Combivent Respimat

1 INDICATIONS AND USAGE COMBIVENT RESPIMAT is a combination of ipratropium bromide (an anticholinergic agent) and albuterol sulfate (a beta 2 -adrenergic agonist) 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 RESPIMAT Inhalation Spray is a combination of ipratropium bromide (an anticholinergic agent) and albuterol sulfate (a beta 2 ‑adrenergic agonist) indicated for: 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 (1)

2 DOSAGE AND ADMINISTRATION The recommended dosage of COMBIVENT RESPIMAT is one inhalation four times a day. Patients may take additional inhalations as required; however, the total number of inhalations should not exceed six in 24 hours. Prior to first use, the COMBIVENT RESPIMAT cartridge is inserted into the COMBIVENT RESPIMAT inhaler and the unit is primed. When using the unit for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use [ see Patient Counseling Information ( 17 ) ]. Safety and efficacy of additional doses of COMBIVENT RESPIMAT beyond six inhalations/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 RESPIMAT have not been studied. For oral inhalation only One inhalation four times a day, not to exceed six inhalations in 24 hours (2)

4 CONTRAINDICATIONS COMBIVENT RESPIMAT is contraindicated in the following conditions [ see Warnings and Precautions (5.6) ]: Hypersensitivity to any of the ingredients in COMBIVENT RESPIMAT Hypersensitivity to atropine or any of its derivatives Hypersensitivity to any of the ingredients in COMBIVENT RESPIMAT (4) Hypersensitivity to atropine or any of its derivatives (4)

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) ].

7 DRUG INTERACTIONS COMBIVENT RESPIMAT has been used concomitantly with other drugs, including beta-adrenergic bronchodilators, methylxanthines, and oral and inhaled steroids, commonly used in the treatment of chronic obstructive pulmonary disease. There are no formal studies fully evaluating the interaction effects of COMBIVENT RESPIMAT and these drugs with respect to safety and effectiveness. Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of COMBIVENT RESPIMAT with other anticholinergic-containing drugs (7.1) Beta-adrenergic agonists: May increase the risk of adverse cardiovascular effects. Avoid coadministration of COMBIVENT RESPIMAT and other sympathomimetic agents (7.2) Beta-blockers: Inhibit the effect of albuterol. Consider alternative therapy in patients with hyperreactive airways (7.3) Diuretics: Electrocardiographic changes and/or hypokalemia associated with diuretics may worsen with concomitant use of beta-agonists. Consider monitoring potassium levels. (7.4) Monoamine oxidase inhibitors (MAOs) or tricyclic antidepressants: May potentiate effect of albuterol on the vascular system. Consider alternative therapy in patients taking MAOs or tricyclic antidepressants. (7.5) 7.1 Anticholinergic Agents There is the potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of COMBIVENT RESPIMAT with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [ see Warnings and Precautions (5.3 , 5.4) ]. 7.2 Beta‑adrenergic Agonists Caution is advised in the coadministration of COMBIVENT RESPIMAT and other sympathomimetic agents due to the increased risk of adverse cardiovascular effects [ see Warnings and Precautions (5.2 , 5.5) ]. 7.3 Beta-receptor Blocking Agents Beta-receptor blocking agents and albuterol inhibit the effect of each other. Beta-receptor blocking agents should be used with caution in patients with hyperreactive airways. 7.4 Diuretics The ECG changes and/or hypokalemia which may result from the administration of non‑potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta 2 -agonists, especially when the recommended dosage of the beta 2 -agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonist‑containing drugs, such as COMBIVENT RESPIMAT, with non‑potassium sparing diuretics. Consider monitoring potassium levels. 7.5 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants COMBIVENT RESPIMAT should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or within 2 weeks of discontinuation of such agents because the action of albuterol on the cardiovascular system may be potentiated. Consider alternative therapy in patients taking MAOs or tricyclic antidepressants [ see Warnings and Precautions (5.2) ].

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.

8.1 Pregnancy Risk Summary There are no randomized clinical studies of COMBIVENT RESPIMAT, or its individual components, ipratropium bromide and albuterol sulfate, in pregnant women. Ipratropium is negligibly absorbed systemically following oral inhalation; therefore, maternal use is not expected to result in fetal exposure to the drug [see Clinical Pharmacology (12.3) ] . Published literature, including cohort studies, case control studies and case series, over several decades have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes with ipratropium bromide. Available data from published epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled albuterol use do not consistently demonstrate a risk of major birth defects or, miscarriage. There are clinical considerations with the use of COMBIVENT RESPIMAT in pregnant women [see Clinical Considerations ] . Animal reproduction studies have not been conducted with COMBIVENT RESPIMAT, however, animal studies are available with its individual components, ipratropium bromide and albuterol sulfate. Based on oral reproduction studies, no evidence of structural alterations was observed when ipratropium bromide was administered to pregnant mice, rats, and rabbits during organogenesis at doses approximately 340, 68,000 and 17,000 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults on a mg/m 2 basis. When albuterol was administered to pregnant mice during organogenesis there was evidence of cleft palate at doses approximately equivalent to the maximum recommended human daily inhalation dose (MRHDID) [see Data ] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Consideration Labor or Delivery Because of the potential for beta-agonist interference with uterine contractility, use of COMBIVENT RESPIMAT for the treatment of COPD during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta 2 -agonists, including albuterol. Data Animal Data Ipratropium bromide In animal reproduction studies, oral and inhalation administration of ipratropium bromide to pregnant mice, rats and rabbits during the period of organogenesis did not show evidence of fetal structural alterations. The ipratropium dose in oral studies in mice, rats, and rabbits was up to approximately 340, 68,000 and 17,000 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mg/m 2 basis at maternal doses in each species of 10, 1,000 and 125 mg/kg/day, respectively). The ipratropium dose in inhalation studies in rats and rabbits was up to approximately 100 and 240 times, respectively, the MRHDID in adults (on a mg/m 2 basis at maternal doses of 1.5 and 1.8 mg/kg/day, respectively). Embryotoxicity was observed as increased resorption in rats at oral doses approximately 6,100 times MRHDID in adults (on a mg/m 2 basis at maternal doses of 90 mg/kg/day and above). This effect is not considered relevant to human use due to the large doses at which it was observed and the difference in route of administration. Albuterol In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at a dose approximately equivalent to the MRHDID in adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg/day) and in 10 of 108 (9.3%) fetuses at approximately 14 times the MRHDID in adults (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg/day). Similar effects were not observed at approximately less than MRHDID in adults (on a mg/m 2 basis at a maternal dose of 0.025 mg/kg/day). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated with 2.5 mg/kg/day isoproterenol (positive control). In a rabbit reproductive study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 (37%) fetuses at approximately 1,100 times the MRHDID in adults (on a mg/m 2 basis at a maternal dose of 50 mg/kg/day). In a rat reproduction study, an albuterol sulfate/HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 80 times the MRHDID (on a mg/m 2 basis at a maternal dose of 10.5 mg/kg). A study in which pregnant rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.