利塞膦酸钠缓释的适应症和用法

绝经后骨质疏松

利塞膦酸钠缓释片可用于治疗绝经后妇女的骨质疏松症。在绝经后妇女中，利塞膦酸钠已被证明可以减少椎骨骨折的发生率以及非椎骨骨质疏松相关性骨折的复合终点[见临床研究（14.1） ]。

重要使用限制

最佳使用期限尚未确定。利塞膦酸钠缓释片治疗骨质疏松症的安全性和有效性基于一年的临床数据。所有接受双膦酸盐治疗的患者均应定期评估是否需要继续治疗。低骨折风险的患者在使用3至5年后应考虑停药。停止治疗的患者应定期重新评估其骨折风险。

利塞膦酸延迟释放剂量和给药

绝经后骨质疏松症的治疗[参见适应症和用法（1.1）]

推荐的方案是：

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每周一次，一次口服一次35毫克延迟释放片剂[请参阅适应症和用法（1.1）]

重要管理说明

指导患者执行以下操作：

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早餐后立即在早晨服用利塞膦酸钠延迟释放片。早餐后立即服用瑞世膦酸钠延迟释放片，而不是在空腹的情况下服用，因为如果在空腹时早餐前服用，会增加腹痛的风险。

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将立瑞妥钠缓释片整体吞下，直立放置，并至少加入4盎司清水以促进向胃的递送。避免在服药后躺30分钟[见警告和注意事项（5.2） ]。

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不要咀嚼，切碎或压碎利塞膦酸钠延迟释放片剂。

补充钙和维生素D的建议

指导患者如果饮食摄入不足，请补充钙和维生素D [见警告和注意事项（5.3） ]，并在一天中的不同时间服用钙补充剂，抗酸剂，镁基补充剂或泻药以及铁制剂。干扰利塞膦酸钠缓释片的吸收。

遗失剂量的管理说明

如果错过了每周一次的剂量，请指示患者记住后的早晨服用一粒药片，并按照他们选择的日期最初的安排每周一次服用一粒。患者不应在同一天服用两片。

剂型和优势

延迟释放片剂：35 mg，椭圆形，黄色的包衣片剂，一侧印有“ S” ，另一侧印有纯色。

禁忌症

下列情况下的患者禁用利升膦酸钠缓释片：

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食道异常会延迟食道排空，例如狭窄或门失弛[[警告和注意事项（5.2） ]

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不能站立或直立至少30分钟[请参阅剂量和用法（2），警告和注意事项（5.2） ]

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低钙血症[请参阅警告和注意事项（5.3） ]

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对本产品任何成分的超敏反应。据报道有血管性水肿，全身性皮疹，大疱性皮肤反应，Stevens-Johnson综合征和毒性表皮坏死溶解[见不良反应（6.2） ]

警告和注意事项

活性成分相同的药品

利塞膦酸钠的延迟释放片剂含有相同的活性成分在Actonel的®找到。用Actonel治疗的患者不应接受利塞膦酸钠延迟释放片。

上消化道不良反应

像其他口服双膦酸盐一样，Riseronate钠可能会引起上消化道粘膜的局部刺激。由于这些可能的刺激作用以及潜在的潜在疾病恶化的危险，当对活动性上消化道问题（例如已知的巴雷特食管，吞咽困难，其他食道疾病，胃炎，十二指肠炎或溃疡）给予利塞膦酸钠时应谨慎）[参见禁忌症（4），不良反应（6.1），患者须知（17） ]。

据报道接受口服双膦酸盐治疗的患者有食道不良经历，如食道炎，食道溃疡和食道糜烂，偶有出血，很少继发食道狭窄或穿孔。在某些情况下，这些病很严重，需要住院治疗。因此，医师应警惕任何信号或症状，表明可能发生食管反应，如果患者出现吞咽困难，吞咽困难，胸骨后疼痛或新发或恶化的烧心症状，应指导患者停用瑞塞膦酸钠并就医。

在服用口服双膦酸盐后躺下和/或未能用推荐的4盎司水吞咽和/或在出现以下症状的症状后继续服用口服双膦酸盐的患者，出现严重食道不良反应的风险似乎更大。食道刺激。因此，将完整的剂量说明提供给患者并由患者理解是非常重要的[参见剂量和用法（2） ]。对于因精神残疾而无法遵守给药说明的患者，应在适当的监督下使用利塞膦酸钠治疗。

上市后有口服双膦酸盐治疗胃和十二指肠溃疡的报道，一些严重且有并发症，尽管在对照临床试验中未观察到增加的风险。

矿物质代谢

据报道服用利塞膦酸钠缓释片的患者发生低钙血症。开始利塞膦酸钠治疗前，应有效治疗低钙血症和其他骨骼及矿物质代谢紊乱。如果饮食摄入不足，请指导患者补充钙和维生素D。钙和维生素D的摄入量对所有患者都很重要[参见禁忌症（4），不良反应（6.1），患者须知（17） ]。

