IPRATROPIUM: 7,540 Adverse Event Reports & Safety Profile

The active ingredient in ATROVENT HFA is ipratropium bromide (monohydrate). It is an anticholinergic bronchodilator chemically described as 8-azoniabicyclo[3.2.1]octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-,bromide monohydrate, (3-endo, 8-syn)-: a synthetic quaternary ammonium compound, chemically related to atropine. The structural formula for ipratropium bromide is: C 20 H 30 BrNO 3 ∙H 2 O ipratropium bromide Mol. Wt.

430.4 Ipratropium bromide is a white to off-white crystalline substance, freely soluble in water and methanol, sparingly soluble in ethanol, and insoluble in lipophilic solvents such as ether, chloroform, and fluorocarbons. ATROVENT HFA is a pressurized metered-dose aerosol unit for oral inhalation that contains a solution of ipratropium bromide.

The

200 inhalation unit has a net weight of 12.9 grams. After priming, each actuation of the inhaler delivers 21 mcg of ipratropium bromide (monohydrate) from the valve in 56 mg of solution and delivers 17 mcg of ipratropium bromide (monohydrate) from the mouthpiece. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the device and inspiration through the delivery system. The excipients are anhydrous citric acid, dehydrated alcohol, HFA-134a (1,1,1,2-tetrafluoroethane) as propellant, and sterile water for irrigation. This product does not contain chlorofluorocarbons (CFCs) as propellants. ATROVENT HFA should be primed before using for the first time by releasing 2 test sprays into the air away from the face. In cases where the inhaler has not been used for more than 3 days, prime the inhaler again by releasing 2 test sprays into the air away from the face.

Chemical

Structure

INDICATIONS AND USAGE: Ipratropium Bromide Nasal Solution 0.06% (Nasal Spray) 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% (Nasal Spray) 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% (Nasal Spray) beyond four days in patients with the common cold or beyond three weeks in patients with seasonal allergic rhinitis has not been established.

DOSAGE AND ADMINISTRATION: For Symptomatic Relief of Rhinorrhea Associated with the Common Cold: The recommended dose of Ipratropium Bromide Nasal Solution 0.06% (Nasal Spray) 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% (Nasal Spray) for children age 5-11 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% (Nasal Spray) 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% (Nasal Spray) 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% (Nasal Spray) 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.

ATROVENT HFA is contraindicated in the following conditions [ see Warnings and Precautions (5.2) ]. Hypersensitivity to ipratropium bromide or other ATROVENT HFA components Hypersensitivity to atropine or any of its derivatives Hypersensitivity to ipratropium bromide or other ATROVENT HFA components ( 4 ) Hypersensitivity to atropine or any of its derivatives ( 4 )

ADVERSE REACTIONS Adverse reaction information on Ipratropium Bromide Nasal Solution 0.03% in patients with perennial rhinitis was derived from four multicenter, vehicle-controlled clinical trials involving 703 patients (356 patients on Ipratropium Bromide Nasal Solution 0.03% 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% three times daily, for eight weeks. In the other trial, Ipratropium Bromide Nasal Solution 0.03% 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%.

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% 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.

AND PRECAUTIONS Not indicated for the initial treatment of acute episodes of bronchospasm where rescue therapy is required for rapid response ( 5.1 ) Hypersensitivity reactions including anaphylaxis: Discontinue ATROVENT HFA at once and consider alternative treatments ( 5.2 ) Paradoxical bronchospasm: Discontinue ATROVENT HFA and consider other treatments if paradoxical bronchospasm occurs ( 5.3 ) Ocular effects: Use with caution in patients with narrow-angle glaucoma and instruct patients to consult a physician immediately if signs or symptoms of narrow-angle glaucoma develop ( 5.4 ) Urinary retention: Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to consult a physician immediately if signs or symptoms of urinary retention develop ( 5.5 )

5.1 Use for Maintenance Treatment Only ATROVENT HFA is a bronchodilator for the maintenance treatment of bronchospasm associated with COPD and is not indicated for the initial treatment of acute episodes of bronchospasm where rescue therapy is required for rapid response.

5.2 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions including urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema may occur after the administration of ATROVENT HFA. In clinical trials and postmarketing experience with ipratropium-containing products, hypersensitivity reactions such as skin rash, pruritus, angioedema of tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions have been reported [ see Adverse Reactions (6.1 , 6.2) ]. If such a reaction occurs, therapy with ATROVENT HFA should be stopped at once and alternative treatment should be considered [ see Contraindications (4) ] .

5.3 Paradoxical Bronchospasm ATROVENT HFA can produce paradoxical bronchospasm that can be life threatening. If this occurs, treatment with ATROVENT HFA should be stopped and other treatments considered.

