Combivent Respimat

5 WARNINGS AND PRECAUTIONS Paradoxical bronchospasm: Discontinue COMBIVENT RESPIMAT immediately and treat with alternative therapy if paradoxical bronchospasm occurs (5.1) Patients with cardiovascular system disorders: Use with caution because of beta-adrenergic stimulation (5.2) Ocular effects: Advise patients to avoid spraying into eyes and to contact a physician if blurred vision, halos, or other visual disturbances occur. Monitor patients with narrow-angle glaucoma. (5.3) Urinary retention: Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction (5.4) Hypersensitivity reactions including anaphylaxis: Discontinue COMBIVENT RESPIMAT and institute alternative therapy if immediate hypersensitivity reactions such as urticaria, angioedema, rash, bronchospasm, anaphylaxis, or oropharyngeal edema occur (5.6) Coexisting conditions: Use with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus (5.7) 5.1 Paradoxical Bronchospasm COMBIVENT RESPIMAT can produce paradoxical bronchospasm that can be life-threatening. If it occurs, therapy with COMBIVENT RESPIMAT should be discontinued immediately and alternative therapy instituted. 5.2 Cardiovascular Effects The albuterol sulfate contained in COMBIVENT RESPIMAT, 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, COMBIVENT RESPIMAT may need to be discontinued. There is some evidence from postmarketing data and published literature of rare occurrences of myocardial ischemia associated with albuterol. In addition, beta‑adrenergic agonists 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 RESPIMAT should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension [ see Drug Interactions (7.2) ]. 5.3 Ocular Effects Ipratropium bromide, a component of COMBIVENT RESPIMAT, is an anticholinergic and may increase intraocular pressure. This may result in precipitation or worsening of narrow-angle glaucoma. Therefore, COMBIVENT RESPIMAT should be used with caution in patients with narrow-angle glaucoma [ see Drug Interactions (7.1) ]. Patients should avoid spraying COMBIVENT RESPIMAT into the eyes. If a patient sprays COMBIVENT RESPIMAT into their eyes they may cause acute eye pain or discomfort, temporary blurring of vision, mydriasis, visual halos, or colored images in association with red eyes from conjunctival or corneal congestion. Advise patients to consult their physician immediately if any of these symptoms develop while using COMBIVENT RESPIMAT. 5.4 Urinary Retention Ipratropium bromide, a component of COMBIVENT RESPIMAT, is an anticholinergic and may cause urinary retention. Therefore, caution is advised when administering this medication to patients with prostatic hyperplasia or bladder-neck obstruction [ see Drug Interactions (7.1) ]. 5.5 Do Not Exceed Recommended Dosage 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 [ see Drug Interactions (7.2) ]. 5.6 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions including urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema may occur after administration of ipratropium bromide or albuterol sulfate. In clinical trials and postmarketing experience with ipratropium containing products, hypersensitivity reactions such as skin rash, pruritus, angioedema of tongue, lips and face, urticaria (including giant urticaria), laryngospasm, and anaphylactic reactions have been reported [ see Adverse Reactions (6.1 , 6.2) ]. If such a reaction occurs, therapy with COMBIVENT RESPIMAT should be stopped at once and alternative treatment should be considered [ see Contraindications (4) ]. 5.7 Coexisting Conditions COMBIVENT RESPIMAT contains albuterol sulfate, a beta 2 -adrenergic sympathomimetic amine and, therefore, should be used with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus, and in patients who are unusually responsive to sympathomimetic amines. 5.8 Hypokalemia Beta 2 ‑adrenergic agonists may produce significant hypokalemia in some patients (possibly through intracellular shunting) which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation [ see Drug Interactions (7.2) ].

