Ipratropium Bromide Inhalation

Ipratropium bromide HFA inhalation aerosol is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Ipratropium bromide HFA inhalation aerosol is an anticholinergic indicated for the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema

The usual starting dose of ipratropium bromide HFA inhalation aerosol is two inhalations four times a day. Patients may take additional inhalations as required; however, the total number of inhalations should not exceed 12 in 24 hours. Ipratropium bromide HFA inhalation aerosol is a solution aerosol that does not require shaking. However, as with any other metered-dose inhaler, some coordination is required between actuating the canister and inhaling the medication. Patients should “prime” or actuate ipratropium bromide HFA inhalation aerosol 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. Patients should avoid spraying ipratropium bromide HFA inhalation aerosol into their eyes. Each inhaler provides sufficient medication for 200 actuations. The inhaler should be discarded after the labeled number of actuations has been used. The amount of medication in each actuation cannot be assured after this point, even though the canister is not completely empty. Patients should be instructed on the proper use of their inhaler [see Patient Counseling Information ( 17 )]. For oral inhalation only

• Two inhalations four times a day, not to exceed 12 inhalations in 24 hours

Ipratropium bromide HFA inhalation aerosol is an inhalation aerosol supplied in a pressurized fluorocarbon polymer-coated aluminum canister as a metered-dose inhaler with a blue mouthpiece and a grey protective cap. Each pressurized metered-dose aerosol unit for oral inhalation contains a 12.9 g solution of ipratropium bromide (monohydrate) that provides sufficient medication for 200 actuations. After priming, each actuation of the inhaler delivers 21 mcg of ipratropium bromide (monohydrate) from the valve and delivers 17 mcg of ipratropium bromide (monohydrate) from the mouthpiece.

• Inhalation Aerosol: Each actuation of ipratropium bromide HFA inhalation aerosol delivers 17 mcg of ipratropium bromide (monohydrate) from mouthpiece
• Supplied in a 12.9 g canister containing 200 actuations

Ipratropium bromide HFA inhalation aerosol is contraindicated in the following conditions [see Warnings and Precautions ( 5.2 )].

• Hypersensitivity to ipratropium bromide or other ipratropium bromide HFA inhalation aerosol components
• Hypersensitivity to atropine or any of its derivatives
• Hypersensitivity to ipratropium bromide or other ipratropium bromide HFA inhalation aerosol components ( 4 )
• Hypersensitivity to atropine or any of its derivatives

5 WARNINGS 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 ipratropium bromide HFA inhalation aerosol at once and consider alternative treatments ( 5.2 )
• Paradoxical bronchospasm: Discontinue ipratropium bromide HFA inhalation aerosol 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 Ipratropium bromide HFA inhalation aerosol 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 ipratropium bromide HFA inhalation aerosol. 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 ipratropium bromide HFA inhalation aerosol should be stopped at once and alternative treatment should be considered [see Contraindications ( 4 )].

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

5.4 Ocular Effects Ipratropium bromide HFA inhalation aerosol is an anticholinergic and its use may increase intraocular pressure. This may result in precipitation or worsening of narrow-angle glaucoma. Therefore, ipratropium bromide HFA inhalation aerosol should be used with caution in patients with narrow-angle glaucoma [see Drug Interactions ( 7.1 )]. Patients should avoid spraying ipratropium bromide HFA inhalation aerosol into their eyes. If a patient sprays ipratropium bromide HFA inhalation aerosol 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 ipratropium bromide HFA inhalation aerosol.

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

Ipratropium bromide HFA inhalation aerosol 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 ipratropium bromide HFA inhalation aerosol and these drugs with respect to safety and effectiveness. Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of ipratropium bromide HFA inhalation aerosol 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 ipratropium bromide HFA inhalation aerosol with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions ( 5.4 , 5.5 )].

Acute overdose by inhalation is unlikely since ipratropium bromide is not well absorbed systemically after inhalation or oral administration.

8.1 Pregnancy Risk Summary Ipratropium is negligibly absorbed systemically following oral inhalation; therefore, maternal use is not expected to result in fetal exposure to the drug [see Clinical Pharmacology ( 12.3 )]. There is limited experience with ipratropium bromide use in pregnant women. Published literature, including cohort studies, case control studies and case series, over several decades have not identified a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Based on animal reproduction animal studies, no evidence of structural alternations was observed when ipratropium bromide was administered to pregnant mice, rats and rabbits during organogenesis at doses up to approximately 200, 40,000, and 10,000 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In animal reproduction studies, oral and inhalation administration of ipratropium bromide to pregnant mice, rats, and rabbits during the period of organogenesis did not show evidence of fetal structural alterations. The ipratropium bromide dose in oral studies in mice, rats, and rabbits was up to approximately 200, 40,000, and 10,000 times, respectively, the MRHDID in adults (on a mg/m 2 basis at maternal doses of 10, 1000, and 125 mg/kg/day, respectively). The ipratropium bromide dose in inhalation studies in rats and rabbits was up to approximately 60 and 140 times, respectively, the MRHDID in adults (on a mg/m 2 basis at maternal doses of 1.5 and 1.8 mg/kg/day, respectively). Embryotoxicity was observed as increased resorption in rats at oral doses approximately 3,600 times the MRHDID in adults (on a mg/m 2 basis at maternal doses of 90 mg/kg/day and above). 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.

