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XGEVA (denosumab)

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XGEVA® Product specifics

XGEVA® (DENOSUMAB) 120 mg subcutaneous injection

XGEVA® is a clear, colourless to slightly yellow solution administered as a 120 mg subcutaneous injection into the upper arm, thigh or abdomen, once every four weeks. Adult patients with giant cell tumour of bone should receive the same dose, but with an additional 120 mg administered on days 8 and 15 of treatment of the first month of therapy. The deliverable volume in the vial is 1.7 ml. The product should be stored in the original outer carton, in the refrigerator. It should be allowed to reach room temperature before administration, for a more comfortable injection.[SmPC, pp. 2, 23; CHMP AR, p. 15]

List of excipients

In addition to denosumab, the active ingredient, XGEVA® contains acetic acid, sodium hydroxide, sorbitol (E420) and water for injections. [SmPC, p. 15]

XGEVA® (DENOSUMAB) indications

XGEVA® is indicated for the prevention of skeletal-related events (SREs) including pathological fracture, radiation to bone, spinal cord compression or surgery to bone in adults with bone metastases from solid tumours.[SmPC, p. 2]

XGEVA® is indicated for the treatment of adults and skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity.[SmPC, p.2]

XGEVA® (DENOSUMAB) is not intended to be used by the following: [SmPC, pp. 3-5]

  • Patients with hypersensitivity to the active substance or any of the ingredients.
  • Patients with unhealed lesions from dental or oral surgery.
  • Patients with severe, untreated hypocalcaemia.
  • Patients with rare hereditary problems involving fructose intolerance. XGEVA® contains sorbitol.
  • Patients being treated concomitantly with other XGEVA® containing products or with bisphosphonates.
  • Pregnant women and women of potential childbearing not using highly effective contraception.
  • Children under the age of 18 years, except for adolescents with giant cell tumour of bone whose bones have stopped growing.

CALCIUM AND VITAMIN D SUPPLEMENTATION

All patients on XGEVA® need calcium and vitamin D supplementation, unless hypercalcaemia is present. If patients have pre-existing hypocalcaemia, this must be corrected prior to initiation of XGEVA® therapy. Monitoring of calcium blood levels should occur prior to the first XGEVA® dose, within two weeks of treatment initiation, and whenever signs or hypocalcaemia symptoms occur.[SmPC, pp. 2, 4]

All patients treated with XGEVA® should receive at least 500 mg calcium and 400 IU vitamin D daily, unless they have hypercalcaemia. [SmPC, p. 2]

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.[SmPC, pp. 3-4]

All patients on XGEVA® (denosumab) need calcium supplementation and
vitamin D supplementation,
unless hypercalcaemia is present. [SmPC, p. 2]


RENAL IMPAIRMENT

Patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia. Regular monitoring of calcium levels is especially important in these patients.[SmPC, p. 4]

OSTEONECROSIS OF THE JAW (ONJ)

ONJ has been reported commonly in patients receiving XGEVA®. 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 preventative dentistry and an individual benefit-risk assessment is recommended prior to treatment with XGEVA®.[SmPC, p. 4]

The following risk factors should be considered when evaluating a patient’s risk of developing ONJ:[SmPC, p. 4]

  • 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, comorbid conditions (e.g. anaemia, coagulopathies, infection), and smoking.
  • Concomitant therapies, including corticosteroids, chemotherapy, angiogenesis inhibitors, and radiotherapy to head and neck.
  • Poor oral hygiene, periodontal disease, poorly fitting dentures, pre-existing dental disease, and invasive dental procedures e.g. tooth extractions.

All patients on XGEVA® should be encouraged to maintain good oral hygiene, receive routine dental checkups, and immediately report oral symptoms such as dental mobility, pain or swelling or non-healing of sores or discharge during treatment. While being treated with XGEVA®, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to XGEVA® administration. [SmPC, p. 4]

The management plan of the patients who develop ONJ should be setup 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.[SmPC, p. 4]

ATYPICAL FRACTURES OF THE FEMUR

Atypical femoral fractures have been reported in patients receiving XGEVA®. 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 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 incomplete femoral fracture. [SmPC, p. 5]

PATIENTS WITH GROWING SKELETONS

XGEVA® is not recommended in patients with growing skeletons. Clinically significant hypercalcaemia has been reported in XGEVA®-treated patients with growing skeletons weeks to months following treatment discontinuation.[SmPC, p. 5]

Patient counselling 

Patients should be informed of potential side effects of XGEVA®. Patients who experience any of the following symptoms should seek medical advice: [Package leaflet]

  • Muscle spasms, muscle twitches, muscle cramps or numbness of the fingers, toes and around the mouth, confusion or loss of consciousness, which could be signs of low calcium levels. Low calcium in the blood may also lead to a change in heart rhythm called QT prolongation, which is seen by electrocardiogram (ECG).
  • Oral symptoms including a loosening of a tooth, pain in the mouth and/or jaw, discharge, numbness or feeling of heaviness in the jaw, swelling or non-healing of sores in the jaw or mouth. These symptoms may suggest osteonecrosis of the jaw (ONJ).
  • New or unusual pain in the hip, thigh or groin area, which may be due to atypical femoral fracture.
  • Allergic reactions including difficulty wheezing or difficulty breathing, skin rashes, itching, or swelling of the face, lips, tongue, throat, or other parts of the body could suggest hypersensitivity.