FDA label c0650ef0-3b4f-44aa-83e9-70111fa25ed1

WARNINGS 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 on ipratropium bromide nasal solution 0.03% (Nasal Spray) in patients with perennial rhinitis was derived from four multicenter, vehicle-controlled clinical trials involving 703 patients (356 patients on ipratropium bromide and 347 patients on vehicle), and a one-year, open-label, follow-up trial. In three of the trials, patients received ipratropium bromide nasal solution 0.03% (Nasal Spray) three times daily, for eight weeks. In the other trial, ipratropium bromide nasal solution 0.03% (Nasal Spray) was given to patients two times daily for four weeks. Of the 285 patients who entered the open-label, follow-up trial, 232 were treated for 3 months, 200 for 6 months, and 159 up to one year. The majority (>86%) of patients treated for one year were maintained on 42 mcg per nostril, two or three times daily of ipratropium bromide nasal solution 0.03% (Nasal Spray). The following table shows adverse events, and the frequency that these adverse events led to the discontinuation of treatment, reported for patients who received ipratropium bromide nasal solution 0.03% (Nasal Spray) at the recommended dose of 42 mcg per nostril, or vehicle two or three times daily for four or eight weeks. Only adverse events reported with the incidence of at least 2.0% in the ipratropium bromide group and higher in the ipratropium bromide group than in the vehicle group are shown. % Of Patients Reporting Events+ Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) (n=356) Vehicle Control (n= 347) Incidence % Discontinued % Incidence % Discontinued % Headache 9.8 0.6 9.2 0.0 Upper respiratory tract infection 9.8 1.4 7.2 1.4 Epistaxis 1 9.0 0.3 4.6 0.3 Rhinitis* Nasal dryness 5.1 0.0 0.9 0.3 Nasal irritation 2 2.0 0.0 1.7 0.6 Other nasal symptoms 3 3.1 1.1 1.7 0.3 Pharyngitis 8.1 0.3 4.6 0.0 Nausea 2.2 0.3 0.9 0.0 + This table includes adverse events which occurred at an incidence rate of at least 2.0% in the ipratropium bromide group and more frequently in the ipratropium bromide group than in the vehicle group. 1 Epistaxis reported by 7.0% of ipratropium bromide patients and 2.3% of vehicle patients, blood-tinged mucus by 2.0% of ipratropium bromide patients and 2.3% of vehicle patients. 2 Nasal irritation includes reports of nasal itching, nasal burning, nasal irritation, and ulcerative rhinitis. 3 Other nasal symptoms include reports of nasal congestion, increased rhinorrhea, increased rhinitis, posterior nasal drip, sneezing, nasal polyps, and nasal edema. * All events are listed by their WHO term; rhinitis has been presented by descriptive terms for clarification. Ipratropium bromide nasal solution 0.03% (Nasal Spray) was well tolerated by most patients. The most frequently reported nasal adverse events were transient episodes of nasal dryness or epistaxis. These adverse events were mild or moderate in nature, none was considered serious, none resulted in hospitalization and most resolved spontaneously or following a dose reduction. Treatment for nasal dryness and epistaxis was required infrequently (2% or less) and consisted of local application of pressure or a moisturizing agent (e.g., petroleum jelly or saline nasal spray). Patient discontinuation for epistaxis or nasal dryness was infrequent in both the controlled (0.3% or less) and one-year, open-label (2% or less) trials. There was no evidence of nasal rebound (i.e., a clinically significant increase in rhinorrhea, posterior nasal drip, sneezing or nasal congestion severity compared to baseline) upon discontinuation of double-blind therapy in these trials. Adverse events reported by less than 2% of the patients receiving ipratropium bromide nasal solution 0.03% (Nasal Spray) during the controlled clinical trials or during the open-label follow-up trial, which are potentially related to ipratropium bromide’s local effects or systemic anticholinergic effects include: dry mouth/throat, dizziness, ocular