Ramelteon片

雷米替丁片的适应症和用法

Ramelteon片适用于治疗以睡眠困难为特征的失眠症。为支持疗效而进行的临床试验持续时间长达六个月。睡眠潜伏期的最终正式评估是在交叉研究中治疗两天后（仅限老年人），六周研究中的五周（成人和老年人）以及六个月研究结束时（成人和老年人）进行的） [参见临床研究（14） ]。

2.剂量和给药

2.1成人剂量

Ramelteon片剂的建议剂量为在睡觉前30分钟内服用8毫克。建议不要在高脂餐后或餐后立即服用Ramelteon片剂。

Ramelteon片剂的总剂量每天不应超过8 mg。

2.1成人剂量

Ramelteon片剂的建议剂量为在睡觉前30分钟内服用8毫克。建议不要在高脂餐后或餐后立即服用Ramelteon片剂。

Ramelteon片剂的总剂量每天不应超过8 mg。

2.2肝功能不全患者的剂量

严重肝功能不全的患者不建议使用Ramelteon片剂。中度肝功能不全的患者应谨慎使用雷美替汀片[见警告和注意事项（5.6），临床药理学（12.4）]。

2.3与其他药物一起给药

Ramelteon片剂不应与氟伏沙明合用。服用其他CYP1A2抑制药物的患者应谨慎使用Ramelteon片剂[见药物相互作用（7），临床药理学（12.5）]。

剂型和优势

Ramelteon片剂可制成8毫克片剂，用于口服。



Ramelteon 8 mg片剂为浅黄色至黄色，薄膜包衣的圆形片剂，一侧凹陷有“ G 28”，另一侧凹陷。

禁忌症

用Ramelteon片剂治疗后出现血管性水肿的患者不应再次服用该药物。



患者不应将雷美替康片与氟伏沙明联用[见药物相互作用（7） ]。

警告和注意事项

5.1严重过敏反应和类过敏反应

在服用首剂或后续剂量的Ramelteon片剂后，患者中出现罕见的舌头，声门或喉部血管性水肿病例。一些患者还有其他症状，例如呼吸困难，喉咙闭合或恶心和呕吐，提示过敏反应。一些患者在急诊室需要药物治疗。如果血管性水肿累及舌头，声门或喉部，则可能发生气道阻塞并致命。用雷莫替恩片治疗后出现血管性水肿的患者不应再次服用该药物。

5.2需要评估合并症诊断

由于睡眠障碍可能是身体和/或精神疾病的表现，因此，只有在仔细评估患者后才能开始对失眠的对症治疗。治疗7至10天后失眠未缓解可能表明存在应评估的原发性精神病和/或医学疾病。失眠加重，或出现新的认知或行为异常，可能是未认识到的潜在精神病或身体疾病的结果，需要对患者进行进一步评估。在临床开发计划期间，使用Ramelteon片剂可观察到失眠加重以及出现认知和行为异常。

5.3思维异常和行为改变

据报道，与催眠药的使用有关的各种认知和行为改变都会发生。据报道，在原发性抑郁症患者中，与催眠药的使用有关，抑郁症的恶化（包括自杀意念和完全自杀）。



Ramelteon片剂的使用已引起幻觉以及行为改变，例如怪异行为，躁动和躁狂。健忘症，焦虑症和其他神经精神症状也可能不可预测地发生。



复杂的行为，例如“睡眠驾驶”（即，在服用催眠药后未完全清醒的情况下驾驶）和其他复杂的行为（例如，准备和饮食，打电话或做爱），并带有健忘症，据报道与催眠使用有关。使用酒精和其他中枢神经系统抑制剂可能会增加此类行为的风险。这些事件可能发生在天真的催眠药以及有催眠经验的人中。使用Ramelteon片剂已报道了复杂的行为。报告有任何复杂睡眠行为的患者应强烈考虑停用Ramelteon片剂。

5.4 CNS效应

服用Ramelteon片剂后，患者应避免进行需要集中注意力的危险活动（例如，驾驶汽车或重型机械）。

服用Ramelteon片剂后，患者应将其活动限制在准备睡觉所需的活动范围内。

建议患者不要与Ramelteon片剂合用，因为酒精和Ramelteon片剂联合使用可能会产生加成作用。

5.5生殖作用

雷默替恩片与成人生殖激素的作用有关，例如降低睾丸激素水平和增加催乳素水平。尚不知道长期使用Ramelteon片对发展中的人的生殖轴有何影响[参见临床试验（14.3）]。

5.6在伴随疾病的患者中使用

Ramelteon片剂尚未在患有严重睡眠呼吸暂停的受试者中进行研究，因此不建议在该人群中使用[请参见在特定人群中使用（8.7）]。



具有严重肝功能不全的患者不应使用Ramelteon片[请参见临床药理学（12.4）]。

5.7实验室测试

监控方式

无需标准监控。

对于出现原因不明的闭经，溢乳，性欲减退或生育问题的患者，应适当评估催乳素水平和睾丸激素水平。

干扰实验室测试

已知Ramelteon片剂不会干扰常用的临床实验室测试。此外，体外数据表明，在两种标准的尿液药物体外筛选方法中，雷梅替尼不会引起苯二氮卓，鸦片，巴比妥酸盐，可卡因，大麻素或苯丙胺的假阳性结果。

不良反应

其他部分将详细讨论以下严重不良反应：

•严重的过敏反应和类过敏反应[请参阅警告和注意事项（5.1） ]

•思维异常，行为改变和复杂行为[请参阅警告和注意事项（5.3） ]

•CNS的影响[请参阅警告和注意事项（5.4） ]

6.1临床试验经验

不良反应导致治疗中断

本节中描述的数据反映了5373名受试者接受Ramelteon片剂的暴露，其中722名受试者暴露了六个月或更长时间，而448名受试者暴露了一年。



在临床研究中，接受Ramelteon片剂治疗的5373名个体受试者中有6％因不良事件而中止治疗，而接受安慰剂的2279名受试者中有2％终止了治疗。导致停用Ramelteon片的受试者中最常见的不良事件是嗜睡，头晕，恶心，疲劳，头痛和失眠。全部发生在1％或更少的患者中。



