INFORMATION FOR HEALTH PROFESSIONALS
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CFC free metered dose inhaler with each actuation contains 0.021 mg ipratropium bromide corresponding to 0.020 mg ipratropium bromide anhydrous. Atrovent is a solution type formulation with the active ingredient, ipratropium bromide, completely dissolved in a blend of the propellant, ethanol and water. It is a clear, colourless liquid, free from suspended particles filled in a metal container with a metering valve.
Trials with a treatment duration of up to three months involving adult asthmatics and COPD patients, and asthmatic children, in which the HFA formulation and the CFC formulation have been compared have shown the two formulations to be therapeutically equivalent.
Atrovent is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In preclinical studies, it appears to inhibit vagally mediated reflexes by antagonising the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increase in intracellular concentration of cyclic guanosine monophosphate (cyclic GMP) caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle.
The bronchodilation following inhalation of ATROVENT is induced by local drug concentrations sufficient for anticholinergic efficacy at the bronchial smooth muscle and not by systemic drug concentrations.
In controlled 90 day studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (chronic bronchitis and emphysema) significant improvements in pulmonary function (FEV1 and FEF25-75% increases of 15% or more) occurred within 15 minutes, reached a peak in 1-2 hours, and persisted in the majority of patients up to 6 hours.
In controlled 90 day studies in patients with bronchospasm associated with asthma, significant improvements in pulmonary function (FEV1 increases of 15% or more) occurred in 40% of the patients.
Preclinical and clinical evidence suggest no deleterious effect of Atrovent on airway mucous secretion, mucociliary clearance or gas exchange.
The bronchodilator effect of ATROVENT in the treatment of acute bronchospasm associated with asthma has been shown in studies in children over 6 years of age. In most of these studies ATROVENT was administered in combination with an inhaled beta-agonist.
Although the data are limited, ATROVENT has been shown to have a therapeutic effect in the treatment of bronchospasm associated with viral bronchiolitis and bronchopulmonary dysplasia in infants and very small children.
The therapeutic effect of ATROVENT is produced by a local action in the airways. Therefore time courses of bronchodilation and systemic pharmacokinetics do not run in parallel.
Following inhalation dose portions from 10 to 30%, depending on the formulation and inhalation technique, are generally deposited in the lungs. The major part of the dose is swallowed and passes the gastro-intestinal tract.
Due to the negligible gastro-intestinal absorption of ipratropium bromide the bioavailability of the swallowed dose portion accounts for only ~2% of the dose. This fraction of the dose does not make a relevant contribution to the plasma concentrations of the active ingredient. The portion of the dose deposited in the lungs reaches the circulation rapidly (within minutes) and has a nearly complete systemic availability.
From data of renal excretion (0-24 hrs) the total systemic bioavailability (pulmonary and gastro-intestinal portions) of inhaled doses of ipratropium bromide was estimated to be in the range 7 to 28%. This is also a valid range for the inhalation from the metered aerosol with HFA 134a propellant because the kinetic results (renal excretion, AUC and Cmax ) from the HFA formulation and the conventional CFC formulation are closely comparable.
Kinetic parameters describing the disposition of ipratropium bromide were calculated from plasma concentrations after i.v. administration.
A rapid biphasic decline in plasma concentrations is observed. The volume of distribution (Vz) is 338 l (≈ 4.6 l/kg). The drug is minimally (less then 20%) bound to plasma proteins. The ipratropium ion does not cross the blood-brain barrier, consistent with the ammonium structure of the molecule. The half-life of the terminal elimination phase is about 1.6 hours.
The mean total clearance of the drug is determined to be 2.3 L/min. The major portion of approximately 60% of the systemic available dose is eliminated by metabolic degradation, probably in the liver. The main urinary metabolites bind poorly to the muscarinic receptor and have to be regarded as ineffective.
A portion of approximately 40% of the systemic available dose is cleared via urinary excretion corresponding to an experimental renal clearance of 0.9 L/min. (After oral dosing less than 1% of the dose is renally excreted indicating an insignificant absorption of ipratropium bromide from the gastro-intestinal tract.)
In excretion balance studies after intravenous administration of a radioactive dose less than 10% of the drug-related radioactivity (including parent compound and all metabolites) are excreted via the biliary-faecal route. The dominant excretion of drug-related radioactivity occurs via the kidneys.
Atrovent is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis, emphysema and asthma.
The dosage should be adapted to the individual requirements. Unless otherwise prescribed, the following dosages are recommended for adults and children over 12 years of age:
Adults: Usually 2 metered doses 4 times daily.
Some patients may need up to 4 puffs at a time to obtain maximal benefit during early treatment. Since a requirement for increasing doses suggests that additional therapeutic modalities may be needed, a total daily dose of 12 puffs should generally not be exceeded.
Children: 6-12 years. Usually 1 or 2 puffs, 3 times daily.
Children under 6 years: Usually 1 puff, 3 times daily.
In order to ensure that the inhaler is used correctly, administration should be supervised by an adult.
If therapy does not produce a significant improvement or if the patient`s condition gets worse, medical advice must be sought in order to determine a new plan of treatment. In the case of acute or rapidly worsening dyspnea (difficulty in breathing) a doctor should be consulted immediately.
For acute exacerbations of chronic obstructive pulmonary disease treatment with Atrovent inhalation solution or unit dose vials may be indicated.
Because of insufficient information in children Atrovent metered aerosol should only be used on medical advice and under the supervision of an adult.
