| 英文药名: Atrovent(Ipratropium Bromide Nasal Spray)
中文药名: 异丙托溴胺气雾鼻喷剂 生产厂家: Boehringer Ingelheim 药品名称 中文药名: 异丙托溴胺 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。 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。 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。 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。 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（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。 对大豆卵磷脂或有关的食品如大豆和花生过敏者禁用（Atrovent）气雾剂。这些患者可以使用不含大豆卵磷脂的Atrovent的其它剂型如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。 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。（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（Atrovent）亦应特别注意。 儿童使用（Atrovent）气雾剂应遵医嘱并在成人监护下进行。 请参见成人用药，目前尚无老年患者用药的特殊注意事项。 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）。 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。 尚未发现特异性过量症状。基于（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。 贮存于30℃ 以下环境。请存放于儿童伸手不及处 包装规格：
Atrovent nasal spray Prescribing Information ATROVENT (ipratropium bromide) Nasal Spray 0.03% is a metered-dose, manual pump spray unit which delivers 21 mcg (70µL) ipratropium bromide per spray on an anhydrous basis in an isotonic, aqueous solution with pH adjusted to 4.7. It also contains benzalkonium chloride, edetate disodium, sodium chloride, sodium hydroxide, hydrochloric acid, and purified water. Each bottle contains 345 sprays. Clinical Pharmacology Mechanism of Action Ipratropium bromide is an anticholinergic agent that inhibits vagally-mediated reflexes by antagonizing the action of acetylcholine at the cholinergic receptor. In humans, ipratropium bromide has antisecretory properties and, when applied locally, inhibits secretions from the serous and seromucous glands lining the nasal mucosa. Ipratropium bromide is a quaternary amine that minimally crosses the nasal and gastrointestinal membrane and the blood-brain barrier, resulting in a reduction of the systemic anticholinergic effects (e.g., neurologic, ophthalmic, cardiovascular, and gastrointestinal effects) that are seen with tertiary anticholinergic amines. Pharmacokinetics Absorption: Ipratropium bromide is poorly absorbed into the systemic circulation following oral administration (2-3%). Less than 20% of an 84 mcg per nostril dose was absorbed from the nasal mucosa of normal volunteers, induced-cold patients, or perennial rhinitis patients. Distribution: Ipratropium bromide is minimally bound (0 to 9% in vitro ) to plasma albumin and (alpha) 1 -acid glycoprotein. Its blood/plasma concentration ratio was estimated to be about 0.89. Studies in rats have shown that ipratropium bromide does not penetrate the blood-brain barrier. Metabolism: Ipratropium bromide is partially metabolized to ester hydrolysis products, tropic acid and tropane. These metabolites appear to be inactive on in vitro receptor affinity studies using rat brain tissue homogenates. Elimination: After intravenous administration of 2 mg ipratropium bromide to 10 healthy volunteers, the terminal half-life of ipratropium was approximately 1.6 hours. The total body clearance and renal clearance were estimated to be 2,505 and 1,019 ml/min, respectively. The amount of the total dose excreted unchanged in the urine (Ae) within 24 hours was approximately one-half of the administered dose. Pediatrics: Following administration of 42 mcg of ipratropium bromide per nostril two or three times a day in perennial rhinitis patients 6-18 years old, the mean amounts of the total dose excreted unchanged in the urine (8.6 to 11.1%) were higher than those reported in adult volunteers or adult perennial rhinitis patients (3.7 to 5.6%). Plasma ipratropium concentrations were relatively low (ranging from undetectable up to 0.49 ng/ml). No correlation of the amount of the total dose excreted unchanged in the urine (Ae) with age or gender was observed in the pediatric population. Special Populations: Gender does not appear to influence the absorption or excretion of nasally administered ipratropium bromide. The pharmacokinetics of ipratropium bromide have not been studied in patients with hepatic or renal insufficiency or in the elderly. Drug-Drug Interaction: No specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions. Pharmacodynamics: In two single-dose trials (n=17), doses up to 336 mcg of ipratropium bromide did not significantly affect pupillary diameter, heart rate, or systolic/diastolic blood pressure. Similarly, in patients with induced-colds, ATROVENT (ipratropium bromide) Nasal Spray 0.06% (84 mcg/nostril four times a day), had no significant effects