汞软膏说明书

化学品安全技术说明书

1、物质的理化常数

国标编号: 83505 ｃａｓ: 7439-97-6 中文名称: 汞

英文名称: mercury

别名: 水银

分子式: hg

分子量: 200.59 熔点:

-38.9℃沸点：356.9?

密度:

相对密度(水=1)13.55?

蒸汽压:

0.13kpa(126.2℃)

溶解性:

不溶于水、盐酸、稀硫酸，溶于浓硝酸，易溶于王水及浓

稳定性: 稳定

外观与性状:

银白色液态金属，在常温下可挥发。洒落可形成小水珠

危险标记: 20(腐蚀品)

用途:

用于制造汞盐，也用于仪表工业

2.对环境的影响:

一、健康危害

侵入途径：吸入、食入、经皮吸收。

健康危害：急性中毒：病人有头痛、头晕、乏力、多梦、发热等全身症状，并有明显口

腔炎表现。可有食欲不振、恶心、腹痛、腹泻等。部分患者皮肤出现红色斑丘疹，少数严重

者可发生间质性肺炎及肾脏损伤。

慢性中毒：最早出现头痛、头晕、乏力、记忆减退等神经衰弱综合征；汞毒性震颤；另

外可有口腔炎，少数病人有肝、肾损伤。

二、毒理学资料及环境行为

污染来源：汞用于仪表制造、电工技术和各种仪器的生产、各种汞化合物用于化学、化

学制药、木材加工、造纸等工业，化学毒剂、颜料、金属电镀、爆竹制造及有机合成的生产

中也常使用汞。此外，汞选矿厂的废水和生产蓄电池等工业废水中也往往有高含量的汞，从

而造成中毒事件。

随饮水进入人体和动物体内的汞及其化合物毒性很大，因为肠对汞及其化合物吸收很快，

并可随血液进入器官和组织中，进而引起剧烈的全身性的毒性作用。随饮水进入成年人体内

的示致死量为75～100mg/d。二价汞或升汞的毒性特别大，因为它们易溶于类脂化合物中并

很快进入组织。烷基汞比无机汞的毒性更大。工业上长期接触汞或长期生活在受汞污染的环

境中可引起慢性中毒，从而发生脑皮质萎缩和中枢及末梢神经脱髓鞘，临床上有精神、表情

和运动障碍、口腔粘膜发生溃疡性炎症。日本所发生的水俣病，是一种中毒性神经疾病，是

工业污染引起的有机汞中毒事件。

迁移转化：天然水体是由水相、固相、生物相组成的复杂体系。汞在这些相中，具有多

种存在状态。在水相中，汞以hg、hg(oh)n、ch3hg、ch3hg(oh)、ch3hgcl、c6h5hg为主要形

态。在固相中，以hg、hg、hgo、hgs、ch3hg(sr)、(ch3hg)2s为主要形态。在生物相中，以

hg、ch3hg、ch3hgch3为主要形态。它们将随着环境条件的变化而发生改变。水体中汞的生

物迁移在数量上是有限的，但由于在微生物的参与下，沉积在水体中的无机汞能转变成剧毒

的甲基汞，并且沉积物中生物合成的甲基汞能连续不断地释放入水中。由于甲基汞具有很强

的亲脂能力，因而水中低量的甲基汞能被水生生物吸收，通过食物链逐级富集与转移，威胁

人类的健康与安全。因此，汞的生物迁移过程，实际上主要是甲基汞的迁移与累积过程，这

与无机汞在气、水中迁移完全不同，它是一种危害人体健康与威胁人类安全的生物地球化学

流迁移。汞进入土壤后95%以上能迅速被土壤吸持或固定。主要是土壤中含有的粘土矿物和

有机质对汞有强烈的吸附作用，因此汞易累积在土壤中。

危险特性：常温下有蒸气挥发，高温下能迅速挥发。与氯酸盐、硝酸盐、热硫酸等混合

可发生爆炸。燃烧(分解)产物：氧化汞。 3.现场应急监测方法: 气体检测管法

试纸比色法；碘化亚铜检气管比度法《空气中有害物质的测定方法》，杭士平主编

2+

+

2-n

+

+

2+ 2+ 速测管法；阳极溶出伏安法《突发性环境污染事故应急监测与处理处置技术》万本太主

编气体速测管（北京劳保所产品、德国德尔格公司产品） 4.实验室监测方法:

5.环境标准:

6.应急处理处置方法:

金属汞不溶于水，易溶于水的汞化合物主要有氯化亚汞、硫酸汞、硝酸汞、次氯酸汞和

各种烷基汞。因此造成水的突发污染事故一般是由这些可溶于水的汞化合物所致。如果发生

汞污染的重大事故，可在受污染的水体中加入苛性碱后，再加入硫化钠或硫化钾。吹空气于

水体吕，在气泡的翻动下使溶于水中的硫离子和汞结合成硫化汞沉淀，待硫化汞沉淀后清除

底质则达到去除水中汞的目的。首先将污水注入中和池，然后流进空气分离器，拉着向其中

加入硫化钠和可溶性苛性钠(以维持碱性环境)，其结果氢氧化物在浓缩池沉淀析出，而开成

的硫化亚汞停留在过滤器上。这种方法可使废水中汞的浓度从15～25mg/l降至0.003～

0.01mg/l。另一种方法是用阳离子交换过滤器回收污水中的汞。事前先将污水中的悬浮物和

其他机械混合物过滤，过滤后的污水送入装有活性炭的空心柱装置，然后进行阳离子过滤。

净化后的污水汞含量可达到0.1mg/l。一、泄漏应急处理

疏散泄漏污染区人员至安全区，禁止无关人员进入污染区，建议应急处理人员戴自给式

呼吸器，穿化学防护服。不要直接接触泄漏物，在确保安全情况下堵漏。收集转移回收。无

法收集的可用多硫化钙或过量的硫磺处理。二、防护措施

呼吸系统防护：可能接触其蒸气时，应该佩带防毒口罩。必要时建议佩带自给式呼吸器。

眼睛防护：戴安全防护眼镜。防护服：穿相应的防护服。手防护：戴防化学品手套。

其它：工作现场禁止吸烟、进食和饮水。工作后，彻底清洗。单独存放被毒物污染的衣

服，洗后再用。进行就业前和定期的体检。三、急救措施

皮肤接触：脱去污染的衣着，立即用流动清水彻底冲洗。眼睛接触：立即提起眼睑，

用大量流动清水或生理盐水冲洗。

吸入：迅速脱离现场至空气新鲜处。注意保暖，必要时进行人工呼吸。就医。食

入：误服者立即漱口，给饮牛奶或蛋清。就医。灭火方法：不燃。篇二：汞化学品安全技术

说明书

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3

4

篇三：化药及生物制品

黄氧化汞眼膏 - sfda药品说明书范本

【英文名称】 yellow mercuric oxide eye ointment 【性状】本品为橙黄色油膏。

【适应症】本品为作用缓和的眼科防腐消毒剂，并能促进局部循环及角膜混浊吸收。用

于治疗疱疹性结膜炎，睑缘炎，巩膜炎，以及角膜瘢痕性混浊等。

甲酚皂溶液 - 天津市中央药业有限公司

【英文名称】 saponated cresol solution 【性状】本品为黄棕色至红棕色的黏稠液体，带有甲酚臭气。能与乙醇混合成澄清液体。

【适应症】本品用于手、器械、环境消毒及处理排泄物。

甲醛溶液 - 太原市卫星制药有限公司

【英文名称】 formaldehyde solution 【性状】为无色或几乎无色的澄明液体；有刺激性的特臭，能刺激鼻、喉的粘膜，味灼

烈。冷处久置、即析出多聚甲醛而发生浑浊。本品与能水或乙醇任意混合。本品为甲醛的水

溶液，含甲醛(hcho)不得少于36%(w/w)。

【适应症】由于对粘膜刺激性太强，多用于房屋、家具、器械的消毒，固定生物标本、

保存尸体与防腐等。

加香甲酚皂溶液 - 河北健宁医药化工厂

【英文名称】 fragrant saponated cresol solution 【性状】本品为黄棕色至红棕色的透明液体，带有芳香气味，能与乙醇混合成澄清液体。

