Xgeva

Dosage Forms And Strengths

Injection: 120 mg/1.7 mL (70 mg/mL) solution in a single-dose vial.

Storage And Handling

Xgeva is supplied in a single-dose vial.

120 mg/1.7 mL 1 vial per carton NDC 55513-730-01

Store Xgevain a refrigerator at 2°C to 8°C (36°F to 46°F) in the originalcarton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label.

Protect Xgeva from direct light and heat.

Avoid vigorous shaking of Xgeva.

Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799. Revised: Jan 2018

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.

Important Administration Instructions

Xgeva is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally.

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.

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.

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.

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-dose or entry.

Hypocalcemia

Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva.

Hypersenstivity

Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva.

WARNINGS

Included as part of the PRECAUTIONS section.

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. Advise patientsto 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 (ONJ)

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 trialsin patients with cancer, the incidence of ONJ was higher with longer duration of exposure. 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 beevaluated to ruleout 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 animalstudies 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 Xgevabased on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripherallymph 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

The carcinogenic potential of denosumab has not been evaluated in long-term animal studies. The genotoxic potential of denosumab has not been evaluated.

Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 6.5-to 25-fold higher than the recommended human dose of 120 mg subcutaneously administered once every 4 weeks, based on body weight (mg/kg).

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 6months 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 minimalto 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. Maternalmammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50mg/kg was evaluated. Mammary gland histopathology at6 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 impairmentof 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 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. 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

Verifythepregnancystatusoffemalesofreproductivepotentialpriortoinitiating Xgevatreatment.

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 13-17years) with giant cell tumor of bone who had reached skeletal maturity, defined by at least 1 mature long bone(e.g., closed epiphysealgrowth 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 Criteriain Solid Tumors (RECIST1.1) 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 doses5 and 25times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4weeks, 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 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 requiringdialysis)received asingle60mg subcutaneous dose of denosumab. In a second study, patients (N = 32) with severe renal dysfunction (creatinine clearance less than 30mL/minuteand/or on dialysis)were given two 120mg 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.

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 3months were similar in patients with and without prior intravenous bisphosphonate therapy and were not altered by concomitant chemotherapy and/or hormone therapy.

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 6months 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 minimalto 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. Maternalmammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50mg/kg was evaluated. Mammary gland histopathology at6 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 impairmentof dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation .

The following adverse reactions are discussed below and elsewhere in the labeling:

• Hypersensitivity
• Hypocalcemia
• Osteonecrosis of the Jaw
• Atypical Subtrochanteric and Diaphyseal Femoral Fracture
• Hypercalcemia following treatment discontinuation in patients with growing skeletons

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 in which a total of 2841patients 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 4mg (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 11.5mg/dL (2 to 2.9mmol/L) and creatinine clearance 30mL/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 dentalor 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 12months (range: 0.1 -41) and median duration on-study was 13months (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 (see Table 1). The most common serious adverse reaction was dyspnea. Themost common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia.

Table 1: Selected^a Adverse Reactions of Any Severity (Studies 20050136, 20050244, and 20050103)

Severe Mineral/Electrolyte Abnormalities

• Severe hypocalcemia (corrected serum calcium less than 7mg/dL or less than 1.75mmol/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.
• 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 120mg once every 4weeks (median overall exposure of 14.9months; 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 20.6months (range: 4-53).

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.

Multiple Myeloma

The safety of Xgeva was evaluated in an international, randomized (1:1), double-blind, active-controlled trial of patients with newly diagnosed multiple myeloma with treatment through disease progression. In this trial, patients received 120 mg Xgeva every 4 weeks as a subcutaneous injection (n=850) or4mg (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 11.5mg/dL (2 to 2.9mmol/L) and creatinine clearance 30mL/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 dentalor jaw condition requiring oralsurgery, 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 63years (range: 29 -91) and allpatients 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.

Hypocalcemia And Hypophosphatemia

Severe hypocalcemia (corrected serum calcium less than 7mg/dL or less than 1.75mmol/L) and severe hypophosphatemia (serum phosphorus less than 2mg/dL or less than 0.6mmol/L) occurred in 2% and 21% patients treated with Xgeva, respectively.

