Ipratroprium Bromide

Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is indicated for the symptomatic relief of rhinorrhea associated with allergic and nonallergic perennial rhinitis in adults and children age 6 years and older. Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) does not relieve nasal congestion, sneezing, or postnasal drip associated with allergic or nonallergic perennial rhinitis.

Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, or to any of the other ingredients.

Immediate hypersensitivity reactions may occur after administration of ipratropium bromide, as demonstrated by urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. If such a reaction occurs, therapy with Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) should be stopped at once and alternative treatment should be considered.

General: 1. Effects Seen with Anticholinergic Drugs: Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia, or bladder neck obstruction, particularly if they are receiving an anticholinergic by another route. 2. Use in Hepatic or Renal Disease: Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in those patient populations. Information for Patients: Patients should be advised that temporary blurring of vision, precipitation or worsening of narrow-angle glaucoma, mydriasis, increased intraocular pressure, acute eye pain or discomfort, visual halos or colored images in association with red eyes from conjunctival and corneal congestion may result if Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) comes into direct contact with the eyes. Patients should be instructed to avoid spraying Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) in or around their eyes. Patients who experience eye pain, blurred vision, excessive nasal dryness or episodes of nasal bleeding should be instructed to contact their doctor. To ensure proper dosing, patients should be advised not to alter the size of the nasal spray opening. Patients should be reminded to carefully read and follow the accompanying INSTRUCTIONS FOR USE . Since dizziness, accommodation disorder, mydriasis, and blurred vision may occur with use of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray), patients should be cautioned about engaging in activities requiring balance and visual acuity such as driving a car or operating appliances, machinery, etc. Drug Interactions: No controlled clinical trials were conducted to investigate potential drug-drug interactions. There is potential for an additive interaction with other concomitantly administered medications with anticholinergic properties, including Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) for oral inhalation. Carcinogenesis, Mutagenesis, Impairment of Fertility: Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic activity at doses up to 6 mg/kg. This dose corresponds in rats and mice to approximately 190 and 95 times the maximum recommended daily intranasal dose in adults, respectively, and approximately 110 and 55 times the maximum recommended daily intranasal dose in children, respectively, on a mg/m 2 basis. 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 (approximately 1,600 times the maximum recommended daily intranasal dose in adults on a mg/m 2 basis) was unaffected by ipratropium bromide administration. At an oral dose of 500 mg/kg (approximately 16,000 times the maximum recommended daily intranasal dose in adults on a mg/m 2 basis), ipratropium bromide produced a decrease in the conception rate. Pregnancy: Teratogenic Effects: There are no adequate and well-controlled studies for Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) in pregnant women. Because animal reproduction studies are not always predictive of human response, Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) should be used during pregnancy only if clearly needed. Oral reproduction studies were performed at ipratropium doses of 10 mg/kg in mice, 1,000 mg/kg in rats and 125 mg/kg in rabbits. These doses correspond, in each species respectively, to approximately 160, 32,000, and 8,000 times the maximum recommended daily intranasal dose (MRDID) in adults on a mg/m 2 basis. Inhalation reproduction studies were conducted in rats and rabbits at doses of 1.5 and 1.8 mg/kg, respectively, (approximately 50 and 120 times, respectively, the MRDID in adults on a mg/m 2 basis). These studies demonstrated no evidence of teratogenic effects as a result of ipratropium bromide. At oral doses 90 mg/kg and above in rats (approximately 2,900 times the MRDID in adults on a mg/m 2 basis), embryotoxicity was observed as increased resorption. 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. Labor and Delivery: The effect of ipratropium bromide on labor and delivery is unknown. Nursing Mothers: It is known that some ipratropium bromide is systemically absorbed following nasal administration; however the portion which may be excreted in human milk is unknown. Because lipid-insoluble quaternary cations pass into breast milk, caution should be exercised when Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is administered to a nursing mother. Pediatric Use: The safety of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) at a dose of two sprays (42 mcg) per nostril two or three times daily (total dose 168 to 252 mcg/day) has been demonstrated in 77 pediatric patients 6 to 12 years of age in placebo-controlled, 4-week trials and in 55 pediatric patients in active-controlled, 6 month trials. The effectiveness of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) for the treatment of rhinorrhea associated with allergic and nonallergic perennial rhinitis in this pediatric age group is based on an extrapolation of the demonstrated efficacy of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) in adults with these conditions and the likelihood that the disease course, pathophysiology, and the drug’s effects are substantially similar to that of adults. The recommended dose for the pediatric population is based on within and cross-study comparisons of the efficacy of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) in adults and pediatric patients and on its safety profile in both adults and pediatric patients. The safety and effectiveness of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) in patients under 6 years of age have not been established.