Atrovent should not be taken by patients with known hypersensitivity to atropine or its derivatives or to any other component of the product.
When using the new formulation of Atrovent metered aerosol for the first time, some patients may notice that the taste is slightly different from that of the CFC-containing formulation. Patients should be made aware of this when changing from one formulation to the other. They should also be told that the formulations have been shown to be interchangeable for all practical purposes and that the difference in taste has no consequences in terms of the safety or the efficacy of the new formulation.
Atrovent should be used with caution in patients predisposed to narrow-angle glaucoma, or with prostatic hypertrophy hyperplasia or bladder-neck obstruction.
Patients with cystic fibrosis may be more prone to gastro-intestinal motility disturbances.
Immediate hypersensitivity reactions may occur after administration of Atrovent metered aerosol, as demonstrated by rare cases of urticaria, angio-oedema, rash, bronchospasm and oropharyngeal oedema and anaphylaxis.
Ocular complications:
There have been isolated reports of ocular complications (i.e. mydriasis, increased intraocular pressure, narrow-angle glaucoma, eye pain) when aerosolised ipratropium bromide either alone or in combination with an adrenergic beta2-agonist, was sprayed into the eyes. Thus patients must be instructed in the correct administration of Atrovent metered aerosol.
Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop, treatment with miotic drops should be initiated and specialist advice sought immediately.
In vitro bacterial mutagenicity assays (Ames test) did not indicate a mutagenic potential. The results of in vivo assays (micronucleus test, dominant lethal test in mice, cytogenic assay on bone marrow cells of Chinese hamsters) did not demonstrate an increase in the rate of chromosomal aberrations.
No tumorigenic or carcinogenic effects were demonstrated in long term studies in mice and rats.
The safety of ATROVENT during human pregnancy has not been established. The benefits of using ATROVENT during a confirmed or suspected pregnancy must be weighed against possible hazards to the unborn child. Preclinical studies have shown no embryotoxic or teratogenic effects following inhalation or intranasal application at doses considerably higher than those recommended in man.
It is not known whether ATROVENT is excreted into breast milk. Although lipid-insoluble quaternary cations pass into breast milk, it is unlikely that ATROVENT would reach the infant to an important extent, when administered by inhalation. However, because many drugs are excreted into breast milk, caution should be exercised when ATROVENT is administered to nursing mothers.
On the basis of the pharmacodynamic profile and the reported adverse drug reactions it is not likely that ipratropium bromide has an effect on the ability to drive or use machines.
The most frequent non-respiratory adverse events reported in clinical trials were gastro-intestinal motility disorders (e.g. constipation, diarrhoea and vomiting) headache and dryness of the mouth.
The following side effects have been observed with ATROVENT®: increased heart rate, palpitations, supraventricular tachycardia and atrial fibrillation, ocular accommodation disturbances, nausea, urinary retention and dizziness. These side effects have been rare and reversible. The risk of urinary retention may be increased in patients with pre-existing outflow tract obstruction.
Ocular side effects have been reported (see: Warnings and Precautions).
As with other inhaled therapy including bronchodilators cough, local irritation and, inhalation induced bronchospasm have been observed.
Allergic-type reactions such as skin rash, pruritis, angio-oedema of the tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions may occur.
Beta-adrenergics and xanthine preparations may intensify the bronchodilatory effect.
Atrovent has been concomitantly used with other drugs commonly used in the treatment of chronic obstructive pulmonary disease, including sympathomimetic bronchodilators, methylxanthines, steroids and disodium cromoglycate without evidence of deleterious medical interactions.
No symptoms specific to overdosage have been encountered. In view of the wide therapeutic range and topical administration of Atrovent metered aerosol, no serious anticholinergic symptoms are to be expected. Minor systemic manifestations of anticholinergic action, including dry mouth, visual accommodation disturbances and increase of heart rate may occur.
None known.
Store below 30ºC. Protect from direct sunlight, heat and frost.
The correct administration of the metered aerosol is essential for successful therapy.
Depress the valve twice before the metered aerosol is used for the first time.
Before each use the following rules should be observed:
(fig. 1)
The container is not transparent. It is not therefore possible to see when it is empty. The aerosol will deliver 200 actuations. When these have all been used the aerosol may still appear to contain a small amount of fluid. The aerosol should, however, be replaced because you may not get the right amount of treatment.
The amount of treatment in your aerosol can be checked as follows:
Remove the aerosol from the plastic mouthpiece and put the aerosol into a container of water. The contents of the aerosol can be estimated by observing its position in the water (see fig. 2).
(fig. 2)
The mouthpiece should always be kept clean and can be washed with warm water. If soap or detergent is used, the mouthpiece should be thoroughly rinsed in clear water.
WARNING:
The plastic mouthpiece has been specially designed for use with ATROVENT metered aerosol to ensure that you always get the right amount of the medicine. The mouthpiece must never be used with any other metered aerosol nor must the ATROVENT metered aerosol be used with any mouthpiece other than the one supplied with the product.
The container is under pressure and should by no account be opened by force or exposed to temperatures above 50ºC.
Only emptied containers should be disposed.
Prescription Medicine
Metered dose inhalers of 200 actuations.
1,1,1,2 - Tetrafluoroethane (HFA 134a)
Ethanol absolute
Purified Water
Citric acid anhydrous.
Boehringer Ingelheim (N.Z.) Limited
PO Box 76-216
Manukau City
Ph (09) 262 1356
Fax (09) 262 1462
25 November 2005
BPI: 0250-03, 27.7.05