8.2 Lactation Risk Summary There are no data on the presence of ipratropium in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Although lipid-insoluble quaternary cations pass into breast milk, ipratropium concentrations in plasma after inhaled therapeutic doses are low, therefore, ipratropium levels in human breast milk are expected to be low [see Clinical Pharmacology ( 12.3 )]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ipratropium bromide HFA inhalation aerosol and any potential adverse effects on the breastfed child from ipratropium bromide HFA inhalation aerosol or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established.

8.5 Geriatric Use In the pivotal 12-week study, both ipratropium bromide HFA inhalation aerosol and ipratropium bromide CFC inhalation aerosol formulations were equally effective in patients over 65 years of age and under 65 years of age. Of the total number of subjects in clinical studies of ipratropium bromide HFA inhalation aerosol, 57% were ≥65 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

The active ingredient in ipratropium bromide HFA inhalation aerosol 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: 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. Ipratropium bromide HFA inhalation aerosol 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. Ipratropium bromide HFA inhalation aerosol 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. structure

12.1 Mechanism of Action 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. Anticholinergics prevent the increases in intracellular concentration of Ca++ which is caused by interaction of acetylcholine with the muscarinic receptors on bronchial smooth muscle.

12.2 Pharmacodynamics Cardiovascular effects At recommended doses, ipratropium bromide does not produce clinically significant changes in pulse rate or blood pressure. Ocular effects In studies without a positive control, ipratropium bromide did not alter pupil size, accommodation, or visual acuity. Mucociliary clearance and respiratory secretions Controlled clinical studies have demonstrated that ipratropium bromide does not alter either mucociliary clearance or the volume or viscosity of respiratory secretions.

12.3 Pharmacokinetics Following administration by oral inhalation from a metered-dose inhaler, the majority of the delivered dose is deposited in the gastrointestinal tract and, to a lesser extent, in the lung, the intended site of action. Ipratropium bromide is a quaternary amine and hence is not readily absorbed into the systemic circulation either from the surface of the lung or from the gastrointestinal tract as confirmed by blood level and renal excretion studies. The half-life of elimination is about 2 hours after inhalation or intravenous administration. Ipratropium bromide is minimally bound (0% to 9% in vitro) to plasma albumin and α 1 -acid glycoprotein. It is partially metabolized to inactive ester hydrolysis products. Following intravenous administration, approximately one-half of the dose is excreted unchanged in the urine. A pharmacokinetic study with 29 chronic obstructive pulmonary disease (COPD) patients (48-79 years of age) demonstrated that mean peak plasma ipratropium concentrations of 59±20 pg/mL were obtained following a single administration of 4 inhalations of ipratropium bromide HFA inhalation aerosol (84 mcg). Plasma ipratropium concentrations declined to 24±15 pg/mL by six hours. When these patients were administered 4 inhalations QID (16 inhalations/day=336 mcg) for one week, the mean peak plasma ipratropium concentration increased to 82±39 pg/mL with a trough (6 hour) concentration of 28±12 pg/mL at steady state. Specific Populations Geriatric Patients In the pharmacokinetic study with 29 COPD patients, a subset of 14 patients were >65 years of age. Mean peak plasma ipratropium concentrations of 56±24 pg/mL were obtained following a single administration of 4 inhalations (21 mcg/puff) of ipratropium bromide HFA inhalation aerosol (84 mcg). When these 14 patients were administered 4 inhalations four times a day (16 inhalations/day) for one week, the mean peak plasma ipratropium concentration only increased to 84±50 pg/mL indicating that the pharmacokinetic behavior of ipratropium bromide in the geriatric population is consistent with younger patients. Renally Impaired Patients The pharmacokinetics of ipratropium bromide HFA inhalation aerosol have not been studied in patients with renal insufficiency. Hepatically Impaired Patients The pharmacokinetics of ipratropium bromide HFA inhalation aerosol have not been studied in patients with hepatic insufficiency. Drug-Drug Interaction No specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions with other medications.