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2011年9月19日，美国食品药品管理局(FDA)已批准了Prolia(狄诺塞麦/德尼单抗)的2项新适应证。该药以RANK配体—破骨细胞的一个关键调控子—为靶点。
Solution for injection (injection).
In a pooled analysis of data from all phase II and phase III placebo controlled studies, Influenza-like illness was reported with a crude incidence rate of 1.2% for denosumab and 0.7% for placebo. Although this imbalance was identified via a pooled analysis, it was not identified via a stratified analysis. Description of selected adverse reactions Hypocalcaemia In two phase III placebo-controlled clinical trials in postmenopausal women with osteoporosis, approximately 0.05% (2 out of 4,050) of patients had declines of serum calcium levels (less than 1.88 mmol/l) following Prolia administration. Declines of serum calcium levels (less than 1.88 mmol/l) were not reported in either the two phase III placebo-controlled clinical trials in patients receiving hormone ablation or the phase III placebo-controlled clinical trial in men with osteoporosis. In the post-marketing setting, rare cases of severe symptomatic hypocalcaemia have been reported in patients at increased risk of hypocalcaemia receiving Prolia. Skin infections In phase III placebo-controlled clinical trials, the overall incidence of skin infections was similar in the placebo and the Prolia groups in postmenopausal women with osteoporosis (placebo [1.2%, 50 out of 4,041] versus Prolia [1.5%, 59 out of 4,050]); in men with osteoporosis (placebo [0.8%, 1 out of 120] versus Prolia [0%, 0 out of 120]) and in breast or prostate cancer patients receiving hormone ablation (placebo [1.7%, 14 out of 845] versus Prolia [1.4%, 12 out of 860]). Skin infections leading to hospitalisation were reported in 0.1% (3 out of 4,041) of postmenopausal women with osteoporosis receiving placebo versus 0.4% (16 out of 4,050) of women receiving Prolia. These cases were predominantly cellulitis. Skin infections reported as serious adverse reactions were similar in the placebo (0.6%, 5 out of 845) and the Prolia (0.6%, 5 out of 860) groups in the breast and prostate cancer studies. Osteonecrosis of the jaw In clinical trials in osteoporosis and in breast or prostate cancer patients receiving hormone ablation the (12347 patients, 9912 treated ≥ 1 year), ONJ was reported rarely with Prolia (see section 4.4). Atypical fractures of the femur In the osteoporosis clinical trial program, atypical femoral fractures were reported rarely in patients treated with Prolia (see section 4.4). Cataracts In a single phase III placebo-controlled clinical trial in patients with prostate cancer receiving androgen deprivation therapy (ADT) an imbalance in cataract adverse events was observed (4.7% denosumab, 1.2% placebo). No imbalance was observed in postmenopausal women or men with osteoporosis or in women undergoing aromatase inhibitor therapy for nonmetastatic breast cancer. Diverticulitis In a single phase III placebo-controlled clinical trial in patients with prostate cancer receiving ADT an imbalance in diverticulitis adverse events was observed (1.2% denosumab, 0% placebo). The incidence of diverticulitis was comparable between treatment groups in postmenopausal women or men with osteoporosis and in women undergoing aromatase inhibitor therapy for nonmetastatic breast cancer. Drug-related hypersensitivity reactions In the post-marketing setting, rare events of drug-related hypersensitivity, including rash, urticaria, facial swelling, erythema, and anaphylactic reactions have been reported in patients receiving Prolia. Other special populations In clinical studies, patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis were at greater risk of developing hypocalcaemia in the absence of calcium supplementation. Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis (see section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: United Kingdom Yellow Card Scheme Tel: Freephone 0808 100 3352 Website: www.mhra.gov.uk/yellowcard Ireland Pharmacovigilance Section Irish Medicines Board Kevin O'Malley House Earlsfort Centre Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6767836 Website: www.imb.ie e-mail: imbpharmacovigilance@imb.ie 4.9 Overdose There is no experience with overdose in clinical studies. Denosumab has been administered in clinical studies using doses up to 180 mg every 4 weeks (cumulative doses up to 1,080 mg over 6 months), and no additional adverse reactions were observed. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Drugs for the treatment of bone diseases – Other drugs affecting bone structure and mineralization, ATC code: M05BX04 Mechanism of action Denosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity and specificity to RANKL, preventing activation of its receptor, RANK, on the surface of osteoclast precursors and osteoclasts. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function and survival, thereby decreasing bone resorption in cortical and trabecular bone. Pharmacodynamic effects Prolia treatment rapidly reduced the rate of bone turnover, reaching a nadir for the bone resorption marker serum type 1 C-telopeptides (CTX) (85% reduction) by 3 days, with reductions maintained over the dosing interval. At the end of each dosing interval, CTX reductions were partially attenuated from maximal reduction of ≥ 87% to approximately ≥ 45% (range 45-80%), reflecting the reversibility of Prolia's effects on bone remodelling once serum levels diminish. These effects were sustained with continued treatment. Bone turnover markers generally reached pre-treatment levels within 9 months after the last dose. Upon re-initiation, reductions in CTX by denosumab were similar to those observed in patients initiating primary denosumab treatment. Immunogenicity In clinical studies, neutralising antibodies have not been observed for Prolia. Using a sensitive immunoassay < 1% of patients treated with denosumab for up to 5 years tested positive for non neutralising binding antibodies with no evidence of altered pharmacokinetics, toxicity, or clinical response. Treatment of osteoporosis in postmenopausal women Efficacy and safety of Prolia administered once every 6 months for 3 years were investigated in post-menopausal women (7,808 women aged 60-91 years, of which 23.6% had prevalent vertebral fractures) with baseline bone mineral density (BMD) T-scores at the lumbar spine or total hip between –2.5 and –4.0 and a mean absolute 10-year fracture probability of 18.60% (deciles: 7.9-32.4%) for major osteoporotic fracture and 7.22% (deciles: 1.4-14.9%) for hip fracture. Women with other diseases or on therapies that may affect bone were excluded from this study. Women received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily. Effect on vertebral fractures Prolia significantly reduced the risk of new vertebral fractures at 1, 2 and 3 years (p < 0.0001) (see table 2). Table 2 The effect of Prolia on the risk of new vertebral fractures
Effect on hip fractures Prolia demonstrated a 40% relative reduction (0.5% absolute risk reduction) in the risk of hip fracture over 3 years (p < 0.05). The incidence of hip fracture was 1.2% in the placebo group compared to 0.7% in the Prolia group at 3 years. In a post-hoc analysis in women > 75 years, a 62% relative risk reduction was observed with Prolia (1.4% absolute risk reduction, p < 0.01). Effect on all clinical fractures Prolia significantly reduced fractures across all fracture types/groups (see table 3). Table 3 The effect of Prolia on the risk of clinical fractures over 3 years
