Xgeva Special Precautions

Drug Products with Same Active Ingredient: Denosumab (XGEVA) includes the same active ingredient (denosumab) found in denosumab (Prolia). Patients receiving denosumab (XGEVA) should not take denosumab (Prolia).
Hypersensitivity: Clinically significant hypersensitivity including anaphylaxis has been reported with use of denosumab (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 denosumab (XGEVA) therapy permanently [see Hypersensitivity under Contraindications and Postmarketing Experience under Adverse Reactions].
Hypocalcemia: Denosumab (XGEVA) can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to denosumab (XGEVA) treatment. Monitor calcium levels, throughout denosumab (XGEVA) therapy, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when denosumab (XGEVA) is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare provider for symptoms of hypocalcemia [see Hypocalcemia under Contraindications and Adverse Reactions].
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 [see Clinical Trials Experience under Adverse Reactions, Renal Impairment under Precautions, and Pharmacology: Pharmacokinetics under Actions].
Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) has been reported in patients receiving denosumab (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 Clinical Trials Experience under Adverse Reactions]. 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 denosumab (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 denosumab (XGEVA) and periodically during denosumab (XGEVA) therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with denosumab (XGEVA). Consider temporary discontinuation of denosumab (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 denosumab (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 denosumab (XGEVA) [see Clinical Trial Experience under Adverse Reactions]. 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 denosumab (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 denosumab (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 and in Patients with Growing Skeletons: Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury has been reported in denosumab (XGEVA)-treated patients with giant cell tumor of bone and patients with growing skeletons. Hypercalcemia has been reported within the first year after treatment discontinuation. After treatment is discontinued, monitor patients for signs and symptoms of hypercalcemia, assess serum calcium periodically, reevaluate the patient's calcium and vitamin D supplementation requirements and manage patients as clinically appropriate [see Adverse Reactions and Use in Children as follows].
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 denosumab (XGEVA) treatment is discontinued, evaluate the individual patient's risk for vertebral fractures.
Embryo-Fetal Toxicity: Based on data from animal studies and its mechanism of action, denosumab (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 denosumab (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 denosumab (XGEVA). Advise pregnant women and females of reproductive potential that exposure to denosumab (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 denosumab (XGEVA) [see Use in Pregnancy & Lactation and Pharmacology: Mechanism of Action under Actions].
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 Hypocalcemia previously, Clinical Trial Experience under Adverse Reactions, and Pharmacology: Pharmacokinetics under Actions].
Use in Children: The safety and efficacy of denosumab (XGEVA) have not been established in pediatric patients except in skeletally mature adolescents with giant cell tumor of bone. Denosumab (XGEVA) is recommended only for treatment of skeletally mature adolescents with giant cell tumor of bone [see Giant Cell Tumor of Bone under Indications]. 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 Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in Patients with Growing Skeletons under Precautions and Postmarketing Experience under Adverse Reactions].
Denosumab (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 Giant Cell Tumor of Bone under Indications and Pharmacology: Pharmacodynamics: Clinical Trials: Giant Cell Tumor of Bone under Actions]. 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 Clinical Trials Experience under Adverse Reactions and Pharmacology: Pharmacodynamics: Clinical Trials: Giant Cell Tumor of Bone under Actions].
Treatment with denosumab (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 denosumab (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 Pregnancy & Lactation].
Use in the Elderly: Of the total number of patients in clinical studies that received denosumab (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 20090482 that received denosumab (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.