【适应症】本品用于器械、环境消毒及处理排泄物。

甲紫溶液 - 北京海德润制药有限公司

【英文名称】 methylrosanilinium chloride solution 【性状】本品为紫色液体。

【适应症】用于皮肤和粘膜的化脓性感染、白色念珠菌引起的口腔炎，也用于烫伤、烧

伤等。聚维酮碘含漱液 - 杭州民生药业集团有限公司

【商品名称】怡速欣

【英文名称】 povidone-iodine gargle and mouthwash 聚维酮碘凝胶 - 深圳市源兴药业有限公司

【商品名称】黛卫?

【英文名称】 povidone iodine gel 【性状】本品为水溶性红棕色的稠厚液体。

【适应症】用于念珠菌性外阴阴道病、细菌性阴道病及混合感染性阴道炎。

聚维酮碘泡腾片 - 上海方大药业股份有限公司

【商品名称】艾迪尔

【英文名称】 povidone iodine effervescent tablets 聚维酮碘溶液 - 成都永安制药有限公司

【商品名称】艾利克

【英文名称】 povidone iodine solution 聚维酮碘溶液 - 江西银涛药业有限公司

【商标名称】可立洁?

【英文名称】 povidone iodine solution

【性状】本品为红棕色液体。

【适应症】用于化脓性皮炎、皮肤真菌感染、小面积轻度烧烫伤，也用于小面积皮肤、

黏膜创口的消毒。

醋酸氯己定痔疮栓 - 锦州九泰药业有限责任公司

【商标名称】九泰至宁

【性状】本品为乳白色栓剂。

【适应症】用于外痔、内痔。

地喹氯铵含片 - 武汉天源药业有限责任公司

【英文名称】 dequalinium chloride buccal tablets 【性状】本品为类白色或着白色，气芳香，味微甜

【适应症】用于急、慢性咽喉炎，口腔黏膜溃疡、齿龈炎。

地喹氯铵含片 - 泰国大西洋制药厂有限公司

【商品名称】利林 delin

【英文名称】 dequalinium chloride buccal tablets 地喹氯铵含片 - 北京双鹤药业股份有限公司

【商标名称】清利

【英文名称】 dequalinium chloride buccal tablets 碘酊 - 北京海德润制药有限公司

【英文名称】 iodine tincture 【性状】本品为红棕色的澄清液体；有碘与乙醇的特臭。

【适应症】用于皮肤感染和消毒。

碘络醚溶液 - sfda药品说明书范本(otc) 【适应症】用于小面积轻度烧伤、烫伤等创面感染的防治。

度米芬滴丸 - sfda药品说明书范本(otc) 【英文名称】 domiphen bromide pills 【适应症】用于咽炎、鹅口疮和口腔溃疡。

度米芬含片 - sfda药品说明书范本(otc) 【英文名称】 domiphen bromide buccal tablets 【适应症】用于咽炎、鹅口疮和口腔溃疡。

复方薄荷脑鼻用吸入剂 - 曼秀雷敦(中国)药业有限公司

【商品名称】良抒

【性状】本品为吸附药液的纤维棒，装入塑料管内，供鼻腔吸入用，气芳香，具有清凉

感。

【适应症】用于感冒引起的鼻塞。

复方薄荷脑软膏 - 曼秀雷敦(中国)药业有限公司

【商品名称】曼秀雷敦栢可

聚维酮碘溶液 - 杭州洁康药业有限公司

【商标名称】丽洁

【英文名称】 povidone iodine solution 聚维酮碘溶液 - 南京南大药业有限责任公司

【商品名称】丽泽

【英文名称】 povidone iodine solution 聚维酮碘溶液 - 江苏济川制药有限公司

【商标名称】淑捷康

【英文名称】 povidone iodine solution 聚维酮碘乳膏 - sfda药品说明书范本(otc) 【英文名称】 povidone iodine cream 【适应症】用于念珠菌性外阴阴道病、细菌性阴道病及混合感染性阴道炎。

聚维酮碘栓 - 南京南大药业有限责任公司

【商品名称】丽乐

【英文名称】 povidone iodine suppositories 聚维酮碘栓 - 四川迪康科技药业股份有限公司成都迪康制药公司

【商品名称】利泰

【英文名称】 povidone iodine suppositories 【性状】本品为棕红色栓。

【适应症】用于念珠菌性外阴阴道病、细菌性阴道病及混合感染性阴道炎。也可用于痔

疮。聚维酮碘药膜 - 成都永安制药有限公司

【商品名称】艾妮亚

【英文名称】 povidone iodine pellicles 【性状】本品为黄棕色或红棕色片状薄膜。

【适应症】适用于治疗霉菌性(念珠菌)阴道炎。

枸橼酸氯己定口胶 - 锦州九泰药业有限责任公司

【商品名称】九泰口胶

【英文名称】 chlorhexidie citrate gummy tablets 硫磺硼砂乳膏 - sfda药品说明书范本(otc) 【适应症】用于脂溢性皮炎、疥疮、痤疮以及湿疹。

硫软膏 - 上海运佳黄浦制药有限公司

【英文名称】 sulfur ointement 【性状】本品为黄色软膏，有硫的特臭。

【适应症】用于疥疮、头癣、痤疮、脂溢性皮炎、酒渣鼻、单纯糠疹、慢性湿疹。

硫酸锌颗粒 - sfda药品说明书范本

【英文名称】 zinc sulfate granules 【适应症】用于锌缺乏引起的肠病性肢端皮炎、口疮、慢性溃疡、结膜炎等。

硫酸锌口服溶液 - sfda药品说明书范本(otc) 【英文名称】 zinc sulfate oral solution 【适应症】用于锌缺乏引起的食欲缺乏、异食癖、贫血、生长发育迟缓；也可用于痤疮、

结膜炎、口疮。

硫酸锌片 - 北京万辉双鹤药业有限责任公司

【英文名称】 zinc sulfate tablets 【性状】本品为糖衣片，除去包衣后显白色。

【适应症】用于锌缺乏引起的食欲缺乏，贫血、生长发育迟缓、营养性侏儒及肠病性肢

端皮炎。也可用于异食癖、类风湿性关节炎、间歇性跛行、肝豆状核变性（适用于不能用青

霉胺者）、痤疮、慢性溃疡、结膜炎、口疮等的辅助治疗。

硫酸锌糖浆 - sfda药品说明书范本(otc) 【英文名称】 zinc sulfate syrup 【适应症】用于防治锌缺乏引起的各种病症。

氯化氨基汞软膏 - sfda药品说明书范本

【英文名称】 hydrargyrum aminochloride ointment

【性状】本品为淡黄色软膏。

【适应症】消毒防腐药。 2%～5%软膏治疗脓疱疮、葡萄球感染所致的皮肤病及皮肤真菌

感染；5%软膏用于湿疹、牛皮癣，各种皮肤癣症，由于蛲虫引起的肛门瘙痒、疥癣等症。

浓过氧化氢溶液 - sfda药品说明书范本

【英文名称】 strong hydrogen peroxide solution 【性状】本品为无色澄明液体；无臭或有类似臭氧的臭气；遇氧化物或还原物即迅速分

解并发生泡沫，遇光易变质。

【适应症】适用于化脓性外耳道炎和中耳炎、文森口腔炎、齿龈脓漏、扁桃体炎及清洁

伤口。硼酸软膏 - sfda药品说明书范本(otc) 【英文名称】 boric acid ointment 【适应症】用于轻度、小面积急性湿疹、急性皮炎、脓疱疮、褥疮。

