Denosumab

Atypical femur fractures have been reported in patients receiving denosumab. The fractures may occur anywhere along the femoral shaft (may be bilateral) and commonly occur with minimal to no trauma to the area. Some patients experience prodromal pain weeks or months before the fracture occurs. Because these fractures also occur in osteoporosis patients not treated with denosumab, it is unclear if denosumab therapy is the cause for the fractures; concomitant glucocorticoids may contribute to fracture risk. Advise patients to report new/unusual hip, thigh, or groin pain; and if so, evaluate for atypical/incomplete fracture. Contralateral limb should be assessed if atypical fracture occurs. Consider interrupting therapy in patients who develop an atypical femoral fracture. Following treatment discontinuation, the fracture risk increases, including risk of multiple vertebral fractures; patients with a history of prior fractures or osteoporosis are at higher risk. Vertebral fractures occurred as early as 7 months (average: 19 months) after the last dose of denosumab. Evaluate benefit/risk before initiating denosumab treatment for osteoporosis, especially in patients with prior vertebral fracture. If denosumab is discontinued, evaluate risk for vertebral fracture and consider transitioning to an alternative osteoporosis therapy. Because denosumab is associated with a severe bone turnover rebound following discontinuation, post-denosumab bisphosphonate therapy (IV or oral; dependent

Dermatitis, eczema, and rash (which are not necessarily specific to the injection site) have been reported. Consider discontinuing if severe symptoms occur.

Clinically significant hypersensitivity (including anaphylaxis) has been reported. May include throat tightness, facial edema, upper airway edema, lip swelling, dyspnea, pruritus, rash, urticaria, and hypotension. If anaphylaxis or clinically significant hypersensitivity occurs, initiate appropriate management and permanently discontinue.

Hypercalcemia (clinically significant) may occur in patients with growing skeletons weeks to months following discontinuation of denosumab therapy. Monitor for signs/symptoms of hypercalcemia (eg, nausea, vomiting, headache, decreased alertness) and treat accordingly.

Denosumab may cause or exacerbate hypocalcemia; severe symptomatic cases (including fatalities) have been reported. An increased risk has been observed with increasing renal dysfunction, most commonly severe dysfunction (creatinine clearance • Infection: Incidence of infections may be increased, including serious skin infections, abdominal, urinary, ear, or periodontal infections. Endocarditis has also been reported following use. Patients should be advised to contact their healthcare provider if signs or symptoms of severe infection or cellulitis develop. Use with caution in patients with impaired immune systems or using concomitant immunosuppressive therapy; may be at increased risk for serious infections. Evaluate the need for continued treatment with serious infection.

Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving denosumab. ONJ may manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth/periodontal infection, toothache, gingival ulceration/erosion. Risk factors include invasive dental procedures (eg, tooth extraction, dental implants, oral surgery), cancer diagnosis, immunosuppressive therapy, angiogenesis inhibitor therapy, chemotherapy, systemic corticosteroids, poor oral hygiene, use of a dental appliance, ill-fitting dentures, periodontal and/or other preexisting dental disease, diabetes and gingival infections, local infection with delayed healing, anemia, and/or coagulopathy. In studies of patients with cancer, a longer duration of denosumab exposure was associated with a higher incidence of ONJ, although a majority of patients had predisposing factors, including a history of poor oral hygiene, tooth extraction, or the use of a dental appliance. Patients should maintain good oral hygiene during treatment. A dental exam and appropriate preventive dentistry should be performed prior to therapy. The manufacturer's labeling recommends avoiding invasive dental procedures in patients with bone metastases receiving denosumab for prevention of skeletal-related events and to consider temporary discontinuation of therapy in these patients if invasive dental procedure is required. According to a position paper by the American Associatio

Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported (time to onset of symptoms has varied from one day to several months after initiating therapy). Consider discontinuing use if severe symptoms develop. Disease-related concerns:

The American Society of Clinical Oncology (ASCO)/Cancer Care Ontario (CCO) updated guidelines on the role of bone-modifying agents (BMAs) in metastatic breast cancer patients (ASCO/CCO [Van Poznak 2017]). The guidelines recommend initiating a BMA (denosumab, pamidronate, zoledronic acid) in patients with metastatic breast cancer to the bone. One BMA is not recommended over another (evidence supporting one BMA over another is insufficient). The optimal duration of BMA therapy is not defined; however, the guidelines recommend continuing BMA therapy indefinitely. The analgesic effect of BMAs are modest and BMAs should not be used alone for pain management; supportive care, analgesics, adjunctive therapies, radiation therapy, surgery, and/or systemic anticancer therapy should be utilized.

The American Society of Clinical Oncology (ASCO) has updated guidelines on the role of bone-modifying agents (BMAs) in multiple myeloma (ASCO [Anderson 2018]). The update now includes denosumab as an alternate to zoledronic acid or pamidronate in patients with lytic disease, and as an additional option in adjunctive pain control in patients with pain due to osteolytic disease and patients receiving other interventions for fractures or impending fractures. Denosumab may also be preferred (to zoledronic acid) in patients with renal impairment. The ASCO guidelines recommend continuing the BMA for up to 2 years in multiple myeloma patients; BMAs may then be resumed upon relapse with new onset skeletal-related events. Denosumab has a reversible mechanism of action and therefore should not be discontinued abruptly (refer to Bone fractures [above] for further information).

Use with caution in patients with renal impairment (CrCl Concomitant drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Packaging may contain natural latex rubber. Special populations:

May impair bone growth in children with open growth plates or inhibit eruption of dentition. Indicated only for the treatment of giant cell tumor of bone in adolescents who are skeletally mature. Other warnings/precautions:

Postmenopausal osteoporosis: For use in women at high risk for fracture which is defined as a history of osteoporotic fracture or multiple risk factors for fracture. May also be used in women who failed or did not tolerate other therapies.

Do not administer Prolia and Xgeva to the same patient for different indications.

Denosumab therapy results in significant suppression of bone turnover; the long-term effects of treatment are not known, but may contribute to adverse outcomes such as ONJ, atypical fractures, or delayed fracture healing; monitor.