IPRATROPIUM BROMIDE

The active ingredient in ipratropium bromide nasal solution is ipratropium bromide monohydrate. It is an anticholinergic agent chemically described as 8-azoniabicyclo (3.2.1) octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-, bromide monohydrate (endo, syn)-, ( + )-: a synthetic quaternary ammonium compound, chemically related to atropine. Its structural formula is: Ipratropium bromide is a white to off-white crystalline substance. It is freely soluble in lower alcohols and water, existing in an ionized state in aqueous solutions, and relatively insoluble in non-polar media. Ipratropium bromide nasal solution, 0.06% is a metered-dose, manual pump spray unit which delivers 42 mcg ipratropium bromide (on an anhydrous basis) per spray (70 mcL) in an isotonic, aqueous solution. It also contains the following inactive ingredients: benzalkonium chloride, edetate disodium, purified water and sodium chloride. Hydrochloric acid and/or sodium hydroxide may be added to adjust the pH to 4.5 to 4.9. Each bottle contains 165 sprays.

Ipratropium bromide nasal solution, 0.06% is indicated for the symptomatic relief of rhinorrhea associated with the common cold or seasonal allergic rhinitis for adults and children age 5 years and older. Ipratropium bromide nasal solution, 0.06% does not relieve nasal congestion or sneezing associated with the common cold or seasonal allergic rhinitis. The safety and effectiveness of the use of ipratropium bromide nasal solution, 0.06% beyond four days in patients with the common cold or beyond three weeks in patients with seasonal allergic rhinitis has not been established.

For Symptomatic Relief of Rhinorrhea Associated with the Common Cold The recommended dose of ipratropium bromide nasal solution, 0.06% is two sprays (84 mcg) per nostril three or four times daily (total dose 504 to 672 mcg/day) in adults and children age 12 years and older. Optimum dosage varies with response of the individual patient. The recommended dose of ipratropium bromide nasal solution, 0.06% for children age 5 to11 years is two sprays (84 mcg) per nostril three times daily (total dose of 504 mcg/day). The safety and effectiveness of the use of ipratropium bromide nasal solution, 0.06% beyond four days in patients with the common cold have not been established. For Symptomatic Relief of Rhinorrhea Associated with Seasonal Allergic Rhinitis The recommended dose of ipratropium bromide nasal solution, 0.06% is two sprays (84 mcg) per nostril four times daily (total dose 672 mcg/day) in adults and children age 5 years and older. The safety and effectiveness of the use of ipratropium bromide nasal solution, 0.06% beyond three weeks in patients with seasonal allergic rhinitis have not been established. Initial pump priming requires seven sprays of the pump. If used regularly as recommended, no further priming is required. If not used for more than 24 hours, the pump will require two sprays, or if not used for more than seven days, the pump will require seven sprays to reprime. Avoid spraying into eyes.

Ipratropium bromide nasal solution, 0.06% is contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, or to any of the other ingredients.

Adverse reaction information on ipratropium bromide nasal solution, 0.06% in patients with the common cold was derived from two multicenter, vehicle-controlled clinical trials involving 1,276 patients (195 patients on ipratropium bromide nasal solution, 0.03%, 352 patients on ipratropium bromide nasal solution, 0.06%, 189 patients on ipratropium bromide nasal spray, 0.12%, 351 patients on vehicle and 189 patients receiving no treatment). Table 1 shows adverse events reported for patients who received ipratropium bromide nasal solution, 0.06% at the recommended dose of 84 mcg per nostril, or vehicle, administered three or four times daily, where the incidence is 1% or greater in the ipratropium bromide group and higher in the ipratropium bromide group than in the vehicle group. Table 1 % of Patients with Common Cold Reporting Events 1 Ipratropium Bromide) Nasal Solution 0.06% Vehicle Control 1 This table includes adverse events for which the incidence was 1% or greater in the ipratropium bromide group and higher in the ipratropium bromide group than in the vehicle group. 2 Epistaxis reported by 5.4% of ipratropium bromide patients and 1.4% of vehicle patients, blood-tinged nasal mucus by 2.8% of ipratropium bromide patients and 0.9% of vehicle patients. No. of Patients 352 351 Epistaxis 2 8.2% 2.3% Nasal Dryness 4.8% 2.8% Dry Mouth/Throat 1.4% 0.3% Nasal Congestion 1.1% 0.0% Ipratropium bromide nasal solution, 0.06% was well tolerated by most patients. The most frequently reported adverse events were transient episodes of nasal dryness or epistaxis. The majority of these adverse events (96%) were mild or moderate in nature, none was considered serious, and none resulted in hospitalization. No patient required treatment for nasal dryness, and only three patients (<1%) required treatment for epistaxis, which consisted of local application of pressure or a moisturizing agent (e.g., petroleum jelly). No patient receiving ipratropium bromide nasal solution, 0.06% was discontinued from the trial due to either nasal dryness or bleeding. Adverse events reported by less than 1% of the patients receiving ipratropium bromide nasal solution, 0.06% during the controlled clinical trials that are potentially related to ipratropium bromide's local effects or systemic anticholinergic effects include: taste perversion, nasal burning, conjunctivitis, coughing, dizziness, hoarseness, palpitation, pharyngitis, tachycardia, thirst, tinnitus, and blurred vision. No controlled trial was conducted to address the relative incidence of adverse events for three times daily versus four times daily therapy. Nasal adverse events seen in the clinical trial with seasonal allergic rhinitis (SAR) patients (see Table 2 ) were similar to those seen in the common cold trials. Additional events were reported at a higher rate in the SAR trial due in part to the longer duration of the trial and the inclusion of Upper Respiratory Tract Infection (URI) as an adverse event. In common cold trials, URI was the disease under study and not an adverse event. Table 2 % of Patients with SAR Reporting Events 1 Ipratropium Bromide) Nasal Solution 0.06% Vehicle Control 1 This table includes adverse events for which the incidence was 1% or greater in the ipratropium bromide group and higher in the ipratropium bromide group than in the vehicle group. 2 Epistaxis reported by 3.7% of ipratropium bromide patients and 2.4% of vehicle patients, blood-tinged nasal mucus by 2.3% of ipratropium bromide patients and 1.9% of vehicle patients. No. of Patients 218 211 Epistaxis 2 6.0% 3.3% Pharyngitis 5.0% 3.8% URI 5.0% 3.3% Nasal Dryness 4.6% 0.9% Headache 4.1% 0.5% Dry Mouth/Throat 4.1% 0.0% Taste Perversion 3.7% 1.4% Sinusitis 2.8% 2.8% Pain 1.8% 0.9% Diarrhea 1.8% 0.5% There were no reports of allergic-type reactions in the controlled clinical common cold and SAR trials. 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, 0.06% 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, ocular irritation wheezing, dryness of the oropharynx, , tachycardia, 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.

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 for oral inhalation.

Store tightly closed at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Avoid freezing. Keep out of reach of children. Do not spray in the eyes. Address medical inquiries to Apotex Corp: (800) 706-5575. Patients should be reminded to read and follow the accompanying Patient's Instructions for Use, which should be dispensed with the product. Manufactured by: Manufactured for: Apotex Inc. Apotex Corp. Toronto, Ontario Weston, FL Canada M9L 1T9 33326 May 2014