FDA label 7645902e-cc17-4864-a3b7-6993b06367f6

WARNINGS 1. Paradoxical Bronchospasm : COMBIVENT Inhalation Aerosol can produce paradoxical bronchospasm that can be life-threatening. If it occurs, the preparation should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister. 2. Cardiovascular Effect : The albuterol sulfate contained in COMBIVENT Inhalation Aerosol, like other beta adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure and/or symptoms. If these symptoms occur, discontinuation of the drug may be indicated. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischemia associated with albuterol. In addition, beta adrenergic agents have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. Therefore, COMBIVENT Inhalation Aerosol should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias and hypertension. 3. Do Not Exceed Recommended Dose : Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs, in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected. 4. Immediate Hypersensitivity Reactions : Immediate hypersensitivity reactions may occur after administration of ipratropium bromide or albuterol sulfate, as demonstrated by urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. If such a reaction occurs, therapy with COMBIVENT Inhalation Aerosol should be stopped at once and alternative treatment should be considered. 5. Storage Conditions : The contents of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol are under pressure. Do not puncture. 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 out of reach of children.

ADVERSE REACTIONS 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. Table 1 All Adverse Events (in percentages), from Two Large Double-blind, Parallel, 12-Week Studies of Patients with COPD* COMBIVENT Ipratropium Bromide 36 mcg/Albuterol Sulfate 206 mcg QID Ipratropium Bromide 36 mcg QID Albuterol Sulfate 206 mcg QID N = 358 N = 362 N = 347 *All adverse events, regardless of drug relationship, reported by two percent or more patients in one or more treatment group in the 12-week controlled clinical trials. Body as a Whole-General Disorders Headache 5.6 3.9 6.6 Pain 2.5 1.9 1.2 Influenza 1.4 2.2 2.9 Chest Pain 0.3 1.4 2.9 Gastrointestinal System Disorders Nausea 2.0 2.5 2.6 Respiratory System Disorders (Lower) Bronchitis 12.3 12.4 17.9 Dyspnea 4.5 3.9 4.0 Coughing 4.2 2.8 2.6 Respiratory Disorders 2.5 1.7 2.3 Pneumonia 1.4 2.5 0.6 Bronchospasm 0.3 3.9 1.7 Respiratory System Disorders (Upper) Upper Respiratory Tract Infection 10.9 12.7 13.0 Pharyngitis 2.2 3.3 2.3 Sinusitis 2.3 1.9 0.9 Rhinitis 1.1 2.5 2.3 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 reactions including rash, pruritus, and urticaria (including giant urticaria), angioedema including that of tongue, lips and face, laryngospasm and anaphylactic reaction have been reported with Combivent® (ipratropium bromide and albuterol sulfate) 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 ). Post-Marketing Experience 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: hypersensitivity, pharyngeal edema, mouth edema, urinary retention, mydriasis, bronchospasm (including paradoxical bronchospasm), cases of precipitation or worsening of narrow-angle glaucoma, glaucoma, intraocular pressure increased, acute eye pain, halo vision, blurred vision, accommodation disorder, ocular irritation, corneal edema, conjuctival hyperaemia, nasal congestion, drying of secretions, mucosal ulcers, stomatitis, irritation from aerosol, throat irritation, dry throat, wheezing, exacerbation of COPD symptoms, hoarseness, palpitations, heartburn, drowsiness, CNS stimulation, coordination difficulty, flushing, alopecia, hypotension, edema, gastrointestinal distress (diarrhea, nausea, vomiting), gastrointestinal motility disorder, constipation, hypokalemia, mental disorder, hyperhidrosis, muscle spasms, muscular weakness, myalgia, asthenia, myocardial ischemia, diastolic blood pressure decreased, and systolic blood pressure increased.

