部份中文盐酸右美托咪定处方资料（仅供参考） 药品英文名 Dexmedetomidine 药品别名 盐酸右美托咪定、DexmedetomidineHydrochloride、Precedex  药理作用 本品为有效的α2-肾上腺素受体激动剂，对α2-肾上腺素受体的亲和力比可乐定高8倍。动物试验显示，缓慢地静注中低剂量本品(10～300mg/kg)对α2-肾上腺素受体具有选择性，而缓慢地静注高剂量本品(1000mg/kg)或快速静注则同时对α1和α2-肾上腺素受体起作用。在接受本品静注的健康志愿者或重病监护室中的手术后患者中，本品显示出镇静、镇痛和抗焦虑作用。10例健康志愿者静注推荐剂量范围内的本品(0.2～0.7mg/kg)后，呼吸率和氧饱和度保持在正常范围内，未见呼吸抑制。 药动学 本品经皮下注射或肌注后快速吸收，达峰值时间为1h，本品静滴后，分布半衰期约为6min，稳态分布容积约为118L。本品在体内经广泛代谢后，代谢物主要随尿液排出。消除半衰期约为2h，清除期约为39L/h。 适应证 本品适用于重病监护治疗期间开始插管和使用呼吸机患者的镇静。 禁忌证 对本品过敏者禁用。 注意事项 怀孕、哺乳期妇女，晚期心脏阻滞患者慎用。 1.患者输注本品时应进行连续监测。 2.本品不可与血液或血浆经同一静注导管合用。 3.有明显心血管机能障碍的患者需预先采取复苏措施。 4.本品连续输注不可超过24h。 不良反应 本品耐受性良好，常见的不良反应包括低血压、恶心、心搏徐缓、组织缺氧和心房颤动。 用法用量 静脉给药：本品应使用0.9%氯化钠溶液稀释，一般开始10min内静注负荷剂量1mg/kg，随后以0.2～0.7mg/(kg·h) 输注维持剂量，保持剂量的输注速率应调整至获得期望的镇静效果。老年人以及肾或肝功能受损者用药剂量酌减。 药物相应作用 1.本品与麻醉剂、镇静剂、催眠药和阿片类药物(如七氟烷，异氟烷，丙泊酚，阿芬太尼，咪达唑仑)合用可能会提高疗效。 2.本品不影响罗库溴铵的神经肌肉阻滞作用。 15～30℃保存。 完整资料附件：http://www.info.pmda.go.jp/go/pack/1129400A1046_1_08/ 盐酸右美托咪定是一种高效、高选择性的α2-肾上腺素受体激动剂，最初由芬兰Orion Pharma公司与美国Abott公司联合研制开发。该药通过作用于两种肾上腺素受体而具有抗交感、镇痛和镇静作用，适用于手术及术后的镇静，尤其适用于重症病人。2000年3月Hospira公司的混合型在美国首次上市，商品名为precedex，共有两种规格：200mcg/50ml、400mcg/100mk.2004年1月Hospira 获日本上市的剂型为注射液，规格为Precedex IV 200μg。 RECENT MAJOR CHANGES DESCRIPTION Precedex (dexmedetomidine hydrochloride) injection is a sterile, nonpyrogenic solution suitable for intravenous infusion following dilution. Dexmedetomidine hydrochloride is the S-enantiomer of medetomidine and is chemically described as (+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole monohydrochloride. Precedex has a molecular weight of 236.7 and the empirical formula is C13H16N2 ∙ HCl and the structural formula is: Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in water and has a pKa of 7.1. Its partition coefficient in-octanol: water at pH 7.4 is 2.89. Precedex is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 7.0. Each mL contains 118 mcg of dexmedetomidine hydrochloride equivalent to 100 mcg of dexmedetomidine and 9 mg of sodium chloride in water. The solution is preservative-free and contains no additives or chemical stabilizers. CLINICAL PHARMACOLOGY Mechanism of Action Precedex is a relatively selective alpha2-adrenergic agonist with sedative properties. Alpha2 selectivity is observed in animals following slow intravenous infusion of low and medium doses (10-300 mcg/kg). Both alpha1 and alpha2 activity is observed following slow intravenous infusion of high doses (≥1000 mcg/kg) or with rapid intravenous administration. Pharmacodynamics In a study in healthy volunteers (N=10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when Precedex was administered by intravenous infusion at doses within the recommended dose range (0.2 – 0.7 mcg/kg/hr). Pharmacokinetics Following intravenous administration, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t1/2) of approximately 6 minutes; a terminal elimination half-life (t1/2) of approximately 2 hours; and steady-state volume of distribution (Vss) of approximately 118 liters. Clearance is estimated to be approximately 39 L/h. The mean body weight associated with this clearance estimate was 72 kg. Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered by intravenous infusion for up to 24 hours. Table 5 shows the main pharmacokinetic parameters when Precedex was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/mL) for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/mL) for 24 hours. Distribution The steady-state volume of distribution (Vss) of dexmedetomidine is approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of Precedex that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects. The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro, and negligible changes in the plasma protein binding of Precedex were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by Precedex was explored in vitro and none of these compounds appeared to be significantly displaced by Precedex. Metabolism Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxy-dexmedetomidine; and N methylation of dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O-glucuronide. Elimination The terminal elimination half-life (t1/2) of dexmedetomidine is approximately 2 hours and clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3- hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3 hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N methyl O glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N Methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified. Gender: There was no observed difference in Precedex pharmacokinetics due to gender. Geriatrics: The pharmacokinetic profile of Precedex was not altered by age. There were no differences in the pharmacokinetics of Precedex in young (18–40 years), middle age (41–65 years), and elderly (>65 years) subjects. Pediatrics: The pharmacokinetic profile of Precedex has not been studied in pediatric patients. Hepatic Impairment: In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for Precedex were lower than in healthy subjects. