Xgeva (Denosumab)

Xgeva is a RANK ligand (RANKL) inhibitor indicated for:

• Prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors. (
  1.1       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.
  )
  
  
• 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       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

  [see Clinical Trials (

  14.2

  )]

  .
  ,
  14.3       Giant Cell Tumor of Bone

  The safety and efficacy of Xgeva for the treatment of giant cell tumor of bone in adults or skeletally mature adolescents were demonstrated in two open-label trials [Study 20040215 (NCT00396279) and Study 20062004 (NCT00680992)] that enrolled patients with histologically confirmed measurable giant cell tumor of bone that was either recurrent, unresectable, or for which planned surgery was likely to result in severe morbidity. Patients received 120 mg Xgeva subcutaneously every 4 weeks with a loading dose on Days 8 and 15 of the first cycle of therapy. Patients who discontinued Xgeva then entered the safety follow-up phase for a minimum of 60 months. Retreatment with Xgeva while in safety follow-up was allowed for patients who initially demonstrated a response to Xgeva (e.g., in the case of recurrent disease).

  Study 20040215 was a single-arm, pharmacodynamic, and proof of concept trial conducted in 37 adult patients with unresectable or recurrent giant cell tumor of bone. Patients were required to have histologically confirmed giant cell tumor of bone and radiologic evidence of measurable disease from a computed tomography (CT) or magnetic resonance imaging (MRI) obtained within 28 days prior to study enrollment. Patients enrolled in Study 20040215 underwent CT or MRI assessment of giant cell tumor of bone at baseline and quarterly during Xgeva treatment.

  Study 20062004 was a parallel-cohort, proof of concept, and safety trial conducted in 535 adult or skeletally mature adolescent patients with histologically confirmed giant cell tumor of bone and evidence of measurable active disease. Study 20062004 enrolled 19 patients who were 12-16 years of age

  [see Use in Specific Populations (

  8.4

  )].

  Patients enrolled into one of three cohorts: Cohort 1 enrolled 268 patients with surgically unsalvageable disease (e.g., sacral or spinal sites of disease, or pulmonary metastases); Cohort 2 enrolled 252 patients with surgically salvageable disease where the investigator determined that the planned surgery was likely to result in severe morbidity (e.g., joint resection, limb amputation, or hemipelvectomy); Cohort 3 enrolled 15 patients who previously participated in Study 20040215. Patients underwent imaging assessment of disease status at intervals determined by their treating physician.

  A retrospective interim analysis concluded by an independent review committee evaluated objective response in 187 patients enrolled and treated in Study 20040215 and Study 20062004 for whom baseline and at least one post-baseline radiographic assessment were available (27 of 37 patients enrolled in Study 20040215 and 160 of 270 patients enrolled in Cohorts 1 and 2 of Study 20062004).  The primary efficacy outcome measure was objective response rate using Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1.

  The overall objective response rate (RECIST 1.1) was 25% (95% CI: 19, 32). All responses were partial responses. The estimated median time to response was 3 months. In the 47 patients with an objective response, the median duration of follow-up was 20 months (range: 2-44 months), and 51% (24/47) had a duration of response lasting at least 8 months. Three patients experienced disease progression following an objective response.
  )
  
  
• Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. (
  1.3       Hypercalcemia of Malignancy

  Xgeva is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.
  )

• Xgeva should be administered by a healthcare provider. (
  2.1       Important Administration Instructions

  Xgeva should be administered by a healthcare provider.

  Xgeva is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally.
  )
• Xgeva is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally. (
  2.1       Important Administration Instructions

  Xgeva should be administered by a healthcare provider.

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

  [see Warnings and Precautions (

  5.3

  )].
  )
  
  
• 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       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

  )].
  )
  
  
• Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia. (
  2.2       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

  [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

  )].
  )
  
  
• 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       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.
  )

Injection: 120 mg/1.7 mL (70 mg/mL) clear, colorless to pale yellow solution in a single-dose vial.

• Pediatric patients:  Recommended only for treatment of skeletally mature adolescents with giant cell tumor of bone. (
  8.4       Pediatric Use

  The safety and efficacy of Xgeva have not been established in pediatric patients except in skeletally mature adolescents (aged 12–16 years) with giant cell tumor of bone. Xgeva is recommended only for treatment of skeletally mature adolescents (aged 12–16 years) with giant cell tumor of bone

  [see Indications and Usage (

  1.2

  )]

  . Clinically significant hypercalcemia after treatment discontinuation has been reported in pediatric patients with growing skeletons who received denosumab for giant cell tumor of bone or for unapproved indications

  [see Adverse Reactions (

  6.2

  ) and Warnings and Precautions (

  5.6

  )].

  Xgeva was studied in an open-label trial that enrolled a subset of 19 adolescent patients (aged 12-16 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 one of five (20%) 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). 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

  )]

  .

  Animal Data

  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

  )

  ]

  .
  )
  
  
• 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       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/min 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

  )]

  .
  )