Drug Action
Denosumab is a human monoclonal antibody that inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption.
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Drug reference
Denosumab is a human monoclonal antibody that inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption.
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PROLIA ® Osteoporosis in postmenopausal women and in men at increased risk of fractures | Bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures | Bone loss associated with long-term systemic glucocorticoid therapy in patients at increased risk of fracture ▶BY SUBCUTANEOUS INJECTION ▶Adult: 60 mg every 6 months, supplement with calcium and Vitamin D, to be administered into the thigh, abdomen or upper arm XGEVA ® Prevention of skeletal related events in patients with bone metastases ▶BY SUBCUTANEOUS INJECTION ▶Adult: 120 mg every 4 weeks, supplementation of at least calcium 500 mg and Vitamin D 400 units daily should also be taken unless hypercalcaemia is present, to be administered into the thigh, abdomen or upper arm Giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity ▶BY SUBCUTANEOUS INJECTION ▶Adult: 120 mg every 4 weeks, give additional dose on days 8 and 15 of the first month of treatment only, supplementation of at least calcium 500 mg and Vitamin D 400 units daily should also be taken unless hypercalcaemia is present, to be administered into the thigh, abdomen or upper arm
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Hypocalcaemia XGEVA ® Unhealed lesions from dental or oral surgery
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Risk factors for osteonecrosis of the external auditory canal. risk factors for osteonecrosis of the jaw— consider temporary interruption of denosumab if occurs during treatment
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NICE decisions ▶Denosumab for the prevention of osteoporotic fractures in postmenopausal women (October 2010) NICE TA204 Denosumab (Prolia ®) is recommended as a treatment option for the primary prevention of osteoporotic fragility fractures in postmenopausal women at increased risk of fractures: . who are unable to comply with the special instructions for administering alendronate and risedronate, or have an intolerance of, or a contra-indication to, those treatments and . who comply with particular combinations of bone mineral density measurement, age, and independent risk factors for fracture, as indicated in the full NICE guidance. Denosumab (Prolia ®) is recommended as a treatment option for the secondary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures who are unable to comply with the special instructions for administering alendronate and risedronate, or have an intolerance of, or a contra- indication to, those treatments. Patients whose treatment was started within the NHS before this guidance was published should have the option to continue treatment, without change to their funding arrangements, until they and their NHS clinician consider it appropriate to stop. www.nice.org.uk/guidance/ta204 ▶Denosumab for the prevention of skeletal-related events in adults with bone metastases from solid tumours (October 2012) NICE TA265 Denosumab (Xgeva ®) is recommended for the prevention of skeletal-related events in adults with bone metastases from breast cancer and from solid tumours other than prostate if: . bisphosphonates would otherwise be prescribed, and . the manufacturer provides denosumab with the discount agreed in the patient access scheme. Denosumab is not recommended for preventing skeletal- related events in adults with bone metastases from prostate cancer. Patients with bone metastases from solid tumours currently receiving denosumab whose disease does not meet the above criteria can continue treatment until they and their clinician consider it appropriate to stop. www.nice.org.uk/guidance/ta265 Endocrine system Scottish Medicines Consortium (SMC) decisions SMC No. 651/10 The Scottish Medicines Consortium has advised (December 2010) that denosumab (Prolia ®) is accepted for restricted use within NHS Scotland for the treatment of osteoporosis in postmenopausal women at increased risk of fractures who have a bone mineral density T-score <–2.5 and –4.0 and for whom oral bisphosphonates are unsuitable.
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MHRA/CHM ADVICE: DENOSUMAB: ATYPICAL FEMORAL FRACTURES (FEBRUARY 2013) Atypical femoral fractures have been reported rarely in patients receiving denosumab for the long-term treatment (2.5 or more years) of postmenopausal osteoporosis. Patients should be advised to report any new or unusual thigh, hip, or groin pain during treatment with denosumab. Discontinuation of denosumab in patients suspected to have an atypical femoral fracture should be considered after an assessment of the benefits and risks of continued treatment. MHRA/CHM ADVICE: DENOSUMAB: MINIMISING THE RISK OF OSTEONECROSIS OF THE JAW; MONITORING FOR HYPOCALCAEMIA—UPDATED RECOMMENDATIONS (SEPTEMBER 2014) AND DENOSUMAB: OSTEONECROSIS OF THE JAW—FURTHER MEASURES TO MINIMISE RISK (JULY 2015) Denosumab is associated with a risk of osteonecrosis of the jaw (ONJ) and with a risk of hypocalcaemia. Osteonecrosis of the jaw Osteonecrosis of the jaw is a well-known and common side-effect in patients receiving denosumab 120 mg for cancer. Risk factors include smoking, old age, poor oral hygiene, invasive dental procedures (including tooth extractions, dental implants, oral surgery), comorbidity (including dental disease, anaemia, coagulopathy, infection), advanced cancer, previous treatment with bisphosphonates, and concomitant treatments (including chemotherapy, anti- angiogenic biologics, corticosteroids, and radiotherapy to head and neck). The following precautions are now recommended to reduce the risk of ONJ: Denosumab 120 mg (cancer indication) . A dental examination and appropriate preventative dentistry before starting treatment are now recommended for all patients . Do not start denosumab in patients with a dental or jaw condition requiring surgery, or in patients who have unhealed lesions from dental or oral surgery Denosumab 60 mg (osteoporosis indication) . Check for ONJ risk factors before starting treatment. A dental examination and appropriate preventative dentistry are now recommended for patients with risk factors All patients should be given a patient reminder card and informed of the risk of ONJ. Advise patients to tell