Label: ATROVENTHFA- ipratropium bromide aerosol, metered

ATTENTION PHARMACIST: Detach "Patient's Instructions for Use" from package insert and dispense with the product.

For Oral Inhalation Only

Prescribing Information

The active ingredient in ATROVENT HFA Inhalation Aerosol is ipratropium bromide (as the 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, (3-endo, 8-syn)-: a synthetic quaternary ammonium compound, chemically related to atropine. The structural formula for ipratropium bromide is:

C20H30BrNO3•H2O                ipratropium bromide                Mol. Wt. 430.4

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

ATROVENT HFA Inhalation Aerosol is a pressurized metered-dose aerosol unit for oral inhalation that contains a solution of ipratropium bromide. The 200 inhalation unit has a net weight of 12.9 grams. After priming, each actuation of the inhaler delivers 21 mcg of ipratropium bromide from the valve in 56 mg of solution and delivers 17 mcg of ipratropium bromide from the mouthpiece. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the device and inspiration through the delivery system. The excipients are HFA-134a (1,1,1,2-tetrafluoroethane) as propellant, sterile water, dehydrated alcohol, and anhydrous citric acid. This product does not contain chlorofluorocarbons (CFCs) as propellants.

Atrovent® HFA (ipratropium bromide HFA) Inhalation Aerosol should be primed before using for the first time by releasing 2 test sprays into the air away from the face. In cases where the inhaler has not been used for more than 3 days, prime the inhaler again by releasing 2 test sprays into the air away from the face.

Conclusions regarding the efficacy of ATROVENT HFA Inhalation Aerosol were derived from two randomized, double-blind, controlled clinical studies. These studies enrolled males and females ages 40 years and older, with a history of COPD, a smoking history of > 10 pack- years, an FEV1 < 65% and an FEV1/FVC < 70%.

One of the studies was a 12-week randomized, double-blind active and placebo controlled study in which 505 of the 507 randomized COPD patients were evaluated for the safety and efficacy of 42 mcg (n=124) and 84 mcg (n=126) ATROVENT HFA Inhalation Aerosol in comparison to 42 mcg (n=127) Atrovent® (ipratropium bromide) Inhalation Aerosol CFC and their respective placebos (HFA n=62, CFC n=66). Data for both placebo HFA and placebo CFC were combined in the evaluation.

Serial FEV1 (shown in Figure 1, below, as means adjusted for center and baseline effects on test day 1 and test day 85 (primary endpoint)) demonstrated that 1 dose (2 inhalations/21 mcg each) of ATROVENT HFA Inhalation Aerosol produced significantly greater improvement in pulmonary function than placebo. During the six hours immediately post-dose on day 1, the average hourly improvement in adjusted mean FEV1 was 0.148 liters for ATROVENT HFA Inhalation Aerosol (42 mcg) and 0.013 liters for placebo. The mean peak improvement in FEV1, relative to baseline, was 0.295 liters, compared to 0.138 liters for placebo. During the six hours immediately post-dose on day 85, the average hourly improvement in adjusted mean FEV1 was 0.141 liters for ATROVENT HFA Inhalation Aerosol (42 mcg) and 0.014 liters for placebo. The mean peak improvement in FEV1, relative to baseline, was 0.295 liters, compared to 0.140 liters for placebo.

ATROVENT HFA Inhalation Aerosol (42 mcg) was shown to be clinically comparable to ATROVENT Inhalation Aerosol CFC (42 mcg).

Figure 1 Day 1 and Day 85 (Primary Endpoint) Results

In this study, both Atrovent® HFA (ipratropium bromide HFA) Inhalation Aerosol and Atrovent® (ipratropium bromide) Inhalation Aerosol CFC formulations were equally effective in patients over 65 years of age and under 65 years of age.

The median time to improvement in pulmonary function (FEV1 increase of 15% or more) was within approximately 15 minutes, reached a peak in 1-2 hours, and persisted for 2 to 4 hours in the majority of the patients. Improvements in Forced Vital Capacity (FVC) were also demonstrated.

The other study was a 12-week, randomized, double-blind, active-controlled clinical study in 174 adults with COPD, in which ATROVENT HFA Inhalation Aerosol 42 mcg (n=118) was compared to ATROVENT Inhalation Aerosol CFC 42 mcg (n=56). Safety and efficacy of HFA and CFC formulations were shown to be comparable.

The bronchodilatory efficacy and comparability of Atrovent® HFA (ipratropium bromide HFA) Inhalation Aerosol vs. Atrovent® (ipratropium bromide) Inhalation Aerosol CFC were also studied in a one-year open-label safety and efficacy study in 456 COPD patients. The safety and efficacy of HFA and CFC formulations were shown to be comparable.

ATROVENT HFA Inhalation Aerosol is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema.

ATROVENT HFA Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to ipratropium bromide or other ATROVENT HFA Inhalation Aerosol components. ATROVENT HFA Inhalation Aerosol is also contraindicated in patients who are hypersensitive to atropine or its derivatives.