on pupillary diameter, heart rate or systolic/diastolic blood pressure. Two nasal provocation trials in perennial rhinitis patients (n=44) using ipratropium bromide nasal spray showed a dose dependent increase in inhibition of methacholine induced nasal secretion with an onset of action within 15 minutes (time of first observation). Controlled clinical trials demonstrated that intranasal fluorocarbon-propelled ipratropium bromide does not alter physiologic nasal functions (e.g., sense of smell, ciliary beat frequency, mucociliary clearance, or the air conditioning capacity of the nose). Clinical Trials The clinical trials for ATROVENT (ipratropium bromide) Nasal Spray 0.03% were conducted in patients with nonallergic perennial rhinitis (NAPR) and in patients with allergic perennial rhinitis (APR). APR patients were those who experienced symptoms of nasal hypersecretion and nasal congestion or sneezing when exposed to specific perennial allergens (e.g., dust mites, molds) and were skin test positive to these allergens. NAPR patients were those who experienced symptoms of nasal hypersecretion and nasal congestion or sneezing throughout the year, but were skin test negative to common perennial allergens. In four controlled, four- and eight-week comparisons of ATROVENT (ipratropium bromide) Nasal Spray 0.03% (42 mcg per nostril, two or three times daily) with its vehicle, in patients with allergic or nonallergic perennial rhinitis, there was a statistically significant decrease in the severity and duration of rhinorrhea in the ATROVENT group throughout the entire study period. An effect was seen as early as the first day of therapy. There was no effect of ATROVENT (ipratropium bromide) Nasal Spray 0.03% on degree of nasal congestion, sneezing, or postnasal drip. The response to ATROVENT (ipratropium bromide) Nasal Spray 0.03% did not appear to be affected by the type of perennial rhinitis (NAPR or APR), age, or gender. No controlled clinical trials directly compared the efficacy of BID versus TID treatment. Indications and Usage ATROVENT (ipratropium bromide) Nasal Spray 0.03% is indicated for the symptomatic relief of rhinorrhea associated with allergic and nonallergic perennial rhinitis in adults and children age 6 years and older. ATROVENT (ipratropium bromide) Nasal Spray 0.03% does not relieve nasal congestion, sneezing, or postnasal drip associated with allergic or nonallergic perennial rhinitis. Contraindications ATROVENT (ipratropium bromide) Nasal Spray 0.03% is contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, or to any of the other ingredients. Warnings 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) Nasal Spray 0.03% should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, or bladder neck obstruction, particularly if they are receiving an anticholinergic by another route. Cases of precipitation or worsening of narrow-angle glaucoma and acute eye pain have been reported with direct eye contact of ipratropium bromide administered by oral inhalation. Information for Patients Patients should be advised that temporary blurring of vision, precipitation or worsening or narrow-angle glaucoma, or eye pain may result if ATROVENT (ipratropium bromide) Nasal Spray 0.03% comes into direct contact with the eyes. Patients should be instructed to avoid spraying ATROVENT (ipratropium bromide) Nasal Spray 0.03% in or around their eyes. Patients who experience eye pain, blurred vision, excessive nasal dryness, or episodes of nasal bleeding should be instructed to contact their doctor. Patients should be reminded to carefully read and follow the accompanying Patient's Instructions for Use. Drug Interactions No controlled clinical trials were conducted to investigate drug-drug interactions. ATROVENT (ipratropium bromide) Nasal Spray 0.03% is minimally absorbed into the systemic circulation; nonetheless, there is some potential for an additive interaction with other concomitantly administered anticholinergic medications, including ATROVENT for oral inhalation. Carcinogenesis, Mutagenesis, Impairment of Fertility In two-year carcinogenicity studies in rats and mice, ipratropium bromide at oral doses up to 6 mg/kg (approximately 190 and 95 times the maximum recommended daily intranasal dose in adults, respectively, and approximately 110 and 60 times the maximum recommended daily intranasal dose in children, respectively on a mg/m 2 basis) showed no carcinogenic activity. 