Meclofenoxate_hydrochloride_HNMR_11015_MedChemExpress
苯海拉明
谢谢观看
1．最常见的有：滞呆、思睡、注意力不集中、疲乏、头晕、头昏、共济失调、恶心、呕吐、食欲不振、口干 等。
2．少见的有：气急、胸闷、咳嗽、肌张力障碍等。有报道在给药后可发生牙关紧闭并伴喉痉挛、过敏性休克、 心律失常。过量应用可致急性中毒、精神障碍。
本品的毒性主要是使中枢神经系统先抑制后兴奋，最后产生衰竭性抑制，严重程度视用量而定。一旦发现误 服或过量服用本品时，应立即送医院急救处理。
3、晕车晕船的防治，有较强的镇吐作用，也可用于防治放射病、手术后呕吐，药物引起的恶心呕吐；
4、用于帕金森病和锥体外系症状；
5、镇静，用于催眠和术前给药；
6、牙科局麻，当病人对常用的局麻药高度过敏时，1%苯海拉明液可作为牙科用局麻药；
7、镇咳，作为一种非成瘾性止咳药适用于治疗感冒或过敏所致咳嗽，但其止咳效应尚未肯定。
1.与H2组胺受体阻断药（西咪替丁等）联用可增强抗过敏疗效，达到全面阻滞组胺受体的效果。 2.苯海拉明有显著的抗胆碱作用，可拮抗胆碱酯酶抑制剂的缩瞳作用，正常剂量下扩瞳作用不明显，二者无 重要的相互作用，但有时应用苯海拉明可影响青光眼的治疗效果。与单胺氧化化酶抑制药同用能增强苯海拉明的 抗胆碱作用，使苯海拉明代谢减低，不良反应增加（抑酶作用）。 3.苯海拉明可增强中枢神经抑制药（催眠，镇静，安定类药物）的作用，应避免同时使用。 4.苯海拉明可治疗三氟拉嗪、甲氧氯普氯普胺（灭吐灵）这两种药所致的锥体外系症状。 5.与对氨基水杨酸钠同用可降低后者肠道的吸收而降低其血药浓度。 6.苯海拉明有可能掩盖链霉素及其他氨基糖苷类抗生素（庆大霉霉素、卡那霉素、阿米卡星等）或其他具有 耳毒性的药物（如依他尼酸）的耳毒性。 7.苯海拉明大剂量可降低肝素的抗凝作用。 8.苯海拉明可拮抗肾上腺素能神经阻滞药的作用。 9.苯海拉明可短暂影响巴比妥类药和磺胺醋醋酰醋酰钠的吸收。
西咪替丁登革热医用原料药
武汉贝尔卡生物医药有限公司登革热类药物简介西咪替丁
CAS号: 51481-61-9
商品别名: 甲氰咪胍; ;
西咪替丁A;西咪替丁;甲腈咪胺;泰胃美;
甲氰咪胺;西米替丁;西米替汀;西眯替丁;西咪替丁号;
分子式: C10H16N6S
精确质量: 252.11600
分子量: 252.33900
PSA: 114.19000
LogP: 1.37918
【外观性状】
白色或类白色结晶性粉末，几无臭，味苦。
易溶于甲醇或稀盐酸，溶于乙醇，略溶于异丙醇，微溶于水。
熔点141～143℃。
37℃时在水中的溶解度为1.14%。
急性毒性LD50小鼠，大鼠(mg/kg)：2600，5000口服；150，106静脉注射；470，650腹腔注射。
【熔点】
139-144°C
【储存条件】
2-8°C
【水溶解性】
0.5 g/100 mL at 20 ºC
【Merck 】
2279
【外观性状】
白色或类白色结晶性粉末，几无臭，味苦。
易溶于甲醇或稀盐酸，溶于乙醇，略溶于异丙醇，微溶于水。
熔点141～143℃。
37℃时在水中的溶解度为1.14%。
急性毒性LD50小鼠，大鼠(mg/kg)：2600，5000口服；150，106静脉注射；470，650腹腔注射。
【熔点】
139-144°C
【储存条件】
2-8°C
【水溶解性】
0.5 g/100 mL at 20 ºC
【Merck 】
2279
核磁图谱
氢谱
碳。
米诺地尔分子量
米诺地尔分子量1. 什么是米诺地尔分子量？米诺地尔（Minoxidil）是一种用于治疗男性脱发和高血压的药物。
它是一种外用药，通过促进血液循环，刺激毛囊生长，从而增加头发的生长和密度。
米诺地尔分子量是指米诺地尔分子的相对分子质量，是衡量米诺地尔分子大小的指标。
2. 米诺地尔分子的组成米诺地尔的化学式为C9H15N5O，其分子结构如下所示：米诺地尔分子由9个碳原子、15个氢原子、5个氮原子和1个氧原子组成。
这些原子通过共价键相连，形成了一个稳定的分子结构。
3. 米诺地尔分子量的计算米诺地尔分子量的计算可以通过将每个原子的相对原子质量相加得到。
根据化学元素周期表，碳的相对原子质量为12.01，氢的相对原子质量为1.01，氮的相对原子质量为14.01，氧的相对原子质量为16.00。
因此，可以计算出米诺地尔的相对分子质量如下：碳的质量：9 * 12.01 = 108.09氢的质量：15 * 1.01 = 15.15氮的质量：5 * 14.01 = 70.05氧的质量：1 * 16.00 = 16.00米诺地尔的相对分子质量 = 108.09 + 15.15 + 70.05 + 16.00 = 209.29因此，米诺地尔的相对分子质量约为209.29。
4. 米诺地尔分子量的意义米诺地尔分子量的大小与其在化学反应和药物研发中的一些性质有关。
较大的分子量通常意味着较大的分子体积和较高的化学反应活性。
米诺地尔分子量较大，可能会对其在体内的吸收和代谢产生影响。
此外，米诺地尔分子量的大小也与其药物释放速率有关。
较大的分子量通常意味着较低的药物释放速率，从而延长药物在体内的作用时间。
5. 其他与米诺地尔分子量相关的研究除了米诺地尔分子量的计算和意义，科学家们还对米诺地尔分子的其他性质进行了深入研究。
例如，研究人员通过分子模拟方法，研究了米诺地尔分子与毛囊细胞的相互作用。
他们发现，米诺地尔分子可以与毛囊细胞表面的特定受体结合，从而刺激毛囊生长。
盐酸非索非那定片说明书
核准日期：2021年4月12日修改日期：2021年6 月8日盐酸非索非那定片说明书请仔细阅读说明书并在医师指导下使用【药品名称】通用名称：盐酸非索非那定片英文名称：Fexofenadine Hydrochloride Tablets汉语拼音：Yansuan Feisuofeinading Pian【成份】本品主要成份为盐酸非索非那定。
化学名称：2-[4-[（1RS）-1-羟基-4-（4-羟基二苯甲基）–哌啶-1-基）丁基]苯基]-2-甲基丙酸盐酸盐化学结构式：分子式：C32H39NO4·HCl分子量：538.13【性状】本品为浅红色胶囊型薄膜包衣片，一面刻有数字“012”，另一面刻有字母“e”，除去包衣后显白色。
【适应症】适用于缓解成人和12岁及12岁以上儿童的季节性过敏性鼻炎的相关症状。
如打喷嚏，流鼻涕，鼻、上腭、喉咙发痒，眼睛发痒、潮湿、发红。
【规格】120mg【用法用量】成人、12岁及12岁以上儿童：口服，一日一次，一次120mg，用水送服。
肾功能不全患者的推荐起始剂量为60mg，一日一次。
【不良反应】以下列出的不良反应的发生率采用如下定义：十分常见（≥10%）；常见（≥1%，＜10%）；偶见（≥0.1%，＜1%）；罕见（≥0.01%，＜0.1%）；十分罕见（＜0.01%）；未知（依据现有数据而不能确定）。
在对季节性过敏性鼻炎等适应症进行的安慰剂对照临床研究中，与安慰剂相比，报告了以下不良事件，其发生率与安慰剂相当：各类神经系统疾病：常见：头痛（＞3%），嗜睡（1-3%），头晕（1-3%）胃肠系统疾病：常见：恶心（1-3%）在对季节性过敏性鼻炎等适应症进行的所有对照临床研究中，报告了以下不良事件，其发生率低于1%且与安慰剂相似：胃肠系统疾病：未知：口干全身性疾病及给药部位各种反应：偶见：疲乏在成人中，在上市后监测期间报告了以下不良事件。
发生率未知，无法从现有数据中确定。
免疫系统疾病：已报告过敏反应，包括面部和颈部突然肿胀（血管神经性水肿），胸闷，呼吸困难，潮热和其它全身性速发过敏反应。
美瑞尼(盐酸美他环素胶囊)
美瑞尼(盐酸美他环素胶囊)【药品名称】商品名称：美瑞尼通用名称：盐酸美他环素胶囊英文名称：Metacycline Hydrochloride Capsules【成份】成分为盐酸美他环素，其化学名为[4S-(4α,4aα,5α,5aα,12aα)]-6-亚甲基-4-（二甲氨基）-3，5，10，12，12a-五羟基-1，11-二氧代-2-并四苯甲酰胺盐酸盐。
其结构式为：分子式：C22H22N2O8·HCl分子量：478.89【适应症】1.本品作为首选或选用药物可用于下列疾病：（1）立克次体病，包括流行性斑疹伤寒、地方性斑疹伤寒、洛矶山热、恙虫病和Q热。
（2）支原体属感染。
（3）衣原体属感...【用法用量】成人口服每12小时300mg，8岁以上小儿口服每12小时按体重5mg/kg。
【不良反应】1.消化系统：胃肠道症状如恶心、呕吐、上腹不适、腹胀、腹泻，偶有胰腺炎等。
偶有食管炎和食管溃疡的报道，多发生于服药后立即上床的患者。
2.肝毒性：通常为脂肪肝变性，妊娠期妇女、原有肾功能损害的患者易发生，亦可发生于并无上述情况的患者。
本品所致胰腺炎也可与肝毒性同时发生，患者并不伴有原发性肝病。
3.变态反应：多为斑丘疹和红斑，此外可见荨麻疹、血管神经性水肿、过敏性紫癜、心包炎以及系统性红斑狼疮皮损加重，表皮剥脱性皮炎并不常见。
偶有过敏性休克和哮喘发生。
某些用本品的患者日晒时可能有光敏现象。
所以，建议患者不要直接暴露于阳光或紫外线下，一旦皮肤有红斑应立即停药。
4.血液系统：偶可引起溶血性贫血、血小板减少、中性粒细胞减少和嗜酸粒细胞减少。
5.中枢神经系统：偶可致良性颅内压增高，可表现为头痛、呕吐、视神经乳头水肿等。
6.肾毒性：原有显著肾功能损害的患者可能发生氮质血症、高磷酸血症和酸中毒。
7.二重感染：长期应用本品可诱发耐药金葡菌、革兰阴性杆菌和真菌等引起的二重感染，严重者可致败血症。
Clomethiazole_氯美噻唑_噻唑衍生物_CAS号533-45-9_M9188说明书_AbMole中国
分子量161.64
溶解性（25°C）
DMSO 10 mM
分子式C6H8ClNS Water
CAS号533-45-9Ethanol
储存条件4°C, dry, sealed
生物活性
Clomethiazole 氯美噻唑是一种结构上与硫胺素(维生素B1)有关的化合物，为噻唑衍生物。
氯美噻唑抑制GABA和甘氨酸介导的中枢神经系统电兴奋。
Clomethiazole is a positive allosteric modulator at the barbiturate/picrotoxin site of the GABAA receptor. It acts as a sedative and hypnotic agent.
不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）
小鼠大鼠兔豚鼠仓鼠狗
重量 (kg)0.020.15 1.80.40.0810
体表面积 (m)0.0070.0250.150.050.020.5
K系数36128520
动物 A (mg/kg) = 动物 B (mg/kg) ×
动物 B的K系数
动物 A的K系数
例如，依据体表面积折算法，将白藜芦醇用于小鼠的剂量22.4 mg/kg 换算成大鼠的剂量，需要将22.4 mg/kg 乘以小鼠的K系数（3），再除以大鼠的K系数（6），得到白藜芦醇用于大鼠的等效剂量为11.2 mg/kg。
Clomethiazole 目录号M9188
化学数据
2
m
m
m
m m。
一种盐酸芬戈莫德的合成方法及其中间体
一种盐酸芬戈莫德的合成方法及其中间体盐酸芬戈莫德（hydrochloride fenclonine）是一种常用的神经调节剂，用于治疗抑郁症和精神病等疾病。