颚骨坏死

下颌骨坏死（ONJ）可自发发生，通常与拔牙和/或局部感染有关，且愈合迟缓，并且在服用双膦酸盐类药物（包括利塞膦酸盐）的患者中已有报道。颌骨坏死的已知危险因素包括侵入性牙科手术（例如拔牙，种植牙，骨外科），癌症诊断，伴随疗法（例如化学疗法，皮质类固醇，血管生成抑制剂），不良口腔卫生和-病态疾病（例如，牙周病和/或其他先前存在的牙齿疾病，贫血，凝血病，感染，假牙不合适）。 ONJ的风险可能会随着双膦酸盐暴露时间的延长而增加。

对于需要侵入性牙科手术的患者，停用双膦酸盐治疗可能会降低ONJ的风险。主治医生和/或口腔外科医生的临床判断应根据个人获益/风险评估来指导每位患者的治疗计划。

在双磷酸盐治疗期间发生ONJ的患者应接受口腔外科医师的护理。在这些患者中，广泛的牙科手术治疗ONJ可能会加重病情。应根据个人获益/风险评估考虑停用双膦酸盐治疗[见不良反应（6.2） ]。

肌肉骨骼疼痛

在上市后的经验中，有报道称服用双膦酸盐类药物的患者的骨，关节和/或肌肉疼痛剧烈，有时甚至丧失能力[见不良反应（6.2） ]。开始服用药物后，症状发作的时间从一天到几个月不等。多数患者在停药后症状缓解。当使用相同的药物或另一种双膦酸酯治疗时，有一部分症状复发。如果出现严重症状，请考虑停止使用。

股骨粗隆下和干Dia端股骨骨折

在双膦酸盐治疗的患者中，已报告股骨干的非典型，低能量或低创伤性骨折。这些骨折可发生在股骨干中的任何位置，从小转子下方到to上张开上方，并且横断或短斜取向，无粉碎迹象。由于这些骨折也发生在未经双膦酸盐治疗的骨质疏松患者中，因此尚无因果关系。

非典型股骨骨折最常见，对患处的损伤很小或没有损伤。他们可能是双侧的，许多患者在受累区域报告前驱性疼痛，通常在完全骨折发生前几周到几个月表现为钝痛，大腿疼痛。许多报告指出，患者在骨折时也接受糖皮质激素（例如强的松）的治疗。

任何有双膦酸盐暴露史且出现大腿或腹股沟疼痛的患者均应被怀疑为非典型骨折，应进行评估以排除股骨不完全骨折。存在非典型骨折的患者也应评估对侧肢体的骨折症状和体征。在风险/获益评估之前，应单独考虑中断双膦酸盐治疗。

肾功能不全

由于缺乏临床经验，不建议将利塞膦酸钠用于严重肾功能不全（肌酐清除率低于30 mL / min）的患者。

实验室测试互动

已知双膦酸盐会干扰骨成像剂的使用。尚未进行利塞膦酸钠的具体研究。

不良反应

临床研究经验

由于临床试验是在广泛不同的条件下进行的，因此无法将在某种药物的临床试验中观察到的不良反应率直接与另一种药物在临床试验中观察到的不良反应率进行比较，并且可能无法反映实际中观察到的不良反应率。

绝经后骨质疏松症的治疗

瑞生膦酸钠延缓释放片每周一次给药

在一项为期1年的双盲，多中心研究中，评估了每周一次一次的瑞塞膦酸钠35 mg的安全性在一项为期1年的双盲，多中心研究中进行了比较，该研究比较了每周一次瑞塞膦酸钠35 mg与瑞塞膦酸钠的临床应用50岁或以上的绝经后妇女每天5 mg速溶钠。在早餐之前（N = 308）至少30分钟或紧接早餐（N = 307）施用Risedronate sodium延迟释放，并在早餐前至少30分钟施用每天5 mg（N = 307）的Rrisedronate钠速释。该临床试验包括患有胃肠道疾病并伴有非甾体类抗炎药，质子泵抑制剂和H 2拮抗剂使用的患者。所有妇女每天接受1000 mg元素钙加800至1000国际单位维生素D的补充。由于在空腹情况下早餐前服用利塞膦酸钠钠导致腹痛的发生率显着增加，因此以下的安全性结果仅指利塞膦酸盐早餐后立即每周一次一次延迟钠释放35毫克，而瑞斯膦酸钠每日一次立即释放5毫克。

每周一次一次的利塞膦酸钠35 mg延迟治疗组的全因死亡率为0.0％，每天一次利塞膦酸钠5 mg延迟治疗组的全因死亡率为0.3％。每周一次一次的利塞膦酸钠延迟释放35 mg组的严重不良反应发生率为6.5％，而每日一次利塞膦酸钠立即释放5 mg组的严重不良反应发生率为7.2％。每周一次一次的利塞膦酸钠延迟释放35 mg组中因不良反应而退出研究的患者百分比为9.1％，而每天一次的利塞膦酸钠延迟释放5 mg组为8.1％。两种给药方案的总体安全性和耐受性相似。表1列出了大于或等于2％的患者报告的不良反应。显示的不良反应没有因果关系。