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). Table 1 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 an 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. Table 1 % of Patients Reporting Events* Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) (n=356) Incidence% Discontinued% Headache 9.8

0.6 Upper respiratory tract infection 9.8

1.4 Epistaxis † 9.0

0.3 Rhinitis ‡ Nasal dryness 5.1

0.0 Nasal irritation § 2.0

0.0 Other nasal symptoms ¶ 3.1

1.1 Pharyngitis 8.1

0.3 Nausea 2.2

0.3 Vehicle Control (n=347) Incidence% Discontinued% Headache 9.2

0.0 Upper respiratory tract infection 7.2

1.4 Epistaxis † 4.6

0.3 Rhinitis ‡ Nasal dryness 0.9

0.3 Nasal irritation § 1.7

0.6 Other nasal symptoms ¶ 1.7

0.3 Pharyngitis 4.6

0.0 Nausea 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. † 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. § Nasal irritation includes reports of nasal itching, nasal burning, nasal irritation, and ulcerative rhinitis. ¶ 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. To report SUSPECTED ADVERSE REACTIONS, contact Oceanside Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

No controlled clinical trials were conducted to investigate potential drug-drug interactions. There is potential for an additive interaction with other concomitantly administered medications with anticholinergic properties, including Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) for oral inhalation.

Teratogenic Effects: There are no adequate and well-controlled studies for Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) in pregnant women. Because animal reproduction studies are not always predictive of human response, Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) should be used during pregnancy only if clearly needed. Oral reproduction studies were performed at ipratropium doses of 10 mg/kg in mice, 1,000 mg/kg in rats and 125 mg/kg in rabbits. These doses correspond, in each species respectively, to approximately 160, 32,000, and 8,000 times the maximum recommended daily intranasal dose (MRDID) in adults on a mg/m 2 basis. Inhalation reproduction studies were conducted in rats and rabbits at doses of 1.5 and 1.8 mg/kg, respectively, (approximately 50 and 120 times, respectively, the MRDID in adults on a mg/m 2 basis). These studies demonstrated no evidence of teratogenic effects as a result of ipratropium bromide. At oral doses 90 mg/kg and above in rats (approximately 2,900 times the MRDID in adults on a mg/m 2 basis), embryotoxicity was observed as increased resorption. 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.

It is known that some ipratropium bromide is systemically absorbed following nasal administration; however the portion which may be excreted in human milk is unknown. Because lipid-insoluble quaternary cations pass into breast milk, caution should be exercised when Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is administered to a nursing mother.

The safety of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) at a dose of two sprays (42 mcg) per nostril two or three times daily (total dose 168 to 252 mcg/day) has been demonstrated in 77 pediatric patients 6 to 12 years of age in placebo-controlled, 4-week trials and in 55 pediatric patients in active-controlled, 6 month trials. The effectiveness of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) for the treatment of rhinorrhea associated with allergic and nonallergic perennial rhinitis in this pediatric age group is based on an extrapolation of the demonstrated efficacy of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) in adults with these conditions and the likelihood that the disease course, pathophysiology, and the drug’s effects are substantially similar to that of adults. The recommended dose for the pediatric population is based on within and cross-study comparisons of the efficacy of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) in adults and pediatric patients and on its safety profile in both adults and pediatric patients. The safety and effectiveness of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) in patients under 6 years of age have not been established.

Ipratropium bromide is an anticholinergic (parasympatholytic) agent which, based on animal studies, appears to inhibit vagally-mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released at the neuromuscular junctions in the lung. In humans, ipratropium bromide has anti-secretory properties and, when applied locally, inhibits secretions from the serous and seromucous glands lining the nasal mucosa. Ipratropium bromide is a quaternary amine that minimally crosses the nasal and gastrointestinal membranes and the blood-brain barrier, resulting in a reduction of the systemic anticholinergic effects (e.g., neurologic, ophthalmic, cardiovascular, and gastrointestinal effects) that are seen with tertiary anticholinergic amines.