The active ingredient in Atrovent (Ipratropium bromide) Inhalation Aerosol is ipratropium bromide. 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 ()-,(±): a synthetic quaternary ammonium compound chemically related to atropine. The structural formula is:

Ipratropium bromide is a white to off-white crystalline substance, freely soluble in water and lower alcohols but insoluble in lipophilic solvents such as ether, chloroform, and fluorocarbons.

Atrovent (Ipratropium bromide) Inhalation Aerosol contains a microcrystalline suspension of ipratropium bromide in a pressurized metered-dose aerosol unit for oral inhalation administration. The net weight is at least 14.7 grams; it yields 200 inhalations. Each actuation meters 21 mcg of ipratropium bromide from the valve and delivers 18 mcg of ipratropium bromide from the mouthpiece. The excipients are dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane as propellants and soya lecithin.

The bronchodilation following inhalation of ipratropium bromide is primarily a local, site-specific effect, not a systemic one. Much of an administered dose is swallowed as shown by fecal excretion studies. Ipratropium bromide is a quaternary amine. It is not readily absorbed into the systemic circulation either from the surface of the lung or from the gastrointestinal tract as confirmed by blood level and renal excretion studies.

The half-life of elimination is about 2 hours after inhalation or intravenous administration. Ipratropium bromide is minimally bound (0 to 9% ) to plasma albumin and α-acid glycoprotein. It is partially metabolized to inactive ester hydrolysis products. Following intravenous administration, approximately one-half of the dose is excreted unchanged in the urine. Autoradiographic studies in rats have shown that ipratropium bromide does not penetrate the blood-brain barrier.

In controlled 90 day studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (chronic bronchitis and emphysema) significant improvements in pulmonary function (FEV and FEF increases of 15% or more) occurred within 15 minutes, reached a peak in 1-2 hours, and persisted for periods of 3 to 4 hours in the majority of patients and up to 6 hours in some patients. In addition, significant increases in Forced Vital Capacity (FVC) have been demonstrated.

Controlled clinical studies have demonstrated that Atrovent (Ipratropium bromide) Inhalation Aerosol does not alter either mucociliary clearance or the volume or viscosity of respiratory secretions. In studies without a positive control Atrovent (Ipratropium bromide) Inhalation Aerosol did not alter pupil size, accommodation or visual acuity (See ). Ventilation/perfusion studies have shown no clinically significant effects on pulmonary gas exchange or arterial oxygen tension. At recommended doses, Atrovent (Ipratropium bromide) Inhalation Aerosol does not produce clinically significant changes in pulse rate or blood pressure.

Atrovent (Ipratropium bromide) Inhalation Aerosol is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema.

Atrovent (Ipratropium bromide) Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to soya lecithin or related food products such as soybean and peanut. Atrovent (Ipratropium bromide) Inhalation Aerosol should also not be taken by patients hypersensitive to any other components of the drug product or to atropine or its derivatives.

Atrovent (Ipratropium bromide) Inhalation Aerosol is not indicated for the initial treatment of acute episodes of bronchospasm where rapid response is required.

Patients should be cautioned to avoid spraying the aerosol into their eyes and be advised that this may result in precipitation or worsening of narrow-angle glaucoma, mydriasis, eye pain or discomfort, temporary blurring of vision, visual halos or colored images in association with red eyes from conjunctival and corneal congestion. Patients should also be advised that should any combination of these symptoms develop, they should consult their physician immediately.

Atrovent (Ipratropium bromide) Inhalation Aerosol should not be used more frequently than recommended. The dose or frequency of Atrovent (Ipratropium bromide) Inhalation Aerosol should not be increased without patients consulting their physician. If treatment with Atrovent (Ipratropium bromide) Inhalation Aerosol becomes less effective for symptomatic relief, their symptoms become worse, and/or patients need to use the product more frequently than usual, medical attention should be sought immediately. The patient, if pregnant or nursing, should be advised to contact their physician about the use of Atrovent (Ipratropium bromide) Inhalation Aerosol. Appropriate use of Atrovent (Ipratropium bromide) Inhalation Aerosol includes an understanding of the way it should be administered (See ).

Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic potential at doses up to 6 mg/kg/day. This dose corresponds to approximately 360 and 180 times the maximum recommended human daily inhalation dose of ipratropium bromide in rats and mice respectively, on a mg/m basis. 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 (approximately 3000 times the maximum recommended human daily inhalation dose on a mg/m basis) was unaffected by ipratropium bromide administration. At doses above 90 mg/kg/day (approximately 5400 times the maximum recommended human daily inhalation dose on a mg/m basis), increased resorption and decreased conception rates were observed.