急性期反应：使用双膦酸盐已报告了与急性期反应一致的症状。每周一次一次的利塞膦酸钠延迟释放35 mg组的急性期反应的总发生率是2.3％，每天一次的利塞膦酸钠延迟释放5 mg组的急性期反应的总发生率是1.3％。这些发生率是基于第一次给药后3天内且持续7天或更短时间内出现的一个或多个预先指定的急性期反应样症状。

胃肠道不良反应：每周一次一次使用瑞思膦酸钠延迟释放35 mg治疗的受试者中有16％发生与上消化道相关的不良反应，每天每天服用瑞瑞膦酸钠立即释放5 mg治疗的受试者中有15％发生与上消化道相关的不良反应。每周一次一次的瑞斯膦酸钠延迟释放35 mg和每天5 mg瑞斯膦酸钠立即释放的上消化道不良反应的发生率是：腹痛（5.2％比2.9％），消化不良（3.9％比3.9） ％），上腹痛（2.9％对2.3％），胃炎（1.0％对1.0％）和胃食管反流病（1.0％对1.6％）。每周一次一次的利塞膦酸钠延迟释放35 mg组中有1.3％的患者因腹痛而中止研究，而每天5 mg的利塞膦酸钠即时释放组中有0.7％导致研究中断。

肌肉骨骼不良反应：每周16次接受利塞膦酸钠延迟释放35 mg治疗的受试者中有16％发生了选定的肌肉骨骼不良反应，而每天服用5 mg利塞膦酸钠即时释放治疗的受试者中有15％发生了骨骼肌不良反应。每周一次一次的瑞斯膦酸钠延迟释放35 mg和每天5 mg瑞斯膦酸钠立即释放肌肉骨骼不良反应的发生率分别是：关节痛（6.8％对7.8％），背痛（6.8％对5.9％） ，肌肉骨骼疼痛（2.0％对1.6％）和肌痛（1.3％对1.0％）。

实验室测试结果：

甲状旁腺激素：绝经后患有骨质疏松症的妇女评估了每周一次一次35mg瑞斯膦酸钠钠和每天5mg瑞斯膦酸钠速释钠对甲状旁腺激素的作用。在第52周时，在基线水平处于正常水平的受试者中，PTH水平高于65 pg / mL（正常上限）的受试者中，有9％的受试者接受每周一次一次35 mg的利塞膦酸钠钠延迟释放，而8％的受试者的PTH高于受试者每天接受5 mg的利塞膦酸钠速释。在基线水平处于正常水平的受试者中，每周接受2次接受利塞膦酸钠延迟释放35 mg受试者的PTH水平高于97 pg / mL（是正常上限的1.5倍），而没有受试者接受利塞膦酸钠钠速释每天5毫克。治疗组之间的钙，磷和镁水平无临床显着差异。

利司膦酸钠速释片5毫克的每日剂量

在4项随机，双盲，安慰剂对照的跨国试验中，对3232名年龄在38至85岁的绝经后骨质疏松症妇女进行了评估，评估了瑞塞膦酸钠速释钠5 mg每天一次在绝经后骨质疏松症中的安全性。该试验的持续时间长达三年，其中1619例患者接受了安慰剂，1613例患者接受了每天5 mg利塞膦酸钠速释。这些临床试验中包括患有胃肠道疾病并伴有非甾体类抗炎药，质子泵抑制剂（PPI）和H 2拮抗剂的患者。如果她们的25-羟基维生素D 3水平低于基线水平，则所有妇女每天接受1000毫克的元素钙加维生素D补充，最多至500国际单位。

安慰剂组的全因死亡率发生率是2％，每天5 mg的利塞膦酸钠速释组的全因死亡率是1.7％。安慰剂组严重不良反应的发生率为24.6％，每天5 mg利塞膦酸钠速释组的严重不良反应发生率为27.2％。安慰剂组因不良反应而退出研究的患者百分比为每日1 mg 5 mg利塞膦酸钠速溶组为15.6％，而利塞膦酸钠速释组为14.8％。在超过10％的受试者中，最常见的不良反应为：背痛，关节痛，腹痛和消化不良。

胃肠道不良反应：每天5 mg安慰剂和利塞膦酸钠速释组的不良反应发生率是：腹痛（9.9％对12.2％），腹泻（10.0％对10.8％），消化不良（10.6％对10.8％） ）和胃炎（2.3％比2.7％）。每天5 mg利塞膦酸钠速释组中很少有十二指肠炎和舌炎的报道（0.1％至1％）。在基线时患有活动性上消化道疾病的患者中，安慰剂和每日5 mg利塞膦酸钠速释组之间的上消化道不良反应发生率相似。

肌肉骨骼不良反应：安慰剂和利塞膦酸钠速释钠5 mg /日组的不良反应发生率是：背痛（26.1％对28.0％），关节痛（22.1％对23.7％），肌痛（6.2％对6.7％） ）和骨骼疼痛（4.8％比5.3％）。

