Ipratropium Bromide Inhalation

1 INDICATIONS AND USAGE Ipratropium bromide HFA inhalation aerosol is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Ipratropium bromide HFA inhalation aerosol is an anticholinergic indicated for the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema

2 DOSAGE AND ADMINISTRATION The usual starting dose of ipratropium bromide 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. Ipratropium bromide 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 ipratropium bromide 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 ipratropium bromide HFA inhalation aerosol into their eyes. Each inhaler provides sufficient medication for 200 actuations. The inhaler 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. Patients should be instructed on the proper use of their inhaler [see Patient Counseling Information ( 17 )]. For oral inhalation only • Two inhalations four times a day, not to exceed 12 inhalations in 24 hours

4 CONTRAINDICATIONS Ipratropium bromide HFA inhalation aerosol is contraindicated in the following conditions [see Warnings and Precautions ( 5.2 )]. • Hypersensitivity to ipratropium bromide or other ipratropium bromide HFA inhalation aerosol components • Hypersensitivity to atropine or any of its derivatives • Hypersensitivity to ipratropium bromide or other ipratropium bromide HFA inhalation aerosol components ( 4 ) • Hypersensitivity to atropine or any of its derivatives

5 WARNINGS AND PRECAUTIONS • Not indicated for the initial treatment of acute episodes of bronchospasm where rescue therapy is required for rapid response ( 5.1 ) • Hypersensitivity reactions including anaphylaxis: Discontinue ipratropium bromide HFA inhalation aerosol at once and consider alternative treatments ( 5.2 ) • Paradoxical bronchospasm: Discontinue ipratropium bromide HFA inhalation aerosol and consider other treatments if paradoxical bronchospasm occurs ( 5.3 ) • Ocular effects: Use with caution in patients with narrow-angle glaucoma and instruct patients to consult a physician immediately if signs or symptoms of narrow-angle glaucoma develop ( 5.4 ) • Urinary retention: Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to consult a physician immediately if signs or symptoms of urinary retention develop ( 5.5 ) 5.1 Use for Maintenance Treatment Only Ipratropium bromide 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. 5.2 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions including urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema may occur after the administration of ipratropium bromide HFA inhalation aerosol. 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 ipratropium bromide HFA inhalation aerosol should be stopped at once and alternative treatment should be considered [see Contraindications ( 4 )]. 5.3 Paradoxical Bronchospasm Ipratropium bromide HFA inhalation aerosol can produce paradoxical bronchospasm that can be life threatening. If this occurs, treatment with ipratropium bromide HFA inhalation aerosol should be stopped and other treatments considered. 5.4 Ocular Effects Ipratropium bromide HFA inhalation aerosol is an anticholinergic and its use may increase intraocular pressure. This may result in precipitation or worsening of narrow-angle glaucoma. Therefore, ipratropium bromide HFA inhalation aerosol should be used with caution in patients with narrow-angle glaucoma [see Drug Interactions ( 7.1 )]. Patients should avoid spraying ipratropium bromide HFA inhalation aerosol into their eyes. If a patient sprays ipratropium bromide HFA inhalation aerosol into their eyes, they may cause eye pain or discomfort, temporary blurring of vision, mydriasis, visual halos or colored images in association with red eyes from conjunctival and corneal congestion. Advise patients to consult their physician immediately if any of these symptoms develop while using ipratropium bromide HFA inhalation aerosol. 5.5 Urinary Retention Ipratropium bromide HFA inhalation aerosol is an anticholinergic and may cause urinary retention. Therefore caution is advised when administering ipratropium bromide HFA inhalation aerosol to patients with prostatic hyperplasia, or bladder-neck obstruction [see Drug Interactions ( 7.1 )].

