英文药名: Atrovent(Ipratropium Bromide Nebulizer Solution) 中文药名: 异丙托溴铵雾化溶液 生产厂家: Boehringer Ingelheim 药品名称 中文药名: 异丙托溴胺 药理作用 爱全乐（Atrovent）是一种具有抗胆碱能（副交感）特性的四价铵化合物。临床前试验显示其通过拮抗迷走神经释放的递质乙酰胆碱而抑制迷走神经的反射。抗胆碱能药物可阻止乙酰胆碱和支气管平滑肌上的毒蕈碱受体相互作用而引起的细胞内环一磷酸鸟苷酸（cGMP）浓度的增高。 吸入爱全乐（Atrovent）的支气管扩张作用基本上是局部的、吸入部位特异性的作用，无全身性作用。 对慢性阻塞性肺部疾病（慢性支气管炎和肺气肿）引起支气管痉挛的患者进行90天的观察研究，治疗后15分钟即产生显著的肺部功能改善（FEV1和FEF25－75%增长15%或15%以上），1－2小时后达到峰值，对大部分患者其持续作用可达6小时。 在90天的对照研究中，40%与哮喘有关的支气管痉孪的患者吸入爱全乐后肺功能明显改善（FEV1 增加15%或15%以上）。 临床前与临床研究证实爱全乐（Atrovent）对气道粘膜分泌、纤毛的粘液清除作用或气体交换均无不良作用。 对一些啮齿类和非啮齿类的动物进行了观察期为14天的急性毒性试验。 吸入给药时，豚鼠的最小致死剂量为199mg/kg，大鼠给予剂量11.5mcg/l/小时 q.i.d.或48mcg/kg/4小时没有引起死亡。口服和静注的LD50比吸入的最小致死量高。小鼠（口服）LD50为2050mg/kg，狗（静注）LD50为17.5mg/kg。 与较高的静注毒性相比，较低的口服毒性说明药物胃肠道吸收较差。 长期服用的动物试验分别在大鼠、家兔、狗和罗猴上进行。 对大鼠、狗和罗猴均进行了长达6个月的吸入研究，未见不良反应的剂量（NOAEL）分别为0.384mg/kg/天，0.4 mg/kg/天和0.8 mg/kg/天。组织病理学检查未发现支气管-肺部系统出现与本品相关的病理损害。大鼠给药18个月后未见不良反应的剂量（NOAEL）为0.5 mg/kg/天。 爱全乐的水溶液（48 mcg/kg/4小时）经大鼠吸入使用的局部耐受性非常好。 豚鼠试验既无主动过敏反应也无被动皮肤过敏反应发生。 体外细菌致突变试验（Ames试验）未发现致突变性。体内试验的结果（微核试验、小鼠显性致死试验、中国仓鼠骨髓细胞的细胞质基因试验）未显示用药后增加染色体的畸变率。 在小鼠和大鼠的长期试验中未发现致瘤性或致癌性。 为研究爱全乐(Atrovent)对生育力、胚胎毒性和围产期发育的影响，分别对小鼠、大鼠和家兔进行了试验。 即使在能导致母体毒性的最高剂量（大鼠1000 mg/kg/天，家兔125 mg/kg/天），也不会引起后代产生畸形。 吸入性气雾剂技术性可行的最高剂量，大鼠1.5 mg/kg/天，家兔1.8 mg/kg/天，对生殖无不良影响。 药代动力学 药物活性成份异丙托溴铵口服后吸收很快。药物吸入后仅几分钟，血浆浓度就达到峰值。异丙托溴铵静脉给药后通过计算血浆水平数据可得到基本的药代动力学参数。血浆中异丙托溴铵快速双相减退。终点清除期的半衰期约为1.6小时。药物和代谢产物清除的半衰期是3.6小时，与放射性标记检测的结果一样。在尿中发现主要代谢产物很少与毒蕈碱受体结合。活性成份异丙托溴铵的清除率是2.3升/分钟。大约40%通过肾脏清除（0.9升/分钟），60%不通过肾脏而主要通过肝脏代谢。分布容积（Vz）是338升（即4.6升/公斤）。46%静脉给药剂量的活性成份通过肾脏排泄，8%气雾剂剂量的活性成份通过肾脏排泄。药物与血浆蛋白的结合率低于20%。由于其四价铵离子的分子结构特点，异丙托溴铵不能通过血脑屏障。 适 应 症 爱全乐 (Atrovent) 为支气管痉挛维持期治疗的支气管扩张剂，适用于慢性支气管炎、肺气肿、哮喘等慢性阻塞性肺疾病。 用法用量 剂量应根据个体需要加以调整。除非医生特别处方，以下为成人及学龄儿童推荐剂量：2喷/次，每日4次。需要增加药物剂量者，一般每天的剂量不宜超过12喷。如果药物治疗不能产生明显的病情改善或患者的状况恶化，应就诊以寻求新的治疗计划。若发生急性呼吸困难或呼吸困难迅速恶化，应立即就诊。 爱全乐（Atrovent）雾化吸入液也可用于慢性阻塞性肺疾病急性发作时的治疗。用法：正确使用气雾剂才能获得满意疗效。首次使用气雾剂前应先将气雾液摇匀，并将气雾器活瓣揿动一至二次。 任何疑问，请遵医嘱！ 不良反应 在临床试验中最常见的非呼吸道的不良事件是头痛、恶心和口干。 由于爱全乐（Atrovent）全身吸收很少，其抗胆碱能副作用如心率增加和心悸、眼部调节障碍、胃肠道蠕动紊乱、尿潴留是很少见的，并且是可逆性的，但对已有尿道梗阻的患者来讲可能增加其尿潴留的危险性。 禁　忌 对大豆卵磷脂或有关的食品如大豆和花生过敏者禁用爱全乐（Atrovent）气雾剂。这些患者可以使用不含大豆卵磷脂的爱全乐（Atrovent）的其它剂型如爱全乐（Atrovent）雾化吸入剂。对阿托品或其衍生物或本品其它成份过敏者禁用。 孕妇及哺乳期妇女用药 临床前试验未显示对妊娠有不良反应，但怀孕期间用药的安全性尚未被确证。怀孕期间尤其是前三个月用药必须谨慎。爱全乐（Atrovent）是否会进入乳汁目前尚不清楚。尽管非脂溶性的四价铵可进入乳汁，但进入婴儿体内的药物量不会很多，特别在吸入给药时。但是，因为很多药物可进入乳汁，哺乳期妇女使用爱全乐（Atrovent）亦应特别注意。 儿童用药 儿童使用爱全乐（Atrovent）气雾剂应遵医嘱并在成人监护下进行。 老年用药 请参见成人用药，目前尚无老年患者用药的特殊注意事项。 注意事项 同其它吸入治疗一样，可观察到支气管扩张性咳嗽、局部刺激，而吸入刺激所产生的支气管收缩较少出现。 过敏样反应如皮疹及舌、唇、脸部血管性水肿，荨麻疹（包括巨型荨麻疹），喉痉挛和过敏反应均有报告，在一些病例中，存在阳性再激发免疫反应。这些患者中有许多人对药物和/或食物包括大豆有过敏史。（见慎用于有闭角型青光眼倾向的患者或有前列腺肥大或膀胱颈梗阻的患者。患有纤维囊泡症的患者可能会引起胃肠道蠕动的紊乱。有极少病例报道，使用爱全乐（Atrovent）后可能会立即发生过敏反应，如出现荨麻疹、血管性水肿、皮疹、支气管痉挛和咽喉部水肿。 眼部并发症有个别病例报告异丙托溴铵单用或与b2受体激动剂合用药物喷到眼内时，可发生眼部并发症（如瞳孔散大、眼内压增加、闭角型青光眼、眼痛）。 患者必须掌握正确使用爱全乐（Atrovent）气雾剂的方法。 与眼结膜充血和角膜水肿相关的眼痛或不适、视力模糊、虹视或有色成像等可能是急性闭角型青光眼的征象。 若上述症状加重，需开始缩瞳治疗并立即就诊治疗。 药物相互作用 使用b-肾上腺素能兴奋剂或黄嘌呤类制剂可加强本品的支气管扩张作用。 