实验室测试结果：在整个3期研究中，在6个月内观察到血清钙（低于1％）和磷酸盐（低于3％）从基线开始短暂降低，血清PTH水平（低于30％）出现补偿性增加。在骨质疏松症患者的临床试验中，每天服用瑞格膦酸钠速释5 mg治疗。安慰剂和利塞膦酸钠速释钠5 mg每天3年之间的血清钙，磷酸盐或PTH水平无显着差异。在18例患者中观察到血清钙水平低于8 mg / dL，每个治疗组中观察到9例（0.5％）（安慰剂和利塞膦酸钠速释每天5 mg）。每天有14例患者的血清磷水平低于2 mg / dL，每天3例（0.2％）接受安慰剂治疗，11例（0.6％）接受利塞膦酸钠速释5 mg每天治疗。很少有报道（少于0.1％）异常的肝功能检查。

内窥镜检查结果：在每天5 mg的利塞膦酸钠速释钠临床试验中，对任何患有中度至重度胃肠道不适的患者都鼓励进行内窥镜检查，同时保持盲目性。在安慰剂组和治疗组之间对相等数量的患者进行内镜检查[75（14.5％）安慰剂； 75（11.9％）利塞膦酸钠速释每天5 mg]。各症状人群之间的临床重要发现（穿孔，溃疡或出血）在各组之间相似（51％的安慰剂； 39％的利塞膦酸钠速释每天5 mg）。

上市后经验

据报道，使用利塞膦酸钠速释剂会产生以下不良反应。由于这些不良反应是从不确定大小的人群中自愿报告的，因此并非总是能够可靠地估计其发生频率或建立与药物暴露的因果关系。

过敏反应

过敏反应和皮肤反应已有报道，包括血管性水肿，全身性皮疹，大疱性皮肤反应，史蒂文斯-约翰逊综合征和中毒性表皮坏死。

胃肠道不良反应

已经报道了涉及上消化道刺激的反应，例如食道炎和食道或胃溃疡[见警告和注意事项（5.2） ]。

肌肉骨骼疼痛

很少有被描述为严重或丧失工作能力的骨头，关节或肌肉疼痛[见警告和注意事项（5.5） ]。

眼睛发炎

很少有眼睛发炎反应，包括虹膜炎和葡萄膜炎。

颚骨坏死

很少有颌骨坏死的报道[见警告和注意事项（5.4） ]。

肺的

哮喘发作

药物相互作用

Riseronate不被代谢，并且不诱导或抑制肝微粒体药物代谢酶（例如Cytochrome P450）。

钙补充剂/抗酸剂

早餐后服用利塞膦酸钠，含有600 mg元素钙和400国际单位维生素D的片剂共同服用会使利塞膦酸盐的生物利用度降低约38％[参见临床药理学（12.3） ]。钙补充剂，抗酸剂，镁基补充剂或泻药以及铁制剂会干扰利塞膦酸钠的吸收，因此不应一起服用。

组胺2（H2）阻滞剂和质子泵抑制剂（PPI）

升高胃液pH值的药物（例如PPI或H 2阻滞剂）可能会导致药物从肠溶衣（延迟释放）药物产品（例如利塞膦酸钠）更快地释放出来。利塞膦酸钠与PPI埃索美拉唑的共同给药可提高利塞膦酸盐的生物利用度。最大血浆浓度（C max ）和血浆浓度下的面积（AUC）分别增加了60％和22％。

不建议同时使用利塞膦酸钠和H 2受体阻滞剂或PPI。

激素疗法

尚未研究利塞膦酸钠与雌激素和雌激素激动剂/拮抗剂同时使用的情况。

阿司匹林/非甾体类抗炎药

在3期研究中，比较早餐后立即每周一次35mg盐酸利舍膦酸钠和每日5mg利塞膦酸钠每天，两组中18％的NSAID使用者（任何使用）均出现上消化道不良反应。在非使用者中，有13％的患者在早餐后每周一次每周一次服用35 mg盐酸利塞膦酸钠，出现上消化道不良反应，而每天服用5 mg利塞膦酸钠的患者为12％。

在特定人群中的使用

怀孕

风险摘要

孕妇使用利塞膦酸钠的现有数据不足以告知与药物相关的不利母婴后果的风险。确认怀孕后停用瑞斯膦酸钠。

在动物生殖研究中，器官形成过程中每天对怀孕大鼠口服瑞斯膦酸盐会降低新生儿存活率和体重，其剂量分别约为人建议的最高每日剂量30毫克（基于体表面积，毫克/米2），约为每日的5倍和26倍。 2 ），指示用于治疗佩吉特氏病的剂量。在以约等于30 mg人每日剂量的剂量治疗的大坝胎儿中，left裂的发生率较低。在以30毫克人每日剂量的2.5倍至5倍处理的水坝胎儿中观察到骨骼延迟骨化。在母鼠和新生儿中，在交配和/或妊娠期间每天向妊娠大鼠口服利塞膦酸盐口服给药，其母体低血钙引起的围产期死亡的剂量开始于相当于人每日30 mg的剂量。双膦酸盐被掺入骨基质中，并在数周至数年的时间内逐渐释放出来。掺入成人骨骼中可释放到体循环中的双膦酸酯的量与双膦酸酯的使用剂量和持续时间直接相关。因此，根据双膦酸盐的作用机理，如果妇女在完成双膦酸盐治疗疗程后怀孕，则有潜在的胎儿伤害风险，主要是骨骼伤害。尚未研究诸如双膦酸盐治疗终止至受孕之间的时间，所使用的特定双膦酸盐以及给药途径（静脉给药与口服给药）对这种风险的影响。