6 ADVERSE REACTIONS The following adverse reactions are described, or described in greater detail, in other sections: • Hypersensitivity Reactions, Including Anaphylaxis [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )] • Paradoxical Bronchospasm [see Warnings and Precautions ( 5.3 )] • Ocular Effects [see Warnings and Precautions ( 5.4 )] • Urinary Retention [see Warnings and Precautions ( 5.5 )] 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 patients. Most common adverse reactions (>5% incidence in the 12-week placebo- controlled trials) were bronchitis, COPD exacerbation, dyspnea, and headache ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Armstrong Pharmaceuticals, Inc. at 1-800-423-4136, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The adverse reaction information concerning ipratropium bromide HFA inhalation aerosol is derived from two 12-week, double-blind, parallel-group studies and one 1-year open-label, parallel group study. These studies compared ipratropium bromide HFA inhalation aerosol, ipratropium bromide CFC inhalation aerosol, and placebo (in one study only) in 1,010 COPD patients. The following table lists the incidence of adverse reactions that occurred at a rate of greater than or equal to 3% in any ipratropium bromide group and greater than placebo in the 12-week study. The frequency of corresponding reactions in the 1-year open label study is included for comparison. TABLE 1 Adverse Reactions (% Patients) in Ipratropium Bromide HFA Inhalation Aerosol Clinical Trials Placebo-controlled 12-week study 244.1405 and Active-controlled 12-week Study 244.1408 Active-controlled 1-year Study 244.2453 Ipratropium Bromide HFA Inhalation Aerosol (N=243) % Ipratropium Bromide CFC Inhalation Aerosol (N=183) % Placebo (N=128) % Ipratropium Bromide HFA Inhalation Aerosol (N=305) % Ipratropium Bromide CFC Inhalation Aerosol (N=151) % BODY AS A WHOLE - GENERAL DISORDERS Back Pain 2 3 2 7 3 Headache 6 9 8 7 5 Influenza-like symptoms 4 2 2 8 5 CENTRAL & PERIPHERAL NERVOUS SYSTEM DISORDERS Dizziness 3 3 2 3 1 GASTROINTESTINAL SYSTEM DISORDERS Dyspepsia 1 3 1 5 3 Mouth dry 4 2 2 2 3 Nausea 4 1 2 4 4 RESPIRATORY SYSTEM DISORDERS Bronchitis 10 11 6 23 19 COPD exacerbation 8 14 13 23 23 Dyspnea 8 8 4 7 4 Sinusitis 1 4 3 11 14 URINARY SYSTEM DISORDER Urinary tract infection 2 3 1 10 8 Cough, rhinitis, and upper respiratory infection occurred in greater than or equal to 3% of patients in either ipratropium treatment group but not greater than placebo in the 12-week study. In the one open-label controlled study in 456 COPD patients, the overall incidence of adverse events was also similar between ipratropium bromide HFA inhalation aerosol and ipratropium bromide CFC inhalation aerosol formulations. Overall, in the above mentioned studies, 9.3% of the patients taking 42 mcg ipratropium bromide HFA inhalation aerosol and 8.7% of the patients taking 42 mcg ipratropium bromide CFC inhalation aerosol 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 ipratropium bromide HFA inhalation aerosol and 0.9% of ipratropium bromide CFC inhalation aerosol patients), and taste perversion (bitter taste) (0.9% of ipratropium bromide HFA inhalation aerosol and 0.3% of ipratropium bromide CFC inhalation aerosol patients). As an anticholinergic drug, cases of precipitation or worsening of narrow-angle glaucoma, glaucoma, halo vision, conjunctival hyperemia, corneal edema, mydriasis, acute eye pain, dry throat, hypotension, palpitations, urinary retention, tachycardia, constipation, bronchospasm, including paradoxical bronchospasm have been reported with the use of ipratropium bromide HFA inhalation aerosol. Additional adverse reactions identified for ipratropium bromide HFA inhalation aerosol 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 Warnings and Precautions ( 5.2 )]. 6.2 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 ipratropium bromide CFC inhalation aerosol. In addition to the adverse reactions reported in the controlled clinical trials, adverse reactions have been identified during post-approval use of ipratropium bromide. Because these reactions 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. Allergic-type reactions such as skin rash, angioedema including that of tongue, lips and face, urticaria (including giant urticaria), laryngospasm, and anaphylactic reactions have been reported, with positive rechallenge in some cases. Additionally, urinary retention, mydriasis, gastrointestinal distress (diarrhea, nausea, vomiting), cough and bronchospasm, including paradoxical bronchospasm, hypersensitivity reactions, intraocular pressure increased, accommodation disorder, heart rate increased, pharyngeal edema, and gastrointestinal motility disorders have been reported during the post-marketing period with use of ipratropium bromide.

7 DRUG INTERACTIONS Ipratropium bromide HFA inhalation aerosol has been used concomitantly with other drugs, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids commonly used in the treatment of COPD. With the exception of albuterol, there are no formal studies fully evaluating the interaction effects of ipratropium bromide HFA inhalation aerosol and these drugs with respect to safety and effectiveness. Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of ipratropium bromide HFA inhalation aerosol with other anticholinergic-containing drugs ( 7.1 ) 7.1 Anticholinergic Agents There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of ipratropium bromide HFA inhalation aerosol with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions ( 5.4 , 5.5 )].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary 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 )]. There is limited experience with ipratropium bromide use in pregnant women. 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. Based on animal reproduction animal studies, no evidence of structural alternations was observed when ipratropium bromide was administered to pregnant mice, rats and rabbits during organogenesis at doses up to approximately 200, 40,000, and 10,000 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (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 background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data 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 bromide dose in oral studies in mice, rats, and rabbits was up to approximately 200, 40,000, and 10,000 times, respectively, the MRHDID in adults (on a mg/m 2 basis at maternal doses of 10, 1000, and 125 mg/kg/day, respectively). The ipratropium bromide dose in inhalation studies in rats and rabbits was up to approximately 60 and 140 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 3,600 times the 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. 8.2 Lactation Risk Summary There are no data on the presence of ipratropium in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Although lipid-insoluble quaternary cations pass into breast milk, ipratropium concentrations in plasma after inhaled therapeutic doses are low, therefore, ipratropium levels in human breast milk are expected to be low [see Clinical Pharmacology ( 12.3 )]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ipratropium bromide HFA inhalation aerosol and any potential adverse effects on the breastfed child from ipratropium bromide HFA inhalation aerosol or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established. 8.5 Geriatric Use In the pivotal 12-week study, both ipratropium bromide HFA inhalation aerosol and ipratropium bromide CFC inhalation aerosol formulations were equally effective in patients over 65 years of age and under 65 years of age. Of the total number of subjects in clinical studies of ipratropium bromide HFA inhalation aerosol, 57% were ≥65 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

10 OVERDOSAGE Acute overdose by inhalation is unlikely since ipratropium bromide is not well absorbed systemically after inhalation or oral administration.