5.4 Ocular Effects ATROVENT HFA is an anticholinergic and its use may increase intraocular pressure. This may result in precipitation or worsening of narrow-angle glaucoma. Therefore, ATROVENT HFA should be used with caution in patients with narrow-angle glaucoma [ see Drug Interactions (7.1) ]. Patients should avoid spraying ATROVENT HFA into their eyes. If a patient sprays ATROVENT HFA into their eyes, they may cause eye pain or discomfort, temporary blurring of vision, mydriasis, visual halos or colored images in association with red eyes from conjunctival and corneal congestion. Advise patients to consult their physician immediately if any of these symptoms develop while using ATROVENT HFA Inhalation Aerosol.

5.5 Urinary Retention ATROVENT HFA is an anticholinergic and may cause urinary retention. Therefore, caution is advised when administering ATROVENT HFA Inhalation Aerosol to patients with prostatic hyperplasia, or bladder-neck obstruction [ see Drug Interactions (7.1) ].

PRECAUTIONS: General: 1.

Effects

Seen with Anticholinergic Drugs: Ipratropium Bromide Nasal Solution 0.06% (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 0.06% (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 0.06% (Nasal Spray) comes into direct contact with the eyes. Patients should be instructed to avoid spraying Ipratropium Bromide Nasal Solution 0.06% (Nasal Spray) in or around the 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 PATIENT'S INSTRUCTIONS FOR USE. Since dizziness, accommodation disorder, mydriasis, and blurred vision may occur with use of Ipratropium Bromide Nasal Solution 0.06% (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 0.06% (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 70 and 35 times the maximum recommended daily intranasal dose in adults, respectively, and approximately 35 and 15 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 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 0.06% (Nasal Spray) in pregnant women. Because animal reproduction studies are not always predictive of human response, Ipratropium Bromide Nasal Solution 0.06% (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 60, 12,000, and 3,000 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 20 and 45 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 above 90 mg/kg in rats (approximately 1,100 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 0.06% (Nasal Spray) is administered to a nursing mother.

Pediatric

Use: The safety of Ipratropium Bromide Nasal Solution 0.06% (Nasal Spray) at a dose of two sprays (84 mcg) per nostril three times a day (total dose 504 mcg/day) for two to four days has been demonstrated in two clinical trials involving 362 pediatric patients 5-11 years of age with naturally acquired common colds. In this pediatric population, Ipratropium Bromide Nasal Solution 0.06% (Nasal Spray) had an adverse event profile similar to that observed in adolescent and adult patients.

When Ipratropium Bromide Nasal Solution

0.06% (Nasal Spray) was concomitantly administered with an oral decongestant (pseudoephedrine HCl) in 122 children ages 5-12 years, and concomitantly administered with an oral decongestant/antihistamine combination (pseudoephedrine HCl/chlorpheniramine maleate) in 123 children ages 5-12 years, adverse event profiles were similar to Ipratropium Bromide Nasal Solution 0.06% (Nasal Spray) alone. The safety of Ipratropium Bromide Nasal Solution 0.06% (Nasal Spray) at a dose of two sprays (84 mcg) per nostril four times a day (total dose 672 mcg/day) for three weeks in pediatric seasonal allergic rhinitis patients down to 5 years is based upon the safety demonstrated in the pediatric common cold trials and the trial in adult and adolescent patients 12 to 75 years of age with seasonal allergic rhinitis. The effectiveness of Ipratropium Bromide Nasal Solution 0.06% (Nasal Spray) for the treatment of rhinorrhea associated with the common cold and seasonal allergic rhinitis in this pediatric age group is based on extrapolation of the demonstrated efficacy of Ipratropium Bromide Nasal Solution 0.06% (Nasal Spray) in adolescents and adults with the 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 common cold for the pediatric population is based on cross-study comparisons of the efficacy of Ipratropium Bromide Nasal Solution 0.06% (Nasal Spray) in adult and pediatric patients and on its safety profile in both adults and pediatric common cold patients. The recommended dose for seasonal allergic rhinitis for the pediatric population down to 5 years is based upon the efficacy and safety of Ipratropium Bromide Nasal Solution 0.06% (Nasal Spray) in adults and adolescents 12 years of age and above with seasonal allergic rhinitis and the safety profile of this dose in both adult and pediatric common cold patients. The safety and effectiveness of Ipratropium Bromide Nasal Solution 0.06% (Nasal Spray) in pediatric patients under 5 years of age have not been established.

INTERACTIONS ATROVENT HFA has been used concomitantly with other drugs, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids commonly used in the treatment of COPD. With the exception of albuterol, there are no formal studies fully evaluating the interaction effects of ATROVENT HFA and these drugs with respect to safety and effectiveness. Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of ATROVENT HFA with other anticholinergic-containing drugs ( 7.1 )

7.1 Anticholinergic Agents There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of ATROVENT HFA with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [ see Warnings and Precautions (5.4 , 5.5) ].