其合成方法一般涉及几个重要的中间体。
首先，盐酸芬戈莫德可以通过对双丙氨基甲苯（dipropyramine）的化学反应来合成。
这个过程包括如下几个步骤。
步骤一：双丙氨基甲苯首先通过酸催化剂在乙酸甲酯（acetic methyl ester）中饱和硝化，形成相应的硝基化合物。
此反应需要加入适量的浓硫酸和硝酸。
步骤二：接下来，硝基化合物通过氢氧化钠（sodium hydroxide）的作用，在醇溶剂中进行还原反应，得到相应的氨基化合物。
步骤三：经过还原反应得到氨基化合物后，通过对其进行氯化处理，生成氯莫衍生物。
此反应需要加入适量的氯化亚砜（thionyl chloride）和五氯硅烷（silicon tetrachloride）等试剂。
步骤四：氯莫衍生物通过将其与氨（ammonia）或二甲基胺（dimethylamine）反应，进行还原反应，得到芬戈基胺。
此反应需要在高压下进行，并在其中加入一定量的氢气气氛。
步骤五：最后，芬戈基胺与盐酸反应，生成最终的盐酸芬戈莫德。
以上所述的合成方法是盐酸芬戈莫德的一种较常用的合成方法。
虽然该方法中所使用的试剂较多，合成步骤较多，但是该方法具有可行性和高产率的特点。
此外，该方法还可以通过合理地选择和改进试剂和反应条件来改进产率和纯度。
盐酸芬戈莫德的中间体包括硝基化合物、氨基化合物、氯莫衍生物和芬戈基胺。
在合成过程中，这些中间体的选择和转化反应是非常关键的。
对这些中间体的制备和转化反应进行优化，可以有效提高盐酸芬戈莫德的产率和纯度。
总的来说，盐酸芬戈莫德是一种重要的神经调节剂，其合成方法包括多个步骤和中间体。
在合成过程中，对中间体的选择和反应条件的控制是非常重要的。
进一步的研究和改进可以提高盐酸芬戈莫德的合成效率和纯度，更好地满足临床需求。
盐酸倍他司汀及其关键中间体的合成综述
盐酸倍他司汀及其关键中间体的合成综述盐酸倍他司汀（Escitalopram hydrobromide）是一种常用的抗抑郁药物，广泛用于治疗抑郁症和焦虑症。
它是一种选择性去甲肾上腺素再摄取抑制剂（SSRI），能有效增加大脑中去甲肾上腺素的水平，从而改善情绪和心理状态。
盐酸倍他司汀的合成工艺涉及多个中间体的合成步骤，下面将从中间体入手，对盐酸倍他司汀及其关键中间体的合成进行综述。
一、关键中间体的合成1. 3-氯-3-(二氯甲基)丙烯（3-Chloro-3-(dichloromethyl)propene）3-氯-3-(二氯甲基)丙烯是合成盐酸倍他司汀的关键中间体之一，它通常通过氯乙腈和三氯乙酸的反应制备。
首先将氯乙腈和三氯乙酸在二氯甲烷中反应，再加入三甲胺，使用活性碳吸附，最后蒸馏得到3-氯-3-(二氯甲基)丙烯。
2. 3-(二氯甲基)-7-氟-1，3-二氢-5-(4-甲基-1-哌啶基)-2H-1,4-苯并二氮在-3-酮（3-(Dichloromethyl)-7-fluoro-1,3-dihydro-5-(4-methyl-1-piperazinyl)-2H-1,4-be nzodiazepin-2-one）以上述3-氯-3-(二氯甲基)丙烯为起始原料，通过串联反应得到3-(二氯甲基)-7-氟-1，3-二氢-5-(4-甲基-1-哌啶基)-2H-1,4-苯并二氮在-3-酮。
将3-氯-3-(二氯甲基)丙烯和对氨基苯甲酮在三甲苯中加热反应，生成中间体，再用氢醌处理，发生串联反应，得到目标产物。
3. 盐酸倍他司汀通过将3-(二氯甲基)-7-氟-1，3-二氢-5-(4-甲基-1-哌啶基)-2H-1,4-苯并二氮在-3-酮与盐酸的反应，得到盐酸倍他司汀的合成。
二、盐酸倍他司汀的合成综述盐酸倍他司汀的合成工艺包括多个中间体的合成步骤，其合成路线如下：以上合成路线中间体的合成步骤相对繁琐，需要多步反应和纯化过程，针对每个中间体的合成过程进行优化是十分重要的。
阿司咪唑
合成方法
合成方法
化合物(I)和碘甲烷在乙醇中回流8h，环合得到化合物(Ⅱ)。再水解脱去酯基，得到化合物(Ⅲ)。用对甲氧 基苯乙基溴进行N-烷基化，得化合物(Ⅳ)。再用对氟苄基溴烷基化，得阿司咪唑。
1. 1-[(4-氟苯基)甲基]-苯并咪唑-2-(3H)-酮的制备
在反应瓶中加入2-羟基苯并咪唑5.0g(37.3mmol)和NaH 1.6g(53mmol)(NaH含量大约为80%,浸入矿物油中) 的DMF 100ml的悬浮液.加毕.在60ºC.(最好有N2保护)搅拌反应1h.再加入4-氟苄基氯(FBC)5.4g(37mmol),加热 ( 6 0 ºC ) 搅 拌 反 应 5 . 5 h . 冷 却 至 室 温 后 加 入 冰 水 7 0 0 m l , 用 二 氯 甲 烷 ( 5 0 0 m l × 2 ) 提 取 . 有 机 层 用 食 盐 水 洗 . 无 水 N a 2 S O 4 干燥.过滤.滤液减压浓缩.剩余物用石油醚析晶.得1-[(4-氟苯基)甲基]-苯并咪唑-2-(3H)-酮固体8.0g,为无色 结 晶 m p 1 7 8 ~ 1 7 9 ºC , 收 率 8 8 % .
治疗措施
阿司咪唑中毒的治疗要点为： 1.大量摄入者予洗胃，后灌服活性炭和导泻。 2.对心肌抑制和Q-T间期延长者予5%碳酸氢钠250ml静注可能有效。 3.对症、支持治疗。
专家点评
专家点评
阿司咪阿司咪唑自1983年上市以来，在许多国家得到了广泛应用。国外研究显示阿司咪唑治疗荨麻疹的总有 效率为74%。国内的一项多中心双盲安慰剂对照试验表明阿司咪唑对急性荨麻疹的总有效率为82.9%，对慢性荨麻 疹的总有效率为86.0%，均显著高于安慰剂，主要不良反应为嗜睡、倦怠、口干等，连续用药3个月的患者中，半 数有食欲及体重增加。阿司咪唑的心脏毒性虽然发生率较低，但由于后果严重，已限制了它的应用。阿司咪唑为 强效和长效的H1受体拮抗剂，无中枢镇静和抗毒蕈碱样作用。代谢产物去甲阿司咪唑仍有抗胆胺作用。长期服用 可增进食欲和增加体重，服用过量可引起心脏Q-T间期延长和室性心律失常。适用于各种原因引起过敏性疾病。
泛昔洛韦
密度：1.4g/cm3 熔点：102-104°C 沸 点 ： 5 5 0 . 2 ºC 闪 点 ： 2 8 6 . 6 ºC 折射率：1.628 外观：灰白色粉末 溶解性：易溶于丙酮或甲醇，难溶于乙醇或异丙醇
摩尔折射率：82.66 摩尔体积（cm3/mol）：239.8 等张比容（90.2K）：639.3 表面张力（dyne/cm）：50.4 极化率（10-24cm3）：32.77
进入人体内后迅速转变成喷昔洛韦，喷昔洛韦可被病毒编码的胸苷激酶磷酸化成OCV单磷酸，再经宿主的磷 酸化成为喷昔洛韦三磷酸盐，三磷酸盐在病毒感染的细胞内迅速形成，缓慢代谢，致半衰期延长，参与HBV DNAp的三磷酸鸟苷(Pgtp)竞争，并进入DNA，作用于DNA合成的起始和延伸步骤，抑制DNA的合成，对水痘-带状疱疹 病毒、单纯疱疹病毒1型和2型和HBV均有较强的抑制作用。
泛昔洛韦
药品
目录
01 化合物简介
03 药典信息
02 药品简介 04 安全信息
泛昔洛韦，是一种有机化合物，化学式为C14H19N5O4，是第二代开环核苷类抗病毒药，主要用于疱疹病毒感 染，尤其是带状疱疹。
化合物简介
基本信息 理化性质
分子数据 化学数据
化学式：C14H19N5O4 分子量：321.332 CAS号：-87-4
疏水参数计算参考值（XlogP）：无 氢键供体数量：1 氢键受体数量：8 可旋转化学键数量：9 互变异构体数量：3 拓扑分子极性表面积：122 重原子数量：23 表面电荷：0 复杂度：404 同位素原子数量：0 确定原子立构中心数量：0
药品简介
作用机理
药代动力学
不良反应
泛昔洛韦口服迅速吸收，生物利用度77%，在体内很快转达变为喷昔洛韦，t1/2约为2h，约60-65%经肾排出。 在水痘-带状疱疹病毒感染的细胞内有一个较长的半衰期（9-10小时），单纯疱疹病毒1型和2型感染的细胞内半 衰期分别为10小时和20小时。
盐酸西维美林半水合物的制备
王信见,等:盐酸西维美林半水合物的制备/2019年第10期收稿日期:2019⁃07⁃11作者简介:王信见(1976-),男,四川彭州人,高级工程师,研究方向:药物合成,E⁃mail :4207678@ ;通讯作者:但国蓉,讲师,E⁃mail :liroy@ 。
doi :10.3969/j.issn.1672-5425.2019.10.016王信见,朱小锋,喻威,等.盐酸西维美林半水合物的制备[J ].化学与生物工程,2019,36(10):10⁃10.WANG X J ,ZHU X F ,YU W ,et al.Preparation of cevimeline hydrochloride hemihydrate [J ].Chemistry &Bioengineering ,2019,36(10):10⁃10.盐酸西维美林半水合物的制备王信见1,朱小锋1,喻 威1,但国蓉2(1.重庆惠源医药有限公司,重庆400039;2.陆军军医大学军事预防医学系,重庆400038)摘 要:在叔丁醇钠催化下,将3⁃喹咛环酮盐酸盐(Ⅱ)与三甲基碘化亚砜反应生成三亚甲基喹咛环氧化物(Ⅲ),再通入硫化氢开环加成得到3⁃羟基⁃3⁃巯基亚甲基喹咛(Ⅳ),化合物Ⅳ与乙醛缩合后生成西维美林碱基(Ⅴ),化合物Ⅴ再与消旋樟脑磺酸成盐并经过多次精制得到高纯度西维美林樟脑磺酸盐(Ⅵ),化合物Ⅵ碱化后与氯化氢成盐得到目标产物盐酸西维美林半水合物(Ⅰ),总收率20.5%。
该合成方法反应条件温和、操作简单、周期短、收率高,利于工业化生产。
关键词:西维美林半水合物;高收率;制备中图分类号:TQ460.31 文献标识码:A 文章编号:1672⁃5425(2019)10⁃0001⁃03Preparation of Cevimeline Hydrochloride HemihydrateWANG Xinjian 1,ZHU Xiaofeng 1,YU Wei 1,DAN Guorong 2(1.Chongqing Huiyuan Pharmaceutical Co.,Ltd ,Chongqing 400039,China ;2.College of Preventive Medicine ,Army Medical University ,Chongqing 400038,China )Abstract :Compound(Ⅲ)is obtained through the reaction between 3⁃quinuclidinone hydrochloride(Ⅱ)and trime⁃thylsulfoxonium iodide in the precence of sodium tert⁃butoxide,then compound Ⅳis obtained through ring⁃opening and addition of compound(Ⅲ)with hydrogen sulfide,and compound Ⅴis obtained through condensation of compound Ⅳwith acetaldehyde.Moreover,high⁃purity compound Ⅵis obtained from compound Ⅴvia reaction with racemic cam⁃phorsulfonic acid,recrystallization for resolution.Furthermore,Cevimeline hydrochloride hemihydrate (Ⅰ)is obtained from compound Ⅵvia alkalization,salt⁃forming reaction with hydrogen chloride with the total yield of 20.5%.This syn⁃thetic method has advantages such as moderate conditions,simple operation,saving time,and high yield,which is favora⁃ble for industrial production.Keywords :Cevimeline hydrochloride hemihydrate;high yield;preparation 盐酸西维美林半水合物,英文名Cevimeline hydro⁃chloride hemihydrate,化学名(+/-)⁃顺式⁃2⁃甲基螺(1,3⁃氧硫杂环戊烷⁃5,3'⁃喹咛环)盐酸半水合物,由Snow Brand 制药公司研制,2000年3月在美国首次上市(商品名Evoxac),2001年在日本批准上市,随后相继在台湾、香港等地上市。
