Denosumab
2018; Elsevier BV; Volume: 56; Issue: 2 Linguagem: Inglês
10.1016/j.jpainsymman.2018.05.021
ISSN1873-6513
AutoresAndrew Wilcock, Sarah Charlesworth, Claire Stark Toller, Rahul Girish, Mary Mihalyo, Paul Howard,
Tópico(s)Bone and Joint Diseases
ResumoTherapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ([email protected]). Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ([email protected]). Off-label use Electrocardiogram End-stage kidney disease Hazard ratio Minute(s) Osteonecrosis of the jaw Palliative Care Formulary Package insert (USA), equivalent to SPC (UK) Per os, by mouth Intravenous Intravenous infusion Non-small cell lung cancer Randomized controlled trial Subcutaneous Skeletal-related event Class: Monoclonal antibody. Indications: Authorized indications vary between products and among countries; consult PI for details. Prevention of skeletal-related events (SRE) in patients with bone metastases from solid tumors and in multiple myeloma; refractory tumor-induced hypercalcemia;1Hu M.I. et al.Denosumab for treatment of hypercalcemia of malignancy.Journal of Endocrinology and Metabolism. 2014; 99: 3144-3152Crossref PubMed Scopus (106) Google Scholar giant cell tumor of bone; treatment of bone loss in patients at high risk of fracture receiving hormone deprivation therapy for early prostate or breast cancer, or long-term systemic glucocorticoid therapy; osteoporosis in postmenopausal women and men. Contra-indications: Hypocalcemia, unhealed lesions from dental or oral surgery (also see Undesirable effects).2MHRA Denosumab (Xgeva, Prolia); intravenous biphosphonates: osteonecrosis of the jaw - further measures to minimise risk.Drug Safety Update. 2015; www.gov.uk/drug-safety-updateGoogle Scholar, 3Ruggiero S.L. et al.Medication-related osteonecrosis of the jaw - 2014 update. Position paper.American Association of Oral and Maxillofacial Surgeons. 2014; www.aaoms.orgGoogle Scholar Denosumab is a human monoclonal antibody that binds Receptor Activator of Nuclear factor Kappa β Ligand (RANKL), a cytokine and member of the tumor necrosis factor superfamily. This prevents interaction between RANKL and the RANK receptor on osteoclasts, inhibiting their maturation, function and survival. Consequentially, bone resorption is inhibited. Bisphosphonates also inhibit osteoclast function (via a different mechanism) and thereby have similar effects. Although denosumab and bisphosphonates share indications and undesirable effects, the latter drugs are significantly less expensive. Denosumab is administered by SC injection. Pharmacokinetics in adults are unaffected by changes in age or renal function, although the risk of hypocalcemia is increased in renal impairment (see Undesirable effects). Pharmacokinetics in hepatic impairment have not been studied but are not expected to be altered. Denosumab is used in a range of clinical settings. It may be the preferred alternative to a bisphosphonate in some settings, e.g. severe renal impairment, or when a bisphosphonate is ineffective. The following highlights its use in populations with serious illness: SRE include pathological fracture, spinal cord compression, pain and need for radiation or surgery to bone. Those used as outcomes vary between studies, as does their definition, e.g. radiological vs. clinical pathological fracture; this variation can limit direct comparison of study findings. Denosumab is superior to zoledronic acid in reducing the risk and rate of SRE in patients with bone metastases from solid tumors, particularly breast cancer.4O'Carrigan B. et al.Bisphosphonates and other bone agents for breast cancer.Cochrane Database of Systematic Reviews. 2017; 10: CD003474PubMed Google Scholar Further, denosumab is more effective in delaying the development of painful SRE and the onset of moderate–severe pain in these patients.5von Moos R. et al.Pain and health-related quality of life in patients with advanced solid tumours and bone metastases: integrated results from three randomized, double-blind studies of denosumab and zoledronic acid.Supportive Care in Cancer. 