爱全乐（Atrovent）与其它治疗慢性阻塞性肺疾病的常用药物包括拟交感神经性支气管扩张剂、甲基黄嘌呤、类固醇、色甘酸二钠等合用，药物间无不良相互作用。 药物过量 尚未发现特异性过量症状。基于爱全乐（Atrovent）气雾剂宽广的治疗范围和使用局部给药方法，不会发生严重的抗胆碱能症状。轻微的抗胆碱能全身表现如口干、视力调节障碍、心率增加等可能发生。 贮　藏 贮存于30℃ 以下环境。请存放于儿童伸手不及处 包装规格： ·250mcg/ml 20个x1ml  DESCRIPTION The active ingredient in Atrovent ® (ipratropium bromide) Inhalation Solution is ipratropium bromide monohydrate. It is an anticholinergic bronchodilator chemically described as 8-azoniabicyclo[3.2.1]-octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-, bromide, monohydrate (endo, syn)-, (±)-; a synthetic quaternary ammonium compound, chemically related to atropine. Ipratropium bromide is a white crystalline substance, freely soluble in water and lower alcohols. It is a quaternary ammonium compound and thus exists in an ionized state in aqueous solutions. It is relatively insoluble in non-polar media. Atrovent Inhalation Solution is administered by oral inhalation with the aid of a nebulizer. It contains ipratropium bromide 0.02% (anhydrous basis) in a sterile, isotonic saline solution, pH-adjusted to 3.4 (3 to 4) with hydrochloric acid. CLINICAL PHARMACOLOGY Atrovent ® (ipratropium bromide) is an anticholinergic (parasympatholytic) agent that, based on animal studies, appears to inhibit vagally-mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increases in intracellular concentration of cyclic guanosine monophosphate (cyclic GMP) that are caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle. The bronchodilation following inhalation of Atrovent is primarily a local, site-specific effect, not a systemic one. Much of an administered dose is swallowed but not absorbed, as shown by fecal excretion studies. Following nebulization of a 2 mg dose, a mean 7% of the dose was absorbed into the systemic circulation either from the surface of the lung or from the gastrointestinal tract. The half-life of elimination is about 1.6 hours after intravenous administration. Ipratropium bromide is minimally (0 to 9% in vitro) bound to plasma albumin and (alpha) 1 -acid glycoproteins. It is partially metabolized. Autoradiographic studies in rats have shown that Atrovent does not penetrate the blood-brain barrier. Atrovent has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in those patient populations. In controlled 12-week studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (chronic bronchitis and emphysema) significant improvements in pulmonary function (FEV 1 increases of 15% or more) occurred within 15 to 30 minutes, reached a peak in 1-2 hours, and persisted for periods of 4-5 hours in the majority of patients, with about 25-38% of the patients demonstrating increases of 15% or more for at least 7-8 hours. Continued effectiveness of Atrovent Inhalation Solution was demonstrated throughout the 12-week period. In addition, significant increases in forced vital capacity (FVC) have been demonstrated. However, Atrovent did not consistently produce