Combivent^®
(ipratropium bromide and albuterol sulfate)
Inhalation Aerosol

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

Bronchodilator Aerosol
For Oral Inhalation Only

Rx only

Prescribing Information

COMBIVENT Inhalation Aerosol is a combination of ipratropium bromide (as the monohydrate) and albuterol sulfate.

Ipratropium bromide 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. 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.

The structural formula is:

C₂₀H₃₀BrNO₃•H₂O   ipratropium bromide   Mol. Wt. 430.4

Albuterol sulfate, chemically known as (1,3-benzenedimethanol, α'-[[(1,1dimethylethyl) amino] methyl]-4-hydroxy, sulfate (2:1)(salt), (±)- is a relatively selective beta₂-adrenergic bronchodilator. Albuterol is the official generic name in the United States. The World Health Organization recommended name for the drug is salbutamol. Albuterol sulfate is a white to off-white crystalline powder, freely soluble in water and slightly soluble in alcohol, chloroform, and ether. The structural formula is:

(C₁₃H₂₁NO₃)₂•H₂SO₄   albuterol sulfate   Mol. Wt. 576.7

Combivent^® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol contains a microcrystalline suspension of ipratropium bromide and albuterol sulfate in a pressurized metered-dose aerosol unit for oral inhalation administration. The 200 inhalation unit has a net weight of 14.7 grams. Each actuation meters 21 mcg of ipratropium bromide and 120 mcg of albuterol sulfate from the valve and delivers 18 mcg of ipratropium bromide and 103 mcg of albuterol sulfate (equivalent to 90 mcg albuterol base) from the mouthpiece. The excipients are dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane as propellants and soya lecithin.

COMBIVENT Inhalation Aerosol is a combination of the anticholinergic bronchodilator, ipratropium bromide, and the beta₂-adrenergic bronchodilator, albuterol sulfate.

The pharmacokinetics of Combivent^® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol or ipratropium bromide have not been studied in patients with hepatic or renal insufficiency or in the elderly (see PRECAUTIONS).

No specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions.

In two 12-week randomized, double-blind, active-controlled clinical trials, 1067 patients with chronic obstructive pulmonary disease (COPD) were evaluated for the bronchodilator efficacy of COMBIVENT Inhalation Aerosol (358 patients) in comparison to its components, ipratropium bromide (362 patients) and albuterol sulfate (347 patients).

Serial FEV₁ measurements (shown below as a percent change from test-day baseline) demonstrated that COMBIVENT Inhalation Aerosol produced significantly greater improvement in pulmonary function than either ipratropium bromide or albuterol sulfate when given separately. The median time to onset of a 15% increase in FEV₁ was 15 minutes and the median time to peak FEV₁ was 1 hour for COMBIVENT Inhalation Aerosol and its components. The median duration of effect as measured by FEV₁ was 4-5 hours for COMBIVENT Inhalation Aerosol compared to 4 hours for ipratropium bromide and 3 hours for albuterol sulfate.

Percent Change in Adjusted Mean^a FEV₁ from Test-Day Baseline – Endpoint Analysis of the Evaluable Data Set

These studies demonstrated that each component of Combivent^® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol contributed to the improvement in pulmonary function produced by the combination, especially during the first 4-5 hours after dosing, and that COMBIVENT Inhalation Aerosol was significantly more effective than ipratropium bromide or albuterol sulfate administered alone.

In the two controlled twelve-week studies, COMBIVENT Inhalation Aerosol did not produce any change in the secondary efficacy parameters including symptom scores, physician global assessments and morning PEFR, all of which were monitored throughout the study period.

COMBIVENT Inhalation Aerosol is indicated for use in patients with chronic obstructive pulmonary disease (COPD) on a regular aerosol bronchodilator who continue to have evidence of bronchospasm and who require a second bronchodilator.

COMBIVENT Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to soya lecithin or related food products such as soybean and peanut. COMBIVENT Inhalation Aerosol is also contraindicated in patients hypersensitive to any other components of the drug product or to atropine or its derivatives.

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, increased intraocular pressure, acute eye pain or discomfort, temporary blurring of vision, visual halos or colored images in association with red eyes from conjunctival and corneal congestion. Patient’s should also be advised that should any combination of these symptoms develop, they should consult their physician immediately.