2013; 21: 3497-3507Crossref PubMed Scopus (71) Google Scholar However, because any analgesic effect of denosumab is modest, patients with existing bone pain should be managed with usual analgesic approaches.6Porta-Sales J. et al.Evidence on the analgesic role of bisphosphonates and denosumab in the treatment of pain due to bone metastases: A systematic review within the European Association for Palliative Care guidelines project.Palliative Medicine. 2017; 31: 5-25Crossref PubMed Scopus (42) Google Scholar, 7Van Poznak C. et al.Role of bone-modifying agents in metastatic breast cancer: An American society of clinical oncology-cancer care Ontario focused guideline update.Journal of Clinical Oncology. 2017; 35: 3978-3986Crossref PubMed Scopus (97) Google Scholar In contrast to zoledronic acid, which is considered cost-effective in the prevention of SRE associated with advanced cancer, denosumab yields modest health gains at substantial additional cost.8Andronis L. et al.Cost-effectiveness of treatments for the management of bone metastases: A systematic literature review.PharmacoEconomics. 2018; 36: 301-322Crossref PubMed Scopus (12) Google Scholar Nonetheless, specialty guidelines generally recommend the preventative use of either zoledronic acid or denosumab for all patients with bone metastases arising from breast or hormone-refractory prostate cancer, and for selected patients with other solid tumors, i.e. those considered at high risk of a SRE with a likely prognosis >3 months.7Van Poznak C. et al.Role of bone-modifying agents in metastatic breast cancer: An American society of clinical oncology-cancer care Ontario focused guideline update.Journal of Clinical Oncology. 2017; 35: 3978-3986Crossref PubMed Scopus (97) Google Scholar, 9Coleman R. et al.Bone health in cancer patients: ESMO Clinical Practice Guidelines.Annals of Oncology. 2014; 25 Suppl 3: 124-137Crossref Scopus (384) Google Scholar Apart from cost, other factors influencing choice between zoledronic acid and denosumab include route of administration (IV vs. SC) and the risks of renal toxicity, an acute phase response (both lower with denosumab), and hypocalcemia (lower with zoledronic acid). The preventative effects on SRE of zoledronic acid and denosumab do not overall translate into improved survival.10Sun L. Yu S. Efficacy and safety of denosumab versus zoledronic acid in patients with bone metastases: a systematic review and meta-analysis.American Journal of Clinical Oncology. 2013; 36: 399-403Crossref PubMed Scopus (40) Google Scholar However, a post hoc analysis of data from one study of patients with NSCLC found that, compared with zoledronic acid, denosumab was associated with a better median survival (9.5 vs. 8 months; HR 0.8 [0.7–0.9], p=0.01).11Scagliotti G.V. et al.Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study.Journal of Thoracic Oncology. 2012; 7: 1823-1829Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar Although this finding is not definitive (results from a large RCT are awaited), it is suggested that it may relate to the potentially disruptive effects of denosumab on the tumor–bone microenvironment ± a direct inhibitory effect on RANK-expressing cancer cells.11Scagliotti G.V. et al.Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study.Journal of Thoracic Oncology. 2012; 7: 1823-1829Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar In multiple myeloma, denosumab is non-inferior to zoledronic acid in delaying the time to first SRE, but is associated with a lower incidence of renal toxicity (12% vs. 17%).12Raje N. et al.Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study.Lancet Oncology. 2018; 19: 370-381Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar Although specialty guidelines note that denosumab is an option, particularly in those with renal impairment, generally they favour an IV bisphosphonate, based on their lower cost and more flexible dosing interval, e.g. zoledronic acid can be reduced to every 3 months in those without active myeloma on maintenance treatment.13Anderson K. et al.Role of bone-modifying agents in multiple myeloma: American Society of Clinical Oncology Clinical Practice guideline update.Journal of Clinical Oncology. 