英文药名: Atrovent(Ipratropium Bromide Inhaler)

中文药名: 异丙托溴胺气雾剂

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：
·20mcg ：200 doses （喷）X 1个
·20mcg ：200 doses （喷）X 3个

DESCRIPTION
The active ingredient in ATROVENT® Nasal Spray is ipratropium bromide monohydrate. It is an anticholinergic agent 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. Its structural formula is:

Ipratropium bromide is a white to off-white, crystalline substance. It is freely soluble in lower alcohols and water, existing in an ionized state in aqueous solutions, and relatively insoluble in non-polar media.

ATROVENT(ipratropium bromide) Nasal Spray 0.06% is a metered-dose, manual pump spray unit which delivers 42 mcg ipratropium bromide (on an anhydrous basis) per spray (70µL) 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 165 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 anti-secretory 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 membranes 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 adult volunteers, naturally acquired common cold pediatric patients, or perennial rhinitis adult 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 based 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 bromide 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 84 mcg of ipratropium bromide per nostril three times a day in patients 5-18 years old (n=42) with a naturally acquired common cold, the mean amount of the total dose excreted unchanged in the urine of 7.8% was comparable to 84 mcg per nostril four times a day in an adult induced common cold population (n=22) of 7.3 to 8.1%. Plasma ipratropium concentrations were relatively low (ranging from undetectable up to 0.62 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 Interactions:  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, ATROVENT Nasal Spray 0.06% in adult patients (n=22) with induced-colds (84 mcg/nostril four times a day) and in pediatric patients (n=45) with naturally acquired common cold (84 mcg/nostril three times a day) had no significant effects on pupillary diameter, heart rate, or systolic/diastolic blood pressure.

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
Clinical trials for ATROVENT (ipratropium bromide) Nasal Spray 0.06% were conducted in patients with rhinorrhea associated with naturally occurring common colds. In two controlled four day comparisons of ATROVENT (ipratropium bromide) Nasal Spray 0.06% (84 mcg per nostril, administered three or four times daily; n=352) with its vehicle (n=351), there was a statistically significant reduction of rhinorrhea, as measured by both nasal discharge weight and the patients' subjective assessment of severity of rhinorrhea using a visual analog scale. These significant differences were evident within one hour following dosing. There was no effect of ATROVENT (ipratropium bromide) Nasal Spray 0.06% on degree of nasal congestion or sneezing. The response to ATROVENT (ipratropium bromide) Nasal Spray 0.06% did not appear to be affected by age or gender. No controlled clinical trials directly compared the efficacy of three times daily versus four times daily treatment.

One clinical trial was conducted with ATROVENT Nasal Spray 0.06%, administered four times daily for three weeks, in 218 patients with rhinorrhea associated with Seasonal Allergic Rhinitis (SAR), compared to its vehicle in 211 patients. Patients in this trial were adults and adolescents 12 years of age and above. ATROVENT (ipratropium bromide) Nasal Spray 0.06% was significantly more effective in reducing the severity and duration of rhinorrhea over the three weeks of the study, as measured by daily patient symptom scores. There was no difference between treatment groups in the effect on nasal congestion, sneezing or itching eyes.

INDICATIONS AND USAGE
ATROVENT ® (ipratropium bromide) Nasal Spray 0.06% is indicated for the symptomatic relief of rhinorrhea associated with the common cold or seasonal allergic rhinitis for adults and children age 5 years and older. ATROVENT (ipratropium bromide) Nasal Spray 0.06% does not relieve nasal congestion or sneezing associated with the common cold or seasonal allergic rhinitis.

The safety and effectiveness of the use of ATROVENT (ipratropium bromide) Nasal Spray 0.06% beyond four days in patients with the common cold or beyond three weeks in patients with seasonal allergic rhinitis has not been established.

CONTRAINDICATIONS
ATROVENT ® (ipratropium bromide) Nasal Spray 0.06% 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 0.06% 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 of narrow-angle glaucoma or eye pain may result if ATROVENT® (ipratropium bromide) Nasal Spray 0.06% comes into direct contact with the eyes. Patients should be instructed to avoid spraying ATROVENT (ipratropium bromide) Nasal Spray 0.06% in or around the 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 potential drug-drug interactions. ATROVENT (ipratropium bromide) Nasal Spray 0.06% is minimally absorbed into the systemic circulation; nonetheless, there is some potential for an additive interaction with other concomitantly administered medications with anticholinergic properties, including ATROVENT for oral inhalation.