The action of COMBIVENT Inhalation Aerosol should last 4-5 hours or longer. COMBIVENT Inhalation Aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of COMBIVENT Inhalation Aerosol without consulting your physician. If you find that treatment with COMBIVENT Inhalation Aerosol becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, medical attention should be sought immediately. While you are taking COMBIVENT Inhalation Aerosol, other inhaled drugs should be taken only as directed by your physician. If you are pregnant or nursing, contact your physician about use of COMBIVENT Inhalation Aerosol. Appropriate use of Combivent^® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol includes an understanding of the way it should be administered (see Patient's Instructions for Use).

COMBIVENT Inhalation Aerosol has been used concomitantly with other drugs, including sympathomimetic bronchodilators, methylxanthines, and oral and inhaled steroids, commonly used in the treatment of chronic obstructive pulmonary disease. With the exception of albuterol, there are no formal studies fully evaluating the interaction effects of COMBIVENT Inhalation Aerosol and these drugs with respect to effectiveness.

Because of the potential for beta-agonist interference with uterine contractility, use of Combivent^® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol for the treatment of COPD during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

It is not known whether the components of COMBIVENT Inhalation Aerosol are excreted in human milk.

Safety and effectiveness in the pediatric population have not been established.

Adverse reaction information concerning Combivent^® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for Combivent Inhalation Aerosol) as seen in Table 1.

Additional adverse reactions, reported in less than two percent of the patients in the COMBIVENT Inhalation Aerosol treatment group include edema, fatigue, hypertension, dizziness, nervousness, paresthesia, tremor, dysphonia, insomnia, diarrhea, dry mouth, dyspepsia, vomiting, arrhythmia, palpitation, tachycardia, arthralgia, angina, increased sputum, taste perversion, and urinary tract infection/dysuria.

Allergic-type reactions such as skin rash, angioedema of tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reaction have been reported with COMBIVENT Inhalation Aerosol, with positive rechallenge in some cases. Many of these patients had a history of allergies to other drugs and/or foods including soybean (see CONTRAINDICATIONS).

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

Additional side effects identified from the published literature and/or post-marketing surveillance on the use of ipratropium bromide-containing products (singly or in combination with albuterol), include: urinary retention, mydriasis, bronchospasm (including paradoxical bronchospasm), cases of precipitation or worsening of narrow-angle glaucoma, acute eye pain, blurred vision, ocular irritation, nasal congestion, drying of secretions, mucosal ulcers, irritation from aerosol, wheezing, exacerbation of COPD symptoms, hoarseness, palpitations, heartburn, drowsiness, CNS stimulation, coordination difficulty, weakness, flushing, alopecia, itching, hypotension, edema, gastrointestinal distress (diarrhea, nausea, vomiting), and constipation.

The effects of overdosage are expected to be related primarily to albuterol sulfate. Acute overdosage with ipratropium bromide by inhalation is unlikely since ipratropium bromide is not well absorbed systemically after aerosol or oral administration. Oral median lethal doses of ipratropium bromide were greater than 1001 mg/kg in mice (approximately 19,000 times the maximum recommended daily inhalation dose in adults on a mg/m² basis); 1663 mg/kg in rats (approximately 62,000 times the maximum recommended daily inhalation dose in adults on a mg/m² basis); and 400 mg/kg in dogs (approximately 50,000 times the maximum recommended daily inhalation dose in adults, on a mg/m² basis).

Whereas the oral median lethal dose of albuterol sulfate in mice and rats was greater than 2,000 mg/kg (approximately 6,600 and 13,000 times the maximum recommended daily inhalation dose, respectively, on a mg/m² basis), the inhalational median lethal dose could not be determined. Manifestations of overdosage with albuterol may include anginal pain, hypertension, hypokalemia, tachycardia with rates up to 200 beats per minute and exaggeration of the pharmacologic effects uled in ADVERSE REACTIONS. As with all sympathomimetic aerosol medications, cardiac arrest and even death may be associated with abuse. Dialysis is not appropriate treatment for overdosage of albuterol as an inhalation aerosol; the judicious use of a cardiovascular beta-receptor blocker, such as metoprolol tartrate may be indicated.

The dose of Combivent^® (ipratropium bromide and albuterol sulfate) 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. Safety and efficacy of additional doses of COMBIVENT Inhalation Aerosol beyond 12 puffs/24 hours have not been studied. Also, safety and efficacy of extra doses of ipratropium or albuterol in addition to the recommended doses of Combivent^® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol have not been studied. 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. Avoid spraying into eyes.