硼酸洗液 - 四川迪康科技药业股份有限公司成都迪康制药公司

【商品名称】殷泰

【英文名称】 boric acid solution 葡萄糖酸氯己定含漱液 - 四川迪康科技药业股份有限公司成都迪康制药公司

【商品名称】雅诺

【英文名称】 chlorhexidine gluconate gargle 葡萄糖酸氯己定溶液 - sfda药品说明书范本

【英文名称】 chlorhexidine gluconate solution 【性状】本品为无色或淡黄色几乎透明略为粘稠的液体。

【适应症】本品可用于咽峡炎和口腔溃疡等。篇四：地球人软膏说明书

地球人抑菌乳膏说明书

[品名]地球人抑菌乳膏

[汉语拼音]diqiurenyijunrugao [性状]本品为乳剂基质软膏

[主要成份]伍倍子、皂角剌、独角莲、土槿皮、黄柏、百部、土伏苓、七星剑、铁冬青、

蛇床子、鞭叶蓉、苦参、白藓皮等。

[适用范围]对引起皮炎(神经性皮炎、过敏性皮炎、日光性皮炎)、湿疹、手足癣(香港脚、

鹅掌风、烂脚丫、脚臭、脚汗、手脚脱皮)、体股癣、花斑癣(汗斑)、牛皮癣、龟头炎、女

阴瘙痒、痔疮、疥疮、蚊虫叮咬、痤疮、水泡、白色糠疹、寻麻疹等感染的葡萄球菌、念球

菌(霉菌、真菌)、大肠杆菌有较强的抑制作用并能预防皮肤感染。

[用法用量] 外用，取本品涂搽皮肤感染处。

1、皮肤：涂抹于洗净患处，每天2-3次；

2、阴道：取本品3g左右纳入阴道搽抹；同时涂抹外阴，每天1-2次；

3、肛门：用温开水洗净患处，取本品3g左右直接涂抹或注入痔疮患处。

[执行标准]q/hz204-2011 [卫生许可证号]赣卫消证字(2011)第0010号 [ 注意事项]详见说明书。

[规格]铝管包装，15g/支

[贮藏]密闭，置阴凉干燥处保存。

尼美舒利治疗小儿高热的临床疗效观察

尼美舒利治疗小儿高热的临床疗效观察 【摘要】目的探讨尼美舒利治疗小儿高热的临床疗效。方法小儿高热患者245例，随机分为三组，在常规治疗的基础上，治疗组用尼美舒利颗粒5 mg/（kg·d），分2～3次服用。对照组用对乙酰氨基酚10～15 mg/（kg·次），4～6 h 1次。布洛芬混悬液5～10 mg／（kg·次），每6～8 h可重复1次，24 h不超过4次。结果治疗组与对照组相比，退热效果显著。结论尼美舒利退热作用显著，副作用少。 【关键词】尼美舒利；小儿高热 高热是小儿急性感染常见症状之一，高热易导致婴儿惊厥，需要及时退热处理。用新型解热镇痛药尼美舒利颗粒治疗小儿急性感染所致高热临床报道较少，经我们治疗观察临床效果显著，现报告如下。 1 资料与方法 1 1 一般资料全部病例均来自我院2009年7至11月门诊高热患儿，其中急性上呼吸道感染142例，随机分成三组，尼美舒利颗粒治疗组42例，男25例，女17例;对乙酰氨基酚组48例，男28例，女20例；布洛芬混悬液组52例，男28例，女24例。急性消化道感染103例，随机分成尼美舒利颗粒治疗组31例，男19例，女12例;对乙酰氨基酚组33例，男20例，女13例；布洛芬混悬液组39

例，男15例，女24例。年龄2～11岁，腋温在38

5 ℃～41 ℃，病程1～3天。一般情况:治疗组及对照组的性别、年龄、病程、发热程度相似，差异无显著性（P>005），具有可比性。 1 2 用药剂量与方法三组均按常规治疗，在此基础上治疗组加服尼美舒利颗粒5 mg/（kg·d），分2～3次餐后服，对乙酰氨基酚组加服对乙酰氨基酚，10～15 mg/（kg·次），4～6 h可重复1次。布洛芬混悬液组加服布洛芬混悬液5～10 mg／（kg·次），每6～8 h 可重复1次，24 h不超过4次。 1 3 疗效判断标准显效:治疗2天（48 h）内退热，诸症状消失;有效:用药2天体温减为低热，诸症状好转;无效:用药后2天体温不减，其他症状也不减轻。 2 结果 急性呼吸道感染伴高热尼美舒利治疗组总有效率857%，对乙酰氨基酚总有效率625%，布洛芬混悬液组总有效率583%；急性消化道感染伴高热尼美舒利治疗组总有效率871%，对乙酰氨基酚总有效率515%，布洛芬混悬液组总有效率535%。三组比较治疗组退热效果明显较两对照组显著。 3 讨论

他克莫司软膏说明书

快易捷医药网 【通用名】他克莫司软膏 【商品名】普特彼 【英文名】英文名：Tacrolimus Ointment 【汉语拼音】Ta Ke Mo Si Ruan Gao 本品主要成分及其化学名称为：他克莫司， 【性状】本品为白色至淡黄色软膏。 【处方组成】每克本品含他克莫司0.03%或0.1%(w/w)，软膏基质为矿 物油、石蜡、碳酸丙烯酯、白凡士林和白蜡。 【适应症】本品适用于因潜在危险而不宜使用传统疗法、或对传统 疗法反应不充分、或无法耐受传统疗法的中到重度特应 性皮炎患者，作为短期或间歇性长期治疗。 0.03%和0.1%浓度的本品均可用于成人，但只有0.03%浓 度的本品可用于2岁及以上的儿童。 【用法与用量】成人 0.03%和0.1%他克莫司软膏 在患处皮肤涂上一薄层本品，轻轻擦匀，并完全覆盖， 一天两次，持续至特应性皮炎症状和体征消失后一周。 封包疗法可能会促进全身性吸收，其安全性未进行过评 价。本品不应采用封包敷料外用。 儿童 0.03%他克莫司软膏 在患处皮肤涂上一薄层本品，轻轻擦匀，并完全覆盖， 一天两次，持续至特应性皮炎症状和体征消失后一周。 封包疗法可能会促进全身性吸收，其安全性未进行过评 价。本品不应采用封包敷料外用。 【禁忌症】对他克莫司或制剂中任何其他成分有过敏史的患者禁用 本品。 【注意事项】外用本品可能会引起局部症状，如皮肤烧灼感（灼热感 、刺痛、疼痛）或瘙痒。局部症状最常见于使用本品的 最初几天，通常会随着特应性皮炎受累皮肤好转而消失 。应用0.1%浓度的本品治疗时，90%的皮肤烧灼感持续时 间介于2分钟至3小时（中位时间为15分钟）之间，90%的 瘙痒症状持续时间介于3分钟至10小时（中位时间为20分 钟）之间。 不推荐使用本品治疗Netherton综合征患者，因为可能会 增加他克莫司的全身性吸收。本品对弥漫性红皮病患者 治疗的安全性尚未建立。 【患者须知】使用本品的患者应接受下列信息和指导： 1．患者应在医生的指导下使用本品。本品仅供外用。 和任何外用药一样，患者或护工在用药后应洗手，如果 手部不是治疗区的话。

