ATROVENT HFA Inhalation aerosol, metered Ref.[10538] Active ingredients: Ipratropium

5.1 Use for Maintenance Treatment Only

ATROVENT HFA 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 ATROVENT HFA. 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 ATROVENT HFA should be stopped at once and alternative treatment should be considered [see Contraindications (4)].

5.3 Paradoxical Bronchospasm

ATROVENT HFA can produce paradoxical bronchospasm that can be life threatening. If this occurs, treatment with ATROVENT HFA should be stopped and other treatments considered.

5.4 Ocular Effects

ATROVENT HFA is an anticholinergic and its use may increase intraocular pressure. This may result in precipitation or worsening of narrow-angle glaucoma. Therefore, ATROVENT HFA should be used with caution in patients with narrow-angle glaucoma [see Drug Interactions (7.1)].

Patients should avoid spraying ATROVENT HFA into their eyes. If a patient sprays ATROVENT HFA 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 ATROVENT HFA Inhalation Aerosol.

5.5 Urinary Retention

ATROVENT HFA is an anticholinergic and may cause urinary retention. Therefore caution is advised when administering ATROVENT HFA Inhalation Aerosol to patients with prostatic hyperplasia, or bladder-neck obstruction [see Drug Interactions (7.1)].

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.

The adverse reaction information concerning ATROVENT HFA is derived from two 12-week, double-blind, parallel-group studies and one 1-year open-label, parallel group study. These studies compared ATROVENT HFA Inhalation Aerosol, ATROVENT CFC Inhalation Aerosol, and placebo (in one study only) in 1010 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 ATROVENT HFA Clinical Trials:

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 ATROVENT HFA and ATROVENT CFC formulations.

Overall, in the above mentioned studies, 9.3% of the patients taking 42 mcg ATROVENT HFA and 8.7% of the patients taking 42 mcg ATROVENT CFC 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 ATROVENT HFA and 0.9% of ATROVENT CFC patients), and taste perversion (bitter taste) (0.9% of ATROVENT HFA and 0.3% of ATROVENT CFC 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 ATROVENT. Additional adverse reactions identified for ATROVENT 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)].

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 CFC.

In addition to the adverse reactions reported in the controlled clinical trials, adverse reactions have been identified during post-approval use of ATROVENT. 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 postmarketing period with use of ATROVENT.

ATROVENT HFA 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 ATROVENT HFA and these drugs with respect to safety and effectiveness.

7.1 Anticholinergic Agents

There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of ATROVENT HFA with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.4, 5.5)].

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 studies, no evidence of structural alterations 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/m² 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/m² 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 3600 times the MRHDID in adults (on a mg/m² 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.

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 ATROVENT HFA and any potential adverse effects on the breastfed child from ATROVENT HFA or from the underlying maternal condition.

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

In the pivotal 12-week study, both ATROVENT HFA and ATROVENT CFC 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 ATROVENT HFA, 57% were ≥65 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.