Denosumab 60mg (Prolia): should not be used in patients under 18 years due to the risk of serious hypercalcaemia
Serious and life-threatening hypercalcaemia has been reported with denosumab 60mg (Prolia) in children and adolescents in clinical trials for osteogenesis imperfecta and during off-label use. Denosumab 60mg (Prolia) is authorised for use in adults with osteoporosis and other bone loss conditions – it should not be used in children and adolescents younger than 18 years.
Advice for healthcare professionals:
- denosumab 60mg (Prolia) is authorised for use only in adults (aged 18 years and older) for treatment of osteoporosis and other bone loss conditions
- serious and life-threatening hypercalcaemia has been reported with denosumab 60mg use in children and adolescents in clinical trials and during off-label use
- hypercalcaemia cases occurred during treatment or in the weeks to months after the last dose
- denosumab 60mg (Prolia) should not be used in children and adolescents younger than 18 years
- denosumab 120mg (as Xgeva) remains authorised for skeletally mature adolescents with giant cell tumour of bone (alongside other authorisations – see Denosumab section below)
- report any suspected adverse drug reactions associated with denosumab or other medicines on a Yellow Card
Advice for healthcare professionals to give to patients or parents and caregivers:
- denosumab 60mg (known as Prolia) is a medicine in adults to treat osteoporosis and other conditions associated with thinning of the bones and an increased risk of fractures
- there have been serious cases of hypercalcaemia (increased calcium in the blood) in children and teenagers receiving denosumab treatment outside of the currently approved indications
- patients on Prolia who are younger than 18 years, and their parents or caregivers, should talk to their specialist about what this means for them
- denosumab 120mg (known as Xgeva) remains authorised for skeletally mature teenagers with some bone tumours (alongside other authorisations – see Denosumab section below)
- all patients on denosumab should read carefully the Patient Information Leaflet and Patient Reminder Card and speak to a healthcare professional if they are concerned about side effects
Denosumab and effects on calcium levels
Denosumab 60mg (Prolia) is indicated in adults for the treatment of osteoporosis in postmenopausal women and men at increased risk of fractures. It is also indicated in adults for treatment of bone loss associated with long-term systemic glucocorticoid therapy or hormone ablation in prostate cancer, in patients who are at increased risk of fractures.
Denosumab 120mg (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. Denosumab 120mg is also indicated in adults for the prevention of skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) with advanced malignancies involving bone.
Denosumab is a monoclonal antibody (IgG2) that prevents bone loss by blocking RANK receptor on the surface of osteoclast precursors and osteoclasts, therefore decreasing bone breakdown. By doing this, bones become stronger and less likely to break easily.
By making bones stronger, denosumab has been associated with low levels of calcium in the blood (hypocalcaemia) – see Drug Safety Update articles from October 2012 and September 2014).
Denosumab 120mg has also been associated with high levels of calcium in the blood (hypercalcaemia) after stopping treatment (rebound hypercalcaemia) in patients with giant cell tumour of bone – see section below.
Cases of hypercalcaemia in children and adolescents with denosumab 60mg
Cases of serious and life-threatening hypercalcaemia requiring hospitalisation and complicated by acute renal injury have been reported in children and adolescents younger than 18 years receiving 60mg denosumab in clinical trials.
These clinical trials were investigating treatment with denosumab in patients younger than 18 years with osteogenesis imperfecta. Osteogenesis imperfecta is a group of rare inherited conditions that cause very fragile bones.
Worldwide, we are also aware of 20 suspected adverse event reports of hypercalcaemia reported up to 26 August 2021, during off-label treatment with Prolia in children and adolescents younger than 18 years. Reports included cases in paediatric patients with osteogenesis imperfecta, as well as in those with various other conditions. There were also a small number of reports of hypercalcaemia in patients younger than 18 years after stopping treatment (rebound hypercalcaemia).
Symptoms of hypercalcaemia include excessive thirst, excessive urination, drowsiness, confusion, loss of concentration, feeling or being sick, constipation, and muscle weakness. Severe hypercalcaemia can cause serious kidney problems (acute renal injury), coma, heart rhythm abnormalities and cardiac arrest.
Review and updates to advice
A recent European review assessed these cases of severe hypercalcaemia and recommended stronger warnings against use of Prolia in children and adolescents younger than 18 years. We have considered this review together with the safety data and agree that the product information should be updated.
The Summary of Product Characteristics (SmPC) for Prolia has been updated to advise that denosumab 60mg should not be used in children and adolescents younger than 18 years because of safety concerns about serious hypercalcaemia. There are also existing warnings that inhibition of RANK/RANK ligand (RANKL) in animal studies may be associated with inhibition of bone growth and lack of tooth eruption.
Denosumab 120mg and risks of clinically significant hypercalcaemia
The SmPC for Xgeva advises that clinically significant hypercalcaemia is a known risk after stopping denosumab 120mg in patients with growing skeletons. Due to the risks, denosumab 120mg is not recommended in patients with growing skeletons.
Clinically significant hypercalcaemia has also been reported in skeletally-mature adolescents and adults for giant cell tumour of bone, sometimes occurring weeks to months after treatment discontinuation (rebound hypercalcaemia) – see advice in Drug Safety Update Xgeva and risk of rebound hypercalcemia.
Report suspected reactions on a Yellow Card
Please continue to report suspected adverse drug reactions to the Yellow Card scheme.
Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:
- the Yellow Card website
- the Yellow Card app; download from the Apple App Store or Google Play Store
- some clinical IT systems for healthcare professionals (EMIS, SystmOne, Vision, MiDatabank, and Ulysses)
When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset timing, treatment dates, and product brand name.
Report suspected side effects to medicines, vaccines, medical device and test kit incidents used in coronavirus (COVID-19) testing and treatment using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.
Article citation: Drug Safety Update volume 15, issue 10: May 2022: 1.