氢溴酸达非那新
适应证
氢溴酸达非那新用于膀胱过度刺激引起的尿频、尿急、尿失禁。
禁忌证
1.对氢溴酸达非那新及其中成分过敏者禁用。 2.尿潴留、胃潴留及未控制的闭角型青光眼患者禁用。 3.重度肝功能损害患者不推荐使用。
注意事项
1.由于尿潴留的可能，有明显膀胱尿道阻塞症状的患者使用时应谨慎。 2.氢溴酸达非那新具有抗胆碱作用，能降低胃肠道动力，胃肠道阻塞性疾病患者有胃潴留的可能，使用时应 谨慎。严重便秘、溃疡性结肠炎和重症肌无力患者慎用。 3.已控制的闭角型青光眼患者慎用。 4.氢溴酸达非那新生殖毒性分级为C，只有当对母体的益处高于对胎儿的危险时方可用于孕妇。 5.氢溴酸达非那新可经大鼠乳汁分泌，尚不知氢溴酸达非那新是否经人乳汁分泌，哺乳期妇女应慎用。
用法用量
口服，推荐剂量为7.5mg，1次/d，整片服下，不得嚼碎、掰开或压碎，可单服或与食物同服。根据个人临床 反应，剂量可增至15mg。中度肝功能损伤患者及与CYP3A4抑制剂（如酮康唑、伊曲康唑、利托那韦、奈非那韦、 克拉霉素、奈法唑酮）同服时，剂量不得超过7.5mg。
药物相互作用
1.氢溴酸达非那新主要经CYP2D6和CYP3A4代谢，CYP3A4抑制剂（酮康唑、伊曲康唑、利托那韦、奈非那韦、 克拉霉素、奈法唑酮）可使氢溴酸达非那新代谢减少，日剂量不应超过7.5mg。
尿失禁治疗药物是一个潜力巨大但尚未完全开发的市场，临床特征均是在24h内需要小便数不少于十次。据 世界卫生组织(WHO)有关人员估计，全球约有10%～15%中年人(50岁以下)和40%～70%老年人不同程度地受到此病 困扰。膀胱过动症一般没有神经源性损伤或疾病，可由膀胱的快速充盈、体位改变、甚至行走、咳嗽诱发。估计 全世界约有4～5亿名尿失禁患者，女性的发生率为男性的2倍。男性的发生率随着年龄的增长而升高，是一种常 见和令人痛苦的疾病。（另有一组数据估计世界7个主要国家受影响的人群达1.54亿，其中0.73亿人被分类为明 显尿失禁症。）。
赛庚啶
抗凝血、抗过敏类新药。可用于荨麻疹、湿疹、过敏性和接触性皮炎、皮肤瘙痒等过敏反应 。
药物说明
01
分类
02
剂型
04
药代动力学
06
禁忌症03药理作用来自05适应症01
用法用量
02
注意事项
04
不良反应
03
药物相互作 用
05
中毒
06
专家点评
抗变态反应药物 >抗组胺药
1.片剂：每片2mg，4mg。 2.霜剂:0.5%（盐酸盐）。
新用途
01
流行性腮腺 炎
02
小儿厌食
03
支气管哮喘
04
小儿喘息性 支气管炎
06
倾倒综合症
05
闭经-泌乳 综合症
肝病性瘙痒
治疗偏头痛
内耳眩晕症
盐酸赛庚啶片
有人发现，扑尔敏合用西咪替丁治疗流行性腮腺炎，具有良好疗效，并证明盐酸赛庚啶的H1拮抗作用比扑尔 敏强5倍以上。由此试用盐酸赛庚啶4～12毫克/天（随年龄调整）和西咪替丁20毫克/(千克·天)，分次口服，共 4～7天。结果：治疗9例中，痊愈者8例，治愈率为88.89%。平均退热时间及腮腺消肿时间，明显优于服用病毒唑、 板蓝根外加敷中药者。
用法：口服，2毫克/次，3次/天，以后每日增加2毫克，逐渐增加至12～20毫克/天，6个月为1个疗程，停药 3～4周后开始下1个疗程。一般用药2周内见效。预防用药可在服药后30分钟发挥作用。
淤胆型肝炎、胆汁性肝硬化、肝炎后肝硬化等患者，常产生难以忍受的皮肤瘙痒，影响入眠和康复，常用抗 过敏剂多难奏效。采用赛庚啶治疗8例淤胆性肝炎并严重瘙痒，经用激素、扑尔敏等无效者，改服赛庚啶，4毫克 /次，3次/天，温开水送服。一般服药3天后症状改善，总有效率为87.5%。
吉非罗齐
孕妇及哺乳期妇女用药
在动物中大剂量使用本品可致胎仔死亡，人体研究未有报道。本品是否进入乳汁不详，故孕妇及哺乳期妇女 不宜服用本品。
儿童用药
儿童服用本品的研究尚不充分，应用时须权衡利弊。
老年患者用药
老年人如有肾功能不良时，须适当减少本品用药量。
药物相互作用
1、可明显增强口服抗凝药的作用，与其同用时应注意降低口服抗凝药的剂量，经常监测凝血酶原时间以调 整抗凝药剂量。其作用机理尚不确定，可能是因为本品能将华法林等从其蛋白结合位点上替换出来，从而使其作 用加强。
药物过量
目前尚无有关本品药物过量的报道，如发生药物过量，应针对中毒症状采取相应支持疗法。
药典信息
基本信息 性状
鉴别 检查
含量测定 类别
贮藏 制剂
基本信息
本品为2,2-二甲基-5-(2,5-二甲苯基氧基)-戊酸，按无水物计算，含C15H22O3应为98.0% ~102.0%。
性状
本品为白色结晶性粉末，无臭。 本品在三氯甲烷中极易溶解，在甲醇、乙醇、丙酮或己烷中易溶，在水中不溶，在氢氧化钠试液中易溶。 熔点 本品的熔点（通则0612）为58~61°C。
4、与胆汁酸结合树脂，如考来替泊等合用，则至少应在服用这些药物之前2小时或2小时之后再服用吉非罗 齐。因胆汁酸结合药物可结合同时服用的其它药物，进而影响其它药的吸收。
5、主要经肾排泄，在与免疫抑制剂，如环孢素合用时，可增加后者的血药浓度和肾毒性，有导致肾功能恶 化的危险，应减量或停药。本品与其它有肾毒性的药物合用时也应0512）测定。 供试品溶液：取本品，加流动相溶解并稀释制成每1mL中约含10mg的溶液。 对照溶液：精密量取供试品溶液适量，用流动相定量稀释制成每1mL中约含20µg的溶液。 系统适用性溶液：取吉非罗齐对照品与杂质Ⅰ适量，加流动相溶解并稀释制成每1mL中分别约含0.2mg和 0.05mg的溶液。 色谱条件：用十八烷基硅烷键合硅胶为填充剂，以甲醇-水-冰醋酸（75:24:1）为流动相，检测波长为 276nm，进样体积10μL。 系统适用性要求：系统适用性溶液色谱图中，吉非罗齐峰与杂质Ⅰ峰的分离度应符合要求，理论板数按吉非 罗齐峰计算不低于1500。 测定法：精密量取供试品溶液与对照溶液，分别注入液相色谱仪，记录色谱图至主成分峰保留时间的2倍。 限度：供试品溶液色谱图中如有杂质峰，单个杂质峰面积不得大于对照溶液的主峰面积（0.
罗氟司特片说明书(美国,FDA,英文)
5 10 15 20 25 30 35 40 1 HIGHLIGHTS OF PRESCRIBING INFORMATION2 These highlights do not include all the information needed3 to use DALIRESP safely and effectively. See full4 prescribing information for DALIRESP. 6 DALIRESP ®(roflumilast) tablets 7 Initial U.S. Approval: 20XX 8 9 ------------------------INDICATIONS AND USAGE----------------------DALIRESP is indicated as a treatment to reduce the risk of11 COPD exacerbations in patients with severe COPD associated 12 with chronic bronchitis and a history of exacerbations. (1, 14) 13 14 Limitations of Use: DALIRESP is not a bronchodilator and is notindicated for the relief of acute bronchospasm. (1, 14) 16 17 ----------------DOSAGE AND ADMINISTRATION--------------------18 The recommended dosage for patients with COPD is one 50019 mcg tablet per day, with or without food. (2)21 ------------------DOSAGE FORMS AND STRENGTHS--------------- 22 Tablets: 500 mcg (3) 23 24 ----------------------CONTRAINDICATIONS---------------------------- • Moderate to severe liver impairment (Child-Pugh B or C) 26 (4)27 28 ----------------WARNINGS AND PRECAUTIONS---------------------- 29 • Acute bronchospasm: Do not use for the relief of acutebronchospasm. (5.1) 31 • Psychiatric Events including Suicidality: Advise patients ,32 their caregivers, and families to be alert for the emergence33 or worsening of insomnia, anxiety, depression, suicidal34 thoughts or other mood changes, and if such changesoccur to contact their healthcare provider. Carefully weigh36 the risks and benefits of treatment with DALIRESP in 37 patients with a history of depression and/or suicidal 38 thoughts or behavior. (5.2) 39 •Weight Decrease: Monitor weight regularly. If unexplainedor clinically significant weight loss occurs, evaluate weight41loss and consider discontinuation of DALIRESP. (5.3)7542•Drug Interactions: Use with strong cytochrome P45043 enzyme inducers (e.g. rifampicin, phenobarbital,44 carbamazepine, phenytoin) is not recommended. (5.4)45 46 -----------------------------ADVERSE REACTIONS----------------------47 Most common adverse reactions (≥ 2%) are diarrhea, weight48 decrease, nausea, headache, back pain, influenza, insomnia, 49 dizziness and decreased appetite. (6.1) 50 51 To report SUSPECTED ADVERSE REACTIONS, Contact52 Forest Laboratories, Inc. at 1-800-678-1605 or FDA at 1-80053 FDA-1088 or /medwatch. 