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Atrovent HFA | ipratropium bromide - bronchodilator
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.
2 DOSAGE AND ADMINISTRATION
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 (17.7)].
3 DOSAGE FORMS AND STRENGTHS
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.
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
5 WARNINGS AND PRECAUTIONS
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.
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 post marketing 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)].
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.
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.
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.
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)].
The following adverse reactions are described, or described in greater detail, in other sections:
Hypersensitivity reactions, including anaphylaxis [see Contraindications (4) and Warnings and Precautions (5.2)]
Paradoxical bronchospasm [see Warnings and Precautions (5.3)]
Ocular effects [see Warnings and Precautions (5.4)]
Urinary retention [see Warnings and Precautions (5.5)]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in patients.
Clinical Trials Experience
The adverse reaction information concerning Atrovent HFA is derived from two 12-week, double-blind, parallel group studies and one 1-year open-label, parallel group study. These studies compared Atrovent HFA Inhalation Aerosol, ATROVENT CFC Inhalation Aerosol, and placebo (in one study only) in 1010 COPD patients. The following table lists the incidence of adverse reactions that occurred at a rate of greater than or equal to 3% in any ipratropium bromide group and greater than placebo in the 12-week study. The frequency of corresponding reactions in the 1-year open label study is included for comparison.
TABLE 1 Adverse Reactions (% Patients) in Atrovent HFA Clinical Trials Placebo-controlled 12 week Study 244.1405 and
Active-controlled 12 week Study 244.1408 Active-controlled 1-year Study 244.2453 Atrovent HFA
(N=243)
% Atrovent CFC
(N=183)
% Placebo
(N=128)
% Atrovent HFA
(N=305)
% Atrovent CFC
(N=151)
% BODY AS A WHOLE – GENERAL DISORDERS Back pain 2 3 2 7 3 Headache 6 9 8 7 5 Influenza-like symptoms 4 2 2 8 5 CENTRAL & PERIPHERAL NERVOUS SYSTEM DISORDERS Dizziness 3 3 2 3 1 GASTROINTESTINAL SYSTEM DISORDERS Dyspepsia 1 3 1 5 3 Mouth dry 4 2 2 2 3 Nausea 4 1 2 4 4 RESPIRATORY SYSTEM DISORDERS Bronchitis 10 11 6 23 19 COPD exacerbation 8 14 13 23 23 Dyspnea 8 8 4 7 4 Sinusitis 1 4 3 11 14 URINARY SYSTEM DISORDERS Urinary tract infection 2 3 1 10 8
Cough, rhinitis, and upper respiratory infection occurred in greater than or equal to 3% of patients in either ipratropium treatment group but not greater than placebo in the 12-week study.
In the one open label controlled study in 456 COPD patients, the overall incidence of adverse events was also similar between Atrovent HFA and ATROVENT CFC formulations.
Overall, in the above mentioned studies, 9.3% of the patients taking 42 mcg Atrovent HFA and 8.7% of the patients taking 42 mcg ATROVENT CFC reported at least one adverse event that was considered by the investigator to be related to the study drug. The most common drug-related adverse events were dry mouth (1.6% of Atrovent HFA and 0.9% of ATROVENT CFC patients), and taste perversion (bitter taste) (0.9% of Atrovent HFA and 0.3% of ATROVENT CFC patients).
As an anticholinergic drug, cases of precipitation or worsening of narrow-angle glaucoma, glaucoma, halo vision, conjunctival hyperaemia, corneal edema, mydriasis, acute eye pain, dry throat, hypotension, palpitations, urinary retention, tachycardia, constipation, bronchospasm, including paradoxical bronchospasm have been reported with the use of ATROVENT. Additional adverse reactions identified for ATROVENT seen in clinical trials include throat irritation, stomatitis, mouth edema, and vision blurred.
Allergic-type reactions such as skin rash, pruritus, angioedema including that of tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions have been reported [see Warnings and Precautions (5.2)].