significant improvement in subjective symptom scores nor in quality of life scores over the 12-week duration of study. Additional controlled 12-week studies were conducted to evaluate the safety and effectiveness of Atrovent Inhalation Solution administered concomitantly with the beta adrenergic bronchodilator solutions metaproterenol and albuterol compared with the administration of each of the beta agonists alone. Combined therapy produced significant additional improvement in FEV 1 and FVC. On combined therapy, the median duration of 15% improvement in FEV 1 was 5-7 hours, compared with 3-4 hours in patients receiving a beta agonist alone. INDICATIONS AND USAGE Atrovent ® (ipratropium bromide) Inhalation Solution administered either alone or with other bronchodilators, especially beta adrenergics, is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. CONTRAINDICATIONS Atrovent ® (ipratropium bromide) is contraindicated in known or suspected cases of hypersensitivity to ipratropium bromide, or to atropine and its derivatives. WARNINGS The use of Atrovent ® (ipratropium bromide) Inhalation Solution as a single agent for the relief of bronchospasm in acute COPD exacerbation has not been adequately studied. Drugs with faster onset of action may be preferable as initial therapy in this situtation. Combination of Atrovent and beta agonists has not been shown to be more effective than either drug alone in reversing the bronchospasm associated with acute COPD exacerbation. Immediate hypersensitivity reactions may occur after administration of ipratropium bromide, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm and oropharyngeal edema. PRECAUTIONS General    Atrovent ® (ipratropium bromide) should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy or bladder-neck obstruction. Information for Patients    Patients should be advised that temporary blurring of vision, precipitation or worsening of narrow-angle glaucoma or eye pain may result if the solution comes into direct contact with the eyes. Use of a nebulizer with mouthpiece rather than face mask may be preferable, to reduce the likelihood of the nebulizer solution reaching the eyes. Patients should be advised that Atrovent Inhalation Solution can be mixed in the nebulizer with albuterol or metaproterenol if used within one hour. Drug stability and safety of Atrovent Inhalation Solution when mixed with other drugs in a nebulizer have not been established. Patients should be reminded that Atrovent Inhalation Solution should be used consistently as prescribed throughout the course of therapy. Drug Interactions    Atrovent has been shown to be a safe and effective bronchodilator when used in conjuction with beta-adrenergic bronchodilators. Atrovent has also been used with other pulmonary medications, including methylxanthines and corticosteroids, without adverse drug interactions. Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic potential at dietary doses up to 6 mg/kg/day of Atrovent. Results of various mutagenicity studies (Ames test, mouse dominant lethal test, mouse micronucleus test and chromosome aberration of bone marrow in Chinese hamsters) were negative. Fertility of male or female rats at oral doses up to 50 mg/kg/day was unaffected by Atrovent administration. At doses above 90 mg/kg, increased resorption and decreased conception rates were observed. Pregnancy TERATOGENIC EFFECTS Pregnancy Category B.    Oral reproduction studies were performed in mice, rats and rabbits at doses of 10, 100, and 125 mg/kg respectively, and inhalation reproduction studies in rats and rabbits at doses of 1.5 and 1.8 mg/kg (or approximately 38 and 45 times the recommended human daily dose) respectively, have demonstrated no evidence of teratogenic effects as a result of Atrovent. However, no adequate or well-controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, Atrovent should be used during pregnancy only if clearly needed. Nursing Mothers    It is not known whether Atrovent is excreted in human milk. Although lipid-insoluble quaternary bases pass into breast milk, it is unlikely that Atrovent ® (ipratropium bromide) would reach the infant to a significant extent, especially when taken by inhalation since Atrovent is not well absorbed systemically after inhalation or oral administration. However, because many drugs are excreted in human milk, caution should be exercised when Atrovent is administered to a nursing woman. Pediatric Use    Safety and effectiveness in the pediatric population below the age of 12 have not been established. ADVERSE REACTIONS Adverse reaction information concerning Atrovent ® (ipratropium bromide) Inhalation Solution is derived from 12-week active-controlled clinical trials. Additional information is derived from foreign post-marketing experience and the published literature. All adverse events, regardless of drug relationship, reported by three percent or more patients in the 12-week controlled clinical trials appear in the table below: All Adverse Events, from a Double-blind, Parallel, 12-week Study of Patients with COPD PERCENT OF PATIENTS Atrovent ® (500 mcg t.i.d) n=219 Alupent ® 15 mg t.i.d) n=212 Atrovent ® /Alupent ® (500 mcg t.i.d/ 15 mg t.i.d) n=108 Albuterol (2.5 mg t.i.d) n=205 Atrovent ® / Albuterol (500 mcg t.i.d/ 2.5 mg t.i.d) n=100 Body as a Whole-General    Disorders Headache 6.4 5.2 6.5 6.3 9.0 Pain 4.1 3.3 0.9 2.9 5.0 Influenza-like symptoms 3.7 4.7 6.5 0.5 1.0 Back pain 3.2 1.9 1.9 2.4 0.0 Chest pain 3.2 4.2 5.6 2.0 1.0 Cardiovascular Disorders Hypertension/Hypertension    Aggravated 0.9 1.9 0.9 1.5 4.0 Central & Peripheral Nervous    System Dizziness 2.3 3.3 1.9 3.9 4.0 Insomnia 0.9 0.5 4.6 1.0 1.0 Tremor 0.9 7.1 8.3 1.0 0.0 Nervousness 0.5 4.7 6.5 1.0 1.0 Gastrointestinal System    Disorders Mouth