their doctor if they have any problems with their mouth or teeth before starting treatment, if they wear dentures they should make sure their dentures fit properly before starting treatment, to maintain good oral hygiene, receive routine dental check-ups during treatment, and immediately report any oral symptoms such as dental mobility, pain, swelling, non-healing sores or discharge to a doctor and dentist. Patients should tell their doctor and dentist that they are receiving denosumab if they need dental treatment or dental surgery. Hypocalcaemia Denosumab is associated with a risk of hypocalcaemia. This risk increases with the degree of renal impairment. Hypocalcaemia usually occurs in the first weeks of denosumab treatment, but it can also occur later in treatment. Plasma-calcium concentration monitoring is recommended for denosumab 120 mg (cancer indication): . before the first dose . within two weeks after the initial dose . if suspected symptoms of hypocalcaemia occur . consider monitoring more frequently in patients with risk factors for hypocalcaemia (e.g. severe renal impairment, creatinine clearance less than 30 mL/minute) Plasma-calcium concentration monitoring is recommended for denosumab 60 mg (osteoporosis indication): . before each dose . within two weeks after the initial dose in patients with risk factors for hypocalcaemia (e.g. severe renal impairment, creatinine clearance less than 30 mL/minute) . if suspected symptoms of hypocalcaemia occur All patients should be advised to report symptoms of hypocalcaemia to their doctor (e.g. muscle spasms, twitches, cramps, numbness or tingling in the fingers, toes, or around the mouth). MHRA/CHM ADVICE: DENOSUMAB: REPORTS OF OSTEONECROSIS OF THE EXTERNAL AUDITORY CANAL (JUNE 2017) Osteonecrosis of the external auditory canal has been reported with denosumab and this should be considered in patients who present with ear symptoms including chronic ear infections or in those with suspected cholesteatoma. Possible risk factors include steroid use and chemotherapy, with or without local risk factors such as infection or trauma. The MHRA recommends advising patients to report any ear pain, discharge from the ear, or an ear infection during denosumab treatment. MHRA/CHM ADVICE: DENOSUMAB (XGEVA ®) FOR GIANT CELL TUMOUR OF BONE: RISK OF CLINICALLY SIGNIFICANT HYPERCALCAEMIA FOLLOWING DISCONTINUATION (JUNE 2018) Cases of clinically significant hypercalcaemia (rebound hypercalcaemia) have been reported up to 9 months after discontinuation of denosumab treatment for giant cell tumour of bone. The MHRA recommends that prescribers should monitor patients for signs and symptoms of hypercalcaemia after discontinuation, consider periodic assessment of serum calcium, re- evaluate the patient’s calcium and vitamin D supplementation requirements, and advise patients to report symptoms of hypercalcaemia. Denosumab is not recommended in patients with growing skeletons. MHRA/CHM ADVICE: DENOSUMAB (XGEVA ®) FOR ADVANCED MALIGNANCIES INVOLVING BONE: STUDY DATA SHOW NEW PRIMARY MALIGNANCIES REPORTED MORE FREQUENTLY COMPARED TO ZOLEDRONIC ACID (ZOLEDRONATE) (JUNE 2018) A pooled analysis has shown an increased rate of new primary malignancies in patients given Xgeva ® (1-year cumulative incidence 1.1%) compared with those given zoledronic acid (0.6%), when used for the prevention of skeletal-related events with advanced malignancies involving bone. No treatment-related pattern in individual cancers or cancer groupings were apparent.
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▶Common or very common Abdominal discomfort. cataract. constipation. hypocalcaemia (including fatal cases). increased risk of infection. pain. sciatica. second primary malignancy. skin reactions ▶Uncommon Cellulitis (seek prompt medical attention). hypercalcaemia (on discontinuation) ▶Rare or very rare Atypical femur fracture. hypersensitivity . osteonecrosis
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Ensure effective contraception in women of child-bearing potential, during treatment and for at least 5 months after stopping treatment. Endocrine system
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Manufacturer advises avoid—toxicity in animal studies; risk of toxicity increases with each trimester.
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Manufacturer advises avoid.
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Increased risk of hypocalcaemia if creatinine clearance less than 30 mL/minute.
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Correct hypocalcaemia and vitamin D deficiency before starting. Monitor plasma- calcium concentration during therapy.
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There can be variation in the licensing of different medicines containing the same drug. Solution for injection CAUTIONARY AND ADVISORY LABELS 10 EXCIPIENTS: May contain Sorbitol ▶Prolia (Amgen Ltd) Denosumab 60 mg per 1 ml Prolia 60mg/1ml solution for injection pre-filled syringes | 1 pre-filled disposable injection P £183.00 DT = £183.00 ▶Xgeva (Amgen Ltd) Denosumab 70 mg per 1 ml Xgeva 120mg/1.7ml solution for injection vials | 1 vial P £309.86 DT = £309.86
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Atypical femoral fractures Patients should be advised to report any new or unusual thigh, hip, or groin pain during treatment with denosumab. Osteonecrosis of the jaw All patients should be informed to maintain good oral hygiene, receive routine dental check- ups, and immediately report any oral symptoms such as dental mobility, pain, or swelling to a doctor and dentist. Hypocalcaemia All patients should be advised to report symptoms of hypocalcaemia to their doctor (e.g. muscle spasms, twitches, cramps, numbness or tingling in the fingers, toes, or around the mouth). Patient reminder card A patient reminder card should be provided (risk of osteonecrosis of the jaw).
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60 mg every 6 months, supplement with calcium
First-line fragment. Read the complete Indications and Dose section above.
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120 mg every 4 weeks, supplementation of at
First-line fragment. Read the complete Indications and Dose section above.
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120 mg every 4 weeks, give additional dose on
First-line fragment. Read the complete Indications and Dose section above.
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