汞安全技术说明书

汞安全技术说明书 文稿归稿存档编号：[KKUY-KKIO69-OTM243-OLUI129-G00I-FDQS58-

汞安全技术说明书 第一部分：危险性概述? 化学品中文名：?汞侵入途径：吸入。? 健康危害：? 短期内大量吸入汞蒸气后引起急性中毒，病人有头痛、头晕、乏力、多梦、睡眠障碍、易激动、手指震颤、发热等全身症状，并有明显口腔炎表现。可有食欲不振、恶心、腹痛、腹泻等。部分患者皮肤出现红色斑丘疹。呼吸道刺激症状有咳嗽、咳痰、胸痛、胸闷等。严重者可发生化学性肺炎。可引起肾脏损伤。口服可溶性汞盐引起急性腐蚀性胃肠炎，严重者发生昏迷、休克、急性肾功能衰竭。慢性中毒：最早出现头痛、头晕、乏力、记忆减退等神经衰弱综合征，并有口腔炎。严重者可有明显的性格改变，汞毒性震颤及四肢共济失调等中毒性脑病表现，可伴有肾脏损害。?? 环境危害：对环境有严重危害，对水体和土壤可造成污染燃爆危险：? 本品不燃，有毒。? 第二部分：急救措施? 皮肤接触：脱去污染的衣着，用大量流动清水冲洗。? 眼睛接触：提起眼睑，用流动清水或生理盐水清洗。就医。? 吸入：迅速脱离现场至空气新鲜处。保持呼吸道通畅。如呼吸困难，给输氧。如呼吸停止，立即进行人工呼吸。就医。? 食入：用水漱口，给饮牛奶或蛋清。就医。? 第三部分：消防措施

危险特性：与叠氮化物、乙炔或氨反应可生成爆炸性化合物。与乙烯、氯、三氮甲烷、碳化钠接触引起剧烈反应。? 有害燃烧产物：氧化汞? 灭火方法：?本品不燃。消防人员必须佩戴过滤式防毒面具(全面罩)或隔离式呼吸器、穿全身防火防毒服，在上风向灭火。尽可能将容器从火场移至空旷处。? 第四部分：泄漏应急处理 应急行动：迅速撤离泄漏污染区人员至安全区，并进行隔离，严格限制出入。建议应急处理人员戴自给正压式呼吸器，穿防毒服。尽可能切断泄漏源。 小量泄漏：转移回收。可用多硫化钙或过量的硫磺处理。大量泄漏：构筑围堤或挖坑收容。收集回收或运至废物处理场所处置。? 第五部分：操作处置与储存 操作注意事项：? 密闭操作，提供充分的局部排风。采取降温措施。操作人员必须经过专门培训，严格遵守操作规程。建议操作人员佩戴自吸过滤式防毒面具（全面罩），戴化学安全防护眼镜，穿胶布防毒衣，戴橡胶手套。远离易燃、可燃物。防止蒸气泄漏到工作场所空气中。避免与酸类接触。搬运时要轻装轻卸，防止包装及容器损坏。配备泄漏应急处理设备。倒空的容器可能残留有害物。? 储存注意事项：? 储存于阴凉、通风的库房。远离火种、热源。库温不宜超过30℃。应与

尼美舒利的不良反应

尼美舒利的不良反应 发表时间：2013-04-15T11:16:31.357Z 来源：《医药前沿》2013年第5期供稿作者：洪玲玲田自有洪敏[导读] 总结近年来尼美舒利不良反应报道，为临床合理用药提供参考。 洪玲玲田自有洪敏(浙江省台州市中心医院浙江台州 318000 ) 【摘要】目的总结近年来尼美舒利不良反应报道，为临床合理用药提供参考。方法对近几年有关尼美舒利不良反应文献资料进行综述。结果其不良反应为消化系统的毒性反应、肝脏毒性反应、泌尿系统反应等。结论临床应重视尼美舒利不良反应的危害性，保证安全用药。【中图分类号】R76 【文献标识码】A 【文章编号】2095-1752（2013）05-0099-02 尼美舒利为非甾体抗炎药,具有抗炎、镇痛、解热作用，临床上主要用于慢性关节炎症（如类风湿性关节炎和骨关节炎等）、手术和急性创伤后的疼痛和炎症、耳鼻咽部炎症引起的疼痛、痛经、上呼吸道感染引起的发热等症状的治疗。近年来国内有文献报道其不良反应，现概述如下。 1 消化系统的毒性反应 王保彩等报道[1]，患者男性，58岁，经眼部清创缝合术后，给予尼美舒利胶囊口服，0.1 g 2 次/d。第8 天患者突然出现恶心伴昏厥约1 min，并呕出鲜红色血液约200 ml，此时患者面色苍白，P 110 次/min，BP 90/50 mmHg，自述口渴，无力。立即给予头低脚高位、吸氧、保暖，并开通静脉通路补充平衡盐溶液，以维持血压。患者生命体征趋于稳定，尼美舒利同其它非甾体消炎药一样，对胃黏膜有明显的刺激和诱发溃疡作用，若使用不当可致胃出血或穿孔，应引起临床注意。 2 肝脏毒性反应 杨万林等报道[2]，患者，女，40岁。因结核变态反应性关节炎，致密性骨炎。遵医嘱给予尼美舒利口服，0.1 g 2 次/d。该患者服用至1 个月时，出现恶心、不适，当日停服此药，发现AST 188 U/ L，LDH 255 U/ L，ALT 386 U/L，GLB 44 G/ L，予以甘草酸二铵(肝利欣) 150 mg，维生素C 0.2加入10 %葡萄糖注射液250 mL中静滴，1 次/d，输液致第10 天时，复查肝功能正常。 梁玉华等 [3] 调查分析2002年-2010年尼美舒利所致肝脏损害的病例报道，结果显示国内有19例与应用尼美舒利有关的导致肝脏损害报道，其中16例经治疗恢复正常，3例死亡。该产品说明书中指出“严重的肝功能不全患者禁用”。建议国内临床医师在使用该药时应注意其特殊的不良反应。 3 泌尿系统疾病 王江军等报道[4]，患者，男，58岁。因双膝关节肿胀、疼痛,活动加剧，诊断为风湿性关节炎，给予尼美舒利口服，0.1 g 2 次/d。服后第4天患者出现下腹部胀痛，尿频、尿痛，尿呈深红色，镜检有大量红细胞和少量白细胞。医生嘱其停药，第2天症状消失，镜检尿常规正常。2周后，患者自行再服用该药，服药后第2天再次出现上述症状，停药3 d后症状消失。因为本品可能导致肾功能损害，一旦发生肾功能损害，应终止本品的治疗。 4 过敏反应 张遂会等报道[5]，患者女性，29岁，因“感冒发烧两日，加重一日伴咽喉肿痛一周”，在零售药店购买尼美舒利颗粒口服，0.1 g 2次/d。服用1日后，出现头面部片状发红、肿大，巩膜充血，头面局部发热，伴全身躯干部分多处片状发红、瘙痒等症状，躯干部位片状红斑直径达4～6厘米。以上症状出现后约4 小时，消费者及家属到药店咨询，经我公司药店驻店药师分析，考虑为尼美舒利所致的全身过敏性反应。遂嘱立即停用该尼美舒利颗粒，并建议该消费者前往医院进行抗过敏治疗。经静脉输注地塞米松10 mg+10%葡萄糖酸钙注射液10 mL静脉推注，每日一次，连续治疗3天后好转，6天后全身体表发热、红肿症状消失，患者自觉好转后结束治疗。非甾体抗炎药包括本品可引起的严重的皮肤不良反应。例如剥脱性皮炎、StevensJohnson综合征（SJS）等。这些严重事件可在没有征兆的情况下出现。应告知患者严重皮肤反应的症状和体征，在第一次出现皮肤皮疹或过敏反应的任何其他征象时，应停用本品。 5 其它 李锦亮等报道[6]，患者,女，1岁2个月。因发热1天，查血常规示WBC8.1×109/L，L52.6%，N44.6%，RBC4.3×1012/L，HGB119g/L，PLT180×109/L，考虑急性上呼吸道感染。给予尼美舒利颗粒25mg口服，体温渐降至正常。约6h后家长发现患儿面部出现小出血点，即来复诊。查体见患儿面部、四肢皮肤散在针尖大小的出血点，压之不褪色。全身淋巴结无肿大。口唇红润，咽部充血。颈软，双肺呼吸音粗，未闻及干湿性啰音。心率108次/min，心音有力，律齐，各瓣膜听诊区未闻及杂音。腹软，肝脾不大，肠鸣音正常。复查血常规示:WBC9.3×109/L，L48.6%，N45.3%，RBC3.9×1012/L，HGB106g/L，PLT39×109/L。在此病程中患儿未服用其他药物。初步考虑为尼美舒利致血小板减少性紫癜。入院后查生化示肝功、肾功、心肌酶、电解质均正常,凝血四项无异常。予常规抗感染,静滴丙种球蛋白及口服强的松治疗。8d 后血小板升至270 ×109/ L，出院后继续口服强的松巩固治疗。随访1 年6 个月，患儿身体健康，血小板正常，全身未再出现出血点。由于尼美舒利在儿科应用较为广泛，且血小板减少性紫癜的病例报道很少，该药品说明书的注意事项中指出“本品可能影响血小板的功能，因此对于伴有出血倾向的患者应谨慎使用”。希望能引起临床医生的足够重视。 顾世照等报道[7]，患者，女性，53 岁。因外伤致右膝关节疼痛、红肿、不适，给予尼美舒利片0.1 g 2 次/d，饭后服。服药3 次后，疼痛减轻，但患者感到眼部不适，视力逐渐下降至视物不清，已闭经多年的月经又至，量少，即停药。停药3 d 后视力逐渐恢复正常，下个月经周期月经未来。服药期间患者未服用其他药物。此文献资料报道的不良反应，应引起临床注意。其机制尚不清楚，有待同行进一步探讨。 连凤枝等报道[8]，患者，男性，8个月，体重9 kg，因患上呼吸道感染高热，测体温39℃，口服尼美舒利颗粒50 mg退热，1 h后家属发现患儿大汗，全身发凉，精神差急诊来院，体温下降到35.0℃，考虑口服尼美舒利过量引起，给予保暖、饮水等处理后体温恢复正常。此外，孔陈苏等[9]调查研究7例因发热，家长自购尼美舒利颗粒服用引起不良反应，7例患儿均有不同程度的消化、神经系统症状，且预后不良，其中1例死亡。因此，因严格遵医嘱和说明书合理用药“仅用于1岁以上儿童”。参考文献 [1]王保彩,代红梅,于夕美.尼美舒利致胃出血1例[J].中国误诊学杂志,2010,07:1524.