54 55 ----------------------DRUG INTERACTIONS------------------------------ 56 •Use with inhibitors of CYP3A4 or dual inhibitors of 57 CYP3A4 and CYP1A2 (e.g, erythromycin, ketoconazole,58 fluvoxamine, enoxacin, cimetidine) will increase roflumilast59 systemic exposure and may result in increased adverse60 reactions. The risk of such concurrent use should be61 weighed carefully against benefit. (7.2) 62 63 ---------------------USE IN SPECIFIC POPULATIONS----------------64 •Nursing Mothers: DALIRESP should not be used by 65 women who are nursing as excretion of roflumilast and/or 66 its metabolites into human milk is probable and there are67 no human studies that have investigated effects of68 DALIRESP on breast-fed infants. (8.3)69 70 See 17 for PATIENT COUNSELING INFORMATON AND71 MEDICATION GUIDE 72 73 74REVISED XX/20XX76FULL PRESCRIBING INFORMATION: CONTENTS*1. INDICATIONS AND USAGE 11. DESCRIPTION2. DOSAGE AND ADMINISTRATION 12. CLINICAL PHARMACOLOGY3. DOSAGE FORMS AND STRENGTHS 12.1 Mechanism of Action4. CONTRAINDICATIONS 12.2 Pharmacodynamics5. WARNINGS AND PRECAUTIONS 12.3 Pharmacokinetics5.1 Treatment of Acute Bronchospasm 13. NONCLINICAL TOXICOLOGY5.2 Psychiatric Events including Suicidality 13.1 Carcinogenesis, Mutagenesis, Impairment ofFertility5.3 Weight Decrease 14. CLINICAL STUDIES5.4 Drug Interactions 14.1 Chronic Obstructive Pulmonary Disease6. ADVERSE REACTIONS 16. HOW SUPPLIED/STORAGE AND HANDLING6.1 Adverse Reactions in Clinical Trials 16.1 How Supplied7. DRUG INTERACTIONS 16.2 Storage and Handling7.1 Drugs that induce Cytochrome P450 (CYP) 17. PATIENT COUNSELING INFORMATIONEnzymesDrugs7.2 that inhibit Cytochrome P450 (CYP) 17.1 BronchospasmEnzymes7.3 Oral combination contraceptives containing 17.2 Psychiatric Events including Suicidalitygestodene and ethinyl estradiol8. USE IN SPECIFIC PATIENT POPULATIONS 17.3 Weight Decrease8.1 Pregnancy 17.4 Drug Interactions8.2 Labor and Delivery8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Hepatic Impairment8.7 Renal Impairment10. OVERDOSAGE10.1 Human Experience10.2 Management of Overdose*Sections or subsections omitted from the full prescribinginformation are not listed77 FULL PRESCRIBING INFORMATION7879 1 INDICATIONSUSAGEAND80 DALIRESP® is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with81 chronic bronchitis and a history of exacerbations.8283 Limitations of Use84 DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm.8586 2 DOSAGEADMINISTRATIONAND87 The recommended dose of DALIRESP is one 500 microgram (mcg) tablet per day, with or without food.8889 3 DOSAGE FORMS AND STRENGTHS90 DALIRESP is supplied as white to off-white, round tablets, embossed with “D” on one side and “500” on the other side. Each tablet91 contains 500 mcg of roflumilast.9293 4 CONTRAINDICATIONS94 The use of DALIRESP is contraindicated in the following conditions:95 •Moderate to severe liver impairment (Child-Pugh B or C) [see Clinical Pharmacology (12.3) and Use in Special Populations (8.6)].9697 5 WARNINGS AND PRECAUTIONS9899 5.1 Treatment of Acute Bronchospasm100 DALIRESP is not a bronchodilator and should not be used for the relief of acute bronchospasm.101102 5.2 Psychiatric Events including Suicidality103 Treatment with DALIRESP is associated with an increase in psychiatric adverse reactions. In 8 controlled clinical trials 5.9% (263) of 104 patients treated with DALIRESP 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo. 105 The most commonly reported psychiatric adverse reactions were insomnia, anxiety, and depression which were reported at higher 106 rates in those treated with DALIRESP 500 mcg daily (2.4%, 1.4%, and 1.2% for DALIRESP versus 1.0%, 0.9%, and 0.9% for placebo, 107 respectively) [see Adverse Reactions (6.1)]. Instances of suicidal ideation and behavior, including completed suicide, have been 108 observed in clinical trials. Three patients experienced suicide-related adverse reactions (one completed suicide and two suicide 109 attempts) while receiving DALIRESP compared to one patient (suicidal ideation) who received placebo.110111 Before using DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully 112 weigh the risks and benefits of treatment with DALIRESP in such patients. Patients, their caregivers, and families should be advised of 113 the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if 114 such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing 115 treatment with DALIRESP if such events occur.116117 5.3 WeightDecrease118 Weight loss was a common adverse reaction in DALIRESP clinical trials and was reported in 7.5% (331) of patients treated with 119 DALIRESP 500 mcg once daily compared to 2.1% (89) treated with placebo [see Adverse Reactions (6.1)]. In addition to being 120 reported as adverse reactions, weight was prospectively assessed in two placebo-controlled clinical trials of one year duration. In 121 these studies, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5-10% of body weight) 122 compared to 7% of patients who received placebo. In addition, 7% of patients who received roflumilast compared to 2% of patients 123 receiving placebo experienced severe (>10% body weight) weight loss. During follow-up after treatment discontinuation, the majority of 124 patients with weight loss regained some of the weight they had lost while receiving DALIRESP. Patients treated with DALIRESP 125 should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be 126 evaluated, and discontinuation of DALIRESP should be considered.127128 5.4 Drug Interactions129 A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. The 130 administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in exposure, which may result in a decrease 131 in the therapeutic effectiveness of DALIRESP. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g. rifampicin, 132 phenobarbital, carbamazepine, phenytoin) with DALIRESP is not recommended. [see Drugs That Induce Cytochrome P450 (CYP) 133 Enzymes (7.1) and Clinical Pharmacology (12.3)].134135 6 ADVERSE REACTIONS136 The following adverse reactions are described in greater detail in other sections:137 • Psychiatric Events Including Suicidality [see Warnings and Precautions (5.2)]138 • Weight Decrease [see Warnings and Precautions (5.3)]139140 6.1 Adverse Reactions in Clinical Studies141 Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug 142 cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.143144 The safety data described below reflect exposure of 4438 patients to DALIRESP 500 mcg once daily in four 1-year placebo-controlled 145 trials, two 6-month placebo-controlled trials, and two 6-month drug add-on trials [see Clinical Studies (14.1)]. In these trials, 3136 and 146 1232 COPD patients were exposed to DALIRESP 500 mcg once daily for 6 months and 1-year, respectively.147148 The population had a median age of 64 years (range 40-91), 73% were male, 92.9% were Caucasian, and had COPD with a mean 149 pre-bronchodilator forced expiratory volume in one second (FEV1) of 8.9 to 89.1% predicted. In these trials, 68.5% of the patients 150 treated with DALIRESP reported an adverse reaction compared with 65.3% treated with placebo.151152 The proportion of patients who discontinued treatment due to adverse reaction was 14.8% for DALIRESP-treated patients and 9.9% 153 for placebo-treated patients. The most common adverse reactions that led to discontinuation of DALIRESP were diarrhea (2.4%) and 154 nausea (1.6%).155156 Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in DALIRESP157 treated patients include diarrhea, atrial fibrillation, lung cancer, prostate cancer, acute pancreatitis, and acute renal failure.158159 Table 1 summarizes the adverse reactions reported by ≥ 2% of patients in the DALIRESP group 8 controlled COPD clinical trials. 160161 Table 1: Adverse Reactions Reported by ≥ 2% of Patients162 Treated with DALIRESP 500 mcg daily and Greater Than PlaceboTreatmentAdverse Reactions (Preferred Term) DALIRESP Placebo (N=4438) (N=4192) n (%) n (%)Diarrhea 420 (9.5) 113 (2.7)Weight decreased 331 (7.5) 89 (2.1)Nausea 209 (4.7) 60 (1.4)Headache 195 (4.4) 87 (2.1)Back pain 142 (3.2) 92 (2.2)Influenza 124 (2.8) 112 (2.7)Insomnia 105 (2.4) 41 (1.0)Dizziness 92 (2.1) 45 (1.1)Decreased appetite 91 (2.1) 15 (0.4)163164 Adverse reactions that occurred in the DALIRESP group at a frequency of 1 to 2% where rates exceeded that in the placebo group 165 include:166167 Gastrointestinal disorders - abdominal pain, dyspepsia, gastritis, vomiting168 Infections and infestations - rhinitis, sinusitis, urinary tract infection,169 Musculoskeletal and connective tissue disorders - muscle spasms170 Nervous system disorders - tremor171 Psychiatric disorders - anxiety, depression172173 7 DRUGINTERACTIONS174 A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2 [see Clinical 175 Pharmacology (12.3)].176177 7.1 Drugs That Induce Cytochrome P450 (CYP) Enzymes178 Strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness of 179 DALIRESP. Therefore the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, and phenytoin) 180 with DALIRESP is not recommended [see Drug Interactions (5.4) and Clinical Pharmacology (12.3)].181182 7.2 Drugs That Inhibit Cytochrome P450 (CYP) Enzymes183 The co-administration of DALIRESP (500 mcg) with CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 184 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and 185 may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit. [see Clinical 186 Pharmacology (12.3)].187188 7.3 Oral Contraceptives Containing Gestodene and Ethinyl Estradiol189 The co-administration of DALIRESP (500 mcg) with oral contraceptives containing gestodene and ethinyl estradiol may increase190 roflumilast systemic exposure and may result in increased side effects. The risk of such concurrent use should be weighed carefully 191 against benefit [see Clinical Pharmacology (12.3)].192193 8 USE IN SPECIFIC POPULATIONS194195 8.1 Pregnancy196 Teratogenic effects: Pregnancy Category C: There are no adequate and well controlled studies of DALIRESP in pregnant women. 197 DALIRESP was not teratogenic in mice, rats, or rabbits. DALIRESP should be used during pregnancy only if the potential benefit 198 justifies the potential risk to the fetus.199200 DALIRESP induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, 201 respectively, the maximum recommended human dose (MRHD) (on a mg/m2 basis at maternal doses > 2 mg/kg/day and 6 mg/kg/day, 202 respectively). DALIRESP induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD 203 (on a mg/m2 basis at maternal doses ≥ 0.6 mg/kg/day). No treatment-related effects on embryo-fetal development were observed in204 mice, rats, and rabbits at approximately 12, 3, and 26 times the MRHD, respectively (on a mg/m2 basis at maternal doses of 1.5, 0.2, 205 and 0.8 mg/kg/day, respectively).206207 Nonteratogenic effects: DALIRESP has been shown to adversely affect pup post-natal development when dams were treated with the 208 drug during pregnancy and lactation periods in mice. These studies found that DALIRESP decreased pup rearing frequencies at 209 approximately 49 times the MRHD (on a mg/mg2 basis at a maternal dose of 6 mg/kg/day) during pregnancy and lactation. DALIRESP 210 also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD 211 (on a mg/m2 basis at a maternal dose of 12 mg/kg/day) during pregnancy and lactation.212213 8.2 Labor and Delivery214 DALIRESP should not be used during labor and delivery. There are no human studies that have investigated effects of DALIRESP on 215 preterm labor or labor at term; however, animal studies showed that DALIRESP disrupted the labor and delivery process in mice. 216 DALIRESP induced delivery retardation in pregnant mice at doses greater than or equal to approximately 16 times the MRHD (on a 217 mg/m2 basis at a maternal dose of > 2 mg/kg/day).218219 8.3 NursingMothers220 Roflumilast and/or its metabolites are excreted into the milk of lactating rats. Excretion of roflumilast and/or its metabolites into human 221 milk is probable. There are no human studies that have investigated effects of DALIRESP on breast-fed infants. DALIRESP should not 222 be used by women who are nursing.223224 8.4 PediatricUse225 COPD does not normally occur in children. The safety and effectiveness of DALIRESP in pediatric patients have not been established. 226227 8.5 GeriatricUse228 Of the 4438 COPD subjects exposed to DALIRESP for up to 12 months in 8 controlled clinical trials, 2022 were > 65 years of age and 229 471 were > 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger 230 subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, 231 but greater sensitivity of some older individuals cannot be ruled out. Based on available data for roflumilast, no adjustment of dosage 232 in geriatric patients is warranted [see Clinical Pharmacology (12.3)].233234 8.6 Hepatic Impairment235 Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh 236 A and B (8 subjects in each group). The AUCs of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively in 237 Child-Pugh A subjects and by 92% and 41%, respectively in Child-Pugh B subjects, as compared to age-, weight- and gender238 matched healthy subjects. The C max of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A 239 subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. DALIRESP 500 mcg has not 240 been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering DALIRESP to patients who 241 have mild liver impairment (Child-Pugh A). DALIRESP is not recommended for use in patients with moderate or severe liver 242 impairment (Child-Pugh B or C) [see Contraindications (4) and Clinical Pharmacology (12.3)].243244 8.7 RenalImpairment245 In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, the AUCs of