2018; 36: 812-818Crossref PubMed Scopus (74) Google Scholar A post hoc analysis of a multiple myeloma subgroup had initially raised concerns that denosumab, compared with zoledronic acid, was associated with a worse overall survival.14Hageman K. et al.The role of denosumab for prevention of skeletal-related complications in multiple myeloma.Annals of Pharmacotherapy. 2013; 47: 1069-1074Crossref PubMed Scopus (19) Google Scholar However, no difference was subsequently found in a large RCT and denosumab is now authorized for use in multiple myeloma.12Raje N. et al.Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study.Lancet Oncology. 2018; 19: 370-381Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar Androgen and estrogen deprivation therapy accelerates bone turnover leading to a reduction in bone mineral density (BMD) and a 40–50% increase in fracture incidence. Thus, specialty guidelines generally suggest that in early stage prostate or breast cancer, men treated with androgen deprivation therapy or women treated with an aromatase inhibitor or ovarian suppression (including premenopausal women rendered prematurely postmenopausal, e.g. by chemotherapy) should have their bone health monitored every 1–2 years for fracture risk.9Coleman R. et al.Bone health in cancer patients: ESMO Clinical Practice Guidelines.Annals of Oncology. 2014; 25 Suppl 3: 124-137Crossref Scopus (384) Google Scholar An overall fracture risk is determined based on BMD and the presence of additional risk factors, e.g. age >65 years, current or past smoker, personal or family history of fragility fracture, long-term glucocorticoid use. Correctable risk factors should be addressed, and all advised to consume a calcium enriched diet, to exercise moderately and take vitamin D supplements, with bisphosphonate or denosumab therapy reserved for those at greatest risk. These recommendations, including monitoring bone health, can also be applied to patients receiving long-term systemic glucocorticoid therapy. In prostate cancer, denosumab 60mg every 6 months reduced the incidence of vertebral fracture from 4% to 1.5% in a 3 year RCT.15Smith M.R. et al.Denosumab in men receiving androgen-deprivation therapy for prostate cancer.New England Journal of Medicine. 2009; 361: 745-755Crossref PubMed Scopus (928) Google Scholar However, zoledronic acid 4mg every 6–12 months is an accepted alternative.9Coleman R. et al.Bone health in cancer patients: ESMO Clinical Practice Guidelines.Annals of Oncology. 2014; 25 Suppl 3: 124-137Crossref Scopus (384) Google Scholar In breast cancer, the use of a bisphosphonate PO/IV or denosumab 60mg appears sufficient to prevent treatment-related bone loss.9Coleman R. et al.Bone health in cancer patients: ESMO Clinical Practice Guidelines.Annals of Oncology. 2014; 25 Suppl 3: 124-137Crossref Scopus (384) Google Scholar Denosumab is of benefit in hypercalcemia (albumin-corrected plasma calcium >12mg/dL) that has failed to respond to bisphosphonate therapy. Initial dosing is at 1–2 week intervals (see Dose and use). In a large case series, calcium levels were ≤11.6mg/dL in two thirds of patients, by day 10, with normocalcemia achieved in one third. Overall, a partial or complete response was seen in 70% and 64% of patients respectively, with a median duration of response of 15 weeks.1Hu M.I. et al.Denosumab for treatment of hypercalcemia of malignancy.Journal of Endocrinology and Metabolism. 2014; 99: 3144-3152Crossref PubMed Scopus (106) Google Scholar Such use is authorized in the USA. Denosumab is used to impede the growth of giant cell tumors of the bone in skeletally mature adolescents and adults, improving local control and/or facilitating less invasive surgical treatments.16Muller D.A. et al.Risks and benefits of combining denosumab and surgery in giant cell tumor of bone-a case series.World Journal of Surgical Oncology. 