Post-Marketing Experience
In a 5-year placebo-controlled trial, hospitalizations for supraventricular tachycardia and/or atrial fibrillation occurred with an incidence rate of 0.5% in COPD patients receiving ATROVENT CFC.
In addition to the adverse reactions reported in the controlled clinical trials, adverse reactions have been identified during post approval use of ATROVENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Allergic-type reactions such as skin rash, angioedema including that of tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions have been reported, with positive rechallenge in some cases.
Additionally, urinary retention, mydriasis, gastrointestinal distress (diarrhea, nausea, vomiting), cough and bronchospasm, including paradoxical bronchospasm, hypersensitivity reactions, intraocular pressure increased, accommodation disorder, heart rate increased, pharyngeal edema, and gastrointestinal motility disorders have been reported during the post-marketing period with use of ATROVENT.
Atrovent HFA has been used concomitantly with other drugs, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids commonly used in the treatment of chronic obstructive pulmonary disease. 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.
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)].
8 USE IN SPECIFIC POPULATIONS
Teratogenic Effects: Pregnancy Category B.
There are no adequate and well-controlled studies of Atrovent HFA (ipratropium bromide) Inhalation Aerosol in pregnant women. Atrovent HFA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Oral reproduction studies were performed in mice, rats and rabbits at doses approximately 200, 40,000, and 10,000 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mg/m2 basis at maternal doses in each species of 10, 1,000, and 125 mg/kg/day, respectively). Inhalation reproduction studies were conducted in rats and rabbits at doses approximately 60 and 140 times, respectively, the MRHDID in adults (on a mg/m2 basis at maternal doses of 1.5 and 1.8 mg/kg/day, respectively). These studies demonstrated no evidence of teratogenic effects as a result of ipratropium bromide. Embryotoxicity was observed as increased resorption in rats at oral doses approximately 3,600 times the MRHDID in adults (on a mg/m2 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.
It is not known whether the active component, ipratropium bromide, is excreted in human milk. Because lipid-insoluble quaternary cations pass into breast milk, caution should be exercised when Atrovent HFA is administered to a nursing mother.
Safety and effectiveness in the pediatric population have not been established.
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.
Acute overdose by inhalation is unlikely since ipratropium bromide is not well absorbed systemically after inhalation or oral administration.
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:
C20H30BrNO3•H2O 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.
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.
At recommended doses, ipratropium bromide does not produce clinically significant changes in pulse rate or blood pressure.
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.
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 α1-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 Atrovent HFA (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.
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 Atrovent HFA (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 Atrovent HFA have not been studied in patients with renal insufficiency.
Hepatically Impaired Patients
The pharmacokinetics of Atrovent HFA have not been studied in patients with hepatic insufficiency.
No specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions with other medications.
13 NONCLINICAL TOXICOLOGY
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 (approximately 240 and 120 times the maximum recommended human daily inhalation dose (MRHDID) in adults on a mg/m2 basis, respectively). Results of various mutagenicity/clastogenicity studies (Ames test, mouse dominant lethal test, mouse micronucleus test and chromosome aberrations of bone marrow in Chinese hamsters) were negative.
Fertility of male or female rats at oral doses up to 50 mg/kg (approximately 2000 times the MRHDID in adults on a mg/m2 basis) was unaffected by ipratropium bromide administration. At an oral dose of 500 mg/kg (approximately 20,000 times the MRHDID in adults on a mg/m2 basis), ipratropium bromide produced a decrease in the conception rate.
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 FEV1 < 65% and an FEV1/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 FEV1 (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 FEV1 was 0.148 liters for Atrovent HFA (42 mcg) and 0.013 liters for placebo. The mean peak improvement in FEV1, 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 FEV1 was 0.141 liters for Atrovent HFA (42 mcg) and 0.014 liters for placebo. The mean peak improvement in FEV1, 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 (FEV1 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.
16 HOW SUPPLIED/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.
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° 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.
Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Licensed from:
Boehringer Ingelheim International GmbH
Copyright 2012 Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