irritation, blurred vision, conjunctivitis, hoarseness, cough, and taste perversion. There were infrequent reports of skin rash in both the controlled and uncontrolled clinical studies. Post-Marketing Experience Allergic-type reactions such as skin rash angioedema of the throat, tongue, lips and face, generalized urticaria (including giant urticaria), laryngospasm, and anaphylactic reactions have been reported with ipratropium bromide nasal solution 0.03% (Nasal Spray) and for other ipratropium bromide-containing products, with positive rechallenge in some cases. Additional side effects identified from the published literature and/or post-marketing surveillance on the use of ipratropium bromide-containing products (singly or in combination with albuterol), include: urinary retention, prostatic disorders, mydriasis, cases of precipitation or worsening of narrow-angle glaucoma, acute eye pain, wheezing, dryness of the oropharynx, sinusitis, tachycardia, palpitations, pain, edema, gastrointestinal distress (diarrhea, nausea, vomiting), bowel obstruction, and constipation. After oral inhalation of ipratropium bromide in patients suffering from COPD/Asthma supraventricular tachycardia and atrial fibrillation have been reported. Overdosage Acute overdosage by intranasal administration is unlikely since ipratropium bromide is not well absorbed systemically after intranasal or oral administration. Following administration of a 20 mg oral dose (equivalent to ingesting more than four bottles of ipratropium bromide nasal solution 0.03% [Nasal Spray]) to 10 male volunteers, no change in heart rate or blood pressure was noted. Following a 2 mg intravenous infusion over 15 minutes to the same 10 male volunteers, plasma ipratropium concentrations of 22-45 ng/mL were observed (>100 times the concentrations observed following intranasal administration). Following intravenous infusion these 10 volunteers had a mean increase of heart rate of 50 bpm and less than 20 mmHg change in systolic or diastolic blood pressure at the time of peak ipratropium levels. Oral median lethal doses of ipratropium bromide were greater than 1,000 mg/kg in mice (approximately 16,000 and 9,500 times the maximum recommended daily intranasal dose in adults and children, respectively, on a mg/m 2 basis), 1,700 mg/kg in rats (approximately 55,000 and 32,000 times the maximum recommended daily intranasal dose in adults and children, respectively, on a mg/m 2 basis), and 400 mg/kg in dogs (approximately 43,000 and 25,000 times the maximum recommended daily intranasal dose in adults and children, respectively, on a mg/m 2 basis).

<table border="1" width="615" ID="i751c2398-8903-42ff-8682-6fa3a981c43b"> <caption>% Of Patients Reporting Events+</caption> <col width="23%"/> <col width="18%"/> <col width="19%"/> <col width="17%"/> <col width="20%"/> <tbody> <tr> <td> </td> <td> <paragraph>Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray)</paragraph> <paragraph>(n=356)</paragraph> </td> <td> <paragraph>Vehicle Control</paragraph> <paragraph>(n= 347)</paragraph> </td> </tr> <tr> <td> </td> <td>Incidence %</td> <td>Discontinued %</td> <td>Incidence %</td> <td>Discontinued %</td> </tr> <tr> <td>Headache</td> <td>9.8</td> <td>0.6</td> <td>9.2</td> <td>0.0</td> </tr> <tr> <td>Upper respiratory tract infection</td> <td>9.8</td> <td>1.4</td> <td>7.2</td> <td>1.4</td> </tr> <tr> <td>Epistaxis ¹ </td> <td>9.0</td> <td>0.3</td> <td>4.6</td> <td>0.3</td> </tr> <tr> <td>Rhinitis*</td> <td> </td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>Nasal dryness</td> <td>5.1</td> <td>0.0</td> <td>0.9</td> <td>0.3</td> </tr> <tr> <td>Nasal irritation ² </td> <td>2.0</td> <td>0.0</td> <td>1.7</td> <td>0.6</td> </tr> <tr> <td>Other nasal symptoms ³ </td> <td>3.1</td> <td>1.1</td> <td>1.7</td> <td>0.3</td> </tr> <tr> <td>Pharyngitis</td> <td>8.1</td> <td>0.3</td> <td>4.6</td> <td>0.0</td> </tr> <tr> <td>Nausea</td> <td>2.2</td> <td>0.3</td> <td>0.9</td> <td>0.0</td> </tr> </tbody> </table>