+ Event rates based on Kaplan-Meier estimates at 3 years. (1) Includes clinical vertebral fractures and non-vertebral fractures. (2) Excludes those of the vertebrae, skull, facial, mandible, metacarpus, and finger and toe phalanges. (3) Includes pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm, and hip. (4) Includes clinical vertebral, hip, forearm, and humerus fractures, as defined by the WHO. In women with baseline femoral neck BMD ≤ -2.5, Prolia reduced the risk of non-vertebral fracture (35% relative risk reduction, 4.1% absolute risk reduction, p < 0.001, exploratory analysis). The reduction in the incidence of new vertebral fractures, hip fractures and non-vertebral fractures by Prolia over 3 years were consistent regardless of the 10-year baseline fracture risk. Effect on bone mineral density Prolia significantly increased BMD at all clinical sites measured, versus placebo at 1, 2 and 3 years. Prolia increased BMD by 9.2% at the lumbar spine, 6.0% at the total hip, 4.8% at the femoral neck, 7.9% at the hip trochanter, 3.5% at the distal 1/3 radius and 4.1% at the total body over 3 years (all p < 0.0001). In clinical studies examining the effects of discontinuation of Prolia, BMD returned to approximately pre-treatment levels and remained above placebo within 18 months of the last dose. These data indicate that continued treatment with Prolia is required to maintain the effect of the medicinal product. Re-initiation of Prolia resulted in gains in BMD similar to those when Prolia was first administered. Open-label Extension Study in the Treatment of Postmenopausal Osteoporosis A total of 4550 patients (2343 Prolia & 2207 placebo) who missed no more than one dose of investigational product in the pivotal study described above and completed all study visits agreed to enroll in a 7-year, multinational, multicenter, open label, single-arm extension study to evaluate the long-term safety and efficacy of Prolia. At month 24 of the extension study, after 5 years of denosumab treatment, the long-term group increased BMD by 13.8% at the lumbar spine, 7.0% at the total hip, 6.2% at the femoral neck and 9.7% at the trochanter from the original pivotal study baseline. Fracture incidence was evaluated as a safety endpoint: continued Prolia treatment maintained a low incidence of new vertebral and non-vertebral fractures in years 4 and 5 (annualised rate of new vertebral fracture was 1.4% in both years 4 and 5, while 1.4% and 1.1% of patients had a nonvertebral fracture in years 4 and 5 respectively). Three cases of osteonecrosis of the jaw (ONJ) occurred during the first 25 months in the study, two cases in the de novo treatment group and one case in the long term treatment group, all cases resolved. Treatment of osteoporosis in men Efficacy and safety of Prolia once every 6 months for 1 year were investigated in 242 men aged 31-84 years. Subjects with an eGFR < 30 ml/min/1.73 m2 were excluded from the study. All men received calcium (at least 1,000 mg) and vitamin D (at least 800 IU) supplementation daily. The primary efficacy variable was percent change in lumbar spine BMD, fracture efficacy was not evaluated. Prolia significantly increased BMD at all clinical sites measured, relative to placebo at 12 months: 4.8% at lumbar spine, 2.0% at total hip, 2.2% at femoral neck, 2.3% at hip trochanter, and 0.9% at distal 1/3 radius (all p < 0.05). Prolia increased lumbar spine BMD from baseline in 94.7% of men at 1 year. Significant increases in BMD at lumbar spine, total hip, femoral neck and hip trochanter were observed by 6 months (p < 0.0001). Bone histology Bone histology was evaluated in 62 postmenopausal women with osteoporosis or with low bone mass who were either naïve to osteoporosis therapies or had transitioned from previous alendronate therapy following 1-3 years treatment with Prolia. Bone biopsy results from both studies showed bone of normal architecture and quality with no evidence of mineralisation defects, woven bone or marrow fibrosis. Treatment of bone loss associated with androgen deprivation Efficacy and safety of Prolia once every 6 months for 3 years were investigated in men with histologically confirmed non-metastatic prostate cancer receiving ADT (1,468 men aged 