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 was unaffected by ipratropium bromide at oral doses up to 50 mg/kg (approximately 1,600 times the maximum recommended daily intranasal dose in adults on a mg/m 2 basis). At an oral dose of 500 mg/kg (approximately 16,000 times the maximum recommended daily intranasal dose in adults on a mg/m 2 basis), ipratropium bromide produced a decrease in the conception rate. Pregnancy TERATOGENIC EFFECTS Pregnancy Category B. Oral reproduction studies were performed at doses of 10 mg/kg in mice, 1000 mg/kg in rats and 125 mg/kg in rabbits. These doses correspond, in each species respectively, to approximately 160, 32,000, and 8,000 times the maximum recommended daily intranasal dose in adults on a mg/m 2 basis. Inhalation reproduction studies were conducted in rats and rabbits at doses of 1.5 and 1.8 mg/kg respectively, (approximately 50 and 120 times, respectively, the maximum recommended daily intranasal dose in adults on a mg/m 2 basis). These studies demonstrated no evidence of teratogenic effects as a result of ipratropium bromide. At oral doses above 90 mg/kg in rats (approximately 2,900 times the maximum recommended daily intranasal dose in adults on a mg/m 2 basis) embryotoxicity was observed as increased resorption. This effect is not considered relevant to human use due to the large doses at which it was observed and the difference in route of administration. 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 (ipratropium bromide) Nasal Spray 0.03% should be used during pregnancy only if clearly needed. Nursing Mothers It is known that some ipratropium bromide is systematically absorbed following nasal administration; however the portion which may be excreted in human milk is unknown. Although lipid-insoluble quaternary bases pass into breast milk, the minimal systemic absorption makes it unlikely that ipratropium bromide would reach the infant in an amount sufficient to cause a clinical effect. However, because many drugs are excreted in human milk, caution should be exercised when ATROVENT (ipratropium bromide) Nasal Spray 0.03% is administered to a nursing woman. Pediatric Use The safety of ATROVENT (ipratropium bromide) Nasal Spray 0.03% at a dose of two sprays (42 mcg) per nostril two or three times daily (total dose 168 to 252 mcg/day) has been demonstrated in 77 pediatric patients 6-12 years of age in placebo-controlled, 4-week trials and 55 pediatric patients in active-controlled, 6 month trials. The effectiveness of ATROVENT (ipratropium bromide) Nasal Spray 0.03% for the treatment of rhinorrhea associated with allergic and nonallergic perennial rhinitis in this pediatric age group is based on an extrapolation of the demonstrated efficacy of ATROVENT (ipratropium bromide) Nasal Spray 0.03% in adults with these conditions and the likelihood that the disease course, pathophysiology, and the drug's effects are substantially similar to that of the adults. The recommended dose for the pediatric population is based on within and cross-study comparisons of the efficacy of ATROVENT (ipratropium bromide) Nasal Spray 0.03% in adults and pediatric patients on its safety profile in both adults and pediatric patients. The safety and effectiveness of ATROVENT (ipratropium bromide) Nasal Spray 0.03% in patients under 6 years of age have not been established. Adverse Reactions Adverse reaction information on ATROVENT (ipratropium bromide) Nasal Spray 0.03% in patients with perennial rhinitis was derived from four multicenter, vehicle-controlled clinical trials involving 703 patients (356 patients on ATROVENT and 347 patients on vehicle), and a one-year, open-label, follow-up trial. In three of the trials, patients received ATROVENT (ipratropium bromide) Nasal Spray 0.03% three times daily, for eight weeks. In the other trial, ATROVENT (ipratropium bromide) Nasal Spray 0.03% was given to patients two times daily for four weeks. Of the 285 patients who entered the open-label, follow-up trial, 232 were treated for 3 months, 200 for 6 months, and 159 up to one year. The majority (>86%) of patients treated for one year were maintained on 42 mcg per nostril, two or three times daily, of ATROVENT (ipratropium bromide) Nasal Spray 0.03%. The following table shows adverse events, and the frequency that these adverse events led to the discontinuation of treatment, reported for patients who received ATROVENT (ipratropium bromide) Nasal Spray 0.03% at the recommended dose of 42 mcg per nostril, or vehicle two or three times daily for four or eight weeks. Only adverse events reported with an incidence of at least 2.0% in the ATROVENT group and higher in the ATROVENT group than in the vehicle group are shown.
