 14.1 )]. 1.2 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. 1.3 Hypercalcemia of Malignancy Xgeva is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy [see Clinical Trials ( 14.3 )].

Learning Zones

An epgonline.org Learning Zone (LZ) is an area of the site dedicated to providing detailed self-directed medical education about a disease, condition or procedure.

Breakthrough Cancer Pain Learning Zone

Breakthrough Cancer Pain Learning Zone

Watch video hightlights from the BeCOn OWN 2017 event, including expert opinion, patient experience and panel discussions in the Breakthrough Cancer Pain Learning Zone.

Chronic Lymphocytic Leukaemia (CLL)

Chronic Lymphocytic Leukaemia (CLL)

Refine your knowledge of chronic lymphocytic leukaemia (CLL) with information on pathophysiology, diagnosis, treatment options and more

+ 1 more

Cushing's Syndrome

Cushing's Syndrome

Cushing’s syndrome shares symptoms such as hypertension, glucose intolerance and obesity with other common conditions – how can you confidently diagnose this rare disorder?

+ 2 more

Load more

Related Content

Advisory information

contraindications
4 CONTRAINDICATIONS Hypocalcemia (4.1) Known clinically significant hypersensitivity to Xgeva (4.2) 4. 1 Hypocalcemia Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva [s ee Warnings and Precautions ( 5.3 )] . 4.2 Hypersensitivity Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.2 )].
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed below and elsewhere in the labeling: Hypocalcemia [s ee Warnings and Precautions ( 5.3 )] Osteonecrosis of the Jaw [see Warnings and Precautions ( 5.4 )] Hypercalcemia following treatment discontinuation in patients with growing skeletons [see Warnings and Precautions ( 5.6 )] The most common adverse reactions in patients (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia. Bone Metastasis from Solid Tumors: Most common adverse reactions (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (6.1) Giant Cell Tumor of Bone: Most common adverse reactions (per-patient incidence greater than or equal to 10%) were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity (6.1) Hypercalcemia of Malignancy: Adverse reactions in greater than 20% of patients were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Bone Metastasis from Solid Tumors The safety of 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 Trials 1, 2, and 3, 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. Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3) Body System Xgeva n = 2841 % Zoledronic Acid n = 2836 % GASTROINTESTINAL Nausea 31 32 Diarrhea 20 19 GENERAL Fatigue/Asthenia 45 46 INVESTIGATIONS Hypocalcemiab 18 9 Hypophosphatemiab 32 20 NEUROLOGICAL Headache 13 14 RESPIRATORY Dyspnea 21 18 Cough 15 15 a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria: At least 1% greater incidence in Xgeva-treated patients, or Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b Laboratory-derived and below the central laboratory lower limit of normal [8.3 - 8.5 mg/dL (2.075 - 2.125 mmol/L) for calcium and 2.2 - 2.8 mg/dL (0.71 - 0.9 mmol/L) for phosphorus] 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 Trials 1, 2, and 3, 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 (Trial 1) or prostate (Trial 3) 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 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 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 )] . Giant Cell Tumor of Bone The safety of Xgeva was evaluated in two single arm trials (Trials 4 and 5) [see Clinical Trials ( 14.2 )] in which a total of 304 adult or skeletally mature adolescent patients with giant cell tumor of bone received at least 1 dose of Xgeva. Patients received 120 mg Xgeva subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Patients receiving concurrent bisphosphonate therapy were excluded from enrollment in both studies. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure were excluded from enrollment in Trial 5. During the trial, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. Of the 304 patients who received Xgeva, 145 patients were treated with Xgeva for ≥ 1 year, 44 patients for ≥ 2 years, and 15 patients for ≥ 3 years. The median number of doses received was 14 (range: 1 to 60 doses) and the median number of months on study was 11 (range: 0 to 54 months). Fifty-eight percent of the enrolled patients were women and 80% were White. The median age was 33 years (range: 13 to 83 years); a total of 10 patients were skeletally mature adolescents (13 to 17 years of age). 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 Prec autions ( 5.4 )]. Hypercalcemia of Malignancy Xgeva was evaluated in an open-label, single-arm trial (Trial 6) in which 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy were enrolled [see Clinical Trials ( 14.3 )]. 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. 6.2 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. 6. 3 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. 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 and none of the 304 patients with giant cell tumor of bone in Trials 4 and 5 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. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result 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 antibodies to denosumab with the incidence of antibodies to other products may be misleading.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Xgeva is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally (2.1) Bone Metastasis from Solid Tumors: Administer 120 mg every 4 weeks as a subcutaneous injection in the upper arm, upper thigh, or abdomen (2.2) Giant Cell Tumor of Bone: Administer 120 mg 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 (2.3) Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (2.2, 2.3) Hypercalcemia of Malignancy: Administer 120 mg 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 (2.4) 2.1 Important Administration Instructions Xgeva is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally. 2.2 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 [see Warnings and Precautions ( 5.3 )]. 2.3 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 [see Warnings and Precautions ( 5.3 )]. 2.4 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. 2. 5 Preparation and Administration Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way [see How Supplied/Storage and Handling ( 16 )]. Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pediatric patients: Recommended only for treatment of skeletally mature adolescents with giant cell tumor of bone (8.4) Renal impairment: Patients with creatinine clearance less than 30 mL/min or receiving dialysis are at risk for hypocalcemia. Adequately supplement with calcium and vitamin D (8.6) 8.1 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 )] . 8. 2 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 [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. 8.3 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. 8.4 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 [s ee 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 ( 14.2 )]. 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 ( 14.2 )]. 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 ) ] . 8.5 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. 8.6 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 )].

Interactions

7 DRUG INTERACTIONS No formal drug-drug interaction trials have been conducted with Xgeva. There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy and were not altered by concomitant chemotherapy and/or hormone therapy.

More information

Category Value
Authorisation number BLA125320
Agency product number 4EQZ6YO2HI
Orphan designation No
Product NDC 55513-730
Date Last Revised 23-05-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1046402
Marketing authorisation holder Amgen Inc