Ramelteon片最常见的不良事件



表1显示了参加Ramelteon片剂安慰剂对照试验的2,861名慢性失眠患者报告的不良事件发生率。



由于临床试验是在广泛不同的条件下进行的，因此不能将在药物临床试验中观察到的不良反应率直接与其他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。但是，来自临床试验的不良反应信息的确为识别似乎与药物使用有关的不良事件和近似发生率提供了基础。

药物相互作用

7.1其他药物对Ramelteon片的影响

Fluvoxamine（强效CYP1A2抑制剂）：

与单独使用雷米替尼相比，雷米替尼的AUC 0-inf增加约190倍，而氟伏沙明和雷米替尼的共同给药时Cmax增加约70倍。 Ramelteon片剂不应与氟伏沙明合用[见禁忌症（4），临床药理学（12.5） ]。其他强度较弱的CYP1A2抑制剂尚未得到充分研究。服用不太强效CYP1A2抑制剂的患者应谨慎服用Ramelteon片剂。



利福平（强CYP酶诱导剂）：

多次服用利福平可导致雷莫替恩和代谢产物M-II的总暴露量平均减少约80％。当将Ramelteon片剂与强CYP酶诱导剂（如利福平）联合使用时，疗效可能会降低[见临床药理学（12.5） ]。



酮康唑（强CYP3A4抑制剂）：

当酮康唑与雷米替尼并用时，雷米替尼的AUC 0-inf和C max分别增加了约84％和36％。拉默尔通

服用强效CYP3A4抑制剂（例如酮康唑）的受试者应谨慎服用片剂[见临床药理学（12.5） ]。



氟康唑（强CYP2C9抑制剂）：

当雷美替尼与氟康唑合用时，雷美替尼的AUC 0-inf和C max增加约150％。服用强效CYP2C9抑制剂如fluconazole的受试者应谨慎服用Ramelteon片[见临床药理学（12.5） ]。



多奈哌齐：

多奈哌齐与雷米替尼并用时，雷米替尼的AUC 0-inf和C max分别增加了约100％和87％。当将Ramelteon片剂与多奈哌齐合用时，应严密监测患者[参见临床药理学（12.5） ]。



多塞平：

当多西平与雷米替尼并用时，雷米替尼的AUC 0-inf和C max分别增加了约66％和69％。当将Ramelteon片剂与多塞平共同使用时，应严密监测患者[见临床药理学（12.5）] 。

7.2酒精对Ramelteon片的影响

酒精本身会损害性能并导致嗜睡。由于雷米替尼的预期作用是促进睡眠，因此应警告患者使用雷莫替恩片时不要饮酒[见临床药理学（12.5） ]。组合使用这些产品可能会产生累加效果。

7.3药物/实验室测试的相互作用

已知Ramelteon片剂不会干扰常用的临床实验室测试。此外，体外数据表明，在两种标准的尿液药物体外筛选方法中，雷梅替尼不会引起苯二氮卓类，阿片类，巴比妥类，可卡因，大麻素或苯丙胺的假阳性结果。

在特定人群中的使用

8.1怀孕

风险摘要

上市后的可用数据报道了孕妇使用mel子酮尚未发现与药物相关的重大先天缺陷，流产或不良的母婴后果的风险。在动物研究中，雷米替丁在大于人体表面积（mg / m 2）的推荐人剂量（RHD）8 mg /天的36倍时，产生了发育毒性，包括致畸作用的证据（见数据）。

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

在器官发生期间口服给怀孕的大鼠服用雷梅替尼（10、40、150或600 mg / kg / day）与剂量大于40 mg / kg / day的胎儿结构异常（畸形和变异）发生率增加相关。基于mg / m 2，无效剂量约为RHD的50倍。在器官生成期间，对怀孕兔子的治疗在口服剂量高达300 mg / kg / day（或以mg / m 2为基础的RHD的高达720倍）时，没有产生胚胎-胎儿毒性的证据。

当大鼠在整个妊娠和哺乳期口服雷米替尼（30、100或300 mg / kg /天）时，在后代中以大于30 mg / kg / day的剂量观察到生长迟缓，发育迟缓和行为改变。无效剂量是RHD的36倍，基于mg / m 2 。在最高剂量下，后代中畸形和死亡的发生率增加。

8.2哺乳

风险摘要

没有关于人乳中存在雷米替宁或其代谢产物，对母乳喂养婴儿的影响或对牛奶生产的影响的数据。 Ramelteon和/或其代谢产物存在于大鼠乳汁中。当动物乳中存在某种药物时，该药物可能存在于人乳中。由于雷梅替尼的作用机理，母乳喂养的婴儿有可能出现嗜睡现象（参见临床注意事项） 。应考虑母乳喂养对发育和健康的好处，以及母亲对Ramelteon片剂的临床需求以及Ramelteon片剂或潜在的母体疾病对母乳喂养婴儿的任何潜在不利影响。

临床注意事项

应监测通过母乳暴露于Ramelteon片剂的婴儿的嗜睡和喂养问题。哺乳期妇女可以考虑在治疗期间以及服用Ramelteon片剂后25小时（大约5个消除半衰期）中断母乳喂养，抽乳和丢弃母乳，以最大程度地减少对母乳喂养婴儿的药物暴露。

8.4小儿使用

Ramelteon片剂在儿科患者中的安全性和有效性尚未确定。在确定该产品可以在青春期前和青春期患者中安全使用之前，需要进行进一步的研究。

8.5老年用途

共有654位接受Ramelteon片的安慰剂对照双盲，功效试验的受试者年龄均在65岁以上。其中199岁年龄在75岁以上。在老年和青年受试者之间未观察到安全性或疗效的总体差异。

一项针对失眠老年患者（n = 33）的双盲，随机，安慰剂对照研究评估了半夜醒来后单剂雷美替丁片对平衡，活动性和记忆功能的影响。没有关于多次给药效果的信息。相对于安慰剂，夜间服用Ramelteon片8 mg不会损害夜间的平衡，活动性或记忆功能。从这项研究中不能确切知道老年人对夜间平衡的影响。