对于指定人群，估计的主要先天缺陷和流产的背景风险尚不清楚。所有怀孕都有出生缺陷，流产或其他不良后果的背景风险。在美国普通人群中，临床公认的怀孕中主要先天缺陷和流产的估计背景风险分别为2％至4％和15％至20％。

数据

动物资料

在动物研究中，怀孕的老鼠在器官发生过程中以人类Paget病剂量30毫克/天（基于体表面积，mg / m 2 ）的1至26倍接受瑞斯膦酸钠。在妊娠期口服剂量约为人剂量5倍的大鼠中，新生鼠的存活率降低，而水坝处理剂量约为人剂量的26倍时，新生婴儿的体重降低。在口服剂量约等于人剂量的雌性大鼠的胎儿中，c裂的发生率较低。与对照相比，用人剂量约2.5倍处理的水坝胸骨或颅骨骨化不完全的胎儿数量显着增加。在口服剂量约为人类剂量5倍的大坝胎儿中，不完全的骨化和未骨化的胸骨都增加了。

在口服剂量约为人剂量（最高测试剂量）的7倍的兔子的胎儿中，未见明显的骨化作用。但是，有14胎中有1胎被中止，有14胎中有1胎早产。

在母鼠和新生儿中，当母鼠每天在交配和/或妊娠期间用等于或大于人的口服剂量的剂量治疗妊娠母鼠时，围产期死亡率会在大坝和新生儿中发生。

哺乳期

风险摘要

没有数据可以评估母乳中利塞膦酸盐的存在，对母乳喂养婴儿的影响或对牛奶产量的影响。哺乳大鼠发生少量乳汁转移。动物乳中药物的浓度不一定能预测人乳中药物的浓度。但是，当动物乳中存在某种药物时，该药物可能存在于人乳中。应当考虑母乳喂养对发育和健康的好处，以及母亲对利塞膦酸钠的临床需求以及利塞膦酸钠或潜在的母体状况对母乳喂养的孩子的任何潜在不利影响。

数据

动物资料

在哺乳大鼠的新生婴儿中，在服药后24小时内口服一次利塞膦酸盐单次口服剂量时，检测到了利塞膦酸

生殖潜力的男性和女性

不孕症

没有人类可用的数据。根据动物研究表明，利塞膦酸钠对生育参数的不利影响，可能会损害女性和男性的生育能力[见非临床毒理学（13.1）] 。

儿科用

未将利塞膦酸钠用于儿童患者。

在一项为期143年的成骨不全症（OI）儿科患者（94名接受利塞膦酸盐）的随机，双盲，安慰剂对照研究中，评估了利塞膦酸钠速释钠的安全性和有效性。入组人群主要为轻度OI（85％I型），4岁至16岁以下，男性50％，白种人82％，腰椎BMD Z评分平均为-2.08（低于2.08标准差）年龄匹配对照组的平均值）。患者每天口服2.5毫克（小于或等于30千克体重）或5毫克（大于30千克体重）。一年后，与安慰剂组相比，利塞膦酸钠速释组的腰椎BMD升高。但是，立即释放利塞膦酸钠治疗并不能降低OI患儿的骨折风险。在利塞膦酸钠速释钠治疗的受试者中，在基线和第12个月获得的成对骨活检标本中未发现矿化缺陷。

在长达12个月的OI患者中，利塞膦酸盐的总体安全性与成年人骨质疏松的总体安全性相似。但是，与安慰剂相比，呕吐的发生率增加。在这项研究中，观察到有15％的利塞膦酸钠速释钠治疗的儿童呕吐和6％的安慰剂治疗的儿童呕吐。在接受利塞膦酸钠速释治疗的患者中，大于或等于10％且发生频率高于安慰剂的其他不良反应为：四肢疼痛（利塞膦酸钠速释为21％，安慰剂为16％），头痛（20％对8％），背痛（17％对10％），疼痛（15％对10％），上腹痛（11％对8％）和骨痛（10％对4％）。

老人用

在绝经后骨质疏松症研究中接受瑞斯膦酸钠治疗的患者中，有59％年龄在65岁以上，而13％年龄在75岁以上。在这些患者和年轻患者之间未观察到安全性或有效性的总体差异，其他报告的临床经验也未发现老年患者和年轻患者之间反应的差异，但是不能排除某些老年患者的敏感性更高。