6 ADVERSE REACTIONS Use of albuterol, a beta 2 -adrenergic agonist, may be associated with the following: Paradoxical bronchospasm [ see Warnings and Precautions (5.1) ] Cardiovascular effects [ see Warnings and Precautions (5.2) ] Hypersensitivity reactions including anaphylaxis [ see Contraindications (4) and Warnings and Precautions (5.6) ] Hypokalemia [ see Warnings and Precautions (5.8) ] Albuterol is a component of COMBIVENT RESPIMAT. Use of ipratropium bromide, an anticholinergic, may result in the following: Ocular effects [ see Warnings and Precautions (5.3) ] Urinary retention [ see Warnings and Precautions (5.4) ] Ipratropium bromide is a component of COMBIVENT RESPIMAT. Most common (≥2%) adverse reactions for COMBIVENT RESPIMAT (20/100 mcg) are upper respiratory infection, nasopharyngitis, cough, bronchitis, headache, and dyspnea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience COMBIVENT RESPIMAT 12-Week Clinical Trials The safety data described in Table 1 below are derived from one 12-week, randomized, multicenter, double-blind, double-dummy, parallel-group trial that compared COMBIVENT RESPIMAT (20/100 mcg), CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg), and ipratropium bromide delivered by the RESPIMAT inhaler (20 mcg) administered four times a day in 1,460 adult COPD patients (955 males and 505 females) 40 years of age and older. Of these patients, 486 were treated with COMBIVENT RESPIMAT. The COMBIVENT RESPIMAT group was composed of mostly Caucasian (88.5%) patients with a mean age of 63.8 years, and a mean percent predicted FEV 1 at screening of 41.5%. Patients with narrow-angle glaucoma, symptomatic prostatic hypertrophy or bladder-neck obstruction were excluded from the trial. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 1 shows all adverse reactions that occurred with a frequency of ≥2% in the COMBIVENT RESPIMAT treatment group in the 12-week COPD trial. The frequency of the corresponding adverse reactions in the CFC-propelled COMBIVENT Inhalation Aerosol and ipratropium bromide delivered by the RESPIMAT inhaler groups is included for comparison. The rates are derived from all reported adverse reactions of that type not present at baseline, whether considered drug-related or not by the clinical investigator. Table 1 Adverse Reactions in ≥2% of Patients in the COMBIVENT RESPIMAT Group in a 12-Week COPD Clinical Trial Body System (Event) 12-Week Ipratropium-Controlled Trial COMBIVENT RESPIMAT (20/100 mcg) CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) Ipratropium bromide by the RESPIMAT Inhaler (20 mcg) [n=486] [n=491] [n=483] Patients with any adverse reaction 46 52 45 Respiratory, thoracic, and mediastinal disorders Cough Dyspnea 3 2 2 2 2 3 Nervous system disorders Headache 3 2 3 Infections and infestations Bronchitis Nasopharyngitis Upper Respiratory infection 3 4 3 3 3 4 1 4 3 Adverse reactions that occurred in <2% in the COMBIVENT RESPIMAT (20/100 mcg) group observed in this 12-week trial include: Vascular disorders: hypertension; Nervous system disorders: dizziness and tremor; Musculoskeletal and connective tissue disorder: muscle spasms and myalgia; Gastrointestinal disorders: diarrhea, nausea, dry mouth, constipation, and vomiting; General disorders and administration site conditions: asthenia, influenza-like illness, and chest discomfort; Eye disorders: eye pain; Metabolism and nutritional disorders: hypokalemia; Cardiac disorders: palpitations and tachycardia; Skin and subcutaneous tissue disorders: pruritus and rash; Respiratory, thoracic, and mediastinal disorders ; pharyngolaryngeal pain and wheezing. A separate 12-week trial evaluated a higher than approved dosage of COMBIVENT RESPIMAT in 1,118 COPD patients. Patients were randomized to COMBIVENT RESPIMAT (40/200 mcg) (n=345), CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) (n=180), ipratropium delivered by the RESPIMAT (40 mcg) (n=252) or placebo (n=341). The overall incidence and nature of adverse reactions observed were similar to the adverse reactions seen with COMBIVENT RESPIMAT 20/100 mcg. COMBIVENT RESPIMAT Long-Term (48-week) Safety Trial Long-term chronic use safety data for COMBIVENT RESPIMAT were obtained from one 48-week, randomized, multicenter, open-label, parallel-group trial that compared COMBIVENT RESPIMAT (20/100 mcg), CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg), and the free combination of ipratropium bromide (34 mcg) and albuterol (180 mcg) HFA inhalation aerosols administered 4 times a day in 465 adult COPD patients (273 males and 192 females) 40 years of age and older. Of these patients, 157 were treated with COMBIVENT RESPIMAT. The COMBIVENT RESPIMAT group was composed of mostly Caucasian (93.5%) patients with a mean age of 62.9 years, and a mean percent predicted FEV 1 at screening of 47.0%. An evaluation of the safety data from the trial revealed that most adverse reactions were similar in type and rate between treatment groups. However, cough occurred more frequently in patients enrolled in the COMBIVENT RESPIMAT group (7.0%) compared to those in the CFC-propelled COMBIVENT Inhalation Aerosol (2.6%) or the free combination of ipratropium