8.6慢性阻塞性肺疾病

在对单剂量16 mg或安慰剂服用轻度至中度COPD的受试者（n = 26）进行的交叉设计研究中评估了雷米替尼的呼吸抑制作用，在另一项研究（n = 25）中，评估了雷米替尼的作用在中度至重度COPD患者（定义为一秒钟强迫呼气量（FEV 1 ）/强迫肺活量比率<70％的患者）中交叉使用8 mg剂量或安慰剂后评估呼吸参数， FEV 1 <预测值的80％，沙丁胺醇的可逆性<12％。通过动脉血O 2饱和度（SaO 2 ）测量，在轻度至重度COPD患者中，单剂量Ramelteon片剂的治疗没有明显的呼吸抑制作用。目前尚无有关多次服用Ramelteon片剂对COPD患者的呼吸作用的信息。从这项研究中不能确切知道COPD患者的呼吸抑制作用。

8.7睡眠呼吸暂停

在对患有轻度至中度阻塞性睡眠呼吸暂停的受试者（n = 26）进行交叉设计后，给予16 mg剂量或安慰剂后评估Ramelteon片剂的效果。用Ramelteon片治疗16夜，与安慰剂相比，其呼吸暂停/呼吸不足指数（主要结局变量），呼吸暂停指数，呼吸不足指数，中枢呼吸暂停指数，混合呼吸暂停指数和阻塞性呼吸暂停指数与安慰剂相比无差异。单一剂量的Ramelteon片治疗不会加剧轻度至中度阻塞性睡眠呼吸暂停。目前尚无有关多次服用Ramelteon片对睡眠呼吸暂停患者的呼吸作用的信息。从这项研究不能确切地知道轻度至中度睡眠呼吸暂停对急性发作的影响。



Ramelteon片尚未在患有严重阻塞性睡眠呼吸暂停的受试者中进行研究；不建议在此类患者中使用Ramelteon片剂。

8.8肝功能不全

在轻度肝功能不全的受试者中，雷莫替恩片的暴露量增加了四倍，在中度肝功能不佳的受试者中，其暴露量增加了十倍以上。中度肝功能不全的患者应谨慎使用拉美替宁片[见临床药理学（12.4） ]。严重肝功能不全的患者不建议使用Ramelteon片剂。

8.9肾功能不全

没有观察到对母体药物或M-II的C max和AUC 0-t的影响。肾功能不全患者无需调整雷米替尼剂量[见临床药理学（12.4） ]。

药物滥用和依赖性

雷默替丁片剂不是受控物质。

长期给药后在动物或人体内停止使用雷梅替尼不会产生戒断症状。 Ramelteon似乎不会产生身体依赖性。

人数据

使用Ramelteon片剂进行了可能的实验室滥用研究[请参阅临床研究（14.2） ] 。

动物资料

Ramelteon没有从动物行为研究中产生任何信号，表明该药物产生了有益的作用。猴子没有自行服用雷蒙替康，该药也没有在大鼠中诱发条件性位置偏爱。雷梅替尼和咪达唑仑之间没有概括。 Ramelteon不会影响旋翼机的性能，这是运动功能中断的指标，并且它没有增强地西epa干扰旋翼机性能的能力。

过量

应使用一般的症状和支持措施，并在适当的情况下立即洗胃。静脉输液应根据需要进行管理。与所有药物过量情况一样，应监测呼吸，脉搏，血压和其他适当的生命体征，并采用一般的支持措施。

血液透析不能有效减少Ramelteon片剂的暴露。因此，在过度剂量的治疗中使用透析是不合适的。

毒物控制中心

与所有超剂量的处理一样，应考虑多种药物摄入的可能性。请与毒物控制中心联系，以获取有关过量管理的最新信息。

Ramelteon片说明

雷米替丁是一种口服活性催眠药，化学上称为（ S ） -N- [2-（1,6,7,8-四氢-2 H-茚满-[5,4- b ]呋喃-8-基）乙基]丙酰胺并包含一个手性中心。该化合物以（ S ）-对映体形式产生，其经验式为C 16 H 21 NO 2 ，分子量为259.34，具有以下化学结构：

Ramelteon易溶于有机溶剂，例如甲醇，乙醇和二甲基亚砜。溶于1-辛醇和乙腈；几乎不溶于水和pH 3至11的水性缓冲液。

每个Ramelteon片剂均包含以下非活性成分：共聚维酮，玉米淀粉，羟丙基纤维素，氧化铁黄，乳糖一水合物，硬脂酸镁，聚乙二醇和二氧化钛。

Ramelteon片-临床药理学

作用机理

Ramelteon是褪黑激素受体激动剂，对褪黑激素MT 1和MT 2受体具有高亲和力，并且相对于MT 3受体具有相对选择性。



雷米替尼对MT 1和MT 2受体的活性被认为有助于促进睡眠，因为这些受体受到内源性褪黑激素的作用，被认为与维持正常睡眠的昼夜节律有关。唤醒周期。



Ramelteon对GABA受体复合物或与结合神经肽，细胞因子，血清素，多巴胺，去甲肾上腺素，乙酰胆碱和鸦片剂的受体没有明显的亲和力。 Ramelteon也不会干扰标准面板中许多选定酶的活性。



雷米替尼的主要代谢物M-II具有药理活性，其母体分子对人MT 1和MT 2受体的结合亲和力分别约为其十分之一和五分之一。但是，与雷米替尼相比， M-II的循环浓度要高于其母体，从而产生的平均全身暴露量要高20至100倍。与拉米替尼类似， M-II不干扰许多内源酶的活性。



拉米酮的所有其他已知代谢产物均无活性。

药代动力学

已在健康受试者以及肝或肾功能不全的受试者中评估了雷梅替尼的药代动力学特征。当口服给人的剂量为4到64 mg时，雷梅替尼经历快速，高首过代谢，并表现出线性药代动力学。最大血清浓度（C max ）和浓度时间曲线下的面积（AUC）数据显示受试者之间存在很大差异，这与高首过效应一致。这些值的变异系数约为100％。在人血清和尿液中已鉴定出几种代谢物。

