ipratropium bromide 0.017 MG/ACTUAT Metered Dose Inhaler, 200 ACTUAT
Generic Name: IPRATROPIUM BROMIDE
Brand Name: Atrovent HFA
- Substance Name(s):
- IPRATROPIUM BROMIDE
DRUG INTERACTIONS
7 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) ].
OVERDOSAGE
10 Acute overdose by inhalation is unlikely since ipratropium bromide is not well absorbed systemically after inhalation or oral administration.
DESCRIPTION
11 The active ingredient in ATROVENT HFA is ipratropium bromide (as the 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 from the valve in 56 mg of solution and delivers 17 mcg of ipratropium bromide 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 HFA-134a (1,1,1,2-tetrafluoroethane) as propellant, sterile water, dehydrated alcohol, and anhydrous citric acid.
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
CLINICAL STUDIES
14 Conclusions regarding the efficacy of ATROVENT HFA were derived from two randomized, double-blind, controlled clinical studies.
These studies enrolled males and females ages 40 years and older, with a history of COPD, a smoking history of >10 pack-years, an FEV 1 <65% and an FEV 1 /FVC <70%.
One of the studies was a 12-week randomized, double-blind active, and placebo-controlled study in which 505 of the 507 randomized COPD patients were evaluated for the safety and efficacy of 42 mcg (n=124) and 84 mcg (n=126) ATROVENT HFA in comparison to 42 mcg (n=127) ATROVENT CFC and their respective placebos (HFA n=62, CFC n=66).
Data for both placebo HFA and placebo CFC were combined in the evaluation.
Serial FEV 1 (shown in Figure 1, below, as means adjusted for center and baseline effects on test day 1 and test day 85 (primary endpoint)) demonstrated that 1 dose (2 inhalations/21 mcg each) of ATROVENT HFA produced significantly greater improvement in pulmonary function than placebo.
During the six hours immediately post-dose on day 1, the average hourly improvement in adjusted mean FEV 1 was 0.148 liters for ATROVENT HFA (42 mcg) and 0.013 liters for placebo.
The mean peak improvement in FEV 1 , relative to baseline, was 0.295 liters, compared to 0.138 liters for placebo.
During the six hours immediately post-dose on day 85, the average hourly improvement in adjusted mean FEV 1 was 0.141 liters for ATROVENT HFA (42 mcg) and 0.014 liters for placebo.
The mean peak improvement in FEV 1 , relative to baseline, was 0.295 liters, compared to 0.140 liters for placebo.
ATROVENT HFA (42 mcg) was shown to be clinically comparable to ATROVENT CFC (42 mcg).
Figure 1 Day 1 and Day 85 (Primary Endpoint) Results In this study, both ATROVENT HFA and ATROVENT CFC formulations were equally effective in patients over 65 years of age and under 65 years of age.
The median time to improvement in pulmonary function (FEV 1 increase of 15% or more) was within approximately 15 minutes, reached a peak in 1 to 2 hours, and persisted for 2 to 4 hours in the majority of the patients.
Improvements in Forced Vital Capacity (FVC) were also demonstrated.
The other study was a 12-week, randomized, double-blind, active-controlled clinical study in 174 adults with COPD, in which ATROVENT HFA 42 mcg (n=118) was compared to ATROVENT CFC 42 mcg (n=56).
Safety and efficacy of HFA and CFC formulations were shown to be comparable.
The bronchodilatory efficacy and comparability of ATROVENT HFA vs ATROVENT CFC were also studied in a one-year open-label safety and efficacy study in 456 COPD patients.
The safety and efficacy of HFA and CFC formulations were shown to be comparable.
Figure 1
HOW SUPPLIED
16 /STORAGE AND HANDLING ATROVENT HFA is supplied in a pressurized stainless steel canister as a metered-dose inhaler with a white mouthpiece that has a clear, colorless sleeve and a green protective cap (NDC 0597-0087-17).
The mouthpiece has an actuation indicator visible through a small window.
The indicator typically moves during every 5 to 7 actuations.
It displays the approximate number of actuations remaining in increments of 20, starting at “200” and decreasing until it reaches “0”.
The ATROVENT HFA canister is to be used only with the accompanying ATROVENT HFA mouthpiece.
This mouthpiece should not be used with other aerosol medications.
Similarly, the canister should not be used with other mouthpieces.