48-97 years) who were at increased risk of fracture (defined as > 70 years, or < 70 years with a BMD T-score at the lumbar spine, total hip, or femoral neck < -1.0 or a history of an osteoporotic fracture.) All men received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily. Prolia significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 3 years: 7.9% at the lumbar spine, 5.7% at the total hip, 4.9% at the femoral neck, 6.9% at the hip trochanter, 6.9% at the distal 1/3 radius and 4.7% at the total body (all p < 0.0001). In a prospectively planned exploratory analysis, significant increases in BMD were observed at the lumbar spine, total hip, femoral neck and the hip trochanter 1 month after the initial dose. Prolia demonstrated a significant relative risk reduction of new vertebral fractures: 85% (1.6% absolute risk reduction) at 1 year, 69% (2.2% absolute risk reduction) at 2 years and 62% (2.4% absolute risk reduction) at 3 years (all p < 0.01). Treatment of bone loss associated with adjuvant aromatase inhibitor therapy Efficacy and safety of Prolia once every 6 months for 2 years was investigated in women with non-metastatic breast cancer (252 women aged 35-84 years) and baseline BMD T-scores between -1.0 to -2.5 at the lumbar spine, total hip or femoral neck. All women received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily. The primary efficacy variable was percent change in lumbar spine BMD, fracture efficacy was not evaluated. Prolia significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 2 years: 7.6% at lumbar spine, 4.7% at total hip, 3.6% at femoral neck, 5.9% at hip trochanter, 6.1% at distal 1/3 radius and 4.2% at total body (all p < 0.0001). Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Prolia in all subsets of the paediatric population in the treatment of bone loss associated with sex hormone ablative therapy, and in subsets of the paediatric population below the age of 2 in the treatment of osteoporosis. See section 4.2 for information on paediatric use. 5.2 Pharmacokinetic properties Absorption Following subcutaneous administration of a 1.0 mg/kg dose, which approximates the approved 60 mg dose, exposure based on AUC was 78% as compared to intravenous administration at the same dose level. For a 60 mg subcutaneous dose, maximum serum denosumab concentrations (Cmax) of 6 μg/ml (range 1-17 μg/ml) occurred in 10 days (range 2-28 days). Biotransformation Denosumab is composed solely of amino acids and carbohydrates as native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids. Elimination After Cmax, serum levels declined with a half-life of 26 days (range 6-52 days) over a period of 3 months (range 1.5-4.5 months). Fifty-three percent (53%) of patients had no measurable amounts of denosumab detected at 6 months post-dose. No accumulation or change in denosumab pharmacokinetics with time was observed upon subcutaneous multiple-dosing of 60 mg once every 6 months. Denosumab pharmacokinetics was not affected by the formation of binding antibodies to denosumab and was similar in men and women. Age (28-87 years), race and disease state (low bone mass or osteoporosis; prostate or breast cancer) do not appear to significantly affect the pharmacokinetics of denosumab. A trend was observed between higher body weight and lower exposure based on AUC and Cmax. However, the trend is not considered clinically important, since pharmacodynamic effects based on bone turnover markers and BMD increases were consistent across a wide range of body weight. Linearity/non-linearity In dose ranging studies, denosumab exhibited non-linear, dose-dependent pharmacokinetics, with lower clearance at higher doses or concentrations, but approximately dose-proportional increases in exposures for doses of 60 mg and greater. Renal impairment In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab. Hepatic impairment No specific study in patients with hepatic impairment was performed. In general, monoclonal antibodies are not eliminated via hepatic metabolic mechanisms. The pharmacokinetics of denosumab is not expected to be affected by hepatic impairment. Paediatric population The pharmacokinetic profile in paediatric populations has not been assessed. 