t, reported for patients who received ipratropium bromide nasal solution 0.03% 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 nasal solution 0.03% group and higher in the ipratropium bromide nasal solution 0.03% group than in the vehicle group are shown. table 1 % of patients reporting events + ipratropium bromide nasal solution 0.03% (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 nasal solution 0.03%group and more frequently in the ipratropium bromide nasal solution 0.03%group than in the vehicle group. 1 epistaxis reported by 7.0% of ipratropium bromide nasal solution 0.03%patients and 2.3% of vehicle patients, blood-tinged mucus by 2.0% of ipratropium bromide nasal solution 0.03%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% 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% during the controlled clinical trials or during the open-label follow-up trial, which are potentially related to ipratropium bromide nasal solution 0.03% 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, including that 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% 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, constipation, nasal discomfort, throat irritation, hypersensitivity, accommodation disorder, intraocular pressure increased, glaucoma, halo vision, conjunctival hyperaemia, corneal edema, heart rate increased, bronchospasm, pharyngeal edema, gastrointestinal motility disorder, mouth edema, stomatitis, and pruritus. after oral inhalation of ipratropium bromide in patients suffering from copd/asthma supraventricular tachycardia and atrial fibrillation have been reported. to report suspected adverse reactions, contact amneal pharmaceuticals at 1-877-835-5472 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

ed from the nasal mucosa of normal volunteers, induced-cold patients, or perennial rhinitis patients. distribution: ipratropium bromide is minimally bound (0% to 9% in vitro ) to plasma albumin and α 1 -acid glycoprotein. its blood/plasma concentration ratio was estimated to be about 0.89. studies in rats have shown that ipratropium bromide does not penetrate the blood-brain barrier. metabolism: ipratropium bromide is partially metabolized to ester hydrolysis products, tropic acid and tropane. these metabolites appear to be inactive based on in vitro receptor affinity studies using rat brain tissue homogenates. elimination: after intravenous administration of 2 mg ipratropium bromide to 10 healthy volunteers, the terminal half-life of ipratropium was approximately 1.6 hours. the total body clearance and renal clearance were estimated to be 2,505 and 1,019 ml/min, respectively. the amount of the total dose excreted unchanged in the urine (ae) within 24 hours was approximately one-half of the administered dose. pediatrics: following administration of 42 mcg of ipratropium bromide per nostril two or three times a day in perennial rhinitis patients 6 to 18 years old, the mean amounts of the total dose excreted unchanged in the urine (8.6% to 11.1%) were higher than those reported in adult volunteers or adult perennial rhinitis patients (3.7% to 5.6%). plasma ipratropium concentrations were relatively low (ranging from undetectable up to 0.49 ng/ml). no correlation of the amount of the total dose excreted unchanged in the urine (ae) with age or gender was observed in the pediatric population. special populations: gender does not appear to influence the absorption or excretion of nasally administered ipratropium bromide. the pharmacokinetics of ipratropium bromide have not been studied in patients with hepatic or renal insufficiency or in the elderly. drug-drug interactions: no specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions. pharmacodynamics in two single-dose trials (n=17), doses up to 336 mcg of ipratropium bromide did not significantly affect pupillary diameter, heart rate, or systolic/diastolic blood pressure. similarly, in patients with induced-colds, ipratropium bromide nasal solution 0.06% (84 mcg/nostril four times a day), had no significant effects on pupillary diameter, heart rate or systolic/diastolic blood pressure. two nasal provocation trials in perennial rhinitis patients (n=44) using ipratropium bromide nasal spray showed a dose dependent increase in inhibition of methacholine induced nasal secretion with an onset of action within 15 minutes (time of first observation). controlled clinical trials demonstrated that intranasal fluorocarbon-propelled ipratropium bromide does not alter physiologic nasal functions (e.g., sense of smell, ciliary beat frequency, mucociliary clearance, or the air conditioning capacity of the nose). clinical trials the clinical trials for ipratropium bromide nasal solution 0.03% were conducted in patients with nonallergic perennial rhinitis (napr) and in patients with allergic perennial rhinitis (apr). apr patients were those who experienced symptoms of nasal hypersecretion and nasal congestion or sneezing when exposed to specific perennial allergens (e.g., dust mites, molds) and were skin test positive to these allergens. napr patients were those who experienced symptoms of nasal hypersecretion and nasal congestion or sneezing throughout the year, but were skin test negative to common perennial allergens. in four controlled, four- and eight-week comparisons of ipratropium bromide nasal solution 0.03% (42 mcg per nostril, two or three times daily) with its vehicle, in patients with allergic or nonallergic perennial rhinitis, there was a statistically significant decrease in the severity and duration of rhinorrhea in the ipratropium bromide nasal solution 0.03% group throughout the entire study period. an effect was seen as early as the first day of therapy. there was no effect of ipratropium bromide nasal solution 0.03% on degree of nasal congestion, sneezing, or postnasal drip. the response to ipratropium bromide nasal solution 0.03% did not appear to be affected by the type of perennial rhinitis (napr or apr), age, or gender. no controlled clinical trials directly compared the efficacy of bid versus tid treatment.

rev. 04-2022-01