Carcinogenesis, Mutagenesis, Impairment of Fertility
In two-year carcinogenicity studies in rats and mice, ipra-tropium bromide at oral doses up to 6 mg/kg (approximately 70 and 35 times the maximum recommended daily intranasal dose in adults, respectively, and approximately 45 and 25 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 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, 1,000 mg/kg in rats and 125 mg/kg in rabbits. These doses correspond, in each species respectively, to approximately 60, 12,000, and 3,000 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 20 and 45 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 1,100 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, ipratropium bromide should be used during pregnancy only if clearly needed.

Nursing Mothers
It is known that some ipratropium bromide is systemically 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 0.06% is administered to a nursing woman.

Pediatric Use
The safety of ATROVENT (ipratropium bromide) Nasal Spray 0.06% at a dose of two sprays (84 mcg) per nostril three times a day (total dose 504 mcg/day) for two to four days has been demonstrated in two clinical trials involving 362 pediatric patients 5-11 years of age with naturally acquired common colds. In this pediatric population ATROVENT (ipratropium bromide) Nasal Spray 0.06% had an adverse event profile similar to that observed in adolescent and adult patients. When ATROVENT was concomitantly administered with an oral decongestant (pseudoephedrine HCl) in 122 children ages 5-12 years, and concomitantly administered with an oral decongestant/antihistamine combination (pseudoephedrine HCl/chlorpheniramine maleate) in 123 children ages 5-12 years, adverse event profiles were similar to ATROVENT alone. The safety of ATROVENT (ipratropium bromide) Nasal Spray 0.06% at a dose of two sprays (84 mcg) per nostril four times a day (total dose 672 mcg/day) for three weeks in pediatric seasonal allergic rhinitis patients down to 5 years is based upon the safety demonstrated in the pediatric common cold trials and the trial in adult and adolescent patients 12 to 75 years of age with seasonal allergic rhinitis. The effectiveness of ATROVENT (ipratropium bromide) Nasal Spray 0.06% for the treatment of rhinorrhea associated with the common cold and seasonal allegic rhinitis in this pediatric age group is based on extrapolation of the demonstrated efficacy of ATROVENT (ipratropium bromide) Nasal Spray 0.06% in adolescents and adults with the conditions and the likelihood that the disease course, pathophysiology, and the drug's effects are substantially similar to that of adults. The recommended dose for common cold for the pediatric population is based on cross-study comparisons of the efficacy of ATROVENT (ipratropium bromide) Nasal Spray 0.06% in adult and pediatric patients and on its safety profile in both adults and pediatric common cold patients. The recommended dose for seasonal allergic rhinitis for the pediatric population down to 5 years is based upon the efficacy and safety of ATROVENT (ipratropium bromide) Nasal Spray in adults and adolescents 12 years of age and above with seasonal allergic rhinitis and the safety profile of this dose in both adult and pediatric common cold patients. The safety and effectiveness of ATROVENT (ipratropium bromide) Nasal Spray 0.06% in pediatric patients under 5 years of age have not been established.

ADVERSE REACTIONS
Adverse reaction information on ATROVENT ® (ipratropium bromide) Nasal Spray 0.06% in patients with the common cold was derived from two multicenter, vehicle-controlled clinical trials involving 1,276 patients (195 patients on ATROVENT ® (ipratropium bromide) Nasal Spray 0.03%, 352 patients on ATROVENT (ipratropium bromide) Nasal Spray 0.06%, 189 patients on ATROVENT (ipratropium bromide) Nasal Spray 0.12%, 351 patients on vehicle and 189 patients receiving no treatment).

Table 1 shows adverse events reported for patients who received ATROVENT (ipratropium bromide) Nasal Spray 0.06% at the recommended dose of 84 mcg per nostril, or vehicle, administered three or four times daily, where the incidence is 1% or greater in the ATROVENT group and higher in the ATROVENT ® group than in the vehicle group.

Table 1 % of Patients with Common Cold Reporting Events ¹

	ATROVENT Nasal Spray 0.06%	Vehicle Control
No. of Patients	352	351
Epistaxis 2	8.2%	2.3%
Nasal Dryness	4.8%	2.8%
Dry Mouth/Throat	1.4%	0.3%
Nasal Congestion	1.1%	0.0%
1 This table includes adverse events for which the incidence was 1% or greater in the ATROVENT group and higher in the ATROVENT group than in the vehicle group.
2 Epistaxis reported by 5.4% of ATROVENT patients and 1.4% of vehicle patients, blood tinged nasal mucus by 2.8% of ATROVENT patients and 0.9% of vehicle patients.

ATROVENT (ipratropium bromide) Nasal Spray 0.06% was well tolerated by most patients. The most frequently reported adverse events were transient episodes of nasal dryness or epistaxis. The majority of these adverse events (96%) were mild or moderate in nature, none was considered serious, and none resulted in hospitalization. No patient required treatment for nasal dryness, and only three patients (<1%) required treatment for epistaxis, which consisted of local application of pressure or a moisturizing agent (e.g., petroleum jelly). No patient receiving ATROVENT (ipratropium bromide) Nasal Spray 0.06% was discontinued from the trial due to either nasal dryness or bleeding.