5.3 Preclinical safety data In single and repeated dose toxicity studies in cynomolgus monkeys, denosumab doses resulting in 100 to 150 times greater systemic exposure than the recommended human dose had no impact on cardiovascular physiology, male or female fertility, or produced specific target organ toxicity. Standard tests to investigate the genotoxicity potential of denosumab have not been evaluated, since such tests are not relevant for this molecule. However, due to its character it is unlikely that denosumab has any potential for genotoxicity. The carcinogenic potential of denosumab has not been evaluated in long-term animal studies. In preclinical studies conducted in knockout mice lacking RANK or RANKL, impairment of lymph node formation was observed in the foetus. An absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy) was also observed in knockout mice lacking RANK or RANKL. In a study of cynomolgus monkeys dosed with denosumab during the period equivalent to the first trimester at AUC exposures up to 99-fold higher than the human dose (60 mg every 6 months), there was no evidence of maternal or foetal harm. In this study, foetal lymph nodes were not examined. In another study of cynomolgus monkeys dosed with denosumab throughout pregnancy at AUC exposures 119-fold higher than the human dose (60 mg every 6 months), there were increased stillbirths and postnatal mortality; abnormal bone growth resulting in reduced bone strength, reduced haematopoiesis, and tooth malalignment; absence of peripheral lymph nodes; and decreased neonatal growth. A no observed adverse effect level for reproductive effects was not established. Following a 6 month period after birth, bone related changes showed recovery and there was no effect on tooth eruption. However, the effects on lymph nodes and tooth malalignment persisted, and minimal to moderate mineralisation in multiple tissues was seen in one animal (relation to treatment uncertain). There was no evidence of maternal harm prior to labour; adverse maternal effects occurred infrequently during labour. Maternal mammary gland development was normal. In preclinical bone quality studies in monkeys on long-term denosumab treatment, decreases in bone turnover were associated with improvement in bone strength and normal bone histology. Calcium levels were transiently decreased and parathyroid hormone levels transiently increased in ovariectomised monkeys treated with denosumab. In male mice genetically engineered to express huRANKL (knock-in mice), which were subjected to a transcortical fracture, denosumab delayed the removal of cartilage and remodelling of the fracture callus compared to control, but biomechanical strength was not adversely affected. Knockout mice (see section 4.6) lacking RANK or RANKL exhibited decreased body weight, reduced bone growth and lack of tooth eruption. In neonatal rats, inhibition of RANKL (target of denosumab therapy) with high doses of a construct of osteoprotegerin bound to Fc (OPG-Fc) was associated with inhibition of bone growth and tooth eruption. These changes were partially reversible in this model when dosing with RANKL inhibitors was discontinued. Adolescent primates dosed with denosumab at 27 and 150 times (10 and 50 mg/kg dose) the clinical exposure had abnormal growth plates. Therefore, treatment with denosumab may impair bone growth in children with open growth plates and may inhibit eruption of dentition. 