Adverse reaction information concerning Atrovent (Ipratropium bromide) Inhalation Aerosol is derived from 90 day controlled clinical trials (N=254), other controlled clinical trials using recommended doses of Atrovent (Ipratropium bromide) Inhalation Aerosol (N=377) and an uncontrolled study (N=1924). Additional information is derived from the post-marketing experience and the published literature.

Adverse reactions occurring in greater than one percent of patients in the 90 day controlled clinical trials appear in

Additional adverse reactions reported in less than one percent of the patients considered possibly due to Atrovent (Ipratropium bromide) Inhalation Aerosol include urinary difficulty, fatigue, insomnia and hoarseness.

The large uncontrolled, open-label study included seriously ill patients. About 7% of patients treated discontinued the program because of adverse events.

Of the 2301 patients treated in the large uncontrolled study and in clinical trials other than the 90 day studies, the most common adverse reactions reported were: dryness of the oropharynx, about 5 in 100; cough, exacerbation of symptoms and irritation from aerosol, each about 3 in 100; headache, about 2 in 100; nausea, dizziness, blurred vision/difficulty in accommodation, and drying of secretions, each about 1 in 100. Less frequently reported adverse reactions that were possibly due to Atrovent (Ipratropium bromide) Inhalation Aerosol include tachycardia, paresthesia, drowsiness, coordination difficulty, itching, hives, flushing, alopecia, constipation, tremor, and mucosal ulcers.

Cases of precipitation or worsening of narrow-angle glaucoma, acute eye pain, and hypotension, have been reported.

In a 5-year placebo-controlled trial, hospitalizations for supraventricular tachycardia and atrial fibrillation occurred with an incidence rate of 0.5% in patients receiving Atrovent (Ipratropium bromide) Inhalation Aerosol.

Acute overdosage by inhalation is unlikely since ipratropium bromide is not well absorbed systemically after aerosol or oral administration. The oral median lethal dose of ipratropium bromide ranged between 1001 and 2010 mg/kg in mice (approximately 30,000 and 60,000 times the maximum recommended human daily inhalation dose on a mg/m basis, respectively); between 1667 and 4000 mg/kg in rats (approximately 100,000 and 240,000 times the maximum recommended human daily inhalation dose, respectively, on a mg/m basis); and between 400 and 1300 mg/kg in dogs (approximately 80,000 and 260,000 times the maximum recommended human daily inhalation dose, respectively, on a mg/m basis).

The usual starting dose of Atrovent (Ipratropium bromide) Inhalation Aerosol is two inhalations (36 mcg) four times a day. Patients may take additional inhalations as required; however, the total number of inhalations should not exceed 12 in 24 hours. It is recommended to “test-spray” three times before using for the first time and in cases where the aerosol has not been used for more than 24 hours.

Atrovent (Ipratropium bromide) Inhalation Aerosol is supplied as a metered dose inhaler with a white mouthpiece which has a clear, colorless sleeve and a green protective cap. The Atrovent (Ipratropium bromide) Inhalation Aerosol canister is to be used with the Atrovent (Ipratropium bromide) Inhalation Aerosol mouthpiece only. This mouthpiece should not be used with other aerosol medications. Similarly, the canister should not be used with other mouthpieces. Each actuation meters 21 mcg of ipratropium bromide from the valve and delivers 18 mcg of ipratropium bromide from the mouthpiece. Each 14.7 gram canister provides sufficient medication for 200 inhalations (NDC 0597-0082-14).

A notice similar to the above has been placed in the information for the patient of this product under the Environmental Protection Agency's (EPA's) regulations. The patient's warning states that the patient should consult with his or her physician if there are questions about alternatives.

Keep out of children's reach. Patients should be reminded to read and follow the accompanying “Patient's Instructions for Use”, which should be dispensed with the product. For optimal results, the canister should be at room temperature before use.

Distributed by:Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877 USA

Manufactured by:3M PharmaceuticalsSt. Paul, MN 55144 USA

Licensed from:Boehringer Ingelheim International GmbH

© Copyright Boehringer IngelheimInternational GmbH2002, ALL RIGHTS RESERVED

Revised 3/27/0210001403/US/110001403/01