bromide and albuterol HFA inhalation aerosols (3.9%) groups. In addition to the adverse reactions reported in the controlled clinical trial with COMBIVENT RESPIMAT, adverse reaction information concerning CFC-propelled COMBIVENT Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for CFC-propelled COMBIVENT Inhalation Aerosol). Adverse reactions reported in ≥2% of patients in the CFC-propelled COMBIVENT Inhalation Aerosol treatment group include: bronchitis, upper respiratory tract infection, headache, dyspnea, cough, pain, respiratory disorder, sinusitis, pharyngitis, and nausea. Adverse reactions reported in <2% of patients in the CFC-propelled COMBIVENT Inhalation Aerosol treatment group include: edema, fatigue, hypertension, dizziness, nervousness, tremor, dysphonia, insomnia, diarrhea, dry mouth, dyspepsia, vomiting, arrhythmia, palpitation, tachycardia, arthralgia, angina, increased sputum, taste perversion, urinary tract infection, dysuria, dry throat, and bronchospasm. 6.2 Postmarketing Experience In addition to the adverse reactions reported during clinical trials, the following adverse reactions have been identified during post-approval use of CFC-propelled COMBIVENT Inhalation Aerosol. Since CFC-propelled COMBIVENT Inhalation Aerosol and COMBIVENT RESPIMAT contain the same active ingredients, one should take into account the fact that the adverse reactions seen with CFC-propelled COMBIVENT Inhalation Aerosol could also occur with COMBIVENT RESPIMAT. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Eye disorders: glaucoma, blurred vision, mydriasis, conjunctival hyperemia, halo vision, accommodation disorder, ocular irritation, and corneal edema Gastrointestinal disorders : gastrointestinal motility disorder, drying of secretions, stomatitis, and mouth edema Immune system disorders: hypersensitivity Investigations: intraocular pressure increased, blood pressure diastolic decreased, and blood pressure systolic increased Musculoskeletal and connective tissue disorders : muscular weakness Psychiatric disorders: CNS stimulation, mental disorder Respiratory, thoracic, and mediastinal disorders: throat irritation, paradoxical bronchospasm, wheezing, nasal congestion, and pharyngeal edema Skin and subcutaneous tissue disorders : angioedema, hyperhidrosis, and skin reaction Urinary disorders: urinary retention Cardiac disorders: myocardial ischemia 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 also been reported with CFC-propelled COMBIVENT Inhalation Aerosol, with positive re-challenge in some cases [ see Warnings and Precautions (5.6) ]. 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 CFC-propelled ATROVENT® (ipratropium bromide) Inhalation Aerosol. Metabolic acidosis has been reported with use of albuterol-containing products.

<table ID="t2326122" border="0" cellpadding="2" cellspacing="1" width="100%"><caption>Table 1 Adverse Reactions in &#x2265;2% of Patients in the COMBIVENT RESPIMAT Group in a 12-Week COPD Clinical Trial</caption><tbody><tr><td styleCode="Toprule Lrule" colspan="2" valign="bottom"><content styleCode="bold"><content styleCode="emphasis">Body System (Event)</content></content></td><td styleCode="Toprule Lrule Rrule" colspan="3"><content styleCode="bold"><content styleCode="emphasis">12-Week </content></content><content styleCode="bold"><content styleCode="emphasis">Ipratropium-Controlled Trial</content></content></td></tr><tr><td styleCode="Toprule Lrule" colspan="2"> </td><td styleCode="Toprule Lrule" valign="top">COMBIVENT RESPIMAT (20/100 mcg) </td><td styleCode="Toprule" valign="top">CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg)</td><td styleCode="Toprule Rrule" valign="top">Ipratropium bromide by the RESPIMAT Inhaler (20 mcg)</td></tr><tr><td styleCode="Lrule" colspan="2"> </td><td styleCode="Lrule">[n=486]</td><td>[n=491]</td><td styleCode="Rrule">[n=483]</td></tr><tr><td styleCode="Toprule Lrule" colspan="2">Patients with any adverse reaction</td><td styleCode="Toprule Lrule">46</td><td styleCode="Toprule">52</td><td styleCode="Toprule Rrule">45</td></tr><tr><td styleCode="Toprule Lrule" colspan="2">Respiratory, thoracic, and mediastinal disorders</td><td styleCode="Toprule Lrule"> </td><td styleCode="Toprule"> </td><td styleCode="Toprule Rrule"> </td></tr><tr><td styleCode="Lrule"> </td><td>Cough Dyspnea </td><td styleCode="Lrule" valign="top">3 2</td><td valign="top">2 2</td><td styleCode="Rrule" valign="top">2 3</td></tr><tr><td styleCode="Toprule Lrule" colspan="2">Nervous system disorders</td><td styleCode="Toprule Lrule"> </td><td styleCode="Toprule"> </td><td styleCode="Toprule Rrule"> </td></tr><tr><td styleCode="Lrule"> </td><td>Headache</td><td styleCode="Lrule">3 </td><td>2 </td><td styleCode="Rrule">3 </td></tr><tr><td styleCode="Lrule Toprule" colspan="2">Infections and infestations </td><td styleCode="Lrule Toprule"> </td><td styleCode="Toprule"> </td><td styleCode="Rrule Toprule"> </td></tr><tr><td styleCode="Lrule Botrule"> </td><td>Bronchitis Nasopharyngitis Upper Respiratory infection</td><td styleCode="Lrule Botrule">3 4 3</td><td styleCode="Botrule">3 3 4</td><td styleCode="Botrule Rrule">1 4 3</td></tr></tbody></table>