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy subjects, respectively. Although Precedex is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [ see Dosage and Administration (2.2), Warnings and Precautions (5.6) ]. Renl Impairment: Precedex pharmacokinetics (Cmax, Tmax, AUC, t1/2, CL, and Vss) were not significantly different in patients with severe renal impairment (creatinine clearance:<30 mL/min) compared to healthy subjects. However, the pharmacokinetics of the metabolites of Precedex have not been evaluated in patients with impaired renal function. Since the majority of metabolites are excreted in the urine, it is possible that the metabolites may accumulate upon long-term infusions in patients with impaired renal function [ see Dosage and Administration (2.2) and Use in Specific Populations (8.7) ]. Drug Interactions: In vitro studies: In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Animal carcinogenicity studies have not been performed with Precedex. Dexmedetomidine was not mutagenic in vitro, in either the bacterial reverse mutation assay (E. coli and Salmonella typhimurium) or the mammalian cell forward mutation assay (mouse lymphoma). Dexmedetomidine was clastogenic in the in vitro human lymphocyte chromosome aberration test with, but not without, rat S9 metabolic activation. In contrast, dexmedetomidine was not clastogenic in the in vitro human lymphocyte chromosome aberration test with or without human S9 metabolic activation. Although dexmedetomidine was clastogenic in an in vivo mouse micronucleus test in NMRI mice, there was no evidence of clastogenicity in CD-1 mice. Fertility in male or female rats was not affected after daily subcutaneous injections at doses up to 54 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m2 basis). Precedex was dosed from 10 weeks prior to mating in males and 3 weeks prior to mating and during mating in females. Animal Toxicology and/or Pharmacology Dexmedetomidine had no effect on adrenocorticotropic hormone-stimulated cortisol release in dogs after a single dose; however, after the subcutaneous infusion of Precedex for one week, the cortisol response to adrenocorticotropic hormone was diminished by approximately 40%, indicating adrenal insufficiency. CLINICAL STUDIES The safety and efficacy of Precedex has been evaluated in four randomized, double-blind, placebo-controlled multicenter clinical trials in 1185 patients. Intensive Care Unit Sedation Two randomized, double-blind, parallel-group, placebo-controlledmulticenter clinical trials included 754 patients being treated in a surgical intensive care unit. All patients were initially intubated and received mechanical ventilation. These trials evaluated the sedative properties of Precedex by comparing the amount of rescue medication (midazolam in one trial and propofol in the second) required to achieve a specified level of sedation (using the standardized Ramsay sedation scale) between Precedex and placebo from onset of treatment to extubation or to a total treatment duration of 24 hours. The Ramsay Level of Sedation Scale is displayed in Table 6. In the first study, 175 patients were randomized to receive placebo and 178 to receive Precedex by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion rate was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive “rescue” midazolam as needed to augment the study drug infusion. In addition, morphine sulfate was administered for pain as needed. The primary outcome measure for this study was the total amount of rescue medication (midazolam) needed to maintain sedation as specified while intubated. Patients randomized to placebo received significantly more midazolam than patients randomized to Precedex (see Table 7). A second prospective primary analysis assessed the sedative effects of Precedex by comparing the percentage of patients who achieved a Ramsay sedation score of≥3 during intubation without the use of additional rescue medication. A significantly greater percentage of patients in the Precedex group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see