他克莫司软膏英文说明书

xxxxxx Tacrolimus Capsules 0-1200-720-inf Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. (See DOSAGE AND ADMINISTRATION ). Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics. Absorption Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus was 17± 10% in adult kidney transplant patients (N=26), 22 ± 6% in adult liver transplant patients (N=17) and 18 ± 5% in healthy volunteers (N=16). A single dose study conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose study in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg capsules. Tacrolimus maximum blood concentrations (C max ) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10 to 12 hours post-dose (C min ) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over a concentration range of 10 to 60 ng/mL, the correlation coefficient was 0.94. Food Effects The rate and extent of tacrolimus absorption were greatest under fasted conditions. The presence and composition of food decreased both the rate and extent of tacrolimus absorption when administered to 15 healthy volunteers. The effect was most pronounced with a high-fat meal (848 kcal, 46% fat): mean AUC and C max were decreased 37% and 77%, respectively; T max was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C max by 28% and 65%, respectively. In healthy volunteers (N=16), the time of the meal also affected tacrolimus bioavailability. When given immediately following the meal, mean C max was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean C max was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition. In 11 liver transplant patients, tacrolimus capsules administered 15 minutes after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27 ± 18%) and C max (50 ± 19%), as compared to a fasted state. Distribution The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. study, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67). Metabolism Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro . The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus. Excretion The mean clearance following IV administration of tacrolimus is 0.040, 0.083, and 0.053, in healthy volunteers, adult kidney transplant patients, adult liver transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine. In a mass balance study of IV administered radiolabeled tacrolimus to 6 healthy volunteers, the mean recovery of radiolabel was 77.8±12.7%. Fecal elimination accounted for 92.4±1% and the elimination half-life based on radioactivity was 48.1±15.9 hours whereas it was 43.5±11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029±0.015 L/hr/kg and clearance of tacrolimus was 0.029±0.009 L/hr/kg. When administered PO, the mean recovery of the radiolabel was 94.9±30.7%. Fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1% and the elimination half-life based on radioactivity was 31.9±10.5 hours whereas it was 48.4± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226±0.116 L/hr/kg and clearance of tacrolimus 0.172± 0.088 L/hr/kg. Special Populations Pediatric Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following oral administration to 9 patients, mean AUC and C max were 337 ± 167 ng±hr/mL and 48.4 ± 27.9 ng/mL, respectively. The absolute bioavailability was 31 ± 24%. Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations. (See DOSAGE AND ADMINISTRATION ). Renal and Hepatic Insufficiency The mean pharmacokinetic parameters for tacrolimus following single administrations to patients with renal and hepatic impairment are given in the following table. Population (No. of Patients) Dose AUC 0 - t (ng·hr/mL) t ? (hr) V (L/kg) CI (L/hr/kg) Renal Impairment (n=12) 0.02 mg/kg/4hr IV 393 ± 123 (t = 60 hr) 26.3 ± 9.2 1.07 ±0.20 0.038 ± 0.014 Mild Hepatic Impairment (n=6) 0.02 mg/kg/4hr IV 367 ± 107 (t = 72 hr) 60.6 ± 43.8 Range: 27.8-141 3.1±1.6 0.042 ± 0.02 7.7 mg PO 488 ± 320 (t = 72 hr) 66.1 ± 44.8 Range: 29.5-138 3.7 ± 4.7* 0.034 ± 0.019* Severe Hepatic Impairment (n=6, IV) 0.02 mg/kg/4hr IV (n=2) 762 ± 204 (t = 120 hr) 198 ± 158 Range: 81-436 3.9 ± 1 0.017 ± 0.013 (n=5, PO)? 0.01 mg/kg/8hr IV (n=4) 8 mg PO (n=1) 289 ± 117 (t = 144 hr) 658 (t =120 hr) 119 ± 35 Range: 85-178 3.1 ± 3.4* 0.016 ± 0.011* 5 mg PO (n=4) 4 mg PO (n=1) 533 ± 156 (t = 144 hr) *corrected for bioavailability; ?1 patient did not receive the PO dose Renal Insufficiency Tacrolimus pharmacokinetics following a single IV administration were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9 ± 1.6 and 12 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (see previous table). Hepatic Insufficiency Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: >10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration. Race A formal study to evaluate the pharmacokinetic disposition of tacrolimus in Black transplant patients has not been conducted. However, a retrospective comparison of Black and Caucasian kidney transplant patients indicated that Black patients required higher tacrolimus doses to attain similar trough concentrations. (See DOSAGE AND ADMINISTRATION ). Gender A formal study to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney and liver transplant patients indicated no gender-based differences. CLINICAL STUDIES Liver Transplantation The safety and efficacy of tacrolimus-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter studies. The active control groups were treated with a cyclosporine-based immunosuppressive regimen. Both studies used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These studies were designed to evaluate whether the two regimens were therapeutically equivalent, with patient and graft survival at 12 months following transplantation as the primary endpoints. The tacrolimus-based immunosuppressive regimen was found to be equivalent to the cyclosporine-based immunosuppressive regimens. In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the tacrolimus-based immunosuppressive regimen and 266 to a cyclosporine-based immunosuppressive regimen (CBIR). In 10 of the 12 sites, the same CBIR protocol was used, while 2 sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (≤ 12 years old) were allowed. In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the tacrolimus-based immunosuppressive regimen and 275 to CBIR. In this study, each center used its local standard CBIR protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases. One-year patient survival and graft survival in the tacrolimus -based treatment groups were equivalent to those in the CBIR treatment groups in both studies. The overall 1-year patient survival (CBIR and tacrolimus-based treatment groups combined) was 88% in the U.S. study and 78% in the European study. The overall 1-year graft survival (CBIR and tacrolimus-based treatment groups combined) was 81% in the U.S. study and 73% in the European study. In both studies, the median time to convert from IV to oral tacrolimus capsules dosing was 2 days. Because of the nature of the study design, comparisons of differences in secondary endpoints, such as incidence of acute rejection, refractory rejection or use of OKT3 for steroid-resistant rejection, could not be reliably made. Kidney Transplantation Tacrolimus/azathioprine Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a Phase 3 randomized, multicenter, non-blinded, prospective study. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine ≤ 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded. There were 205 patients randomized to tacrolimus-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids and azathioprine. Overall 1 year patient and graft survival was 96.1% and 89.6%, respectively and was equivalent between treatment arms. Because of the nature of the study design, comparisons of differences in secondary endpoints, such as incidence of acute rejection, refractory rejection or use of OKT3 for steroid-resistant rejection, could not be reliably made. Tacrolimus/mycophenolate mofetil(MMF) Tacrolimus-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multi-center trial (Study 1), 1589 kidney transplant patients received tacrolimus (Group C, n=401), sirolimus (Group D, n=399), or one of two cyclosporine regimens (Group A, n=390 and Group B, n=399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The study was conducted outside the United States; the study population was 93% Caucasian. In this study, mortality at 12 months in patients receiving tacrolimus/MMF was similar (2.7%) compared to patients receiving cyclosporine/MMF (3.3% and 1.8%) or sirolimus/MMF (3 %). Patients in the tacrolimus group exhibited higher estimated creatinine clearance rates (eCL cr ) using the Cockcroft-Gault formula (Table 1) and experienced fewer efficacy failures, defined as biopsy proven acute rejection (BPAR), graft loss, death, and/or lost to follow-up (Table 2) in comparison to each of the other three groups. Patients randomized to tacrolimus/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen (see ADVERSE REACTIONS ). Table 1: Estimated Creatinine Clearance at 12 Months in Study 1 Group eCLcr [mL/min] at Month 12a N MEAN SD MEDIAN Treatment Difference with Group C (99.2%CI b ) (A) CsA/MMF/CS 390 56.5 25.8 56.9 -8.6 (-13.7,-3.7) (B) CsA/MMF/CS/Daclizumab 399 58.9 25.6 60.9 -6.2 (-11.2,-1.2) (C) Tac/MMF/CS/Daclizumab 401 65.1 27.4 66.2 -(D) Siro/MMF/CS/Daclizumab 399 56.2 27.4 57.3 -8.9 (-14.1, -3.9) Total 1589 59.2 26.8 60.5 Key: CsA=Cyclosporine, CS=Corticosteroids, Tac=Tacrolimus, Siro=Sirolimus a) All death/graft loss (n=41,27, 23 and 42 in Groups A, B, C and D) and patients whose last recorded creatinine values were prior to month 3 visit (n=10, 9, 7 and 9 in Groups A, B, C and D) were inputed with GFR of 10 mL/min; a subject’s last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n=11, 12, 15 and 19 for Groups A, B, C and D). Weight was also imputed in the calculation of estimated GFR, if missing b) Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. Table 2: Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months in Study 1 A B C D N=390 N=399 N=401 N=399 Overall Failure 141 (36.2%) 126(31.6%) 82 (20.4%) 185 (46.4%) Components of efficacy failure BPAR 113(29%) 106 (26.6%) 60 (15%) 152(38.1%) Graft loss excluding death 28 (7.2%) 20 (5%) 12 (3%) 30 (7.5%) Mortality 13 (3.3%) 7(1.8%) 11(2.7%) 12 (3%) Lost to follow-up 5(1.3%) 7(1.8%) 5 (1.3%) 6(1.5%) Treatment Difference of efficacy failure compared to 15.8% (7.1%, 11.2% (2.7%, -26% (17.2%, Group C (99.2% CI a ) 24.3%) 19.5%) 34.7%) Group A =CsA/MMF/CS, B =CsA/MMF/CS/Daclizumab, C=Tac/MMF/CS/Daclizumab, and D=Siro/MMF/CS/Daclizumab a) Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. The protocol-specified target tacrolimus trough concentrations (C ,Tac) were 3-7 ng/mL; however, the trough observed median C ,Tac approximated 7 ng/mL throughout the 12 month study (Table 3).troughs Table 3: Tacrolimus Whole Blood Trough Concentrations (Study 1) Time Median (P10-P90 a ) tacrolimus whole blood trough concentrations (ng/mL) Day 30 (N=366) 6.9 (4.4-11.3) Day90 (N=351) 6.8 (4.1-10.7) Day 180 (N=355) 6.5 (4 - 9.6) Day 365 (N=346) 6.5 (3.8 -10) a) Range of C trough , Tac that excludes lowest 10% and highest 10% of C trough , Tac The protocol-specified target cyclosporine trough concentrations (C trough ,CsA) for Group B were 50-100 ng/mL; however, the observed median C trougs , CsA approximated 100 ng/mL throughout the 12 month study. The protocol-specified target C trougs ,CsA for Group A were 150-300 ng/mL for the first 3 months and 100-200 ng/mL from month 4 to month 12; the observed median C trougs , CsA approximated 225 ng/mL for the first 3 months and 140 ng/mL from month 4 to month 12. While patients in all groups started MMF at 1g BID, the MMF dose was reduced to <2 g/day in 63% of patients in the tacrolimus treatment arm by month 12 (Table 4); approximately 50% of these MMF dose reductions were due to adverse events. By comparison, the MMF dose was reduced to <2 g/day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse events. Table 4: MMF Dose Over Time in tacrolimus/MMF (Group C) (Study 1) Time period (Days) Time-averaged MMF dose (g/day)a <2 2 >2 0-30 (N=364) 37% 60% 2% 0-90 (N=373) 47% 51% 2% 0-180 (N=377) 56% 42% 2% 0-365 (N=380) 63% 36% 1% Time-averaged MMF dose = (total MMF dose)/(duration of treatment) a) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two g/day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods. In a second randomized, open-label, multi-center trial (Study 2), 424 kidney transplant patients received tacrolimus (n=212) or cyclosporine (n=212) in combination with MMF 1 gram BID, basiliximab induction, and corticosteroids. In this study, the rate for the combined endpoint of biopsy proven acute rejection, graft failure, death, and/or lost to follow-up at 12 months in the tacrolimus/MMF group was similar to the rate in the cyclosporine/MMF group. There was, however, an imbalance in mortality at 12 months in those patients receiving tacrolimus/MMF (4.2%) compared to those receiving cyclosporine/MMF (2.4%), including cases attributed to overimmunosuppression (Table 5). Table 5: Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months in Study 2 Tacrolimus/MMF (n=212) Cyclosporine/MMF (n=212) Overall Failure 32(15.1%) 36 (17%) Components of efficacy failure BPAR 16 (7.5%) 29 (13.7%) Graft loss excluding death 6 (2.8%) 4(1.9%) Mortality 9 (4.2%) 5 (2.4%) Lost to follow-up 4(1.9%) 1 (0.5%) Treatment Difference of efficacy failure compared to tacrolimus/MMF group (95% CI a ) - 1.9% (-5.2%, 9%) a) 95% confidence interval calculated using Fisher’s Exact Test The protocol-specified target tacrolimus whole blood trough concentrations (C trough ,Tac) in Study 2 were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter. The observed median C troughs ,Tac approximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 (Table 6). Table 6: Tacrolimus Whole Blood Trough Concentrations (Study 2) Time Median (P10-P90a ) tacrolimus whole blood trough concentrations ng/mL Day 30 (N=174) 10.5 (6.3 -16.8) Day 60 (N=179) 9.2(5.9-15.3) Day 120 (N=176) 8.3 (4.6 -13.3) Day 180(N=171) 7.8 (5.5 -13.2) Day 365 (N=178) 7.1(4.2-12.4) a) Range of C troughs , Tac that excludes lowest 10% and highest 10% of C troughs Tac The protocol-specified target cyclosporine whole blood concentrations (Ctr o ugh,CsA) were 125 to 400 ng/ mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median Ctroughs, CsA approximated 280 ng/mL during the first three months and 190 ng/mL from month 4 to month 12. Patients in both groups started MMF at 1g BID. The MMF dose was reduced to <2 g/day by month 12 in 62% of patients in the tacrolimus/MMF group (Table 7) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse events in the tacrolimus/MMF group and the cyclosporine/MMF group, respectively. Table 7: MMF Dose Over Time in the tacrolimus/MMF group (Study 2) Time period (Days) Time-averaged MMF dose (g/day)a <2 2 >2 0-30(N=212) 25% 69% 6% 0-90 (N=212) 41% 53% 6% 0-180 (N=212) 52% 41% 7% 0-365 (N=212) 62% 34% 4% Time-averaged MMF dose=(total MMF dose)/(duration of treatment) a) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two g/day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods. INDICATIONS AND USAGE Tacrolimus capsules are indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver, or kidney transplants. It is recommended that tacrolimus be used concomitantly with adrenal corticosteroids. In kidney transplant recipients, it is recommended that tacrolimus be used in conjunction with azathioprine or mycophenolate mofetil (MMF). The safety and efficacy of the use of tacrolimus with sirolimus has not been established (see CLINICAL STUDIES ). CONTRAINDICATIONS Tacrolimus capsules are contraindicated in patients with a hypersensitivity to tacrolimus. WARNINGS (See boxed WARNING .) Post-Transplant Diabetes Mellitus Insulin-dependent post-transplant diabetes mellitus (PTDM) was reported in 20% of tacrolimus-treated kidney transplant patients without pretransplant history of diabetes mellitus in the Phase III study (See Tables Below). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM. Incidence of Post Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in the Phase III study Status of PTDM* Tacrolimus CBIR Patients without pretransplant history of diabetes mellitus. 151 151 New onset PTDM*, 1st Year 30/151 (20%) 6/151 (4%) Still insulin dependent at one year in those without prior history of diabetes. 25/151 (17%) 5/151 (3%) New onset PTDM* post 1 year 1 Patients with PTDM* at 2 years 16/151 (11%) 5/151 (3%) * use of insulin for 30 or more consecutive days, with <5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus. Development of Post Transplant Diabetes Mellitus by Race and by Treatment Group during First Year Post Kidney Transplantation in the Phase III study Tacrolimus CBIR Patient Race No. of Patients at Risk Patients Who Developed PTDM* No. of Patients At Risk Patients Who Developed PTDM* Black 41 15 (37%) 36 3 (8%) Hispanic 17 5 (29%) 18 1 (6%) Caucasian 82 10 (12%) 87 1 (1%) Other 11 0 (0%) 10 1 (10%) Total 151 30 (20%) 151 6 (4%) *use of insulin for 30 or more consecutive days, with <5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus. Insulin-dependent post-transplant diabetes mellitus was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post transplant, in the U.S. and European randomized studies, respectively (See Table below). Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized studies, respectively, and may require treatment (see ADVERSE REACTIONS ) Incidence of Post Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients Status of PTDM* U.S. Study European Study Tacrolimus CBIR Tacrolimus CBIR Patients at risk** 239 236 239 249 New Onset PTDM* 42(18%) 30(13%) 26(11%) 12(5%) Patients still on insulin at 1 year 23(10%) 19(8%) 18(8%) 6 (2%) * use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus ** Patients without pretransplant history of diabetes mellitus Nephrotoxicity Tacrolimus can cause nephrotoxicity, particularly when used in high doses. Nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials, respectively (see ADVERSE REACTIONS ). More overt nephrotoxicity is seen early after transplantation, characterized by increasing serum creatinine and a decrease in urine output. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy. Care should be taken in using tacrolimus with other nephrotoxic drugs. In particular, to avoid excess nephrotoxicity, tacrolimus should not be used simultaneously with cyclosporine. tacrolimus or cyclosporine should be discontinued at least 24 hours prior to initiating the other. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be further delayed. Hyperkalemia Mild to severe hyperkalemia was reported in 31% of kidney transplant recipients and in 45% and 13% of liver transplant recipients treated with tacrolimus capsules in the U.S. and European randomized trials, respectively, and may require treatment (see ADVERSE REACTIONS ). Serum potassium levels should be monitored and potassium-sparing diuretics should not be used during tacrolimus capsules therapy (see PRECAUTIONS ). Neurotoxicity Tacrolimus capsules can cause neurotoxicity, particularly when used in high doses. Neurotoxicity, including tremor, headache, and other changes in motor function, mental status, and sensory function were reported in approximately 55% of liver transplant recipients in the two randomized studies. Tremor occurred more often in tacrolimus capsules-treated kidney transplant patients (54%) compared to cyclosporine-treated patients. The incidence of other neurological events in kidney transplant patients was similar in the two treatment groups (see ADVERSE REACTI ONS ). Tremor and headache have been associated with high whole-blood concentrations of tacrolimus and may respond to dosage adjustment. Seizures have occurred in adult and pediatric patients receiving tacrolimus capsules (see ADVERSE REACTIONS ). Coma and delirium also have been associated with high plasma concentrations of tacrolimus. Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). Symptoms indicating PRES include headache, altered mental status, seizures, visual disturbances and hypertension. Diagnosis may be confirmed by radiological procedure. If PRES is suspected or diagnosed, blood pressure control should be maintained and immediate reduction of immunosuppression is advised. This syndrome is characterized by reversal of symptoms upon reduction or discontinuation of immunosuppression. Malignacy and Lymphoproliferative Disorders As in patients receiving other immunosuppressants, patients receiving tacrolimus capsules are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. A lymphoproliferative disorder (LPD) related to Epstein-Barr Virus (EBV) infection has been reported in immunosuppressed organ transplant recipients. The risk of LPD appears greatest in young children who are at risk for primary EBV infection while immunosuppressed or who are switched to tacrolimus capsules following long-term immunosuppression therapy. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution. Latent Viral Infections Immunosuppressed patients are at increased risk for opportunistic infections, including latent viral infections. These include BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML) which have been observed in patients receiving tacrolimus. These infections may lead to serious, including fatal, outcomes. PRECAUTIONS General Hypertension is a common adverse effect of tacrolimus therapy (see ADVERSE REACTIONS ). Mild or moderate hypertension is more frequently reported than severe hypertension. Antihypertensive therapy may be required; the control of blood pressure can be accomplished with any of the common antihypertensive agents. Since tacrolimus may cause hyperkalemia, potassium-sparing diuretics should be avoided. While calcium-channel blocking agents can be effective in treating tacrolimus-associated hypertension, care should be taken since interference with tacrolimus metabolism may require a dosage reduction (see Drug Interactions ). Renally and Hepatically Impaired Patients For patients with renal insufficiency some evidence suggests that lower doses should be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ). The use of tacrolimus capsules in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood levels of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients (see DOSAGE AND ADMINISTRATION ). Myocardial Hypertrophy Myocardial hypertrophy has been reported in association with the administration of tacrolimus capsules, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. Hypertrophy has been observed in infants, children and adults. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In a group of 20 patients with pre- and post-treatment echocardiograms who showed evidence of myocardial hypertrophy, mean tacrolimus whole blood concentrations during the period prior to diagnosis of myocardial hypertrophy ranged from 11 to 53 ng/mL in infants (N=10, age 0.4 to 2 years), 4 to 46 ng/ mL in children (N=7, age 2 to 15 years) and 11 to 24 ng/mL in adults (N=3, age 37 to 53 years). In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus should be considered. Information for Patients Patients should be informed of the need for repeated appropriate laboratory tests while they are receiving tacrolimus capsules. They should be given complete dosage instructions, advised of the potential risks during pregnancy, and informed of the increased risk of neoplasia. Patients should be informed that changes in dosage should not be undertaken without first consulting their physician. Patients should be informed that tacrolimus capsules can cause diabetes mellitus and should be advised of the need to see their physician if they develop frequent urination, increased thirst or hunger. As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Laboratory Tests Serum creatinine, potassium, and fasting glucose should be assessed regularly. Routine monitoring of metabolic and hematologic systems should be performed as clinically warranted. Drug Interactions Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering tacrolimus capsules with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, amphotericin B, and cisplatin. Initial clinical experience with the co-administration of tacrolimus and cyclosporine resulted in additive/synergistic nephrotoxicity. Patients switched from cyclosporine to tacrolimus should receive the first tacrolimus capsules dose no sooner than 24 hours after the last cyclosporine dose. Dosing may be further delayed in the presence of elevated cyclosporine levels. Drugs that May Alter Tacrolimus Concentrations Since tacrolimus is metabolized mainly by the CYP3A enzyme systems, substances known to inhibit these enzymes may decrease the metabolism or increase bioavailability of tacrolimus as indicated by increased whole blood or plasma concentrations. Drugs known to induce these enzyme systems may result in an increased metabolism of tacrolimus or decreased bioavailability as indicated by decreased whole blood or plasma concentrations. Monitoring of blood concentrations and appropriate dosage adjustments are essential when such drugs are used concomitantly. *Drugs That May Increase Tacrolimus Blood Concentrations Calcium Channel Blockers Antifungal Agents Macrolide Antibiotics diltiazem clotrimazole clarithromycin nicardipine fluconazole erythromycin nifedipine itraconazole troleandomycin verapamil ketoconazole** voriconazole Gastrointestinal Prokinetic Agents Other Drugs cisapride bromocriptine metoclopramide chloramphenicol cimetidine cyclosporine danazol ethinyl estradiol methylprednisolone lansoprazole*** omeprazole protease inhibitors nefazodone magnesium-aluminum-hydroxide * This table is not all inclusive **In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients. *** Lansoprazole (CYP2C19, CYP3A4 substrate) may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers. *Drugs That May Decrease Tacrolimus Blood Concentrations Anticonvulsants Antimicrobials carbamazepine rifabutin phenobarbital caspofungin phenytoin rifampin Herbal Preparations Other Drugs St. John’s Wort sirolimus *This table is not all inclusive. St. John’s Wort (Hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since tacrolimus is a substrate for CYP3A4, there is the potential that the use of St. John’s Wort in patients receiving tacrolimus capsules could result in reduced tacrolimus levels. In a single-dose crossover study in healthy volunteers, co-administration of tacrolimus and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus C max relative to tacrolimus administration alone. In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14 ± 6% vs. 7 ± 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance (0.036 ± 0.008 L/hr/kg vs. 0.053 ± 0.01 L/hr/kg) with concomitant rifampin administration. Interaction studies with drugs used in HIV therapy have not been conducted. However, care should be exercised when drugs that are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A (e.g., nelfinavir, ritonavir) are administered concomitantly with tacrolimus. Based on a clinical study of 5 liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as a result, a reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. Thus, frequent monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are essential when nelfinavir is used concomitantly. Tacrolimus may affect the pharmacokinetics of other drugs (e.g., phenytoin) and increase their concentration. Grapefruit juice affects CYP3A-mediated metabolism and should be avoided (see DOSAGE AND ADMINISTRATION ). Following co-administration of tacrolimus and sirolimus (2 or 5 mg/day) in stable renal transplant patients, mean tacrolimus AUC 0-12 and C min decreased approximately by 30% relative to tacrolimus alone. Mean tacrolimus AUC 0-12 and C min following co-administration of 1 mg/day of sirolimus decreased approximately 3% and 11%, respectively. The safety and efficacy of tacrolimus used in combination with sirolimus for the prevention of graft rejection has not been established and is not recommended. Other Drug Interactions Immunosuppressants may affect vaccination. Therefore, during treatment with tacrolimus capsules, vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, and TY 21a typhoid.1 At a given MMF dose, mycophenolic acid (MPA) exposure is higher with tacrolimus co-administration than with cyclosporine co-administration due to the differences in the interruption of the enterohepatic recirculation of MPA. Clinicians should be aware that there is also a potential for increased MPA exposure after crossover from cyclosporine to tacrolimus in patients concomitantly receiving MMF or MPA. Carcinogenesis, Mutagenesis, Impairment of Fertility An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin’s lymphomas and carcinomas of the skin. As with other immunosuppressive therapies, the risk of malignancies in tacrolimus recipients may be higher than in the normal, healthy population. Lymphoproliferative disorders associated with Epstein-Barr Virus infection have been seen. It has been reported that reduction or discontinuation of immunosuppression may cause the lesions to regress. No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes. Carcinogenicity studies were carried out in male and female rats and mice. In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to tacrolimus dosage was found. The highest doses used in the mouse and rat studies were 0.8 - 2.5 times (mice) and 3.5 - 7.1 times (rats) the recommended clinical dose range of 0.1 - 0.2 mg/kg/day when corrected for body surface area. No impairment of fertility was demonstrated in studies of male and female rats. Tacrolimus, given orally at 1 mg/kg (0.7 - 1.4X the recommended clinical dose range of 0.1 - 0.2 mg/kg/day based on body surface area corrections) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.3 - 4.6X the recommended clinical dose range based on body surface area correction), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.