吸收性

Ramelteon被快速吸收，在禁食口服后约0.75小时（0.5至1.5小时）出现中值峰值浓度。尽管拉米替丁的总吸收至少为84％，但由于广泛的首过代谢，绝对的口服生物利用度仅为1.8％。

分配

人血清中拉梅替顿的体外蛋白结合率约为82％，与浓度无关。与白蛋白的结合是该结合的主要部分，因为70％的药物结合在人血清白蛋白中。 Ramelteon不能选择性地分布在红细胞上。

静脉注射后，Ramelteon的平均分布量为73.6 L，表明组织分布明显。

代谢

雷梅替尼的代谢主要包括氧化为羟基和羰基衍生物，并通过次级代谢产生葡糖醛酸苷共轭物。 CYP1A2是参与雷梅替尼肝代谢的主要同工酶。 CYP2C亚家族和CYP3A4同工酶也有少量参与。

在人血清中，主要代谢物的流行程度为M-II，M-IV，MI和M-III 。这些代谢物迅速形成并表现出单相下降和快速消除。 M-II的总体平均全身暴露量比母体药物高约20至100倍。

消除

口服放射性标记的雷米替丁后，总放射性的84％从尿中排出，大约4％从粪便中排出，平均回收率为88％。小于0.1％的剂量作为母体化合物排泄在尿液和粪便中。给药后96小时基本消除。

由于拉梅替尼的消除半衰期短（平均约1至2.6小时），因此每天使用Ramelteon片剂重复给药一次不会导致明显的积累。

M-II的半衰期为2至5小时，与剂量无关。人体中母体药物及其代谢产物的血清浓度在24小时内等于或低于定量下限。

食物的作用

与高脂餐食相比，单剂量16毫克Ramelteon片剂的AUC 0-inf比禁食时高31％， Cmax则低22％。当将Ramelteon片剂与食物一起施用时，中值T max会延迟约45分钟。食物对M-II的AUC值的影响相似。因此，建议不要在高脂餐时或餐后立即服用Ramelteon片[见剂量和用法（2.1） ]。

特殊人群的药代动力学

年龄

在24位年龄在63至79岁之间的老年受试者中，服用了16毫克的雷梅替尼单剂量，其平均C max和AUC 0-inf值分别为11.6 ng / mL（SD，13.8）和18.7 ng·hr / mL（SD， 19.4）。消除半衰期为2.6小时（SD，1.1）。与年轻人相比，老年受试者中雷莫替恩的总暴露量（AUC 0-inf ）和C max分别高出97％和86％。在老年受试者中， M-II的AUC 0-inf和C max分别增加了30％和13％。


性别

雷米替尼或其代谢产物的药代动力学没有与临床相关的性别相关差异。

肝功能不全

在服用7天剂量为16 mg / day的轻度肝功能不全的受试者中，接受雷莫替汀的暴露量几乎增加了四倍；中度肝功能不全患者的暴露水平进一步增加（超过十倍）。相对于健康匹配的对照组，在轻度和中度受损的受试者中， M-II的暴露仅略有增加。 Ramelteon片的药代动力学尚未在患有严重肝功能不全（Child-Pugh C级）的受试者中进行评估。中度肝功能不全的患者应谨慎使用拉美替宁片[见警告和注意事项（5.6） ]。

肾功能不全

根据剂量前肌酐清除率（53至95、35至49或15至30 mL / min / 1.73 m 2 ，对轻度，中度或重度肾功能不全的受试者给予16 mg剂量后，研究了雷梅替尼的药代动力学特性。分别）和需要进行慢性血液透析的受试者。在拉梅顿，暴露参数中观察到受试者间的广泛变异性。但是，在任何一个治疗组中均未观察到对母体药物或M-II的C max或AUC 0-t的影响。各组之间不良事件的发生率相似。这些结果与雷米替尼的肾脏清除率可忽略不计，后者主要通过肝代谢消除。肾功能不全的患者，包括严重肾功能不全（肌酐清除率≤30mL / min / 1.73 m 2 ）的患者和需要慢性血液透析的患者，无需调整雷米替尼剂量。

药物相互作用

Ramelteon具有高度可变的受试者间药代动力学特征（Cmax和AUC的变异系数约为100％）。如上所述，CYP1A2是参与雷梅替尼代谢的主要同工酶。 CYP2C亚家族和CYP3A4同工酶也有少量参与。

其他药物对雷默替丁片代谢的影响


Fluvoxamine（强效CYP1A2抑制剂）

与氟哌丁胺单剂共同给药前，将氟伏沙明100 mg氟伏沙明每天两次给药三天，然后分别服用雷美替丁16 mg和氟伏沙明，AUC 0-inf升高约190倍，Cmax升高约70倍。单独。雷莫替恩不宜与氟伏沙明合用。其他强度较弱的CYP1A2抑制剂尚未得到充分研究。服用弱效CYP1A2抑制剂的患者应谨慎使用雷美替宁[见禁忌症（4），药物相互作用（7）]。


利福平（强CYP酶诱导剂）

每天一次给予利福平600 mg，共11天，一次服用32次后，雷莫替尼和代谢产物M-II （AUC 0-inf和C max ）的总暴露量平均减少约80％（40至90％）毫克剂量的拉梅替尼。当雷米替尼与强效CYP酶诱导剂（如利福平）联合使用时，疗效可能会降低[见药物相互作用（7）]。

酮康唑（强CYP3A4抑制剂）

与单独使用雷美替尼相比，当酮康唑200 mg第四天每天两次单次给药16 mg时，雷美替尼的AUC 0-inf和Cmax分别增加了约84％和36％。在M-II药代动力学变量中也观察到类似的增加。服用强效CYP3A4抑制剂（例如酮康唑）的受试者应谨慎使用Ramelteon [见药物相互作用（7）]。