肾功能不全

由于缺乏临床经验，不建议将利塞膦酸钠用于严重肾功能不全（肌酐清除率低于30 mL / min）的患者。肌酐清除率大于或等于30 mL / min的患者无需调整剂量。

肝功能不全

没有研究评估利塞膦酸钠在肝功能不全患者中的安全性或有效性。利塞膦酸在人肝制剂中不代谢。肝功能不全的患者不太可能需要调整剂量。

过量

在某些患者中过量服用后，血清钙和磷可能会减少。这些患者中的一些也可能发生低钙血症的体征和症状。虽然可以给予牛奶或含钙的抗酸剂以结合利塞膦酸钠速释并减少药物的吸收，但尚未评估这种干预对利塞膦酸钠延迟释放片剂的影响。

在大量过量的情况下，可以考虑洗胃以除去未吸收的药物。可以有效治疗低血钙症的标准程序，包括静脉内给予钙，可以恢复生理量的离子钙并减轻低血钙症的体征和症状。

雌性大鼠以903 mg / kg服用一次利塞膦酸盐单次口服后的致死率，雄性大鼠以1703 mg / kg服用。小鼠和兔子的最小致死剂量分别为4000 mg / kg和1000 mg / kg。这些值代表人类佩吉特氏病剂量30毫克/天（基于表面积（mg / m 2 ））的320到620倍。

Risedronate延迟发布说明

Risedronate钠延迟释放片剂含有pH敏感的肠溶衣和螯合剂（EDTA）。

Risedronate是一种吡啶基双膦酸盐，可抑制破骨细胞介导的骨吸收并调节骨代谢。每个口服口服的利舍膦酸钠缓释片含有相当于35毫克的利舍膦酸钠（无定形）。利塞膦酸钠（无定形）的分子式为C 7 H 10 NNaO 7 P 2。利塞膦酸钠的化学名称为[1-羟基-2-（3-吡啶基）亚乙基]双[膦酸]钠盐。 The chemical structure of risedronate sodium (amorphous) is the following:

Molecular Weight: 305.09

Risedronate sodium is a white to off-white, amorphous powder. It is soluble in water, practically insoluble in methanol and dichloromethane.

非活性成分

Colloidal silicon dioxide, edetate disodium, ferric oxide yellow, hypromellose, lactose monohydrate, methacrylic acid copolymer, microcrystalline cellulose, polysorbate 80, sodium starch glycolate, sodium stearyl fumarate, talc, and triethyl citrate. The imprinting ink contains ferric oxide black, propylene glycol, and shellac glaze.

Risedronate Delayed Release - Clinical Pharmacology

作用机理

Risedronate has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, risedronate inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (for example, lack of ruffled border). Histomorphometry in rats, dogs, and minipigs showed that risedronate treatment reduces bone turnover (activation frequency, that is, the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.

药效学

Risedronate treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of risedronate sodium immediate-release to postmenopausal women resulted in decreases in biochemical markers of bone turnover, including urinary deoxypyridinoline/creatinine and urinary collagen cross-linked N-telopeptide (markers of bone resorption) and serum bone-specific alkaline phosphatase (a marker of bone formation). At the 5 mg daily dose, decreases in deoxypyridinoline/creatinine were evident within 14 days of treatment. Changes in bone formation markers were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and bone formation; decreases in bone-specific alkaline phosphatase of about 20% were evident within 3 months of treatment. Bone turnover markers reached a nadir of about 40% below baseline values by the sixth month of treatment and remained stable with continued treatment for up to 3 years. Bone turnover is decreased as early as 14 days and maximally within about 6 months of treatment, with achievement of a new steady-state that more nearly approximates the rate of bone turnover seen in premenopausal women. In a 1-year study comparing risedronate sodium delayed-release 35 mg weekly taken immediately after breakfast versus risedronate sodium immediate-release 5 mg daily oral dosing regimens in postmenopausal women, mean decreases from baseline at 1 year in urinary collagen cross-linked N-telopeptide were 47% in the risedronate sodium delayed-release 35 mg once-a-week following breakfast group and 42% in the risedronate sodium immediate-release 5 mg daily group. In addition, serum bone-specific alkaline phosphatase at 1 year was reduced by 33% in the risedronate sodium delayed-release 35 mg once-a-week following breakfast group and 32% in the risedronate sodium immediate-release 5 mg daily group.

药代动力学

吸收性

The mean absolute oral bioavailability of the 30 mg risedronate sodium immediate-release tablet taken 4 hours prior to a meal is 0.63% (90% confidence interval [CI]: 0.54% to 0.75%) and is similar to an oral solution. The time to peak concentration (T max ) for risedronate sodium delayed-release tablet is approximately 3 hours when administered in the morning 4 hours prior to a meal.

食物效应

In a crossover pharmacokinetic study, the bioavailability of risedronate sodium 35 mg delayed-release tablets decreased by approximately 30% when administered immediately after a high-fat breakfast compared to administration in the morning 4 hours before a meal.