2016; 14: 281Crossref PubMed Scopus (56) Google Scholar Bio-availability 60–80% SC (partly due to pre-systemic catabolism). Onset of action 3 days (80% reduction in bone resorption markers ≤1 week). Time to peak plasma concentration 10 days. Plasma halflife 28 days. Duration of action weeks–months. Renal impairment or ESKD (increased risk of hypocalcemia). Patients with risk factors for osteonecrosis of the jaw or of the external auditory canal (see Undesirable effects). Clinically significant pharmacokinetic interactions have not been reported and are unlikely. Very common (>10%): breathlessness, diarrhea, hypocalcemia (see below), musculoskeletal pain. Common ( 1%): hypophosphatemia, hyperhidrosis, osteonecrosis of jaw (see below), tooth extraction, rash. New primary cancers (see below). Rare ( 0.01%): atypical femoral fracture. Not known: osteonecrosis of external auditory canal. In patients with bone metastases from solid tumors, hypocalcemia is twice as common with denosumab 120mg (10%) than zoledronic acid (5%).17Lipton A. et al.Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials.European Journal of Cancer. 2012; 48: 3082-3092Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar In multiple myeloma, the incidence is 17% vs. 12%, respectively.12Raje N. et al.Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study.Lancet Oncology. 2018; 19: 370-381Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar It mostly occurs ≤2 weeks of starting treatment and can be severe and life-threating.18MHRA Denosumab: updated recommendations.Drug Safety Update. 2014; www.gov.uk/drug-safety-updateGoogle Scholar Those with renal impairment or ESKD are at increased risk. Severe hypocalcemia is rare with denosumab 60mg, and generally occurs in those with additional risk factors for hypocalcemia, e.g. electrolyte imbalance, severe renal impairment/dialysis.17Lipton A. et al.Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials.European Journal of Cancer. 2012; 48: 3082-3092Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 19Agarwal M. et al.Severe symptomatic hypocalcemia after denosumab administration in an end-stage renal disease patient on peritoneal dialysis with controlled secondary hyperparathyroidism.British Journal of Medicine and Medical Research. 2013; 3: 1398-1406Crossref Google Scholar Pre-existing hypocalcemia must be corrected before starting denosumab. Except when used for tumor-induced hypercalcemia, daily oral supplementation with calcium and vitamin D is recommended. Calcium levels should be monitored regularly, particularly in those at increased risk, e.g. severe renal impairment/dialysis (see Dose and use).18MHRA Denosumab: updated recommendations.Drug Safety Update. 2014; www.gov.uk/drug-safety-updateGoogle Scholar The incidence of osteonecrosis of the jaw (ONJ) with denosumab 120mg is similar to that with zoledronic acid in patients with bone metastases from solid tumors (∼1.5%) and multiple myeloma (∼4%).12Raje N. et al.Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study.Lancet Oncology. 2018; 19: 370-381Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, 17Lipton A. et al.Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials.European Journal of Cancer. 2012; 48: 3082-3092Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar Duration of exposure, history of tooth extraction, poor oral hygiene, use of a dental appliance and concurrent or previous chemotherapy affect the risk of ONJ. The risk of this complication continues for ≤5 months after stopping treatment. Patients should be counselled and issued with cards to remind them of the precautions to follow before and during treatment, including the need for dental check-ups. Unhealed lesions from dental or other oral surgery is a contra-indication to the use of denosumab 120mg.2MHRA Denosumab (Xgeva, Prolia); intravenous biphosphonates: osteonecrosis of the jaw - further measures to minimise risk.Drug Safety Update. 2015; www.gov.uk/drug-safety-updateGoogle Scholar, 3Ruggiero S.L. et al.Medication-related osteonecrosis of the jaw - 2014 update. Position paper.American Association of Oral and Maxillofacial Surgeons. 2014; www.aaoms.orgGoogle Scholar As with bisphosphonates, osteonecrosis of the external auditory canal can also occur. The incidence is unknown. Possible risk factors include corticosteroid use, chemotherapy ± local infection or trauma. Patients should be counselled to report ear pain, discharge, or infection during treatment.20MHRA Denosumab (Prolia, Xgeva): reports of osteonecrosis of the external auditory canal.Drug Safety Update. 