6. Pharmaceutical particulars 6.1 List of excipients Acetic acid, glacial* Sodium hydroxide (for pH adjustment)* Sorbitol (E420) Polysorbate 20 Water for injections * Acetate buffer is formed by mixing acetic acid with sodium hydroxide 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 3 years. Prolia may be stored at room temperature (up to 25°C) for up to 30 days in the original container. Once removed from the refrigerator, Prolia must be used within this 30 day period. 6.4 Special precautions for storage Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. Do not shake excessively. 6.5 Nature and contents of container One ml solution in a single use pre-filled syringe made from type I glass with stainless steel 27 gauge needle, with or without needle guard. The needle cover of the pre-filled syringe contains dry natural rubber, which is a derivative of latex (see section 4.4). Pack size of one, presented in blistered (pre-filled syringe with or without a needle guard) or unblistered packaging (pre-filled syringe only). 6.6 Special precautions for disposal and other handling Before administration, the Prolia solution should be inspected. Do not inject the solution if it contains particles, or is cloudy or discoloured. Do not shake excessively. To avoid discomfort at the site of injection, allow the pre-filled syringe to reach room temperature (up to 25°C) before injecting and inject slowly. Inject the entire contents of the pre-filled syringe. Dispose of any medicinal product remaining in the pre-filled syringe. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Amgen Europe B.V. Minervum 7061 NL-4817 ZK Breda The Netherlands 8. Marketing authorisation number(s) EU/1/10/618/001 EU/1/10/618/002 EU/1/10/618/003 9. Date of first authorisation/renewal of the authorisation 26 May 2010 10. Date of revision of the text June 2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 美国FDA批准新适应症为Prolia(Dnosumab)为治疗骨丢失在男性对骨折高危风险骨质疏松症。 2012年9月20日宣布美国食品和药品监管局(FDA)批准新适应症对Prolia®(德尼单抗)作为一种治疗在男性对骨折高危风险骨质疏松症增加骨质量。Prolia，FDA-第一个批准的RANK配体抑制剂，是一个由健康保健工作人员每6个月皮下注射给药。 Amgen公司研究和开发执行副总裁Sean E. Harper，M.D.说“当骨质疏松症和骨质疏松症-效果绝经后妇女更常伴随骨折，在男性中骨质疏松症是一个重大的问题预期寿命上升增加患病率。”“骨折可能是改变生活的事件，所以我们很高兴可以对越来越多对骨折高危风险骨质疏松症提供一个新的治疗选择。” 根据美国国家骨质疏松症基金会，在美国有两百万男性骨质疏松症和另外12百万处于风险。在男性中骨质疏松症和骨质疏松性骨折仍然被诊断和被治疗。 Prolia的新适应症是基于来自ADAMO试验3(一项在骨质疏松症男性中多中心，随机，双盲，安慰剂-对照研究德尼单抗60 mg每6个月相比安慰剂的疗效和安全性)的结果，关键性3期研究涉及 242例有低骨矿物质密度(BMD)男性。在这项研究中，用Prolia治疗导致在腰椎当与安慰剂比较时有更显著的增量(5.7 %相比0.9%)。Prolia对BMD的影响与年龄，基线睾丸酮水平，BMD状态和估计的骨折风险无关. 在这项研究中另外结果显示接受用Prolia治疗患者与安慰剂比较经受BMD在所有被评估骨骼部位增加，包括在全髋关节(2.4%相比0.3%)和在股骨颈(2.1%相比0.0%)。安全性发现与Prolia在骨质疏松症绝经后妇女其他研究观察到一致。最常报道不良反应每例患者发生率 > 5%)是背痛，关节炎和鼻咽炎。 Prolia临床数据 批准是根据ADAMO试验12-个月数据。男性年龄30和85岁间有低BMD(T-计分 ≤–2.0和≥–3.5在腰椎或股骨颈)或既往曾经受重大骨质疏松性骨折和有T-计分 ≤–1.0和≥–3.5被纳入这项研究中。患者被随机(1:1) 接受或60 mg的Prolia每6个月或安慰剂。研究3所有患者始终每天接受钙和维生素D 补充。 主要研究终点是在12个月时腰椎BMD从基线变化百分率。次要疗效终点包括在总髋和股骨颈 BMD从基线至1年的变化。 关于男性骨质疏松症 最近认识到在男性中骨质疏松症是一个重要公共健康问题，因男性生命期望值升高而超过70岁以上男性数增长。 2010和2020年间男性骨质疏松症数预计增加17%。在美国约1/4超过50岁男性在其余生将有骨质疏松症-相关骨折。 适应症和用途 Prolia是一种RANK配体(RANKL)抑制剂适用于： （1）治疗绝经后妇女骨质疏松症对骨折高危风险 （2）治疗在男性骨质疏松症对骨折高危风险增加骨质量 （3）在男性中对非转移性前列腺癌接受雄激素剥夺治疗对骨折高危风险治疗增加骨质量 （4）在妇女中接受辅助芳香化酶抑制剂治疗对乳癌对骨折高危风险治疗增加骨质量 剂量和给药方法 （1）Prolia应由医疗保健工作人员给药 （2）作为皮下注射在上臂，上腿，或腹部给予60 mg每6个月 （3）指导患者服用钙1000 mg每天和至少400 IU维生素D每天 剂型和规格 （1）单次使用预装注射器含60mg在1mL溶液中 （2）单次使用小瓶含60 mg在1mL溶液中 禁忌症 （1）低钾血症 （2）妊娠 （3）已知对Prolia超敏性 警告和注意事项 （1）相同活性成分：接受Prolia患者不应接受XGEVA®(是德尼单抗在实体瘤骨转移患者预防骨骼相关事件的商品名) （2）低钙血症：开始用Prolia前必须纠正。特别是在肾受损患者中可能变坏。患者适当补充钙和维生素D （3）严重感染包括皮肤感染：可能发生，包括导致住院。劝告患者如发生感染体征和症状立即求医，包括蜂窝组织炎 （4）皮肤学反应：曾报道皮炎，皮疹，和湿疹。如发生严重症状考虑终止 （5）颚骨坏死：用Prolia曾报道。监视症状 （6）非典型股骨骨折：曾报道。评价有腿或腹股沟痛患者除外股骨骨折 （7）骨更新抑制：曾证实显著抑制。监视骨过度抑制的后果 不良反应 （1）绝经后骨质疏松症：最常见不良反应(> 5%和比安慰剂更常见)是：背痛，肢体痛，高胆固醇血症，肌肉骨骼痛，和膀胱炎。在临床试验中曾报道胰腺炎 （2）男性骨质疏松症：最常见不良反应(> 5%和比安慰剂更常见)是：背痛，关节炎，和鼻咽炎 （3）由于激素消融癌症骨丢失：最常见不良反应(≥ 10%和比安慰剂更常见)是：关节炎和背痛。肢体痛和在临床试验中也曾报道肌肉骨骼痛 报告怀疑不良反应，联系Amgen Inc.公司电话1-800-77-AMGEN(1-800-772-6436)或FDA电话1-800-FDA-1088 orwww.fda.gov/medwatch. 在特殊人群中使用 （1）哺乳母亲：终止药物或哺乳老吕药物对母亲的重要性 （2）儿童患者：未确定 安全性和疗效。 （3）肾受损：肾受损患者无需剂量调整。肌酐清除率 < 30mL/min或接受透析患者是处在低钙血症危险。补充钙和维生素D，和考虑检测血清钙 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