ATROVENT (ipratropium bromide) Nasal Spray 0.03% was well tolerated by most patients. The most frequently reported nasal adverse events were transient episodes of nasal dryness or epistaxis. These adverse events were mild or moderate in nature, none was considered serious, none resulted in hospitalization and most resolved spontaneously or following a dose reduction. Treatment for nasal dryness and epistaxis was required infrequently (2% or less) and consisted of local application of pressure or a moisturizing agent (e.g., petroleum jelly or saline nasal spray). Patient discontinuation for epistaxis or nasal dryness was infrequent in both the controlled (0.3% or less) and one-year, open-label (2% or less) trials. There was no evidence of nasal rebound (i.e., a clinically significant increase in rhinorrhea, posterior nasal drip, sneezing or nasal congestion severity compared to baseline) upon discontinuation of double-blind therapy in these trials. Adverse events reported by less than 2% of the patients receiving ATROVENT (ipratropium bromide) Nasal Spray 0.03% during the controlled clinical trials or during the open-label follow-up trial, which are potentially related to ATROVENT's local effects or systemic anticholinergic effects include: dry mouth/throat, dizziness, ocular irritation, blurred vision, conjunctivitis, hoarseness, cough, and taste perversion. Additional anticholinergic effects noted with other ATROVENT dosage forms (ATROVENT Inhalation Solution, ATROVENT Inhalation Aerosol, and ATROVENT Nasal Spray 0.06%) include: precipitation or worsening of narrow angle glaucoma, urinary retention, prostatic disorders, tachycardia, constipation, and bowel obstruction. There were infrequent reports of skin rash in both the controlled and uncontrolled clinical studies. Allergic-type reactions such as skin rash, angioedema of the throat, lips and face, generalized urticaria, laryngospasm, and anaphylactic reactions have been reported with ATROVENT Nasal Spray 0.03% and other ipratropium bromide products. Overdosage Acute overdosage by intranasal administration is unlikely since ipratropium bromide is not well absorbed systemically after intranasal or oral administration. Following administration of a 20 mg oral dose (equivalent to ingesting more than four bottles of ATROVENT Nasal Spray 0.03%) to 10 male volunteers, no change in heart rate or blood pressure was noted. Following a 2 mg intravenous infusion over 15 minutes to the same 10 male volunteers, plasma ipratropium concentrations of 22-45 ng/mL were observed (>100 times the concentrations observed following intranasal administration). Following intravenous infusion these 10 volunteers had a mean increase of heart rate of 50 bpm and less than 20 mmHg change in systolic or diastolic blood pressure at the time of peak ipratropium levels. Oral median lethal doses of ipratropium bromide were greater than 1,000 mg/kg in mice (approximately 16,000 and 9,500 times the maximum recommended daily intranasal dose in adults and children, respectively, on a mg/m 2 basis), 1,700 mg/kg in rats (approximately 55,000 and 32,000 times the maximum recommended daily intranasal dose in adults and children, respectively, on a mg/m 2 basis), and 400 mg/kg in dogs (approximately 43,000 and 25,000 times the maximum recommended daily intranasal dose in adults and children, respectively, on a mg/m 2 basis). Dosage and Administration The recommended dose of ATROVENT (ipratropium bromide) Nasal Spray 0.03% is two sprays (42 mcg) per nostril two or three times daily (total dose 168 to 252 mcg/day) for the symptomatic relief of rhinorrhea associated with allergic and nonallergic perennial rhinitis in adults and children age 6 years and older. Optimum dosage varies with the response of the individual patient. Initial pump priming requires seven sprays of the pump. If used regularly as recommended, no further priming is required. If not used for more than 24 hours, the pump will require two sprays, or if not used for more than seven days, the pump will require seven sprays to reprime. How Supplied ATROVENT (ipratropium bromide) Nasal Spray 0.03% is supplied in a white high density polyethylene (HDPE) bottle fitted with a white and clear metered nasal spray pump, a green safety clip to prevent accidental discharge of the spray, and a clear plastic dust cap. It contains 31.1g of product formulation, 345 sprays, each delivering 21 mcg (70µL) of ipratropium per spray, or 28 days of therapy at the maximum recommended dose (two sprays per nostril three times a day). Store tightly closed between 59°F (15°C) and 86°F (30°C). Avoid freezing. Keep out of reach of children. Do not spray in the eyes. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