氟康唑（强CYP2C9抑制剂）

与氟康唑一起服用时，单剂16 mg雷米替尼后，雷米替尼的总全身暴露和峰值全身暴露（AUC 0-inf和C max ）增加了约150％。在M-II暴露中也看到了类似的增加。服用强效CYP2C9抑制剂（如fluconazole）的受试者应谨慎使用Ramelteon [请参阅药物相互作用（7）]。

多奈哌齐

每天一次服用多奈哌齐10 mg，持续26天，导致在接受雷莫替尼治疗后，其总暴露量平均增加约100％（AUC 0-inf ），并且对雷莫替丁的最大暴露量（C max ）平均增加约87％。单次8毫克剂量的雷梅替尼。 M-II暴露量未见变化。拉莫替尼与多奈哌齐合用时应密切监测患者[见药物相互作用（7）]。

多塞平

每天一次服用多西平10 mg，持续23天，导致大鼠接受雷莫替恩的总暴露量平均增加约66％（AUC 0-inf ），而接受雷莫替恩的最大暴露量（C max ）平均增加约69％。单次8毫克剂量的雷梅替尼。 M-II暴露量未见变化。当雷莫替丁与多塞平合用时，应严密监测患者[见药物相互作用（7）]。

拉美替尼与氟西汀（CYP2D6抑制剂），奥美拉唑（CYP1A2诱导剂/ CYP2C19抑制剂），茶碱（CYP1A2底物），右美沙芬（CYP2D6底物），舍曲林，文拉法辛，依巴西地普，依那西多拉梅顿或M-II代谢产物的峰值或总暴露量发生变化。

雷米替丁片对其他药物代谢的影响

唑吡坦

每天一次服用雷米替宁8 mg，持续11天，导致唑吡坦的中值Tmax增加约20分钟，单剂量10 mg唑吡坦后，唑吡坦的暴露量（AUC 0-inf和C max ）均未改变。服用拉美替宁片的患者通常不宜服用唑吡坦。

Ramelteon片与奥美拉唑（CYP2C19底物），右美沙芬（CYP2D6底物），咪达唑仑（CYP3A4底物），茶碱（CYP1A2底物），地高辛（p-糖蛋白底物），华法林（CYP2C9 [S] / CYP1A2 [ ），文拉法辛，氟伏沙明，多奈哌齐，多塞平，舍曲林，依他普仑和加巴喷丁对这些药物的峰值和总暴露量均未产生临床上有意义的变化。

酒精对雷莫替恩片的影响

每日一次联合应用雷米替恩32 mg和酒精（0.6 g / kg）时，没有临床意义
或对雷米替尼的高峰或总暴露量具有统计学意义的影响。 However, an additive effect was seen on some measures of psychomotor performance (ie, the Digit Symbol Substitution Test, the Psychomotor Vigilance Task Test, and a Visual Analog Scale of Sedation) at some postdose time points. No additive effect was seen on the Delayed Word Recognition Test. Because alcohol by itself impairs performance, and the intended effect of ramelteon is to promote
sleep, patients should be cautioned not to consume alcohol when using Ramelteon Tablets.

非临床毒理学

13.1致癌，诱变，生育力受损

致癌作用



Ramelteon was administered to mice and rats at oral doses of 0, 30, 100, 300, or 1000 mg/kg/day (mice) and 0, 15, 60, 250, or 1000 mg/kg/day (rats). Mice and rats were dosed for two years, except at the high dose (94 weeks for male and female mice and female rats). In mice, dose-related increases in the incidence of hepatic tumors (adenomas, carcinomas, hepatoblastomas) were observed in males and females. The no-effect dose for hepatic tumors in mice (30 mg/kg/day) is approximately 20 times the recommended human dose (RHD) of 8 mg/day based on body surface area (mg/m 2 ).

In rats, the incidence of hepatic adenoma and benign Leydig cell tumors of the testis was increased in males at doses ≥250 mg/kg/day. In females, the incidence of hepatic adenoma was increased at doses ≥60 mg/kg/day. The incidence of hepatic carcinoma was increased in males and female rats at 1000 mg/kg/day.The no-effect dose for tumors in rats (15 mg/kg/day) is approximately 20 times the RHD based on mg/m 2 .

诱变

Ramelteon was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma TK +/- assay, and in in vivo oral micronucleus assays in mouse and rat. Ramelteon was clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells.

Separate studies indicated that the concentration of the M-II metabolite formed in the presence of metabolic activation exceeded the concentration of ramelteon; therefore, the genotoxic potential of the M-II metabolite was also assessed in the in vitro studies.

生育能力受损



When ramelteon (doses of 6 to 600 mg/kg/day) was administered orally to male and female rats prior to and during mating and early gestation, alterations in estrus cyclicity and decreased numbers of corpora lutea, implantations, and live embryos were observed at doses greater than 20 mg/kg/day. The no-effect dose is approximately 24 times the RHD of 8 mg/day based on (mg/m 2 ). Oral administration of ramelteon (up to 600 mg/kg/day) to male rats had no effects on sperm quality or reproductive performance.

临床研究

14.1 Controlled Clinical Trials

Chronic Insomnia

Three randomized, double-blind trials in subjects with chronic insomnia employing polysomnography (PSG) were provided as objective support of ramelteon's effectiveness in sleep initiation.

One study enrolled younger adults (aged 18 to 64 years, inclusive) with chronic insomnia and employed a parallel design in which the subjects received a single, nightly dose of Ramelteon Tablets (8 or 16 mg) or matching placebo for 35 days. PSG was performed on the first two nights in each of Weeks 1, 3, and 5 of treatment. Ramelteon Tablets reduced the average latency to persistent sleep at each of the time points when compared to placebo. The 16 mg dose conferred no additional benefit for sleep initiation.

The second study employing PSG was a three-period crossover trial performed in subjects aged 65 years and older with a history of chronic insomnia. Subjects received Ramelteon Tablets (4 or 8 mg) or placebo and underwent PSG assessment in a sleep laboratory for two consecutive nights in each of the three study periods. Both doses of Ramelteon Tablets reduced latency to persistent sleep when compared to placebo.

