Xgeva Special Precautions

Hypocalcemia: Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA. Supplementation of calcium and vitamin D is required in all patients, unless hypercalcemia is present. Hypocalcemia can occur during therapy with XGEVA. Monitoring of calcium levels is recommended during treatment, especially in the first weeks of initiating therapy.
In the post-marketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). If hypocalcemia occurs, additional short-term calcium supplementation may be necessary (see Renal Impairment as follows and Adverse Reactions).
Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) has occurred in patients treated with denosumab. In clinical trials, the incidence of ONJ was higher with longer duration of exposure (see Adverse Reactions).
Poor oral hygiene, invasive dental procedures (e.g., tooth extraction), treatment with anti-angiogenic medication, local gum or oral infection were risk factors for ONJ in patients receiving XGEVA in clinical trials.
A dental examination with appropriate preventive dentistry is recommended prior to treatment with XGEVA, especially in patients with risk factors for ONJ. Good oral hygiene practices should be maintained during treatment with XGEVA.
Avoid invasive dental procedures during treatment with XGEVA. For patients in whom invasive dental procedures cannot be avoided, the clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. In patients who develop ONJ during treatment with XGEVA, a temporary interruption of treatment should be considered based on individual risk/benefit assessment until the condition resolves.
Atypical Femoral Fractures: Atypical femoral fracture has been reported with XGEVA. Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur and may be bilateral. Specific radiographic findings characterize these events. Atypical femoral fractures have also been reported in patients with certain comorbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with use of certain pharmaceutical agents (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred without antiresorptive therapy. During XGEVA treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture, and the contralateral femur should also be examined.
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 XGEVA-treated patients with giant cell tumor of bone and patients with growing skeletons weeks to months following treatment discontinuation. After treatment is discontinued, monitor patients for signs and symptoms of hypercalcemia, consider periodic assessment of serum calcium as clinically indicated, and reevaluate the patients' calcium and vitamin D supplementation requirements. Manage hypercalcemia as clinically appropriate (see Hepatic Impairment as follows and Adverse Reactions).
Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation: Multiple vertebral fractures (MVF), not due to bone metastases, may occur following discontinuation of treatment with XGEVA, particularly in patients with risk factors such as osteoporosis or prior fractures.
Advise patients not to interrupt XGEVA therapy without their physician's advice. When XGEVA treatment is discontinued, evaluate the individual patient's risk for vertebral fractures.
Drugs with Same Active Ingredient: XGEVA contains the same active ingredient as found in PROLIA (denosumab). Patients being treated with XGEVA should not receive PROLIA.
Effects on Ability to Drive and Use Machines: No studies on the effect on the ability to drive or use heavy machinery have been performed in patients receiving denosumab.
Renal Impairment: No dosage adjustment is necessary in patients with renal impairment.
There is no need for renal monitoring with XGEVA dosing.
In clinical studies of subjects without advanced cancer with varying degrees of renal function (including patients with severe renal impairment [creatinine clearance < 30 mL/min] or receiving dialysis), there was a greater risk of developing hypocalcemia with increasing degree of renal impairment and in the absence of calcium supplementation. Monitoring calcium levels and adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis (see Hypocalcemia in the previous text).
Hepatic Impairment: No clinical studies were conducted in subjects with hepatic impairment.
Use in Children: The safety and efficacy of XGEVA have not been established in pediatric patients other than skeletally mature pediatric patients with giant cell tumor of bone.
XGEVA is not recommended for use in pediatric patients other than skeletally mature pediatric patients with giant cell tumor of bone. Clinically significant hypercalcemia after treatment discontinuation has been reported in the post-marketing setting in pediatric patients with growing skeletons who received denosumab for giant cell tumor of bone or for unapproved indications (see Hypercalcemia as previously mentioned).
XGEVA was studied in a phase 2 open-label trial that enrolled a subset of 10 pediatric patients (aged 12-17 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 body weight ≥ 45 kg (see Indications and Pharmacology: Pharmacodynamics: Clinical data under Actions).
Adolescent primates dosed with denosumab at 2.8 and 15 times (10 and 50 mg/kg dose) the clinical exposure based on AUC had abnormal growth plates. In neonatal cynomolgus monkeys exposed in utero to denosumab at 50 mg/kg, there was increased postnatal mortality; abnormal bone growth resulting in reduced bone strength, reduced hematopoiesis, and tooth malalignment; absence of peripheral lymph nodes; and decreased neonatal growth. Following a recovery period from birth out to 6 months of age, the effects on bone returned to normal; there were no adverse effects on tooth eruption; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. In neonatal rats, inhibition of RANK ligand (target of denosumab therapy) was associated with inhibition of bone growth, altered growth plates and inhibited tooth eruption, and these changes were partially reversible upon cessation of RANKL inhibition. Therefore, treatment with denosumab may impair bone growth in children with open growth plates and may inhibit eruption of dentition (see Pharmacology: Toxicology: Animal Pharmacology under Actions).
Use in the Elderly: No overall differences in safety or efficacy were observed between older patients and younger patients. Controlled clinical studies of XGEVA in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 revealed similar efficacy and safety in older and younger patients.