It is important to identify patients at risk for hypocalcaemia. Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiating therapy. Clinical monitoring of calcium levels is recommended before each dose and in patients predisposed to hypocalcaemia within 2 weeks after the initial dose. If any patient presents with suspected symptoms of hypocalcaemia during treatment (see section 4.8 of the SmPC for symptoms) calcium levels should be measured. Patients should be encouraged to report symptoms indicative of hypocalcaemia.
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 it can occur later.
Concomitant glucocorticoid treatment is an additional risk factor for hypocalcaemia.
Patients receiving Prolia® may develop skin infections (predominantly cellulitis) leading to hospitalization. Patients should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis.
Osteonecrosis of the jaw (ONJ)
ONJ has been reported rarely in patients receiving Prolia® for osteoporosis (see section 4.8 of the SmPC).
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 in patients with concomitant risk factors.
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. anaemia, coagulopathies, infection), smoking.
- Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.
- Poor oral hygiene, periodontal disease, poorly fitting dentures, history of 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 Prolia® 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 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 femoral fractures
Atypical femoral fractures have been reported in patients receiving denosumab. 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 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 anti-resorptive 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 Prolia® 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.
Long-term anti-resorptive treatment
Long-term anti-resorptive treatment (including both denosumab and bisphosphonates) may contribute to an increased risk for adverse outcomes such as osteonecrosis of the jaw and atypical femoral fractures due to significant suppression of bone remodelling.
Concomitant treatment with other denosumab-containing medicinal products
Patients being treated with Prolia® should not be treated concomitantly with other denosumab-containing medicinal products (for prevention of skeletal-related events in adults with bone metastases from solid tumours).
Patients with severe renal impairment (creatinine clearance <30 mL/min) or receiving dialysis are at greater risk of developing hypocalcaemia. The risks of developing hypocalcaemia and accompanying parathyroid hormone elevations increase with increasing degree of renal impairment. Adequate intake of calcium, vitamin D and regular monitoring of calcium is especially important in these patients, see above.
Dry natural rubber
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.
Warnings for excipients
This medicine contains 47 mg sorbitol in each mL of solution. The additive effect of concomitantly administered products contaning sorbitol (or frutose) and dietary intake of sorbitol (or frutose) should be taken into account.
This medicinal product contains less than 1 mmol sodium (23 mg) per 60 mg that is to say essentially 'sodium-free'.