Adverse events reported by less than 1% of the patients receiving ATROVENT (ipratropium bromide) Nasal Spray 0.06% during the controlled clinical trials that are potentially related to ATROVENT's local effects or systemic anticholinergic effects include: taste perversion, nasal burning, conjunctivitis, coughing, dizziness, hoarseness, palpitation, pharyngitis, tachycardia, thirst, tinnitus, and blurred vision. No controlled trial was conducted to address the relative incidence of adverse events for three times daily versus four times daily therapy.

Nasal adverse events seen in the clinical trial with seasonal allergic rhinitis (SAR) patients (see Table 2) were similar to those seen in the common cold trials. Additional events were reported at a higher rate in the SAR trial due in part to the longer duration of the trial and the inclusion of upper respiratory tract infection (URI) as an adverse event. In common cold trials, URI was the disease under study and not an adverse event.

Table 2   % of Patients with SAR Reporting Events ¹

	ATROVENT ® Nasal Spray 0.06%	Vehicle Control
No. of Patients	218	211
Epistaxis 2	6.0%	3.3%
Pharyngitis	5.0%	3.8%
URI	5.0%	3.3%
Nasal Dryness	4.6%	0.9%
Headache	4.1%	0.5%
Dry Mouth/Throat	4.1%	0.0%
Taste Perversion	3.7%	1.4%
Sinusitis	2.8%	2.8%
Pain	1.8%	0.9%
Diarrhea	1.8%	0.5%

1 This table includes adverse events for which the incidence was 1% or greater in the ATROVENT group and higher in the ATROVENT group than in the vehicle group.

2 Epistaxis reported by 3.7% of ATROVENT patients and 2.4% of vehicle patients, blood tinged nasal mucus by 2.3% of ATROVENT patients and 1.9% of vehicle patients.

Additional anticholinergic effects noted with other ATROVENT dosage forms (ATROVENT Inhalation Solution, ATROVENT Inhalation Aerosol and ATROVENT Nasal Spray 0.03%) include: precipitation or worsening of narrow-angle glaucoma, urinary retention, prostate disorders, constipation, and bowel obstruction.

There were no reports of allergic-type reactions in the controlled clinical trials. Allergic-type reactions such as skin rash, angioedema of the throat, tongue, lips and face, generalized urticaria, laryngospasm and anaphylactic reactions have been reported with ATROVENT Nasal Spray 0.06% 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 two bottles of ATROVENT ® Nasal Spray 0.06%) 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 mm Hg 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 6,000 and 3,800 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 21,000 and 13,000 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 16,000 and 10,000 times the maximum recommended daily intranasal dose in adults and children, respectively, on a mg/m 2 basis).

DOSAGE AND ADMINISTRATION
For Symptomatic Relief of Rhinorrhea Associated with the Common Cold

The recommended dose of ATROVENT ® (ipratropium bromide) Nasal Spray 0.06% is two sprays (84 mcg) per nostril three or four times daily (total dose 504 to 672 mcg/day) in adults and children age 12 years and older. Optimum dosage varies with response of the individual patient. The recommended dose of ATROVENT (ipratropium bromide) Nasal Spray 0.06% for children age 5-11 years is two sprays (84 mcg) per nostril three times daily (total dose of 504 mcg/day).

The safety and effectiveness of the use of ATROVENT (ipratropium bromide) Nasal Spray 0.06% beyond four days in patients with the common cold have not been established.

For Symptomatic Relief of Rhinorrhea Associated with Seasonal Allergic Rhinitis

The recommended dose of ATROVENT (ipratropium bromide) Nasal Spray 0.06% is two sprays (84 mcg) per nostril four times daily (total dose 672 mcg/day) in adults and children age 5 years and older.

The safety and effectiveness of the use of ATROVENT (ipratropium bromide) Nasal Spray 0.06% beyond three weeks in patients with seasonal allergic rhinitis have not been established.

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 0.06% is supplied in a white high density polyethylene (HDPE) bottle fitted with a metered nasal spray pump, a green safety clip to prevent accidental discharge of the spray, and a clear plastic dust cap. It contains 16.6 g of product formulation, 165 sprays, each delivering 42 mcg of ipratropium bromide per spray (70 µL), or 10 days of therapy at the maximum recommended dose (two sprays per nostril four 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.

Patients should be reminded to read and follow the accompanying Patient's Instructions for Use, which should be dispensed with the product.

Rx only

Boehringer Ingelheim Pharmaceuticals, Inc.