The third study evaluated long term efficacy and safety in adults with chronic insomnia. Subjects received a single, nightly dose of Ramelteon Tablets 8 mg or matching placebo for six months. PSG was performed on the first two nights of Week 1 and Months 1, 3, 5, and 6. Ramelteon Tablets reduced sleep latency at each time point when compared to placebo. In this study, when the PSG results from nights 1 and 2 of Month 7 were compared to the results from nights 22 and 23 of Month 6, there was a statistically significant increase in LPS of 33% (9.5 minutes) in the ramelteon group. There was no increase in LPS in the placebo group when the same time periods were compared.

A randomized, double-blind, parallel group study was conducted in outpatients aged 65 years and older with chronic insomnia and employed subjective measures of efficacy (sleep diaries). Subjects received Ramelteon Tablets (4 or 8 mg) or placebo for 35 nights. Ramelteon Tablets reduced patient-reported sleep latency compared to placebo. A similarly designed study performed in younger adults (aged 18 to 64 years) using 8 and 16 mg of ramelteon did not replicate this finding of reduced patient-reported sleep latency compared to placebo.

While the 16 mg dose was evaluated as a potential treatment for adults, it was shown to confer no additional benefit for sleep initiation and was associated with higher incidences of fatigue, headache and next-day somnolence.

Transient Insomnia

In a randomized, double-blind, parallel-group trial using a first-night-effect model, healthy adults received placebo or Ramelteon Tablets before spending one night in a sleep laboratory and being evaluated with PSG. Ramelteon Tablets demonstrated a decrease in mean latency to persistent sleep as compared to placebo.

14.2 Studies Pertinent to Safety Concerns for Sleep-Promoting Drugs

Results from Human Laboratory Abuse Liability Studies

A human laboratory abuse potential study was performed in 14 subjects with a history of sedative/hypnotic or anxiolytic drug abuse. Subjects received single oral doses of Ramelteon Tablets (16, 80, or 160 mg), triazolam (0.25, 0.50, or 0.75 mg) or placebo. All subjects received each of the seven treatments separated by a wash-out period and underwent multiple standard tests of abuse potential. No differences in subjective responses indicative of abuse potential were found between Ramelteon Tablets and placebo at doses up to 20 times the recommended therapeutic dose. The positive control drug, triazolam, consistently showed a dose-response effect on these subjective measures, as demonstrated by the differences from placebo in peak effect and overall 24 hour effect.

Residual Pharmacological Effect in Insomnia Trials

In order to evaluate potential next-day residual effects, the following scales were used: a Memory Recall Test, a Word List Memory Test, a Visual Analog Mood and Feeling Scale, the Digit-Symbol Substitution Test, and a post-sleep questionnaire to assess alertness and ability to concentrate. There was no evidence of next-day residual effect seen after two nights of ramelteon use during the crossover studies.

In a 35 night, double-blind, placebo-controlled, parallel-group study in adults with chronic insomnia, measures of residual effects were performed at three time points. Overall, the magnitudes of any observed differences were small. At Week 1, patients who received 8 mg of Ramelteon Tablets had a mean VAS score (46 mm on a 100 mm scale) indicating more fatigue in comparison to patients who received placebo (42 mm). At Week 3, patients who received 8 mg of Ramelteon Tablets had a lower mean score for immediate recall (7.5 out of 16 words) compared to patients who received placebo (8.2 words); and the patients treated with Ramelteon Tablets had a mean VAS score indicating more sluggishness (27 mm on a 100 mm VAS) in comparison to the placebo-treated patients (22 mm). Patients who received Ramelteon Tablets did not have next-morning residual effects that were different from placebo at Week 5.

Rebound Insomnia/Withdrawal

Potential rebound insomnia and withdrawal effects were assessed in four studies in which subjects received Ramelteon Tablets or placebo for up to six months; three were 35 day studies, one was a six month study. These studies included a total of 2,533 subjects, of whom 854 were elderly.

Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ)



The BWSQ is a self-report questionnaire that solicits specific information on 20 symptoms commonly experienced during withdrawal from benzodiazepine receptor agonists; Ramelteon Tablets is not a benzodiazepine receptor agonist.

In two of the three 35 day insomnia studies, the questionnaire was administered one week after completion of treatment; in the third study, the questionnaire was administered on Days 1 and 2 after completion. In all three of the 35 day studies, subjects receiving Ramelteon Tablets 4, 8 or 16 mg daily reported BWSQ scores similar to those of subjects receiving placebo.

In the six month study, there was no evidence of withdrawal from the 8 mg dose as measured by the BWSQ.

Rebound Insomnia



Rebound insomnia was assessed in the 35 day studies by measuring sleep latency after abrupt treatment discontinuation. One of these studies employed PSG in younger adult subjects receiving Ramelteon Tablets 8 or 16 mg; the other two studies employed subjective measures of sleep-onset insomnia in elderly subjects receiving Ramelteon Tablets 4 or 8 mg, and in younger adult subjects receiving Ramelteon Tablets 8 or 16 mg. There was no evidence that Ramelteon Tablets caused rebound insomnia during the post-treatment period.

14.3 Studies to Evaluate Effects on Endocrine Function

Two controlled studies evaluated the effects of ramelteon on endocrine function.

In the first trial, Ramelteon Tablets 16 mg once daily or placebo was administered to 99 healthy volunteer subjects for four weeks. This study evaluated the thyroid axis, adrenal axis and reproductive axis. No clinically significant endocrinopathies were demonstrated in this study. However, the study was limited in its ability to detect such abnormalities due to its limited duration.