ATROVENT HFA Inhalation Aerosol is a bronchodilator for the maintenance treatment of bronchospasm associated with COPD and is not indicated for the initial treatment of acute episodes of bronchospasm where rescue therapy is required for rapid response.

Immediate hypersensitivity reactions may occur after administration of ipratropium bromide, as demonstrated by urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. If such a reaction occurs, therapy with ATROVENT HFA should be stopped at once and alternative treatment should be considered.

Inhaled medicines, including ATROVENT HFA Inhalation Aerosol, may cause paradoxical bronchospasm. If this occurs, treatment with ATROVENT HFA Inhalation Aerosol should be stopped and other treatments considered.

The adverse reaction information concerning ATROVENT HFA Inhalation Aerosol is derived from two 12-week, double-blind, parallel group studies and one open-label, parallel group study that compared ATROVENT HFA Inhalation Aerosol, ATROVENT Inhalation Aerosol CFC, and placebo (in one study only) in 1,010 COPD patients. The following table lists the incidence of adverse events that occurred at a rate of greater than or equal to 3% in any ipratropium bromide group. Overall, the incidence and nature of the adverse events reported for ATROVENT HFA Inhalation Aerosol, ATROVENT Inhalation Aerosol CFC, and placebo were comparable.

In the one open label controlled study in 456 COPD patients, the overall incidence of adverse events was also similar between Atrovent® HFA (ipratropium bromide HFA) Inhalation Aerosol and Atrovent® (ipratropium bromide) Inhalation Aerosol CFC formulations.

Overall, in the above mentioned studies, 9.3% of the patients taking 42 mcg ATROVENT HFA Inhalation Aerosol and 8.7% of the patients taking 42 mcg ATROVENT Inhalation Aerosol CFC reported at least one adverse event that was considered by the investigator to be related to the study drug. The most common drug-related adverse events were dry mouth (1.6% of ATROVENT HFA Inhalation Aerosol and 0.9% of ATROVENT Inhalation Aerosol CFC patients), and taste perversion (bitter taste) (0.9% of ATROVENT HFA Inhalation Aerosol and 0.3% of ATROVENT Inhalation Aerosol CFC patients).

As an anticholinergic drug, cases of precipitation or worsening of narrow-angle glaucoma, glaucoma, halo vision, conjunctival hyperaemia, corneal edema, mydriasis, acute eye pain, dry throat, hypotension, palpitations, urinary retention, tachycardia, constipation, bronchospasm, including paradoxical bronchospasm have been reported. Additional cases identified for ATROVENT seen in clinical trials include throat irritation, stomatitis, mouth edema, and vision blurred.

Allergic-type reactions such as skin rash, pruritus, angioedema including that of tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions have been reported (see CONTRAINDICATIONS).

Acute overdose by inhalation is unlikely since ipratropium bromide is not well absorbed systemically after inhalation or oral administration. Oral median lethal doses of ipratropium bromide were greater than 1001 mg/kg in mice (approximately 20,000 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis); 1,663 mg/kg in rats (approximately 66,000 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis); and 400 mg/kg in dogs (approximately 53,000 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis).

Patients should be instructed on the proper use of their inhaler (see Patient's Instructions for Use).

Patients should be advised that although Atrovent® HFA (ipratropium bromide HFA) Inhalation Aerosol may have a slightly different taste and inhalation sensation than that of an inhaler containing Atrovent® (ipratropium bromide) Inhalation Aerosol CFC, they are comparable in terms of the safety and efficacy.

ATROVENT HFA Inhalation Aerosol is a solution aerosol that does not require shaking. However, as with any other metered dose inhaler, some coordination is required between actuating the canister and inhaling the medication.

Patients should "prime" or actuate ATROVENT HFA Inhalation Aerosol before using for the first time by releasing 2 test sprays into the air away from the face. In cases where the inhaler has not been used for more than 3 days, prime the inhaler again by releasing 2 test sprays into the air away from the face. Patients should avoid spraying ATROVENT HFA Inhalation Aerosol into their eyes.

The usual starting dose of ATROVENT HFA Inhalation Aerosol is two inhalations four times a day. Patients may take additional inhalations as required; however, the total number of inhalations should not exceed 12 in 24 hours. Each actuation of ATROVENT HFA Inhalation Aerosol delivers 17 mcg of ipratropium bromide from the mouthpiece.

ATROVENT HFA Inhalation Aerosol is supplied in a 12.9 g pressurized stainless steel canister as a metered-dose inhaler with a white mouthpiece that has a clear, colorless sleeve and a green protective cap (NDC 54868-5511-0).

The ATROVENT HFA Inhalation Aerosol canister is to be used only with the accompanying ATROVENT HFA Inhalation Aerosol mouthpiece. This mouthpiece should not be used with other aerosol medications. Similarly, the canister should not be used with other mouthpieces. Each actuation of ATROVENT HFA Inhalation Aerosol delivers 21 mcg of ipratropium bromide from the valve and 17 mcg from the mouthpiece. Each 12.9 gram canister provides sufficient medication for 200 actuations. The canister should be discarded after the labeled number of actuations has been used. The amount of medication in each actuation cannot be assured after this point, even though the canister is not completely empty.

