Special Warning : אזהרת שימוש

4.4    Special warnings and precautions for use
Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Calcium and vitamin D supplementation

Supplementation with calcium and vitamin D is required in all patients unless hypercalcemia is present (see section 4.2).

Hypocalcemia

Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA. Hypocalcemia can occur at any time during therapy with XGEVA. Monitoring of calcium levels should be conducted (i) prior to the initial dose of XGEVA, (ii) within two weeks after the initial dose, (iii) if suspected symptoms of hypocalcemia occur (see section 4.8 for symptoms). Additional monitoring of calcium level should be considered during therapy in patients with risk factors for hypocalcemia, or if otherwise indicated based on the clinical condition of the patient.

Patients should be encouraged to report symptoms indicative of hypocalcemia. If hypocalcemia occurs while receiving XGEVA, additional calcium supplementation and additional monitoring may be necessary.

In the post-marketing setting, severe symptomatic hypocalcemia (including fatal cases) has been reported (see section 4.8), with most cases occurring in the first weeks of initiating therapy, but can occur later.

Renal impairment

Patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis are at greater risk of developing hypocalcemia. The risk of developing hypocalcemia and accompanying elevations in parathyroid hormone increases with increasing degree of renal impairment. Regular monitoring of calcium levels is especially important in these patients.

Osteonecrosis of the jaw (ONJ)

ONJ has been reported commonly in patients receiving XGEVA (see section 4.8).
The start of treatment/new treatment course should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with denosumab.

The following risk factors should be considered when evaluating a patient’s risk of developing ONJ:
•     potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy.
•     cancer, co-morbid conditions (e.g., anemia, coagulopathies, infection), smoking.
•     concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.
•     poor oral hygiene, periodontal disease, poorly fitting dentures, pre-existing dental disease, invasive dental procedures (e.g., tooth extractions).

All patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with denosumab. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to XGEVA administration.

The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of XGEVA treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with denosumab. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or 

trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving denosumab who present with ear symptoms including chronic ear infections.

Atypical fractures of the femur

Atypical femoral fractures have been reported in patients receiving denosumab (see section 4.8). Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Specific radiographic findings characterize these events. Atypical femoral fractures have also been reported in patients with certain co-morbid 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. Similar fractures reported in association with bisphosphonates are often bilateral; therefore the contralateral femur should be examined in denosumab-treated patients who have sustained a femoral shaft fracture. Discontinuation of XGEVA therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient based on an individual benefit-risk assessment. During denosumab 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.

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 weeks to months following treatment discontinuation.

After treatment is discontinued, monitor patients for signs and symptoms of hypercalcemia, consider periodic assessment of serum calcium and re-evaluate the patient’s calcium and vitamin D supplementation requirements (see section 4.8).

XGEVA is not recommended in patients with growing skeletons (see section 4.2). Clinically significant hypercalcemia has also been reported in this patient group weeks to months following treatment discontinuation.

Multiple vertebral fractures (MVF) following treatment discontinuation Cases of multiple vertebral fractures (MVF) have occurred rarely following discontinuation of XGEVA in patients participating in ongoing clinical trials. These fractures were not due to bone metastases and occurred approximately 1 year following discontinuation of treatment with XGEVA, particularly in post-menopausal women with malignancies with risk factors such as osteoporosis or prior (non-vertebral or vertebral) fractures.

Consistent with the pharmacological properties of XGEVA, effects on bone are known to be reversible and bone turnover increases after XGEVA is discontinued.

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.
Others

Patients being treated with XGEVA should not be treated concomitantly with other denosumab containing medicinal products (for osteoporosis indications).

Patients being treated with XGEVA should not be treated concomitantly with bisphosphonates.

Malignancy in giant cell tumor of bone or progression to metastatic disease is an infrequent event and a known risk in patients with giant cell tumor of bone. Patients should be monitored for radiological signs of malignancy, new radiolucency or osteolysis. Available clinical data does not suggest an increased risk of malignancy in giant cell tumor of bone patients treated with XGEVA.

Warnings for excipients

This medicinal product contains sorbitol. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

This medicinal product contains less than 1 mmol sodium (23 mg) per 120 mg dose, that is to say essentially ‘sodium-free’.

Patients with Phenylketonuria (PKU)

The XGEVA 120 mg/1.7 mL solution in a single use vial does not contain phenylalanine. Patients with PKU should be administered XGEVA from the single use vial containing 120 mg in 1.7 mL solution.

Effects on Driving

4.7    Effects on ability to drive and use machines

XGEVA has no or negligible influence on the ability to drive and use machines.