2017; www.gov.uk/drug-safety-updateGoogle Scholar The risk of ONJ and osteonecrosis of the external auditory canal is related to cumulative dose and is thus less with denosumab 60mg. Atypical femoral fractures: Denosumab (like bisphosphonates) is associated with rare cases of atypical femoral fracture affecting the subtrochanteric and diaphyseal regions, often bilaterally and occurring with minimal or no trauma. Patients should be advised to report new or unusual thigh, hip or groin pain.21MHRA Denosumab 60mg (Prolia). Rare cases of atypical femoral fracture with long-term use.Drug Safety Update. 2013; www.gov.uk/drug-safety-updateGoogle Scholar If a fracture occurs, denosumab should be discontinued and an orthopedic opinion obtained. Discontinuation fractures: Unlike bisphosphonates, denosumab is not taken up into bone. In osteoporosis, after discontinuation of denosumab, bone turnover increases within 3 months, bone mineral density falls to baseline levels within 12 months and there is an increased risk of multiple vertebral fractures.22Cummings S.R. et al.Vertebral fractures after discontinuation of denosumab: A post hoc analysis of the randomized placebo-controlled FREEDOM Trial and its extension.Journal of Bone Mineral Research. 2018; 33: 190-198Crossref PubMed Scopus (375) Google Scholar Thus, when used for osteoporosis, denosumab should be administered regularly, and if discontinued, a bisphosphonate used instead. By extrapolation, the same considerations apply to its use in the cancer setting and denosumab is generally given indefinitely, until the patient is in the last weeks of life. Infection: RANK receptors are also expressed on immune cells, e.g. lymphocytes, macrophages. Although denosumab potentially could impede immune activation, a meta-analysis of RCTs in osteoporosis suggests no significantly increased risk of severe infection.23von Keyserlingk C. et al.Clinical efficacy and safety of denosumab in postmenopausal women with low bone mineral density and osteoporosis: a meta-analysis.Seminars in Arthritis and Rheumatism. 2011; 41: 178-186Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Nonetheless, in one large RCT, more participants receiving denosumab than placebo experienced severe skin infections, mostly erysipelas/cellulitis of the lower limb, although numbers affected were small (15 vs. 3).24Cummings S.R. et al.Denosumab for prevention of fractures in postmenopausal women with osteoporosis.New England Journal of Medicine. 2009; 361: 756-765Crossref PubMed Scopus (2436) Google Scholar It is suggested that inhibition of RANKL in keratinocytes could reduce the number of regulatory T cells, increasing the inflammatory response to a skin infection and thereby resulting in a more severe appearance.25Watts N.B. et al.Infections in postmenopausal women with osteoporosis treated with denosumab or placebo: coincidence or causal association?.Osteoporosis International. 2012; 23: 327-337Crossref PubMed Scopus (100) Google Scholar Studies in other settings, including advanced cancer, have found no increased risk of infection.25Watts N.B. et al.Infections in postmenopausal women with osteoporosis treated with denosumab or placebo: coincidence or causal association?.Osteoporosis International. 2012; 23: 327-337Crossref PubMed Scopus (100) Google Scholar New primary cancers: In a pooled analysis of four studies of patients with advanced cancer receiving treatment to reduce SRE (median duration ∼1 year), the incidence of a new primary cancer was twice as common with denosumab 120mg (1.1%) vs. zoledronic acid 4mg (0.6%); the full implications of this recent observation are currently uncertain (Amgen, Direct Healthcare Professional Communication, 2018). Generally, either denosumab or a bisphosphonate is used, but not both concurrently. Pre-existing hypocalcemia must be corrected before starting denosumab. During treatment with denosumab (unless given for hypercalcemia) daily oral supplements of elemental calcium ≥500mg and vitamin D 400 units should be given, e.g. Caltrate® 600+D. Denosumab is administered as a SC injection into the thigh, abdomen or upper arm. To reduce discomfort at the site of injection, allow the vial to reach room temperature before use (also see Supply). All plasma calcium values are albumin-corrected. Unless hypercalcemia is present, plasma calcium should be within the normal range before the initial dose of denosumab is given. Thereafter, it should be monitored, at minimum:18MHRA Denosumab: updated recommendations.Drug Safety Update. 