The bioavailability of the 35 mg risedronate sodium delayed-release tablet administered after a high-fat breakfast was similar to risedronate sodium 35 mg immediate-release tablet dosed 4 hours before a meal in one study and was approximately 2- to 4-fold greater than the immediate-release 35 mg tablet administered 30 minutes prior to a high-fat breakfast.

In a separate study, risedronate sodium administered after dinner exhibited approximately 87% increase in risedronate exposure compared to administration following a breakfast. The safety and efficacy of dosing risedronate sodium after dinner has not been evaluated [ see Dosage and Administration (2) ].

分配

The mean steady-state volume of distribution for risedronate is 13.8 L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [ 14 C] risedronate indicate that approximately 60% of the dose is distributed to bone. The remainder of the dose is excreted in the urine. After multiple oral dosing in rats, the uptake of risedronate in soft tissues was in the range of 0.001% to 0.01%.

代谢

There is no evidence of systemic metabolism of risedronate.

排泄

In young healthy subjects, approximately half of the absorbed dose of risedronate was excreted in urine within 24 hours, and 85% of an intravenous dose was recovered in the urine over 28 days. Based on simultaneous modeling of serum and urine data for the risedronate sodium immediate-release tablets, mean renal clearance was 105 mL/min (CV = 34%) and mean total clearance was 122 mL/min (CV = 19%), with the difference primarily reflecting nonrenal clearance or clearance due to adsorption to bone. The renal clearance is not concentration dependent, and there is a linear relationship between renal clearance and creatinine clearance. Unabsorbed drug is eliminated unchanged in feces. In osteopenic postmenopausal women, the terminal exponential half-life was 561 hours, mean renal clearance was 52 mL/min (CV = 25%), and mean total clearance was 73 mL/min (CV = 15%).

特定人群

Pediatric: Risedronate sodium is not indicated for use in pediatric patients [ see Pediatric Use (8.4) ].

Geriatric: Effect of age on bioavailability of risedronate sodium delayed-release has not been evaluated. Based on data from risedronate immediate-release tablet, bioavailability and disposition of risedronate are similar in elderly (greater than 60 years of age) and younger subjects. No dosage adjustment is necessary.

Race: Pharmacokinetic differences due to race have not been studied. The clinical trial of risedronate sodium was conducted mostly in Caucasians.

Renal Impairment: Risedronate is excreted unchanged primarily via the kidney. As compared to persons with normal renal function, the renal clearance of risedronate was decreased by about 70% in patients with creatinine clearance of approximately 30 mL/min. Risedronate sodium is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min). No dosage adjustment is necessary in patients with a creatinine clearance greater than or equal to 30 mL/min.

Hepatic Impairment: No studies have been performed to assess risedronate's safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in rat, dog, and human liver preparations. Insignificant amounts (less than 0.1% of intravenous dose) of drug are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment.

Drug Interactions: Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (for example, Cytochrome P450).

Calcium supplement: A Phase 1 single-dose, cross-over study in 101 postmenopausal women evaluated the relative bioavailability of risedronate sodium 35 mg delayed-release tablets taken after breakfast and following a 600 mg elemental calcium/400 international units vitamin D supplement, compared to risedronate sodium alone taken after breakfast without calcium or vitamin D supplementation. The addition of the calcium/vitamin D supplement following the meal resulted in an approximate 38% reduction in the amount of risedronate absorbed [ see Drug Interactions (7) ].

Proton Pump Inhibitors: A Phase 1, 2-period, cross-over study in 60 healthy postmenopausal female subjects evaluated the relative bioavailability of a single dose risedronate sodium 35 mg delayed-release tablet taken after breakfast following 6 days of esomeprazole magnesium delayed release 40 mg capsules. On Day 6, esomeprazole 40 mg capsule was administered with 240 mL water one hour before breakfast and risedronate sodium 35 mg tablet was administered with 240 mL water within 10 minutes after a standard breakfast. The C max and AUC inf of risedronate were increased by 60 percent and 22 percent, respectively, in presence of esomeprazole.

非临床毒理学

致癌，诱变，生育力受损

致癌作用

In a 104-week carcinogenicity study, rats were administered daily oral doses up to approximately 8 times the human Paget's disease dose of 30 mg/day. There were no significant drug-induced tumor findings in male or female rats. The high dose male group was terminated early in the study (Week 93) due to excessive toxicity, and data from this group were not included in the statistical evaluation of the study results. In an 80-week carcinogenicity study, mice were administered daily oral doses approximately 6.5 times the human dose. There were no significant drug-induced tumor findings in male or female mice.

诱变

Risedronate did not exhibit genetic toxicity in the following assays: In vitro bacterial mutagenesis in Salmonella and E. coli (Ames assay), mammalian cell mutagenesis in CHO/HGPRT assay, unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal aberrations in vivo in rat bone marrow. Risedronate was positive in a chromosomal aberration assay in CHO cells at highly cytotoxic concentrations (greater than 675 mcg/mL, survival of 6% to 7%). When the assay was repeated at doses exhibiting appropriate cell survival (29%), there was no evidence of chromosomal damage.

