Ipratropium Bromide .5 mg/2.5mL Solution — NDC 76204-100-25 (Billing 76204-0100-25)

WARNINGS The use of ipratropium bromide inhalation solution as a single agent for the relief of bronchospasm in acute COPD exacerbation has not been adequately studied. Drugs with faster onset of action may be preferable as initial therapy in this situation. Combination of ipratropium bromide and beta agonists has not been shown to be more effective than either drug alone in reversing the bronchospasm associated with acute COPD exacerbation.

Immediate hypersensitivity reactions may occur after administration of ipratropium bromide, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm and oropharyngeal edema.

ADVERSE REACTIONS Adverse reaction information concerning ipratropium bromide inhalation solution is derived from 12-week active-controlled clinical trials. Additional information is derived from foreign post-marketing experience and the published literature. All adverse events, regardless of drug relationship, reported by three percent or more patients in the 12-week controlled clinical trials appear in the table below.

Additional adverse reactions reported in less than three percent of the patients treated with ipratropium bromide include tachycardia, palpitations, eye pain, urinary retention, urinary tract infection and urticaria. Cases of precipitation or worsening of narrow-angle glaucoma, mydriasis, and acute eye pain have been reported. Lower respiratory adverse reactions (bronchitis, dyspnea and bronchospasm) were the most common events leading to discontinuation of ipratropium bromide therapy in the 12-week trials.

Headache, mouth dryness and aggravation of COPD symptoms are more common when the total daily dose of ipratropium bromide equals or exceeds 2,000 mcg. Allergic-type reactions such as skin-rash, angioedema of tongue, lips and face, urticaria, laryngospasm and anaphylactic reaction have been reported. Many of the patients had a history of allergies to other drugs and/or foods.

All Adverse Events, from a Double-blind, Parallel, 12-week Study of patients with COPD All adverse events, regardless of drug relationship, reported by three percent or more patients in the 12-week controlled clinical trials. PERCENT OF PATIENTS Ipratropium Metaproterenol Ipratropium/ Metaproterenol Albuterol Ipratropium/ Albuterol (500 mcg t.i.d.) (15 mg t.i.d.) (500 mcg t.i.d./ 15 mg t.i.d.) (2.5 mg t.i.d.) (500 mcg t.i.d./ 2.5 mg t.i.d.) n = 219 n = 212 n = 108 n = 205 n = 100 Body as a Whole-General Disorders Headache 6.4 5.2 6.5 6.3

9.0Pain 4.1 3.3 0.9 2.9

5.0Influenza-like symptoms 3.7 4.7 6.5 0.5

1.0Back Pain 3.2 1.9 1.9 2.4

0.0Chest Pain 3.2 4.2 5.6 2.0

1.0Cardiovascular Disorders Hypertension/Hypertension Aggravated 0.9 1.9 0.9 1.5

4.0Central & Peripheral Nervous System Dizziness 2.3 3.3 1.9 3.9

4.0Insomnia 0.9 0.5 4.6 1.0

1.0Tremor 0.9 7.1 8.3 1.0

0.0Nervousness 0.5 4.7 6.5 1.0

1.0Gastrointestinal System Disorders Mouth Dryness 3.2 0.0 1.9 2.0

3.0Nausea 4.1 3.8 1.9 2.9

2.0Constipation 0.9 0.0 3.7 1.0

1.0Musculo-skeletal System Disorders Arthritis 0.9 1.4 0.9 0.5

3.0Respiratory System Disorders (Lower) Coughing 4.6 8.0 6.5 5.4

6.0Dyspnea 9.6 13.2 16.7 12.7

9.0Bronchitis 14.6 24.5 15.7 16.6

20.0Bronchospasm 2.3 2.8 4.6 5.4

5.0Sputum Increased 1.4 1.4 4.6 3.4

0.0Respiratory Disorder 0.0 6.1 6.5 2.0

4.0Respiratory System Disorders (Upper) Upper Respiratory Tract Infection 13.2 11.3 9.3 12.2

16.0Pharyngitis 3.7 4.2 5.6 2.9

4.0Rhinitis 2.3 4.2 1.9 2.4

0.0Sinusitus 2.3 2.8 0.9 5.4 4.0

Drug Interactions Ipratropium bromide has been shown to be a safe and effective bronchodilator when used in conjunction with beta adrenergic bronchodilators. Ipratropium bromide has also been used with other pulmonary medications, including methylxanthines and corticosteroids, without adverse drug interactions.

PRECAUTIONS General Ipratropium bromide should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy or bladder-neck obstruction. Information for Patients Patients should be advised that temporary blurring of vision, precipitation or worsening of narrow-angle glaucoma or eye pain may result if the solution comes into direct contact with the eyes. Use of a nebulizer with mouthpiece rather than face mask may be preferable, to reduce the likelihood of the nebulizer solution reaching the eyes.

Patients should be advised that ipratropium bromide inhalation solution can be mixed in the nebulizer with albuterol or metaproterenol if used within one hour. Drug stability and safety of Ipratropium Bromide Inhalation Solution when mixed with other drugs in a nebulizer have not been established. Patients should be reminded that ipratropium bromide inhalation solution should be used consistently as prescribed throughout the course of therapy.

Drug Interactions Ipratropium bromide has been shown to be a safe and effective bronchodilator when used in conjunction with beta adrenergic bronchodilators. Ipratropium bromide has also been used with other pulmonary medications, including methylxanthines and corticosteroids, without adverse drug interactions. Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic potential at dietary doses up to 6 mg/kg/day of ipratropium bromide.

Results of various mutagenicity studies (Ames test, mouse dominant lethal test, mouse micronucleus test and chromosome aberration of bone marrow in Chinese hamsters) were negative. Fertility of male or female rats at oral doses up to 50 mg/kg/day was unaffected by ipratropium bromide administration. At doses above 90 mg/kg increased resorption and decreased conception rates were observed.

Pregnancy TERATOGENIC EFFECTS Pregnancy Category B Oral reproduction studies performed in mice, rats and rabbits at doses of 10, 100, and 125 mg/kg respectively, and inhalation reproduction studies in rats and rabbits at doses of 1.5 and 1.8 mg/kg (or approximately 38 and 45 times the recommended human daily dose) respectively, have demonstrated no evidence of teratogenic effects as a result of ipratropium bromide. However, no adequate or well-controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, ipratropium bromide should be used during pregnancy only if clearly needed.

Nursing Mothers It is not known whether ipratropium bromide is excreted in human milk. Although lipid-insoluble quaternary bases pass into breast milk, it is unlikely that ipratropium bromide would reach the infant to a significant extent, especially when taken by inhalation since ipratropium bromide is not well absorbed systemically after inhalation or oral administration. However, because many drugs are excreted in human milk, caution should be exercised when ipratropium bromide is administered to a nursing woman.

Pediatric Use Safety and effectiveness in the pediatric population below the age of 12 have not been established.