After priming, each actuation of ATROVENT HFA delivers 21 mcg of ipratropium bromide from the valve and 17 mcg from the mouthpiece.
Each canister has a net weight of 12.9 grams and provides sufficient medication for 200 actuations.
The inhaler should be discarded after the labeled number of actuations has been used when the indicator displays “0”.
The amount of medication in each actuation cannot be assured after this point, even though the canister is not completely empty.
Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
For optimal results, the canister should be at room temperature before use.
Contents Under Pressure: Do not puncture.
Do not use or store near heat or open flame.
Exposure to temperatures above 120°F may cause bursting.
Never throw the inhaler into a fire or incinerator.
Keep out of reach of children.
Avoid spraying in eyes .
GERIATRIC USE
8.5 Geriatric Use In the pivotal 12-week study, both ATROVENT HFA and ATROVENT CFC 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 ATROVENT HFA, 57% were ≥65 years of age.
No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
DOSAGE FORMS AND STRENGTHS
3 ATROVENT HFA is an inhalation aerosol supplied in a pressurized stainless steel canister as a metered-dose inhaler with a white mouthpiece that has a clear, colorless sleeve and a green protective cap.
Each pressurized metered-dose aerosol unit for oral inhalation contains a 12.9 g solution of ipratropium bromide that provides sufficient medication for 200 actuations.
After priming, each actuation of the inhaler delivers 21 mcg of ipratropium bromide (as the monohydrate) from the valve and delivers 17 mcg of ipratropium bromide from the mouthpiece.
Inhalation Aerosol: Each actuation of ATROVENT HFA Inhalation Aerosol delivers 17 mcg of ipratropium bromide from mouthpiece ( 3 ) Supplied in a 12.9 g canister containing 200 actuations ( 3 )
MECHANISM OF ACTION
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.
INDICATIONS AND USAGE
1 ATROVENT 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.
ATROVENT HFA is an anticholinergic indicated for the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema ( 1 )
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established.
PREGNANCY
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 studies, no evidence of structural alterations 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 3600 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.
WARNING AND CAUTIONS
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 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) ].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
Appropriate and safe use of ATROVENT HFA includes providing the patient with the information listed below and an understanding of the way it should be administered.
Advise patients that 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.
Hypersensitivity Reactions Inform patients that hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema, may occur after the administration of ATROVENT HFA.
Advise patients to immediately discontinue ATROVENT HFA and consult a physician [ see Warnings and Precautions (5.2) ].
Paradoxical Bronchospasm Inform patients that ATROVENT HFA can produce paradoxical bronchospasm that can be life-threatening.
If paradoxical bronchospasm occurs, patients should discontinue using ATROVENT HFA.
Ocular Effects Caution patients to avoid spraying the aerosol into their eyes and be advised that this may result in precipitation or worsening of narrow-angle glaucoma, mydriasis, increased intraocular pressure, acute eye pain or discomfort, temporary blurring of vision, visual halos or colored images in association with red eyes from conjunctival and corneal congestion.
Patients should also be advised that should any combination of these symptoms develop, they should consult their physician immediately.
Since dizziness, accommodation disorder, mydriasis, and blurred vision may occur with use of ATROVENT HFA, patients should be cautioned about engaging in activities requiring balance and visual acuity such as driving a car or operating appliances or machinery.
Urinary Retention Inform patients that ATROVENT HFA may cause urinary retention and should be advised to consult their physicians if they experience difficulty with urination.
Frequency of Use The action of ATROVENT HFA should last 2 to 4 hours.
Advise patients not to increase the dose or frequency of ATROVENT HFA without patients consulting their physician.
Advise patients to seek immediate medical attention if treatment with ATROVENT HFA becomes less effective for symptomatic relief, their symptoms become worse, and/or patients need to use the product more frequently than usual.
Concomitant Drug Use Advise patients on the use of ATROVENT HFA in relation to other inhaled drugs [ see Drug Interactions (7.1) ].
Use Only as Prescribed Remind patients that ATROVENT HFA should be used consistently as prescribed throughout the course of therapy.
Preparation for Use and Priming Instruct patients that priming ATROVENT HFA is essential to ensure appropriate content of the medication in each actuation.
Patients do not have to shake the ATROVENT HFA canister before use .
DOSAGE AND ADMINISTRATION
2 The usual starting dose of ATROVENT HFA 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.
ATROVENT HFA 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 ATROVENT HFA 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 ATROVENT HFA 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 ( 2 )