生育能力受损

In female rats, ovulation was inhibited at an oral dose approximately 5 times the human dose. Decreased implantation was noted in female rats treated with doses approximately 2.5 times the human dose. In male rats, testicular and epididymal atrophy and inflammation were noted at approximately 13 times the human dose. Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses approximately 5 times the human dose. There was moderate-to severe spermatid maturation block after 13 weeks in male dogs at an oral dose approximately 8 times the human dose. These findings tended to increase in severity with increased dose and exposure time.

Dosing multiples provided above are based on the recommended human Paget's disease dose of 30 mg/day and normalized using body surface area (mg/m 2 ). Actual doses were 24 mg/kg/day in rats, 32 mg/kg/day in mice, and 8, 16 and 40 mg/kg/day in dogs.

动物毒理学和/或药理学

Risedronate demonstrated potent anti-osteoclast, antiresorptive activity in ovariectomized rats and minipigs. Bone mass and biomechanical strength were increased dose-dependently at daily oral doses up to 4 and 25 times the recommended human dose of 5 mg/day for rats and minipigs, respectively. Risedronate treatment maintained the positive correlation between BMD and bone strength and did not have a negative effect on bone structure or mineralization. In intact dogs, risedronate induced positive bone balance at the level of the bone remodeling unit at oral doses ranging from 0.5 to 1.5 times the human dose of 5 mg/day.

In dogs treated with an oral dose approximately 5 times the human dose of 5 mg/day, risedronate caused a delay in fracture healing of the radius. The observed delay in fracture healing is similar to other bisphosphonates. This effect did not occur at a dose approximately 0.5 times the human daily dose.

The Schenk rat assay, based on histologic examination of the epiphyses of growing rats after drug treatment, demonstrated that risedronate did not interfere with bone mineralization even at the highest dose tested, which was approximately 3500 times the lowest antiresorptive dose in this model (1.5 mcg/kg/day) and approximately 800 times the human dose of 5 mg/day. This indicates that risedronate sodium administered at the therapeutic dose is unlikely to induce osteomalacia. Dosing multiples provided above are based on the recommended human osteoporosis dose of 5 mg/day and normalized using body surface area (mg/m 2 ).

临床研究

Treatment of Osteoporosis in Postmenopausal Women

The efficacy of risedronate sodium delayed-release 35 mg once-a-week in the treatment of postmenopausal osteoporosis was demonstrated in a randomized, double-blind, active-control trial of approximately 900 subjects. All patients in this study received supplemental calcium (1000 mg/day) and vitamin D (800 to 1000 international units/day). The primary efficacy endpoint was percent change in lumbar spine bone mineral density at 1 year.

Risedronate sodium delayed-release 35 mg once-a-week administered after breakfast was shown to be non-inferior to risedronate sodium immediate-release 5 mg daily. Table 2 presents the primary efficacy analysis, percent change in lumbar spine BMD, in the intent-to-treat population with last observation carried forward (LOCF).

Table 2

N = number of intent-to-treat patients within specified treatment; n = number of patients with values at the visit.

* Indicates a statistically significant difference from baseline determined from 95% CI unadjusted for multiple comparisons.

LS = Least Squares

[a] at 1 year LOCF

[b] LS Mean Difference is 5 mg daily minus 35 mg weekly treatment.

Fracture efficacy with Risedronate Sodium Immediate-Release 5 mg daily

The fracture efficacy of risedronate sodium immediate-release 5 mg daily in the treatment of postmenopausal osteoporosis was demonstrated in 2 large, randomized, placebo-controlled, double-blind studies that enrolled a total of almost 4000 postmenopausal women under similar protocols. The Multinational study (VERT MN) (risedronate sodium immediate-release 5 mg daily, N = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (risedronate sodium immediate-release 5 mg daily, N = 821). Patients were selected on the basis of radiographic evidence of previous vertebral fracture, and therefore, had established disease. The average number of prevalent vertebral fractures per patient at study entry was 4 in VERT MN, and 2.5 in VERT NA, with a broad range of baseline BMD levels. All patients in these studies received supplemental calcium 1000 mg/day. Patients with low 25-hydroxyvitamin D 3 levels (approximately 40 nmol/L or less) also received 500 international units/day supplemental vitamin D.

Effect on Vertebral Fractures

Fractures of previously undeformed vertebrae (new fractures) and worsening of pre-existing vertebral fractures were diagnosed radiographically; some of these fractures were also associated with symptoms (that is, clinical fractures). Spinal radiographs were scheduled annually and prospectively planned analyses were based on the time to a patient's first diagnosed fracture. The primary endpoint for these studies was the incidence of new and worsening vertebral fractures across the period of 0 to 3 years. Risedronate sodium immediate-release 5 mg daily significantly reduced the incidence of new and worsening vertebral fractures and of new vertebral fractures in both VERT NA and VERT MN at all time points (Table 3). The reduction in risk seen in the subgroup of patients who had 2 or more vertebral fractures at study entry was similar to that seen in the overall study population.

Table 3