Xgeva

/ Amgen

Supplementation of at least 500 mg calcium and 400 IU vitamin D daily is required in all patients, unless hypercalcemia is present.
Patients treated with XGEVA should be given the package leaflet and the patient safety information card.
Prevention of skeletal related events in adults with multiple myeloma and in adults with bone metastases from solid tumors: The recommended dose is 120 mg administered as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm.
Giant cell tumor of bone: The recommended dose of XGEVA is 120 mg administered as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm with additional 120 mg doses on days 8 and 15 of treatment of the first month of therapy.
Patients in the phase II study who underwent complete resection of giant cell tumor of bone did receive an additional 6 months of treatment following the surgery as per study protocol.
Patients with giant cell tumor of bone should be evaluated at regular intervals to determine whether they continue to benefit from treatment. In patients whose disease is controlled by XGEVA, the effect of interruption or cessation of treatment has not been evaluated, however limited data in these patients does not indicate a rebound effect upon cessation of treatment.
Renal impairment: No dose adjustment is required in patients with renal impairment.
Hepatic impairment: The safety and efficacy of denosumab have not been studied in patients with hepatic impairment.
Elderly patients (age ≥ 65): No dose adjustment is required in elderly patients.
Pediatric population: Treatment of skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity: the posology is the same as in adults.
XGEVA is not recommended in pediatric patients (age < 18) other than skeletally mature adolescents with giant cell tumor of bone.
The safety and efficacy of XGEVA have not been established in pediatric patients (age < 18) other than skeletally mature adolescents with giant cell tumor of bone.
Inhibition of RANK/RANK ligand (RANKL) in animal studies has been coupled to inhibition of bone growth and lack of tooth eruption, and these changes were partially reversible upon cessation of RANKL inhibition.
Method of administration: For subcutaneous use.

Prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with multiple myeloma and in adults with bone metastases from solid tumors.
Treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

Hypersensitivity to the active substance or to any of the excipients.
Severe, untreated hypocalcaemia.
Unhealed lesions from dental or oral surgery.

Calcium and Vitamin D supplementation: Supplementation with calcium and vitamin D is required in all patients unless hypercalcaemia is present.
Hypocalcaemia: Pre-existing hypocalcaemia must be corrected prior to initiating therapy with the drug. Hypocalcaemia can occur at any time during therapy with this drug. Monitoring of calcium levels should be conducted (i) prior to the initial dose of the drug, (ii) within two weeks after the initial dose, (iii) if suspected symptoms of hypocalcaemia occur. Additional monitoring of calcium level should be considered during therapy in patients with risk factors for hypocalcaemia, or if otherwise indicated based on the clinical condition of the patient. Patients should be encouraged to report symptoms indicative of hypocalcaemia. If hypocalcaemia occurs while receiving the drug, additional calcium supplementation and additional monitoring may be necessary. In the post marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported, 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 hypocalcaemia. The risk of developing hypocalcaemia 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: Osteonecrosis of the jaw (ONJ) has occurred commonly in patients treated with the drug. In clinical trials, the incidence of ONJ was higher with longer duration of exposure. ONJ has also been diagnosed after treatment with the drug with the majority of cases occurring within 5 months after the last dose. Known risk factors for ONJ, include invasive dental procedures (e.g., tooth extraction, dental implants, oral surgery), poor oral hygiene or other pre-existing dental disease, advanced malignancies, infections, older age, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors, radiotherapy to the head and neck),) smoking, and previous treatment with bisphosphonates. In patients with risk factors for ONJ, an individual benefit-risk assessment should be performed before initiating therapy with this drug.
A dental examination with appropriate preventive dentistry is recommended prior to treatment with this drug. The drug should not be initiated in patients with an active dental or jaw condition requiring surgery or in patients who have not recovered following oral surgery. 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 during treatment with the drug.
While on treatment, patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on therapy with this drug, dental surgery may exacerbate the condition. The management plan of individual 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 treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.
Atypical fractures of the femur: Atypical femoral fractures have been reported in patients receiving this drug. Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Specific radiographic findings characterise 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. 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 therapy with this drug 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 treatment with this drug, 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.
XGEVA is not recommended in patients with growing skeletons. 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 this drug should not be treated concomitantly with other denosumab containing medicinal products (for osteoporosis indications). Patients being treated with this drug should not be treated concomitantly with bisphosphonates. Malignancy in Giant Cell Tumour of Bone or progression to metastatic disease is an infrequent event and a known risk in patients with Giant Cell Tumour 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 GCTB patients treated with this drug.
Warnings for excipients: Patients with rare hereditary problems of fructose intolerance should not use this drug. This medicinal product contains less than 1 mmol sodium (23 mg) per 120 mg i.e. essentially ‘sodium-free’.
See prescribing information for full details.

Overall safety profile is consistent in all approved indications for XGEVA.
Hypocalcemia has very commonly been reported following XGEVA administration, mostly within the first 2 weeks.
Hypocalcemia can be severe and symptomatic. The decreases in serum calcium were generally appropriately managed by calcium and vitamin D supplementation. The most common adverse reactions with XGEVA are musculoskeletal pain. Cases of osteonecrosis of the jaw have been commonly observed in patients taking XGEVA.
See prescribing information for full details.

No interaction studies have been performed. In clinical trials, the drug has been administered in combination with standard anti-cancer treatment and in subjects previously receiving bisphosphonates. There were no clinically-relevant alterations in trough serum concentration and pharmacodynamics of denosumab (creatinine adjusted urinary N-telopeptide, uNTx/Cr) by concomitant chemotherapy and/or hormone therapy or by previous intravenous bisphosphonate exposure.

Pregnancy: There are no or limited amount of data from the use of denosumab in pregnant women. Studies in animals have shown reproductive toxicity.
XGEVA is not recommended for use in pregnant women and women of child-bearing potential not using contraception. Women should be advised not to become pregnant during and for at least 5 months after treatment with XGEVA. Any effects of XGEVA are likely to be greater during the second and third trimesters of pregnancy since monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester.
Breast-feeding: It is unknown whether denosumab is excreted in human milk. A risk to the newborns/infants cannot be excluded.
A decision must be made on whether to abstain from breast-feeding or to abstain from XGEVA therapy, taking into account the benefit of breast-feeding to
the newborn/infant and the benefit of therapy for the woman.
See prescribing information for full details.

There is no experience with overdose in clinical studies. The drug has been administered in clinical studies using doses up to 180 mg every 4 weeks and 120 mg weekly for 3 weeks.

Excipients: Each 1.7 ml of solution contains 78 mg sorbitol (E420).
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Storage: Store in a refrigerator (2°C – 8°C). Do not freeze. Once removed from the refrigerator, XGEVA may be stored at room temperature (up to 25°C) for up to 30 days in the original container. It must be used within this 30 days period.