roflumilast and 246 roflumilast N-oxide were decreased by 21% and 7%, respectively and C max were reduced by 16% and 12%, respectively. No dosage 247 adjustment is necessary for patients with renal impairment [see Clinical Pharmacology (12.3)].248249 10 OVERDOSAGE250251 10.1 Human Experience252 No case of overdose has been reported in clinical studies with DALIRESP. During the Phase I studies of DALIRESP, the 253 following symptoms were observed at an increased rate after a single oral dose of 2500 mcg and a single dose of 5000 mcg: 254 headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess and arterial hypotension.255256 10.2 Management of Overdose257 In case of overdose, patients should seek immediate medical help. Appropriate supportive medical care should be provided. Since 258 roflumilast is highly protein bound, hemodialysis is not likely to be an efficient method of drug removal. It is not known whether 259 roflumilast is dialyzable by peritoneal dialysis.260261 11 DESCRIPTION262 The active ingredient in DALIRESP tablets is roflumilast. Roflumilast and its active metabolite (roflumilast N-oxide) are selective 263 phosphodiesterase 4 (PDE4) inhibitors. The chemical name of roflumilast is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4264 difluoromethoxy-benzamide. Its empirical formula is C17H14Cl2F2N2O3 and the molecular weight is 403.22.265266 The chemical structure is:267268269270271 The drug substance is a white to off-white non-hygroscopic powder with a melting point of 160°C. It is practically insoluble in water and 272 hexane, sparingly soluble in ethanol and freely soluble in acetone.273274 DALIRESP is supplied as white to off-white, round tablets, embossed with “D” on one side and “500” on the other side. Each tablet 275 contains 500 mcg of roflumilast.276277 Each tablet of DALIRESP for oral administration contains the following inactive ingredients: lactose monohydrate, corn starch, 278 povidone and magnesium stearate.279280 12 CLINICALPHARMACOLOGY281282 12.1 Mechanism of Action283 Roflumilast and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase 4 (PDE4). Roflumilast and 284 roflumilast N-oxide inhibition of PDE4 (a major cyclic-3′,5′-adenosine monophosphate (cyclic AMP)-metabolizing enzyme in lung 285 tissue) activity leads to accumulation of intracellular cyclic AMP. While the specific mechanism(s) by which DALIRESP exerts its 286 therapeutic action in COPD patients is not well defined, it is thought to be related to the effects of increased intracellular cyclic AMP in 287 lung cells.288289 12.2 Pharmacodynamics290 In COPD patients, 4 week treatment with DALIRESP 500 mcg oral once daily reduced sputum neutrophils and eosinophils by 31%, 291 and 42%, respectively. In a pharmacodynamic study in healthy volunteers, DALIRESP 500 mcg once daily reduced the number of total 292 cells, neutrophils and eosinophils found in bronchoalveolar lavage fluid following segmental pulmonary lipopolysaccharide (LPS) 293 challenge by 35%, 38% and 73%, respectively. The clinical significance of these findings is unknown.294295 12.3 Pharmacokinetics296 Absorption297 The absolute bioavailability of roflumilast following a 500 mcg oral dose is approximately 80%. Maximum plasma concentrations (C max) 298 of roflumilast typically occur approximately one hour after dosing (ranging from 0.5 to 2 hours) in the fasted state while plateau-like 299 maximum concentrations of the N-oxide metabolite are reached in approximately eight hours (ranging from 4 to 13 hours). Food has 300 no affect on total drug absorption, but delays time to maximum concentration (T max) of roflumilast by one hour and reduces C max by 301 approximately 40%, however, C max and T max of roflumilast N-oxide are unaffected. An in vitro study showed that roflumilast and 302 roflumilast N-oxide did not inhibit P-gp transporter.303304 Distribution305 Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Volume of distribution for 306 single dose 500 mcg roflumilast is about 2.9 L/kg. Studies in rats with radiolabeled roflumilast indicate low penetration across the 307 blood-brain barrier.308309 Metabolism310 Roflumilast is extensively metabolized via Phase I (cytochrome P450) and Phase II (conjugation) reactions. The N-oxide metabolite is 311 the only major metabolite observed in the plasma of humans. Together, roflumilast and roflumilast N-oxide account for the majority 312 (87.5%) of total dose administered in plasma. In urine, roflumilast was not detectable while roflumilast N-oxide was only a trace 313 metabolite (less than 1%). Other conjugated metabolites such as roflumilast N-oxide glucuronide and 4-amino-3,5-dichloropyridine N314 oxide were detected in urine.315316 While roflumilast is three times more potent than roflumilast N-oxide at inhibition of the PDE4 enzyme in vitro, the plasma AUC of 317 roflumilast N-oxide on average is about 10-fold greater than the plasma AUC of roflumilast.318319 In vitro studies and clinical drug-drug interaction studies suggest that the biotransformation of roflumilast to its N-oxide metabolite is 320 mediated by CYP 1A2 and 3A4. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of 321 roflumilast and roflumilast N-oxide do not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11. Therefore, there is 322 a low probability of relevant interactions with substances metabolized by these P450 enzymes. In addition, in vitro studies 323 demonstrated no induction of the CYP 1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP 2B6 by roflumilast.324325 Elimination326 The plasma clearance after short-term intravenous infusion of roflumilast is on average about 9.6 L/h. Following an oral dose, the 327 median plasma effective half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively. Steady 328 state plasma concentrations of roflumilast and its N-oxide metabolite are reached after approximately 4 days for roflumilast and 6 days 329 for roflumilast N-oxide following once daily dosing. Following intravenous or oral administration of radiolabeled roflumilast, about 70%330 of the radioactivity was recovered in the urine.331332 Special Populations333334 Hepatic Impairment335 Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh 336 A and B (8 subjects in each group). The AUC of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively in 337 Child-Pugh A subjects and by 92% and 41%, respectively in Child-Pugh B subjects, as compared to age-, weight- and gender338 matched healthy subjects. The C max of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A 339 subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. DALIRESP 500 mcg has not 340 been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering DALIRESP to patients who 341 have mild liver impairment (Child-Pugh A). DALIRESP is not recommended for use in patients with moderate or severe liver 342 impairment (Child-Pugh B or C) [see Contraindications (4) and Use in Specific Populations (8.6)].343344 Renal Impairment345 In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, roflumilast and roflumilast N-oxide 346 AUCs were decreased by 21% and 7%, respectively and C max were reduced by 16% and 12%, respectively. No dosage adjustment is 347 necessary for patients with renal impairment [see Use in Specific Populations (8.7)].348349 Age350 Roflumilast 500 mcg once daily for 15 days was studied in young, middle aged, and elderly healthy subjects. The exposure in elderly 351 (> 65 years of age) were 27% higher in AUC and 16% higher in C max for roflumilast and 19% higher in AUC and 13% higher in C max for 352 roflumilast-N-oxide than that in young volunteers (18-45 years old). No dosage adjustment is necessary for elderly patients [see Use in 353 Specific Populations (8.5)].354355 Gender356 In a Phase I study evaluating the effect of age and gender on the pharmacokinetics of roflumilast and roflumilast N-oxide, a 39% and 357 33% increase in roflumilast and roflumilast N-oxide AUC were noted in healthy female subjects as compared to healthy male subjects. 358 No dosage adjustment is necessary based on gender.359360 Smoking361 The pharmacokinetics of roflumilast and roflumilast N-oxide were comparable in smokers as compared to non-smokers. There was no 362 difference in C max between smokers and non-smokers when roflumilast 500 mcg was administered as a single dose to 12 smokers and 363 12 non-smokers. The AUC of roflumilast in smokers was 13% less than that in non-smokers while the AUC of roflumilast N-oxide in 364 smokers was 17% more than that in non-smokers.365366 Race367 As compared to Caucasians, African Americans, Hispanics, and Japanese showed 16%, 41%, and 15% higher AUC, respectively, for 368 roflumilast and 43%, 27%, and 16% higher AUC, respectively, for roflumilast N-oxide. As compared to Caucasians, African Americans, 369 Hispanics, and Japanese showed 8%, 21%, and 5% higher C max, respectively, for roflumilast and 43%, 27%, and 17% higher C max, 370 respectively, for roflumilast N-oxide. No dosage adjustment is necessary for race.371372 Drug Interactions373 Drug interaction studies were performed with roflumilast and other drugs likely to be coadministered or drugs commonly used as 374 probes for pharmacokinetic interaction [see Drug Interactions]. No significant drug interactions were observed when 500 mcg oral 375 roflumilast was administered with inhaled salbutamol, formoterol, budesonide and oral montelukast, digoxin, theophylline, warfarin, 376 sildenafil, midazolam, or antacids.377378 The effect of concomitant drugs on the exposure of roflumilast and roflumilast N-oxide is shown in the Figure 1 below.379380。