Indication
XGEVA® is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors.
  • Solid Tumors
  • Multiple Myeloma

From three clinical trials comparing XGEVA® with ZA in patients with bone metastases from solid tumors

Most common ARs reported with XGEVA® in ≥25% of patients 1

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aLaboratory-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]. 1

AR, adverse reaction; ZA, zoledronic acid.

  • The most common serious AR with XGEVA® was dyspnea (any grade, 21%) 1
  • The most common ARs leading to discontinuation of XGEVA® were osteonecrosis and hypocalcemia 1

From a clinical trial comparing XGEVA® with ZA in patients with multiple myeloma

Common ARs reported with XGEVA® in ≥10% of patients 1,2 

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  • The most common serious AR with XGEVA® (≥5%) was pneumonia (8%) 1
  • The most common AR leading to discontinuation of XGEVA® (≥1%) was osteonecrosis of the jaw 1

In an ad hoc analysis,

Acute phase reactions were reported in fewer patients with XGEVA® than with ZA 3,4,†,‡

XGEVA® 120 mg Q4W: n=46 (5%); ZA 4 mg Q4W: n=74 (9%)

Acute phase reaction events were defined as those occurring within the first 3 days of treatment, the most common being pyrexia, fatigue, bone pain, arthralgia, and chills. 4

Not powered for statistical significance.

Q4W, every 4 weeks.

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In the 2-year open-label extension (OLE) of the phase 3 trials in solid tumors,*

No new safety signals were observed in patients who continued or transitioned to XGEVA® 5

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    Objectives
  • Primary: long-term safety and tolerability 5
  • Select: patient incidence of treatment-emergent adverse events 5
  • Treatment transition
  • The OLE phase was not designed to evaluate the efficacy of patients transitioning from ZA to XGEVA® 5
  • Eligible patients (n=1,961) continued on XGEVA® or transitioned from ZA to XGEVA® at their next scheduled dose during the OLE phase 5
  • Results
  • Adverse events in patients who transitioned from ZA to XGEVA® were similar to those observed in patients who continued on XGEVA®  5

*A safety and efficacy evaluation of the primary treatment phase occurred during a double-blinded extension for the 3 independent trials to determine appropriate evaluable patients for an open-label extension phase. Researchers in breast and prostate cancer trials were eligible to continue their patients into a 2-year, open-label extension phase, and the patients in those trials could continue on or transition to XGEVA® 120 mg Q4W at their next scheduled dose. 5

IV, intravenous; MM, multiple myeloma; OST, other solid tumors; Q4W, every 4 weeks; SC, subcutaneous.

Osteonecrosis of the jaw (ONJ) is a serious adverse reaction reported in the XGEVA® clinical trials

  • Rates
  • Management

SCROLL DOWN FOR RATES IN SOLID TUMORS AND MULTIPLE MYELOMA

Solid tumors

PIVOTAL TRIALS2

In a clinical trial evaluating XGEVA® 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 ONJ was 1.1% during the first year of treatment, 3.0% in the second year, and 7.1% per year thereafter. 1

SRE, skeletal-related event.

Majority of patients with ONJ had known risk factors:

  • 79% of ONJ patients in the trials had a history of tooth extraction, poor oral hygiene, or use of a dental appliance 1

In clinical trials in patients with cancer, the incidence of ONJ was higher with longer duration of exposure. 1

Advise patients to avoid invasive dental procedures while taking XGEVA® 1

Multiple myeloma

multiple-myeloma-sre

Majority of patients who developed ONJ had known risk factors:

  • 54% (n=19) of patients had invasive dental procedures 2
    • In the ZA arm: 54% (n=13) of patients
  • 16 out of 19 patients with invasive dental procedures had teeth extracted 2
    • In the ZA arm: 12 of the 13 patients

Advise patients to avoid invasive dental procedures while taking XGEVA® 1

*Represents initial ONJ grade of triggering event. There were no Grade 4 or Grade 5 ONJ events. 2

SCROLL DOWN FOR MANAGEMENT STRATEGIES IN SOLID TUMORS AND MULTIPLE MYELOMA

Management strategies used in patients who experienced ONJ in the XGEVA® clinical trials

Solid tumors

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Oral rinses and antibiotics were frequently used to treat ONJ in the trials 5,8

Multiple myeloma

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Important Safety Information

Hypocalcemia

Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®. XGEVA® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Concomitant use of calcimimetics and other drugs that can lower calcium levels may worsen hypocalcemia risk and serum calcium should be closely monitored. Advise patients to contact a healthcare professional 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.

Hypersensitivity

XGEVA® is contraindicated in patients with known clinically significant hypersensitivity to XGEVA®, including anaphylaxis that 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.

Drug Products with Same Active Ingredient

Patients receiving XGEVA® should not take Prolia® (denosumab).

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.

Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections.

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 temporarily interrupting XGEVA® therapy if an invasive dental procedure must be performed.

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.

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. Patients 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 Giant Cell Tumor of Bone (GCTB) and in Patients with Growing Skeletons

Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury has been reported in XGEVA®-treated patients with GCTB and in patients with growing skeletons within one year of treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia after treatment discontinuation 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.

Embryo-Fetal Toxicity

XGEVA® can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA® is expected to result in adverse reproductive effects.

Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of XGEVA®. Apprise the patient of the potential hazard to a fetus if XGEVA® is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA®.

Adverse Reactions

The most common adverse reactions in patients receiving XGEVA® with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

For multiple myeloma patients receiving XGEVA®, the most common adverse reactions were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. The most common serious adverse reaction was pneumonia. The most common adverse reaction resulting in discontinuation of XGEVA® was osteonecrosis of the jaw.

Indication

XGEVA® is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors.

Please see full Prescribing Information.

 

Important Safety Information

Hypocalcemia

Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®. XGEVA® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Concomitant use of calcimimetics and other drugs that can lower calcium levels may worsen hypocalcemia risk and serum calcium should be..

References:

  1. XGEVA® (denosumab) prescribing information, Amgen.
  2. Data on file, Amgen; 2018.
  3. Raje N, Terpos E, Willenbacher W, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomized, controlled, phase 3 study. Lancet Oncol. 2018;19(3):370-381.
  4. ZOMETA® (zoledronic acid) prescribing information, Novartis.
  5. Stopeck AT, Fizazi K, Body JJ, et al. Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer. Support Care Cancer. 2016;24(1):447-455.
  6. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer. 2012;48(16):3082-3092.
  7. Data on file, Amgen; 2009.
  8. Saad F, Brown JE, Van Poznak C, et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol. 2012;23(5):1341-1347.