<table border="0" cellpadding="1" cellspacing="1" width="100%" ID="i27c92863-06a3-46fb-86fb-43ab50d83a8f"> <caption>Table 1 All Adverse Events (in percentages), from Two Large Double-blind, Parallel, 12-Week Studies of Patients with COPD*</caption> <colgroup> <col align="left" width="40%"/> <col align="center" width="15%"/> <col align="center" width="15%"/> <col align="center" width="15%"/> </colgroup> <thead> <tr valign="top"> <th/> <th>COMBIVENT Ipratropium Bromide 36 mcg/Albuterol Sulfate 206 mcg QID</th> <th>Ipratropium Bromide 36 mcg QID</th> <th>Albuterol Sulfate 206 mcg QID</th> </tr> <tr> <th/> <th>N = 358</th> <th>N = 362</th> <th>N = 347</th> </tr> </thead> <tfoot> <tr> <td colspan="4">*All adverse events, regardless of drug relationship, reported by two percent or more patients in one or more treatment group in the 12-week controlled clinical trials.</td> </tr> </tfoot> <tbody> <tr> <td colspan="2"> <content styleCode="bold"> <content styleCode="emphasis">Body as a Whole-General Disorders</content> </content> </td> <td> </td> <td> </td> </tr> <tr> <td styleCode="toprule"> Headache</td> <td styleCode="toprule">5.6</td> <td styleCode="toprule">3.9</td> <td styleCode="toprule">6.6</td> </tr> <tr> <td styleCode="toprule"> Pain</td> <td styleCode="toprule">2.5</td> <td styleCode="toprule">1.9</td> <td styleCode="toprule">1.2</td> </tr> <tr> <td styleCode="toprule"> Influenza</td> <td styleCode="toprule">1.4</td> <td styleCode="toprule">2.2</td> <td styleCode="toprule">2.9</td> </tr> <tr> <td styleCode="toprule"> Chest Pain</td> <td styleCode="toprule">0.3</td> <td styleCode="toprule">1.4</td> <td styleCode="toprule">2.9</td> </tr> <tr> <td styleCode="toprule" colspan="2"> <content styleCode="bold"> <content styleCode="emphasis">Gastrointestinal System Disorders</content> </content> </td> <td styleCode="toprule"> </td> <td styleCode="toprule"> </td> </tr> <tr> <td styleCode="toprule"> Nausea</td> <td styleCode="toprule">2.0</td> <td styleCode="toprule">2.5</td> <td styleCode="toprule">2.6</td> </tr> <tr> <td styleCode="toprule" colspan="2"> <content styleCode="bold"> <content styleCode="emphasis">Respiratory System Disorders (Lower)</content> </content> </td> <td styleCode="toprule"> </td> <td styleCode="toprule"> </td> </tr> <tr> <td styleCode="toprule"> Bronchitis</td> <td styleCode="toprule">12.3</td> <td styleCode="toprule">12.4</td> <td styleCode="toprule">17.9</td> </tr> <tr> <td styleCode="toprule"> Dyspnea</td> <td styleCode="toprule">4.5</td> <td styleCode="toprule">3.9</td> <td styleCode="toprule">4.0</td> </tr> <tr> <td styleCode="toprule"> Coughing</td> <td styleCode="toprule">4.2</td> <td styleCode="toprule">2.8</td> <td styleCode="toprule">2.6</td> </tr> <tr> <td styleCode="toprule"> Respiratory Disorders</td> <td styleCode="toprule">2.5</td> <td styleCode="toprule">1.7</td> <td styleCode="toprule">2.3</td> </tr> <tr> <td styleCode="toprule"> Pneumonia</td> <td styleCode="toprule">1.4</td> <td styleCode="toprule">2.5</td> <td styleCode="toprule">0.6</td> </tr> <tr> <td styleCode="toprule"> Bronchospasm</td> <td styleCode="toprule">0.3</td> <td styleCode="toprule">3.9</td> <td styleCode="toprule">1.7</td> </tr> <tr> <td styleCode="toprule" colspan="2"> <content styleCode="bold"> <content styleCode="emphasis">Respiratory System Disorders (Upper)</content> </content> </td> <td styleCode="toprule"> </td> <td styleCode="toprule"> </td> </tr> <tr> <td styleCode="toprule"> Upper Respiratory Tract Infection</td> <td styleCode="toprule">10.9</td> <td styleCode="toprule">12.7</td> <td styleCode="toprule">13.0</td> </tr> <tr> <td styleCode="toprule"> Pharyngitis</td> <td styleCode="toprule">2.2</td> <td styleCode="toprule">3.3</td> <td styleCode="toprule">2.3</td> </tr> <tr> <td styleCode="toprule"> Sinusitis</td> <td styleCode="toprule">2.3</td> <td styleCode="toprule">1.9</td> <td styleCode="toprule">0.9</td> </tr> <tr> <td styleCode="toprule"> Rhinitis</td> <td styleCode="toprule">1.1</td> <td styleCode="toprule">2.5</td> <td styleCode="toprule">2.3</td> </tr> </tbody> </table>