In the second trial, Ramelteon Tablets 16 mg once daily or placebo was administered to 122 subjects with chronic insomnia for six months. This study evaluated the thyroid axis, adrenal axis and reproductive axis. There were no significant abnormalities seen in either the thyroid or the adrenal axes. Abnormalities were, however, noted within the reproductive axis. Overall, the mean serum prolactin level change from baseline was 4.9 mcg/L (34% increase) for women in the Ramelteon Tablets group compared with -0.6 mcg/L (4% decrease) for women in the placebo group (p=0.003). No differences between active- and placebo-treated groups occurred among men. Thirty two percent of all patients who were treated with ramelteon in this study (women and men) had prolactin levels that increased from normal baseline levels compared to 19% of patients who were treated with placebo. Subject-reported menstrual patterns were similar between the two treatment groups.

In a 12 month, open-label study in adult and elderly patients, there were two patients who were noted to have abnormal morning cortisol levels, and subsequent abnormal ACTH stimulation tests. A 29 yearold female patient was diagnosed with a prolactinoma. The relationship of these events to Ramelteon Tablets therapy is not clear.

供应/存储和处理方式

Ramelteon Tablets are available in light yellow to yellow, film coated round tablets debossed with'G 28' on one side and plain on the other side.



NDC 70010-028-03 Bottles of 30

NDC 70010-028-05 Bottles of 500



Store at 20° to 25°C (68° to 77°F); [see USP Controlled Room Temperature]. Keep container tightly closed and protected from moisture and humidity.

病人咨询信息

建议患者阅读FDA批准的患者标签（用药指南）。


Severe Anaphylactic and Anaphylactoid Reactions


Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with ramelteon.Describe the relevant signs/symptoms and advise seeking immediate medical attention if any such things occur.


Sleep-Driving and other Complex Behaviors

There have been reports of people getting out of bed after taking a sleep medication and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since "sleep-driving" can be dangerous. This behavior is more likely to occur when sleep medications are taken with alcohol or other central nervous system depressants. Other complex behaviors (eg, preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sleep medication. As with sleep-driving, patients usually do not remember these events.


内分泌作用


Patients should consult their healthcare providers if they experience one of the following: cessation of menses or galactorrhea in females, decreased libido, or problems with fertility. Describe the relevant signs/symptoms and advise seeking medical attention if any such things occur.


Administration Instructions


• Patients should be advised to take Ramelteon Tablets within 30 minutes prior to going to bed and should confine their activities to those necessary to prepare for bed.

• Patients should be advised that they should not take Ramelteon Tablets with or immediately after a high-fat meal.

• Do not break the tablet; it should be swallowed whole.


哺乳期

Advise mothers using Ramelteon Tablets to monitor neonates for signs of somnolence and feeding problems. A lactating woman may consider pumping and discarding breast milk during treatment and for 25 hours after Ramelteon Tablets administration to minimize drug exposure to a breastfed infant [see Use in Specific Populations (8.2)]

由制造：
Granules Pharmaceuticals Inc.
Chantilly, VA 20151

Rev. 09/20

SPL MEDGUIDE SECTION

Ramelteon Tablets

(ram-EL-tee-on)

Read the Medication Guide that comes with Ramelteon Tablets before you start taking it and each time you get a refill.可能有新的信息。 This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment.

What is the most important information I should know about Ramelteon Tablets?

Ramelteon Tablets may cause severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms after taking Ramelteon Tablets.


After taking Ramelteon Tablets, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with Ramelteon Tablets. Activities may include:


• driving a car ("sleep-driving")

• making and eating food

• talking on the phone

• having sex

• sleep-walking


Call your doctor right away if you find out that you have done any of the above activities after taking Ramelteon Tablets.

重要：

1. Take Ramelteon Tablets exactly as prescribed

• Do not take more Ramelteon Tablets than prescribed.

• Take Ramelteon Tablets within 30 minutes of going to bed, not sooner.

2. Do not take Ramelteon Tablets if you:

• drink alcohol

• take other medicines that can make you sleepy. Talk to your doctor about all of your medicines. Your doctor will tell you if you can take Ramelteon Tablets with your other medicines

• cannot get a full night's sleep



What are Ramelteon Tablets?

Ramelteon Tablets are a hypnotic (sleep) medicine. Ramelteon Tablets are used in adults for the treatment of the symptom of trouble falling asleep from insomnia.

Ramelteon Tablets are not for children.


Who should not take Ramelteon Tablets?

Do not take Ramelteon Tablets if you are allergic to anything in it. See the end of this Medication Guide for a complete list of ingredients in Ramelteon Tablets.

Do not take Ramelteon Tablets if you are currently taking Luvox (fluvoxamine).


Ramelteon Tablets may not be right for you. Before starting Ramelteon Tablets, tell your doctor about all of your health conditions, including if you:

• have a history of depression, mental illness, or suicidal thoughts

• have liver disease

• have a lung disease or breathing problems

• are pregnant, or planning to become pregnant, or breastfeeding

• are breastfeeding or plan to breastfeed. Ramelteon Tablets may cause somnolence in a breastfed infant. You may consider interrupting breastfeeding and pumping and discarding breastmilk during treatment and for 25 hours after administration of Ramelteon Tablets.

Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Medicines can interact with each other, sometimes causing serious side effects.


Do not take Ramelteon Tablets with:

• other medicines that can make you sleepy

• Luvox (fluvoxamine)

知道你吃的药。 Keep a list of your medicines with you to show your doctor and pharmacist each time you get a new medicine.

How should I take Ramelteon Tablets?

• Take Ramelteon Tablets exactly as prescribed. Do not take more Ramelteon Tablets than prescribed for you.

• Do not break the tablets. They should be swallowed whole.

• Take Ramelteon Tablets within 30 minutes of going to bed. After taking Ramelteon Tablets only do activities to get ready for bed.

• Do not take Ramelteon Tablets with or right after a meal.

• Do not take Ramelteon Tablets unless you are able to get a full night's sleep before you must be active again.

• Call your doctor if your insomnia worsens or is not better within 7 to 10 days. This may mean that there is another condition causing your sleep problems.

• If you take too much Ramelteon Tablets or overdose, call your doctor or poison control center right away, or get emergency treatment.


What are the possible side effects of Ramelteon Tablets?

Possible serious side effects of Ramelteon Tablets include:

• severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms after taking Ramelteon Tablets.