COMBIVENT Inhalation Aerosol is supplied as a metered-dose inhaler with a white mouthpiece that has a clear, colorless sleeve and an orange protective cap. The COMBIVENT Inhalation Aerosol canister is to be used only with the COMBIVENT Inhalation Aerosol mouthpiece and not with other mouthpieces. This mouthpiece should not be used with other aerosol medications. Each actuation meters 21 mcg of ipratropium bromide and 120 mcg of albuterol sulfate from the valve and delivers 18 mcg of ipratropium bromide and 103 mcg of albuterol sulfate (equivalent to 90 mcg albuterol base) from the mouthpiece.

Each 14.7 gram canister provides sufficient medication for 200 actuations (NDC 0597-0013-14).

Warning: The canister should be discarded after the labeled number of actuations has been used. The correct amount of medication in each actuation cannot be assured after this point, even though the canister is not completely empty.

Combivent^®
(ipratropium bromide and albuterol sulfate)
Inhalation Aerosol

Read complete instructions carefully before using

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

Tell your doctor about all of the medicines you take. COMBIVENT Inhalation Aerosol and some other medicines may interact with each other. Do not use other inhaled medicines with COMBIVENT Inhalation Aerosol unless prescribed by your doctor.

• Insert metal canister into clear end of mouthpiece (see Figure 1). Make sure the canister is fully and firmly inserted into the mouthpiece. The COMBIVENT Inhalation Aerosol canister is to be used only with the COMBIVENT Inhalation Aerosol mouthpiece. This mouthpiece should not be used with other inhaled medicines.Figure 1
• Remove orange 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.
• Shake and Test Spray. Perform this step before using for the first time, and whenever the aerosol has not been used for more than 24 hours; otherwise, proceed directly to Step 4.

  After vigorously shaking the canister for at least 10 seconds (see step 4 for instructions on shaking), “test-spray” into the air 3 times. Avoid spraying in eyes.

• Shake the canister vigorously for at least 10 seconds. Hold canister as illustrated in Figure 2.

  IMPORTANT: Vigorous shaking for at least 10 seconds before each spray is very important for proper product performance.

  For best results, perform Steps 5-6 within 30 seconds of shaking the canister.

  Figure 2
• Breathe out (exhale) deeply through your mouth. Holding the canister upright as shown in Figure 3, between your thumb and finger(s), put the mouthpiece in your mouth and close your lips. Keep your eyes closed so that no medicine will be sprayed into your eyes. Combivent^® (ipratropium bromide and albuterol sulfate) 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 3
• Breathe in (inhale) slowly through your mouth and at the same time spray the product into your mouth.

  To spray the product, firmly press once on the canister against the mouthpiece as shown in Figure 4. Keep breathing in deeply.

  Figure 4
• Hold your breath for 10 seconds, remove the mouthpiece from your mouth andbreathe outslowly, as in Figure 5.Figure 5
• Wait approximately 2 minutes, shake the inhaler vigorously for at least 10 seconds again (as described in Step 4) and repeat Steps 5 – 7.
• Replace the orange protective dust cap after use.
• Keep the mouthpiece clean. Wash with hot water. If soap is used, rinse thoroughly with plain water. Dry thoroughly before use. When dry, replace cap on the mouthpiece when not using the drug product.
• Keep track of the number of sprays used and discard 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.
• If your prescribed dose does not provide relief or your breathing symptoms become worse, get medical help right away.

Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs):

•   This product contains trichloromonofluoromethane (CFC-11), dichlorodifluoromethane (CFC-12) and dichlorotetrafluoroethane (CFC-114), substances which harm the environment by destroying ozone in the upper atmosphere.

The spans of Combivent® (ipratropium bromide and albuterol sulfate) 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 COMBIVENT Inhalation Aerosol out of reach of children.

Avoid spraying in 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). [see USP Controlled Room Temperature]. For best results, store the canister at room temperature before use. Avoid excessive humidity.

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

Ipratropium bromide licensed from:
Boehringer Ingelheim International GmbH

©Copyright Boehringer Ingelheim Pharmaceuticals, Inc.
2007, ALL RIGHTS RESERVED

Rev: July 2007
IT9011CG1707
10004145/02 10004145/US/2