Table 7). A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the Precedex and placebo groups. On average, Precedex-treated patients received less morphine sulfate for pain than placebo-treated patients (0.47 versus 0.83 mg/h). In addition, 44% (79 of 178 patients) of Precedex patients received no morphine sulfate for pain versus 19% (33 of 175 patients) in the placebo group. In a second study, 198 patients were randomized to receive placebo and 203 to receive Precedex by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive “rescue” propofol as needed to augment the study drug infusion. In addition, morphine sulfate was administered as needed for pain. The primary outcome measure for this study was the total amount of rescue medication (propofol) needed to maintain sedation as specified while intubated. Patients randomized to placebo received significantly more propofol than patients randomized to Precedex (see Table 8). A significantly greater percentage of patients in the Precedex group compared to the placebo group maintained a Ramsay sedation score of≥3 without receiving any propofol rescue (see Table 8). A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the Precedex and placebo groups. On average, Precedex-treated patients received less morphine sulfate for pain than placebo-treated patients (0.43 versus 0.89 mg/h). In addition, 41% (83 of 203 patients) of Precedex patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group. Procedural Sedation The safety and efficacy of Precedex for sedation of non-intubated patients prior to and/or during surgical and other procedures was evaluated in two randomized, double-blind, placebo-controlled multicenter clinical trials. Study 1 evaluated the sedative properties of Precedex in patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated Precedex in patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure. In Study 1, the sedative properties of Precedex were evaluated by comparing the percent of patients not requiring rescue midazolam to achieve a specified level of sedation using the standardized Observer’s Assessment of Alertness/Sedation Scale (see Table 9). Patients were randomized to receive a loading infusion of either Precedex 1 mcg/kg, Precedex 0.5 mcg/kg, or placebo (normal saline) given over 10 minutes and followed by a maintenance infusion started at 0.6 mcg/kg/hr. The maintenance infusion of study drug could be titrated from 0.2 mcg/kg/hr to 1 mcg/kg/hr to achieve the targeted sedation score (Observer’s Assessment of Alertness/Sedation Scale ≤4). Patients were allowed to receive rescue midazolam as needed to achieve and/or maintain an Observer’s Assessment of Alertness/Sedation Scale ≤4. After achieving the desired level of sedation, a local or regional anesthetic block was performed. Demographic characteristics were similar between the Precedex and comparator groups. Efficacy results showed that Precedex was more effective than the comparator group when used to sedate non-intubated patients requiring monitored anesthesia care during surgical and other procedures (see Table 10). In Study 2, the sedative properties of Precedex were evaluated by comparing the percent of patients requiring rescue midazolam to achieve or maintain a specified level of sedation using the Ramsay Sedation Scale score ≥2 (see Table 6). Patients were randomized to receive a loading infusion of Precedex 1 mcg/kg or placebo (normal saline) given over 10 minutes and followed by a fixed maintenance infusion of 0.7 mcg/kg/hr. After achieving the desired level of sedation, topicalization of the airway occurred. Patients were allowed to receive rescue midazolam as needed to achieve and/or maintain a Ramsay Sedation Scale ≥2. Demographic characteristics were similar between the Precedex and comparator groups. For efficacy results see Table 10. http://www.maruishi-pharm.co.jp/med2/product-detail65.html 提示：本品属控制药品，不供于临床，仅有科研单位。 ------------------------------------------------- 产地国家: 日本 原产地英文商品名: PRECEDEX inj（プレセデックス静注液）200mcg;2ml/Vials 5Vials 原产地英文药品名: Dexmedetomidine Hydrochloride 中文参考商品译名: 普利斯德（プレセデックス静注液）200微克/2毫升 5瓶/盒 中文参考药品译名: 盐酸右美托咪定 中文参考化合物名称: (+)-4-(S)-[1-(2,3-二甲基苯基)乙基]-1H-咪唑盐酸盐 生产厂家中文参考译名: HOSPIRA 生产厂家英文名: HOSPIRA ------------------------------------------------- 产地国家: 日本 原产地英文商品名: PRECEDEX inj（プレセデックス静注液）200mcg;2ml/Vials 5Vials 原产地英文药品名: Dexmedetomidine Hydrochloride 中文参考商品译名: PRECEDEX（プレセデックス静注液）200微克/2毫升 5瓶/盒 中文参考药品译名: 盐酸右美托咪定 中文参考化合物名称: (+)-4-(S)-[1-(2,3-二甲基苯基)乙基]-1H-咪唑盐酸盐 生产厂家中文参考译名: 丸石製薬 生产厂家英文名: Cobblestone Pharmaceutical