Osteonecrosis Of The Jaw (ONJ)

In the primary treatment phase of Study 2009482, ONJ was confirmed in 4.1% of patients in the Xgeva group (median exposure of 16 months; range: 1 -50) and 2.8% of patients in the zoledronic acid group (median 15 months, range: 1 -45 months). At the completion of the double-blind treatment phase of Study 2009482, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ in the Xgeva group (median exposure of 19.4 months; range 1 -52)was 2.0%during the first year of treatment,5.0%in the second year, and 4.5%per year thereafter. The median time to ONJ was18.7 months (range: 1 -44).

Giant Cell Tumor Of Bone

The safety of Xgeva was evaluated in two single arm trials (Study 20062004 and Study 20040215) 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 Study 20040215. 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:1to60doses) and the median number of months on study was 11 (range: 0 to 54months). Fifty-eight percent of the enrolled patients were women and 80% were White. The median age was 33years (range: 13 to 83 years); a total of 10patients were skeletally mature adolescents (13 to 17years of age).

The adverse reaction profile of Xgeva in patients with giant cell tumor of bone was similar to that reported in Studies 20050136, 20050244, and 20050103. The most common adverse reactions in patients (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 (incidence of 0.7%). The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis of the jaw (incidence of 0.7%), and tooth abscess or tooth infection (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 Study 20062004 and Study 20040215, ONJ was confirmed in 4 of 304 (1.3%) patients who received Xgeva. Themediantime to ONJ was 16months (range: 13 to 20months).

Hypercalcemia Of Malignancy

Xgeva was evaluated in an open-label, single-arm trial (Study 20070315) in which 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy were enrolled.

The adverse reaction profile of Xgeva in patients with hypercalcemia of malignancy was similar to that reported in Studies20050136, 20050244, 20050103, 20062004, and 20040215. 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.

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.
• Hypersensitivity, including anaphylactic reactions.
• Musculoskeletalpain, including severe musculoskeletal pain. Positive re-challenge 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.

There is no experience with overdosage of Xgeva.

In patients with breast cancer and bone metastases, the median reduction in uNTx/Cr was 82% within 1 week following initiation of Xgeva 120 mg administered subcutaneously. In Studies 20050136, 20050244, and 20050103, the median reduction in uNTx/Cr from baseline to Month 3 was approximately 80% in 2075 Xgeva-treated patients.

In a phase 3 study of patients with newly diagnosed multiple myeloma who received SC doses of Xgeva 120 mg every 4 weeks (Q4W), median reductions in uNTx/Cr of approximately 75% were observed by week 5. Reductions in bone turnover markers were maintained, with median reductions of 74% to 79% for uNTx/Cr from weeks 9 to 49 of continued 120 mg Q4W dosing.

Following subcutaneous administration, bioavailability was 62%. Denosumab displayed nonlinear pharmacokinetics at doses below 60mg, but approximately dose-proportional increases in exposure at higher doses.

With multiple subcutaneous doses of 120mg once every 4weeks, up to 2.8-fold accumulation in serum denosumab concentrations was observed and steady state was achieved by 6months. A mean (± standard deviation) serum steady-state trough concentration of 20.5 (± 13.5)mcg/mL was achieved by 6 months. The mean elimination half-life was 28 days.

In patients with newly diagnosed multiple myeloma who received 120 mg every 4 weeks, denosumab concentrations appear to reach steady-state by month 6. In patients with giant cell tumor of bone, after administration of subcutaneous doses of 120mg once every 4weeks with additional 120mg doses on Days 8 and 15 of the first month of therapy, mean (± standard deviation) serum trough concentrations on Day8, 15, and one month after the first dose were 19.0 (± 24.1), 31.6 (± 27.3), 36.4(±20.6) mcg/mL, respectively. Steady-state was achieved in 3 months after initiation of treatment with a mean serum trough concentration of 23.4 (± 12.1) mcg/mL.