Dryness 3.2 0.0 1.9 2.0 3.0 Nausea 4.1 3.8 1.9 2.9 2.0 Constipation 0.9 0.0 3.7 1.0 1.0 Musculo-skeletal System    Disorders Arthritis 0.9 1.4 0.9 0.5 3.0 Respiratory System Disorders   (Lower) Coughing 4.6 8.0 6.5 5.4 6.0 Dyspnea 9.6 13.2 16.7 12.7 9.0 Bronchitis 14.6 24.5 15.7 16.6 20.0 Bronchospasm 2.3 2.8 4.6 5.4 5.0 Sputum Increased 1.4 1.4 4.6 3.4 0.0 Respiratory Disorder 0.0 6.1 6.5 2.0 4.0 Respiratory System Disorders   (Upper) Upper Respiratory Tract    Infection 13.2 11.3 9.3 12.2 16.0 Pharyngitis 3.7 4.2 5.6 2.9 4.0 Rhinitis 2.3 4.2 1.9 2.4 0.0 Sinusitis 2.3 2.8 0.9 5.4 4.0 * All adverse events, regardless of drug relationship, reported by three percent or more patients in the 12-week controlled clinical trials. Additional adverse reactions reported in less than three percent of the patients treated with Atrovent include tachy-cardia, palpitations, eye pain, urinary retention, urinary tract infection and urticaria. Cases of precipitation or worsening of narrow-angle glaucoma and acute eye pain have been reported. Lower respiratory adverse reactions (bronchitis, dyspnea and bronchospasm) were the most common events leading to discontinuation of Atrovent therapy in the 12-week trials. Headache, mouth dryness and aggravation of COPD symptoms are more common when the total daily dose of Atrovent equals or exceeds 2,000 mcg. Allergic-type reactions such as skin rash, angioedema of tongue, lips and face, urticaria, laryngospasm and anaphylactic reaction have been reported. Many of the patients had a history of allergies to other drugs and/or foods. OVERDOSAGE Acute systemic overdosage by inhalation is unlikely since Atrovent ® (ipratropium bromide) is not well absorbed after inhalation at up to four-fold the recommended dose, or after oral administration at up to forty-fold the recommended dose. The oral LD 50 of Atrovent ranged between 1001 and 2010 mg/kg in mice; between 1667 and 4000 mg/kg in rats; and between 400 and 1300 mg/kg in dogs. DOSAGE AND ADMINISTRATION The usual dosage of Atrovent ® (ipratropium bromide) Inhalation Solution is 500 mcg (1 Unit-Dose Vial) administered three to four times a day by oral nebulization, with doses 6 to 8 hours apart. Atrovent Inhalation Solution Unit-Dose Vials contain 500 mcg ipratropium bromide anhydrous in 2.5 ml normal saline. Atrovent Inhalation Solution can be mixed in the nebulizer with albuterol or metaproterenol if used within one hour. Drug stability and safety of Atrovent Inhalation Solution when mixed with other drugs in a nebulizer have not been established. HOW SUPPLIED Atrovent ® (ipratropium bromide) Inhalation Solution Unit Dose Vial is supplied as a 0.02% clear, colorless solution containing 2.5 ml with 5 Unit Dose Vials per pouch, 5 pouches per carton (NDC 0597-0080-62). Each vial is made from a low density polyethylene (LDPE) resin. Store between 59°F (15°C) and 86°F (30°C). Protect from light.