• getting out of bed while not being fully awake and do an activity that you do not know you are doing. (See "What is the most important information I should know about Ramelteon Tablets?")

• abnormal thoughts and behavior. Symptoms include worsening of depression, suicidal thoughts or actions, nightmares, and hallucinations.

• hormone effects. Ramelteon Tablets can decrease testosterone levels and increase prolactin levels in the blood. Symptoms of low testosterone or high prolactin levels are:

o decreased interest in sex

o problems getting pregnant

o irregular menstrual periods or no menstrual periods

o leakage of milk from the nipples of a person who is not breast feeding

Call your doctor right away if you have any of the above side effects or any other side effects that worry you while using Ramelteon Tablets.打电话给您的医生，征求有关副作用的医疗建议。您可以通过1-800-FDA-1088向FDA报告副作用。

The most common side effects of Ramelteon Tablets are:

• drowsiness

• tiredness

• dizziness

• You may still feel drowsy the next day after taking Ramelteon Tablets . Do not drive or do other dangerous activities after taking Ramelteon Tablets until you feel fully awake.

These are not all the side effects of Ramelteon Tablets. Ask your doctor or pharmacist for more information.

How should I Store Ramelteon Tablets?

• Store Ramelteon Tablets at room temperature, 59° to 86°F (15° to 30°C). Keep the container tightly closed and protected from moisture and humidity.

• Keep Ramelteon Tablets and all medicines out of reach of children .


General Information about Ramelteon Tablets

• Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

• Do not use Ramelteon Tablets for a condition for which it was not prescribed.

• Do not share Ramelteon Tablets with other people, even if you think they have the same symptoms that you have.可能会伤害他们。

This Medication Guide summarizes the most important information about Ramelteon Tablets.如果您想了解更多信息，请咨询您的医生。 You can ask your doctor or pharmacist for information about Ramelteon Tablets that is written for healthcare professionals. For more information about Ramelteon Tablets, please contact Granules Pharmaceuticals Inc. at 1-877-770-3183 or visit www.granulesindia.com.


What are the ingredients in Ramelteon T

综上所述

较常见的副作用包括：头晕，嗜睡和疲劳。有关不良影响的完整列表，请参见下文。

对于消费者

适用于ramelteon：口服片

需要立即就医的副作用

除了其所需的效果，ra子可能会引起一些不良影响。尽管并非所有这些副作用都可能发生，但如果确实发生了，则可能需要医疗护理。

不需要立即就医的副作用

雷米替尼可能会发生一些副作用，通常不需要医治。随着身体对药物的适应，这些副作用可能会在治疗期间消失。另外，您的医疗保健专业人员可能会告诉您一些预防或减少这些副作用的方法。

请咨询您的医疗保健专业人员，是否持续存在以下不良反应或令人讨厌，或者是否对这些副作用有任何疑问：

比较普遍;普遍上

• 头晕
• 嗜睡或异常嗜睡

不常见

• 身体酸痛或疼痛
• 口味改变
• 发冷
• 咳嗽
• 呼吸困难
• 移动困难
• 灰心
• 耳部充血
• 疲劳
• 感到悲伤或空虚
• 发热
• 普遍感到不适或生病
• 易怒
• 关节痛
• 食欲不振
• 失去兴趣或愉悦
• 味觉丧失
• 失去声音
• 肌肉酸痛或抽筋
• 肌肉疼痛或僵硬
• 鼻充血
• 恶心
• 关节疼痛
• 流鼻涕
• 发抖
• 失眠
• 打喷嚏
• 咽喉痛
• 出汗
• 关节肿胀
• 麻烦集中
• 睡眠困难
• 无法入睡
• 异常疲倦或虚弱
• 呕吐

对于医疗保健专业人员

适用于ramelteon：口服片

精神科

常见（1％至10％）：失眠加剧

未报告的频率：行为改变，复杂行为，健忘症，幻觉，焦虑^[参考]

神经系统

常见（1％至10％）：嗜睡，头晕^[Ref]

免疫学的

罕见（小于0.1％）：严重的过敏反应和类过敏反应（例如，血管性水肿） ^[参考]

胃肠道

常见（1％至10％）：恶心^[参考]

其他

普通（1％至10％）：疲劳^[参考]

某些副作用可能没有报道。您可以将其报告给FDA。

成年人失眠的常用剂量

上床30分钟内口服8毫克

最大剂量：每天8毫克

评论：不应在高脂餐后或餐后立即服用该药。

用途：治疗以睡眠困难为特征的失眠症

肾脏剂量调整

不建议调整。

肝剂量调整

-轻度肝功能不全（Child-Pugh A）：无可用数据。
-中度肝功能不全（Child-Pugh B）：谨慎使用。
-严重肝功能不全（Child-Pugh C）：不推荐。

剂量调整

-CYP450 1A2抑制药物的同时使用：禁忌氟伏沙明；与其他CYP450 1A2抑制剂一起使用时，建议谨慎。

-患有严重睡眠呼吸暂停的患者：不建议。

预防措施

未确定18岁以下患者的安全性和疗效。

有关其他预防措施，请参阅“警告”部分。

透析

-血液透析：不建议调整。
-腹膜透析：无可用数据。

其他的建议

行政建议：
-药物片剂应完全吞服；药片不应该被打破。

储存要求：
-容器应密闭，以防潮湿。

一般：
-该药物似乎不产生身体依赖性；长期给药后停止治疗不会在人或动物中产生戒断症状。
-如果发生过量，应使用一般的对症和支持措施，并在适当情况下立即洗胃，并根据需要静脉输液。

患者咨询：
-服用这种药物时不要喝酒。
-请勿服用其他会使您昏昏欲睡的药物。
-请勿与食物或饭后服用此药。
-不要服用这种药物，除非您在必须再次运动之前能够睡一整夜。
-服用此药后，避免驾驶和其他需要集中注意力的活动，例如操作机器；将您的活动限制为准备睡觉所需的活动。
-如果您的失眠在7至10天内恶化或没有好转，请咨询您的医疗保健提供者。