2014; www.gov.uk/drug-safety-updateGoogle Scholar•within two weeks of an initial 120mg dose; consider ongoing monitoring, e.g. prior to each dose, in patients with risk factors for hypocalcemia, e.g. severe renal impairment/dialysis•within two weeks of an initial 60mg dose in patients with risk factors for hypocalcemia•before each 6 monthly 60mg dose•if symptoms of hypocalcemia occur; counsel patients to report muscle spasms, twitches, cramps, numbness or tingling in the fingers, toes, or around the mouth. If hypocalcemia occurs, when mild (plasma calcium ≥7.6–8.8mg/dL and asymptomatic) an increase in PO calcium supplementation to 2–4g/24h may suffice. However, severe (plasma calcium 3 months) or multiple myeloma:•give 120mg SC every 4 weeks•continue indefinitely, until patient is in last weeks of life (also see Box B).Box BPrevention of SRE in patients with a limited prognosisPCF notes that:•the cost-effectiveness of the additional benefit of denosumab over zoledronic acid for the prevention of SRE is questionable•the risk of discontinuation fractures is greater with denosumab than zoledronic acid•speciality guidelines generally recommend the use of either.Thus, for patients with cancer referred to a specialist palliative care service who have progressive metastatic bone disease despite monthly denosumab, unless there is severe renal impairment, PCF recommends considering substituting the denosumab for zoledronic acid. For patients with a limited prognosis, the zoledronic acid would need to be given only once, 4 weeks after the last dose of denosumab. However, if necessary, the zoledronic acid can be repeated every 3 months. PCF notes that:•the cost-effectiveness of the additional benefit of denosumab over zoledronic acid for the prevention of SRE is questionable•the risk of discontinuation fractures is greater with denosumab than zoledronic acid•speciality guidelines generally recommend the use of either. Thus, for patients with cancer referred to a specialist palliative care service who have progressive metastatic bone disease despite monthly denosumab, unless there is severe renal impairment, PCF recommends considering substituting the denosumab for zoledronic acid. For patients with a limited prognosis, the zoledronic acid would need to be given only once, 4 weeks after the last dose of denosumab. However, if necessary, the zoledronic acid can be repeated every 3 months. Ongoing trials are comparing dosing intervals of 4 vs. 12 weeks in breast and prostate cancer.7Van Poznak C. et al.Role of bone-modifying agents in metastatic breast cancer: An American society of clinical oncology-cancer care Ontario focused guideline update.Journal of Clinical Oncology. 2017; 35: 3978-3986Crossref PubMed Scopus (97) Google Scholar In multiple myeloma, IV bisphosphonates are generally preferred.13Anderson K. et al.Role of bone-modifying agents in multiple myeloma: American Society of Clinical Oncology Clinical Practice guideline update.Journal of Clinical Oncology. 2018; 36: 812-818Crossref PubMed Scopus (74) Google Scholar In addition to general measures (see Pharmacology):•give 60mg SC every 6 months. Bisphosphonates are suitable alternatives. Generally, used for hypercalcemia refractory to bisphosphonate therapy (see Pharmacology):•give 120mg SC every 4 weeks; give additional 120mg SC doses on days 8 and 15 of the first month of therapy•monitor at regular intervals for ongoing benefit. Authorized as an alternative to surgery. Dose schedule as per tumor-induced hypercalcemia above. XGEVA® (Amgen) Injection 70mg/mL, 120mg vial = $2,661. Prolia® (Amgen) Injection (pre-filled syringe) 60mg/mL, 1mL = $1,420. XGEVA® and Prolia® should be stored long-term in a refrigerator (2–8oC), do not freeze. They may be removed and stored at room temperature, in the original cartons, to protect from light, for up to 14 days (see PIs). Do not shake the vial or injection.
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