Atrovent® HFA
(ipratropium bromide HFA)
Inhalation Aerosol

Read complete instructions carefully before using.

Important Points to Remember About Using ATROVENT HFA Inhalation Aerosol

   Although ATROVENT HFA Inhalation Aerosol may taste and feel different
   when breathed in compared to your Atrovent® (ipratropium
   bromide) Inhalation Aerosol CFC inhaler, they contain the same
   medicine.

   You do not have to shake the ATROVENT HFA Inhalation Aerosol canister
   before using it.

   ATROVENT HFA Inhalation Aerosol should be "primed" two times before
   taking the first dose from a new inhaler or when the inhaler has not been used for
   more than three days. To prime, push the canister against the mouthpiece (see
  Figure 1), allowing the medicine to spray into the air. Avoid spraying the
   medicine into your eyes while priming ATROVENT HFA Inhalation
   Aerosol.

Ask your doctor how to use other inhaled medicines with ATROVENT HFA Inhalation Aerosol.

Use ATROVENT HFA Inhalation Aerosol exactly as prescribed by your doctor. Do not change your dose or how often you use ATROVENT HFA Inhalation Aerosol without talking with your doctor. Talk to your doctor if you have questions about your medical condition or your treatment.

Instructions

1. Insert the metal canister into the clear end of the mouthpiece (see Figure 1). Make sure the canister is fully and firmly inserted into the mouthpiece. The ATROVENT HFA Inhalation Aerosol canister is for use only with the ATROVENT HFA Inhalation Aerosol mouthpiece. Do not use the ATROVENT HFA Inhalation Aerosol canister with other mouthpieces. This mouthpiece should not be used with other inhaled medicines.
   

   Figure 1

2. Remove the green protective dust cap. If the cap is not on the mouthpiece, make sure there is nothing in the mouthpiece before use. For best results, the canister should be at room temperature before use.
   
3. Breathe out (exhale) deeply through your mouth. Hold the canister upright as shown in Figure 2, between your thumb and first 2 fingers. Put the mouthpiece in your mouth and close your lips. Keep your eyes closed so that no medicine will be sprayed into your eyes. Atrovent® HFA (ipratropium bromide HFA) Inhalation Aerosol can cause blurry vision, narrow-angle glaucoma or worsening of this condition or eye pain if the medicine is sprayed into your eyes.
   

   Figure 2

4. Breathe in (inhale) slowly through your mouth and at the same time firmly press once on the canister against the mouthpiece as shown in Figure 3. Keep breathing in deeply.
   

   Figure 3

5. Hold your breath for ten seconds and then remove the mouthpiece from your mouth and breathe out slowly, as in Figure 4. Wait at least 15 seconds and repeat steps 3 to 5 again.
   

   Figure 4

6. Replace the green protective dust cap after use.
   
7. Keep the mouthpiece clean. It is very important to keep the mouthpiece clean. At least once a week, wash the mouthpiece, shake it to remove excess water and let it air dry all the way (see the instructions below).
   
   

   Mouthpiece Cleaning Instructions:

   Step A. Remove and set aside the canister and dust cap from the mouthpiece (see Figure 1).
   
   

   Step B. Wash the mouthpiece through the top and bottom with warm running water for at least 30 seconds (see Figure 5). Do not use anything other than water to wash the mouthpiece.
   
   

   

   Figure 5

   Step C. Dry the mouthpiece by shaking off the excess water and allow it to air-dry all the way.
   
   

   Step D. When the mouthpiece is dry, replace the canister. Make sure the canister is fully and firmly inserted into the mouthpiece.
   
   

   Step E. Replace the green protective dust cap.
   
   

   If the mouthpiece becomes blocked, and little or no medicine comes out of the mouthpiece, wash the mouthpiece as described in Steps A to E under the “Mouthpiece Cleaning Instructions”.

   
   
8. Keep track of the number of sprays used. Discard the canister after 200 sprays. Even though the canister is not empty, you cannot be sure of the amount of medicine in each spray after 200 sprays.

This product does not contain any chlorofluorocarbon (CFC) propellants.

The contents of Atrovent® HFA (ipratropium bromide HFA) Inhalation Aerosol are under pressure. Do not puncture the canister. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw the container into a fire or incinerator.

Keep ATROVENT HFA Inhalation Aerosol and all medicines out of the reach of children.

Avoid spraying into eyes.

Address medical inquiries to: http://us.boehringer-ingelheim.com, (800) 542-6257 or (800) 459-9906 TTY.

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). For best results, store the canister at room temperature before use.

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

Licensed from:
Boehringer Ingelheim International GmbH

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

Licensed from:
Boehringer Ingelheim International GmbH

Copyright 2010 Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED

Rev: July 2010

IT1902GG1710
10003001/06

Atrovent® HFA
Inhalation Aerosol
12.9 grams (200 metered actuations)